TAP Vol 4 Issue 9 by Harborside Press LLC

Pediatric Leukemia

| Predicting Toxicity in Older Patients

| Renal Cell Carcinoma

VOLUME 4, ISSUE 9

JUNE 10, 2013

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

ASCO Annual Meeting

Impressive Results Shown for Immune Checkpoint Inhibitors: Anti-PD1 and Anti-PD-L1 Antibodies

ASCOPost.com

One Cancer Center’s Approach to Death with Dignity

By Caroline Helwick

By Frederick R. Appelbaum, MD

ntibody-mediated blockade of the programmed death 1 protein (PD-1) and its ligand (PDL1) resulted in potent and durable tumor regression and prolonged stabilization of disease in patients with advanced solid tumors, according to early data on Jedd D. Wolchok, MD, PhD these drugs presented at the 2013 ASCO Annual Meeting. While these investigations are phase I studies, the promising findings earned a slot for the investigators at the first Annual Meeting press briefing, where they were peppered with questions by journalists. The anti-PD-1 and anti-PD-L1 antibodies potentiate immune responses by blocking the interaction between the PD-1 protein, a T-cell co-inhibitory recep-

tor, and one of its ligands, PD-L1—critical players in the ability of tumor cells to evade the host’s immune system (see sidebar on page 11). The anti-PD-L1 antibody MPDL3280A yielded impressive singleagent activity against a variety of solid tumors. The anti-PD-1 antibody nivolumab (BMS-936558) was part of a two-pronged immunologic strategy, paired with ipilimumab.

Dual Immunomodulation in Melanoma Concurrent treatment with nivolumab plus ipilimumab, which targets the cytotoxic T-lymphocyte antigen 4 (CTLA-4), led to objective responses in 40% of patients with previously treated stage III or IV melanoma, reported Jedd D. Wolchok, MD, PhD, Associate Attending Physician at Memorial Sloan-Kettering Cancer

Procedures and Outcomes Briefly, patients with a terminal illness and a prognosis of less than 6 months to live continued on page 23

continued on page 11

Expert’s Corner

Caring for the Whole Patient Both during Active Treatment and at End of Life A Conversation with Ira Byock, MD

Dr. Appelbaum is Director of the Clinical Research Division at Fred Hutchinson Cancer Research Center, Executive Director of the Seattle Cancer Care Alliance, and Professor of Medical Oncology at the University of Washington, Seattle.

MORE IN THIS ISSUE

By Jo Cavallo

n November 2008, the Washington State legislature passed the Washington Death with Dignity Act allowing patients with a terminal diagnosis and less than 6 months to live to request and self-administer lethal medication. After considerable internal debate, our cancer center elected to develop a Death with Dignity Policy, which was subsequently approved by our Medical Executive Committee. The essential elements of the policy are outlined in our recent publication in The New England Journal of Medicine1 and in this issue of The ASCO Post (see page 19).

espite studies showing that a majority of patients prefer to die at home rather than in an institutional setting,1 in many parts of the country, over 30% die in nursing homes and over 50% die in hospitals, according to Ira Byock, MD, Director of

Palliative Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, and Professor of Medicine at the Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. The author of The Best Care Possible: A Physician’s Quest to Transform Care Through the End of Life (Avery Trade, 2013), Dr. Byock contends that In addition to offering the best because the focus of care treatments possible for a patient’s disease, is often solely on treatments to sustain life, critiwe really have to find out what the ‘best cally ill and dying patients care’ is for a given patient by inquiring in may endure their last months or weeks of life a personal way. As physicians, we can’t in physical distress and assume that we know what someone emotional despair, feeling undignified and a burden would want. to loved ones. “While dy—Ira Byock, MD

Oncology Meetings Coverage ASCO Annual Meeting �� 3, 8, 9 ASBS Meeting�� 30, 119 EMCTO Meeting �� 66-68 ONS Congress �� 86-88 FDA Update �� 16-18, 70 Diet and Cancer �� 46-51 Direct from ASCO �� 60-63 Rapid Learning Health-care Systems �� 77 Cancer Genomics �� 92 Breast Cancer Risk Reduction �� 116

continued on page 58

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A Harborside Press® Publication

The ASCO Post | JUNE 10, 2013

PAGE 2

Inside This Issue

Don’t Miss These

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

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Michael P. Link, MD Stanford University Medical Center

Associate Editors Joseph S. Bailes, MD Texas Oncology Laurence H. Baker, DO University of Michigan Comprehensive Cancer Center Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine and Public Health Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD National Comprehensive Cancer Network

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center William T. McGivney, PhD Philadelphia, Pennsylvania

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lee S. Schwartzberg, MD University of Tennessee Health Science Center

George W. Sledge, MD Indiana University Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Jay S. Cooper, MD Maimonides Medical Center

Lynn D. Wilson, MD Yale University School of Medicine

John Cox, DO Texas Oncology

Stanley H. Winokur, MD Singer Island, Florida

E. David Crawford, MD University of Colorado

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

Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Bishoy Morris Faltas, MD Weill Cornell Medical College John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

International Editors

Arlene H. Sharpe, MD, PhD, on PD-1/PD-L1 Pathway see page 11

Stuart M. Lichtman, MD, on Care and Study of Older Patients with Cancer see page 56

Robert J. Motzer, MD, on Axitinib or Sorafenib in Advanced Renal Cell Carcinoma see page 71

Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital, Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel

Mario E. Lacouture, MD Memorial Sloan-Kettering Cancer Center

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

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

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

Harborside Press® Publishing Staff Conor Lynch, Executive Editor Conor@harborsidepress.com

Gail Van Koot, Editorial Coordinator Gail@harborsidepress.com

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

Wendy McGullam, Director of Production Wendy@harborsidepress.com

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

Frank Buchner, Chief Technology Officer Frank@harborsidepress.com

Sarah McGullam, Assistant Editor Sarah@harborsidepress.com

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

Michael Buckley, Art Director Michael@harborsidepress.com

Anthony Cutrone, President Anthony@harborsidepress.com

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

John A. Gentile, Jr., Chairman Jack@harborsidepress.com

Contributing Writers: Charlotte Bath, Jo Cavallo, Alice Goodman, Caroline Helwick, Susan

London, Caroline McNeil, Eileen O’Gara-Kurtis, Ronald Piana, Matthew Stenger, Marian Wiseman

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations. Disclosure information available at ASCOPost.com.

Andrew D. Zelenetz, MD, PhD, on Imaging After Treatment for Diffuse Large B-cell Lymphoma see page 10

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

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

George D. Demetri, MD Dana-Farber Cancer Institute

in This Issue of The ASCO Post

James L. Mulshine, MD Rush University Medical Center

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

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

Important Reports

Visit The ASCO Post online at ASCOPost.com 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. 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.

ASCOPost.com | JUNE 10, 2013

PAGE 3

ASCO Annual Meeting Thoracic Oncology

‘Less Is More’ with Regard to Adjuvant Radiation in Stage III Non–Small Cell Lung Cancer By Alice Goodman

tandard-dose conformal radiotherapy (60 Gy) is more effective and safer than high-dose radiotherapy (74 Gy) in patients with locally advanced stage III non–small cell lung cancer (NSCLC) undergoing chemotherapy, according to results of the phase III randomized, controlled Radiation Therapy Oncology Group (RTOG) 0617 trial presented at the ASCO Annual Meeting.1 Earlier phase I and II clinical trials suggested that high-dose radiotherapy might have advantages over standarddose radiotherapy in this setting, but this

study found that high-dose radiotherapy increased the risk of death by 56% compared with standard-dose radiotherapy. Further, the risk of local failure was increased by 37% in the high-dose arms of the trial compared with standard doses.

Take-home Message “We expected to find that high-dose radiation therapy would achieve better outcomes. We are both surprised and pleased to discover that less intense treatment led to better control of cancer progression and spread, and even improved overall survival,” said lead author Jeffrey D. Bradley MD, S. Lee Kling Professor of Radiation Oncol-

EXPERT POINT OF VIEW

his study should be placed in the context of treating to cure, said Roy S. Herbst, MD, PhD, Ensign Professor of Medicine and Chief of Medical Oncology at Yale University School of Medicine, New Haven, Connecticut. “If we can further increase the cure rate in stage III non–small cell lung cancer (NSCLC), that would be a major advance. Some earlier studies suggested that higher doses of radiation would improve outcomes but would lead to higher toxicity despite improved techniques. The surprising negative finding Roy S. Herbst, MD, PhD for higher-dose radiation in this study suggests that not only is it not better than low-dose radiation, but in fact it leads to worse outcomes. More is not always better.” Dr. Herbst commented. “The fact that an increased dose of radiation does not appear to improve survival does not preclude the benefits of higher doses of radiation with other new radiation techniques, but demonstrating that would require new randomized controlled trials,” he added.

Question Answered “For now, this study answers the question to my satisfaction. More standard doses of radiation are adequate for treatment of stage III NSCLC,” Dr. Herbst stated. He is eagerly awaiting final results of the cetuximab comparison in this study. “Previous studies suggested that cetuximab holds promise in the treatment of NSCLC,” he noted. Dr. Herbst is also lead investigator of the Southwest Oncology Group (SWOG) 0819 trial, which is evaluating chemotherapy with or without cetuximab in patients with metastatic stage IV IV NSCLC. In that study, tissue samples were obtained for biomarker analysis, and epidermal growth factor receptor (EGFR) status will be determined by fluorescence in situ hybridization gene copy number analysis or H-score based on immunohistochemistry. This will hopefully determine whether EGFR is a predictive marker for benefit of cetuximab in this group of patients, he said. n Disclosure: Dr. Herbst reported no potential conflicts of interest.

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and

Jeffrey D. Bradley MD

ogy, Chief of the Thoracic Service, and Director of the S. Lee Kling Center for Proton Therapy at Washington University School of Medicine in St. Louis. Dr. Bradley said the biologic explanation of these findings is not clear. “The take-home message from this trial is that radiation oncologists outside of clinical trials should be using the standard dose of 60 Gy in patients with stage III NSCLC treated with concurrent chemotherapy,” Dr. Bradley stated. Sophisticated and precise techniques were used to deliver radiotherapy in this trial, including three-dimensional radiotherapy and intensity-modulated radiotherapy. The study had a 2�2 �22 factorial design and randomly assigned 464 patients to treatment with lower-dose and high-dose radiation therapy along with standard chemotherapy. In each treatment arm, patients were also randomly assigned to treatment with cetuximab (Erbitux) or no additional therapy. Data on cetuximab’s effects will be reported in 2014, Dr. Bradley said. The high-dose arm was closed when an interim analysis found that it was not superior to standard-dose radiation. Overall survival was superior in the standard-dose arm: 90 deaths were reported with 60-Gy radiation vs 117 in the 74-Gy arm (P � .0007), � .0007), .0007), representing a 56% increased risk of death with high-dose radiation. Median survival

was 28.7 months for standard-dose therapy vs 19.5 months for the highdose arm. The estimated 18-month overall survival rates were higher for the standard-dose arm: 66.9% vs 53.9%. Local failure was also significantly worse in the high-dose arm: 81 failures vs 65 failures in the standard-dose arm (P � .0319). At 18 months, local recurrence rates were 34.3% vs 25.1%, respectively, while distant recurrence rates were 44% vs 35.3%, respectively. The only significant difference in side effects between the two arms was a higher rate of esophagitis in patients undergoing high-dose radiation: 21% vs 7%, respectively. The number of treatment-related deaths was higher in the high-dose arm: 10 vs 2, respectively.

Surprising Results “These are surprising results, especially with more precise modern techniques. After a decade of research, we can finally close the chapter on the high-dose vs standard-dose therapy debate in stage III lung cancer therapy,” stated ASCO Immediate Past President Sandra M. Swain, MD, FACP. “This study should influence practice and reduce the use of higher-dose radiation for NSCLC,” said ASCO President Clifford A. Hudis, MD. n

Disclosure: Dr. Swain’s institution has received research funds from Bristol-Myers Squibb. Drs. Bradley and Hudis reported no potential conflicts of interest.

Reference 1. Bradley JD, Paulus R, Komaki R, et al: A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer. ASCO Annual Meeting. Abstract 7501. Presented June 4, 2013.

Radiation Dose in Non–Small Cell Lung Cancer ■ A randomized controlled phase III trial found that standard-dose

radiotherapy was superior to high-dose radiotherapy in stage III NSCLC.

■ Higher-dose radiation therapy increased the risk of death by 56% and the risk of local recurrence by 37% compared with standard-dose radiation.

the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

VOTRIENT® (pazopanib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).1

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

11.1

12 10

MONTHS

9.2

MONTHS

7.4

8 Months

VOTRIENT Placebo

MONTHS

4.2

MONTHS

4.2

MONTHS

2.8

MONTHS

2 0 HR 0.46; 95% CI 0.34-0.62 (P<0.001)

HR 0.40; 95% CI 0.27-0.60 (P<0.001)

HR 0.54; 95% CI 0.35-0.84 (P<0.001)

All patients

Treatment-naïve patients

Cytokine-pretreated patients

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of VOTRIENT in patients (N=435) with advanced RCC. Patients with locally advanced or metastatic RCC of clear cell or predominantly clear cell histology were randomized (2:1) to receive either VOTRIENT 800 mg (n=290) once daily or placebo (n=145). The study included treatment-naïve patients receiving VOTRIENT (n=155) or placebo (n=78) as well as cytokine-pretreated patients receiving VOTRIENT (n=135) or placebo (n=67).1

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

• Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thrombotic Events: Arterial thrombotic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thrombotic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, venous thromboembolic

events were reported in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended.

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

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In advanced RCC, initial dose reduction should be 400 mg and additional dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced RCC trial, 42% of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose reduced • The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • Monitor serum liver tests before initiation of treatment and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modifications based on drug interactions, please see Section 2.2 in accompanying Brief Summary

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

NCCN Guidelines Category 1 recommendation as a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology. These Guidelines also include therapies other than pazopanib (VOTRIENT) as first-line treatment options.3

T:14”

B:14.25”

S:13”

• Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. • Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT.

• Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. • Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax. • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

The most common adverse reactions (≥20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.1.2013. ©National Comprehensive Cancer Network, Inc. 2013. All rights reserved. Accessed February 1, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. • Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced.

VOTRIENT.com/HCP GSKSource.com

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had postbaseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/ intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thrombotic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy

and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.10 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.14 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.15 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.16 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290) All All Gradesa Gradesa Grade 3 Grade 4 % % % % Adverse Reactions Diarrhea 52 3 <1 9 Hypertension 40 4 0 10 Hair color changes 38 <1 0 3 Nausea 26 <1 0 9 Anorexia 22 2 0 10 Vomiting 21 2 <1 8 Fatigue 19 2 0 8 Asthenia 14 3 0 8 Abdominal pain 11 2 0 1 Headache 10 0 0 5 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

(N=145) Grade 3 % <1 <1 0 0 <1 2 1 0 0 0

Grade 4 % 0 0 0 0 0 0 1 0 0 0

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=290) All Gradesa %

Grade 3 %

Placebo (N=145) Grade 4 %

All Gradesa %

Parameters Hematologic Leukopenia 37 0 0 6 Neutropenia 34 1 <1 6 Thrombocytopenia 32 <1 <1 5 Lymphocytopenia 31 4 <1 24 Chemistry ALT increased 53 10 2 22 AST increased 53 7 <1 19 Glucose increased 41 <1 0 33 Total bilirubin increased 36 3 <1 10 Phosphorus decreased 34 4 0 11 Sodium decreased 31 4 1 24 Magnesium decreased 26 <1 1 14 Glucose decreased 17 0 <1 3 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Grade 3 %

Grade 4 %

0 0 0 1

0 0 <1 0

1 <1 1 1 0 4 0 0

0 0 0 <1 0 0 0 0

T:14”

B:14.25”

S:13”

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)]. 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drugdrug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.16)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.15)]. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility

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

VOTRIENT is a registered trademark of GlaxoSmithKline.

The ASCO Post | JUNE 10, 2013

PAGE 8

ASCO Annual Meeting Hematology

Potent Activity Shown for First-in-class PI3K-delta Inhibitor in Chronic Lymphocytic Leukemia By Caroline Helwick

eavily pretreated patients with chronic lymphocytic leukemia (CLL) responded robustly to the firstin-class small-molecule inhibitor idelalisib (formerly GS1101), in a phase I dose-finding study reported in a press briefing prior to the 2013 ASCO Annual Meeting.1 Idelalisib, a specific inhibitor of PI3K-delta, led to rapid, major lymph node responses in about two-thirds of patients who would otherwise have few if any treatment options, reported Jennifer R. Brown, MD, PhD, Assistant Professor of Medicine at Dana-Farber Cancer Institute in Boston. “Drugs like idelalisib are probably going to change the landscape of this disease in the next few years,” Dr. Brown predicted. PI3K-delta is the predominant isoform in an aberrantly hyperactivated signaling pathway

that drives CLL, she explained.

Study Details The phase I study involved 54 patients with relapsed/refractory CLL, who had received a median of five prior regimens; 70% were refractory to their most recent regimen. Patients received idelalisib at 50 to 350 mg twice daily by continuous oral dosing in 28-day cycles for 48 weeks. Therapy continued as long as the patient benefited. Responses were observed in 39 of the 54 patients, leading to a median progression-free survival of 17.1 months, Dr. Brown reported. “Idelalisib rapidly induced deep and durable lymph node responses in the vast majority of patients,” she told the media. “The nodal responses appeared to be independent of the very high-risk mutations, deletion 17p or TP53.” Laboratory studies showed that idelalisib significantly inhibited PI3K-delta

EXPERT POINT OF VIEW

andra M. Swain, MD, FACP, Immediate Past President of ASCO commented on the findings. “This is an exciting discovery and an example of early success in precision medicine. It’s targeting PI3K-delta, which is overactive in B-cell malignancies and is used in a disease that is very refractory to treatment. The overall response rate was 56%, but even more striking, the progression-free survival was 17 months. I think this is pretty incredible. Two patients had full reSandra M. Swain, MD, FACP missions.” She noted that many patients with CLL are aged 70 and older, and that the good tolerability of this regimen would be important in this group. “The study demonstrates that we may soon have alternatives to chemotherapy for slowgrowing blood cancers, and we can offer simpler oral treatments and therefore improved quality of life for patients,” Dr. Swain said. n Disclosure: Dr. Swain reported no potential conflicts of interest.

New from The ASCO Post

Drugs like idelalisib are probably going to change the landscape of this disease in the next few years. —Jennifer R. Brown, MD, PhD

in CLL cells (P < .0001 vs baseline). Hemoglobin, platelet counts, and absolute neutrophil counts improved during treatment. The drug was well tolerated, and the most common drug-related adverse events were elevated liver function tests, diarrhea, and rash, said Dr. Brown. “While this research is still early and ongoing, we hope this drug, along with others like it, will lead to prolonged survival and eventually help turn CLL into a condition that is treated like high blood pressure,” she said.

Alternatives to Chemotherapy Idelalisib joins another drug recently garnering great interest in CLL, the Bruton’s tyrosine kinase inhibitor ibrutinib. Dr. Brown would not compare the activity of the two drugs, and pointed out that ibrutinib is in phase II trials, whereas hers was a phase I dose-finding study. “But I would say that these are both extremely promising drugs, and

we in the CLL community are excited to have them both,” she said. “There is certainly interest in thinking about how to combine them to further downregulate their pathways, which do intersect.” Meanwhile, she said, these drugs may provide alternatives to chemotherapy in elderly patients who tend not to tolerate chemotherapy well. “We believe the substantial clinical activity of idelalisib justifies further clinical development in CLL, and phase III trials are in progress,” she said. A dose of 150 mg twice daily was chosen for future studies. n

Disclosure: Dr. Brown has served as a consultant for Pharmacyclics.

Reference 1. Brown JR, Furman RR, Flinn A, et al: Final results of a phase I study of idelalisib (GS-1101) a selective inhibitor of PI3Kdelta, in patients with relapsed or refractory CLL. 2013 ASCO Annual Meeting. Abstract 7003. Presented June 4, 2013.

Idelalisib in CLL ■ Idelalisib is the first specific inhibitor of PI3K-delta, the predominant

isoform in an aberrantly hyperactivated signaling pathway driving chronic lymphocytic leukemia.

■ In a phase I dose-finding study of 54 relapsed/refractory patients, idelalisib produced responses in > 70% of patients.

ASCOPost.com | JUNE 10, 2013

PAGE 9

ASCO Annual Meeting Hematology

Study Questions Routine Use of Imaging after Treatment for Diffuse Large B-cell Lymphoma By Alice Goodman

ost relapses following treatment for diffuse large B-cell lymphoma are detected by abnormalities on physical exam, lab tests, and symptoms—not by routine imaging, according to a study presented at the ASCO Annual Meeting.1 In fact, in a prospective study assessing post-treatment outcomes of patients on surveillance, only 1.5% of relapses were detected in asymptomatic patients by planned scans. “Our results were surprising, because the current standard of care is to include scans for the follow-up of [dif-

patients who are in remission after initial treatment. The optimal surveillance strategy

is unclear. Current guidelines recommend routine computed tomography (CT) scans every 6 months for 2

years after treatment is finished, and thereafter, as clinically indicated. Pacontinued on page 10

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fuse large B-cell lymphoma]. We found that scans detected relapse in only a handful of patients who didn’t have any of those other signs and symptoms. We are getting closer to understanding how to optimize follow-up in this patient population,” said lead author Carrie A. Thompson, MD, a hematologist at the Mayo Clinic in Rochester, Minnesota.

• Preparation for the rash, itching, or dry skin that may come with cancer treatment • Care for the fingernails, and suggested products that will contribute to their health • Awareness of the risks for hair loss, and resources your patients may need • Suggested moisturizers and cosmetics that are appropriate for your patients’ use • Specific information for survivors

Tailored Surveillance “Scans expose patients to radiation, and that theoretically increases the risk of a second cancer. Surveillance scans can also increase patient anxiety and lead to unnecessary biopsies. While our study found that the majority of relapses are not detected by routine scans, the decision of whether to obtain surveillance scans and how often should be individually tailored to patient characteristics,” she commented. Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma, with about 20,000 new cases diagnosed each year in the United States. The disease is potentially curable with chemotherapy, but relapses occur in about 20% to 30% of

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About the Author Mario E. Lacouture, MD Associate Member Memorial Sloan-Kettering Cancer Center New York, NY Mario E. Lacouture, MD, is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. His clinical focus is the recognition and management of the side effects and conditions of the skin, hair, and nails that may arise in cancer patients and survivors as a consequence of surgery, chemotherapy, radiation, or transplantation. His research focuses on exploring new skin treatments that do not interfere with the effectiveness of anticancer medications.

The ASCO Post | JUNE 10, 2013

PAGE 10

ASCO Annual Meeting Diffuse Large B-cell Lymphoma continued from page 9

tients also undergo physical exams and blood tests during follow-up.

Study Design The study sought to identify how relapses in diffuse large B-cell lymphoma were detected. From a cohort of 644 patients with newly diagnosed diffuse large

Clifford A. Hudis, MD

B-cell lymphoma treated with anthracycline-based immunochemotherapy, 537 patients were judged to be in remission after initial treatment and entered posttreatment surveillance. The study was part of a multi-institutional study called University of Iowa/Mayo Clinic Special Program of Research Excellence Molecular Epidemiology Resource. Median age was 63 years (range, 18–92 years). Management was at the discretion of the treating hematologist/ oncologist. Patients were followed for

events that included relapse, retreatment, and death. Events were verified by medical records. Of the 537 patients, 109 relapsed (20%) and 41 died of unrelated causes. About 42% of relapses occurred within the first 12 months following diagnosis, 27% between 12 and 24 months, and 31% after 24 months.

Relapse Details Among the 109 patients who relapsed, 62% consulted their physician at an unplanned visit because they were experiencing symptoms that included enlarged lymph nodes, fever, night sweats, pain, or weight loss. At relapse, 68% had symptoms, 42% had an abnormal physical exam, and 55% had an abnormal blood test. Surveillance CT scans detected relapse in eight patients (1.5%) who were asymptomatic. “The majority of relapses occur outside of planned follow-up visits and are accompanied by symptoms or abnormalities in physical exam or lab tests. This is important in decision-making,” Dr. Thompson emphasized. “The optimal way to follow patients with [diffuse large B-cell lymphoma] has been unclear,” said Clifford A. Hudis, MD, ASCO President-Elect, speaking at an official ASCO press briefing before the Annual Meeting. “This large study shows that the vast majority of recurrences are not detected by CT

Relapse of Diffuse Large B-cell Lymphoma ■ A prospective epidemiologic study found that routine imaging—which

is associated with increased costs and radiation exposure, unnecessary biopsies, and patient anxiety—detected relapse in only 1.5% of patients with diffuse large B-cell lymphoma post-treatment.

■ The vast majority of relapses were signaled by symptoms of diffuse large B-cell lymphoma or abnormalities on physical exams and/or lab tests.

■ The decision to implement surveillance scans should be individualized according to patient characteristics.

scans, and this is consistent with some other cancers. Physicians should discuss these findings with patients. These data will help physicians develop guidelines for patients in remission from [diffuse large B-cell lymphoma] and spare costs, exposure to radiation therapy, and the impact of false-positive findings.” n

Disclosure: Drs. Thompson and Hudis reported no potential conflicts of interest.

Reference 1. Thompson CA, Maurer MJ, Ghesquieres H, et al: Utility of post-therapy surveillance scans in DLBCL. ASCO Annual Meeting. Abstract 8504. Presented June 1, 2013.

EXPERT POINT OF VIEW

n a separate interview, Andrew D. Zelenetz, MD, PhD, Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center in New York, said that he found the relapse rate of 20% observed in this study to be quite low, and he wanted to know the characteristics of the 537 patients included in the postsurveillance study. Mayo Clinic hematologist Carrie A. Thompson, MD, the study’s lead author, said that those characteristics were available for the total Andrew D. Zelenetz, MD, PhD cohort of 644 patients. She said that patients who entered post-treatment surveillance, by definition, had not had an early relapse and were not treatment-refractory. Dr. Zelenetz said that if the scan-detected relapse rate of 1.5% of relapses was “true,” then routine post-treatment scans could be avoided in diffuse large B-cell lymphoma. “However, in our hands, about 80% of [diffuse large B-cell lymphoma] relapses are detected by scans,” he noted.

Identifying Patients at Risk “The present study is too small a dataset to try to identify a subgroup of patients who are at risk and in whom routine imaging would be useful. Patients with a negative scan don’t need imaging, but maybe patients with an equivocal scan do. The risks associated with four scans in 2 years are quite low, and the study does not unequivocally suggest that imaging is not needed,” Dr. Zelenetz continued. “To be conservative, the greatest risk of relapse in [diffuse large B-cell lymphoma] is within the first 2 years after treatment. It is not inappropriate to use routine imaging until we have more data,” he said. The present study was a retrospective analysis. The ideal study to show whether imaging improves outcomes would be a prospective trial randomly assigning patients to two different follow-up regimens—one arm that includes imaging and one arm that doesn’t, he continued. “This is a good study, and it is provocative. We need to continue to think about whether routine imaging is needed and, if so, in which patients,” Dr. Zelenetz said. n Disclosure: Drs. Zelenetz and Thompson reported no potential conflicts of interest.

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In the newly metastatic CRPC patient who is asymptomatic or minimally symptomatic

STARTS THE FIGHT

AND HELPS HIS IMMUNE SYSTEM SUSTAIN* IT 1

• Targets and attacks prostate cancer cells • Statistically significant overall survival advantage1,2 • Sustained* immune response *A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1 INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache. For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages. www.PROVENGEHCP.com

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. DOSAGE AND ADMINISTRATION • For Autologous Use Only. • The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals. • Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine. • Before infusion, confirm that the patient’s identity matches the patient identifiers on the infusion bag. • Do Not Initiate Infusion of Expired Product. • Infuse PROVENGE intravenously over a period of approximately 60 minutes. Do Not Use a Cell Filter. • Interrupt or slow infusion as necessary for acute infusion reactions, depending on the severity of the reaction. (See Dosage and Administration [2] of full Prescribing Information.) CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS • PROVENGE is intended solely for autologous use. • Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction. In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed. • Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed. • Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. • Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination. (See Warnings and Precautions [5] of full Prescribing Information.) 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 practice.

The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells. The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group. Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare. PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended. Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%). Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer. The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian. Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever Back pain Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting Anemia Constipation Pain Paresthesia oral Pain in extremity Dizziness Muscle ache Asthenia Diarrhea Influenza-like illness Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3) 319 (53.1) 247 (41.1) 188 (31.3) 178 (29.6) 129 (21.5) 118 (19.6) 109 (18.1) 89 (14.8) 85 (14.1) 80 (13.3) 75 (12.5) 74 (12.3) 74 (12.3) 74 (12.3) 73 (12.1) 71 (11.8) 71 (11.8) 65 (10.8) 60 (10.0) 58 (9.7) 54 (9.0) 52 (8.7) 50 (8.3) 49 (8.2) 46 (7.7) 46 (7.7)

186 (30.9) 13 (2.2) 6 (1.0) 6 (1.0) 18 (3.0) 3 (0.5) 11 (1.8) 4 (0.7) 0 (0.0) 1 (0.2) 2 (0.3) 11 (1.8) 1 (0.2) 7 (1.2) 0 (0.0) 5 (0.8) 2 (0.3) 3 (0.5) 6 (1.0) 1 (0.2) 0 (0.0) 3 (0.5) 11 (1.8) 1 (0.2) 2 (0.3) 6 (1.0) 2 (0.3)

291 (96.0) 33 (10.9) 105 (34.7) 29 (9.6) 87 (28.7) 45 (14.9) 62 (20.5) 20 (6.6) 43 (14.2) 43 (14.2) 23 (7.6) 34 (11.2) 40 (13.2) 20 (6.6) 43 (14.2) 40 (13.2) 34 (11.2) 17 (5.6) 20 (6.6) 34 (11.2) 11 (3.6) 31 (10.2) 14 (4.6) 31 (10.2) 29 (9.6) 18 (5.9) 17 (5.6)

Grade 3-5 n (%) 97 (32.0) 0 (0.0) 4 (1.3) 3 (1.0) 9 (3.0) 0 (0.0) 5 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (2.3) 3 (1.0) 3 (1.0) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 2 (0.7) 3 (1.0) 0 (0.0) 3 (1.0) 3 (1.0) 1 (0.3) 1 (0.3) 3 (1.0) 0 (0.0)

(Table 1 continued on next page.)

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

45 (7.5) 39 (6.5) 38 (6.3) 38 (6.3)

3 (0.5) 1 (0.2) 4 (0.7) 0 (0.0)

14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)

0 (0.0) 3 (1.0) 3 (1.0) 0 (0.0)

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

35 (5.8) 34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2) 30 (5.0) 30 (5.0)

0 (0.0) 3 (0.5) 2 (0.3) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0)

17 (5.6) 14 (4.6) 24 (7.9) 18 (5.9) 10 (3.3) 3 (1.0) 9 (3.0)

0 (0.0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0.0) 0 (0.0) 0 (0.0)

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group. (See Adverse Reactions [6] of full Prescribing Information.) To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011. 2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

ASCOPost.com | JUNE 10, 2013

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ASCO Annual Meeting Immune Checkpoint Inhibitors continued from page 1

Center and Associate Member of the Ludwig Institute for Cancer Research in New York.1 “What was unique in our experience was that most responding patients had rapid and deep regression by the time of the first CT scan,” Dr. Wolchok announced. The agents were given concurrently or in sequence in varying doses. Of 86 patients, 52 received concurrent therapy for four cycles, then nivolumab every 3 weeks for four cycles; at week 24, patients received concurrent treatment every 3 months. Sequential treatment involved administration of nivolumab alone to patients who had previously received ipilimumab.

Responses were observed in 40% of patients in the concurrent group, including tumor reductions ≥ 80% in 31% of patients. The most active regimen was ipilimumab at 3 mg/kg plus nivolumab at 1 mg/kg, which produced responses in 53%. The inclusion of patients with delayed responses and stable disease increased the clinical benefit rate to 65%, Dr. Wolchok reported. “The majority of patients had a decrease in tumor burden, with a surprisingly high number showing more than 80% regression,” he commented. Activity was less robust in the sequential group, in which 38% patients treated with 1 mg/kg of nivolumab had ≥ 50% tumor shrinkage, but no responses were observed with 3 mg/kg. “Responses were noted even in patients with previous pro-

Anti-PD-1 and Anti-PD-L1 Antibodies as Immunotherapy ■ The anti-PD-1 monoclonal antibody MPDL3280A produced responses in

21% of heavily pretreated patients with metastatic solid tumors, and 36% of those staining positive for PD-1.

■ The anti-PD-L1 monoclonal antibody nivolumab, paired with the anti-

CTLA-4 antibody ipilimumab, produced responses in 40% of heavily pretreated metastatic melanoma patients, and led to durable responses in the vast majority.

gression on ipilimumab, which tells us that patients can respond to another immune modulator,” he said. Side effects were manageable and reversible using standard protocol algorithms. Concurrent treatment was associated with a rate of grade 3/4 adverse events of 53%, primarily immune-related inflammation. About 13% of patients had asymptomatic laboratory abnormalities.

New Perspective on Melanoma Therapy Dr. Wolchok told The ASCO Post that the findings “do change the way we think about melanoma treatment,” in that this concurrent immune strategy produces a “more predictable onset of action with more straightforward kinetics” than are typically seen with immunotherapeutic approaches. “The continued on page 12

Understanding the PD-1/PD-L1 Pathway and Its Promise By Arlene H. Sharpe, MD, PhD

umors can be recognized by the immune system, but they have multiple mechanisms for evading eradication by the immune system. The tumor microenvironment suppresses the immune response, partly because tumors can express molecules that inhibit immune responses. The cancer clinical trials summarized by Dr. Herbst and Dr. Wolchok use a new strategy that blocks major pathways the tumor uses to suppress the immune response.

Underlying Mechanisms Immunoinhibitory receptors regulate T-cell activation, tolerance, and “exhaustion.” T-cell exhaustion is a dysfunctional state that develops in the setting of chronic antigen stimulation (such as occurs in a chronic infection or tumor). Immune responses against tumors are an ongoing chronic fight. Multiple inhibitory receptors contribute to T-cell exhaustion, and these are targets for immunotherapy. Tumor infiltrating lymphocytes can express many immunoinhibitory receptors, and these are druggable targets for immunotherapy. This inhibitory strategy is often called “checkpoint blockade.” The PD-1 pathway is an important Dr. Sharpe is George Fabyan Professor of Comparative Pathology, Department of Microbiology and Immunobiology, and Co-Director, Harvard Institute of Translational Immunology, Harvard Medical School, Boston.

immunoinhibitory pathway that inhibits tumor-specific T cells. The PD-1 pathway is a key mediator of T-cell exhaustion; blockade of this pathway can reinvigorate exhausted T cells, enabling them to expand and perform effector

Tumors exploit PD-L1 and use it to inhibit immune responses. Herbst and colleagues target the PD-1 pathway using a blocking antibody to PD-L1. Anti-PD-L1 antibodies have the potential to exert their effects

This trial has revealed synergies with anti-PD-1 and anti-CTLA-4. Targeting of these pathways has the potential to disrupt the natural function of PD-1 and CTLA-4 in tolerance and the termination of immune responses. —Arlene H. Sharpe, MD, PhD

functions (such as killing tumor cells). PD-1 is highly expressed on tumorinfiltrating lymphocytes, and these are functionally exhausted T cells. PD-1 has two ligands, PD-L1 and PD-L2. PD-L1 is expressed on many tumors and inhibits immune attack. PD-L1 is also expressed on a variety of hematopoietic cells (eg, dendritic cells and macrophages) as well as nonhematopoietic cells (eg, stromal cells, vascular endothelial cells). PD-L1 on these cell types also can inhibit T-cell responses. The PDL1:PD-1 pathway has a natural role in regulating T-cell tolerance and termination of immune responses.

by blocking PD-L1 on tumor cells, hematopoietic cells, or nonhematopoietic cells. Herbst and colleagues correlate functional response to anti-PD-L1 with PD-L1 expression on the tumor.

Synergistic Inhibition T cells often coexpress several inhibitory receptors. Studies in animal models have shown that coblockade of two inhibitory pathways enables better rescue of exhausted T cells than PD-1/PD-L1 blockade alone. Wolchok and colleagues use a strategy that targets two inhibitory receptors—CTLA-4 and PD-1—to promote antitumor immunity. The FDA-approved anti-CTLA-4

antibody (ipilimumab [Yervoy]) is the first in this class of tumor immunotherapy agents that target inhibitory receptors. The goal of the study by Wolchok and colleagues is to further improve antitumor immunity and tumor eradication by simultaneously targeting the CTLA-4 and PD-1 inhibitory pathways. This trial has revealed synergies with anti-PD-1 and anti-CTLA-4. In addition to their inhibitory roles in cancer and chronic infections, PD-1 and CTLA-4 also have roles in controlling T-cell tolerance and the strength and duration of immune responses. Targeting of these pathways has the potential to disrupt the natural function of PD-1 and CTLA-4 in tolerance and the termination of immune responses. The success of these therapies is a balance between activating antitumor immunity and breaking tolerance. Some adverse events of an immunologic nature are seen and need to be anticipated and managed. Combination therapy has the potential to have a greater impact on T-cell tolerance than targeting each pathway alone. The clinical trial design employed several dose and sequence combination strategies to determine the combination that best promotes effective antitumor immunity. n

Disclosure: Dr. Sharpe has patents in the PD-1 pathway that have been licensed to Roche/Genentech, BMS, Merck, DMD Serono, Boehringer Ingelheim, Amplimmune, and Costim Pharmaceuticals. She is also the cofounder of Costim Pharmaceuticals.

The ASCO Post | JUNE 10, 2013

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ASCO Annual Meeting Immune Checkpoint Inhibitors continued from page 11

rapidity of response with this combination reminds us of the kinetics we are accustomed to seeing with BRAF inhibitors, so if the combination becomes FDA-approved, this would change how we think about things. If responses can be achieved in a short period, with the kind of durability we see with immune therapies, this regimen would be advantageous.” A phase III trial evaluating concurrent therapy vs either agent alone will be conducted, he said. “This combination is being investigated in non–small cell lung cancer and renal cell cancer, too.”

MPDL3280A Robust as Single Agent When MPDL3280A attaches to the PD-L1 protein, which is frequently overexpressed on cancer cells, the cancer cells can no longer hide and the body’s T cells are able to attack the cancer. Development of MPDL3280A arose from the theory that blocking expression or activity of PDL1 would restore immune cells’ ability to detect and kill cancer cells. This hypothesis was tested in a multicenter phase I trial of patients with metastatic solid tumors, including cancers of the lung, kidney, colon, stomach, and head and neck, and melanoma. Findings were reported for 171 patients who had received a median of three prior therapies and were given MPDL3280A intravenously every 3 weeks until disease progression.2 Overall, 29 of 140 (21%) patients

responded to MPDL3280A, including 36% of patients whose tumors tested positive for PD-L1 and, somewhat surprisingly, 13% of those who were PD-L1-negative. This response rate may, in fact, be an underestimate, due to additional delayed responses and the immune-related (nontumor) masses sometimes seen with immunotherapy, said Roy Herbst, MD, PhD, Ensign Professor of Medicine and Chief of Medical Oncology at Yale University School of Medicine, New Haven, Connecticut. “Importantly, these responses tended to occur quickly in many cases, and they were also quite durable. I have been impressed by this in our patients here at Yale,” Dr. Herbst told the media. Responses were observed across

tumor types but were greatest for non– small cell lung cancer, renal cancer, and melanomas. At their last assessment, 26 of 29 responders were continuing to respond to treatment after 3 to 15 or more months on study, Dr. Herbst reported.

Enhanced Safety and Efficacy Although 43% of patients developed grade 3/4 adverse events, most events (all but 13%) were unrelated to treatment. The most common grade 3/4 adverse events were hyperglycemia, fatigue, elevated liver function tests, dyspnea, and hypoxia, each of which occurred in 3% to 5% of patients. Dr. Herbst explained to The ASCO Post that MPDL3280A was specifically engineered for enhanced safety

EXPERT POINT OF VIEW

“T

his is the beginning of an exciting new chapter in the treatment of cancer,” commented Clifford A. Hudis, MD, President-Elect of ASCO and moderator of the press briefing. “These studies focus on our ability to productively manipulate the immune system by targeting PD-L1 and PD-1, which allows the body’s natural immunity to ramp up and target cancer.” Dr. Hudis noted that while phase I studies historically evaluate safety only, the phase I data for Clifford A. Hudis, MD MPDL3280A already show evidence of efficacy, with responses lasting more than 1 year in heavily pretreated patients. “The clearest indications of activity were in non–small cell lung cancer and melanoma, and in tumors testing positive for the marker, suggesting that maybe in the future we can develop a biomarker that identifies tumors that will be more responsive to this approach,” he suggested. n Disclosure: Dr. Hudis reported no potential conflicts of interest.

and efficacy compared to earlier PDL1 or PD-1 targeted agents. In a study presented at the ASCO Annual Meeting last year, the anti-PD-1 antibody BMS956338 was associated with three treatment-related deaths, including two due to pneumonitis.3 “MPDL3280A should not activate antibody-dependent cell-mediated cytotoxicity, which is important because we don’t want to kill T cells, just block the interaction,” Dr. Herbst explained. “We have seen only lowgrade pneumonitis with this drug, and no deaths from it. Does that mean this is a better/safer drug [than previous anti-PD-1 antibodies]? No, but it’s consistent with that. So far we are impressed with the safety profile, but further studies are needed.” n Disclosure: Dr. Wolchok reported no potential conflicts of interest. Dr. Herbst received research support from Genentech.

References 1. Wolchok JD, Kluger HM, Callahan MK, et al: Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients with advanced melanoma. 2013 ASCO Annual Meeting. Abstract 9012. Presented June 2, 2013. 2. Herbst RS, Gordon MS, Fine GD, et al: A study of MPD3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. 2013 ASCO Annual Meeting. Abstract 3000. Presented June 3, 2013. 3. Topalian SL, Brahmer JR, Hodi FS, et al: Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: Clinical activity, safety, and a potential biomarker for response. 2012 ASCO Annual Meeting. Abstract CRA2509. Presented June 2, 2012.

Narratives in Oncology

A Special Supplement to The ASCO Post

Narratives in Oncology is a special edition of The ASCO Post and features personal profiles about oncology leaders who have made an important contribution to the clinical research and care of patients with cancer. This issue is the second annual special edition of The ASCO Post profiling leaders in oncology.

Look for your copy of the supplement with this issue of The ASCO Post or visit ASCOPost.com

POMALYST® (pomalidomide) indicated for patients with multiple myeloma who have received at least two prior PAGE therapies ASCOPost.com is| JUNE 10, 2013 13 including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of Corner the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival orExpert’s symptoms, has not been verified.

NOW APPROVED Introducing an oral medication for patients with refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages. To find out more information about POMALYST, go to www.pomalyst.com or use your smartphone to scan this code.

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity

• Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors. Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia. Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN. Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. © 2013 Celgene Corporation 04/13 US-POM120044a(1)

The ASCO Post | JUNE 10, 2013

PAGE 16

FDA Update

FDA Approves Expanded Use for Erlotinib, Companion Diagnostic to Detect Genetic Mutations in NSCLC

he FDA has approved erlotinib (Tarceva) for the first-line treatment of patients with metastatic non– small cell lung cancer (NSCLC) whose

tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. This indication for erlotinib was

Erlotinib Trial

approved concurrently with the cobas EGFR Mutation Test, a companion diagnostic test for patient selection.

The approval was based on the results of a randomized, multicenter, open-label trial comparing erlotinib to platinum-

T:7”

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

Cosmos Communications

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1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities

Toxicity

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FDA Update

based doublet chemotherapy in patients with metastatic NSCLC whose tumors had EGFR exon 19 deletions or exon 21 (L858R) substitution mutations determined by a clinical trial assay. Eligible patients were randomly allocated (1:1) to receive erlotinib at 150 mg/day orally, or platinum-based doublet chemotherapy. Randomization was stratified by EGFR

mutation and ECOG performance status. Tumor samples from 134 patients were tested retrospectively by the cobas EGFR Mutation Test.

� 0.23–0.49); P < .001). The median overall survival was 22.9 months in the erlotinib arm and 19.5 months in the platinum-based chemotherapy arm (HR � 0.93, 95% CI � 0.64–1.35; P � .6482). The recommended daily dose of erlotinib for NSCLC is 150 mg taken orally at least 1 hour before or 2 hours after the ingestion of food. n

The trial’s primary endpoint was investigator-assessed progression-free survival. Secondary endpoints included overall survival and objective response rate. The median progression-free survival was 10.4 months in the erlotinib arm and 5.2 months in the platinum-based chemotherapy arm (HR � 0.34, 95% CI

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(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112). Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established.

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• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

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FDA Update

Radium-223 Dichloride Approved for Patients with Castration-resistant Prostate Cancer

n May 15, 2013, the U.S. Food and Drug Administration approved radium Ra 223 dichloride (Xofigo) for the treatment of patients with castration-

resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. Radium-223 dichloride is an alpha-particle–emitting radio-

Study Details

therapeutic drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover, such as bone metastases.

The approval was based on a doubleblind, randomized, placebo-controlled trial in patients with metastatic castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease. Patients were allocated 2:1 to radium-223 dichloride at 50 kBq/kg (1.35 microcurie/kg) intravenously every 4 weeks for six cycles plus best standard of care (n � 541) or to matching placebo plus best standard of care (n � 268). Best standard of care in-

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13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide). Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and

Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved. POMBSv.001a 02/13

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8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

cluded local radiotherapy, corticosteroids, antiandrogens, estrogens, estramustine, or ketoconazole. All patients were to continue androgen deprivation therapy. The median age was 71 years, 94% were Caucasian, 86% had an ECOG performance status of 0-1, and 58% had received prior docetaxel. Fifty-four percent of patients used opiate and 44% used nonopiate pain medications. Overall survival was the primary endpoint. At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated (HR � 0.70, 95% CI � 0.55–0.88; P � .00185). The median overall survival was 14.0 and 11.2 months in the radium-223 dichloride and placebo arms, respectively. The improvement in overall survival was supported by a delay in time to first symptomatic skeletal event favoring the radium-223 arm.

Side Effects The most common (≥ 10%) adverse reactions in patients receiving radium-223 dichloride were nausea, diarrhea, vomiting, and peripheral edema. The most common hematologic laboratory abnormalities were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia. Two percent of patients on the radium-223 arm experienced bone marrow failure or ongoing pancytopenia. No patients on the placebo arm experienced bone marrow failure or pancytopenia. The recommended dose and schedule for radium-223 is 50 kBq/kg (1.35 microcuries/kg) administered by slow intravenous injection over 1 minute every 4 weeks for 6 doses. n

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Journal Spotlight Issues in Oncology

Death with Dignity Program at Seattle Cancer Care Alliance By Matthew Stenger

fter passage of the Washington Death with Dignity Act in November 2008, the Seattle Cancer Care Alliance—the site of outpatient care for patients with cancer from Fred Hutchinson–University of Washington Cancer Consortium—developed a Death with Dignity program. The program is adapted from existing programs in Oregon, which, in 1997 became the first state to pass legislation that offered a physician-assisted approach to dying for adults with poor short-term prognoses. Under the Washington law, competent adults residing in the state who have a life expectancy of 6 months or less because of a diagnosed medical condition can request and self-administer lethal medication prescribed by a physician. In a recent New England Journal of Medicine article, Elizabeth Trice Loggers, MD, PhD, and colleagues described their experience with the program at Seattle Cancer Care Alliance.1

Elements of Washington State Law Essential elements of the Washington law are as follows: The patient must make both an initial oral and written request to participate in the program, and must wait 15 days to make a requisite second oral request. Before prescribing the lethal medication, the prescribing physician must determine the terminal nature of the disease; determine the patient’s competency and voluntary nature of the request; confirm Washington State residency; assess informed consent on the basis of the patient’s awareness of the medical diagnosis, prognosis, risks of the medication, result of the medication (death), and alternatives (ie, palliative care, hospice, and pain control); and recommend that the patient notify next of kin, have someone present at ingestion, and not take the medication in a public place. A consulting physician must confirm the diagnosis, patient competency, and voluntary nature of the request. At the time of prescribing, the prescribing physician must offer the patient the opportunity to rescind the request, verify that the patient is making an informed decision, and deliver the prescription directly to the pharmacist. The pharmacist dispenses the

medication directly to the patient or an identified agent of the patient. At the Seattle Cancer Care Alliance program, secobarbital currently is used as the lethal medication, due to lack of pentobarbital. Overall, pentobarbital has been used in 16.9% and 36.1% of program participants in Washington and Oregon, respectively.

Role of Advocates In the Seattle Cancer Care Alliance program, each potential participant is assigned a patient advocate, a social worker who assists patients, families, pharmacists, and physicians throughout the program process. The advocate’s role includes providing information to patients and families about

No staff or faculty members at Seattle Cancer Care Alliance are compelled to participate in the program. Of physicians responding to a confidential survey, 35.8% were willing to act as a prescribing or consulting physician, 25.9% as a consulting physician only, and 38.3% were unwilling to participate or undecided about participation.

Program Participation As of December 2011, 255 Washington State residents had participated in the Washington Death with Dignity program, with 78% of these patients having cancer as their underlying terminal diagnosis. Among a total of 596 residents participating in

Our Death with Dignity program has been well accepted by patients, families, and staff. We attribute this to the professionalism of our advocates, the great care taken by our clinicians, and the willingness of the Seattle Cancer Care Alliance leadership to allow considerable debate before the program was developed. —Elizabeth Trice Loggers, MD, PhD, and colleagues

the process and its alternatives; tracking program compliance; assessing the patient’s rationale for and interest in further participation; making referrals to the psychiatry and psychology service if warranted; determining whether the attending physician will act as the prescribing physician; and identifying a prescribing physician, if the attending physician declines, and a consulting physician from among willing providers. In addition, the advocate arranges for a physician to be present at time of medication ingestion if requested, provides grief support and legacy support, and requests that the family inform the program when the patient ingests the medication. In this way, program personnel can provide assistance in case of complications, offer bereavement support, and assist the prescribing physician in completing required after-death reporting forms.

Oregon programs, 81% had cancer as the underlying diagnosis. At Seattle Cancer Care Alliance, 114 patients inquired about the program between March 5, 2009, and December 31, 2011. Of these, 44 (38.6%) did not pursue the program further or were deemed ineligible. Participation was refused to only one patient, who expressed unwillingness to ingest the medication in a private setting. A total of 30 patients (26.3%) initiated participation via an initial oral request but either chose to not pursue the process or died before completing it. In total, 40 patients (35.1%) received prescriptions for lethal medication. All 40 of these patients have died, 24 (60% of those receiving prescriptions) after ingesting the medication. In all of Washington State, 241 (94.5%) of 255 patients receiving prescriptions have died, with 157

(65.1%) of the 241 dying after ingesting medication. In Oregon programs, 596 patients (63.7%) of the 935 receiving prescriptions died after ingesting medication. In the Seattle Cancer Care Alliance program, 13 (54.2%) of the 24 patients who died after ingesting medication were enrolled in hospice at the time of their initial request and 20 (83.3%) died at home. The median time to death after ingestion of medication was 35 minutes in Seattle Care Alliance patients.

Participant Characteristics Among the 40 patients who received prescriptions at the Seattle Cancer Care Alliance, 55.0% were male, 72.5% were non-Hispanic whites, 55.0% were married, 97.5% had at least completed high school, and 35.0% were aged 18 to 64 years, 57.5% were aged 65 to 84 years, and 7.5% were 85 years or older. With regard to insurance status, 30.0% had private insurance, 32.5% had Medicare, Medicaid, or other public insurance, 27.5% had a combination of private and public insurance, and 10.0% had no insurance. Of 36 Seattle Cancer Care Alliance patients receiving prescriptions for whom information was available, the most frequently cited end-of-life concerns were loss of autonomy (97.2%), inability to engage in enjoyable activities (88.9%), and loss of dignity (75.0%). Similar proportions of all patients in Washington (90.6%, 88.8%, and 74.8%, respectively) and Oregon (90.9%, 88.3%, and 65.2%) expressed such concerns. Other frequently cited reasons among the Seattle Care Alliance patients included loss of control of bodily functions (27.8%), burden on family, friends, or caregivers (22.2%), and inadequate pain control or concern about it (22.2%). Of all 40 patients receiving prescriptions, 80% informed family of their decision (as did 93.6% of all Washington patients and 94.4% of Oregon patients). The median duration of patient-physician relationship was 33 weeks (14 weeks for all Washington patients and 12 weeks for Oregon patients). It is unknown whether prescribing physicians or other providers were present at ingestion of medication for the 24 patients continued on page 22

THORACIC ONCOLOGY UPDATE:

Molecular Biomarker Testing Is Essential for Non-Small Cell Lung Cancer Patients During the past decade the identification of molecular biomarkers for clinically relevant mutations or other genetic abnormalities in non-small cell lung cancer (NSCLC) has improved the understanding of lung cancer pathogenesis, and of the proliferation and survival of cancer cells.1 This significant development is setting the stage for a paradigm shift toward the adoption of treatments directed to the particular genetic makeup of the tumor.1,2

Over 50% of NSCLC Cases Are Linked to Known Molecular Biomarkers

At Least 10 Known Molecular Biomarkers in NSCLC3

with similar clinical stage and tumor histology can have dramatically different

50% of NSCLC cases are linked to one of

clinical outcomes.4

KRAS

at least 10 currently known biomarkers

Indeed, biomarkers may give clinicians

for NSCLC — and many of these patients genetic abnormalities that are “drivers” for their cancers and are treatable with approved biomarker-driven therapies or

Unknown EGFR

as well as the treatment sensitivity/

ALK

resistance of the tumor to specific agents.4,5

TP53

Moreover, as genomic and mutational PIK3CA

IDH1

CTTNB1

HER2 NRAS

BRAF

research continues, more biomarkers will inevitably be discovered, so that the proportion of NSCLC cases with unknown drivers will continue its decline. The

Now that more than half of NSCLC cases

ultimate goal of this approach to

can be linked to one or more of these

treatment is to identify every driver

biomarkers, it is possible to subdivide

mutation for non-small cell lung cancer,

the histological subtypes of NSCLC

and design a corresponding treatment

— adenocarcinoma, squamous cell

for each of these oncogenes.1,2,4

carcinoma, and large cell carcinoma — into clinically relevant molecular subsets.1

In partnership with:

an indication of the patient’s prognosis (outcome independent of treatment),

investigational agents in clinical trials.2,3

Sponsored by:

considerable heterogeneity of non-small cell tumors and suggest why patients

According to recent studies, more than

may test positive for mutations or other

These molecular subsets show the

Curbside Consult New Diagnostic Paradigm: Histology + Molecular Profile

For patients whose tumors test positive

David R. Gandara, MD Director, Thoracic Oncology Program, UC Davis Comprehensive Cancer Center

for a biomarker that is treatable with approved or investigational agents, the

Recently it has been proposed that

benefits of testing are self-evident.1,5,6

lung cancer treatment be based on the histology of the tumor. But there is

But in the future, molecular profiling

a growing consensus that molecular

will help an increasing proportion

profiling — testing the tumor at biopsy

of patients with NSCLC because the

for all appropriate biomarkers — should

additional information it reveals about

be part of the clinician’s standard

their tumor has the potential to guide

approach to pathologic evaluation.1,2

clinical management.2,7

And this is supported by the National Comprehensive Cancer Network (NCCN®)

Molecular Profiling Is Key in NSCLC

Clinical Practice Guidelines in Oncology

The discovery of biomarkers has

(NCCN Guidelines®) for all non-squamous

demonstrated the molecular complexity

non-small cell lung cancer (NSCLC)

of NSCLC, and it highlights the need

histologies, which state :

to move toward molecularly based

classification and treatment of these tumors.1,4 But only if patients are tested is it possible for them to potentially benefit

of “ Determination the specific molecular

from these developments. As additional mutations are discovered

abnormalities of the tumor is critical for predicting sensitivity or resistance to a growing number of targeted therapies.

through efforts such as the National Cancer Institute’s Lung Cancer Mutation Consortium (LCMC) and the Cancer Genome Atlas — and as new agents are

”

developed to address these abnormalities — the hope for the over 215,000 people

– NCCN Guidelines® Version 3.2012, for Non-Small Cell Lung Cancer 5

diagnosed with lung cancer each year is that these advances will lead to more treatment options.1,8-10 In the words of Dr. David Gandara, Director of Thoracic

The NCCN® recommends EGFR and ALK

Oncology at UC Davis Comprehensive

testing for all advanced non-squamous

Cancer Center, “Our goal is to learn the

NSCLC, in order to guide treatment

‘molecular fingerprint’ of each person’s

decisions. Multiplex molecular profiling

lung cancer, and to personalize their

assays may make the prospective

therapy based on this information. The

discoveries that could make this possible

genotyping of tumors possible, to aid clinical decision making and management.

What is the most significant development you’ve seen in the treatment of lung cancer today? DG Knowing what is driving the cancer! We have recently been using histology to treat cancer based on the appearance of the cells. But cells that look identical under the microscope can have dramatically different clinical outcomes because of what is driving them at the molecular level. And that is leading us to molecularly based treatment options.

Can many NSCLC patients benefit from this testing? Who should be tested? DG When you consider both approved and investigational agents, yes, a considerable proportion of NSCLC patients can receive therapy based on molecular testing. But at present I believe that all patients with NSCLC of the adenocarcinoma subtype should be tested.

That seems like a lot of testing. Wouldn’t that require a re-biopsy for many patients? DG These tests do require adequate tumor tissue. Some patients will need to be re-biopsied — some for lack of sample tissue, but also to look for changes that have occurred over time and as a result of therapy. Other patients may not have to be re-biopsied. To do the testing that reveals the “molecular fingerprint” of each person’s lung cancer, we have to get sufficient tumor tissue at biopsy.

Visit www.lungcancerprofiles.com for the patient perspective on molecular profiling.

are being made at a rapid pace.”

References: 1. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12:175-180. 2. Gandara DR, Li T, Lara PN Jr, et al. Algorithm for codevelopment of new drug-predictive biomarker combinations: accounting for inter- and intrapatient tumor heterogeneity. Clin Lung Cancer. 2012;13(5):321-325. 3. Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011;22(12):2616-2624. 4. Herbst RS, Heymach JV, Lippman SM. Molecular origins of cancer: lung cancer. N Engl J Med. 2008;359(13):1367-1380. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Non-small Cell Lung Cancer V.3.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed August 20, 2012. To view the most recent and complete version of the guideline, go online to http://www.nccn.org/. NATIONAL COMPREHENSIVE CANCER NETWORK,® NCCN,® NCCN GUIDELINES,® and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 6. Carr LL, Finigan JH, Kern JH. Evaluation and treatment of patients with non-small cell lung cancer. Med Clin N Am. 2011;95:1041-1054. 7. Goetsch CM. Genetic tumor profiling and genetically targeted cancer therapy. Semin Oncol Nurs. 2011;27(1):34-44. 8. National Institutes of Health. Lung cancer mutation consortium protocol. http://clinicaltrials.gov/ct2/show/NCT01014286. Accessed January 19, 2012. 9. National Cancer Institute. The cancer genome atlas. http://cancergenome.nih.gov/abouttcga/overview. Accessed January 19, 2012. 10. Boland JM, Erdogan S, Vasmatzis G, et al. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol. 2009;40:1152-1158. © 2012 Pfizer Inc.

Printed in USA/November 2012

CRI433117-04

The ASCO Post | JUNE 10, 2013

PAGE 22

Journal Spotlight

Death with Dignity continued from page 19

from Seattle Care Alliance who took the medication. Among cases with information available, the prescribing physician was present at ingestion for 4.5% of all patients in Washington State and for 19.0% of patients in Oregon, with another provider (and not the prescribing physician) being present in 51.0% and 43.9% of cases, respectively. In total, 11 patients lived longer than the life expectancy of 6 months; of these, 9 died after ingesting medication at an average of 7.4 weeks after the 6-month period. The program does not inform prescribing and consulting physicians when program participants live longer than the expected 6 months, due to concern that such information might result in unintentional delay of prognostic conversations until clinicians feel more certain of timing and that this might reinforce “the more persistent and likely problem of communicating prognosis (too) late in the course of illness.” None of the patients who enquired about the program at Seattle Cancer Care Alliance and were found to have current or previous depression or decisional incapacity chose to continue the process, and none of the patients continuing the process were found to require mental health evaluation for

depression or decisional capacity during the process.

Patient, Family, and Staff Experience In the Seattle Cancer Care Alliance program, no unexpected complications have occurred. One patient, however, died a day after taking medication, with the prolongation of the process causing distress for family members and clinicians; similar cases have occurred in other Washington and Oregon programs. No complaints regarding the program process or manner of death have been received from family or caregivers. Families have described the death as peaceful, even in cases in which death has taken longer than the average of approximately 35 minutes. Both patients and families have frequently expressed gratitude after the patient has received the prescription—irrespective of whether the prescription was filled

or the medication ingested—citing the importance of gaining a sense of control over their situation. The authors stated:

Our Death with Dignity program has been well accepted by patients, families, and staff. We attribute this to the professionalism of our advocates, the great care taken by our prescribing and consulting clinicians when interacting with patients and families, the low profile of the program overall, and the willingness of the Seattle Cancer Care Alliance leadership to allow considerable debate before the program was developed. A few clinicians who were strongly opposed to the Death with Dignity program subsequently expressed their willingness to participate as consulting or prescribing clinicians, which further supports acceptance of the program.

The authors noted that while the program has been well accepted by patients and clinicians, there remain issues to be addressed. For example,

Notes from a Death with Dignity Program

articipation in the Seattle Cancer Care Alliance Death with Dignity program reflects concerns about autonomy, dignity, and functional status rather than disease-related symptoms or depression. The Death with Dignity program “both allows patients with cancer who wish to consider this option to do so within the context of their ongoing care and accommodates variation in clinicians’ willingness to participate.” n

the authors note that 8 of 36 patients receiving prescriptions cited uncontrolled pain or fear of future symptoms among their end-of-life concerns, despite the fact that Seattle Cancer Care Alliance provides specialized care for pain and palliative care services. Program participants have only infrequently requested these services. Although this may be because patients do not have pain at the time of their initial request, the program will henceforward routinely offer palliative care consultations to all program participants. The authors concluded, “[O]ur Death with Dignity program both allows patients with cancer who wish to consider this option to do so within the context of their ongoing care and accommodates variation in clinicians’ willingness to participate. The program ensures that patients (and families) are aware of all the options for high-quality end-oflife care, including palliative and hospice care, with the opportunity to have any concerns or fears addressed, while also meeting state requirements.” n

Disclosure: For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Loggers ET, Starks H, Shannon-Dudley M, et al: Implementing a Death with Dignity program at a comprehensive cancer center. N Engl J Med 368:1417-1424, 2013.

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

Frederick R. Appelbaum, MD, on Death with Dignity see page 1

Lynn Etheredge on Rapid Learning Health-care Systems see page 77

Barrie R. Cassileth, MS, PhD, on Integrative Oncology see page 90

Burt Vogelstein, MD, on Prevention and Early Detection of Cancer see page 92

Pioneers in Oncology: Francis Crick, PhD see page 111

Heidi D. Nelson, MD, MPH, on Breast Cancer Risk Reduction see page 116

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | JUNE 10, 2013

PAGE 23

Perspective

Frederick R. Appelbaum, MD continued from page 1

who are being cared for at our center may request a prescription for a lethal dose of a barbiturate. Once they make such a request, they are assigned a patient advocate (a specifically trained social worker) who helps guide them through the entire process. If, after a 2-week waiting period and explanation of the process by the advocate, the patient remains interested in obtaining the prescription, he or she makes a second request. The prescribing physician then confirms the diagnosis and the patient’s competency, and assures informed consent including full awareness of palliative care and hospice services. A second, consulting physician reconfirms the diagnosis, competency, and the informed and voluntary nature of the request. Only then does the prescribing physician write the prescription, which our pharmacist then fills. No staff or faculty members are compelled to participate in this program. Additional details are available in the original article1 and The ASCO Post summary (on page 19). Our policy was adopted in March 2009. Overall, the program has proceeded quietly, with little internal or external publicity or notoriety. Relatively few patients make inquiries or access the program. We see about 5,000 new patients with cancer at our center every year, and in the 2 years since we adopted the policy, 114 patients (about 1%) have made formal inquiries. A total of 40 lethal prescriptions have been written (< 0.5% 0.5% of patients), and 24 patients have ingested the medication (around 0.2%). Very few patients have mentioned pain or disease-related symptoms as the reason for their request. Loss of autonomy (inability to care for self) was the most common reason for the request, cited in 97.2% of cases. Generally, patients and families were grateful to receive the lethal prescription, whether it was used or not. The Washington Death with Dignity Act is very similar to one previously approved in Oregon. The similarities in outcomes in the two states are strik-

ing. In both states, the programs have proceeded without major complications and are not heavily solicited. In both Oregon and Washington, the majority of individuals who have accessed Death with Dignity Programs are white, male, and educated (95% have a high school or higher degree). Cancer is by far the leading diagnosis (80% in both states). In both states, patients cite loss of autonomy as their leading end-of-life concern, and in both states, family members were involved in the decision more than 90% of the time.

Unintended Consequence One unintended consequence of adopting a Death with Dignity policy at our center is that it focused increased attention on our palliative care and hospice services. These are, of course, vital services for any cancer center and demand attention no matter the situation. When discussing a Death with Dignity policy, the first response from almost everyone is that having expert

A goal in publishing our results was to further the discussion on the role of the physician and institution in endof-life care and physician-assisted suicide. We encourage others to join in the conversation. —Frederick R. Appelbaum, MD

palliative care and hospice services to offer patients is essential before considering this alternative. A second article appearing in the same issue of The New England Journal of Medicine2 presented the case of a 72-year-old patient with metastatic pancreatic cancer, and allows the reader to vote for or against instituting physician-assisted suicide and to post comments online. Two brief editorials are provided, as well. You can go to the New England Journal of Medicine

Physician-assisted Suicide Readers’ comments extracted from www.nejm.org To force people to live simply because we possess the technology to do so does not speak to either the ethics or the morality of such a decision. Suffering has existential dimensions. Symptoms can be treated with greatest chance. My grandfather supported the [Nazi ideology], that there are humans who are without worth, meaning and dignity. He supported ideas that led to the world’s utmost catastrophy. You cannot end suffering by ending the sufferer. Assisted suicide is not liberating to those with disabilities, to me [a disabled individual] at least it confirms that I am a burden, not worthy of life. We human beings already have the innate right to die or to refuse excessive medical treatment. Understanding this right is essential for the betterment of our society. It is when you have nothing to offer a patient that he needs YOU the most. Do not fail him and provide all the moral and psychological support your can offer when accompanying his last days. Sometimes holding hands with a patient is the most helpful medicine. We must learn more and engage in a more substantive debate of this subject. See all comments at www.nejm.org From N Engl J Med 368:1450-1452, 2013.

What’s Your Opinion?

website and read through over 200 comments, which, as one might guess, run the gamut from highly in favor to deeply opposed (see sidebar). I found comments coming from foreign countries where safeguards for informed consent and human rights are perhaps not as well developed as in the United States to be particularly interesting. While our Death with Dignity Program has been proceeding relatively smoothly, that does not mean it can’t be improved upon. We continue to make efforts to provide palliative care consultations for all patients with a terminal diagnosis and enroll patients in hospice earlier. Opponents of Death with Dignity legislation have raised the concern that it might disproportionally affect vulnerable populations. That has not been the experience in Washington and Oregon. However, that doesn’t ensure that such programs can be adopted universally without risk. A goal in publishing our results was to provide data from our program and to further the discussion on the general topic of the role of the physician and institution in end-of-life care and the difficult issue of physician-assisted suicide. We encourage others to join in the conversation. n Disclosure: Dr. Appelbaum reported no potential conflicts of interest.

References 1. Loggers ET, Starks H, ShannonDudley M, et al: Implementing a Death with Dignity program at a comprehensive cancer center. N Engl J Med 368:14171424, 2013. 2. Boudreau JD, Somerville MA, BillerAndorno N: Clinical decisions. Physicianassisted suicide. N Engl J Med 368:14501452, 2013.

Share your thoughts about physician-assisted suicide. Write to editor@ASCOPost.com

Important Safety Information

Additional Important Safety Information

Boxed WARNING: Embryo-Fetal Toxicity • Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception — Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant — Encourage women who may be exposed to PERJETA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 — Monitor patients who become pregnant during PERJETA therapy for oligohydramnios

Left Ventricular Dysfunction • Left ventricular dysfunction, which includes symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) and decreases in left ventricular ejection fraction (LVEF), occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during treatment to ensure that LVEF is within your institution’s normal limits • Withhold PERJETA and Herceptin and repeat LVEF assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if the LVEF has not improved or has declined further Infusion‑Associated Reactions, Hypersensitivity Reactions/Anaphylaxis • PERJETA has been associated with infusion and hypersensitivity reactions • When all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

F O R T H E F I R S T‑ L I N E T R E AT M E N T O F H E R 2 +* M E TA S TAT I C B R E A S T C A N C E R

STRENGTHEN HER DEFENSE

Indication: PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2‑positive metastatic breast cancer who have not received prior anti‑HER2 therapy or chemotherapy for metastatic disease.

Extend progression‑free survival (PFS) with an FDA‑approved HER2 dimerization inhibitor1,2 were observed across several • Consistent PFS results 1

•

Placebo + Herceptin + docetaxel

PERJETA + Herceptin + docetaxel

100 90

HR = 0.62‡ 95% CI [0.51‑0.75] P<0.0001

80 70

18.5 MONTHS

60 PFS (%)

•

patient subgroups At the time of analysis, there were 191 (47.5%) and 242 (59.6%) patients with a PFS event in the PERJETA + Herceptin + docetaxel and placebo + Herceptin + docetaxel arms, respectively1 The most common adverse reactions (ARs) (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy1

6.1-Month Improvement in Median IRF†-Assessed PFS1

12.4 MONTHS

40 30 20 10 0 0

* HER2+ = human epidermal growth factor receptor 2 positive. † IRF = independent review facility. ‡ Stratified by prior treatment status and geographic region.

32 17

10 7

0 0

MONTHS P+H+D Pl+H+D

402 406

345 311

267 209

139 93

83 42 Patients at risk

• In the randomized trial, the overall frequency of hypersensitivity reactions/anaphylaxis

was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group • If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions HER2 Testing • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown Most Common Adverse Reactions • The most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. You may report side effects to the FDA at (800) FDA‑1088 or www.fda.gov/ medwatch. You may also report side effects to Genentech at (888) 835‑2555. For more information, scan the QR code or visit www.PERJETA.com.

PER0001010502

References: 1. PERJETA Prescribing Information. Genentech, Inc. June 2012. 2. Baselga J, Cortés J, Kim S‑B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109‑119.

Printed in USA.

(01/13)

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In the randomized trial, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebotreated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis PERJETA has been associated with infusion and hypersensitivity reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in the randomized trial as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETAtreated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In the randomized trial, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2% in the PERJETAtreated group and 2.5% in the placebo-treated group according to National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI - CTCAE) (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by

Dako Herceptest™ or FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In clinical trials, PERJETA has been evaluated in more than 1400 patients with various malignancies and treatment with PERJETA was predominantly in combination with other anti-neoplastic agents. The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in the randomized trial. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients on the PERJETA-treated group. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in the Randomized Trial PERJETA Placebo Body System/ + trastuzumab + trastuzumab Adverse Reactions + docetaxel + docetaxel n=407 n=397 Frequency rate % All Grades %

Grades 3-4 %

Frequency rate % All Grades %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 Asthenia 26.0 2.5 30.2 Edema peripheral 23.1 0.5 30.0 Mucosal inflammation 27.8 1.5 19.9 Pyrexia 18.7 1.2 17.9 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 Rash 33.7 0.7 24.2 Nail disorder 22.9 1.2 22.9 Pruritus 14.0 0.0 10.1 Dry skin 10.6 0.0 4.3 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 Nausea 42.3 1.2 41.6 Vomiting 24.1 1.5 23.9 Constipation 15.0 0.0 24.9 Stomatitis 18.9 0.5 15.4 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 Anemia 23.1 2.5 18.9 Leukopenia 18.2 12.3 20.4 Febrile neutropenia* 13.8 13.0 7.6 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 Headache 20.9 1.2 16.9 Dysgeusia 18.4 0.0 15.6 Dizziness 12.5 0.5 12.1 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 Arthralgia 15.5 0.2 16.1 Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

Grades 3-4 %

3.3 1.5 0.8 1.0 0.5 0.3 0.8 0.3 0.0 0.0 5.0 0.5 1.5 1.0 0.3 45.8 3.5 14.6 7.3 2.0 0.5 0.0 0.0 0.8 0.8 0.0 0.3 2.0 1.5 0.0 0.0

*In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the

PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebotreated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebotreated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In the randomized trial, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in the randomized trial were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/ hypersensitivity reactions that were clearly related to the antitherapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in the randomized trial, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA.

PERJETA® (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

ASCOPost.com | JUNE 10, 2013

PAGE 27

JCO Spotlight Supportive Care

Once-daily Moxifloxacin for Low-risk Patients with Febrile Neutropenia By Susan London

nce-daily oral moxifloxacin works at least as well as twicedaily oral ciprofloxacin plus amoxicillin–clavulanic acid when it comes to treating febrile neutropenia in patients who are at low risk for complications, according to a randomized, double-blind trial reported in the Journal of Clinical Oncology.1 Investigators led by Winfried V. Kern, MD, of the Universitatsklinikum Freiburg, in Freiburg, Germany, found that about four out of five patients given each regimen met criteria for therapy success such as defervescence and improved clinical status, with the difference between groups falling within the predefined cutoff for equivalence. The two regimens were generally similar in terms of tolerability, safety, and reasons for therapy failure. Patients in the combination therapy group had a somewhat higher rate of gastrointestinal adverse effects, whereas their counterparts in the moxifloxacin group more often had microbiologically documented failures, partly due to more cases of Pseudomonas aeruginosa infection. Nearly 6 in 10 patients overall were able to go home on their oral regimen, and readmissions in this subset were rare. As the investigators note, such outpatient therapy has numerous potential advantages that include shortened hospital stays, better quality of life, a reduced likelihood of complications from intravenous access devices, and less exposure to hospital pathogens that may be multidrug resistant.

Study Details Oncology patients were eligible for the trial, formally known as EORTC (European Organisation for Research and Treatment of Cancer) Infectious Diseases Group Trial XV, if they had febrile neutropenia, a low risk of complications as predicted by a Multinational Association for Supportive Care in Cancer (MASCC) score of greater than 20 (see Table 1 on page 28), and ability to swallow, and had received at most a single intravenous dose of empiric antibiotics. The patients were assigned to receive either moxifloxacin therapy (400 mg once daily) or combination therapy consisting of ciprofloxacin (750 mg twice daily) plus amoxicillin

with clavulanic acid (1,000 mg twice daily). Treating physicians were encouraged to discharge patients early if they met predefined criteria, such as absence of comorbidities requiring monitoring. The trial was designed to test equivalence of the two regimens. Equivalence was defined as a difference of less than 10% between regimens in the rate of therapy success— defervescence and improvement in clinical status during study drug treatment, freedom from infection relapse, and absence of documented infection caused by bacteria resistant

to study drugs. In terms of characteristics, slightly more than half of the patients studied had a hematologic malignancy. Overall, 43% had a MASCC score of 21 to 23. Twenty-seven percent received an initial (parenteral) antibiotic dose before starting their study therapy.

Main Trial Outcomes An intention-to-treat analysis among the 333 patients studied showed the rate of therapy success was 80% with moxifloxacin therapy and 82% with combination therapy, with the difference meeting the defi-

EXPERT POINT OF VIEW

he EORTC Infectious Diseases Group Trial XV “is a long-awaited study because it finally is an investigation of outpatient management of low-risk fever and neutropenia in a large number of patients,” Alison Freifeld, MD, of the University of Nebraska Medical Center in Omaha, commented in an interview with The ASCO Post. “It actually confirms what we have known for a long time, which is that low-risk patients who are carefully selected by the MASCC scoring criteria generally do well when Alison Freifeld, MD they receive empiric oral antibiotics in the outpatient setting.” A 2008 survey of practicing oncologists in the United States found that 82% were already using outpatient oral antibiotic therapy for their low-risk patients,1 according to Dr. Freifeld. Thus, “the study by Kern et al essentially validates an approach that has been employed by most [U.S.] oncologists for a number of years now, but the data provide strong support for the safety and efficacy of early discharge for low-risk febrile neutropenic patients who can tolerate oral antibiotic therapy.” (See MASCC Scoring System on page 28.)

Feasibility of Discharge The impact of oral antibiotic therapy in this population in terms of cost, convenience, and other such outcomes will ultimately depend on the feasibility of discharge, she said, concurring with the editorialists. “The issue will be whether or not the patient and the physician can manage the complexities of fever and neutropenia in the outpatient setting.” The study points to at least two additional topics for research, according to Dr. Freifeld. “One is to further refine how to choose the lowest-risk patients [as candidates for discharge]; there are still patients who require readmission—about 5% in this study—so we need to better define that,” she elaborated. “And secondly, we need to understand the social, psychological, and physical barriers that prevent us from being able to treat more patients at home. I think that these issues are important to evaluate in research studies so that we can facilitate more patients being treated outside of a hospital setting.” n Disclosure: Dr. Freifeld repoted no potential conflicts of interest.

Reference 1. Freifeld A, Sankaranarayanan J, Ullrich F, et al: Clinical practice patterns of managing low-risk adult febrile neutropenia during cancer chemotherapy in the USA. Support Care Cancer 16:181-191, 2008.

nition for equivalence. The findings were similar in patient subgroups and in a per-protocol analysis. More than half of patients were afebrile on day 2, and the time to defervescence was statistically indistinguishable between groups. Nearly all patients in both groups (99%) were alive at 30 days. The two groups had somewhat different reasons for treatment failure. The moxifloxacin group had more microbiologically documented failures, including some cases of P aeruginosa infection; the combination therapy group had more cases of discontinuation because of intolerance and adverse events. Overall, 59% of the patients were discharged on their assigned therapy; the main reasons for remaining hospitalized were related to transport/ logistics and psychosocial problems. Just 5% of the discharged patients were readmitted; the majority of readmissions were due to clinical deterioration and medical complications, including fever and infection. The rate of any adverse event was 44% with moxifloxacin and 52% with combination therapy, a nonsignificant difference; the leading events were diarrhea and abdominal pain. Overall, 7% of patients experienced serious adverse events, with no significant difference between groups. The combination therapy group had more cases of diarrhea, whereas the moxifloxacin group had more cases of neurologic events. The groups were similar in terms of liver and cardiac function abnormalities. The moxifloxacin group had a borderline significant lower rate of superinfections (7% vs 14%, P � .05).

Concluding Thoughts “[T]he data from this doubleblind trial provide evidence that single-drug oral therapy in low-risk febrile neutropenia with moxifloxacin is equivalent to the combination therapy so far considered standard. Local monitoring, particularly regarding the frequency of P aeruginosa infection and fluoroquinolone resistance among E coli and other Gramnegative enteric bacteria, is advisable continued on page 28

The ASCO Post | JUNE 10, 2013

PAGE 28

European Multidisciplinary Conference in Thoracic Oncology Pulmonary Metastasectomy in Patients with Colorectal Cancer

he largest-to-date and only prospective Spanish series of 549 patients who underwent surgical resection of lung metastases from colorectal carcinoma demonstrated a good postoperative recovery from the procedure. A further analysis on morbidity, the correlation between imaging studies and pathologic findings, and survival after 3 years is underway. The initial findings from this study were presented by Laureano Molins, MD, PhD, of the Department of Thoracic Surgery, Sagrat Cor University Hospital and Hospital Clinic, Barcelona, Spain, at the recent European Multidisciplinary Conference in Thoracic Oncology.1 Pulmonary metastasectomy is a commonly performed surgical treatment in patients with lung metastases from colorectal cancer, despite the lack of evidence from any controlled study of survival benefit. Claims for a survival benefit derive from case series.

tigators at cancer centers throughout Spain in conducting a prospective cohort study using data from the Registry of the Spanish Group for Surgery of Lung Metastases from Colorectal Carcinoma. The study objective was to analyze the main clinical factors involved in the prognosis of patients undergoing surgery for lung metastases from colorectal carcinoma. From March 2008 to March 2010, a total of 549 patients underwent at least one episode of radical lung metastasectomy and were enrolled in this study. The mean number of nodules detected by computed tomography (CT) was 1.88 (range, 1–12); 314 (59%) patients presented with a single node, 96 (18%) had multiple unilateral nodules, and 120 (23%) had multiple bilateral nodules in lung. Synchronous lung metastases and colorectal carcinoma were detected in 78 (15%) patients. Patients with metachronous lesions showed a mean disease-free interval of 24 months.

Prospective Cohort Study

Key Data

Dr. Molins headed a team of inves-

Febrile Neutropenia

A video-assisted thoracoscopic

cer Centre in Melbourne, Australia, continued from page 27 wrote, “This study has important imand may influence the choice of the plications for treatment of fever and best suitable drug for initial therapy,” neutropenia in patients with cancer the investigators concluded. but translating these trial findings into clinical practice will require changes to treatment algorithms, the way patients with fever and neutropenia are assessed, and the way antibiotic therapy is delivered in hospitals.”2 They continued, “Key to successful implementation of an outpatient oral antibiotic program will be making Monica A. Slavin, MD, MBBS Karin A. Thursky, MD, MBBS the correct choice of patient and antibiotic. Additionally “The data also represent the first the infrastructure must be in place confirmation to our knowledge in a for follow-up and readmission of multicenter setting that febrile neuoutpatients if required as well as for tropenic patients with cancer idenongoing surveillance of antimicrobial tified with the help of the MASCC susceptibility in isolates from this pascore as being low risk and treated tient group.” with an adequate oral antibiotic regiDr. Thursky also told The ASCO men can often be discharged and Post that “the real significance of this safely treated at home,” they added. paper is that it was a multicenter proIn an accompanying editorial, spective validation and application of Monica A. Slavin, MD, MBBS, and the MASCC score.” n Disclosure: Dr. Kern has received Karin A. Thursky, MD, MBBS, honoraria from Bayer HealthCare both of the Peter MacCallum Can-

approach was decided on for 75 (17%) of the 446 patients who had unilateral clinical involvement. Wedge resection was performed in 80% of patients. Occult metastases were detected by CT in 23% of patients showing bilateral pathologic involvement, compared to 7% of patients without bilateral involvement (P < .001). .001). Staging was done by positron-emission tomography (PET) or PET-CT in 75% of patients, with the following diagnostic values: sensitivity 84%, specificity 78%, positive predictive value 98%, and negative predictive value 26%. Patients who underwent pulmonary metastasectomy experienced few complications in this series; postoperative morbidity was observed in 81 (15%) patients. Postoperative mortality was exceptionally low, with two deaths (0.4%) occurring after resection of lung metastasis from colorectal cancer. Thoracotomy and wedge resection were the most frequently performed surgical techniques in this setting. The authors commented that the Pharmaceuticals, Pfizer, and Sanofi-Aventis, and research funding from Pfizer and SanofiAventis. Drs. Slavin and Thursky reported no potential conflicts of interest. For full disclosures of the other study authors, visit jco.ascopubs.org.

References 1. Kern WK, Marchetti O, Drgona L, et al: Oral antibiotics for fever in lowrisk neutropenic patients with cancer: a double-blind, randomized, multicenter

imaging tests used—CT and PET or PET-CT— had clear limitations in preoperative evaluation of patients as candidates for lung metastasectomy. They pointed out that this is the only prospective data collection regarding pulmonary metastasectomy in Spain, with a larger database than previously seen in the literature. Resection of lung metastases from colorectal carcinoma is a procedure with low morbidity and mortality. Their analyses are ongoing, and 3-year follow-up data on morbidity, the correlation between imaging studies and pathologic findings, and survival will be reported as data become mature. n

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

Reference 1. Molins L, Fibla JJ, Embun R, et al: Surgical treatment of 549 patients with lung metastases from colorectal carcinoma. Initial results of a prospective Spanish study. European Multidisciplinary Conference in Thoracic Oncology. Abstract 950. Presented May 11, 2013. trial comparing single daily moxifloxacin with twice daily ciprofloxacin plus amoxicillin/clavulanic acid combination therapy—EORTC Infectious Diseases Group Trial XV. J Clin Oncol 31:11491156, 2013. 2. Slavin MA, Thursky KA: Outpatient therapy for fever and neutropenia is safe but implementation is the key [editorial]. J Clin Oncol 31:1128-1129, 2013.

Table 1: Multinational Association for Supportive Care in Cancer (MASCC) Risk Index Scoring System for Febrile Neutropenic Patients with Cancera Risk Characteristic

Points

Burden of febrile neutropenia

■ No or mild symptoms

■ Moderate symptoms

No hypotension

No chronic obstructive pulmonary disease

Solid tumor or hematologic malignancy with no previous fungal infection

Outpatient status

No dehydration requiring parenteral fluids

Age < 60 years

Cumulative point score of 21 or more defines a low-risk patient. The maximum theoretical score is 26. Adapted with permission from Klastersky J, et al: J Clin Oncol 18:3038-3051, 2000. Copyright © 2000 by the American Society of Clinical Oncology. All rights reserved. a

NOW ENROLLING A Phase 3 Trial for Newly Diagnosed EGFRvIII-Positive Glioblastoma • Rindopepimut is an investigational therapeutic vaccine. It is thought to target EGFRvIII, a constitutively activated deletion mutant that is found only in tumors. About a third of glioblastoma patients are found to express EGFRvIII, and its presence has been linked to poor long-term survival1-3 • ACT IV is an international, randomized, double-blind, controlled, phase 3 study of rindopepimut added to standard of care temozolomide in patients with newly diagnosed EGFRvIII-positive glioblastoma Rindopepimut Every 2 weeks x 2, then monthly

1:1 Randomization

Diagnosis/Resection Chemoradiation EGFRvIII-positive glioblastoma

Temozolomide Days 1-5 in 28 day cycle 6-12 cycles

Treat until tumor progression, intolerance, or withdrawal of consent

Blinded KLH Control Every 2 weeks x 2, then monthly

N=~440

Temozolomide Days 1-5 in 28 day cycle 6-12 cycles KLH=keyhole limpet hemocyanin.

Key Inclusion Criteria

Key Exclusion Criteria

• Newly diagnosed glioblastoma

• Evidence of metastatic disease, diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial disease

• Attempted resection followed by chemoradiation with temozolomide • Provide a tumor specimen which tests positive for EGFRvIII at the protocol specified central laboratory • ECOG PS ≤ 2, and dexamethasone ≤ 2 mg/day (or equivalent) for ≥ 3 days prior to randomization

• Other treatments for glioblastoma • Unequivocal progression during chemoradiation therapy Key Trial Endpoints: • Primary: Overall Survival (OS) • Secondary: Progression-free Survival (PFS)

ECOG PS=Eastern Cooperative Oncology Group Performance Status.

For more information visit glioblastomastudy.com and http://www.clinicaltrials.gov/show/NCT01480479 or e-mail info@celldextherapeutics.com. 1. Pelloski CE, Ballman KV, Furth AF, et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol. 2007;25(16):2288-2294. 2. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28(31):4722-4729. 3. Sampson JH, Aldape KD, Archer GE, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13(3):324-333. ©2013 Celldex Therapeutics, Inc.

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The ASCO Post | JUNE 10, 2013

PAGE 30

American Society of Breast Surgeons Annual Meeting Breast Cancer

Double the Mastectomy, Double the Complications By Caroline Helwick

retrospective analysis of a large surgical database has documented that bilateral mastectomy is associated with a doubling in complication rates, compared with unilateral mastectomy. Researchers reported the findings at the 14th Annual Meeting of the American Society of Breast Surgeons in Chicago.1

Underlying Misperception Recent studies have shown that women with unilateral breast cancer are choosing contralateral prophylactic mastectomy at an increasing rate despite the well-established evidence of a low risk for future contralateral breast cancer and no strong evidence supporting a survival benefit. (There is evidence showing benefit, however, that evidence is not strong.) With the exception of a minority of high-risk patients who benefit from risk reduction with contralateral prophylactic mastectomy, there is evidence suggesting that the majority of women choose contralateral mastectomies based on fear of recurrence and a perceived survival benefit, said Fahima Osman, MD, a fellow at the University of Toronto. “For the majority of women, the risk of contralateral breast cancer is

very low. We want them to know that this is not a risk-free operation. Removing a healthy breast is associated with complications,” Dr. Osman said. Few studies have evaluated the

lection of low-risk patients, we found increased complications associated with bilateral mastectomies. The complication rate can potentially be higher if a reconstruction procedure

For the majority of women, the risk of contralateral breast cancer is very low. We want them to know that [prophylactic mastectomy] is not a risk-free operation. —Fahima Osman, MD

postoperative complication rates associated with contralateral prophylactic mastectomy without breast reconstruction. Using data from the American College of Surgeons Surgery Quality Improvement Program (ACS NSQIP) Participant Use Data Files from 2007 to 2010, Dr. Osman and colleagues compared patients with breast cancer undergoing unilateral mastectomies to those with bilateral mastectomies. Both groups had unilateral sentinel lymph node biopsy, and none had immediate reconstruction. “We wanted to estimate the risk of complications in low-risk patients. We used several exclusion criteria to create a group of patients that had low operative risk factors. Despite that se-

Bilateral Mastectomy in Low-risk Patients ■ A retrospective review of 4,219 patients found that low-risk patients

with breast cancer undergoing bilateral (prophylactic) mastectomy had double the rate of complications, compared with patients with unilateral mastectomy.

■ The wound complication rate was 5.8% in the bilateral mastectomy group vs 2.9% in the unilateral mastectomy group.

■ The increased risk of surgical complications should be discussed with lowrisk patients opting for prophylactic mastectomy.

is added,” she told The ASCO Post. “It makes sense that more operations can translate into more potential for complications.”

Large Database Probed The study identified 4,219 patients who underwent sentinel lymph node biopsy, of whom 3,722 (88.2%) had a unilateral mastectomy and 497 (11.8%) a bilateral mastectomy. Wound and infectious complications were significantly higher in the bilateral mastectomy group. The overall 30-day complication rate was nearly doubled: 7.6% vs 4.2%, for an unadjusted odds ratio of 1.9 (P < .05), Dr. Osman reported. The wound complication rate (infection and wound dehiscence) was 5.8% for the bilateral group vs 2.9% in the unilateral group, for an unadjusted odds ratio of 2.1 (P < .05). Infectious complications occurred in 2.2% vs 0.8% (P < .05). In the multivariable analysis, which accounted for a number of preoperative risk factors, bilateral mastectomy still carried an odds ratio for overall postoperative complications of 1.9 (P � .001). Independent predictors were body mass index (on

a continuous scale; average, 29.1 kg/ m2)(odds ratio � 1.05; P < .001) and smoking (odds ratio � 2.21; P < .001).

‘Deal With the Cancer First’ When a woman with unilateral breast cancer and a low risk of developing contralateral breast cancer insists on having mastectomies simultaneously, Dr. Osman tries to discourage that. “It is always best to deal with the cancer first,” she said. After patients have “digested the news of the cancer diagnosis,” she discusses the actual risk vs the patient’s perceived risk of a second breast cancer and the risks associated with contralateral prophylactic mastectomy. “I tell them we need to concentrate on treating the primary tumor and not take a risk on delaying chemotherapy and radiation due to complications. I would also advise patients with high preoperative risk factors such as smoking and obesity to look at these risks carefully. It is important that we, surgeons discuss these complication rates with patients contemplating contralateral prophylactic mastectomy. n

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

Reference 1. Osman F, Saleh F, Corrigan M, et al: Increased postoperative complications in bilateral mastectomy patients compared to unilateral mastectomy: An analysis of NSQIP data. American Society of Breast Surgeons Annual Meeting. Abstract 0167. Presented May 3, 2013.

News and Views from the World of Clinical Oncology and Hematology Visit The ASCO Post website at

www.ASCOPost.com

Up the AntiEGFR Start ERBITUX® (cetuximab) in 1st-Line I N D I C AT I O N S Head and Neck Cancer—ERBITUX is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck Colorectal Cancer—ERBITUX is indicated for the treatment of KRAS mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use, in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer EGFR=epidermal growth factor receptor.

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Approximately 90% of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In 3 patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7 (3%) of the 219 patients with squamous cell carcinoma of the head and neck treated with platinum-based therapy with 5-fluorouracil (5-FU) and European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin — Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks — Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS, on adjacent pages.

START WITH THE EXTREME

Regimen

EXTREME=ERBITUX® (cetuximab) in first-line Treatment of REcurrent or MEtastatic head and neck cancer. EXTREME Regimen=EU-approved cetuximab combined with platinum-based therapy with 5-FU.

The First Regimen Approved in 30 Years With Extended Overall Survival for Recurrent Locoregional or Metastatic SCCHN EXTREME REGIMEN (n=222)1

PLATINUM-BASED THERAPY WITH 5-FU (n=220)1

EXTENDED Median Overall Survival

(OS) (Primary Endpoint)

10.1 MONTHS

36% IMPROVEMENT IN OS*

7.4

MONTHS

HR=0.80 (95% CI: 0.64–0.98); p=0.034

IMPROVED Objective Response Rates (Reduced Tumor Size)†

20%

36%

PATIENTS

OR=2.33 (95% CI: 1.50–3.60); p=0.0001

PROLONGED Median Progression-Free Survival

5.5

MONTHS

3.3

MONTHS

HR=0.57 (95% CI: 0.46–0.72); p<0.0001 * Relative improvement in median overall survival for the EXTREME regimen was ([10.1-7.4]/7.4) x 100%=36%.1 †

Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2,3 CI=confidence interval; CT=platinum-based therapy with 5-FU; HR=hazard ratio; OR=odds ratio; SCCHN=squamous cell carcinoma of the head and neck.

The EXTREME Study was an open-label, randomized (1:1), multicenter, controlled clinical trial that compared EU-approved cetuximab + CT versus CT alone. Choice of platinum therapy (cisplatin or carboplatin) was up to the treating physician. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately 15% of the patients in the cisplatin-alone arm switched to carboplatin during the treatment period. In exploratory subgroup analyses of the EXTREME Study by initial platinum therapy (cisplatin or carboplatin), for patients (n=284) receiving cetuximab plus cisplatin with 5-FU compared to cisplatin with 5-FU alone, the difference in median overall survival was 3.3 months (10.6 vs 7.3 months, respectively; HR=0.71 [95% CI: 0.54–0.93]). The difference in median progression-free survival was 2.1 months (5.6 vs 3.5 months, respectively; HR=0.55 [95% CI: 0.41–0.73]). The objective response rate was 39% and 23%, respectively (OR=2.18 [95% CI: 1.29–3.69]). For patients (n=149) receiving cetuximab plus carboplatin with 5-FU compared to carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months (9.7 vs 8.3 months; HR=0.99 [95% CI: 0.69–1.43]). The difference in median progression-free survival was 1.7 months (4.8 vs 3.1 months, respectively; HR=0.61 [95% CI: 0.42–0.89]). The objective response rate was 30% and 15%, respectively (OR=2.45 [95% CI: 1.10–5.46]).1 The EXTREME Study was conducted outside the U.S. using European Union (EU)-approved cetuximab as the clinical trial material. ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab used in these studies; these pharmacokinetic data, together with the results of the EXTREME Study, and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in SCCHN.1

IMPORTANT SAFETY INFORMATION (continued) Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD Select Adverse Reactions ■ The most frequent adverse reactions seen in patients with carcinomas of the head and neck receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) versus CT alone (n=215) (incidence ≥40%) were acneiform rash (70% vs 2%), nausea (54% vs 47%), and infection (44% vs 27%). The most common grade 3/4 adverse reactions for cetuximab in combination with CT (≥10%) versus CT alone included: infection (11% vs 8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX

START WITH THE CRYSTAL

Regimen

CRYSTAL=Cetuximab combined with iRinotecan in first-line therapY for metaSTatic colorectAL cancer. CRYSTAL Regimen=EU-approved cetuximab + FOLFIRI; FOLFIRI=irinotecan, 5-fluorouracil, and leucovorin.

The First and Only Biomarker-Directed Therapy for Newly Diagnosed KRAS Mutation-Negative (Wild-Type) EGFR-Expressing mCRC1 ALL-RANDOMIZED PATIENT POPULATION1 CRYSTAL Regimen (n=608)

Median Overall Survival*

KRAS WILD-TYPE SUBPOPULATION1 P O S T- H O C A N A LY S I S

FOLFIRI alone (n=609)

CRYSTAL Regimen (n=320)

18.5

23.5

(95% CI: 18–21)

(95% CI: 17–20)

(95% CI: 21–26)

MONTHS

HR=0.88 (95% CI: 0.78–1.0)

Objective Response Rates (Reduced Tumor Size)‡

46%

19.5 MONTHS

(95% CI: 17–21)

HR=0.80 (95% CI: 0.67–0.94)†

38%

57%

IMPROVED

39%

PATIENTS

(95% CI: 42–50)

(95% CI: 34–42)

(95% CI: 51–62)

(95% CI: 34–44)

PRIMARY ENDPOINT Median Progression-Free Survival

EXTENDED

19.6 MONTHS

FOLFIRI alone (n=356)

8.9

8.1

9.5

MONTHS

(95% CI: 8.0–9.4)

(95% CI: 7.6–8.8)

PROLONGED

8.1

MONTHS

(95% CI: 8.9–11.1)

(95% CI: 7.4–9.2)

HR=0.85 (95% CI: 0.74–0.99); p=0.0358

HR=0.70 (95% CI: 0.57–0.86)

In all randomized patients, overall survival was not significantly different at the planned, final analysis based on 838 events (HR=0.93 [95% CI: 0.8–1.1]; p=0.327). Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer. •The primary endpoint for the study was progression-free survival in the all-randomized patient population. * Post-hoc updated overall survival analysis based on an additional 162 events.1

Not significantly different.1 Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2,3 § Based on the stratified log-rank test.1 CI=confidence interval; HR=hazard ratio; mCRC=metastatic colorectal cancer.

†

‡

The CRYSTAL Study was a Phase 3, open-label, randomized, multicenter study of 1217 patients with EGFR-expressing mCRC. Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI (the CRYSTAL Regimen) or FOLFIRI alone as first-line treatment. KRAS mutational status was available for 1079/1217 (89%) of the patients: 676 (63%) patients had KRAS mutation-negative (wild-type) tumors. Post-hoc analyses of efficacy data were performed on patient subgroups defined by KRAS mutation status.1 The CRYSTAL Study was conducted outside the U.S. using European Union (EU)-approved cetuximab as the clinical trial material. ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab used in this study; these pharmacokinetic data, together with the results of the CRYSTAL Study, and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in mCRC.1

IMPORTANT SAFETY INFORMATION (continued) Select Adverse Reactions ■ The most frequent adverse reactions seen in patients with KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer treated with EU-approved cetuximab + FOLFIRI (n=317) versus FOLFIRI alone (n=350) (incidence ≥50%) were acne-like rash (86% vs 13%) and diarrhea (66% vs 60%). The most common grade 3/4 adverse reactions (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs <1%), and diarrhea (16% vs 10%). U.S.-licensed ERBITUX provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided above are consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS, on adjacent pages.

UP THE ANTI-EGFR

Dermatologic Toxicities ■ In clinical studies of ERBITUX (cetuximab), dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1-17% of patients —Acneiform rash usually developed within the first 2 weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae —Sun exposure may exacerbate these effects Electrolyte Depletion ■ Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC grades 3 & 4) in 6-17%. In Study 2 the addition of EU-approved cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs 6%) and of grade 3–4 hypomagnesemia (7% vs 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs 4%). No patient experienced grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia, and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy —Replete electrolytes as necessary Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX Adverse Reactions ■ The most serious adverse reactions associated with ERBITUX are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) across all studies were cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection

CONTACT your sales representative or call 1-800-805-1058 (8 AM-8 PM EST, M-F) to receive patient education materials, enrollment information, and forms

Phone 1-800-861-0048 or Fax 1-888-776-2370 8 AM to 8 PM EST, M-F Please see enclosed Full Prescribing Information, including Boxed WARNINGS. References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; March 2013. 2. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer. 1981;47(1):207-214. 3. Van Cutsem E, Köhne C-H, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011-2019.

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Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2013 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US13BR00848-03-01

4/13

UP THE ANTI-EGFR

ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4) in Full Prescribing Information, Warnings and Precautions.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing Information.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] K-Ras Mutation-negative, EGFR-expressing Colorectal Cancer: Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2) in Full Prescribing Information, Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]

• i n combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, • in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, • as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information.]

Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Infusion Reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.] Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.] Pulmonary Toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin: In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Erbitux in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of Erbitux resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Erbitux combination arm and 14 patients (3.0%) in the control arm. Nine patients in the Erbitux arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of Erbitux to radiation and cisplatin did not improve PFS. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%. In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary. K-Ras Testing in Metastatic or Advanced Colorectal Cancer Patients: Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2) in Full Prescribing Information, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information]. Perform the assessment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Erbitux. Epidermal Growth Factor Receptor (EGFR) Expression and Response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/ faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 b 15 3 2 0 Infusion Reaction Infection 13 1 9 1 a 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 c 43 2 21 1 Alanine Transaminase, high Aspartate Transaminase, highc 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, highc Respiratory Pharyngitis 26 3 19 4 Skin/Appendages d 87 17 10 1 Acneiform Rash Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux (cetuximab) in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups. Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 2 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89). Table 2:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Recurrent Locoregional Disease or Metastatic SCCHN EU-Approved Cetuximab Platinum-based plus Platinum-based Therapy with Therapy with 5-FU 5-FU Alone (n=219) (n=215) System Organ Class Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Eye Disorders Conjunctivitis 10 0 0 0 Gastrointestinal Disorders Nausea 54 4 47 4 Diarrhea 26 5 16 1 General Disorders and Administration Site Conditions Pyrexia 22 0 13 1 10 2 <1 0 Infusion Reactiona Infections and Infestations 44 11 27 8 Infectionb Metabolism and Nutrition Disorders Anorexia 25 5 14 1 Hypocalcemia 12 4 5 1 Hypokalemia 12 7 7 5 Hypomagnesemia 11 5 5 1 Skin and Subcutaneous Tissue Disorders 70 9 2 0 Acneiform Rashc Rash 28 5 2 0 Acne 22 2 0 0 Dermatitis Acneiform 15 2 0 0 Dry Skin 14 0 <1 0 Alopecia 12 0 7 0 a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. b Infection – this term excludes sepsis-related events which are presented separately. c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”. Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm. Colorectal Cancer Study 4: EU-Approved Cetuximab in Combination with FOLFIRI — Study 4 used EU-approved cetuximab. U.S.-licensed Erbitux provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Erbitux in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 3 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4 [see Warnings and Precautions]. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224). Table 3:

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Table 3: (Continued)

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFR-expressing, Metastatic Colorectal Cancera EU-Approved Cetuximab plus FOLFIRI FOLFIRI Alone (n=317) (n=350) Grades Grades Grades Body System Grades 1–4b 3 and 4 1–4 3 and 4 Preferred Term % of Patients Skin and Subcutaneous Tissue Disorders 86 18 13 <1 Acne-like Rashd Rash 44 9 4 0 Dermatitis Acneiform 26 5 <1 0 Dry Skin 22 0 4 0 Acne 14 2 0 0 Pruritus 14 0 3 0 Palmar-plantar Erythrodysesthesia Syndrome 19 4 4 <1 Skin Fissures 19 2 1 0 a Adverse reactions occurring in at least 10% of Erbitux (cetuximab) combination arm with a frequency at least 5% greater than that seen in the FOLFIRI arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischaemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”. d Acne-like rash is defined by the events using MedDRA preferred terms and included “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”. Erbitux Monotherapy — Table 4 contains selected adverse reactions in 242 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer who received best supportive care (BSC) alone or with Erbitux in Study 5 [see Warnings and Precautions]. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 17 infusions (range 1–51). Table 4:

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type), EGFR-expressing, Metastatic Colorectal Cancer Treated with Erbitux Monotherapya Erbitux plus BSC BSC alone (n=118) (n=124) Grades Grades Grades Body System Grades 3 and 4 1–4 3 and 4 Preferred Term 1–4b % of Patients Dermatology/Skin Rash/Desquamation 95 16 21 1 Dry Skin 57 0 15 0 Pruritus 47 2 11 0 Other-Dermatology 35 0 7 2 Nail Changes 31 0 4 0 Constitutional Symptoms Fatigue 91 31 79 29 Fever 25 3 16 0 18 3 0 0 Infusion Reactionsc Rigors, Chills 16 1 3 0 Pain Pain-Other 59 18 37 10 Headache 38 2 11 0 Bone Pain 15 4 8 2 Pulmonary Dyspnea 49 16 44 13 Cough 30 2 19 2 Gastrointestinal Nausea 64 6 50 6 Constipation 53 3 38 3 Diarrhea 42 2 23 2 Vomiting 40 5 26 5 Stomatitis 32 1 10 0 Other-Gastrointestinal 22 12 16 5 Dehydration 13 5 3 0 Mouth Dryness 12 0 6 0 Taste Disturbance 10 0 5 0 Infection Infection without neutropenia 38 11 19 5 Musculoskeletal Arthralgia 14 3 6 0 Neurology Neuropathy-sensory 45 1 38 2 Insomnia 27 0 13 0 Confusion 18 6 10 2 Anxiety 14 1 5 1 Depression 14 0 5 0 a Adverse reactions occurring in at least 10% of Erbitux plus BSC arm with a frequency at least 5% greater than that seen in the BSC alone arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related. Erbitux in Combination with Irinotecan — The most frequently reported adverse reactions in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%). Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

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The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux (cetuximab) with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions have been identified during post-approval use of Erbitux. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Aseptic meningitis • Mucosal inflammation DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C — There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use: The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

Geriatric Use: Of the 1662 patients who received Erbitux (cetuximab) with irinotecan, FOLFIRI or Erbitux monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

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News

Cancer Organizations Recognize Sen. Shelby and Rep. DeLauro for Their Commitment to the Fight against Cancer

en. Richard Shelby (R-AL) and Rep. Rosa DeLauro (D-CT) were recognized recently by the American Society of Clinical Oncology, the American Association for Cancer Research, the Association of American Cancer Institutes, and Friends of Cancer Research for their outstanding commitment to cancer research and leadership in funding for biomedical science. The two Members of Congress were honored at a reception May 15 attended by the leadership and members of the cancer organizations, who came to Capitol Hill to meet with House and Senate offices. The physicians, researchers, and advocates called on legislators to support increased funding for the National Institutes of Health (NIH)

tion’s economic future. “As a cancer survivor, I appreciate the importance of promoting life-saving scientific advancements,” Sen. Shelby said. “Therefore, I am proud to support the advocacy efforts of cancer researchers, physicians, and Sen. Richard Shelby Rep. Rosa DeLauro patient advocates in their efforts to make a difference in the lives of all who are affected by and the National Cancer Institute cancer.” (NCI) to sustain the momentum in As Ranking Member of the making progress against cancer. House Appropriations Labor HHS Both Cancer Survivors Subcommittee, Rep. DeLauro has Sen. Shelby, Ranking Member on been a tireless advocate for federal the Senate Committee on Approfunding of biomedical research. priations, has been outspoken about “Before I came to Congress, I surthe role of the NIH both in saving vived ovarian cancer,” Rep. DeLauro lives and as an investment in our nasaid. “I was one of the lucky ones,

with my cancer found by chance in its earliest stage and I have now been cancer-free for 27 years. But no one should survive by luck. Biomedical research saved my life, as it has saved the lives of countless others. We need to invest more in medical research and our public health infrastructure, not less. I am proud to support those efforts and will keep fighting for those priorities.” “We applaud Sen. Shelby and Rep. DeLauro for their leadership in supporting cancer research that has significantly improved the lives of people with cancer,” said Sandra M. Swain, MD, FACP, ASCO Immediate Past President. “They have been steadfast partners in their commitment to sustained support for biomedical research.” n

The ASCO Post | JUNE 10, 2013

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JCO Spotlight Hematology

Postinduction Dexamethasone and Individualized Dosing of Asparaginase Improve Outcome in Pediatric ALL By Matthew Stenger

indings from the Dana-Farber Cancer Institute ALL Consortium Protocol 00-01, recently reported by Lynda M. Vrooman, MD, Dana-Farber Cancer Institute, and colleagues in Journal of Clinical Oncology, indicate that postinduction dexamethasone and individualized dosing of Escherichia coli–derived L-asparaginase (Elspar) improved outcomes in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL) compared with prednisone and fixed-dose E coli asparaginase.1 Prior studies had suggested that dexamethasone might have greater antileukemic activity than prednisone, and optimal dosing of asparaginase has remained undefined. In the study, patients who achieved complete remission during induction treatment were eligible for two randomizations: (1) dexamethasone or prednisone given as 5-day pulses every 3 weeks; and (2) weekly E coli asparaginase given as a 25,000 IU/m2 fixed dose or as an individualized dose starting at 12,500 IU/m2 and adjusted every 3 weeks according to an algorithm to maintain nadir serum asparaginase activity between 0.10 and 0.14 IU/mL. The study enrolled 492 evaluable patients aged 1 to 18 years between 2000 and 2004, of whom 473 had achieved complete remission. Of these, 408 patients (86%) were randomly assigned to prednisone (n� � �� 207) or dexamethasone (n � 201) and 384 (81%) were randomly assigned to fixed-dose E coli asparaginase (n� � �� 195) or individualized-dose E coli asparaginase (n � 189). Overall, patients had a median age of 4.75 years (range, 1–18 years;

77% aged 1–9 years), 54% were male, 43% were high-risk, 79% had white blood cell (WBC) counts less than 50,000 × 109/L, 90% had B lineage immunophenotype, and 83% had CNS1 status. Over a median followup of 4.9 years, 5-year event-free survival among all patients was 80% and 5-year overall survival was 91%.

Steroid Comparison Estimates of event-free and overall survival included only patients who were alive and in complete remission at the start of intensification therapy. Five-year event-free survival was sig-

curred significantly more frequently in those aged 10 to 18 years than in younger patients 23% vs 3%, P < .01). Among high-risk patients receiving prednisone, there was no difference in incidence of osteonecrosis by age. There was no difference in overall incidence of bone fracture between steroid groups; however, among patients aged 10 to 18 years, there was a borderline significantly greater incidence in those receiving dexamethasone (29% vs 10%, P � .06). Infections occurred significantly more frequently in dexamethasone patients overall (19% vs 11%,

Our results suggest that pharmacokinetic monitoring during treatment with [E coli asparaginase] to identify patients with silent inactivation may be an effective strategy to improve the outcome of children and adolescents with ALL. —Lynda M. Vrooman, MD, and colleagues

nificantly greater in patients randomized to dexamethasone compared with those randomized to prednisone (90% vs 81%, P � .01). The trend toward superior event-free survival with dexamethasone was observed in patient subsets defined by age, risk group, phenotype, and other characteristics. There was no significant difference between groups in 5-year overall survival (95% vs 94%). The overall incidence of osteonecrosis did not differ by steroid group. However, dexamethasone was associated with a significantly greater incidence in patients aged 10 to 18 years (23% vs 5%, P � .02). Among high-risk patients receiving dexamethasone, osteonecrosis oc-

Improving Survival in Acute Lymphoblastic Leukemia ■ Both postinduction dexamethasone and individualized dosing of

Escherichia coli L-asparaginase improved 5-year even-free survival compared with prednisone and fixed-dose E coli asparaginase in pediatric ALL patients.

■ Monitoring nadir serum asparaginase activity during treatment may be an effective strategy to improve outcome in pediatric ALL.

P � .03) and among dexamethasone patients aged 10 to 18 years (23% vs 2%, P � .004). One infection-related death occurred in a patient in the prednisone group.

Asparaginase Dose Comparison There was no difference between groups with regard to E coli asparaginase toxicity; for the individualizeddose group vs the fixed-dose group, any toxicity occurred in 31% vs 32%, with asparaginase clinical allergy occurring in 21% vs 20%, pancreatitis in 6% vs 5%, and thrombosis in 7% and 8%. Moreover, there was no difference between individualized-dose and fixed-dose groups with regard to proportion of patients completing at least 25 weeks of asparaginase treatment (86% and 88%). Five-year event-free survival was significantly greater in the individualized-dose group compared with the fixed-dose group (90% vs 82%, P � �� .04), with trends toward improved event-free survival with individualized dosing being observed in

subgroups defined by age, risk group, phenotype, and other characteristics. There was no significant difference in 5-year overall survival between groups (96% vs 93%). On the individualized-dose arm, patients with silent inactivation of asparaginase were prospectively identified based on persistently low nadir asparaginase enzyme levels and/or a low level in the presence of an anti-asparaginase antibody occurring in the absence of clinical allergy. Patients with silent inactivation on the individualized-dose arm were switched to an alternative asparaginase preparation (either Erwinia chrysanthemi [Erwinaze] or pegaspargase [Oncaspar]), similar to patients with clinical allergy. On the fixed-dose arm, patients with silent inactivation were not prospectively identified. Only those with clinical allergy to E coli asparaginase changed asparaginase preparations. Significantly more patients in the individualized-dose group were switched from E coli asparaginase to another asparaginase preparation (34% vs 22%, P � �� .01); similar proportions on both arms switched due to clinical allergy (21% and 20%), but an additional 10% of individualizeddose patients switched due to silent inactivation. Most (90%) of these latter patients subsequently had at least one nadir serum asparaginase activity of 0.1 IU/mL or greater, while 9% of the fixed-dose group never had nadir serum asparaginase activity of at least 0.1 IU/mL, never developed clinical allergies, and never switched formulations. The 5-year event-free survival rate among patients with persistently low nadir serum asparaginase activity who never switched preparations was similar in the individualized-dose group (78%, n � 12) and the fixeddose group (76%, n � 18); in contrast, 5-year event-free survival was high in individualized-dose patients who switched to a different preparation due to silent inactivation (95%, n � 19). As noted by the investigators, these results “suggest that prospectively monitoring for the development of silent inactivation (and not just clinical allergy) and continued on page 39

ASCOPost.com | JUNE 10, 2013

PAGE 39

Journal Spotlight Hematology

Intensified Liposomal Daunorubicin May Offer High Survival Rates without Added Cardiotoxicity for Children with Leukemia

reating pediatric leukemia patients with a liposomal formulation of anthracycline-based chemotherapy at an intensified dose during initial treatment may result in high survival rates without causing any added heart toxicity, according to the results of a study published online in Blood.1 Acute myeloid leukemia (AML), is the second most common form of leukemia in children. Standard induction regimens in children typically consist of 3 days of an anthracycline such as daunorubicin or idarubicin and 7 to 10 days of another chemotherapy such as cytarabine. Approximately 60% to 70% of children with AML achieve long-term survival with this combination of drugs.

Anthracycline Toxicity Recent evidence has suggested that increasing the intensity of induction treatment might improve remission rates and perhaps overall survival in AML patients. However, clinicians have used this approach sparingly in pediatric patients because of documented dose-related anthracycline toxicity in children, particularly the significant risk of damage to the developing heart muscle. In an effort to increase the effectiveness of this treatment for children with AML but reduce the cardiac risk profile, researchers are now investigating a liposomal formulation of daunorubicin that allows for more targeted delivery of the drug in the cancerous cells and diffuses at a slower pace in the body, which leads to a lower accumu-

Pediatric ALL continued from page 38

changing asparaginase preparations may improve outcome.” A total of 361 patients participated in both randomization schemes. Proportional hazards analysis including only these patients showed that both dexamethasone (hazard ratio [HR]� � 0.49, P � .02) and individualized-dose asparaginase (HR� � 0.52, P � .04) were independent predictors of better event-free survival. The investigators concluded: Our study demonstrates that postinduction dexamethasone and [indi-

lation in the heart. Results from early preclinical studies of the lipid-based formulation suggest that liposomal daunorubicin (DaunoXome) may be effective at higher-than-standard doses without causing added cardiotoxicity. “We know that the standard induction treatment regimen is effective in pediatric leukemia patients, but recognize that the toxicities associated with this therapy can be damaging to young patients who are still growing and developing,” said lead study author Ursula Creutzig, MD, PhD, of the Hannover Medical School in Germany. “This unique formulation of daunorubicin might offer us a way to effectively manage AML in these young patients while reducing their risk of experiencing the acute and long-term toxicities associated with traditional regimens.”

Trial Details Between 2004 and 2010, Dr. Creutzig and colleagues randomly assigned 521 patients under age 18 to treatment with either liposomal daunorubicin or idarubicin induction therapy. Patients treated with liposomal daunorubicin received a higher dose (80 mg/m²/d ×3) than the equivalent dose of idarubicin (12 mg/ m²/d ×3) during induction. Both groups also received additional treatment with cytarabine and etoposide. High-risk patients (defined roughly as those who were not in the favorable cytogenetic group) also received supplemental treatment with a chemotherapeutic agent (2-CDA) after the induction period. Additional cycles of maintenance treatment were adminisvidualized dosing] of L-asparaginase improves [event-free survival] in pediatric patients with newly diagnosed ALL…. Dexamethasone was associated with a higher infection rate and, in older children, increased incidence of osteonecrosis and fracture … [and] we found no difference in asparaginaserelated toxicity by [E coli asparaginase] dosing method…. Importantly, dexamethasone was associated with a better outcome in younger patients (1 to 10 years old) without any increased risk of skeletal toxicity. Considering its beneficial impact in reducing relapse risk, we continue to use dexamethasone in postinduction therapy for all

tered to all participants, excluding those who received a stem cell transplant.

Promising Results After a 5-year observational period, researchers noted similar results in both treatment arms (76% overall survival in the liposomal daunorubicin group vs 75% in the idarubicin group). The probability of event-free survival was also similar in the liposomal daunorubicin (59%) and idarubicin groups (53%), as were the probability of event-free survival results for standard-risk (72% for liposomal daunorubicin vs 68% for idarubin) and high-risk patients (51% vs 46%, respectively). Overall, treatment with this intensified induction regimen had a similar safety and tolerability profile to the traditional idarubicin dose. Treatmentrelated mortality was lower in the liposomal daunorubicin group than in the idarubicin group (2/257 vs 10/264 patients), and there were no unusual or persistent toxicities seen when compared with previous related trials. The team observed generally low rates of cardiotoxicities across the treatment groups in the study, though, fewer events were reported among the liposomal daunorubicin–treated

patients than the idarubicin-treated patients. In the liposomal daunorubicin group, there were four reports of severe acute cardiotoxicities, such as functional impairment, vs five events in the idarubicin group. There was a single patient reported to have late cardiotoxicity during follow-up in the liposomal daunorubicin group, as compared with three patients in the idarubicin treatment group. “These findings signal an important step forward in our goal to identify treatments that can give pediatric patients the best chance for long-term survival with minimal toxic side effects, and we believe the approach could have a number of extended applications. For example, this treatment formulation may be appropriate to use in adults or elderly patients to reduce the toxicity profile, or it may be of value for other malignant diseases in both children and adults,” said Dr. Creutzig. n

Disclosure: For full disclosures of the study authors, see bloodjournal.hematologylibrary.org.

Reference 1. Creutzig U, Zimmermann M, Bourquin JP, et al: Randomized trial comparing liposomal daunorubicin with idarubicin in induction for pediatric acute myeloid leukemia. Blood. May 23, 2013 (early release online).

Intensified Liposomal Daunorubicin in Pediatric Leukemia ■ In a randomized trial comparing intensified liposomal daunorubicin

with standard-dose idarubicin in patients with pediatric acute myeloid leukemia, antileukemic activity was comparable in both treatment arms.

■ Low rates of cardiotoxicities were observed across treatment groups, and fewer events were reported among liposomal daunorubicin recipients.

age groups. Future studies should focus on minimizing the toxicity of dexamethasone in older pediatric patients without compromising efficacy. Our results suggest that pharmacokinetic monitoring during treatment with [E coli asparaginase] to identify patients with silent inactivation may be an effective strategy to improve the outcome of children and adolescents with ALL. n Disclosure: Dr. Lewis B. Silverman has served as a consultant or advisor for Enzon Pharmaceuticals and EUSA Pharma, Dr. Jeffrey G. Supko has received research funding from EUSA Pharma, Dr. Mary V. Relling has received research funding from Sigma-Tau

Pharmaceuticals and Enzon Pharmaceuticals, and Dr. Stephen E. Sallan has received research funding from Enzon Pharmaceuticals and EUSA Pharma. All other authors of the study reported no potential conflicts of interest.

Reference 1. Vrooman LM, Stevenson KE, Supko JG, et al: Postinduction dexamethasone and individualized dosing of Escherichia coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: Results from a randomized study—DanaFarber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31:12021210, 2013.

The ASCO Post | JUNE 10, 2013

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Expert’s Corner Hematology

A New Center for Lymphoid Malignancies Aims to Provide Precision Patient Care A Conversation with Owen A. O’Connor, MD, PhD By Jo Cavallo

Owen A. O’Connor, MD, PhD

n January, New York-Presbyterian Hospital/Columbia University Medical Center opened the Center for Lymphoid Malignancies, a 3,700 square foot outpatient clinic, in the heart of Midtown Manhattan. The Center is solely focused on the treatment of all forms of Hodgkin and non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia/lymphoma. It was developed to provide patients with centralized multidisciplinary care and access to translational medicine to more precisely treat these complex lymphoid malignancies. Currently, the facility is engaged in over 20 phase I, II, and III clinical trials. The ASCO Post talked with Owen A. O’Connor, MD, PhD, Director for the Center for Lymphoid Malignancies, Professor of Medicine and Experimental Therapeutics, and Co-Director of the Program for Lymphoid Development and Malignancies at the Herbert Irving Comprehensive Cancer Center at New York-Presbyterian Hospital/ Columbia University Medical Center, about the goals of the new Center, how advances in more effective therapies for hematologic malignancies are extending survival rates, and the impact the federal budget sequester may have on future cancer advances.

Goals and Resources What are your goals for the Center for Lymphoid Malignancies? The Center for Lymphoid Malignancies is part of an institution-wide interest in building and bolstering a focus on hematologic malignancies with an effort to try to establish areas of expertise in the treatment of lymphoid

malignancies, myeloid malignancies, multiple myeloma and amyloidosis, and myelodysplasia. Each of these settings is linked, where appropriate, to a program focused on bone marrow transplantation and immunobiology. While providing traditional breadand-butter care for patients with nonHodgkin and Hodgkin lymphoma, the Center is unique in its focus on translational cancer medicine in an academic medical center. In this context, we can herald resources from all corners of the institution—scientific and clinical— to come up with practical solutions to even the most complex situations. For example, we have a large laboratory effort focused on developing new

molecular roots. These new drugs have the potential to achieve meaningful clinical benefit with the possibility of less toxicity. Another successful feature of our approach has been to exploit our large portfolio of over 20 clinical trials as a bridge to help patients who have disease that hasn’t responded well to conventional therapy get to an autologous or allogeneic stem cell transplant. Because many of these new drugs and drug combinations are not cross-resistant with conventional cytotoxic therapy, they offer a chance to achieve real remissions in the face of conventional chemotherapy resistance. For patients with multiply relapsed or refractory

The intent of the Center is to try and bring this new science to the patient and translate these concepts as quickly as possible. For patients in whom conventional therapies haven’t achieved the desired goal, we have access to a host of promising new drugs and drug combinations that are beginning to target these diseases at their genetic and molecular roots. —Owen A. O’Connor, MD, PhD

drugs and, with Dr. Donald W. Landry [the Samuel Bard Chair of the Department of Medicine at the Columbia University College of Physicians and Surgeons], we have just finished filing patents on very promising new drugs that look to modulate the impact of nuclear factor-kappaB. This transcription factor is known to modulate over 400 different genes, many of which contribute to the misbehavior of cancer cells. Leveraging that kind of science, we’ve actually developed a new inhibitor, which in the laboratory seems to have remarkably potent effects against a whole variety of cancers, including lymphoma. The intent of the Center is to try and bring this new science to the patient and translate these concepts as quickly as possible. For patients in whom conventional therapies haven’t achieved the desired goal, we have access to a host of promising new drugs and drug combinations that are beginning to target these diseases at their genetic and

disease, successive lines of combination cytotoxic chemotherapy are rarely associated with the most favorable risk-benefit ratio.

New Challenges Is the pace quickening regarding advances in treating hematologic cancers? There is no question that the ratelimiting step in our ability to make improvements against these diseases is no longer our ability to identify relevant biology, and it’s no longer our ability to find the novel small molecules that target that biology. The major challenge is in trying to expedite the time it takes us to go from concept and proof-of-principle in the laboratory to opening and accruing the appropriate clinical trials in a way that will support the preclinical rationale and hasten the regulatory process as well. There is also no question that the number of new drugs and potential new drug combinations for lymphoid malignancies has blossomed. But these

times of truly remarkable riches create new challenges as well. For example, recognizing that all these drugs will be used in some combination in the future, there are major questions regarding how best to combine them. Do we simply add everything onto an R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) backbone, or should we be thinking about new treatment platforms that are not completely addicted to cytotoxic therapy and are instead based more on a biologically relevant rationale? Both approaches have merits. In rare diseases, the challenges are amplified even more.

Treatment Progress Which blood cancers are seeing the most progress in terms of extended survival rates? In the case of diseases that can potentially be cured, Hodgkin lymphoma is a great example where we have made enormous strides that have impacted natural history. Presently, there are basically two lines of investigation. One strategy is to develop better risk-stratified approaches for the treatment of patients with Hodgkin disease, as is being shown now with the use of imaging modalities like positron-emission tomography (PET scanning). This sort of functional imaging can help us limit the amount of cytotoxic therapy patients are exposed to without compromising their long-term survival, and may help us define the optimal patient population to move forward to autologous stem cell transplant. The second line of research involves the development of new drugs, and in particular novel antibody-drug conjugates like brentuximab vedotin (Adcetris). Brentuximab is a spectacular example of bringing together new concepts in monoclonal antibodies and the development of linkers, which allow the conjugation of highly cytotoxic small molecules that can very precisely deliver a toxic payload directly to the tumor. This antibody drug conjugate, which targets CD30, delivers monomethyl auristatin E to CD30-positive tumors like those seen in patients with Hodgkin disease and anaplastic large-cell lymphoma. It has been associated with very high re-

ASCOPost.com | JUNE 10, 2013

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Expert’s Corner

sponse rates and durable remissions. In many forms of non-Hodgkin lymphoma, such as follicular, lymphocytic, and marginal zone lymphomas, we are trying to move away from a chemotherapy-centric platform and adopt more immunologically or targeted therapies to convert these cancers into truly chronic diseases. We have already seen the impact of rituximab on follicular lymphoma and the change it has made in the natural history of that disease. I think the exciting question moving forward is, can we now develop chemotherapy-free platforms for many of these other subtypes of lymphoma? New or older monoclonal antibodies coupled with new small molecules like Bruton’s tyrosine kinase (BTK) inhibitors that affect the B-cell receptorsignaling pathway, PI3-kinase inhibitors, and immunomodulatory drugs will create novel targeted approaches. I have no doubt that these strategies will allow us to manage these cancers as chronic diseases with less reliance on nonspecific cytotoxic chemotherapy. The field is moving at an amazingly fast pace, and I expect that in our lifetime we will see, and have already seen, substantial changes in the natural history of many forms of lymphoma.

Laboratory Research Please talk about the focus of your laboratory work. We have a program that is focusing on the biologic basis of select subtypes of lymphoma. For example, we are very focused on developing therapies specific for subtypes of diffuse large B-cell lymphoma that are derived from the germinal center. We know that there’s an important pathogenetic pathway or axis, the BCL6:p53 axis, that is actually dysregulated in diffuse large B-cell lymphoma

derived from the germinal center. In B�cells �cells cells derived from the germinal center, the oncogene BCL6 turns off the tumor-suppressor gene p53, which sets up the “DNA damage phenotype,” allowing for somatic hypermutation and isotype switching. This natural interaction generates diverse B cells capable of recognizing diverse antigens, but can lead to lymphomagenesis. Work in our

which includes several durable complete remissions. There is little to no expectation that niacinamide will be active in this setting, and vorinostat has already been proven inactive in this setting. Interestingly, niacinamide has been shown to activate p53 by enforcing the accumulation of acetylated p53. We are now working with chemists at Columbia to find better

Center for Lymphoid Malignancies at New York-Presbyterian Hospital/Columbia University Medical Center is in the heart of Midtown Manhattan. Photo: Ed Caraballo.

laboratory, and in others, has shown that both BCL6 and p53 can be modulated in an epigenetic way by histone deacetylase inhibitors. These epigenetic modifiers have been shown to reverse the relationship by turning off the oncogene and turning on the p53 gene. We are in the midst of a clinical trial with vorinostat (Zolinza) and niacinamide—a form of vitamin B3 that inhibits class�III III histone deacetylases—in patients with all types of aggressive lymphomas who had been heavily pretreated. To date, we have seen an overall response rate of 25%,

ways to inhibit class I, II, and, III histone deacetylases and develop a platform of more potent drugs. We also have a long-standing interest in developing better drugs for T-cell lymphoma. We’ve been doing a number of preclinical studies using pralatrexate (Folotyn)—the first drug approved for relapsed peripheral Tcell lymphoma—in a variety of combinations, including with the histone deacetylase inhibitor romidepsin (Istodax). These studies show that the pralatrexate/romidepsin combination seems to be remarkably synergistic

and has resulted in cures and complete remissions in mice. Those studies have paved the way for the launch of a phase I clinical trial looking at this drug combination for T-cell lymphoma.

Impact of Sequestration How will cancer research be affected by the federal sequestration cuts made to the National Institutes of Health budget? There is no question that the enormous momentum we have achieved over the years in terms of thinking about how to develop novel therapeutics for cancer based on a biologic context has been absolutely remarkable. The reduction in funding at the federal level does threaten the pace of those developments over the next 5 to 10 years, and every physician, physician/ scientist, and scientist involved in cancer research is going to be impacted. We are going to have to be very innovative in how we maintain the trajectory of our progress for the benefit of patients, which may require us to look to private foundations for support, and possibly even philanthropy. It’s unfortunate that a lot of important programs supported by the government are going to be affected adversely. In our field, it means that there is a potential that the present trajectory of our translational research for these challenging diseases will be adversely affected. This situation will require all of us to become involved in the political process to make sure the support is still there to maintain the momentum. Fortunately, most people working in this field are pretty clever, and I think in the end, we will find ways to make sure that nothing compromises our ambition to help every patient dealing with cancer. n Disclosure: Dr. O’Connor reported no potential conflicts of interset.

Contact The ASCO Post Editorial Office

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

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The ASCO Post | JUNE 10, 2013

PAGE 46

Journal Spotlight Breast Cancer

Higher Fruit and Vegetable Consumption Associated with Reduced Risk of ER-negative Breast Cancer By Matthew Stenger

n analysis of a large pooled data set from the Pooling Project of Prospective Studies of Diet and Cancer reported by Seungyoun Jung, ScD, Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues in Journal of the National Cancer Institute indicates that high fruit and vegetable consumption, particularly vegetable consumption, is associated with a significantly reduced risk of estrogen receptor (ER)-negative breast cancer.1 The analysis found no significant association between fruit and vegetable intake and risk of overall cancer or risk of ER-positive breast cancer.

Study Details The study included prospectively collected data from 993,466 women followed for up to 11 to 20 years in 20 cohort studies. The primary analyses examined associations of fruit and vegetable intake with the risk of developing breast cancer subtypes defined by ER status, and secondary analyses evaluated associations with breast cancer subtypes defined by progesterone receptor (PR) status. Studies had to meet the following criteria to be included in the analyses: at least one publication on any diet and cancer association, comprehensive assessment of usual dietary intake, validation of the dietary assessment method or closely related instrument, and at least 25 incident breast cancer cases of the specific hormone receptor subtype being evaluated. Overall, there were 34,526 incident invasive breast cancers diagnosed during follow-up in the population; hormone receptor status information was available for 24,673 cases, among which there were 19,869 ER-positive cancers, 4,821 ER-negative cancers, 16,162 PR-positive cancers, and 7,488 PRnegative cancers. Across studies, median fruit intake ranged from 118 to 392 g/d and median vegetable intake ranged from 61 to 259 g/d.

Reduced Risk for ER-negative Breast Cancer In the multivariable analyses, there was no significant association of total fruit and vegetable, fruit, or vegetable intake with risk of total breast cancer. Total fruit and vegetable intake was associated with a significant reduction in risk for ER-negative breast cancer (P � .03 for trend; relative risk [RR]� � 0.90 comparing the 5th vs 1st quintile). Total vegetable intake was significantly associated with an 18% lower risk of ERnegative breast cancer (P < .001), comparing the 5th vs 1st quintile. Fruit intake had a nonsignificant inverse association with risk of ERnegative breast cancer (P � .13; RR � 0.94 comparing 5th vs 1st quintile). There was no significant association between fruit and vegetable, fruit, or vegetable intake and ERpositive breast cancer risk. (P ≥ .06 for trend; RR� � 0.99–1.04 for these three food groups comparing 5th vs 1st quintile). There were no signifi-

Fruits, Vegetables, and Breast Cancer Risk ■ There are significant inverse associations between total fruit and vegetable and total vegetable consumption and risk for ER-negative breast cancer.

■ Significant and nonsignificant inverse relationships with risk for ER-

negative breast cancer were found for several botanical families of fruits and vegetables and for several individual fruits and vegetables.

Adjustment for intake of betacarotene, lutein, and fiber—which are concentrated in vegetables and thus could be driving the association between vegetable consumption and reduced ER-negative breast cancer risk—did not substantially change the inverse association observed between vegetable intake and ER-negative breast cancer risk.

Subtype Analysis by ER/PR Status Multivariable analyses of joint ER and PR status showed no significant associations of total fruit and vegetable intake or fruit intake with any of the breast cancer subtypes defined

Our results support a beneficial effect of overall fruit and vegetable consumption rather than consumption of a few specific fruits and vegetables. —Seungyoun Jung, ScD, and colleagues

cant associations between fruit and vegetable, fruit, or vegetable intake and risk for PR-positive or PR-negative breast cancers. When the fruit and vegetable intakes were modeled as continuous variables, the relative risks for ER-negative breast cancer for a 300-g/d increment (approximately three servings per day) were 0.94 (95% confidence interval [CI]� � 0.91–0.98) for total fruits and vegetables, 0.88 (95% CI�� 0.81–0.95) for vegetables, and 0.96 (95% CI�� 0.91–1.00) for fruits. Intake of these three food groups was nonsignificantly associated with risk of ER-positive, PR-positive, and PRnegative breast cancer.

jointly by ER/PR status. Higher vegetable intake was associated with a significant 16% reduction in risk for ER-negative/PR-negative breast cancer (P � .001 for trend; RR � 0.84 for 5th vs 1st quintile).

Analysis by Botanical Family and Specific Fruits and Vegetables Analyses according to botanical taxonomy of fruits and vegetables showed that higher intake of the Rosaceae family (eg, apples, peaches) was significantly associated with reduced risk for ER-negative breast cancer (100-g/d increment, RR � 0.91). Nonsignificant inverse associations were observed for intake of

Cruciferae (eg, broccoli, cabbage), Cucurbitaceae (eg, melon, squash), and Leguminosae (eg, beans, peas) families and risk of ER-negative breast cancer. No association was observed for intake of any of these families with risk of ER-positive breast cancers (RRs ranged from 1.00 to 1.04). Intake of Rutaceae (eg, grapefruits, oranges) and Solanaceae (eg, potatoes, tomatoes) was not associated with risk of either type of cancer. Analyses of risks according to intake of specific fruits and vegetables showed significantly reduced risk of ER-negative breast cancer with increased intake of apples/pears (138 g/d increment, RR� � 0.92), peaches/nectarines/ apricots (87 g/d increment, RR� � 0.81), strawberries (75�� g/d increment, RR� � 0.56), carrots (57 g/d increment, 0.92), and lettuce/salad (56 g/d increment, RR�� 0.91), but no association with risk for ER-positive breast cancer. No significant associations with risk for either ER-positive or ERnegative breast cancers were observed for intake of bananas, cantaloupe, grapefruit, oranges, fruit juice, broccoli, cabbage, spinach, tomatoes, yams, or potatoes.

Analysis by Participant Subgroups Associations of fruit and vegetable, fruit, and vegetable intake with ER-positive and ER-negative breast cancer risk were also analyzed by participant subgroups, defined by menopausal status, postmenopausal hormone use, oral contraceptive use, multivitamin use, alcohol consumption, smoking status, body mass index, age at diagnosis, family history of breast cancer, and race. Although the differences in risk estimates continued on page 50

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

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

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

DECODE metastatic melanoma.

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

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

Percentage surviving

80 60 Not reached

7.9

40 20 0

10 12 14 OS (months)

ZELBORAF (n=337)

Dacarbazine (n=338)

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

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

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

Learn more at Zelboraf.com/DECODE

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

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

Percentage surviving

80 60

13.6 9.7

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

20 0

22 24

OS (months) Updated analysis of ZELBORAF

Updated analysis of dacarbazine

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

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

The ASCO Post | JUNE 10, 2013

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Journal Spotlight

Breast Cancer Risk continued from page 46

across subgroups were not appreciably different, risk of ER-negative breast cancer was nonsignificantly reduced in most of the subgroups examined. With regard to potential mechanisms for the reduced risk of ERZELBORAF ® (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

negative breast cancers with increased vegetable consumption, the authors speculated that the beneficial effect of bioactive compounds in vegetables may be more detectable in preventing the less hormonally dependent ER-negative tumors than ER-positive tumors. Epidermal growth factor receptor tends to 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.

overexpressed in ER-negative breast tumors and this overexpression triggers nuclear factor-kappaB, which controls the transcription of DNA that is involved in immune responses. Further, the cell-cycle regulator cyclin E is overexpressed in ER-negative cancers. The lesser effect of fruit con-

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

*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

sumption on risk may reflect greater preventive effectiveness of bioactive constituents that are more concentrated in commonly consumed vegetables. The authors concluded, “[This analysis] provides compelling support for an association of high vegetable and fruit consumption, especially vegetable consumption, and reduced risk of ER-negative breast cancer. Our results support a beneficial effect of overall fruit and vegetable consumption rather than consumption of a few specific fruits and vegetables because associations were observed for several botanical families and several specific fruits and vegetables. In addition, when we controlled for several potential bioactive constituents concentrated in fruits and vegetables…, the inverse association for total vegetable consumption and risk of ER-negative breast cancer remained.” n

Disclosure: This work was supported by grants from National Institute of Health and the Breast Cancer Research Foundation and a fellowship from Samsung Scholarship to Dr. Jung.

Reference 1. Jung S, Spiegelman D, Baglietto L, et al: Fruit and vegetable intake and risk of breast cancer by hormone receptor status. J Natl Cancer Inst 105:219-236, 2013.

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Journal Spotlight

Determining the Best Diet for Patients with Cancer

Conflicting data on nutritional strategies during and after cancer treatment can cause confusion for oncologists and their patients. By Jo Cavallo

ow much does diet and body weight influence the effectiveness of cancer treatment and reduce the risk of cancer recurrence? What is the optimal diet for patients with cancer and survivors to follow? There are currently no hard and fast rules, but some dietary clues are starting to emerge.

not just the medicine we pump into our patients’ veins, but also the food they put into their mouths as anticancer treatments.”

We are introducing nutritional approaches into standard treatment regimens and combining the best of both worlds.

Search for Evidence According to a prospective, observational study of more than 1,000 patients with stage III colon cancer published last year in the Journal of the National Cancer Institute,1 overweight and obese patients who consistently ate a high-carbohydrate diet that caused high levels of blood glucose and insulin had an increased risk of cancer recurrence and death. The diet did not adversely affect the outcomes of patients with a healthy weight. Now, a new randomized controlled trial is underway to study whether calorie restriction through a low-carbohydrate diet can slow tumor growth in overweight or obese men with prostate cancer. Other studies looking at calorie restriction are also being planned or are already underway in breast, pancreatic, and lung cancers. “We came through the age of chemotherapy, when chemotherapy was going to cure everyone. Then we needed to give high-dose chemotherapy with stem cell rescue, and we thought that would save everyone. Next the ideal treatment was going to be immunotherapy, and now it is small-molecule targeted therapies,” said Stephen Freedland, MD, Associate Professor of Urology and Pathology at Duke University Medical Center, Durham, North Carolina, and lead author of the prostate cancer study. “While we are making major strides in our understanding of cancer and its treatment, we are not getting to where we want to go, and I think we need to take a more holistic approach,” he continued. “We are introducing nutritional approaches into standard treatment regimens and combining the best of both worlds. We want to use

is saying to eat plenty of fat and eat as many calorically dense foods as possible—and that’s pretty worrisome,” he commented.

—Stephen Freedland, MD

Dietary Confusion Although numerous studies show that weight gain after a cancer diagnosis is associated with a higher risk of disease recurrence in several types of cancer, including breast and prostate cancers, there is not enough evidencebased data showing exactly which type of diet—low-fat/high-carbohydrate or high-fat/low-carbohydrate—is best to follow during cancer treatment and survivorship. The result is confusion among both physicians and patients looking for definitive answers. In a study of 21 National Comprehensive Cancer Network (NCCN) member institution websites evaluating nutritional recommendations for patients with cancer undergoing treatment and during survivorship, only 4 sites provided nutritional guidelines. Half of the NCCN sites promoted a low-fat, high-carbohydrate diet, recommending 5:1 and 7:1 ratios of carbohydrate to fat food types, and half endorsed weight maintenance during treatment, recommending a 1:1 ratio of carbohydrate to fat.1 Onethird of the NCCN sites had links to external websites, including commercial websites like WebMD, and many contained inconsistent dietary recommendations. “The information was so varied,” said Colin E. Champ, MD, Assistant Professor in the Department of Radiation Oncology at the University of Pittsburgh, and the lead author of the website dietary recommendations study.2 “One site is telling readers to avoid all fat sources, and another site

“For patients with gastrointestinal cancers or head and neck cancers who need to maintain weight during treatment, eating a high-calorie diet is fine,” he said. “But for patients with breast cancer or prostate cancer—many of whom are already overweight—giving recommendations to eat whatever you can to avoid losing weight could put them in a bad spot. Studies show that patients who gain about 10 lb during or after treatment have a higher rate of recurrence.” The study result is especially alarming, said Dr. Champ, since data show that as many as 1 in 3 patients seek online dietary and nutritional advice during cancer treatment and survivorship.

Tailoring Diet Based on Cancer Type Because cancer type, stage of disease, and treatment modalities (and

Colin E. Champ, MD

their side effects) can all impact a patient’s nutritional requirements, dietary recommendations should be customized to fit those needs, also

taking into account a patient’s cultural heritage and food preferences and the patient’s resources with regard to buying and cooking wholesome foods, according to Jody Gilman, MS, RDN, CDN, Outpatient Clinical Dietitian at Memorial Sloan-Kettering Cancer Center, New York City. “Nutritional counseling is part art and part science. A diet plan and medical nutrition therapy will incorporate the clinical judgment of the provider but also be specifically tailored to the patient’s needs and challenges,” said Ms. Gilman. “A patient with head and neck cancer receiving chemotherapy or radia-

Jody Gilman, MS, RDN, CDN

tion therapy who has damage to her esophagus and oral cavity is going to present with much different symptoms from treatment side effects than a patient with breast cancer on endocrine therapy,” she explained. “The former patient may require food consistency modifications, such as purees, or the need for nutrition through a feeding tube, for example. The latter may need a diet tailored to weight control. The ideal diet for a patient with cancer will be based on all these types of information.” And because a patient’s nutritional needs may change during each step in the aftermath of a cancer diagnosis— while undergoing treatment and after cure, remission, or disease progression—the patient’s diet should be reevaluated and altered accordingly, said Ms. Gilman.

Managing Cancer through Diet Although having cancer and going through treatment is often associated with severe weight loss, recent continued on page 52

The ASCO Post | JUNE 10, 2013

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Journal Spotlight

Diet and Cancer

Study Diet

continued from page 51

In Dr. Freedland’s observational prostate cancer study, patients are encouraged to eat a diet of less than 20 g of carbohydrates a day, few or no fruits, low or no sugar and mainly meat, cheese, beans, nuts, and vegetables, with no limit on the amount of those foods participants consume. “In mouse studies, cutting calories by 20% slows cancer tumor growth,” said Dr. Freedland. “If you can get a

data show that only a small minority of patients actually experience severe weight loss. In fact, it is more common for patients to gain weight during treatment,3,4 a problem that can result in poorer responses to therapy, disease progression, and disease recurrence, according to studies.5,6 “Plenty of studies show that overweight patients have worse outcomes than normal weight patients and that obese patients are at higher risk of having elevated insulin and serum glucose levels, which can feed tumors and make treatment less effective. For cancers requiring radiation treatment, planning the course of therapy for obese patients is a lot more difficult, and we have to use higher radiation doses to penetrate the body fat and reach the tumor, which also creates problems,” said Dr. Champ. Although there have not been many randomized studies examining whether a diet low in fat and high in carbohydrates or one that is low in carbohydrates and high in fat is best for patients with cancer, oncologists can consider the results of dietary studies in patients without cancer for guidance, noted Dr. Champ. “I looked at a lot of studies examining the risk factors in obese patients in a number of diseases, including diabetes and heart disease, and found that a low-fat, high-carbohydrate diet may not be the right choice,” he said. “We need to start extrapolating these data in cancer and look at how we can reduce obesity as one of the risk factors for cancer incidence and recurrence.”

patient on a diet of 2,500 calories per day to reduce his food intake to 2,000 calories a day, that’s enough of a reduction in the equivalent mouse model to slow tumor growth.” “Now, I’ve treated a lot of mice with different diets, but I haven’t cured one, so diet is unlikely to be a cure,” he added. “But I would argue that medications don’t cure diabetes or heart disease either; they help manage these diseases, and that’s our goal

Online Resources for Nutritional Guidance during and after Cancer Treatment

lthough many major cancer centers have onsite-registered dietitians to provide patients with nutritional guidance while undergoing treatment and during survivorship, an estimated 64% of patients with cancer use the Internet to find nutritional advice.1 These websites can help provide patients with accurate nutritional information: Academy of Nutrition and Dietetics (eatright.org): Formerly the American Dietetic Association, this site includes a “Find a Registered Dietitian” search feature and food and nutrition topics, including how to eat a healthy diet on a tight budget and how to read package nutrition labels. American Cancer Society (cancer.org): Topics include nutritional guidance for both adults and children undergoing cancer treatment, information on physical activity and dietary supplements, and free online interactive programs focusing on nutrition, treatment side-effect management, and recovery. American Society of Clinical Oncology (cancer.net): ASCO’s site provides nutrition recommendations for patients with cancer during and after treatment, tips on managing a healthy weight, information on food safety, and how to maintain nutritional intake while overcoming treatment side effects. National Cancer Institute (cancer.gov): This website provides a comprehensive book, Coping with Cancer: Supportive and Palliative Care, which includes information on the dietary needs of patients with cancer, how feelings can affect appetite during cancer treatment, and how to manage eating problems. n Reference 1. Huang GJ, Penson DF: Internet health resources and the cancer patient. Cancer Investigation 26:202-207, 2008.

with diet and cancer. I’m not trying to cure cancer with my diets. I’m trying to convert cancer to a chronic disease that doesn’t cause patients problems and won’t metastasize or kill them.” The bottom line: “We need to invest more thought, time, and money into nutritional studies for patients with cancer,” said Dr. Champ. n

Disclosure: Drs. Freedland and Champ and Ms. Gilman reported no potential conflicts of interest.

References 1. Meyerhardt JA, Sato K, Niedzwiecki D, et al: Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: Findings from CALGB 89803. J Natl Cancer Inst 104:17021711, 2012. 2. Champ CE, Mishra MV, Showalter TM, et al: Dietary recommendations during and after cancer treatment: Consistently inconsistent? Nutr Cancer 65, 430-439, 2013. 3. Demark-Wahnefried W, Rimer BK, Winer EP: Weight gain in women diagnosed with breast cancer. J Am Diet Assoc 97:519-529, 1997. 4. Kim HS, Moreira DM, Smith MR, et al: A natural history of weight change in men with prostate cancer on androgendeprivation therapy (ADT): Results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BJU Int 107:924-928, 2011. 5. Stebbing J. Sharma A, North B, et al: A metabolic phenotyping approach to understanding relationships between metabolic syndrome and breast tumor responses to chemotherapy. ASCO Annual Meeting. Abstract 10544. Presented June 6, 2011. 6. Goodwin PJ, Ennis M, Pritchard KI, et al: Fasting insulin and outcome in earlystage breast cancer: Results of a prospective cohort study. J Clin Oncol 20:42-51, 2002.

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Announcements

John P. Leonard, MD, Leads NCI’s Alliance for Clinical Trials in Oncology Lymphoma Committee

ohn P. Leonard, MD, a hematology and oncology expert specializing in the treatment of lymphomas at Weill Cornell Medical College, has been named Chair of the Lymphoma Committee for the National Cancer Institute (NCI)-sponsored group, the Alliance for Clinical Trials in Oncology. Dr. Leonard is the Associate Dean for Clinical Research at Weill Cornell and Director of the Joint Clinical Trials Office at Weill Cornell and NewYork-Presbyterian Hospital/Weill Cornell Medical Center. In his role as Chair, Dr. Leonard will help guide the national agenda for lymphoma research by developing, supporting, and shepherding phase II and III clinical trials funded by the NCI at medical centers across the country. He will direct a team of lymphoma clinical and translational researchers from academic and community medical centers across the United States to create and implement new standards of treatment as well as foster the development of novel therapeutics. “I am honored and deeply humbled to be chosen to lead this vital national effort to improve cancer care for patients in the United States,” said Dr. Leonard, who also serves as the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology, Vice Chairman for Clinical Research in the Department of Medicine and Professor of Medicine at Weill Cornell.

of the cooperative clinical trials groups that comprise the NCI-funded National Clinical Trials Network. As the main mechanism by which na-

tional phase III lymphoma clinical trials are conducted, the Lymphoma Committee, one of the Alliance’s nine scientific committees, is dedicated to developing

novel therapies and therapeutics that advance the standards of care for patients with the disease. n

SPECIFIC

IMMUNOTHERAPY EMPOWERS THE IMMUNE SYSTEM TO FIGHT CANCER Immunotherapy primes T cells and B cells to recognize and target cancer cells expressing specific tumor antigens.1-3

About the Alliance The Alliance for Clinical Trials in Oncology is a national clinical trials network sponsored by the NCI that consists of nearly 10,000 cancer specialists at hospitals, medical centers, and community clinics across the United States and Canada. The Alliance is dedicated to developing and conducting clinical trials with promising new cancer therapies, and utilizes the best science to develop optimal treatment and prevention strategies for cancer, as well as researching methods to alleviate side effects of cancer and cancer treatments. The Alliance was formed in 2011 by the merger of three NCI-funded cooperative groups with a history dating back more than 50 years: the American College of Surgeons Oncology Group, Cancer and Leukemia Group B, and the North Central Cancer Treatment Group. The merged organization is one

It’s time to consider

IMMUNOTHERAPY

as an important treatment in your fight against cancer. For more information go to www.FightCancerWithImmunotherapy.com References: 1. Murphy K, et al, eds. Janeway’s Immunobiology. 7th ed. Garland Science, Taylor & Francis Group, LLC. New York, NY: 2008. 2. Namm JP, et al. J Surg Oncol. 2012;105:431-435. 3. Sharma P, et al. Nat Rev Cancer. 2011;11:805-812.

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JCO Spotlight Gastrointestinal Oncology

Geriatric Factors Predict Severe Toxicity in Elderly Patients on First-line Treatment for Metastatic Colorectal Cancer By Matthew Stenger

lderly patients differ with respect to tolerance of therapy for colorectal cancer. In a study reported in Journal of Clinical Oncology, Thomas Aparicio, MD, PhD, of the University of Paris, and colleagues analyzed geriatric factors for potential association with severe toxicity, dose-intensity reduction, and hospitalization among elderly patients receiving fluorouracil (5-FU)based therapy alone or in combination with irinotecan as first-line treatment for metastatic colorectal cancer.1 This ancillary geriatric study was conducted in a subset of patients in the Fédération Francophone de Cancérologie Digestive 2001-02 trial, which was conducted exclusively in patients aged 75 years or older. The investigators found that cognitive impairment on the Mini-Mental State Examination (MMSE) and impaired autonomy on the Instrumental Activities of Daily Living (IADL) scale were associated with increased risk of severe toxicity, with cognitive impairment also being associated with increased risk of unexpected hospitalization. Data on progression-free survival, the primary endpoint of the trial, are not yet available.

Study Details The FFCD 2001-02 trial included 282 patients who received 5-FU/leucovorin (as LV5FU2 or simplified LV5FU2; 5-FU group) or in combination with irinotecan (as LV5FU2-irinotecan or FOLFIRI; irinotecan group); irinotecan was given at 150 mg/m2 for two cycles and, in the absence of toxicity, at 180 mg/m2 in subsequent cycles. The current analysis involved 123 of these patients (44% of the total population; 62 in the 5FU group and 61 in the 5-FU/irinotecan group) who were treated at trial centers participating in the ancillary geriatric study (32 of 50 centers). Patients completed the MMSE, which assesses cognitive function, the IADL, which assesses dependence, and the Geriatric Depression Scale. Lower scores on the MMSE and IADL indicate greater impairment, whereas lower score on the GDS indicates better mood

rating. Patients with lower scores on the MMSE (≤ 27/30), IADL (≤ 7/8), and GDS (≤ 2) were compared with those with higher scores for frequency of grade 3 or 4 toxicity, dose-intensity reduction of more than 33%, and unexpected hospitalization (for any reason other than receipt of chemotherapy) over the first 4�months �months months of treatment. Associations of other clinical and disease factors with these outcomes were also analyzed. Overall, patients had a median age of 80 years, 54% were male, 80% had two or fewer metastatic sites, 80% had liver metastases, 85% had no prior adjuvant chemotherapy, and 75% had alkaline

Cognition, Autonomy, Older Age, and Chemotherapy ■ Impaired cognition on the MMSE and impaired autonomy on the IADL

scale were associated with increased risk of grade 3 or 4 toxicity in elderly patients receiving first-line therapy for metastatic colorectal cancer.

■ Impaired cognition was also associated with increased risk of unexpected hospitalization.

Tumor and geriatric variables were similar between patients in the 5-FU group and those in the irinotecan group except for greater proportions of patients in the irinotecan group with more than two metastatic sites (26% vs 11%, P � .04) and with comorbidities on the Charlson index (31% vs 16%, P � .06).

[O]ur study is the first to prospectively demonstrate that geriatric characteristics are independent predictive factors of tolerance to chemotherapy and toxicity in [metastatic colorectal cancer]. —Thomas Aparicio, MD, PhD, and colleagues

phosphatase ≤ 2 times upper limit of normal. Karnofsky performance status was 60 to 70 in 32% and 80 to 90 in 50%, Charlson comorbidity index was 0 to 1 in 75%, and mean score on a visual analog quality-of-life test was 60. MMSE scores were > 27/30 in 43% of patients and ≤ 27/30 in 31%, with 26% of patients not being evaluated (completion of less than half of the items on the instrument). IADL scores were 8/8 in 37% and ≤ 7/8 in 34%, with 29% not being evaluated. GDS scores were > 2 in 10% and ≤ 2 in 63%, with 27% not being evaluated.

Univariate Analysis On univariate analysis, grade 3 or 4 toxicity was significantly associated with absence of prior adjuvant therapy, irinotecan treatment group, MMSE score ≤ 27/30, and IADL score ≤ 7/8. On multivariate analysis, significant predictors of severe toxicity were irinotecan treatment group (odds ratio [OR]� � 5.03, P � .006), MMSE score ≤ 27/30 (OR�� 3.84, P � .019), and IADL score ≤ 7/8 (OR�� 4.67, P � ��.011). �.011). .011). The The presence of either lower MMSE score or lower IADL score was associated with an odds ratio of 5.43 (P � .001).

Scales Used in the FFCD 2001-02 Triala ■ Geriatric Depression Scale (GDS), a 4-item self-assessment used to detect depression in the elderly

■ Instrumental Activities of Daily Living (IADL), an indicator of an

individual’s daily self-care functionality and independence, as measured by a variety of evaluation tools

■ Mini-Mental State Examination (MMSE), a 30-point questionnaire used to screen for cognitive impairment

FFCD = Fédération Francophone de Cancerologie Digestive

Significant predictors of dose-intensity reduction of more than 33% on univariate analysis were presence of more than two metastatic sites, alkaline phosphatase > 2 times the upper limit of normal, and irinotecan treatment group. On multivariate analysis, significant predictors were alkaline phosphatase level > 2 times the upper limit of normal (OR�� 4.16, P � .047) and irinotecan treatment group (OR�� 6.86, P � .004). Exploratory analyses of MMSE and IADL scores as continuous variables indicated that a linear decrease in MMSE was an independent prognostic factor (OR�� 24.33 for every 10% decrease in MMSE score, P � .035). On univariate analysis, MMSE ≤ 27/30 was a significant predictor of unexpected hospitalization and the effect of female sex approached significance. On multivariate analysis, significant predictors were MMSE ≤ 27/30 (OR�� 4.56, P � .005) and, surprisingly, better mood on the GDS (≤ 2; OR� � 5.52, P � .035).

Analysis by Treatment Group When the predictive effects of MMSE and IADL for severe toxicity and the effect of MMSE for hospitalization were analyzed by treatment group, there were no significant statistical interactions, indicating similar predictable effects in both groups. However, there were numerical differences between groups with regard to these risks. Among patients with MMSE ≤ 27/30, 89% in the irinotecan group vs 50% in the 5-FU group had grade 3 or 4 toxicity; among those with MMSE >�� 27/30, 58% vs 30% had severe toxicity. Among patients with impaired IADL, 89% in the irinotecan group vs 55% in the 5-FU group had severe toxicity; among those with normal IADL, severe toxicity occurred in 56% vs 23%. In patients with impairment on both MMSE and IADL, severe toxicity occurred in 89% of the irinotecan group

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JCO Spotlight

vs 50% of the 5-FU group, and in those without impairment on both measures, severe toxicity occurred in 44% vs 13%. Unexpected hospitalization occurred in 61% of 5-FU patients vs 67% of irinotecan patients with MMSE ≤ 27/30 and in 35% vs 36% of those with MMSE > 27/30. The authors noted that nearly 90% of patients with impaired cognitive function and autonomy treated with irinotecan experienced severe toxicity. The data also suggested that patients without impairment in these domains can benefit from the addition of irinotecan without having toxicity risk greater than that observed in patients with impairment in both domains treated with 5-FU alone.

onstrate that geriatric characteristics are independent predictive factors of tolerance to chemotherapy and toxicity in [metastatic colorectal cancer]. Intensive chemotherapy should be used with caution in patients who have cognitive impairment or dependency. Larger studies are needed to confirm our results.” n

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

Reference 1. Aparicio T, Jouve J-L, Teillet L, et al: Geriatric factors predict chemotherapy feasibility: Ancillary results of FFCD 2002-02 phase III study in first-line chemotherapy for metastatic colorectal cancer in elderly patients. J Clin Oncol 31:1464-1470, 2013.

Commentary See page 56 for Commentary by Stuart M. Lichtman, MD

Cautionary Notes With regard to the finding that better mood on the GDS was significantly predictive of unexpected hospitalization, the investigators stated that the unexpected result suggests that the GDS score should be used with caution in the metastatic setting. Consistent with other findings, depression was not associated with toxicity in the current analysis. The authors also noted that the trial was not powered for the geriatric study, and that some of the findings in the study may have been affected by the inadequate statistical power. The authors concluded, “[O]ur study is the first to prospectively dem-

ADAPTABLE IMMUNOTHERAPY EMPOWERS THE IMMUNE SYSTEM TO FIGHT CANCER As tumor cells mutate, many cancers can become resistant to traditional cancer therapies.1-3 The activated immune system can adapt and recognize new tumor antigens to continue the attack over time.1,4--6

The ASCO Post It’s time to consider

IMMUNOTHERAPY

as an important treatment in your fight against cancer. Like us on

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For more information go to www.FightCancerWithImmunotherapy.com References: 1. Murphy K, et al, eds. Janeway’s Immunobiology. 7th ed. Garland Science, Taylor & Francis Group, LLC. New York, NY: 2008. 2. DeVita VT, et al, eds. Cancer: Principles & Practice of Oncology. 8th ed. Lippincott, Williams & Wilkins; Philadelphia, PA: 2008. 3. Chabner BA, et al, eds. Cancer Chemotherapy & Biotherapy: Principles & Practices. 4th ed. Lippincott, Williams & Wilkins; Philadelphia, PA: 2006. 4. Ribas A, et al. J Clin Oncol. 2003;21:2415-2432. 5. Namm JP, et al. J Surg Oncol. 2012;105:431-435. 6. Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335.

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Journal Spotlight

Improving the Care and Study of Older Patients with Cancer By Stuart M. Lichtman, MD

redicting toxicity in older patients receiving chemotherapy is an important clinical problem. It has been shown that standard oncology measures such as performance status are not adequate to predict outcomes in the elderly. Clinical measures that are important in geriatric oncology are not routinely assessed in clinical practice. In addition, the objective database for making clinical decisions in older patients is inadequate. Older patients are underrepresented in clinical trials, and when they are included, they do not represent the general population of older patients; those in clinical trials tend to have less comorbidity and better performance status and rarely are over 80 years of age.

Further, in the trial, which included a fluoropyrimidine-irinotecan combination, the multiagent chemotherapy arm was also predictive of severe toxicity. The latter finding emphasizes that when administering a palliative regimen, extreme care must be taken to avoid toxicity. The effect of grade 3 or greater toxicity on an older patient can be devastating and

This is particularly important in the palliative setting, when goals such as quality of life, maintenance of independence, and avoidance of toxicity are paramount. It is not acceptable to say that such evaluation is too timeconsuming or not helpful. Most of the data needed for assessment are obtained via patient self-assessment with minimal time

Older cancer patients need to be a focus of our endeavors. They deserve nothing less. —Stuart M. Lichtman, MD

Easily Measured Geriatric Parameters The study by Aparicio et al1 makes a valuable contribution to the care of older patients. The strengths of the study are that it was designed specifically for older patients (median age of 80 years, with patients up to age 91), evaluated treatment of a common malignancy, and most important, included easily measured geriatric parameters. The formal geriatric assessment performed by geriatricians requires a specialized expertise, is multidisciplinary and time-consuming, and has not been shown to be predictive of treatment toxicity and other outcomes such as ability to complete therapy or relapse-free or overall survival. In the Aparicio et al study, two easily obtained parameters—the Mini-Mental State Examination and Instrumental Activities of Daily Living—were predictive of severe toxicity or unexpected hospitalization.

can negate any small benefit that the chemotherapy regimen may provide. The results of the Aparicio et al analysis confirm the findings of a prospective evaluation in the Cancer and Aging Research Group trial.2 That study showed that severe toxicity can be predicted from simply obtained clinical factors; the predictive model that was developed included age greater than 71 years, polychemotherapy, creatinine clearance < 35 mL/min, hemoglobin < 11 g/ dL, decreased hearing, falls, social isolation, limited activity, and deficiency in Instrumental Activities of Daily Life. A study by Extermann et al3 also demonstrated that chemotherapy toxicity can be predicted in an older population using Instrumental Activities of Daily Life and other easily obtained clinical information.

Dr. Lichtman is Attending Physician, 65+ Clinical Geriatrics Program, Memorial SloanKettering Cancer Center, and Professor of Medicine, Weill Cornell Medical College, New York.

These studies demonstrate that some form of geriatric assessment should be performed in older patients to aid in clinical decision-making.

Additional Vital Sign

Save the Date

expenditure for the clinical staff. This methodology has been validated in a number of settings. The inclusion of geriatric parameters should be thought of as an additional vital sign, along with blood pressure, pulse, and temperature.

Newly Designed Trials The aging of the population requires changes in the design of clinical trials.4 Elderly-specific trials are important but may be difficult to implement and accrue, particularly in less common malignancies. In those situations where older patients constitute a large proportion of the cancer population, eligibility requirements must take into account the particular issues of older patients to make the results meaningful. Testing requirements should be realistic in terms of time commitments for patients and caregivers. Toxicity evaluation should be amended to include functional impairments. Outcomes need to include loss of independence. A geriatric assess-

ment should be incorporated in the initial study design so that longitudinal evaluations can be performed to help refine the predictive value of the assessment and better determine risks of chronic toxicities and impairments. Clinical trial reporting also needs to be more descriptive of the outcomes relevant to the elderly.5 Older patients need to be included in phase I trials, since they will ultimately be the consumers of the drugs being tested; geriatric assessment thus needs to be incorporated into the design of phase I trials. Such assessment also needs to be incorporated into the design of studies of biologic therapies, since there may be differences in toxicity risks compared to chemotherapy in older patients. Older cancer patients need to be a focus of our endeavors. They deserve nothing less. n Disclosure: Dr. Lichtman reported no potential conflicts of interest.

References 1. Aparicio T, Jouve JL, Teillet L, et al: Geriatric factors predict chemotherapy feasibility: Ancillary results of FFCD 2001-02 phase III study in first-line chemotherapy for metastatic colorectal cancer in elderly patients. J Clin Oncol 31:1464-1470, 2013. 2. Hurria A, Togawa K, Mohile SG, et al: Predicting chemotherapy toxicity in older adults with cancer: A prospective multicenter study. J Clin Oncol 29:34573465, 2011. 3. Extermann M, Boler I, Reich RR, et al: Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for HighAge Patients (CRASH) score. Cancer 118:3377-3386, 2012. 4. Lichtman SM: Clinical trial design in older adults with cancer—the need for new paradigms. J Geriatr Oncol 3:368375, 2012. 5. Lichtman SM: Call for changes in clinical trial reporting of older patients with cancer. J Clin Oncol 30:893-894, 2012.

SIOG 2013 October 24-26, 2013, Copenhagen, Denmark International Society of Geriatric Oncology For more information, visit www.siog.org

ASCOPost.com | JUNE 10, 2013

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Announcements

Joseph A. Sparano, MD, Named Vice Chair of ECOG-ACRIN Cancer Research Group

he Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group recently announced that it has appointed Joseph A. Sparano, MD, as its Vice Chair. In his new role, Dr. Sparano will assist the Group leadership in defining research priorities and implementing its broad research portfolio, which includes programs in cancer control and outcomes, therapeutic studies, and biomarker sciences.

Joseph A. Sparano, MD

Dr. Sparano is Professor of Medicine and Professor of Obstetrics, Gynecology, and Women’s Health at the Albert Einstein College of Medicine and Associate Chairman of the Department of Oncology at the Montefiore Medical Center in New York. He is also Associate Director for Clinical Research at the Einstein Cancer Center and leads the Einstein Breast Cancer Working Group, a multidisciplinary group of physicians and scientists focused on translational breast cancer research. In addition, he serves as Vice Chair of the National Cancer Institute Breast Cancer Correlative Science Committee and Vice Chair of the AIDS Malignancy Consortium.

ment, Dr. Sparano first joined ECOG in 1991 as a member of the Biological Response Modifier Committee and Breast Committee. He has held the position of Co-Chair or Chair of the

ECOG Breast Committee since 2002 and Associate Chair for Disease and Modality Research since 2001. He has also chaired or co-chaired 16 therapeutic clinical trials for the

Group, including the historic Trial Assigning IndividuaLized Options for Treatment (Rx)—or TAILORx—an ongoing study in women with earlystage breast cancer. n

DURABLE

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References: 1. Murphy K, et al, eds. Janeway’s Immunobiology. 7th ed. Garland Science, Taylor & Francis Group, LLC. New York, NY: 2008. 2. Abbas AK, et al, eds. Basic Immunology. Functions and Disorders of the Immune System. 3rd ed. Saunders Elsevier; Philadelphia, PA: 2011. 3. Atanackovic D, et al. PNAS. 2008;105(5):1650-1655. 4. Perret R, et al. Tissue Antigens. 2008;72:187-194.

Dendreon and the Dendreon logo are registered trademarks of Dendreon Corporation.

The ASCO Post | JUNE 10, 2013

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JCO Spotlight

Caring for the Whole Patient continued from page 1

ing is hard,” said Dr. Byock, “it doesn’t have to be this hard.” The ASCO Post talked with Dr. Byock about when the initiation of palliative care is appropriate, how to engage patients in shared decision-making about their endof-life care, and what it means to die well.

Timing of Palliative Care When should patients be considered for palliative care? In our medical center, we introduce palliative care as early as possible for patients with newly diagnosed pancreatic cancer, stage III lung carcinomas, and glioblastomas, for example. But the intensity of our involvement may vary during the course of a patient’s illness. For people with early pancreatic cancer, our palliative specialists are now part of the oncology team that helps get them through neoadjuvant treatment and to definitive curative surgeries. We also help patients with metastatic disease manage their symptoms and nutritional requirements as well as cope with the difficult emotional challenges and spiritual issues that often arise when people have an incurable condition and they know that they will die of their disease.

Integrating Palliative Care Is palliative care being incorporated into traditional cancer care more consistently now? Yes, there is no question that that is happening. We know that we provide better care for our patients when palliative care specialists and oncologists work together. There are a number of evolving models for integrating palliative care services into oncology care. Some community practices may have only started thinking about incorporating palliative services into their patients’ care, but most leading cancer centers now have palliative care teams in place working together with the oncology care team. There is still a large unmet need, and we know that there are workforce issues with palliative care. As a specialty, hospice and palliative medicine is developing practical and intensive medical training courses so that evidence-based care and the skill set of palliative care specialists are available to oncologists and other medical specialists.

Patient Fears What do patients fear most about dying? For many people, it’s not death or no

longer existing that they fear as much as dying badly. They may fear dying while suffering, in pain, and feeling undignified, but also dying with things left undone and worrying about what will happen to their spouse or their children. As highly personal as these issues are, we actually have therapeutic responses. In my own writing and research, I’ve applied a developmental framework to thinking about the challenges and issues that confront people during this phase of life. It has helped me understand the nature of the real suffering that people can experience. It has also given me a better appreciation of the opportunities dying presents, to help patients go through these difficult, unwanted challenges in ways that not only enable them to feel inner peace, but that also help family members during their grief after the patient’s death. In my experience, complicated grief is usually the product of not just the pain of loss of a loved one, but the doubts, regrets, and recriminations—the what ifs—and the missed opportunities of

ing, but it is more powerful to read it as an adjective instead. Can a person be well even as he or she is dying? My clinical and personal experiences lead me to answer with a resounding yes. And all of us as professionals, family members, and members of our communities can care for people in ways that at least preserve patients’ capacity to have a sense of well-being during this time.

Preparing the Patient How can oncologists help prepare their terminally ill patients for end-of-life care? During my career as a physician, I’ve felt many times the tightness in my own chest and stomach when having to give bad news to a patient—often to a patient with whom I’ve had a relationship for some time, and that is particularly hard. I hate the fact that people die, but I can’t apologize for mortality. It’s a part of living. So I deliver the news seated, leaning forward, and facing the person. I

There is always care to be provided. How much we have to offer becomes evident when we make the shift from seeing illness as solely medical—problems to be solved—to understanding that illness is first and foremost personal. —Ira Byock, MD

leaving things unsaid. We can often prevent those sources of future sufferings simply by being honest with patients and their loved ones. As clinicians we can help people to mend and nurture relationships and work through the practical matters of life’s completion.

A ‘Good Death’ Can you describe what constitutes a “good death”? A “good death” cannot be derived from any medical criteria that I could elaborate. For most people, it has to do with having a sense of well-being, a sense that there is nothing critically important left undone or unsaid between the patient and those he or she loves. It involves having a sense that you will be remembered in a positive way, knowing that people you love know you love them, and not worrying that your very existence at this moment is too heavy a burden on your family. I much prefer the term “dying well.” People initially read the word “well” as an adverb describing the process of dy-

allow all the compassion that I’m feeling and all the pangs that I’m feeling to be evident. I describe the situation simply, stating the facts as they are— for example, “The disease is back, it looks like it has grown through the last treatment, and I think we are at a stage where more treatment may harm you more than it would likely help you.” There is always care to be provided. How much we have to offer becomes evident when we make the shift from seeing illness as solely medical—problems to be solved—to understanding that illness is first and foremost personal. Ironically, when illness is understood as a life experience for the patient and his or her family, it becomes simpler to serve the person who is ill and meet his or her real needs. Often patients are afraid of what comes next and grasp at the straws of illusory advantages of the next chemotherapy or the phase I trial. Of course, for some people that is the right path. But for patients who will not benefit from additional active treatment, we

can respond effectively to their physical suffering, ease their fears, and help them face the future. Our mission in the palliative care service at Dartmouth-Hitchcock is to help patients get through their active medical treatments by addressing their physical symptoms, such as pain, anorexia, and fatigue, and to also help them through the very difficult but normal challenges of completing a life. The medical literature clearly shows that by taking care of patients holistically, often they are able to stay on clinical trials a little longer, they sleep better, they eat a little better, and they are less fearful about getting their pain under control. It is not surprising that studies show that when palliative care is concurrent with cancer care, people tend to live longer.2

Shared Decision-making Please talk about the role of shared decision-making in end-of-life care. Although discussions about treatment options often require nuanced conversations, the process of shared decision-making is straightforward. When I was growing up in the 1960s, shared decision-making happened when the doctor shared his decisions with his patient. Now we understand that the patient is an expert in his or her values, preferences, and life’s priorities, and we are expert in the diagnostics and therapeutics of disease. In addition to offering the best treatments possible for a patient’s disease, we really have to find out what the “best care” is for a given patient by inquiring in a personal way. As physicians, we can’t assume that we know what someone would want. I think that the very definition of quality care is when the best medical treatments are applied in conjunction with the values, preferences, and priorities of the patients we serve. Delivering quality care in this tailored, highly personalized way is also deeply satisfying for physicians. n

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

References 1. Fischer S, Min SH, Cervantes L, et al: Where do you want to spend your last days of life? Low concordance between preferred and actual site of death among hospitalized adults. J Hosp Med 8(4):178183, 2013. 2. Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with metastatic non–small cell lung cancer. N Engl J Med 363:733–742, 2010.

Now Enrolling Nivolumab Clinical Research Studies Non-small Cell Lung Cancer (NSCLC)

You may have patients who are eligible to participate in a clinical research study to evaluate an investigational PD-1 receptor blocking antibody for previously treated advanced/metastatic squamous or non-squamous cell NSCLC Key eligibility criteria include:

• • • • •

≥18 years of age Stage IIIB/IV or recurrent squamous or non-squamous cell NSCLC Progression or recurrence during or after prior platinum-containing chemotherapy ECOG PS ≤1 No prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4, or other antibody-targeting T-cell co-stimulation or checkpoint pathways

For more information, including a list of study sites, please visit ClinicalTrials.gov and use the following study identifiers in the search fields:

• NCT01642004 (Squamous cell NSCLC/CA209-017) • NCT01673867 (Non-squamous cell NSCLC/CA209-057) • NCT01721759 (Squamous cell NSCLC/CA209-063) 136486 04/2013

The ASCO Post | JUNE 10, 2013

PAGE 60

Direct from ASCO

Transforming Grand Rounds into Chartrounds: Technology and the Improving Cancer Care Grant Advance Patient Care

hen Patricia Hardenbergh, MD, moved from her academic position as a breast radiation oncologist at Duke University to a small, rural practice in Edwards, Colorado, she realized that being a community oncologist was a very different experience. She was an expert in treating breast cancer and also treated some pediatric cancers, but now, as the only radiation oncologist at her practice, she was treating cancer in every organ. “How can you be an expert at everything?” she asked. “You can’t.” She looked for resources, but found that the technology changed so quickly that her best resources were academic colleagues at major cancer centers who saw a large number of patients and could discuss their experiences in treatment planning with her.

Improving Cancer Care Grant At the same time, the Conquer Cancer Foundation of the American Society of Clinical Oncology, through a collaboration with Susan G. Komen for the Cure®, was developing a new grant program: a large research grant focused on making a major impact on the quality of cancer care and access to that care. Unlike previous grants, the new grant

Addressing an Unmet Need Among Providers

would be open not only to academic investigators but also to oncology providers like Dr. Hardenbergh who practiced in community settings. Dr. Hardenbergh applied for the inaugural $1.35 million Conquer Cancer Foundation of ASCO Improving Cancer Care Grant, funded by Susan G. Komen for the Cure®, with a simple concept: online “rounds.” “Grand rounds” is a teaching method in which an expert provides insight and feedback on the care of a patient to other oncologists. Dr. Hardenbergh proposed that with recent advances in technology, grand rounds

could also be facilitated online as a way to continuously improve cancer treatment and patient care. Dr. Hardenbergh was one of the first two recipients of the Improving Cancer Care Grant and used it to launch Chartrounds (www.chartrounds.com) in December 2010. The concept remains simple. Each session includes a diseasearea expert from a major academic cancer center. Doctors present difficult cases and the treatment plan that they are considering and then get feedback from the expert and the other attendees during a one-hour online discussion.

SENIOR DIRECTOR EDUCATION, SCIENCE, AND PROFESSIONAL DEVELOPMENT PROGRAMS The American Society of Clinical Oncology (www.asco.org) is a growing, progressive association, seeking to expand our success as a world-class leader in support of medical education for oncologists. The Senior Director of the Education, Science, and Professional Development Department reports to the CEO and serves as a key member of the internal leadership team. This new leader will provide strategic vision and operational leadership for the planning, development, implementation, and evaluation of a broad array of innovative education programs that serve the needs of ASCO members and constituents. He or she will actively collaborate with physician volunteers and the Board of Directors in strategic planning to ensure the development of the highest quality content for live meetings, workshops, and a host of new delivery channels. Ideal experience for this exciting position is a minimum of 10 years of related experience in leadership roles involving the dissemination of knowledge in the healthcare field. A qualified candidate will also have proven skills that encompass strategic planning related to program development, staff resource management, and budgeting. Applications from physicians are welcome.

To learn more about working at ASCO, please visit our career site and apply online at www.asco.org/jobs.

Building on Dr. Hardenbergh’s expertise, the initial pilot phase of the program was to just focus on the treatment of breast cancer with radiation. Two years later, Chartrounds has grown immensely and now covers both medical and radiation oncology for 10 different types of cancer. The success of this program has demonstrated that Dr. Hardenbergh recognized an unmet need among oncology providers. As a result, she presented data about the impact of Chartrounds at ASCO’s Quality Care Symposium on December 1, 2012. Chartrounds has amassed almost 750 members from the United States and 15 other countries in just two years. More than half of the members practice in rural communities with less than 50,000 people—doctors who are unlikely to have a lot of local colleagues with whom to discuss treatment plans. Nearly 250 sessions have taken place, with a combined attendance of 1,932 professionals. Most importantly, 80% of those who attended a Chartrounds session reported that they planned to change their patients’ treatment plans based on what they learned. Participants also report that the sessions are useful even to the 20% of doctors who did not change their treatment plans after the discussion. Dr. Hardenbergh, who often presents cases for feedback, notes that this has been true in her own practice. “Having discussed the case gives you more confidence when presenting the treatment plan to the patient,” she said. “It is really valuable to the patients to be able to tell them that you discussed their case with a national expert.” “I think that it was really insightful for the Improving Cancer Care Grant funders to recognize and fund a project that came from within the community,” Dr. Hardenbergh says of the Conquer Cancer Foundation and Susan G. Komen for the Cure®. “There was trust and vision that there were needs in the community that this project could meet. Chartrounds may not have existed if the funding required an academic appointment, as many grants currently do.” n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | JUNE 10, 2013

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Direct from ASCO

Best of ASCO® Meetings Provide Intimate Access to Latest Research

iming to facilitate widespread dissemination of practicechanging research, ASCO offers the Best of ASCO ® Meetings, which condense the most cuttingedge science and education from the ASCO Annual Meeting into a 2-day program. The smaller size of these meetings, compared to the

pert discussion of the findings in a compact and focused setting.”�The program will particularly benefit those who were not able to attend the Annual Meeting and those who did attend the Annual Meeting but were not able to absorb it all, given the larger venue, he adds.

The Best of ASCO Meetings provide a unique opportunity to hear presentations on high-impact studies from the Annual Meeting. —Douglas Yee, MD

Annual Meeting, provides greater opportunities for attendees to network with peers and interact with faculty. This year’s meetings will be held in Chicago (August 9–10), Los Angeles (August 16–17), and Boston (August 23–24). According to Douglas Yee, MD, Chair of the 2013 Chicago and Los Angeles events, “The Best of ASCO Meetings provide a unique opportunity to hear presentations on high-impact studies from the Annual Meeting and ex-

Smaller Scale Facilitates Easy Access, In-depth Analysis The highlighted abstracts represent the foremost research that will directly impact patient care, and presentations go into greater depth of analysis than time allows at the Annual Meeting. In this setting, presenting faculty—selected based on first-hand experience with the research in their field— provide more insight on the clinical implications of the studies.

Session topics cover the latest scientific findings in primary disease sites and advances in cancer prevention and treatment. They are based upon the various tracks presented at the Annual Meeting, including breast cancer, central nervous system tumors, developmental therapeutics, gastrointestinal (colorectal and noncolorectal) cancer, genitourinary cancer, gynecologic cancer, head and neck cancer, health services research, leukemia, lung cancer, lymphoma and myeloma, melanoma, and patient and survivor care. Additional education sessions address how to apply molecular profiling in clinical practice, highlight new and noteworthy developments in hereditary cancer genetics and syndromes, and cover advances in the genetics, screening, and treatment of familial upper gastrointestinal cancer syndromes. Providing an opportunity to delve even deeper into the subjects and engage directly with the experts, the Best of ASCO Meetings also feature faculty case question-and-answer panels. These sessions allow attendees to ask for clarification on issues raised during the presentations and seek advice on challenging patient cases they encounter in their practices.

Virtual Meeting Subscription In addition to the in-person experience, all Best of ASCO attendees receive a subscription to the Best of ASCO Virtual Meeting, which provides digital access to sessions recorded at the Best of ASCO Meeting in Chicago. Users may stream the video or audio content or download podcasts of selected presentations with a computer, tablet, or mobile phone, using a free application for iPad and iPhone, or a mobile-friendly site for Android devices.

For More Information For the latest information on all three Best of ASCO Meetings, visit boa.asco.org, where you can register for a meeting, make housing arrangements, apply for a travel grant, find preliminary agendas, access CME eligibility information, and view a list of exhibiting companies. Register by July 10 at 11:59 PM EDT to take advantage of the best registration rates and housing availability. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCO Publishes New Conflict of Interest Policy

SCO has released its new conflict of interest policy,�ASCO Policy for Relationships With Companies, which updates its earlier policy in key ways that are designed to increase transparency in relationships with commercial interests.

Comprehensive Framework The new policy establishes a more comprehensive disclosure framework that will gather information about financial relationships between individuals and healthcare companies and impose new restrictions for au-

thors of original research who publish in or present at ASCO forums. “As a leading source of evidencebased cancer information worldwide, ASCO deeply values the trust of its members, the wider oncology community, and the public,” said ASCO Immediate Past President Sandra M. Swain, MD, FACP. “In adopting this new conflict of interest policy, ASCO’s goal is to recognize beneficial collaborations that advance scientific progress, while remaining vigilant about the potential for bias in science and professional education.”

Disclosure Types Specifically, the new ASCO policy

requires disclosure of eight types of interactions with health-care companies: (1) compensated employment, (2) leadership positions, (3) consulting activities, (4) speaking engagements, (5) expert testimony, (6) ownership interests, (7) research funding, and (8) patents or other intellectual property interests. ASCO is establishing a “general disclosure” requirement that will gather a range of information about an individual’s interactions with compa-

nies to help inform any ASCO activity in which someone might be involved. This requirement allows for greater transparency and consistency across ASCO’s scientific and educational programs. ASCO’s earlier policy required authors, presenters, and ASCO volunteers to complete a separate disclosure for each ASCO activity.

New Author Restrictions Additionally, the new ASCO continued on page 62

The ASCO Post | JUNE 10, 2013

PAGE 62

Direct from ASCO

Conflict of Interest Policy

becomes effectively immediately, the author restrictions will apply to original research� initiated after April 22, 2014. Until that time, clinical trial abstracts and articles will still be subject to ASCO’s�earlier COI policy, which focuses on the role of principal investigators.

continued from page 61

policy will require first, last, and corresponding authors of original research to meet a clear standard of financial independence from commercial funders of their research. While the conflict of interest policy

Sandra M. Swain, MD, FACP

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

Trials Now Enrolling

The new ASCO policy applies to individuals who engage in ASCO volunteer activities, present research findings through ASCO’s continuing medical education programs, and develop ASCO clinical practice guidelines, and authors who submit abstracts and publish in its journals (Journal of Clinical Oncology� and Journal of Oncology Practice). To read the policy, please go to: http://jco.ascopubs.org/content/early/2013/04/22/JCO.2013.49.5002 n © 2013. American Society of Clinical Oncology. All rights reserved.

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

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

Primary Endpoint: • Progression-free survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

Combination Therapy Phase* Maintenance Phase (6 cycles) (for additional 18 months)

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

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

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + PLD 50 mg/m2 IV Q4W

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

Trebananib IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Trebananib IV QW Monotherapy

ENDPOINTS

Primary

PFS 2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Key Secondary

Placebo IV QW Monotherapy

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

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

Cancer.Net Features Patient-friendly News from the ASCO Annual Meeting

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

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

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

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

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

ow that the 2013 ASCO Annual Meeting is over, direct your patients to www.cancer.net/ascoannualmeeting to find podcasts and videos with ASCO experts and read summaries on the research highlighted at the meeting. In addition, your patients can continue to hear about the latest research throughout the summer in Cancer.Net’s Research Round-Up podcast series at www.cancer.net/ podcasts. n

Save the Date Breast Cancer Symposium 2013 September 7-9 San Francisco, California See page 118 for details

ASCOPost.com | JUNE 10, 2013

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Direct from ASCO

CancerProgress.Net Patient and Advocate Video Series Highlights Value and Impact of Cancer Research

“I

’ve been living with melanoma for 7 years.” That’s a statement that, at the outset of her diagnosis, Joanne Maricle would have found surprising. Yet Joanne, who is featured in a video that is part of a new Patient and Advocate Video Series on ASCO’s CancerProgress.

don’t know what you’re going to be here for and what you’re not going to be here for,” said Joanne. Thanks to her participation in three clinical trials, Joanne has seen her son get married, held her first grandchild, and experienced many other milestones with her family that she didn’t think she would have 7 years ago.

New Video Series

Marcia S. Brose, MD, PhD

Net website, is able to lay claim to it— and all of the memories and milestones of those 7 years. She acknowledges that it didn’t always seem that way. “When you’re first diagnosed with cancer, the uncertainty of your life is pretty great. You don’t know if you’re going to see your next birthday, you

Joanne’s story, as well as the stories of four other cancer survivors, are highlighted in a new video series on ASCO’s CancerProgress.Net (www. cancerprogress.net) website. These stories bring to light the importance of clinical trials and the progress being made in cancer prevention, diagnosis, and treatment. Each patient speaks personally to the value of cancer research and the impact it has had on their lives. “Without clinical trials, we’d have no progress,” said Marcia S. Brose, MD, PhD, who is featured in one of the videos and is the Assistant Professor of Otorhinolaryngology at the Univer-

Conquering

sity of Pennsylvania Abramson Cancer Center. “So essentially, clinical trials are the process where we take what we’ve learned in the lab and apply it to the patients to find out if we can really improve things.…If we didn’t do clinical trials, we would never know whether some of the things we were discovering are going to work or not and [and we would never] develop new therapies. So nothing would actually get done and the patients would have no hope.”

Interactive Timeline of Cancer Treatment ASCO has long been an advocate for increased funding for clinical trials. To help tell the story of progress against cancer, ASCO launched CancerProgress.Net in 2011. The site is intended as a resource for media, policymakers, oncologists, advocates, and the public. The central feature of the site is an interactive timeline of major milestones in cancer treatment, prevention, and detection, covering 17 different cancer types. The site was developed

under the guidance of an ASCO editorial board of expert oncologists. To help users delve even more deeply into the significant progress made in recent decades, the CancerProgress.Net Editorial Board reviewed hundreds of journal articles and added links to the primary research articles that led to the advances chronicled on the website. These linked references are a useful resource for oncology fellows, training directors, advocates of patients with cancer, science writers, or anyone interested in following the history of progress against specific cancer types. And late last year, three new cancer timelines were added to the site—liver, stomach, and head and neck cancer, bringing the total number of cancer types chronicled on the site to 17. n © 2013. American Society of Clinical Oncology. All rights reserved.

Cancer. Together, anything is possible. The Conquer Cancer Foundation. Our name says a lot. Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supportingthe world’s preeminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

DonATe ToDAY! ConquerCancerFoundation.org

What if

engineering the antiBody could iMPRoVE adcc?

Immune Effector Cell

Therapeutic Antibody

Target Cell

*Based on preclinical models.

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

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

Sugar Residue

Sugar Removal

Increased Binding

SugarS MaY aY coMproMiSe iMMuNe a

gLYcoeNgiNeeriNg MaY a iNcreaSe aY

gLYcoeNgiNeeriNg couLD LeaD

eFFecTor–aNTiBoDY BiNDiNg

BiNDiNg aFFiNiTY

To iMproVeD aDcc

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

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

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

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

For more information, visit ResearchBcell.com

The ASCO Post | JUNE 10, 2013

PAGE 66

European Multidisciplinary Conference in Thoracic Oncology Simultaneous EGFR Mutations and HER2 Gene Amplifications in Large Series of Patients with Non–Small Cell Lung Cancer

n a molecular profile analysis of 2,271 cases of non–small cell lung cancer (NSCLC), EGFR was mutated in 12% and KRAS in 32% of cases. HER2 gene amplification was confirmed as a rare event in NSCLC (4%). Coexistence of HER2 gene amplification and EGFR mutation was identified in three cases, while KRAS was mutated in seven HER2amplified cases. Double EGFR mutations were found in only two cases. NSCLC with HER2 amplification were frequently (39%) associated with KRAS-activating mutation. A rare A859T mutation was found in one case and was associated with HER2 gene amplification. This mutation was previously associated with resistance to tyrosine kinase inhibitors. This novel molecular insight in a large sample of NSCLC cases was presented by Zoran Gatalica, MD, DSc, Adjunct Professor of Pathology at Creighton University School of Medicine, Omaha, and Director of Oncologic Pathology at Caris Life Sciences International, at the European Multidisciplinary Conference in Thoracic Oncology in Lugano, Switzerland.1

Underlying Mechanisms HER2 is a member of the EGFR family of receptor tyrosine kinases. It forms heterodimers with other family members enhancing kinasemediated activation of the downstream signaling pathways. HER2 amplification has been implicated as a mechanism of acquired resistance to EGFR–tyrosine kinase inhibitors, occurring in a subset of tumors that do not show the acquired, somatic resistance EGFR T790M mutation. Activating mutations in the tyrosine kinase domain of HER2 have been described in a subset of lung adenocarcinomas and as mutually exclusive with EGFR and KRAS mutations. Arcila et al previously reported2 that HER2 mutation was significantly associated with NSCLC patients who were never smokers

but not associated with sex, race, or disease stage. They concluded that HER2 mutations identify a distinct subset of lung adenocarcinomas. Given the high prevalence of lung cancer worldwide and the availability of standard and investigational therapies targeting HER2, they advocated that routine clinical ge-

with 3+ protein expression. There was no evidence that HER2 amplification associated with T790M mutation. Coexistence of HER2 gene amplification and KRAS mutations were seen in seven cases. Simultaneous HER2 gene amplification and EGFR mutation was demonstrated

Previously reported resistance to tyrosine kinase inhibitors may have been due to HER2 gene amplification rather than an effect of the EGFR-mutated protein. —Zoran Gatalica, MD, DSc, and colleagues

notyping of lung adenocarcinoma should include HER2. However, no association between HER2 mutation and HER2 overexpression was shown in their study or in results reported by Stephens et al,3 who determined the prevalence of HER2 mutations in primary NSCLC to be 4.2%, with prevalence increasing to 9.8% in patients with adenocarcinoma.

Current Study In this latest analysis, Dr. Gatalica headed a team of investigators from Caris Life Sciences, Phoenix, Arizona, and Basel, Switzerland, in characterizing the molecular profiles of 2,271 patients with NSCLC. They used the Molecular Intelligence technique to evaluate samples for HER2 protein expression (immunohistochemistry), HER2 gene amplification (FISH), and EGFR and KRAS gene mutations (sequencing). Their goal was to analyze the frequency of the simultaneous occurrence of EGFR mutations and HER2 gene amplifications. As determined by sequencing, EGFR was mutated in 12% and KRAS mutations were seen in 32% of NSCLC patients. Consistent with earlier reports, HER2 gene amplification was detected by FISH in 22 (4%) of 589 tested cases, associated

in three cases. Double EGFR mutations were found in only two cases. The most frequent association was seen between HER2 amplification and KRAS-activating mutation, which occurred with a frequency of 39%. One sample showed the rare A859T mutation, which had been reported by Han et al4 to be associated with resistance to tyrosine kinase inhibitors (HER2 status was unknown). However, this mutation

was associated with HER2 gene amplification in the current analysis. The authors speculated that previously reported resistance to tyrosine kinase inhibitors may have been due to HER2 gene amplification rather than an effect of the EGFR-mutated protein. n

Disclosure: All study authors are employed by Caris Life Sciences, which funded this study.

References 1. Gatalica Z, Gupta P, Ghazalpour A, et al: HER2 in non-small cell lung carcinomas. European Multidisciplinary Conference in Thoracic Oncology. Abstract 650. Presented May 10, 2013. 2. Arcila ME, Chaft JE, Nafa K, et al: Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res 18:4910-4918, 2012. 3. Stephens P, Hunter C, Bignell G, et al: Lung cancer: Intragenic ERBB2 kinase mutations in tumours. Nature 431:525-526, 2004. 4. Han SW, Kim TY, Hwang PG, et al: Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 23:2493-2501, 2005.

About EMCTO

he European Multidisciplinary Conference in Thoracic Oncology (EMCTO) was held May 9–11, 2013, in Lugano, Switzerland. EMCTO is organized in partnership between the European Society for Medical Oncology (ESMO), The European Society for Radiotherapy and Oncology (ESTRO), the European Society of Thoracic Surgeons (ESTS) and the European Respiratory Society (ERS), and the European Thoracic Oncology Platform (ETOP).

Lugano, Switzerland

ASCOPost.com | JUNE 10, 2013

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European Multidisciplinary Conference in Thoracic Oncology Meta-analysis Slightly Favors Platinum-based First-line Treatment in Patients with Advanced NSCLC

everal meta-analyses conducted in the past have suggested that survival of patients with advanced non–small cell lung cancer (NSCLC) is improved if first-line chemotherapy includes platinum derivatives. Results from a new meta-analysis of randomized clinical trials show that platinum-based regimens slightly improve survival compared with nonplatinum strategies, and this effect is restricted to cisplatin combinations. The findings were presented by Thierry Berghmans, MD, of the Department of Intensive Care and Emergencies and the Clinic of Tho-

racic Oncology, Institute Jules Bordet in Brussels, Belgium, at the European Multidisciplinary Conference in Thoracic Oncology, held recently in Lugano, Switzerland.1

Study Design The Belgian researchers evaluated all studies published in French and English that compared first-line platinum to nonplatinum regimens in patients with advanced/metastatic NSCLC. For each of 25 studies published between 2001 and 2012 that were eligible for the systematic review, the authors extracted an es-

EXPERT POINT OF VIEW

he study discussant, Elisabeth Quoix, MD, of the University Hospitals of Strasbourg, France, said that this meta-analysis confirmed that platinum-based doublets remain the standard treatment in this setting. Benefit of platinum-based doublets over non–platinum-based chemotherapy is essentially due to cisplatin (only a trend was seen for carboplatin). However, in special populations (patients with performance status 2, elderly patients) a carboplatin-based doublet should be considered and is probably superior to single new agents.

Need for Meta-analyses Furthermore, Dr. Quoix emphasized that the high number of meta-analyses performed in advanced NSCLC probably reflects the heterogeneity of patients included in randomized controlled trials (regarding age, performance status, and so forth), which lead to conflicting or at least inconclusive results. Thus, meta-analyses are required to answer important questions, but a good question is why repeated results of meta-analyses do not convince doctors to modify their clinical attitude, she noted. n Disclosure: Dr. Quoix reported no potential conflicts of interest.

timate of the hazard ratio associated with platinum or nonplatinum treatment and combined the individual hazard ratios into an aggregate num-

one favoring nonplatinum therapy. Overall, the data showed a slightly improved survival in patients who received platinum-based regimens over

Overall, the data showed a slightly improved survival in patients who received platinumbased regimens over patients treated with non–platinum-containing regimens. —Thierry Berghmans, MD, and colleagues

ber for each treatment modality. Either a fixed or a random-effects model (if heterogeneity was statistically significant) was used for this purpose, using data from 23 trials that allowed a quantitative aggregation for meta-analysis. The number of patients per trial ranged from 80 to 557 and totalled 6,930 for all trials. Cisplatin was the comparator in 15 trials involving 4,644 participants, and carboplatin was compared in 8 trials comprising 2,286 patients; the hazard ratio was 1.075 for cisplatin and 1.099 for carboplatin. Values for the heterogeneity test were P = .001 with cisplatin and P = .53 with carboplatin. In all 23 studies, the hazard ratio was 1.084 (P = .02).

Major Findings Only four studies demonstrated a statistically significant survival difference between treatments, with three studies favoring platinum and

patients treated with non–platinumcontaining regimens. However, this effect was seen only with cisplatin combinations. Ongoing analyses of patient subgroups according to quality trial assessment (based on Cochrane guidelines) and to the type of nonplatinum comparator are underway to better define the role of nonplatinum regimens for first-line treatment of patients with advanced NSCLC. n

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

Reference 1. Berghmans T, Paesmans M, Meert AP, et al: Are first-line platinum-based regimens improving survival in comparison with non-platinum chemotherapy in advanced non-small cell lung cancer? A meta-analysis of randomised trials. European Multidisciplinary Conference in Thoracic Oncology. Abstract 670. Presented May 10, 2013.

News and Views from the World of Clinical Oncology and Hematology

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The ASCO Post | JUNE 10, 2013

PAGE 68

European Multidisciplinary Conference in Thoracic Oncology Evaluation of Lung Cancer Screening Strategy in the First Three Rounds of the NELSON Trial

he Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON study) was designed to investigate whether screening for lung cancer by low-dose multidetector computed tomography (CT) in high-risk subjects would lead to a decrease in 10-year lung cancer mortality of at least 25% compared with a control group without screening. The study was initiated in 2003, and findings from an evaluation of the screening strategy in the first three rounds of the study, as well as risk

of 50 to 500 mm� or volume-doubling times of 400 to 600 days indeterminate; and all other nodules as negative. Dr. Horeweg reported that one or more positive screening results were seen in 6% of the subjects, and 200 participants were subsequently diagnosed with lung cancer, yielding a positive predictive value of 40.6% for the scans. False-positive results were seen in just 1.2% of all scans. Over the 5.5-year evaluation, the investigators found that the risk of lung cancer detected by screening was influenced by the results of the first scan; the risk was 1.0% after a negative primary scan at baseline, 5.7% after an indeterminate baseline, and rose to 48.3% in par-

The positive predictive value and low false-positive rate arising from these results support the use of lowdose CT for lung cancer screening.

he study discussant, Giulia Veronesi, MD, of the Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy, said that diagnostic algorithms aim to strike a balance between a too-invasive workup that exposes screened persons to useless invasive procedures and overtreatment, and insufficient surveillance that increases the risks of delayed diagnosis and false-negatives. Many screening programs have adopted 5 mm mm as the cutoff between positive and negative nodules on CT, she noted. The Fleischner Society guidelines suggested 4 mm as the threshold below which no follow-up was needed.1 This cutoff was used by the National Lung Screening Trial (NLST) and resulted in a very high rate of baseline positivity. Other investigators consider nodule volumes instead of nodule diameter to obtain more reliable assessments of nodule growth. Dr. Veronesi noted that NELSON is the largest randomized controlled trial with low-dose CT screening in Europe and the first study to incorporate software-calculated volume-doubling time of nodules into a management algorithm to distinguish between positive and negative.

Remaining Questions

—Nanda Horeweg, MD, and colleagues

calculations made for a follow-up period of 5.5 years, were reported by Nanda Horeweg, MD, of the Department of Public Health and Pulmonology at Erasmus Medical Center in Rotterdam, Netherlands, at the recent European Multidisciplinary Conference in Thoracic Oncology.

EXPERT POINT OF VIEW

ticipants with a positive baseline scan. The authors concluded that the positive predictive value and low falsepositive rate arising from these results support the use of low-dose CT for lung cancer screening and provide an additional tool for counseling potential candidates for screening. n

Study Details

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

Low-dose CT scanning has been proposed as one sensitive screening modality in lung cancer. Proponents estimate that it could detect approximately three times as many small lung nodules as chest x-ray. The NELSON screening strategy considers lung nodules with a volume > 500 mm� or a volume-doubling time < 400 days positive; volumes

Reference Horeweg N, van der Aalst C, Vliegenhart R, et al: Volumetric computer tomography screening for lung cancer: Three rounds of the NELSON trial. European Multidisciplinary Conference in Thoracic Oncology. Abstract 150. Presented May 10, 2013.

According to Dr. Veronesi, remaining questions for the authors to address include the recall rate after baseline and after consecutive screening rounds. The NELSON recall rate is lower than that of the NLST study, even when considering positive and indeterminate nodules together. She asked if the higher rate of recalls in the NLST was due only to the lower size cutoff or if there might be other causes. Dr. Veronesi speculated that when the multidisciplinary staff decides how to consider nodules, the rate of recalls is reduced. Dr. Veronesi also asked the NELSON study authors about the standard treatment of positive cases. Should that entail CT/positron-emission tomography or routine fine-needle aspiration biopsy in every positive case? She then asked about slow-growing nodules suspicious for malignancy—should they be managed with a wait-and-see strategy or surgical resection. In the case of surgery, would a limited resection, as opposed to lobectomy, be adequate? The results from NELSON and other ongoing screening studies are expected to answer these questions, she said. n Disclosure: Dr. Veronesi reported no potential conflicts of interest.

Reference 1. MacMahon H, Austin JH, Gamsu G, et al: Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology 237:395-400, 2005.

Don’t Miss These Important Reports in This Issue of The ASCO Post Alison Freifeld, MD, on Febrile Neutropenia see page 27

Owen A. O’Connor, MD, on Lymphoid Malignancies see page 44

Visit The ASCO Post online at ASCOPost.com

Maha Hussain, MD, FACP, on Castration-resistant Metastatic Prostate Cancer see page 84

For indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen

Established treatment, demonstrated results Single-agent TREANDA® (bendamustine HCl) for Injection provided durable responses that lasted a median of 9 months Median DR

9.2 months

All responders (n=74)

(95% CI: 7.1, 10.8)

Patients who achieved a CR/CRu

10.4 months

(95% CI: 9.3, 13.6)

8.3 months

Patients who achieved a PR

(95% CI: 6.3, 10.8)

Months

The efficacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. In 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176), the most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%). TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. • TREANDA is administered with a convenient dosing schedule – The recommended dose is 120 mg/m² administered intravenously over 60 minutes on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA • The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia Learn more www.TREANDAHCP.com Learnatmore at www.TREANDAHCP.com Please see accompanying brief summary of full Prescribing Information. ©2013 Cephalon, Inc., a wholly owned subsidiary Reference: 1. Data on file. Teva Pharmaceuticals.

The ASCO Post | JUNE 10, 2013

PAGE 70

FDA Update

Peregrine Pharmaceuticals Reaches Agreement with FDA on Phase III Trial Design for Bavituximab in NSCLC

eregrine Pharmaceuticals recently announced that it has reached agreement with the U.S. Food and Drug Administration (FDA) on

a phase III registration trial design of the company’s lead clinical immunotherapeutic candidate bavituximab in second-line non–small cell lung can-

Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin Lymphoma That Has Progressed INDICATION AND USAGE: TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. 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 following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176). System organ class, preferred term, and number (%) of patients* are shown. Total number of patients with at least 1 adverse reaction— All Grades: 176 (100); Grade 3/4: 94 (53). Cardiac disorders, All Grades and Grade 3/4—Tachycardia: 13 (7), 0. Gastrointestinal disorders, All Grades and Grade 3/4—Nausea: 132 (75), 7 (4); Vomiting: 71 (40), 5 (3); Diarrhea: 65 (37), 6 (3); Constipation: 51 (29), 1 (<1); Stomatitis: 27 (15), 1 (<1); Abdominal pain: 22 (13), 2 (1); Dyspepsia: 20 (11), 0; Gastroesophageal reflux disease: 18 (10), 0; Dry mouth: 15 (9), 1 (<1); Abdominal pain upper: 8 (5), 0; Abdominal distension: 8 (5), 0. General disorders and administration site conditions, All Grades and Grade 3/4—Fatigue: 101 (57), 19 (11); Pyrexia: 59 (34), 3 (2); Chills: 24 (14), 0; Edema peripheral: 23 (13), 1 (<1); Asthenia: 19 (11), 4 (2); Chest pain: 11 (6), 1 (<1); Infusion site pain: 11 (6), 0; Pain: 10 (6), 0; Catheter site pain: 8 (5), 0. Infections and infestations, All Grades and Grade 3/4—Herpes zoster: 18 (10), 5 (3); Upper respiratory tract infection: 18 (10), 0; Urinary tract infection: 17 (10), 4 (2); Sinusitis: 15 (9), 0; Pneumonia: 14 (8), 9 (5); Febrile Neutropenia: 11 (6), 11 (6); Oral Candidiasis: 11 (6), 2 (1); Nasopharyngitis: 11 (6), 0. Investigations, All Grades and Grade 3/4—Weight decreased: 31 (18), 3 (2). Metabolism and nutrition disorders, All Grades and Grade 3/4—Anorexia: 40 (23), 3 (2); Dehydration: 24 (14), 8 (5); Decreased appetite: 22 (13), 1 (<1); Hypokalemia: 15 (9), 9 (5). Musculoskeletal and connective tissue disorders, All Grades and Grade 3/4—Back pain: 25 (14), 5 (3); Arthralgia: 11 (6), 0; Pain in extremity: 8 (5), 2 (1); Bone pain: 8 (5), 0. Nervous system disorders, All Grades and Grade 3/4—Headache: 36 (21), 0; Dizziness: 25 (14), 0; Dysgeusia: 13 (7), 0. Psychiatric disorders, All Grades and Grade 3/4—Insomnia: 23 (13), 0; Anxiety: 14 (8), 1 (<1); Depression: 10 (6), 0. Respiratory, thoracic and mediastinal disorders, All Grades and Grade 3/4—Cough: 38 (22), 1 (<1); Dyspnea: 28 (16), 3 (2); Pharyngolaryngeal pain: 14 (8), 1 (<1); Wheezing: 8 (5), 0; Nasal congestion: 8 (5), 0. Skin and subcutaneous tissue disorders, All Grades and Grade 3/4—Rash: 28 (16), 1 (<1); Pruritus: 11 (6), 0; Dry skin: 9 (5), 0; Night sweats: 9 (5), 0; Hyperhidrosis: 8 (5), 0. Vascular disorders, All Grades and Grade 3/4—Hypotension: 10 (6), 2 (1). *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

cer (NSCLC). The trial design was supported by promising data from a phase IIb trial in patients treated with bavituximab plus docetaxel.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology Variable All Grades Grade 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates. TRE-2486a November 2012 (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

Trial Design The phase III clinical trial will be a randomized, double-blind, placebocontrolled trial evaluating bavituximab plus docetaxel vs docetaxel alone, enrolling approximately 600 patients at sites worldwide. The trial will enroll stage IIIB/IV nonsquamous NSCLC patients who have had disease progression after standard front-line treatment. The primary endpoint of the trial will be overall survival. This agreement on a phase III trial design with the FDA is a critical milestone for the bavituximab program,

said Steven King, President and Chief Executive Officer of Peregrine. “We will now focus on starting the phase III trial while continuing ongoing partnering discussions. With immunotherapies at the forefront of new approaches to treating cancer, we are well positioned with bavituximab’s novel immune activation mechanism to help advance this rapidly evolving field.”

Targeted Immunotherapy Bavituximab is a first-in-class phosphatidylserine-targeting monoclonal antibody that represents a new approach to treating cancer. Phosphatidylserine is a highly immunosuppressive phospholipid component, usually located inside the membrane of healthy cells. However, when a cell undergoes apoptosis, the phosphatidylserine molecule “flips” and becomes exposed on the outside of cells that line tumor blood vessels, causing the tumor to evade immune detection. Bavituximab targets phosphatidylserine and blocks this immunosuppressive signal, resulting in the maturation of dendritic cells and cancer-fighting (M1) macrophages, leading to the development of cytotoxic T cells that fight solid tumors. Bavituximab is the lead drug candidate from the company’s phosphatidylserine-targeting technology platform and is currently being evaluated in several solid tumor indications, including non–small cell lung cancer, breast cancer, liver cancer, and rectal cancer. n

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Journal Spotlight Genitourinary Oncology

No Difference in Overall Survival with Axitinib or Sorafenib in Second-line Treatment for Advanced Renal Cell Carcinoma By Matthew Stenger

he phase III open-label AXIS trial comparing axitinib (Inlyta) vs sorafenib (Nexavar) as second-line treatment for metastatic renal cell carcinoma showed significantly prolonged independent radiology committee–assessed progression-free survival with axitinib treatment (hazard ratio [HR] = 0.665, P < .0001), leading to approval of axitinib for second-line treatment of advanced renal cell carcinoma.1 AXIS was the first phase III trial to compare an investigational targeted agent with an approved targeted agent in renal cell carcinoma. As recently reported in Lancet Oncology by Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center, New York, and colleagues, overall survival, a secondary outcome measure of the trial, did not differ between treatments.2 The updated analysis showed a continued, investigator-judged, prolongation of progression-free survival with axitinib treatment. In the trial, 723 patients with clear cell metastatic renal cell carcinoma and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had disease progression after systemic therapy received axitinib at 5 mg twice daily (n = 361) or sorafenib at 400 mg twice daily (n = 362). Baseline characteristics were similar between the two groups. Overall, 91% of patients had prior nephrectomy. Prior first-line therapy consisted of sunitinib (Sutent) in 54% of patients, cytokines in 35%, bevacizumab (Avastin) plus interferon alfa in 8%, and temsirolimus (Torisel) in 3%.

Overall Survival Analysis As of the cutoff date for the overall survival analysis (November 1, 2011), median overall survival was 20.1 months in the axitinib group and 19.2 months in the sorafenib group (hazard ratio [HR] = 0.969, P = .374). There were no significant differences between the axitinib group and the sorafenib group in median overall survival according to first-line treatment with sunitinib (15.2 vs 16.5 months, HR = 0.997, P = .490) or cytokines (29.4 vs 27.8 months, HR = 0.813, P= .1435) or in the smaller patient subgroups who previously received

bevacizumab plus interferon alfa (14.7 vs 19.8 months, HR = 1.825, P = .965), or temsirolimus (14.0 vs 8.5 months, HR = 0.459, P = .064). After discontinuation of study treatment, 54% of the axitinib group and 57% of the sorafenib group received subsequent systemic treatment, including mammalian target of rapamycin (mTOR) inhibitors (39% and 41%) and vascular endothelial growth factor (VEGF) inhibitors (33% and 32%). Median progression-free survival on investigator assessment was 8.3 months in the axitinib group vs 5.7 months in the sorafenib group (HR = 0.656, P < .0001). Median progression-free survival was significantly longer with axitinib in patients previously treated with sunitinib (6.5 vs 4.4 months, HR = 0.719, P = .0022) or cytokines (12.2 vs 8.2 months, HR = 0.505, P < .0001). No between-group differences were observed according to prior treatment with bevacizumab plus interferon alfa or temsirolimus. Investigator-assessed objective response rate was higher with axitinib (23% vs 12%, P = .0001)

Factors Associated with Overall Survival On multivariate analysis, baseline factors significantly associated with overall survival were cytokine vs sunitinib treatment (HR = 0.50), ECOG performance status of 1 vs 0 (HR = 1.45), < 11 year vs � 11 year from diagnosis to study treatment (HR = 1.55), > 1 vs 1 metastatic site (HR = 1.74), liver metastases (HR = 1.30), bone metastases (HR = 1.36), corrected calcium > 10 vs ≤ 10 mg/dL (HR = 2.74), alkaline phosphatase > upper limit of normal vs ≤ upper limit of normal (HR = 1.41), lactate dehydrogenase > 1.5 times upper limit of normal vs ≤ 1.5 times upper limit of normal (HR = = 2.68), hemoglobin < lower lower lim-

it of normal vs � lower limit of normal (HR = 1.69), and neutrophils > upper limit of normal vs ≤ upper upper limit of normal (HR = 1.69), with P < .05 for all these comparisons. An analysis of overall survival according to quartile of time to progression on prior sunitinib therapy in pa-

14.8 months in the sorafenib group (P = .002). Multivariable analysis including baseline factors showed that among all patients, the hazard ratios for overall survival were 0.63 for diastolic pressure � 90 90 vs < 90 mm Hg 90 mm Hg mm Hg Hg and 0.49 for systolic pressure � 140 vs < 140 mm Hg

Investigator-assessed [progressionfree survival] remained longer in the axitinib group compared with the sorafenib group. —Robert J. Motzer, MD, and colleagues

tients receiving the agent as first-line treatment suggested a relationship between shorter overall survival and shorter time to progression on sunitinib, with overall survival being lower in axitinib patients in the lower two quartiles and in sorafenib patients in the lowest quartile. As noted by the investigators, these findings “might be indicative of a more aggressive natural history, resistance to VEGF-targeted treatment, or both.”

Hypertension and Overall Survival A post hoc landmark analysis showed that development of hypertension (diastolic pressure � 90 mm Hg or systolic � 140 mm Hg) within the first 8 and 12 weeks of treatment was independently predictive of overall survival in both treatment groups. For example, median overall survival was 20.7 months in patients developing diastolic pressure � 90 mm Hg by 12 weeks vs 12.9 months in those with diastolic pressure < 90 mm Hg in the axitinib group (P = .012) and 20.2 vs

Second-line Axitinib vs Sorafenib for Advanced Kidney Cancer ■ Median overall survival did not differ between the axitinib and sorafenib treatment groups; progression-free survival remained significantly prolonged in the axitinib group.

■ Development of hypertension during treatment with either agent was associated with significantly prolonged overall survival.

(both P < .0001). These results are consistent with findings in other studies indicating that the association of treatment-induced hypertension with improved overall survival is a class effect of VEGF inhibitors. There was no significant relationship between development of hypertension and progression-free survival. The most common treatment-related grade 3 or higher adverse events were hypertension (17%), diarrhea (11%), fatigue (10%), and hand-foot syndrome (6%) in the axitinib group and hand-foot syndrome (17%), hypertension (12%), and diarrhea (8%) in the sorafenib group. Among treatment-related adverse events of any grade, hypertension, nausea, dysphonia, and hypothyroidism were more common in the axitinib group (> 10% difference), whereas hand-foot syndrome, alopecia, and rash were more common in the sorafenib group. Quality-of-life assessment with the Functional Assessment of Cancer Therapy Kidney Symptom Index (FKSI-15) and the FKSI–Disease-Related Symptoms subscale showed little change from baseline in either group during treatment. However, quality-oflife scores in both groups decreased at the end of treatment assessment, when patients were coming off study treatment predominantly due to disease progression. continued on page 72

The ASCO Post | JUNE 10, 2013

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News Thoracic Oncology

Low-dose CT Detects Twice as Many Early-stage Lung Cancers as Chest X-ray, According to Additional NLST Results

esults of the first of three planned annual screening examinations from the National Lung Screening Trial (NLST) were recently published and physicians may now have more information to share with their patients about the benefits and risks of low-dose computed tomography lung cancer screening. 1 “For a cancer screening to work, it’s important to verify that it can in fact discover cancers early. The analysis of NLST participants’ initial annual screening examination provides evidence that the number of early-stage cancers detected in the trial’s CT arm were significantly greater than the number detected in the chest x-ray arm,” said Timothy Church, PhD, a biostatistician and Professor in the School of Public Health at the University of Minnesota who has been involved with the NLST’s design, implementation, and analysis. Dr. Church also pointed out that a reduction in mortality is the ultimate indicator of a successful cancer screening strategy. The NLST is a large-scale, longitudinal clinical trial that randomly assigned over 53,400 study participants equally into either the low-dose CT or standard chest x-ray arm to evaluate whether lung cancer screening saves lives. Published results reported a 20% reduction in lung cancer deaths among study participants (all at high risk for the disease) screened with low-dose CT vs those screened with chest x-ray.2

Initial Screening Results

High Rate of Compliance

The authors reported that the NLST initial-screening results are reflective of other large trials with regard to positive low-dose CT vs chest x-ray results, with more positive screening exams (7,191 vs 2,387, respectively), more diagnostic procedures (6,369 vs 2,176, respectively), more biopsies and other

Another result reported is the high rate of compliance in performing the low-dose CT examination as specified in the research protocol across the 33 imaging facilities that carried out the study. “The sites complied with the low-dose CT imaging protocol specifications in 98.5% of all studies performed, which is outstanding con-

Axitinib vs Sorafenib

translated into a lead-time benefit for patients previously treated with cytokines. Additionally, patients in the prior cytokine subgroup had their first exposure to VEGF-targeted therapy during [the study] and thus did not have previous resistance to this class of agents. Patients previously treated with sunitinib, however, had already shown clinical resistance to VEGF-targeted therapy and might have had shorter overall survival after

continued from page 71

With regard to the longer overall survival observed in the subset of patients in both groups who received cytokines as first-line treatment, the investigators noted that median duration of first-line treatment was longer in those receiving sunitinib (9.5–10.1 months) than in those receiving cytokines (6.0–6.6 months). As they stated, “[T]his difference could have

Today’s publication represents the type of immensely important data NLST will continue to provide about lung cancer screening in the United States. —Mitchell D. Schnall, MD, PhD

invasive procedures (297 vs 121, respectively), and more lung cancers seen in the low-dose CT arm than in the chest x-ray arm during the first screening round of NLST (292 vs 190, respectively).

Need for Follow-up Small Although these results were generally anticipated, a key reason to publish the data was to document the exact differences between the two arms. “Although we did see that CT resulted in referring more patients for additional testing, the question comes down to whether the 20% reduction in mortality is worth the additional morbidity introduced by screening high-risk patients,” said Dr. Church. He noted that although there were more follow-up procedures in the low-dose CT arm vs the chest x-ray arm, it was encouraging to confirm that the number of individuals who actually had a more invasive followup procedure was quite small.

sidering the many thousands of scans performed,” stated Denise R. Aberle, MD, the national principal investigator for NLST-ACRIN and site coprincipal investigator for the UCLA NLST team. Dr. Aberle, a member of the UCLA Jonsson Comprehensive Cancer Center, Professor of Radiology and Bioengineering and Vice Chair for Research in Radiology at UCLA, also emphasized that the first-screen result strongly suggests that CT lung cancer screening programs with radiologists who possess similar expertise and interpret similar numbers of CT

Low-dose CT Screening ■ The first-screening results

strongly suggest that the 20% reduction in lung cancer mortality with low-dose CT vs x-ray reported in the original NLST paper is achievable at experienced screening centers.

treatment with either agent.” The investigators concluded, “Although overall survival … did not differ between the two groups, investigatorassessed [progression-free survival] remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic [renal cell carcinoma].” n Disclosure: The study was funded by Pfizer Inc.

cases that are obtained on scanners of the same caliber or better as those required for the NLST are likely to have results similar to those reported in the paper.

Valuable Results “What we’ve learned from the analysis of the first-screen results provides clinicians additional facts to discuss with patients who share similar characteristics as the NLST participants (current or former heavy smokers over the age of 55),” said Dr. Church. “The results also caution against making blanket lung cancer screening recommendations, because each person’s trade-off between the risk of having an unnecessary procedure and the fear of dying of lung cancer is uniquely individual.” “Today’s publication represents the type of immensely important data NLST will continue to provide about lung cancer screening in the United States,” said Mitchell D. Schnall, MD, PhD, ACRIN Network Chair, group Co-Chair of the ECOGACRIN Cancer Research Group and Chair of the Radiology Department of the University of Pennsylvania. n

Disclosure: The NLST was supported by the National Cancer Institute through the grants U01 CA079778 and U01 CA080098.

References 1. The National Lung Screening Trial Research Team: Results of initial lowdose computed tomographic screening for lung cancer. N Engl J Med 368:19801991, 2013. 2. The National Lung Screening Trial Research Team: Reduced lung-cancer mortality with low-dose ccomputed tomographic screening. N Engl J Med 365:395-409, 2011.

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

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Empowering antibodies by linking precision with potency Seattle Genetics has developed proprietary, industry-leading technology that employs a monoclonal antibody specific for a tumor-associated antigen, plus potent cytotoxic agents connected by stable linker systems designed to securely bind the cytotoxic agent to the antibody and then release the agent within the targeted cell.

Cytotoxic agent Designed to kill target cells when internalized and released.1,2

Linker Antibody Specific for a tumorassociated antigen that has restricted expression on normal cells.1,2

Attaches the cytotoxic agent to the antibody. Seattle Genetics’ linker system is designed to be stable in circulation and release the cytotoxic agent inside targeted cells.1-3

In addition to licensing its ADC technology, Seattle Genetics is developing 7 proprietary ADCs. The company’s robust pipeline of empowered antibody-based therapies and one approved ADC are designed to address significant unmet medical needs.

For more information about our ADC technology and to download an educational slide deck, please visit seattlegenetics.com/technology. REFERENCES: 1. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14(3):154-169. 2. Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235-244. 3. Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the treatment of non–Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6):2358-2364.

The ASCO Post | JUNE 10, 2013

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Journal Spotlight Gastrointestinal Oncology

HIV Infection Does Not Adversely Affect Outcomes of Liver Transplantation for Hepatocellular Carcinoma

iver transplantation for hepatocellular carcinoma is feasible for HIV-infected patients, with no differences in post-transplant survival or hepatocellular carcinoma recurrence rates compared with liver transplantation for hepatocellular carcinoma in HIV-uninfected patients. The study, published in The Oncologist,1 was led by Fabrizio Di Benedetto, MD, PhD, Associate Professor of Surgery, University of Modena and Reggio Emilia, Modena, Italy, and represents the largest multicenter study of liver transplant for hepatocellular carcinoma in HIV-infected patients to date.

tation for hepatocellular carcinoma in HIV-infected patients is a recent indication, and its viability as a treatment option has been a matter of debate. In the current study, researchers evaluated post-transplant outcomes in 30 HIV-positive patients and 125 HIV-

Takeaway Message “The key message of this study is that liver transplantation is a valid option for hepatocellular carcinoma treatment in HIV-infected patients,” Dr. Di Benedetto and colleagues wrote. “We suggest that HIV-infected patients must be offered the same

We suggest that HIV-infected patients must be offered the same liver transplant options for hepatocellular carcinoma treatment currently provided to HIVuninfected subjects. —Fabrizio Di Benedetto, MD, PhD, and colleagues

Matter of Debate Patients infected with HIV experience a more aggressive course of hepatocellular carcinoma, in part due to the tumor-enhancing effects of HIV proteins, including increased growth signaling and diminished antitumor immune response. Moreover, as highly active antiretroviral therapy (HAART) prolongs the life expectancy of HIV-infected patients, the progression of underlying liver disease toward hepatocellular carcinoma is increasingly a major cause of morbidity and mortality in this patient population. Liver transplan-

uninfected patients who underwent liver transplantation for hepatocellular carcinoma at three transplantation centers in northern Italy between 2004 and 2009. Two patients in the HIV-positive cohort (6.7%) and 18 uninfected patients (14.4%) experienced a recurrence of hepatocellular carcinoma during the follow-up period of approximately 32 months (P = .15). Overall survival was similar for HIVinfected and -uninfected patients at 1 year (77% vs 86.4%) and 3 years (65% vs 70%), respectively, after liver transplantation (P = .32).

liver transplant options for hepatocellular carcinoma treatment currently provided to HIV-uninfected subjects.” All HIV-infected patients were given HAART until liver transplantation, and antiviral therapy was discontinued only until liver function stabilized. No patients developed AIDS-defining events during the follow-up period, which the study authors attributed to early HAART resumption following transplantation. In particular, ritonavir-boosted protease inhibitor therapy appeared

to induce more rapid increases in immunosuppressive drug serum levels than unboosted protease inhibitor therapy, and is the preferred HAART regimen. In the future, new options for antiviral therapy may further improve HIV control and post-transplantation outcomes in HIV-infected patients undergoing liver transplantation for hepatocellular carcinoma. The transplantation centers used a multidisciplinary approach to patient care that included input from oncologists, radiologists, gastroenterologists, liver surgeons, and infectious disease specialists. Dr. Di Benedetto and colleagues urged clinicians to adopt a similar collaborative approach to optimize outcomes for HIV-infected patients undergoing liver transplantation for hepatocellular carcinoma. n

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

Reference 1. Di Benedetto F, Tarantino G, Ercolani G, et al: Multicenter Italian experience in liver transplantation for hepatocellular carcinoma in HIV-infected patients. Oncologist. May 10, 2013 (early release online).

Breaking News on Lymphoma and Myeloma to Be Reported at European Hematology Congress in Stockholm

n order to support high-quality science, the European Hematology Association collaborates with 16 Scientific Working Groups (SWGs) and concentrates on fostering activities directed towards basic and translational research. In simultaneous sessions on Thursday, June 13, during the European Hematology Congress in Stockholm, two of the SWGs will discuss progress in lymphoma and myeloma.

and undertreatment of patients. Detection of minimal residual disease with advanced methods has established individualized risk-dependent treatment strategies. Also presented will be the latest results of treatment of younger patients—both upfront and in the relapse setting—with molecular approaches/ smart molecules, which should lead to an improvement in survival. Special attention will be paid to new treatment options for the elderly with the aim of achieving a better prognosis.

European Mantle Cell Lymphoma Network

SWG Myeloma

The European Mantle Cell Lymphoma Network will extensively discuss developments in new biological prognostic factors, which may prevent over-

The SWG Myeloma will focus on “Models for Drug Resistance,” which represent one of the major problems in maintaining today’s effective treatment. New insights into mechanisms

of resistance, including identification and prediction of this unwanted phenomenon, will be discussed. In particular, researchers will report on emerging knowledge of the genetic signature of defined resistant subgroups of patients. A new preclinical disease model

mimicking the clinical condition and providing opportunity to accelerate the development of new drugs will be presented as well as the mechanisms through which evolution from “smoldering” disease to aggressive disease takes place. n

18th Congress of the European Hematology Association June 13–16, 2013 Stockholm, Sweden For more information, visit www.ehaweb.org

ASCOPost.com | JUNE 10, 2013

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Journal Spotlight Head and Neck Cancer

Genetic Diversity May Predict Outcomes in Head and Neck Cancer

new measure of cell heterogeneity within a tumor may predict treatment outcomes of patients with squamous cell carcinoma of the head and neck. In a recent report,1 investigators at Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary reported how the mutant allele tumor heterogeneity measure, referred to as “MATH” was a better predictor of survival than most traditional risk factors in a small group of patients with squamous cell carcinoma of the head and neck. “Our findings will eventually allow better matching of treatments to individual patients, based on this characteristic of their tumors,” said lead author Edmund Mroz, PhD, of the MGH Center for Cancer Research. “This method of measuring heterogeneity can be applied to most types of cancer, so our work should help researchers determine whether a similar relationship between heterogeneity and outcome occurs in other tumors,” Dr. Mroz reported.

Measuring Tumor Heterogeneity For decades investigators have hypothesized that tumors with a high degree of genetic heterogeneity would be more difficult to treat because particular subgroups might be more likely to survive a particular drug or radiation or to have spread before diagnosis. Although recent studies have identified specific genes and proteins that can confer treatment resistance in tumors, there previously has been no way of conveniently measuring tumor heterogeneity.

Gene Sequencing Data Working in the laboratory of senior author James Rocco, MD, PhD, Director of the Massachusetts Eye and Ear Infirmary/Massachusetts General Hospital Head and Neck Molecular Oncology Research Laboratory, Dr.

Mroz and his colleagues developed their new measure by analyzing advanced gene sequencing data to produce a value reflecting the genetic diversity within a tumor—not only the number of genetic mutations but how broadly particular mutations are shared within different subgroups of tumor cells. They first described this measure, called mutant-allele tumor heterogeneity, or MATH in an earlier report.2

Study Details In the current study, the investigators used mutant-allele tumor heterogeneity to analyze genetic data from the tumors of 74 patients with squamous cell head and neck carcinoma for whom they had complete treatment and outcome information. Not

Mutant-allele Tumor Heterogeneity (‘MATH’) Measure ■ Mutant-allele tumor heterogeneity is a quantitative measure of genetic heterogeneity based on next-generation sequencing data.

■ Higher mutant-allele tumor heterogeneity values were strongly associated with shorter overall survival, and that relationship was also seen within groups of patients already at risk for poor outcome.

■ The impact of mutant-allele tumor heterogeneity value on outcome appeared strongest among patients treated with chemotherapy.

all other risk factors the researchers examined. The impact of mutant-allele tumor heterogeneity value on outcome appeared strongest among patients treated with chemotherapy, which may reflect a greater likelihood that highly heterogeneous tumors contain treatment-resistant cells, Dr. Mroz said. He also noted that what reduces

This method of measuring heterogeneity can be applied to most types of cancer, so our work should help researchers determine whether a similar relationship between heterogeneity and outcome occurs in other tumors. —Edmund Mroz, PhD

only did they find that higher mutantallele tumor heterogeneity values were strongly associated with shorter overall survival—with each unit of increase reflecting a 5% increase in the risk of death—but that relationship was also seen within groups of patients already at risk for poor outcome. For example, among patients with human papillomavirus–negative tumors, those with higher mutant-allele tumor heterogeneity values were less likely to survive than those with lower values.

Mutant-allele Tumor Heterogeneity Values Strongly Related to Outcomes Overall, mutant-allele tumor heterogeneity values were more strongly related to outcomes than most previously identified risk factors and improved outcome predictions based on

the chance of survival appears to be the subgroups of cells with different mutations within a tumor, not the process of mutation itself. “If all the tumor cells have gone through the same series of mutations, a single treatment might still be able to kill all of them. But if there are subgroups with different sets of mutations, one subgroup might be resistant to one type of treatment, while another subgroup might resist a different therapy,” he said

Future Implications In addition to combining mutantallele tumor heterogeneity values with clinical characteristics to better predict a patient’s chance of successful treatment, Dr. Mroz noted that mutant-allele tumor heterogeneity could someday help determine treatment choice—directing the use of more aggressive therapies against tumors

with higher values, while allowing patients with lower values to receive less intense standard treatment. Mutantallele tumor heterogeneity could be just as useful at predicting outcomes for other solid tumors, the investigators noted, but added that would need to be shown in future studies. “Our results have important implications for the future of oncology care,” said Dr. Rocco, the Daniel Miller Associate Professor of Otology and Laryngology at Harvard Medical School. “Mutant-allele tumor heterogeneity offers a simple, quantitative way to test hypotheses about intratumor genetic heterogeneity, including the likelihood that targeted therapy will succeed. They also raise important questions about how genetic heterogeneity develops within a tumor and whether heterogeneity can be exploited therapeutically.” n Disclosure: The authors reported that the study was supported by National Institute of Dental and Craniofacial Research grants R01DE022087 and RC2DE020958, National Cancer Institute grant R21CA119591, Cancer Prevention Research Institute of Texas grant RP100233, and the Bacardi MEEI Biobank Fund. Massachusetts General Hospital has filed a patent application for the mutant-allele tumor heterogeneity measure.

References 1. Mroz EA, Tward AD, Pickering CR, et al: High intratumor genetic heterogeneity is related to worse outcome in patients with head and neck squamous cell carcinoma. Cancer. May 20, 2013 (early release online). 2. Mroz EA, Rocco JW: MATH, a novel measure of intrtumor genetic heterogeneity, is high in poor-outcome classes of head and neck squamous cell carcinoma. Oral Oncol 49(3): 211-215, 2013.

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ASCOPost.com | JUNE 10, 2013

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Expert’s Corner Health-care Policy

Utilizing the Power of Rapid Learning Health-care Systems to Improve Patient Care A Conversation with Lynn Etheredge By Jo Cavallo Rapid Learning Project at George Washington University. The ASCO Post talked with Mr. Etheredge about ASCO’s health information technology initiative CancerLinQ™ and how this type of resource is changing the way oncologists will treat patients in the future.

Benefits of CancerLinQ Lynn Etheredge

ynn Etheredge’s career in shaping national health-care and social policy spans more than 4 decades and four Presidential administrations. He was the lead analyst in the development of health insurance proposals for Medicare and Medicaid while working in the White House Office of Management and Budget (OMB) during both the Nixon and Ford administrations and later headed OMB’s professional health staff in the Carter and Reagan administrations. In 1986, he was a founding member of the National Academy of Social Insurance, and during the 1990s, he continued to focus his efforts on crafting health-care reforms to reduce costs and improve health insurance coverage and quality, especially for lowincome and elderly people. In 2007, Mr. Etheredge proposed the concept of a “rapid learning” health-care system. His aim was to harness the information collected in patient electronic health records and utilize the power of the Internet and computing systems to build national medical databases and research registries, to facilitate best practices in clinical care and biomedical studies. Today, he is continuing his work in the development of a national rapid-leaning health-care system with support from the Robert Wood Johnson Foundation. He is an advisor on health-care policy for a number of organizations, including ASCO, and is the Director of the

How can rapid-learning health systems like CancerLinQ improve cancer care? Most importantly, they will give every oncologist immediate access on their computer to the latest published research information, to help them make better treatment deci-

These women get cancers but are not included in randomized clinical trials, so there isn’t a lot of information about how to treat them. Having the ability to look up a database of thousands of patients with a particular characteristic or a particular problem will give physicians a lot more information to make a better decision regarding treatment. So this technology really fills in a lot of the gaps with regard to the issues that individual physicians and individual patients face that are rarely addressed in the academic literature. I think community oncologists are going to be the greatest beneficiaries of CancerLinQ, because

CancerLinQ is a flagship health-care model not only in the treatment of cancer but for other disease specialties as well. If we learn how to make this kind of system successful in the treatment of cancer, it will become the model for every area of medicine. —Lynn Etheredge

sions. For example, the CancerLinQ prototype, which includes “deidentified” data from over 100,000 patients with breast cancer and is being tested now, should make it possible for oncologists to make a much more accurate diagnosis and determine more effective personalized therapies to improve the quality of care. Health information systems like CancerLinQ will also provide oncologists with the ability to consult with each other on difficult cancer cases. For example, there are relatively few specific questions about safety and effectiveness that get addressed in the U.S. Food and Drug Administration (FDA) drug approval process. While we may know that a new drug is safe and effective in general, there are many questions that come up in clinical practices that don’t get addressed in clinical trials. One example is how chemotherapies affect pregnant women.

it is in those private practices where most cancer care takes place. Community oncologists will have the ability to ask not just one or two colleagues about their experiences in similar clinical situations, but thousands of physicians participating in CancerLinQ.

Impact on Survivors In addition to providing oncologists with resources on individualizing treatment strategies, how else will CancerLinQ improve patient care? CancerLinQ will also give us insights into the progress of the understudied long-term cancer survivor. Most of the research by drug companies and academic institutions is on the treatment and cure of current patients. Cancer survivors are a very understudied group and a population that is growing rapidly. According to the National Cancer Institute, there are nearly 14 million cancer survivors in the United States, and

that number is expected to climb to almost 18 million by 2022.1 I think CancerLinQ is one of the tools that will give us a unique set of insights and information about how to do a better job of monitoring and improving the quality of health status of cancer survivors long-term.

Research and Cost Issues Will the use of health information technology also speed the dissemination of information on biomedical and comparative effectiveness research? Absolutely. By building a database of patient health records, including treatment outcomes, as well as a database of national research registries, biobanks, and genomic data, and linking them, our understanding of science will advance very quickly. In addition to the potential for improving patient care, will health information technology also be instrumental in reducing health-care costs? We hope so, but I wouldn’t want to forecast that. It’s a complicated issue. The hope is that if we can prevent cancer and treat it more effectively once it is diagnosed, both of those accomplishments will reduce health-care costs. We are entering a world of precision diagnostics and gaining the ability to have targeted therapeutics and personalized medicine. The hope—and the expectation—is that we will save a lot of money in the process.

CancerLinQ vs Watson How does CancerLinQ differ from IBM’s Watson supercomputer now being tested at Memorial Sloan-Kettering Cancer Center in New York and at other institutions? IBM’s Watson is a very large software program that doesn’t start with medical knowledge and medical logic, so it needs to learn those things. The supercomputer may get to where it is a very useful medical decision tool eventually, but CancerLinQ is being built specifically for cancer care, and it will have the ability to look up existing patient continued on page 78

The ASCO Post | JUNE 10, 2013

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Expert’s Corner

Rapid Learning Health-care Systems continued from page 77

databases, existing research registries, and existing scientific literature and analyze the information. At the moment, I view Watson as a very interesting exercise in basic research that may ultimately prove very useful. Currently, however, I think it’s more useful for hypothesis-generating and -testing then it is for coming up with solid scientific information that can be useful in treatment decision-making.

Key Goal Will rapid-learning health-care systems make overall health care in the United States more cohesive and uniform? I think the technology is going to help standardize the approach to scientific research and delivery of care around best practices. Health information technology should help oncologists deliver the very best care for each patient, and that is the key goal here. I’m confident that we will make progress in that area. Whether it will alter the business side of medicine at health insurance and drug companies,

I’m not sure. What is extraordinarily important about ASCO’s approach in the development of CancerLinQ is that the physician community is taking the lead to build the databases that they and their patients need. Clearly, no other entity is going to be building the kind of resource CancerLinQ provides, so I think it’s imperative that we find a way to make this system successful. Also, we have a lot to learn about how to build rapid-learning systems like CancerLinQ. CancerLinQ is a flagship health-care model not only in

the treatment of cancer but for other disease specialties as well. If we learn how to make this kind of system successful in the treatment of cancer, it will become the model for every area of medicine. n

Disclosure: Mr. Etheredge reported no potential conflicts of interest.

Reference 1. National Cancer Institute: Survivorship-related statistics and graphs. Available at http://dccps.nci.nih.gov/ ocs/prevalence. Accessed May 10, 2013.

EGFR Prevents Maturation of microRNAs under Hypoxic Conditions

he epidermal growth factor receptor (EGFR) sends signals that thwart the development of tumor-suppressing microRNAs under conditions of hypoxia, an international team led by scientists at The University of Texas MD Anderson Cancer Center discovered. The results were reported in an early online publication in Nature.1 “When hypoxia stresses a cell, signaling by EGFR prevents immature microRNAs from growing up to fight cancer,” said senior author Mien-Chie Hung, PhD, Professor and Chair of MD Anderson’s Department of Molecular and Cellular Oncology and holder of the Ruth Legett Jones Distinguished Chair.

nese,” Dr. Hung said. “This is the first paper to show how they communicate.” The scientists established the relationship in cell line experiments, confirmed it in a mouse model and human breast cancer samples, then found that it reduced breast cancer patient survival in a review of 125 cases.

Growth Factor Signaling Pathway

EGFR penetrates the cell membrane to receive signals from growth factors outside of the cell. After a growth factor binds to it, EGFR conveys the signal into the cell by attaching phosphate groups to other proteins, often acting as a molecular “on switch.” Dr. Hung and colleagues found that EGFR also fuels cancer progression by stifling tumor-suppressing microRNAs. As a tumor grows, large portions of its interior can become hypoxic for lack of adequate blood vessels. This stress suffocates many tumor cells, but

The group’s findings point to a potential new prognostic marker for breast cancer, Dr. Hung noted, but also provide the first evidence of a growth factor signaling pathway regulating microRNA maturation. “Inside of a cell, you have signal induction, in this case through EGFR, and you also have a protein complex that processes precursors into mature microRNA to perform a function. They didn’t appear to talk to each other; it’s as if one speaks English and the other Chi-

This is a turning-point paper; it will induce lots of new questions for scientists to pursue. —Mien-Chie Hung, PhD

New Role for EGFR

EGFR-mediated AGO2 Phosphorylation ■ Researchers found that EGFR fuels cancer progression by stifling tumorsuppressing microRNAs.

■ EGFR-mediated AGO2 phosphorylation blocks cell death and enhances invasiveness under hypoxia.

■ The hypoxia-EGFR-AGO2 connection was strong in tumor samples from

128 breast cancer patients, but it was low or absent in normal breast tissue, pointing to a new prognostic marker for breast cancer.

the few that endure become highly malignant, resist treatment, and are most likely to spread, Dr. Hung said. Antiangiogenesis drugs often succeed at first, Dr. Hung said, but then fail against the more malignant cells that survive hypoxia.

Effect of Hypoxia Low-oxygen conditions cause EGFR overexpression. EGFR also is pulled into the cell interior, captured in vesicles, and eventually fed into lysosomes loaded with enzymes to dissolve proteins. It was known that EGFR continues to signal even while caught in the vesicles, which actually prolongs its activation. Dr. Hung and colleagues found that EGFR signals to a key protein in microRNA processing called argonaute 2, or AGO2. AGO2 connects with two other proteins called Dicer and TRBP to form a complex that processes microRNA precursors into mature microRNAs, which regulate gene expression after messenger RNA has been expressed but before it’s translated into a protein. The scientists found that EGFR attaches phosphate groups to AGO2, which in turn weakens AGO2’s ability to connect with Dicer to produce mature microRNAs. EGFR’s effect is stronger during oxygen starvation than under normal conditions. The team identified a number of specific microRNAs affected by EGFR, most of which have been reported to have tumor suppressor characteristics. The microRNAs regulated by phosphorylated AGO2, including miR-31, miR-192, and miR-193a-5p, also shared a long-loop structure in their precursors that microRNAs unaf-

fected by AGO2 phosphorylation lack. Hypoxic environments around tumors promote metastasis by helping cells evade programmed cell death. Dr. Hung and colleagues showed that EGFR-mediated AGO2 phosphorylation blocks cell death and enhances invasiveness under hypoxia. Experiments in a mouse model of breast cancer confirmed that expression of EGFR and the presence of phosphorylated AGO2 increase during tumor progression under oxygenstarved conditions.

EGFR-AGO2 Connection Found in Breast Tumors The hypoxia-EGFR-AGO2 connection was strong in tumor samples from 128 breast cancer patients, but it was low or absent in normal breast tissue. In 125 breast cancer cases analyzed by the team, half of 62 patients with high levels of phosphorylated AGO2 survived to 48 months and beyond. Median survival had not been reached for the 63 patients in the lowlevel group, but 78% had survived to 48 months. “One can imagine other receptors for platelet-derived growth factor and insulin-like growth factor also regulating microRNAs, perhaps by regulating Dicer or TBRP,” Dr. Hung said. “This is a turning-point paper; it will induce lots of new questions for scientists to pursue.” n

Disclosure: Dr. Hung and colleagues reported no potential conflicts of interest.

Reference 1. Xia SH, Khotskaya YB, Huo L, et al: EGFR Modulates microRNA maturation in response to hypoxia through phosphyrylation of AGO2. Nature 497(7449): 383-387, 2013.

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

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

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

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

With FASLODEX 500 mg vs 250 mg in CONFIRM

FASLODEX 500 mg showed a

20% reduction

in relative risk of progression vs 250 mg2

Median 6.5 months with FASLODEX 500 mg vs

5.4 months with 250 mg

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

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

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

Updat ed

Ove Survirvall Analy al s

THE FASLODEX STORY CONTINUES

Overall Survival (OS)

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

FASLODEX 500 mg showed a

19% reduction

in relative risk of death vs 250 mg2

Median 26.4 months with FASLODEX 500 mg vs

22.3 months with 250 mg

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

Learn more at www.FASLODEXStoryContinues.com

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

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

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

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

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

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

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

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

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

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

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

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JCO Spotlight Gastrointestinal Oncology

Smoking Linked to Shorter Disease-free Survival in Stage III Colon Cancer Effect most evident in BRAF wild-type and KRAS mutant disease By Matthew Stenger

ccording to an analysis reported by Amanda Phipps, PhD, MPH, Assistant Professor of Epidemiology at the University of Washington and Assistant Member at Fred Hutchinson Cancer Research Center, Seattle, and colleagues in the Journal of Clinical Oncology, patients with stage III colon cancer who ever smoked had significantly reduced disease-free survival compared with never-smokers.1 The association between smoking and reduced disease-free survival was most marked in patients with BRAF wild-type or KRAS mutant colon cancer. Prior studies have indicated that cigarette smoking is associated with a modestly increased risk for colon cancer, particularly after long durations or high levels of exposure.

were never-consumers, and 45% vs 33% were current consumers, overall P < .001). There was a borderline significant trend for never-smokers to have greater body mass index (� 30.0 kg/ m2 for 38% vs 32%, overall P = .06). There were no significant differences between groups in allocation to adjuvant therapy study arm, tumor subsite, number of affected nodes, T stage, or KRAS mutation status.

This analysis ... provides evidence that the effects of smoking may extend beyond an adverse impact on colon cancer risk to also adversely impact outcomes after diagnosis.

Study Details The study involved 1,968 patients with stage III disease from the North Central Cancer Treatment Group phase III trial N0147 examining FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) vs FOLFOX plus cetuximab (Erbitux) as adjuvant therapy. Questionnaires regarding smoking and other risk factors were completed by patients prior to study randomization. Of the total of 2,686 patients enrolled, 718 did not complete questionnaires. A number of significant differences were seen between never-smokers (n = 931) and ever-smokers (n = 1028) at baseline. Ever-smokers were more likely to be older (mean age = 59.4 vs 56.6 years, P < .001), be male (57% vs 47%, overall P < .001), have mismatch repair gene–deficient status (15% vs 10%, overall P = .001), have mutated BRAF (16% vs 11%, overall P = .006), have poorer ECOG performance status (0 in 74% vs 79%, and 1 in 25% vs 20%, overall P = .02), never engage in vigorous physical activity (71% vs 64%, overall P < .001), and be current alcohol consumers (18% vs 45%

With regard to associations of disease-free survival with smoking patterns, there were no statistically significant associations with patterns of numbers of cigarettes per day, time since smoking cessation, or duration of smoking interval, although the data suggested that disease-free survival was poorest among patients who smoked more than 30 cigarettes per day (HR = 1.35, 95% CI = 0.86–2.12, for those smoking 31–40 per day; HR = 1.40,

—Amanda Phipps, PhD, MPH, and colleagues

Disease-free Survival in Ever-smokers Median follow up in patients not experiencing events was 3.5 years. On unadjusted analysis, ever-smokers had a significant 21% increased risk of recurrence or death (3-year diseasefree survival 70% vs 74%, hazard ratio [HR] = 1.21, P = .03). Associations with smoking status were assessed in multivariate analysis adjusting for tumor site, number of involved lymph nodes, T stage, mismatch repair gene status, performance status, physical activity, body mass index, alcohol consumption, age, and sex. On multivariate analysis, the significantly increased risk for recurrence or death persisted for ever-smokers (HR = 1.23, P = .03). The association with poorer disease-free survival was somewhat stronger for current smokers (HR = = 1.47, 95% confi confidence dence interval [CI] = 1.04–2.09) than for former smokers (HR = 1.20, 95% CI = 0.99– 1.46).

Smoking and Colon Cancer Survival ■ Ever-smokers with stage III colon cancer had significantly shorter diseasefree survival and time to recurrence than never-smokers.

■ The relationship between smoking and reduced disease-free survival was most evident in patients with BRAF wild-type or KRAS mutant disease.

95% CI = 0.80–2.44, for those smoking > 40). There was a significant trend for greater risk for recurrence or death in patients who initiated smoking at age 20 or older (HR = 1.39, 95% CI = 1.08–1.80, P = .04 for trend across age at initiation).

BRAF Wild-type or KRAS Mutant Disease Analyses stratified by patient and clinical characteristics, and adjusted for the same factors noted above, showed a significant interaction between smoking and BRAF mutation status in relation to disease-free survival (overall P = .03). Poorer diseasefree survival in ever-smokers vs neversmokers was limited to patients with BRAF wild-type tumors (HR = 1.36, 95% CI = 1.11–1.66), with smokers with BRAF mutant tumors having nonsignificantly reduced risk (HR = 0.80, 95% CI = 0.50–1.29). Although the interaction of KRAS mutation status and smoking status for disease-free survival only approached statistical significance (P = .07), there was evidence of poorer disease-free survival for smokers vs nonsmokers with KRAS mutant disease. Among patients with KRAS mutant disease, ever-smokers had a significant 50% increased risk for recurrence or death

(HR = 1.50, 95% CI = 1.12–2.00), whereas risk was not significantly increased in ever-smokers with KRAS wild-type disease (HR = 1.09, 95% CI = 0.85–1.39). The effects of BRAF and KRAS mutation status were most marked in comparisons of current smokers vs never-smokers, with significantly poorer disease-free survival observed for current vs never-smokers with BRAF wild-type disease (HR = 1.60, 95% CI = 1.10–2.32) and KRAS mutant disease (HR = 2.30, 95% CI = 1.40–3.77). Compared with neversmokers, risk in current smokers was nonsignificantly reduced among those with BRAF mutant disease (HR = 0.82, 95% CI = 0.29–2.35) and nonsignificantly increased in those with KRAS wild-type disease (HR = 1.08, 95% CI = 0.65–1.77). There were no significant interactions among smoking status and disease-free survival across sex, age, T stage, number of involved nodes, tumor subsite, or mismatch repair gene status stratifications. However, disease-free survival was significantly poorer for ever-smokers vs neversmokers who were male (HR = 1.33, 95% CI = 1.02–1.73), aged 50 years or less (HR = 1.53, 95% CI = 1.03–2.26), had stage T3 disease (HR = 1.29, 95% CI = 1.04–1.60), had one to three involved nodes (HR = 1.52, 95% CI = 1.13–2.04), had disease of the distal colon (HR = 1.36, 95% CI = 1.01– 1.82), and had mismatch repair gene– proficient status (HR = 1.25, 95% CI = 1.03–1.53). Analyses of time to recurrence among ever-smokers and never-smokers produced results similar to the analyses of disease-free survival.

Mechanisms Underlying Effects? The authors noted that the finding of significantly reduced disease-free survival in smokers with BRAF wildtype, KRAS mutant, or mismatch repair gene–proficient tumors—disease subtypes not previously associated with smoking in risk factor studies— suggests an impact of smoking on colon cancer progression or response to treatment via as yet undefined continued on page 84

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PAGE 84

News Genitourinary Oncology

Phase II Trial Targeting Genetic Anomaly in Castration-resistant Metastatic Prostate Cancer Underway

new clinical trial is testing whether targeting treatments to a genetic anomaly can lead to better treatments for castration-resistant metastatic prostate cancer. The trial, led by investigators at the University of Michigan Comprehensive Cancer Center, is being conducted at 11 sites throughout the country. The target of this phase II trial of patients with castration-resistant metastatic prostate cancer is a genomic rearrangement that causes the genes TMPRSS2 and ERG to fuse together. This gene fusion, believed to be the triggering event of prostate cancer, was initially discovered in 2005 by U-M researchers led by Arul Chinnaiyan, MD, PhD. “We hope this study will help us understand why certain patients respond to therapy and certain patients do not. By better understanding the evolving biology of prostate cancer, we will have the ability to better treat the disease,” said the clinical trial’s principal investigator, Maha Hussain, MD, FACP, Professor of Internal Medicine and Urology, and Associate Director of Clinical Research at the U-M Comprehensive Cancer Center.

occurs in about half of all prostate cancers. All participants will receive the standard hormone-based therapy abiraterone (Zytiga). Each group (gene fusion–positive and gene fusion–negative) will then be randomly assigned so that half the participants will also take the experimental drug ABT-888 in addition to abiraterone. The trial’s design is based on scientific data indicating the potential for improving abiraterone’s effect on the tumor and that this improvement may be more evident in patients whose tumors have the gene fusion. “Can we better select treatments for prostate cancer based on the genes in the patient’s cancer? We hope that what we learn from this study will help

Targeted Therapy for Metastatic Castration-resistant Prostate Cancer ■ A randomized phase II trial is testing the effects of abiraterone with or without the PARP inhibitor ABT-888 on gene fusion in patients with metastatic castration-resistant prostate cancer.

■ The fusion of the genes TMPRSS2 and ERG is thought to be the triggering event of prostate cancer.

■ Lab studies have found that PARP inhibitors, when added to hormone

therapy, helped shrink tumors in general and especially those expressing the TMPRSS2:ERG gene fusion.

PARP Inhibitor May Play Crucial Role ABT-888 is a PARP inhibitor that is known to directly interact with the TMPRSS2:ERG gene fusion, leading

Can we better select treatments for prostate cancer based on the genes in the patient’s cancer? We hope that what we learn from this study will help us to better control and better treat the deadly stage of prostate cancer. —Maha Hussain, MD, FACP

Study Details Study participants will undergo a biopsy to determine whether their tumor expresses the gene fusion, which

us to better control and better treat the deadly stage of prostate cancer,” Dr. Hussain said.

Smoking and Colon Cancer

pathway; this effect could be amplified in the presence of a KRAS mutation, since KRAS also activates PI3K. The authors concluded:

continued from page 83

pathway-specific mechanisms. As an example of one of the many ways the numerous compounds in cigarette smoke could affect multiple pathways of tumor initiation and progression and treatment response, they cite the effect of nicotine in increasing proliferation and decreasing apoptosis, perhaps via activation of the PI3K/AKT

Overall, smoking was significantly associated with shorter [disease-free survival] and time to recurrence in patients with colon cancer. These adverse relationships were most evident in patients with BRAF wild-type or KRAS mutated colon cancer…. This analysis contrib-

Contact The ASCO Post

to cancer growth and progression. Lab studies have found that a PARP inhibitor, when added to hormone therapy, helped utes to a sparse literature [on the effects of smoking on outcomes of colon cancer] and provides evidence that the effects of smoking may extend beyond an adverse impact on colon cancer risk to also adversely impact outcomes after diagnosis. Further research is needed to confirm and better understand observed differences in the association between smoking and survival outcomes in patients with colon cancer according to BRAF and KRAS mutation status and

shrink tumors in general and especially those expressing the TMPRSS2:ERG gene fusion. This new clinical trial will test that finding in patients. “In order to beat your enemy, you’ve got to understand it. We are getting closer and closer to understanding the enemy that is cancer,” Dr. Hussain added. n

Disclosure: The study is funded by National Cancer Institute grant N01-CM2011-00071C, U.S. Department of Defense grant PC080189, and the Prostate Cancer Foundation. The University of Michigan has received a patent on the detection of gene fusions in prostate cancer (US 7,718,369), on which faculty members Scott Tomlins, MD, PhD, and Arul Chinnaiyan, MD, PhD, are coinventors. The diagnostic field of use has been licensed to Gen-Probe Inc. Dr. Chinnaiyan also has a sponsored research agreement with Gen-Probe. Gen-Probe has no role in the design or experimentation of this study.

the mechanisms responsible for these patterns of association. n Disclosure: Dr. Phipps reported no potential conflicts of interest.

Reference 1. Phipps AI, Shi Q, Newcomb PA, et al: Associations between cigarette smoking status and colon cancer prognosis among participants in North Central Cancer Treatment Group phase III trial N0147. J Clin Oncol. April 1, 2013 (early release online).

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PAGE 86

Best of ASCO® Oncology Nursing Society Annual Congress Quality of Care

Attention to Patient Concerns Leads to Customized Treatment and Improved Care, Explains Oncology Nurse Researcher By Keegan Bales

he Mara Mogensen Flagherty Lecture at this year’s 38th Annual Congress of the Oncology Nursing Society in Washington, DC, focused on the importance of listening to and acknowledging the individual stories of patients with cancer and survivors. Once they are adept at listening, clini-

tients spend only a small slice of their life in the clinic. They have many identities outside of their disease. Within their communities, they are mothers and fathers, sons and daughters, workers and homeowners, and much more. These varied individualities shape how they experience cancer.

ties. We provide informed consent. We provide public and patient education. We have reams of educational material. But do we truly help patients navigate the decision? Do we prepare them for possible outcomes? And do we honor the parts of their lives that are not with us in that clinic?”

Tailored Information

The enormity of the task that patients have—to place their cancer experience and their journey in the context of their lives—that is so huge. —Donna L. Berry, PhD, RN, AOCN, FAAN

cians need to use this “sensitive ear” to improve care, said cancer nursing research expert Donna L. Berry, PhD, RN, AOCN, FAAN, Associate Professor of Medicine at Harvard Medical School and Director of the Phyllis F. Cantor Center for Research in Nursing & Patient Care Services at DanaFarber Cancer Institute, Boston.1 Dr. Berry’s “bottom line” was that oncology nurses need to create opportunities and the proper environment for people to express themselves about their health conditions and personal journey. She stressed that oncology nurses need to be active listeners and patient advocates. Her goal as a researcher is to “ask the questions that if answered would make a difference in how oncology clinicians practice,” she said.

Experience and Context “The enormity of the task that patients have—to place their cancer experience and their journey in the context of their lives—that is so huge,” she added. Dr. Berry acknowledged that pa-

Men with prostate cancer face the difficult decision of which treatment to undergo, but professionals cannot give them an absolute medical answer about the best intervention. Lifestyle, profession, personality, anxiety, intimate relationships, and other factors come into play. Many men later regret their treatment selection because of side effects about which they may have been unaware. Dr. Berry found that individuals of color were more likely to follow their first doctor’s treatment recommendation and not read any informational material, say, before surgery. However, studies have found that the more knowledgeable patients are, the more satisfied they are with their care. For example, those who used the Internet for additional information were more pleased with their treatment than those who did not. Accurate and accessible information relayed to patients clearly is essential, noted Dr. Berry. For most cancers, “there are menus of options,” Dr. Berry said. “Each one has its own set of potential outcomes, and each one has its set of uncertain-

Dr. Berry’s goal was to create an easy program that nurses could bring back to their clinics to help men with newly diagnosed localized prostate cancer pick a treatment. She and her colleagues at the University of Washington embarked upon a new study, developing an Internet-based decision-support system that could automatically generate tailored information to help men make their decision. This was a multisite clinical trial across the country. First, participants completed an online screener with a variety of questions. They had the option to answer at home. Then, coaching was customized based on patient responses as well as race and age. The investigators concluded that the tailored intervention significantly reduced patient-reported decisional conflict compared with traditional patient education methods. Dr. Berry noted that shrinking resources have left some nurses with little opportunity for interpersonal interaction with their patients. Emotional distress and related symptoms like insomnia often go unexplored.

Technology helps patients deal with issues that are awkward to discuss. A computer “never raises an eyebrow.” Patients were given language to use so that they would feel comfortable telling their doctor their exact symptom experiences. A helpful color-coded report was generated to tell doctors and nurses how the patient was doing and where to probe further. Dr. Berry’s symptom support system, the Electronic Self-Report Assessment-Cancer has been shown to significantly increase discussion of symptoms and reduce symptom distress during cancer therapy. Dr. Berry’s intervention not only teaches clinicians how to identify and address psychosocial and symptom issues, but also instructs patients how to engage in self-care activities outside the clinic. “You are going to continue to dig deeper until you find out the nature of the problem that is troubling the patient outside the clinic. And you will gather your resources to address it,” Dr. Berry encouraged the audience. “I know you will, because I know you.” n

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

Reference 1. Berry DL: Mara Mogensen Flagherty Lecture: The patient’s voice: Are we hard of hearing? Oncology Nursing Society Annual Congress. Presented April 27, 2013.

Mara Mogensen Flagherty Lecture

he annual memorial lecture is named for a remarkable patient with cancer who was the “model of survivorship,” sharing her story and helping others cope with the disease. The talk always focuses on a psychosocial aspect of cancer. Since its inception, over 125,000 nurses have attended Mara Mogensen Flagherty lectures. Ms. Flagherty, who lived for 14 years after her diagnoses, had a particular admiration and affection for oncology nurses. n

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Best of ASCO® Oncology Nursing Society Annual Congress Hematology

Genetically Modified T-cell Therapy for Patients with CLL: The Role of the Oncology Nurse By Keegan Bales

uality nursing and ongoing education are critical for success in using gene-modified T-cell therapy for patients with chronic lymphocytic leukemia (CLL), said Cheryl Caravano, RN, at the recent Annual Congress of the Oncology Nursing Society. Ms. Caravano is a clinical nurse IV at Memorial Sloan-Kettering Cancer Center in New York. “Nursing plays a pivotal role in delivering cutting-edge technology to the bedside,” Ms. Caravano said. In her presentation, she discussed the novel T-cell therapy, the nurse’s role in treatment of patients with CLL, and the multidisciplinary collaboration required in the care of outpatients receiving genetically modified T-cell therapy.

Education Key to Success

a crucial role in ensuring that this therapy was delivered to patients safely in the outpatient setting. Ms. Caravano explained that “cut-

ting-edge technologies [like geneB:7.875 will in modified T-cell therapy] likely be T:7.625 in delivered at the bedside by a nurse. It S:6.625 is of utmost importance toinincorporate

CLINICAL EVIDENCE INDICATES...

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

One goal of the project was to give oncology nurses the education tools and standard operating procedures needed to deliver excellent care to patients. The overall objective was to better understand how to use nursing to ensure safe T-cell treatment in an outpatient setting. All nurses in the infusion and office practice areas were educated on T-cell therapy for CLL, including administration of therapy, patient eligibility for treatment, potential side effects, and nursing interventions. Standard operating procedures were developed for infusion of genetically modified T cells and management of side effects. Before receiving outpatient treatment, patients were required to have had a partial or complete response with minimal residual disease after treatment with combination chemotherapy. Ms. Caravano reported that nursing played

BLOCK THE ANDROGEN RECEPTOR

s of the ONS Annual Congress, three patients at Memorial Sloan-Kettering Cancer Center had been successfully treated in the outpatient setting with genetically modified T cell therapy, without major events or readmissions to the hospital, reported study author Cheryl Caravano, RN. Ms. Caravano hopes that her study will serve as a model for oncology nurses involved in using T-cell treatment for CLL.

[nurses] into the multidisciplinary team and to provide nurses with the education and procedures necessary to provide quality care,” she said. n

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

The ASCO Post | JUNE 10, 2013

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Best of ASCO® Oncology Nursing Society Annual Congress Tailored Intervention Protocol for Oral Chemotherapy Adherence Studied By Keegan Bales

n a study testing the effectiveness of three strategies to improve oral chemotherapy adherence, tailored coaching was beneficial for some patients, reducing barriers to adherence, reported Susan M. Schneider, PhD, RN, AOCN, ACNS-BC, FAAN, Associate Professor and Director of Oncology Nursing Specialty at the Duke University School of Nursing, Durham, North Carolina, at the recent Oncology Nurses Society Annual Congress in Washington, DC.1 However, the differences between the study’s control and experimental groups were not significant. Patients with cancer prefer oral medications but do not always follow treatment instructions. Lack of understanding, inadequate support, and treatment-related side effects are leading reasons patients do not take their medication. Those who do adhere to their chemotherapy regimen have less recurrence and better long-term quality of life. “We can’t assume that patients will adhere to their oral chemotherapy regimen,” Dr. Schneider said. “They often need support to remain compliant. And helping patients tolerate oral

chemotherapy regimens is critical to their survival.”

Overcoming Personal Barriers Dr. Schneider and her colleagues designed a program based on a selfregulatory model of adherence. Patient knowledge, behavioral skills, and

Most patients were female with some college education. No correlation was found between adherence rates and age, gender, or depression. The control group received standard chemotherapy education, whereas the experimental group received an assessment and tailored intervention

We can’t assume that patients will adhere to their oral chemotherapy regimen. They often need support to remain compliant. —Susan M. Schneider, PhD, RN, AOCN, ACNS-BC, FAAN

support system are considered. Strategies are then conceived to overcome each patient’s personal barriers. The clinical trial examined the adherence rates of 48 adults started on a new oral chemotherapeutic agent. The patients were diagnosed with a range of cancers: breast, colorectal, renal cell, hepatocellular carcinoma, multiple myeloma, or chronic leukemia. The majority of patients were Caucasian. The average age was 60 years old.

delivered by an advanced practice nurse over the telephone in addition to the standard chemotherapy education. At 2 and 4 months, patient adherence rates were measured in both groups using self-reporting and pharmacy fill rates. Chi-squared tests were used to analyze the data.

Key Results “The differences between the intervention group and the control group

suggest that for some participants, the tailored coaching intervention was beneficial in promoting adherence,” Dr. Schneider said. At both the 2- and 4-month landmarks, by self-reporting, the intervention group showed greater adherence than the control group: 91% and 95% vs 80% and 82%. According to pharmacy refill data, however, adherence rates were lower: 80% and 74% vs 65% and 69%. Unexpectedly, the study found that system barriers, such as late pharmacy deliveries and lack of coordination by providers, interfered with adherence in 10% of participants. The study was funded by the National Cancer Institute, and the Duke group has submitted a follow-up proposal for funding. This new study would utilize a variety of coaching and electronic approaches to monitor medication adherence and symptom management. n

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

Reference 1. Schneider SM, et al: Tailored intervention protocol for oral chemotherapy adherence. Oncology Nursing Society Annual Congress. Presented April 26, 2013.

Mayo Clinic Genomic Analysis Lends Insight to Prostate Cancer

ayo Clinic researchers have used next-generation genomic analysis to determine that some of the more aggressive prostate cancer tumors have similar genetic origins, which may help in predicting cancer progression. The findings appeared online recently in the journal Cancer Research.1

Gleason Patterns “This is the first study to examine DNA alterations using next-generation sequencing in adjacent Gleason patterns in the same tumor allowing us to correlate genomics with changes in pathology,” said John Cheville, MD,

Mayo Clinic pathologist and one of the authors on the paper. The standard method of evaluating prostate cancer biopsy samples is a numerical scoring system called Gleason grading. A pathologist examines the tumor sample under the microscope, giving it a Gleason score based on the pattern of its cells. Since many prostate cancers contain more than one pattern, the two most common patterns are added together to provide the Gleason score. The Gleason score is the strongest predictor of outcome, with high scores indicating more aggressive prostate cancer.

Genetic Origins of Prostate Cancer ■ Gleason patterns 3 and 4 shared identical breakpoints, which implies a common origin.

■ By understanding lineage relationships within a tumor, physicians may be

better able to predict progression of the cancer and better manage patients.

Study Details This study focused on Gleason patterns of 3 and 4 (Gleason score 7), a combination that indicates a cancer with increased risk of progression. “While each pattern had its own breakpoints, they shared identical ones, which implies a common origin,” Dr. Cheville said. DNA changes associated with aggressive prostate cancer were identified in the lower Gleason pattern, indicating that genomic changes occurred before they could be recognized by a pathologist. By understanding these lineage relationships within a tumor, he said, physicians will be better able to predict progression of the cancer and, in turn, better manage patients including those who chose active surveillance and no treatment. To determine relationships among the Gleason patterns of each tumor sample the team used laser capture microdissection, whole genome am-

plification, and next-generation sequencing. They examined 14 tumors and found over 3,000 unique chromosomal alterations among all tumors and 300 that appeared in at least two of the tumors. They also found that Gleason pattern 3 in each tumor had more alterations in common with its corresponding Gleason pattern 4 than it did with Gleason pattern 3 from other patients. n

Disclosure: The research was supported by a Waterman Biomarker Discovery grant; and by the Center for Individualized Medicine, the Office of Intellectual Property, and the Department of Laboratory Medicine and Pathology, all at Mayo Clinic. Tissue samples were provided by the National Institutes of Health.

Reference 1. Kovtun IV, Cheville JC, Murphy SJ, et al: Lineage relationship of Gleason patterns in Gleason score 7 prostate cancer. Cancer Res. May 21, 2013 (early release online).

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Announcements

American Association for Cancer Research CEO Recognized with Prestigious Award from Fox Chase Cancer Center

argaret Foti, PhD, MD (hc), Chief Executive Officer of the American Association for Cancer Research (AACR), was honored with the 2013 Stanley P. Reimann Honor Award for her deep and far-reaching contributions to cancer science and medicine at a celebration hosted by Fox Chase Cancer Center, held recently in Philadelphia. “I am deeply honored and humbled

research and patient advocates in the United States and more than 90 other countries. Dr. Foti’s efforts to accelerate the dissemination of new research findings

among scientists and others dedicated to the conquest of cancer have included the launch of seven peer-reviewed scientific journals: Cancer Discovery; Clinical Cancer Research; Molecular

Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; Cancer Prevention Research; and Cancer Immunology Research. n

Margaret Foti, PhD, MD (hc)

to receive the 2013 Stanley P. Reimann Honor Award,” said Dr. Foti. “Dr. Riemann was a true pioneer in the cancer research community. His vision and commitment to discovery and collaborative science continue to define the cutting-edge research program conducted at the Fox Chase Cancer Center. The Stanley P. Reimann Honor Award is bestowed by Fox Chase Cancer Center to individuals from different spheres of influence who bring exceptional ingenuity and expertise to the cancer cause. Previous awardees include Nancy Brinker, C. Everett Koop, Frank Rauscher Jr, and Baruch S. Blumberg. The award was established to perpetuate the memory of Stanley P. Reimann, MD, the founder of the Institute for Cancer Research, which merged with the American Oncologic Hospital to form Fox Chase Cancer Center in 1974.

AACR Career Highlights Dr. Foti became CEO of the AACR in 1982. Working collaboratively with the elected officers of the AACR, she has provided the continuity of leadership that has been critical to the association’s progress and its mission to prevent and cure cancer. During her tenure, the AACR’s membership has grown from about 3,000 to 34,000 laboratory, translational, and clinical researchers; health-care professionals; students; cancer survivors; and

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

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Integrative Oncology Ginger

By Jyothirmai Gubili, MS Editor, Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center Scientific name: Zingiber officinale Common names: Ginger root, shen jian

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

Integrative Oncology is compiled by Barrie R. Cassileth, MS, PhD, and Jyothirmai Gubili, MS, Memorial Sloan-Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, LAc, Memorial Sloan-Kettering Cancer Center.

Overview The rhizome or the underground stem of the plant Zingiber officinale, ginger has been used as a culinary spice and medicine in Asian and Arabic traditions for thousands of years.

Native to Asia, ginger is used to treat a range of ailments including the common cold, headache, fevers, and gastrointestinal and inflammatory disorders.

Fresh ginger is used in cooking and for preparing tea. Both fresh and dried forms of ginger are marketed in the form of extracts, tinctures, oils, and capsules. Current evidence supports the effectiveness of ginger in controlling nausea and vomiting following surgery and associated with pregnancy and motion sickness. However, its therapeutic value against chemotherapy-induced nausea and vomiting await more definitive data.

The Science

Ginger has demonstrated antiemetic,1 anticancer,2-4 anti-inflammatory,5 and hypoglycemic5 effects in vitro, and may protect against Alzheimer’s disease.6 Shogaol and gingerol, two bioactive constituents of ginger, are thought responsible for its antiemetic properties.1

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial SloanKettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective Barrie R. Cassileth, MS, PhD and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan-Kettering Cancer Center’s very first mobile application, was launched last fall. In the week following its release on September 21, the app was downloaded more than 6,300 times, making it #4 on the top new medical apps chart. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http:// itunes.apple.com/us/app/about-herbs/id554267162?mt=8. Clinical trials indicate that ginger can effectively reduce nausea and vomiting due to pregnancy,7,8 motion sickness,9 and following surgery.10 But data on its efficacy in preventing chemotherapy-induced nausea are conflicting.11,12

OF NOTE Ginger is a popular supplement used to relieve chemotherapy-induced nausea and vomiting. Oncologists should be aware of its potential interactions with certain prescription drugs.

A systematic review found moderate efficacy for the use of ginger in treating osteoarthritic and chronic low back pain.13 Ginger can also influence gastric emptying in healthy individuals.14

Adverse Effects

Elevated international normalized ratio (INR) and epistaxis were reported in a patient on long-term phenprocoumon therapy, following use of ginger products.15

Herb-Drug Interactions

Anticoagulants/antiplatelets: Ginger inhibits thromboxane formation and platelet aggregation.

Learn More About

Herbs, Botanicals, & Other Products Visit the About Herbs website at

www.mskcc.org/aboutherbs

ASCOPost.com | JUNE 10, 2013

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Integrative Oncology Therefore, concomitant use with anticoagulants may increase the risk of bleeding.16 Hypoglycemics/insulin: Studies in mice indicate that ginger has hypoglycemic effects. Therefore, concurrent use with hypoglycemics may result in greater reduction in blood glucose levels.5 Tacrolimus (an immunosuppressive agent): Pretreatment with ginger increased plasma levels of tacrolimus in a study of rats.17 n References 1. Haniadka R, Rajeev AG, Palatty PL, et al: Zingiber officinale (ginger) as an anti-emetic in cancer chemotherapy: a review. J Altern Complement Med 18:440444, 2012. 2. Hessien M, El-Gendy S, Donia T, et al: Growth inhibition of human non-small lung cancer cells h460 by green tea and ginger polyphenols. Anticancer Agents Med Chem 12:383-390, 2012. 3. Ishiguro K, Ando T, Maeda O, et al: Ginger ingredients reduce viability of gastric cancer cells via distinct mechanisms. Biochem Biophys Res Commun 362:218-223, 2007. 4. Lee SH, Cekanova M, Baek SJ: Multiple mechanisms are involved in 6-gingerolinduced cell growth arrest and apoptosis in human colorectal cancer cells. Mol Carcinog 47:197-208, 2008. 5. Ojewole JA: Analgesic, antiinflammatory and hypoglycaemic effects of ethanol extract of Zingiber officinale (Roscoe) rhizomes (Zingiberaceae) in mice and rats. Phytother Res 20:764-772, 2006. 6. Lee C, Park GH, Kim CY, et al: [6]-Gingerol attenuates β-amyloid-induced oxidative cell death via fortifying cellular antioxidant defense system. Food Chem Toxicol 49:1261-1269, 2011. 7. Smith C, Crowther C, Willson K, et al: A randomized controlled trial of ginger to treat nausea and vomiting in pregnancy. Obstet Gynecol 103:639-645, 2004. 8. Ding M, Leach M, Bradley H: The effectiveness and safety of ginger for pregnancy-induced nausea and vomiting: A systematic review. Women Birth 26:e26-e30, 2013. 9. Lien HC, Sun WM, Chen YH, et al: Effects of ginger on motion sickness and gastric slowwave dysrhythmias induced by circular vection. Am J Physiol Gastrointest Liver Physiol 284:G481-G489, 2003. 10. Nanthakomon T, Pongrojpaw D: The efficacy of ginger in prevention of postoperative nausea and vomiting after major gynecologic surgery. J Med Assoc Thai 89(suppl 4):S130-S136, 2006. 11. Ryan JL, Heckler CE, Roscoe JA, et al: Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: A URCC CCOP study of 576 patients. Support Care Cancer 20:1479-1489, 2012. 12. Zick SM, Ruffin MT, Lee J, et al:

Phase II trial of encapsulated ginger as a treatment for chemotherapy-induced nausea and vomiting. Support Care Cancer 17:563-572, 2009. 13. Chrubasik JE, Roufogalis BD, Chrubasik S: Evidence of effectiveness of herbal antiinflammatory drugs in the treatment of painful osteoarthritis and chronic low back pain. Phytother Res 21:675-683, 2007.

14. Wu KL, Rayner CK, Chuah SK, et al: Effects of ginger on gastric emptying and motility in healthy humans. Eur J Gastroenterol Hepatol 20:436-440, 2008. 15. Krüth P, Brosi E, Fux R, et al: Ginger-associated overanticoagulation by phenprocoumon. Ann Pharmacother 38:257-260, 2004. B:7.875 in T:7.625L, in Richardson 16. Shalansky S, Lynd S:6.625 in K, et al: Risk of warfarin-related bleed-

ing events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: a longitudinal analysis. Pharmacotherapy 27:1237-1247, 2007. 17. Egashira K, Sasaki H, Higuchi S, et al: Food-drug interaction of tacrolimus with pomelo, ginger, and turmeric juice in rats. Drug Metab Pharmacokinet 27:242247, 2012.

In mCRPC, is it appropriate to

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

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Expert’s Corner Genomics

Making Prevention and Early Detection of Cancer a Priority A Conversation with Bert Vogelstein, MD By Jo Cavallo of his early research on genomic sequencing, and his current investigations of the prevention and early detection of cancer.

Current Research

Bert Vogelstein, MD

onquering cancer has been the goal of Bert Vogelstein, MD, since he was a teenager in Baltimore. For more than 3 decades, Dr. Vogelstein, Co-Director of the Ludwig Center for Cancer Genetics and Therapeutics and Investigator of the Howard Hughes Medical Institute at Johns Hopkins Medical Institution, has been at work researching the molecular changes that drive malignant tumor initiation and progression. In 1989, Dr. Vogelstein’s studies of colorectal cancer led to his discovery that p53—believed to be an oncogene—was actually a tumor-suppressor gene on chromosome 17p. That research led to the understanding that p53 was involved not just in the development of colon cancer but in most types of cancer. In February, Dr. Vogelstein was recognized for this early discovery and for his life’s achievements in cancer research with a $3 million Breakthrough Prize in Life Sciences award. The award—which also acknowledged the work of 10 other scientists, many of whom have also done research in the genetics of malignant cell growth— was established by a group of Silicon Valley entrepreneurs, including Anne Wojcicki, the founder of the genetics company 23andMe. Ms. Wojcicki told The New York Times that the prize is meant to reward scientists “who think big, take risks, and have made a significant impact on our lives.” (For a complete list of award winners, see “Inaugural Winners of $3 million Breakthrough Prize in Life Sciences Announced,” at ASCOPost.com.) Recently, The ASCO Post talked with Dr. Vogelstein about how he will use his $3 million prize, the impact

There are no restrictions on how you can spend your $3 million Breakthrough Prize in Life Sciences award. How do you plan to use the money? Some of the money will go to pay for my grandchildren’s education, some will go to support my wife’s passion, which is in early childhood education, and some of it will go to support my current research. What is the focus of your current research? Our laboratory is trying to develop genetic tests for the early detection of cancer. One of the major outcomes of the revolution in cancer research is an elucidation of the genetic alterations that are responsible for the onset and

One example is a test that Luis Diaz, Jr, MD [Director of Translational Medicine], Kenneth W. Kinzler, PhD [Professor of Oncology], Isaac Kinde [MD-PhD candidate], and others in our lab developed called the PapGene test. This test relies on the sequencing of DNA obtained from routine Pap tests to detect ovarian and endometrial cancers. Historically, Pap tests have been remarkably successful in the early detection of cervical cancer, and we reasoned that the same specimens might also be used to search for endometrial and ovarian cancers. In particular, we hoped that neoplastic cells from the ovary or the uterine body would lodge in the cervix and be scraped off as part of a routine Pap test. This turned out to be true. In a pilot study, the PapGene test accurately detected all 24 endometrial cancers (100%) and 9 of 22 (41%) ovarian cancers.1 The next step will be

Cancer is no longer a black box. The path forward is clear, and I think that path needs to be followed, not only for its therapeutic implications, but also for its implications for cancer prevention and early detection. —Bert Vogelstein, MD

progression of cancer. These studies began in the 1980s, and in the past 6 or 7 years have reached a new level by virtue of the ability to examine all the genes at once. Through these genomewide studies, our team and others have found that there is a small group of common genes and pathways that are altered in different cancers. In addition to their value for potential therapeutics, we believe that these genes and pathways are equally valuable for their capacity to serve as new diagnostic tools. These tools can be used to track treatment effectiveness, and most importantly, as biomarkers to detect cancers when they are still curable by surgery and adjuvant therapy.

PapGene Test How will the discovery of the mutations in cancer cells be used to improve the early detection of cancer?

to extend the test to a larger number of women and validate it. If validated, it might be used to detect uterine and ovarian cancers at a stage when they can be cured by surgery or adjuvant therapy. We are trying to develop similar gene sequence–based tests for gastrointestinal cancer through the examination of stool, bladder and kidney cancers through the examination of urine, lung cancer through the examination of sputum, and other cancers through the analysis of plasma. In the long run, we believe that the best way to reduce cancer morbidity and mortality is through prevention and early detection. Most major advances in public health come from prevention rather than cure. Plan A should be prevention and early detection, and Plan B, cure, which is, of course, important but should only be followed when Plan A fails. Right now

there’s much more emphasis and funding devoted to Plan B than Plan A, and I hope that there can be more of a balance between the two in the future.

Potential Impact What impact would prevention measures and earlier detection have on cancer mortality? An article published in Science Translational Medicine2 a year ago showed that if what we know today about the modifiable causes of cancer—such as tobacco smoking, obesity, and physical inactivity—were widely appreciated and acted upon, cancer deaths could be reduced by more than 50%. I think that early detection of cancer has the capacity to easily reduce cancer deaths by 50%. So, if you combine the information that we already know about cancer prevention and early detection and these measures are implemented, I think it’s feasible to reduce cancer deaths in the next few decades by three-quarters. And that’s exclusive of advances in therapy that may allow further reductions in deaths. While there is obviously still much to be learned, I think we now know at least the outline of cancer pathogenesis, particularly its genetic underpinnings. Cancer is no longer a black box. The path forward is clear, and I think that path needs to be followed, not only for its therapeutic implications, but also for its implications for cancer prevention and early detection. n

Disclosure: Dr. Vogelstein is a founder of Personal Genome Diagnostics, Inc, a company focused on the identification of genetic alterations in human cancer for diagnostic and therapeutic purposes. He is also a member of the Scientific Advisory Board of Inostics, a company that is developing technologies for the molecular diagnosis of cancer using plasma samples. These companies and others have licensed several patent applications from Johns Hopkins, on which Vogelstein is an inventor. The terms of these arrangements are being managed by the university, in accordance with its conflict of interest policies.

References 1. Kinde I, Bettegowda C, Wang Y, et al: Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers. Sci Transl Med 5:167ra4, 2013. 2. Colditz G, Wolin KY, Gehlert S, et al: Applying what we know to accelerate cancer prevention. Sci Transl Med 4:127rv4, 2012.

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News

American Cancer Society Marks 100th Year Anniversary A Century Later: Progress and Next Steps

he American Cancer Society announced the Society’s 100th birthday on May 22, 2013. Founded 100 years ago by 15 prominent physicians and business leaders in New York, the American Cancer Society, first known as the American Society for the Control of Cancer, launched the fight against a disease then considered a death sentence. A century later, the American Cancer Society observes 100 years of progress; this year saw a 20% decline in cancer death rates since the 1990s according to the Society’s latest Cancer Facts & Figures.1

The New Reality Today, two out of three people diagnosed with cancer are surviving the disease for 5 years or longer. More than 400 people a day in the United States are celebrating birthdays that would have otherwise been lost to cancer. “In 1970, it was projected that cancer incidence and mortality would continue to rise beyond the

we are looking to put ourselves out of business by making it cancer’s last century,” he said.

Services for Patients and Families

Vincent T. DeVita, Jr., MD

year 2000,” said Vincent T. DeVita, Jr, MD, National Volunteer President of the American Cancer Society. “Today, not only have mortality rates declined since the early 1990s, but we’re averting more than 400 cancer deaths every day. Due in part to the work of the American Cancer Society, what seemed nearly impossible is now reality.” “We began our fight against cancer at a time when the word ‘cancer’ was rarely mentioned in public,” said John R. Seffrin, Chief Executive Officer of the American Cancer Society. “In our 100 years of existence, we have contributed to many groundbreaking discoveries that have brought us closer to understanding, preventing and treating the disease, and this century,

The American Cancer Society has funded researchers that have contributed to nearly every major cancer research breakthrough; helped establish the link between cancer and smoking; and contributed to a 50% decline in

smoking rates. The Society continues to help cancer patients get the help they need through services like the 1-800-227-2345 help line, free lodging for patients and their families traveling for treatment, and free rides to and from treatment. The American Cancer Society is using its 100th birthday on May 22nd to encourage people to join together, make noise, and take action to finish the fight against cancer. n

How to Help

he American Cancer Society encourages all to assist in efforts to fight cancer by: • Donating at cancer.org/fight • Participating in a local Relay For Life or Making Strides Against Breast Cancer walk in their community • Enrolling in its Cancer Prevention Study-3 to find better ways to prevent cancer. • Creating a “life list” with the American Cancer Society’s Facebook application • Taking a “Moment Against Silence” by pledging to do one thing to help finish the fight against cancer

Reference 1. Cancer Facts & Figures 2013. American Cancer Society, 2013.

Gold Nanoparticles Can Help Fight Ovarian Cancer

ositively charged gold nanoparticles are usually toxic to cells, but cancer cells somehow manage to avoid nanoparticle toxicity. Mayo Clinic researchers found out why and determined how to make the nanoparticles effective against ovarian cancer cells. The discovery is detailed in the current online issue of the Journal of Biological Chemistry.1

“This study identifies a novel mechanism that protects ovarian cancer cells by preventing the cell death, or apoptosis, which should occur when they encounter positively charged nanoparticles,” said the senior authors of this study, Priyabrata Mukherjee, PhD, a Mayo Clinic molecular biologist, and Y.S. Prakash, MD, PhD, a Mayo Clinic anesthesiologist and physiologist.

Novel Mechanisms in Treating Ovarian Cancer ■ Positively charged gold nanoparticles kill cells by causing cellular calcium ion levels to increase, but a regulatory protein in the mitochondria of ovarian cancer cells transports the rising calcium into the mitochondria, thus subverting apoptosis.

■ If calcium uptake into the mitochondria is inhibited, sufficient cellular stress builds up, making the gold nanoparticles more effective in destroying cancer cells.

Why Cancer Cells Survived Gold nanoparticles can have many medical uses, from imaging and aiding diagnoses to delivering therapies. In this case, using a special preparation to put positive ionic charges on the surface, the nanoparticle is intended to act as a targeted destructor of tumor cells while leaving healthy cells alone. The nanoparticles are supposed to kill cells by causing cellular calcium ion levels to increase. But researchers discovered that a regulatory protein in the mitochondria essentially buffers the rising calcium by transporting it into the mitochondria, thus subverting cell death. Cancer cells have an abundance of this transporter and may thus be protected from nanoparticle toxicity. The research team discovered that

if they inhibit calcium uptake into the mitochondria, sufficient cellular stress builds up, making the gold nanoparticles more effective in destroying cancer cells. The researchers say that understanding how mitochondrial transport mechanisms work will help in the design of targeted therapies against cancer. They called for nanoparticle developers to integrate this new mechanistic knowledge into their processes for designing nanoparticle properties to be used in therapy. n Reference 1. Arvizo RR, Moyano DF, Saha S, et al: Probing novel roles of the mitochondrial uniporter in ovarian cancer cells using nanoparticles. J Biol Chem. April 24, 2013 (early release online).

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The ASCO Post | JUNE 10, 2013

Announcements

University of New Mexico Health Sciences and Cancer Centers Recruit Four Cancer Experts to Top Positions

he University of New Mexico Health Sciences Center and the University of New Mexico Cancer Center, Albuquerque, recently announced the recruitment of four cancer physicians and scientists. The UNM Cancer Center is the Official Cancer Center of the State of New Mexico and one of the nation’s 60 National Cancer Institute (NCI)-Designated Cancer Centers. Joining the UNM Cancer Center and UMN School of Medicine are: Wadih Arap, MD, PhD, and Renata Pasqualini, PhD, recruited from The University of Texas MD Anderson Cancer Center in Houston; Martin J. Edelman, MD, FACP, recruited from the University of Maryland Greenebaum Cancer Center in Baltimore; and Anita Kinney, PhD, recruited from the Huntsman Cancer Center at the University of Utah. “These four world-renowned experts in cancer prevention, diagnosis, treatment, and the development of new cancer drugs and therapies will take the outstanding cancer research and treatment programs at the UNM Cancer Center to a whole new level,” said Cheryl Willman, MD, Director and CEO of the UNM Cancer Center, and the Maurice and Marguerite Liberman Distinguished Chair in Cancer Research. “We are absolutely thrilled to have them join our team. Their expertise will not only greatly benefit New Mexicans in their fight against cancer, but their success in the discovery of new cancer drugs and the development of new biotechnology companies will spur New Mexico’s economic development.”

Wadih Arap, MD, PhD Wadih Arap, MD, PhD will join UNM as the new Deputy Director of the UNM Cancer Center and Chief of the Division of Hematology/Oncology in the Department of Internal Medicine in the School of Medicine. He will hold the Victor and Ruby Hansen Surface Endowed Chair in Cancer Medicine. Currently the Stringer Professor of Medicine and Experimental Diagnostic Imaging and Deputy Chair of the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine at MD Anderson Cancer Center, Dr. Arap earned his MD degree from the University of São Paulo Medi-

cal School in Brazil and completed his clinical training at Memorial Sloan-Kettering Cancer Center in New York. He earned his PhD in Cancer Biology from Stanford University and the Ludwig Institute for Cancer Wadih Arap, MD, PhD Renata Pasqualini, PhD Martin J. Edelman, MD, FACP Anita Kinney, PhD Research in La Jolla. During his 14-year tenure at MD School and the Dana-Farber Cancer baum Cancer Center, Dr. Edelman Anderson, Dr. Arap gained internaInstitute in Boston and at the Sanearned his medical degree from The Altional recognition for his expertise in ford-Burnham Medical Research Inbany Medical College and completed the treatment of prostate cancer. His stitute in San Diego. his clinical training at the Naval Mediresearch focused on the development During her 14-year tenure at MD cal Center, San Diego. Following active of new cancer drugs and therapies that Anderson, Dr. Pasqualini has won inmilitary service, he held faculty posicould be precisely targeted to cancer ternational acclaim for her scientific tions at the University of California at cells. His research, supported by the contributions in cancer biology and Davis and the VA Northern California National Institutes of Health, the Dedrug development. Working with her Health Care System before joining the partment of Defense, and several philhusband, Dr. Arap, in their joint laboraUniversity of Maryland. anthropic foundations, has led to over tory program, she has developed novel Anita Kinney, PhD 60 patents worldwide and the publicadiagnostic and imaging tools for cancer Anita Kinney, Ph.D., will join UNM tion of over 150 scientific studies. and obesity. as a Professor of Internal Medicine and Renata Pasqualini, PhD Martin J. Edelman, MD, FACP as the new Associate Director for CanRenata Pasqualini, PhD, will join Martin J. Edelman, MD, FACP, will cer Control and Population Sciences UNM as the new Associate Director join UNM as a Professor of Hematolin the UNM Cancer Center. Holding for Translational Research. She will ogy/Oncology in the Department of the Victor and Ruby Hansen Surface Endowed Chair in Cancer Population Sciences, Dr. Kinney will also assist in These four world-renowned experts in cancer the development of the new College of prevention, diagnosis, treatment, and the development Public Health at UNM. She is currently a Professor of Interof new cancer drugs and therapies will take the nal Medicine in the Division of Epideoutstanding cancer research and treatment programs at miology, Leader of the Cancer Control and Population Sciences Program, and the UNM Cancer Center to a whole new level. a Jon and Karen Huntsman Presiden—Cheryl Willman, MD tial Professor in Cancer Research at Huntsman Cancer Institute and the co-lead the UNM Cancer Center’s Internal Medicine. He will be the new University of Utah. Dr. Kinney first Program in Experimental Therapeutics Associate Director for Clinical Reearned degrees in Nursing from Seton and Drug Discovery with Larry Sklar, search at the UNM Cancer Center and Hall University and the University of PhD, Distinguished Regents Professor will co-lead the UNM Cancer Center’s Pennsylvania. She earned her doctorof Pathology. Dr. Pasqualini will be a Program in Lung Cancer and Aerodiate in Epidemiology from the UniverProfessor in the Department of Intergestive Malignancies with Stephen sity of Texas School of Public Health nal Medicine and will hold the MaraBelinsky, PhD, of the Lovelace Respiin Houston. She completed a National lyn S. Budke Endowed Chair in Cancer ratory Research Institute. Dr. Edelman Cancer Institute–funded postdoctoral Experimental Therapeutics. will also lead the New Mexico Cancer fellowship in epidemiology and canCurrently the Helen Buchanan & Care Alliance, a collaborative statewide cer control at the University of North Stanley Seeger Professor of Medicine cancer clinical trials network between Carolina-Chapel Hill. and Experimental Diagnostic Imagthe UNM Cancer Center and several Dr. Kinney is a population sciening in the Division of Cancer Medicommunity health-care systems. He tist. During her 15-year tenure at the cine at MD Anderson Cancer Center, will hold the Victor and Ruby Hansen University of Utah, she has received she earned her PhD in Biochemistry Surface Endowed Chair in Clinical international recognition for work in from the Ludwig Institute for Cancer Cancer Research. cancer prevention and control, disResearch and the Institute of ChemCurrently Professor of Medicine, parities and behavioral epidemiology. istry at the University of São Paulo, Director of the Solid Tumor Oncology, She has published over 150 scientific Brazil. Dr. Pasqualini completed her and Director of Thoracic Oncology at articles and abstracts, and has won research training at Harvard Medical the University of Maryland’s Greenenumerous awards. n

When hemoglobin falls...

Catch hemoglobin levels before they fall too far Reduce RBC transfusions and achieve a gradual and steady Hb rise with Aranesp

®1-4

• In untreated patients whose Hb fell below 10 g/dL, 1 in 3 required an RBC transfusion within 6 weeks.5* • Aranesp® significantly reduced the need for RBC transfusions by 48% compared to placebo.2,3† • Aranesp® can be synchronized with the majority of chemotherapy regimens, including Q3W.6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa ACC trials. Patients had baseline Hb ≥ 10 g/dL and decline to Hb < 10 g/dL at least once during the study-treatment period. Kaplan-Meier (K-M) estimates were calculated for the incidence of patients with transfusions by Weeks 0, 3, 6, and 9 after Hb < 10 g/dL was reached. Seventy-two percent of patients had lung cancer.5 †Data from a randomized, double-blind, placebo-controlled trial of 314 anemic (Hb ≤ 11 g/dL) patients with lung cancer receiving platinum-containing chemotherapy. Patients received once-weekly treatment with either Aranesp® (2.25 mcg/kg) or placebo, administered by subcutaneous injection, for up to 12 weeks. Per the pivotal trial protocol, doses were withheld if Hb exceeded 14 g/dL for women or 15 g/dL for men.2,3

Aranesp® (darbepoetin alfa) Indication Aranesp® is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

Limitations of Use: Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp® is not for use: • In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. • In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure. • As a substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia.

References: 1. Vansteenkiste J, Hedenus M, Gascon P, et al. BMC Cancer. 2009;9:311. doi:10.1186/1471-2407-9-311. 2. Aranesp® (darbepoetin alfa) Prescribing Information, Amgen. 3. Vansteenkiste J, Pirker R, Massuti B, et al. J Natl Cancer Inst. 2002;94:1211-1220. 4. Canon JL, Vansteenkiste J, Bodoky G, et al. J Natl Cancer Inst. 2006;98:273-284. 5. Pirker R, Collins H, Legg J, et al. J Clin Oncol. 2011;29(suppl). Abstract e19637. 6. Data on file, Amgen; [Tandem Anti-cancer and Tumor Audit].

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799 www.amgen.com

RBC = red blood cell.

Hb = hemoglobin.

Q3W = once every three weeks.

Important Safety Information including Boxed WARNINGS for Aranesp® (darbepoetin alfa) WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, Aranesp® dose, or dosing strategy that does not increase these risks. • Use the lowest Aranesp® dose sufficient to reduce the need for red blood cell (RBC) transfusions. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. • Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/ or dispense Aranesp® to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions. • Use ESAs only for anemia from myelosuppressive chemotherapy. • ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. • Discontinue following the completion of a chemotherapy course. • Aranesp® is contraindicated in patients with: − Uncontrolled hypertension − Pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other erythropoietin protein drugs − Serious allergic reactions to Aranesp®

• In controlled clinical trials of patients with cancer, Aranesp® and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures. • Control hypertension prior to initiating and during treatment with Aranesp®. • For lack or loss of hemoglobin response to Aranesp®, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. • Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp®. − This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. − PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Aranesp® is not approved). − If severe anemia and low reticulocyte count develop during treatment with Aranesp®, withhold Aranesp® and evaluate patients for neutralizing antibodies to erythropoietin. − Permanently discontinue Aranesp® in patients who develop PRCA following treatment with Aranesp® or other erythropoietin protein drugs. Do not switch patients to other ESAs. • Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp®. Immediately and permanently discontinue Aranesp® if a serious allergic reaction occurs. • Adverse reactions (≥ 1%) in clinical studies in cancer patients receiving chemotherapy were abdominal pain, edema, and thrombovascular events. Please see Aranesp® brief summary of prescribing information, including Boxed WARNINGS, on the adjacent page. Visit Aranesp.com for more information.

BRIEF SUMMARY: Consult package insert for complete prescribing information. Aranesp┬о (darbepoetin alfa) Injection, for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: t *O DPOUSPMMFE USJBMT QBUJFOUT FYQFSJFODFE HSFBUFS SJTLT GPS EFBUI TFSJPVT BEWFSTF DBSEJPWBTDVMBS SFBDUJPOT BOE TUSPLF XIFO BENJOJTUFSFE FSZUISPQPJFTJT TUJNVMBUJOH BHFOUT &4"T UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- t /P USJBM IBT JEFOUJmFE B IFNPHMPCJO UBSHFU MFWFM "SBOFTQ EPTF PS EPTJOH TUSBUFHZ UIBU EPFT OPU JODSFBTF UIFTF SJTLT t 6TF UIF MPXFTU "SBOFTQ EPTF TVGmDJFOU UP SFEVDF UIF OFFE GPS SFE CMPPE cell (RBC) transfusions. Cancer: t &4"T TIPSUFOFE PWFSBMM TVSWJWBM BOE PS JODSFBTFE UIF SJTL PG UVNPS QSPHSFTTJPO PS SFDVSSFODF JO DMJOJDBM TUVEJFT PG QBUJFOUT XJUI CSFBTU OPO TNBMM DFMM MVOH IFBE BOE OFDL MZNQIPJE BOE DFSWJDBM DBODFST t #FDBVTF PG UIFTF SJTLT QSFTDSJCFST BOE IPTQJUBMT NVTU FOSPMM JO BOE DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS 5P FOSPMM JO UIF &4" "113*4& 0ODPMPHZ 1SPHSBN WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF t 5P EFDSFBTF UIFTF SJTLT BT XFMM BT UIF SJTL PG TFSJPVT DBSEJPWBTDVMBS BOE UISPNCPFNCPMJD SFBDUJPOT VTF UIF MPXFTU EPTF OFFEFE UP BWPJE RBC transfusions. t 6TF &4"T POMZ GPS BOFNJB GSPN NZFMPTVQQSFTTJWF DIFNPUIFSBQZ t &4"T BSF OPU JOEJDBUFE GPS QBUJFOUT SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF BOUJDJQBUFE PVUDPNF JT DVSF t %JTDPOUJOVF GPMMPXJOH UIF DPNQMFUJPO PG B DIFNPUIFSBQZ DPVSTF

INDICATION AND USAGE "OFNJB %VF UP $IFNPUIFSBQZ JO 1BUJFOUT 8JUI $BODFS Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp is not indicated for use: t *O QBUJFOUT XJUI DBODFS SFDFJWJOH IPSNPOBM BHFOUT CJPMPHJD QSPEVDUT or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. t *O QBUJFOUT XJUI DBODFS SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF anticipated outcome is cure. t "T B TVCTUJUVUF GPS 3#$ USBOTGVTJPOT JO QBUJFOUT XIP SFRVJSF JNNFEJBUF correction of anemia.

CONTRAINDICATIONS

Aranesp is contraindicated in patients with: t 6ODPOUSPMMFE IZQFSUFOTJPO t 1VSF SFE DFMM BQMBTJB 13$" UIBU CFHJOT BGUFS USFBUNFOU XJUI "SBOFTQ PS PUIFS erythropoietin protein drugs. t 4FSJPVT BMMFSHJD SFBDUJPOT UP "SBOFTQ

WARNINGS AND PRECAUTIONS *ODSFBTFE .PSUBMJUZ .ZPDBSEJBM *OGBSDUJPO 4USPLF BOE 5ISPNCPFNCPMJTN *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI $,% DPNQBSJOH IJHIFS IFNPHMPCJO UBSHFUT H E- UP MPXFS UBSHFUT H E- "SBOFTQ BOE PUIFS &4"T increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. 6TJOH "SBOFTQ UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- JODSFBTFT UIF SJTL of serious adverse cardiovascular reactions and has not been shown to provide BEEJUJPOBM CFOFmU 6TF DBVUJPO JO QBUJFOUT XJUI DPFYJTUFOU DBSEJPWBTDVMBS EJTFBTF BOE TUSPLF 1BUJFOUT XJUI $,% BOE BO JOTVGmDJFOU IFNPHMPCJO SFTQPOTF UP &4" UIFSBQZ may be at even greater risk for cardiovascular reactions and mortality than other QBUJFOUT " SBUF PG IFNPHMPCJO SJTF PG HSFBUFS UIBO H E- PWFS XFFLT NBZ DPOUSJCVUF to these risks. * O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI DBODFS "SBOFTQ BOE PUIFS &4"T increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. *O DPOUSPMMFE DMJOJDBM USJBMT &4"T JODSFBTFE UIF SJTL PG EFBUI JO QBUJFOUT VOEFSHPJOH DPSPOBSZ BSUFSZ CZQBTT HSBGU TVSHFSZ $"#( BOE UIF SJTL PG EFFQ WFOPVT UISPNCPTJT %75 JO QBUJFOUT VOEFSHPJOH PSUIPQFEJD QSPDFEVSFT 1BUJFOUT XJUI $BODFS An increased incidence of thromboembolic reactions, some serious and lifeUISFBUFOJOH PDDVSSFE JO QBUJFOUT XJUI DBODFS USFBUFE XJUI &4"T *O B SBOEPNJ[FE QMBDFCP DPOUSPMMFE TUVEZ TFF 4UVEZ JO 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO PG XPNFO XJUI NFUBTUBUJD CSFBTU DBODFS SFDFJWJOH DIFNPUIFSBQZ patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered UP QSFWFOU BOFNJB NBJOUBJO IFNPHMPCJO MFWFMT CFUXFFO BOE H E- PS IFNBUPDSJU CFUXFFO BOE 5IJT TUVEZ XBT UFSNJOBUFE QSFNBUVSFMZ XIFO JOUFSJN SFTVMUT EFNPOTUSBUFE B IJHIFS NPSUBMJUZ BU NPOUIT WT BOE B IJHIFS SBUF PG GBUBM UISPNCPUJD SFBDUJPOT WT JO UIF mSTU NPOUIT PG UIF TUVEZ BNPOH QBUJFOUT USFBUFE XJUI FQPFUJO BMGB #BTFE PO ,BQMBO .FJFS FTUJNBUFT BU UIF UJNF PG TUVEZ UFSNJOBUJPO UIF NPOUI TVSWJWBM XBT MPXFS JO UIF FQPFUJO BMGB HSPVQ UIBO JO UIF QMBDFCP HSPVQ WT )3 $* Q 1SFTDSJCJOH BOE %JTUSJCVUJPO 1SPHSBN GPS "SBOFTQ JO 1BUJFOUT 8JUI $BODFS *O PSEFS UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS BOE BOFNJB due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN SFRVJSFNFOUT 5P FOSPMM WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF "EEJUJPOBMMZ QSJPS UP each new course of Aranesp in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Aranesp.

*ODSFBTFE .PSUBMJUZ BOE PS *ODSFBTFE 3JTL PG 5VNPS 1SPHSFTTJPO PS 3FDVSSFODF JO 1BUJFOUT 8JUI $BODFS &4"T SFTVMUFE JO EFDSFBTFE MPDPSFHJPOBM DPOUSPM QSPHSFTTJPO GSFF TVSWJWBM BOE PS PWFSBMM TVSWJWBM 4FF 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO 5IFTF mOEJOHT XFSF observed in studies of patients with advanced head and neck cancer receiving SBEJBUJPO UIFSBQZ 4UVEJFT BOE JO QBUJFOUT SFDFJWJOH DIFNPUIFSBQZ GPS NFUBTUBUJD CSFBTU DBODFS 4UVEZ PS MZNQIPJE NBMJHOBODZ 4UVEZ BOE JO QBUJFOUT XJUI OPO small cell lung cancer or various malignancies who were not receiving chemotherapy PS SBEJPUIFSBQZ 4UVEJFT BOE Hypertension "SBOFTQ JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI VODPOUSPMMFE IZQFSUFOTJPO *O "SBOFTQ DMJOJDBM TUVEJFT BQQSPYJNBUFMZ PG QBUJFOUT XJUI $,% SFRVJSFE JOJUJBUJPO PS intensiямБcation of antihypertensive therapy during the early phase of treatment. )ZQFSUFOTJWF FODFQIBMPQBUIZ BOE TFJ[VSFT IBWF CFFO SFQPSUFE JO QBUJFOUT XJUI $,% receiving Aranesp. Appropriately control hypertension prior to initiation of and during treatment with "SBOFTQ 3FEVDF PS XJUIIPME "SBOFTQ JG CMPPE QSFTTVSF CFDPNFT EJGmDVMU UP DPOUSPM Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Seizures "SBOFTQ JODSFBTFT UIF SJTL PG TFJ[VSFT JO QBUJFOUT XJUI $,% %VSJOH UIF mSTU TFWFSBM months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for OFX POTFU TFJ[VSFT QSFNPOJUPSZ TZNQUPNT PS DIBOHF JO TFJ[VSF GSFRVFODZ Lack or Loss of Hemoglobin Response to Aranesp For lack or loss of hemoglobin response to Aranesp, initiate a search for causative GBDUPST F H JSPO EFmDJFODZ JOGFDUJPO JOnBNNBUJPO CMFFEJOH *G UZQJDBM DBVTFT PG MBDL PS MPTT PG IFNPHMPCJO SFTQPOTF BSF FYDMVEFE FWBMVBUF GPS 13$" *O UIF BCTFODF PG 13$" GPMMPX EPTJOH SFDPNNFOEBUJPOT GPS NBOBHFNFOU PG QBUJFOUT XJUI BO insufямБcient hemoglobin response to Aranesp therapy. Pure Red Cell Aplasia $BTFT PG 13$" BOE PG TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT UIBU BSJTF GPMMPXJOH UIF EFWFMPQNFOU PG OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO IBWF CFFO reported in patients treated with Aranesp. This has been reported predominantly in QBUJFOUT XJUI $,% SFDFJWJOH &4"T CZ TVCDVUBOFPVT BENJOJTUSBUJPO 13$" IBT BMTP CFFO SFQPSUFE JO QBUJFOUT SFDFJWJOH &4"T GPS BOFNJB SFMBUFE UP IFQBUJUJT $ USFBUNFOU BO JOEJDBUJPO GPS XIJDI "SBOFTQ JT OPU BQQSPWFE *G TFWFSF BOFNJB BOE MPX SFUJDVMPDZUF DPVOU EFWFMPQ EVSJOH USFBUNFOU XJUI "SBOFTQ XJUIIPME "SBOFTQ BOE FWBMVBUF QBUJFOUT GPS OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO $POUBDU "NHFO ".(&/ UP QFSGPSN BTTBZT GPS CJOEJOH BOE OFVUSBMJ[JOH BOUJCPEJFT 1FSNBOFOUMZ EJTDPOUJOVF "SBOFTQ JO QBUJFOUT XIP EFWFMPQ 13$" GPMMPXJOH USFBUNFOU XJUI "SBOFTQ PS PUIFS FSZUISPQPJFUJO QSPUFJO ESVHT %P OPU TXJUDI QBUJFOUT UP PUIFS &4"T Serious Allergic Reactions 4FSJPVT BMMFSHJD SFBDUJPOT JODMVEJOH BOBQIZMBDUJD SFBDUJPOT BOHJPFEFNB CSPODIPTQBTN TLJO SBTI BOE VSUJDBSJB NBZ PDDVS XJUI "SBOFTQ *NNFEJBUFMZ BOE permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs. Dialysis Management 1BUJFOUT NBZ SFRVJSF BEKVTUNFOUT JO UIFJS EJBMZTJT QSFTDSJQUJPOT BGUFS JOJUJBUJPO PG "SBOFTQ 1BUJFOUT SFDFJWJOH "SBOFTQ NBZ SFRVJSF JODSFBTFE BOUJDPBHVMBUJPO XJUI IFQBSJO UP QSFWFOU DMPUUJOH PG UIF FYUSBDPSQPSFBM DJSDVJU EVSJOH IFNPEJBMZTJT Laboratory Monitoring &WBMVBUF USBOTGFSSJO TBUVSBUJPO BOE TFSVN GFSSJUJO QSJPS UP BOE EVSJOH "SBOFTQ treatment. Administer supplemental iron therapy when serum ferritin is less than NDH - PS XIFO TFSVN USBOTGFSSJO TBUVSBUJPO JT MFTT UIBO 5IF NBKPSJUZ PG QBUJFOUT XJUI $,% XJMM SFRVJSF TVQQMFNFOUBM JSPO EVSJOH UIF DPVSTF PG &4" UIFSBQZ 'PMMPXJOH JOJUJBUJPO PG UIFSBQZ BOE BGUFS FBDI EPTF BEKVTUNFOU NPOJUPS IFNPHMPCJO XFFLMZ VOUJM UIF IFNPHMPCJO JT TUBCMF BOE TVGmDJFOU UP NJOJNJ[F UIF OFFE GPS 3#$ transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

ADVERSE REACTIONS $MJOJDBM 5SJBM &YQFSJFODF #FDBVTF DMJOJDBM USJBMT BSF DPOEVDUFE VOEFS XJEFMZ WBSZJOH DPOEJUJPOT BEWFSTF reaction rates observed in the clinical trials of a drug cannot be directly compared UP SBUFT JO UIF DMJOJDBM USJBMT PG PUIFS ESVHT BOE NBZ OPU SFnFDU UIF SBUFT PCTFSWFE in practice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tudy Adverse Reaction 5ISPNCPFNCPMJD "EWFSTF 3FBDUJPOT O

Arterial .ZPDBSEJBM JOGBSDUJPO 7FOPVT 1VMNPOBSZ FNCPMJTN $FSFCSPWBTDVMBS EJTPSEFST

"MM 1MBDFCP controlled Studies

*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

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ASCOPost.com | JUNE 10, 2013

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ASCO State Affiliates Focus on the Delaware Society for Clinical Oncology By Jo Cavallo

Jon Strasser, MD

lthough the state of Delaware comprises just 2,489 square miles, giving it an area ranking of 49 out of 50 states, its small size gives its population of nearly 1 million an advantage many larger states do not have: ready access to local politicians to address complex issues such as improving cancer care. At the forefront of that effort is the Delaware Society for Clinical Oncology. Since its founding in 1994, the Society has worked with state legislators to advocate for better cancer care and develop strategies to reduce the state’s cancer mortality rate, which is much higher (193.5 per 100,000 persons) than the national average (183.8 per 100,000 persons).1 Nevertheless, recent improvements in access to cancer screenings and cancer treatments are resulting in declining cancer death rates. Recent legislative accomplishments should also help increase

patient accessibility to cancer care and improve outcomes. Last year, the Society was instrumental in getting Delaware’s Oral Chemotherapy Parity bill signed into law with bipartisan, unanimous support. The Society also worked with Representative John Carney (D-DE) to address the problem of chemotherapy drug shortages in the United States and had another success in 2012 with the reauthorization of the Prescription Drug User Fee Act. The ASCO Post talked with Jon Strasser, MD, President of the Delaware Society for Clinical Oncology, about the Society’s legislative successes, the ongoing challenges it faces, and its future goals.

Affiliation with ASCO Why is it important for your Society to be an ASCO state affiliate? ASCO supports many of the is-

Challenges and Strengths What challenges do you face that are unique to your community and oncology practice? We are still struggling with im-

Delaware is a unique state—it’s small, our politicians are readily accessible, and we are pioneers in getting legislative priorities moved forward. —Jon Strasser, MD

sues that are important to us and gives us a backbone for collaboration with other states in terms of influencing public policy, both on a state and national level. Delaware is a unique state—it’s small, our politicians are readily accessible, and we

Fast Facts ■ ■ ■ ■

are pioneers in getting legislative priorities moved forward. We see the accomplishments other states have made in providing better care for patients with cancer, and we try to adopt things we think might fit best for our patients.

Founded in 1994 Jon Strasser, MD, President 72 members Mission principles include fostering the highest quality of cancer care for Delaware residents by increasing access to the best cancer care, being an advocate for patients, facilitating the education of physicians, supporting a multidisciplinary approach to cancer care, increasing clinical trial participation, and obtaining appropriate reimbursement for care.

■ The Society holds monthly dinner meetings with members, usually

including a segment devoted to Society business as well as an educational presentation by a leading expert in a specific cancer. In April, the Society hosted a CME lecture on New Approaches to the Management of DCIS, presented by Shelley Hwang, MD, MPH, Professor of Surgery at Duke University School of Medicine, Durham, North Carolina.

proving the health of our population. We have high rates of smoking and obesity and high incidences of cancer, as well as continued high cancer mortality rates. I think we have risen to those challenges, and we are starting to see the results of our efforts with significant reductions in cancer mortalities. Although Delaware’s cancer mortality rates still exceed the national average, we have dropped from having the highest national mortality to number 14, and our mortality rates are dropping at two times the national average. As a Society, we do a lot of community outreach to support programs that affect our patients’ health. With support from the Society, our state created the Delaware Cancer Treatment Program, which provides uninsured cancer patients with 2 years of coverage through Delaware Medicaid policy and was funded by our state’s share of the tobacco settlement. It is open to those

cancer patients who are uninsured with incomes up to 650% of the federal poverty limit. We’re also involved in making sure our patients have access to high-quality care and support the practice of stateof-the-art, evidence-based medicine. The majority of our members are involved in the Helen F. Graham Cancer Center at Christiana Care Health System in Newark, which is the dominant cancer center in Delaware, and we all participate in multidisciplinary clinics and in managing patients in a multidisciplinary format. We are strong leaders in advocating multidisciplinary care, and that has probably had the biggest impact in terms of reducing cancer mortality in our state. We also have extremely high enrollment into national clinical trials. And because of our reputation, we have been very successful in attracting top-notch oncology clinicians to Delaware, which is enormously helpful.

Legislative Issues Your Society is very active legislatively. What are your current areas of concern? We try to focus on promoting good policy that impacts our patients positively. When it comes to health-care reform, a lot of the issues we grapple with involve how to make care more efficient and more cost-effective. On a local level, we are interested in making sure our patients have access to care, and we supported the Delaware Cancer Treatment Program, so patients don’t have to worry about how they’re going to pay for their care. continued on page 100

The ASCO Post | JUNE 10, 2013

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ASCO State Affiliates Delaware Society for Clinical Oncology continued from page 99

We’re trying to minimize the stress in our patients’ lives, so they can focus on getting well.

Key Objectives What are your immediate goals? We are primarily working on improving health-care access for patients. Our next goals are to consider how the Affordable Care Act will impact cancer care and how we, as leaders in our state, can make health care more cost-effective. We

want to be participants with a voice in these issues and, at the same time, make sure that any reforms don’t sacrifice the ability of our patients to get the high-quality care they need. n Disclosure: Dr. Strasser reported no potential conflicts of interest.

Reference 1. Department of Health and Social Services: Cancer Incidence and Mortality in Delaware: 2003-2007. Issued March 2012. Available at dhss.delaware. gov/dhss/dph/dpc/cancer.html. Accessed May 2, 2013.

Accomplishments ■ In 2012, the Delaware Society for Clinical Oncology was instrumental in the passage of two pieces of legislation that impact patient care:

1. Delaware’s Oral Chemotherapy Parity Law requiring state-regulated insurance companies and HMOs to cover oral cancer drugs “on a basis no less favorable than” intravenously administered anticancer medications. Currently, the Food and Drug Administration (FDA) has approved more than 40 oral anticancer therapies for the treatment of at least 54 different types of cancer. 2. Reauthorization of the national Prescription Drug User Fee Act, which included components of Delaware Congressman John Carney’s Drug Shortage Prevention Act. The latter legislation mandates an expedited review of a drug’s vulnerability to shortage and requires the FDA to use a refined regulatory process that addresses manufacturing problems without causing drug shortages. JCO Spotlight

Innovative State Program Reduces Colorectal Cancer Disparities, Mortality Rates Among African American Patients

study analyzing the impact of the Delaware Cancer Consortium, the state’s cancer control program, reports a 41% reduction in colorectal mortality rates for African Americans.1 The recently published study provided analysis on a novel design and approach used to eliminate colorectal cancer disparities for the first time by a state cancer control program. The findings show the percentage of colorectal cancer cases diagnosed at advanced and regional stages among African Americans declined from 79% to 40%. Overall incidence rates per 100,000 also declined from 67% to 58% for African Americans and whites, respectively, in 2002 to 45% for both in 2009. “We can achieve tremendous progress when governments, insurers, and providers work together to reduce disparities,” said Stephen S. Grubbs, MD, lead coauthor of the study and oncologist at Christiana Care’s Helen F. Graham Cancer Center. “Eliminating disparities in cancer screening, diagnosis, treatment, and mortality is an essential step toward improved health outcomes for all Americans with cancer,” he said.

Statewide Colorectal Cancer Screening Program The Delaware Cancer Consortium, designed to create a comprehensive statewide colorectal cancer screening program, included insurance coverage for screening, the use of nurse navigators to conduct screening outreach and recruitment, and ultimately treatment for those with a colorectal cancer diagnosis. With funding from the state legislature,

Delaware Governor Ruth Ann Minner developed the program in 2003. Delaware law tasked the Consortium with coordinating cancer prevention and control activities in the state. Members of the Consortium include representatives from the Delaware House of Representatives and State Senate, the Governor’s Office, the Secretary of the Department of Health and Social Services and physicians from cancer centers.

ty level. Other residents were eligible for coverage through Medicaid, Medicare and private insurers. From its inception through 2011, the program has provided over 5,000 colorectal cancer screenings. A companion program, the Delaware Cancer Treatment program, was developed to cover the costs of cancer care for 2 years for the uninsured who are newly diagnosed. Combined, the Delaware Cancer Consortium and the

Eliminating disparities in cancer screening, diagnosis, treatment, and mortality is an essential step toward improved health outcomes for all Americans with cancer. —Stephen S. Grubbs, MD

State’s Program Could Serve as Model for Nation “The results we achieved in Delaware can be replicated across the country,” said Congressman John Carney, a member of the Cancer Consortium’s Advisory Committee and former Chair of its Disparities Committee. “Forming strong partnerships, ensuring access to care for all, and focusing on prevention is what really makes the difference,” he said. Using colonoscopy as the preferred screening method, the Delaware Cancer Consortium provided reimbursement for screening starting in 2002 for any uninsured Delaware resident with an income of up to 650% of the federal pover-

Delaware Cancer Treatment program provided Delaware residents with universal colorectal cancer screening and treatment.

Equal Care and Access Mitigate Disparities “The Consortium demonstrated that racial disparities can be mitigated by providing equal care and equal access,” said Blase N. Polite, MD, MPP, lead coauthor and oncologist at University of Chicago Medical Center. “They were able to identify cancers at an earlier stage and likely found and removed precancerous lesions before they could become cancer.”

Blase N. Polite, MD, MPP

The authors also note the longterm financial savings produced through the state program. In the United States, annual costs of colorectal cancer detection and treatment are estimated to total $14 billion. While the Delaware Cancer Consortium screening costs approximately $1 million annually, the increase in screening in Delaware through its expanded program saved approximately $8.5 million annually from reduced incidence of cancers that would have required aggressive therapy. These annual savings more than offset the $6 million annual cost of the Cancer Treatment Program, which provided universal treatment for all cancers. n

Disclosure: For disclosure information of all of the contributing authors, see the original report at JCO.org.

Reference 1. Grubbs SS, Polite BN, Carney Jr J, et al: Eliminating racial disparities in colorectal cancer in the real world: It took a village. J Clin Oncol. April 15, 2013 (early release online).

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Patient’s Corner

Coping with Tongue Cancer: A Lonely Journey

I’ve never found a support group for my type of cancer or anyone else with a similar experience. By Betsy Keller, as told to Jo Cavallo

hirteen years ago, at just 34 years old, I never expected that my life could be interrupted by cancer. A nonsmoker and nondrinker, I had always practiced a healthy lifestyle and wasn’t concerned initially when what looked like a cold sore popped up on the left side of my tongue. But as several weeks went by and the sore didn’t go away, I saw an oral surgeon who removed some tissue for a biopsy and said that it was negative for cancer. I tried putting the problem out of my mind, but when the sore wouldn’t heal and, in fact, started to hurt and bleed, I saw another oral surgeon. This time the doctor took a significant amount of tissue from my left lateral tongue and tongue base, and even before the biopsy results came back, announced that he was sure I had cancer. The biopsy report confirmed stage IV tongue cancer, and I had surgery to remove 25% of the left side of my tongue along with salivary glands and lymph nodes.

Another Scare I thought that would be the end of my ordeal. My doctor had told me that once the tumor is removed, the cancer usually doesn’t come back. But in 2006, I had another scare when a tumor appeared in the same spot. Once again tissue was taken for a biopsy, and although the results were negative, so much of my tongue was now removed it became difficult to speak and eat normally. Last year, the cancer recurred and I faced the greatest challenge of my life. Afraid that more surgery and treat-

ment would completely disfigure me, I sought out a couple of medical opinions from two of the top cancer centers near my home. The first oncologist I saw said that in order to remove all the cancer he would have to do extensive surgery on my tongue, but that I could have reconstructive surgery in which he would build a

chemotherapy—and it took a long time to recover, I’m grateful that I’m slowly getting my life back, although I know it will never be normal again. Despite all the surgeries and treatment, the wound in my tongue has never really healed, and I continue to see my oncologist monthly for checkups.

In addition to all the physical and mental adjustments I’ve had to make since my diagnosis, what has been so frustrating is the realization of how little research there is in my type of cancer, especially in finding more effective treatments. —Betsy Keller

new tongue using cadaver tissue. However, even with the reconstructive surgery, the chances were high, said the doctor, that I probably wouldn’t be able to speak clearly and that I would need a permanent feeding tube to get nourishment— two possibilities I couldn’t fathom. The second oncologist I saw said that rather than do additional surgery, he would laser the cancerous growth, preserving the amount of tongue I had left, and prescribe 39 sessions of radiation therapy, followed by several weeks of cisplatin and carboplatin chemotherapy. I decided on the latter course. While the treatment was rough—I had to be hospitalized for 5 days because of near renal failure from the

Learning to Cope When I was first diagnosed with tongue cancer, I was young and strong and I didn’t have much fear. But this last bout was terrifying, not just because I realized I could die but because I knew my life would be irrevocably altered. Although I can speak fairly clearly, my mouth and throat are so dry, chewing and swallowing food is difficult and it is easy for me to choke. I have been self-conscious of eating in public, and for much of the last year, I wouldn’t leave my house—I experienced panic attacks at just the thought of going outside. At one point, I was so despondent that I wanted to die, but antidepressants

have helped me cope. Even though I have no sense of taste, I get pleasure in being able to eat small amounts of food, and I’m slowly regaining enough confidence to have friends over for dinner and venture out to restaurants.

Searching for Answers In addition to all the physical and mental adjustments I’ve had to make since my diagnosis, what has been so frustrating is the realization of how little research there is in my type of cancer, especially in finding more effective treatments. And in the 13 years since my diagnosis, I’ve never found a support group for my type of cancer. I don’t know anyone else with a similar experience to talk to, so this has been a lonely journey. Still, I’ve learned to accept my life as it is now. I’m grateful to be alive and have the chance to be with my family. I know that not every cancer patient is so lucky. n Betsy Keller lives in Boca Raton, Florida.

Support and Resource Links For a list of national, not-forprofit organizations that provide programs, information, services, and support for people with cancer, please visit: www.cancer.net/publicationsand-resources/support-andresource-links

National Cancer Survivors' Day Sunday, June 2, 2013, was National Cancer Survivors' Day and events were held around the United States in recognition of the more than 12 million survivors of cancer. In Chicago, the Robert H. Lurie Comprehensive Cancer Center held its 20th Annual Cancer Survivors' Celebration & Walk in tribute to cancer survivors and the advances being made in cancer treatment and research. Visit www.cancer.northwestern.edu.

Photo credit: Randy Belice

The ASCO Post | JUNE 10, 2013

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2013

2013 Oncology Meetings June Molecular and Translational Oncology Workshop June 14-18 • Fort Myers, Florida For more information: www.cancereducationconsortium. org/programs_mtow.html 12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch British Gynaecological Cancer Society Annual Scientific Meeting June 20-21 • Belfast, Ireland For more information: bgcsconference.com 6th International Nasopharyngeal Carcinoma Symposium June 20-22 • Istanbul, Turkey For more information: www.npc2013.org 2nd International Breakthrough Breast Cancer Conference– Triple Negative Breast Cancer June 26-28 • London, United Kingdom For more information: www.breakthroughconference.org.uk

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

Hematology and Medical Oncology Best Practices August 15-22 • Arlington, Virginia For more information: www.gwumc.edu/cehp/ hemoncbestpractices/

12th International Congress on the Future of Breast Cancer July 18-20 • Huntington Beach, California For more information: www.gotoper.com/conferences

Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org

Indiana Oncology Society Fall Membership Conference July 25 • Indianapolis, Indiana For more information: www.accc-cancer.org/ossn_ network/IN/INevents.asp 14th International Lung Cancer Congress July 25-27 • Huntington Beach, California For more information: www.gotoper.com/conferences Up Close and Personalized: The 2nd International Congress on Personalized Medicine July 25-28 • Paris, France For more information: www.upcp.org Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences

MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes. com

Second Annual 2013 World Cutaneous Malignancies Congress July 26-28 • San Diego, California For more information: www.cutaneousmalignancies.com

July

August

ASCO Palliative Care Training July 1-5 • Accra, Ghana For more information: www.asco.org/palliativecare

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

2nd International Michelangelo Conference on Promises and Challenges of Developing New Drugs in Oncology July 4-5 • Milan, Italy For more information: www.fondazionemichelangelo.org

South Carolina Oncology Society Fall 2013 Membership Conference August 9-10 • Charleston, South Carolina For more information: www.scosonline.com

ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org North Carolina Oncology Association Fall Membership Conference August 24 • Greensboro, North Carolina For more information: www.ncoa-northcarolina.com 11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

September George Society of Clinical Oncology 2013 GASCO Annual Meeting September 6 • Atlanta, Georgia For more information: www.gasco.us SGI Summit Turkey 2013: Innovations in Obstetrics and Gynecology September 6-8 • Istanbul, Turkey For more information: www.sgiturkey2013.org/ Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org

Rocky Mountain Oncology Society Fall Membership Conference September 12 • Denver, Colorado For more information: www.rmos-colorado.com International Liver Cancer Association Seventh Annual Conference September 13-15 • Washington, DC For more information: www.ilca2013.org/ Inflammation, Microbiota, and Cancer September 19-20 • Bethesda, Maryland For more information: ncifrederick.cancer.gov/events/ microbiota/agenda.asp Tennessee Oncology Practice Society 2013 Membership Conference September 20 • Nashville, Tennessee For more information www.tops-tennessee.com Michigan Society of Hematology and Oncology Annual Meeting September 20-21 • Traverse City, Michigan For more information: www.msho.org NCCN 8th Annual Congress: Hematologic Malignancies September 20-21, 2013 New York, New York For more information: www.nccn. org ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13 Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences continued on page 110

Because Endocrine Monotherapy Can Only Take You So Far

In postmenopausal women with advanced HR+, HER2-negative breast cancer after failure of treatment with letrozole or anastrozole

Change the Treatment Paradigm With AFINITOR Plus Exemestane AFINITOR plus exemestane more than doubles median progression-free survival (PFS) over exemestane monotherapy1

Median PFS in BOLERO-2 (Investigator Radiological Review)1 100

HR=0.45 [95% CI, 0.38-0.54] Log-rank P value: <0.0001

7.8 months Placebo plus exemestane: 3.2 months

AFINITOR plus exemestane:

PFS Probability (%)

Median PFS: 3.2 months

55%

Median PFS: 7.8 months

reduction in risk of progression or death2

20 AFINITOR plus exemestane (n/N=310/485) Placebo plus exemestane (n/N=200/239)

0 0

Time (months)

• Median PFS was 7.8 months with AFINITOR® (everolimus) Tablets plus exemestane [95% CI, 6.9-8.5] vs 3.2 months with placebo plus exemestane

[95% CI, 2.8-4.1] (P<0.0001)1

PFS curves for the 2 treatment arms began to diverge at 6 weeks (the first tumor assessment)1,2 An independent central review confirmed a significant PFS improvement with AFINITOR plus exemestane treatment vs placebo plus exemestane1,2 • Median PFS was 11.0 months with AFINITOR plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6]

(HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

BOLERO-2=Breast Cancer Trials of Oral Everolimus; HR=hazard ratio.

T:14”

B:14.25”

S:13”

AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. Important Safety Information.

• AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients • There have been reports of noninfectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR, some with

fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared with patients <65 years of age

• Oral ulceration is the most frequently occurring adverse event and occurred in 44% to 86% of AFINITOR-treated patients across the clinical trial

experience. Most of these events were grade 1/2. Grade 3/4 stomatitis was reported in 4% to 9% of patients

• Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have

also been reported; monitoring of laboratory tests is recommended

• The use of live vaccines and close contact with those who have received live vaccines should be avoided • AFINITOR can cause fetal harm when administered to a pregnant woman

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

References: 1. AFINITOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2012. 2. Data on file. Study CRAD001Y2301. Novartis Pharmaceuticals Corp; 2012.

• Careful monitoring and appropriate dose adjustments for adverse

Important Safety Information. AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, patients should be managed with dose interruption until symptoms improve • The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 • AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR • The development of pneumonitis has been reported even at a reduced dose Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred • Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR • Treatment of preexisting invasive fungal infections should be completed prior to starting treatment • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients • In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed Renal Failure: • Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR Geriatric Patients: • In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared to 2% in patients <65 years of age • Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

reactions are recommended Laboratory Tests and Monitoring: • Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported • Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter • When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) • Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments Hepatic Impairment: • Exposure of everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended Vaccinations: • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%) • The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%) Laboratory Abnormalities: • The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%) • The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%)

Please see Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

10/12

AFB-1043056

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009

B:14.25”

T:14”

S:13”

Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations]. Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. 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. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 e Median duration of treatment 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration

Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo c

Key observed laboratory abnormalities are presented in Table 3. Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory Parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Agents That May Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information]. Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

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A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 Pediatric use of AFINITOR Tablets is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in diseaserelated symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown. Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least one serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups. Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information].The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information]. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (ChildPugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Distributed by: Novartis Pharma Stein AG Novartis Pharmaceuticals Corporation Stein, Switzerland East Hanover, New Jersey 07936 © Novartis T2012-153 August 2012

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2013

2013 Oncology Meetings continued from page 102

Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences 2013 ASH State-of-the-Art Symposium September 27-28 • Chicago, Illinois For more information: www.hematology.org ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu 28th Annual Offering of Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: from Bench to Bedside to Biomarkers September 30-October 3 • Boston, Massachusetts For more information: steelelab.mgh.harvard.edu/ tumorcourse/

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

Merrill J. Egorin Workshop in Cancer Therapeutics and Drug Development October 11-14 • Leesburg, Virginia For more information: www.cancereducationconsortium. org/programs_paaw.html 9th International Symposium on Hodgkin Lymphoma October 12-15, 2013 • Cologne, Germany For more information: www.hodgkinsymposium.org/ International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/ About+ASCO/International+Affairs/ International+Clinical+Trials+Wor kshops 4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in 18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 10th International Conference of the Society for Integrative Oncology: Translational Science in Integrative Oncology October 20-22, 2013 • Vancouver, British Columbia For more information: www.integrativeonc.org

Virginia Association of Hematologists and Oncologists Fall Membership Conference October 11 • Virginia Beach, Virginia For more information: www.vah-o.org 4th International Breast Cancer Prevention Symposium: Genes, the Environment, and Breast Cancer Risks October 11-13 • Beirut, Lebanon For more information: www.purdue.edu/breastcancer/

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

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

Illinois Medical Oncology Society 2013 Membership Conference October 25 • Itasca, Illinois For more information: www.imos-illinois.com

Advanced Breast Cancer Second International Consensus Conference November 7-9 • Lisbon, Portugal For more information: www.abc-lisbon.org/

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

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

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

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

International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw 11th Annual School of Breast Oncology November 7-10 • Atlanta, Georgia For more information: www.gotoper.com/conferences Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro New York Lung Cancer Symposium November 9 • New York, New York For more information: www.gotoper.com/conferences African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information: www.aortic2013.org

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

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Pioneers in Oncology Francis Crick’s Discovery of the Structure of DNA Transformed 20th Century Biologic Sciences

Courtesy of the Salk Institute for Biological Studies.

By Jo Cavallo

Francis Crick, PhD

“M

y Dear Michael, Jim Watson and I have probably made a most important discovery. We have built a model for the structure of des-oxy-ribose-nucleic-acid, called DNA for short.… In other words we think we have found the basic copying mechanism by which life comes from life,” wrote Francis Crick, PhD, on March 19, 1953, to his 12-year-old son Michael, who was a student at Bedales, a British boarding school. The 7-page handwritten letter, signed “Lots of love, Daddy,” just fetched $6 million at Christie’s auction house. Half of the money will go to Michael, now 72, and the other half to the Salk Institute for Biological Studies in California, where Francis Crick worked until his death from colon cancer on July 28, 2004, at the age of 88. The letter was sent to Michael just weeks before Dr. Crick and his scientific collaborator James D. Watson, PhD, published their findings on the double-helix structure for DNA in the British scientific weekly Nature.1 In the paper, the authors described how pairs of bases on the inside of the two DNA backbones— adenine (purine) with thymine (pyrimidine), and guanine (purine) with cytosine (pyrimidine), or A-T and C-G—bond together in the middle of the double helix, suggesting a copying mechanism for the genetic material. In a follow-up article in Nature the next month, the two described the mechanism for DNA self-duplication.2 “We feel that the proposed structure for deoxyribonucleic acid may help to solve one of the fundamental biological problems—the

molecular basis of the template needed for genetic replication. The hypothesis we are suggesting is that the template is the pattern of bases formed by one chain of the deoxyribonucleic acid and that the gene contains a complementary pair of such templates,” wrote Dr. Crick and Dr. Watson.

The Gossip Test Born Francis Harry Compton Crick on June 8, 1916, in Northampton, England, during the middle of World War I, Dr. Crick’s interest in science was evident from the time he was a young child. In his autobiography, What Mad Pursuit: A Personal View of Scientific Discovery (Basic Books, 1990), Dr. Crick describes how his constant questions about the world forced his parents

ics, including penicillin, led him to realize his interest wasn’t really in physics after all but in the life sciences. “I had discovered the gossip test—what you are really interested in is what you gossip about. Without hesitation, I applied it to my recent conversations. Quickly I narrowed down my interests to two main areas: the borderline between the living and the nonliving, and the workings of the brain,” wrote Dr. Crick.

Race to Discover DNA In 1947, Dr. Crick took a position at Strangeways Research Laboratory in Cambridge, studying the physical properties of cytoplasm in cultured fibroblast cells. Two years later, he joined the staff of the Medical Research Council Unit at Cavendish Laboratory, where a scientific team

He is a giant. It’s fair to say Francis Crick defined the discipline of theoretical biology, and so far no other practitioners of that art have come up to that standard. —Francis S. Collins, MD, PhD

to buy him the complete set of The Children’s Encyclopedia. Although he writes that he read all the sections on art, science, history, mythology, and literature “avidly,” it was the sections about science that captured his interest the most. Dr. Crick earned a Bachelor of Science degree in physics from University College in London and planned to stay to work on a graduate degree in physics, when World War II erupted, altering his plans. He took a civilian job at the British Admiralty Research Laboratory developing radar and magnetic mines for naval warfare and helped design a new mine that was effective against German minesweepers. After the war, feeling intellectually restless, unsatisfied in his chosen field of physics, and unsure about what he wanted to do, he decided to change careers. While still a member of the scientific staff at the Admiralty, Dr. Crick recounts in What Mad Pursuit, his conversations with naval officers about recent advances in antibiot-

led by molecular biologist Max Perutz was using x-ray crystallography to study the structure of proteins, a subject that became the focus of Dr. Crick’s doctoral thesis. It was while working at Cavendish Laboratory that Dr. Crick began his friendship—and scientific collaboration—with American-born biologist James Watson, who joined the lab in 1951. By the time the two met, the race to discover the structure of DNA had already been going on for several years, and the experimental findings from those earlier efforts eventually led the two men to develop a theory of genetic transfer. In 1948, Linus Pauling had discovered the single-stranded alpha helix, the structure found in many proteins, which prompted biologists to think of helical forms. It was Dr. Pauling’s method of model building in chemistry that Dr. Crick and Dr. Watson used to uncover the structure of DNA. But perhaps the greatest boost to their DNA discovery came from the work of British molecular biologist

Rosalind Franklin, who along with New Zealand–born physicist Maurice Wilkins, was studying DNA at King’s College in London the year Drs. Crick and Watson met. Dr. Franklin, an authority in the field of x-ray crystallography, was investigating x-ray diffraction images of DNA to understand the physical structure of the DNA molecule. She found that DNA can exist in two forms, depending on the humidity in the surrounding air. Her x-ray diffractions showed that the “wet” form of DNA had all the characteristics of a helix, and she suspected that all DNA was helical. In January 1953, Dr. Wilkins showed Dr. Crick one of Dr. Franklin’s crystallographic portraits of DNA— reportedly without her knowledge—which enabled Drs. Crick and Watson to take the next conceptual step, suggesting that the molecule was made of two chains of nucleotides, each in a helix as Dr. Franklin had found but with one chain going up and the other down. In the spring of that year, Drs. Crick and Watson published their findings in Nature, acknowledging Drs. Franklin and Wilkins for their “unpublished experimental results.” In 1962, Drs. Crick, Watson, and Wilkins jointly received the Nobel Prize in Physiology or Medicine for their discovery of the structure of DNA. Because the Nobel Prize is given only to the living, Dr. Franklin, who had died of ovarian cancer 4 years earlier, could not be considered for the award.

Discovery That Altered Science Throughout the 1950s and 1960s, Dr. Crick investigated the relationship between DNA and genetic coding and explored other fields of study, including developmental biology and how genes control the growth and specialization of organs. In 1977, Dr. Crick changed the focus of his work again, this time to neurobiology and the neural underpinnings of consciousness. Also that year, he accepted an appointment as J.W. Kieckhefer Research Professor continued on page 112

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Pioneers in Oncology Francis Crick, PhD continued from page 111

at the Salk Institute for Biological Studies. Understanding the structure of DNA has led to the unraveling of how genetic instructions are passed on from one generation to the next and paved the way for the Human

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Genome Project. In an obituary of Francis Crick published in The Washington Post in 2004, then Director of the National Human Genome Research Institute, Francis S. Collins, MD, PhD, said, “He is a giant. It’s fair to say Francis Crick defined the discipline of theoretical biology, and so far no other practi-

tioners of that art have come up to that standard.” In What Mad Pursuit, Dr. Crick was more circumspect of his and Dr. Watson’s accomplishment. “We both believed that DNA was important though I don’tS:6.75” think we realized just how important it would turn out to be.” n

References 1. Watson JD, Crick FHC: Molecular structure of nucleic acids: A structure for deoxyribose nucleic acid. Nature 171:737-738, 1953. 2. Watson JD, Crick FHC: Genetical implications of the structure of deoxyribonucleic acid. Nature 171:964-967, 1953.

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

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

Rights & Permissions e-mail: Permissions@harborsidepress.com

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

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WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE • Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. • Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and 1 GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo

(3% vs 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs 3% and arterial thromboembolism: 2% vs 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication. Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension (modified JNC criteria stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo, respectively). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery.

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Innovator Award Won by Kenneth Tsai, MD, PhD, for Plan to Map Molecular Path to Skin Cancer proposal to examine the cellular journey from normal skin to precancerous lesion to skin cancer earned Kenneth Tsai, MD, PhD, the Sixth

Annual Landon Foundation–AACR Innovator Award for Cancer PrevenS:6.75” tion Research at the American Association for Cancer Research (AACR)

Annual Meeting, held recently in Washington, DC. An Assistant Professor in the Departments of Dermatology and Immu-

nology at The University of Texas MD Anderson Cancer Center, Dr. Tsai said the project will provide rare insight continued on page 114

PROD

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

median

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COMETRIQ™ (n=219)

Progression-free survival (PFS)

> Significantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) > COMETRIQ™ demonstrated a greater than 2.5-fold increase in median PFS vs placebo —Median PFS was 11.2 months with COMETRIQ™ vs 4.0 months with placebo > Partial response rate was 27% with COMETRIQ™ vs 0% with placebo (P<0.0001) —Median duration of objective response was 14.7 months (95% CI: 11.1, 19.3) > Adverse reactions occurring in ≥25% of patients treated with COMETRIQ™ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation; the most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia

TC QC PG

Adverse Reactions: Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, PPES, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo.

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

COMETRIQ.com

DATE

SIGNOFF

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

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Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

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

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Kenneth Tsai, MD, PhD continued from page 113

into the process that starts with normal skin and progresses to squamous cell carcinoma. The award is one of six earned by MD Anderson faculty at this year’s AACR meeting. “Skin is ideally suited for this type

of analysis because it’s easily accessible for sampling. Furthermore, squamous cell carcinoma and its precancerous lesions are relatively common and well-defined clinically and histologically,” Dr. Tsai said. But “we don’t have a good understanding of the genetic events that occur along the way,” he added.

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

Identifying Targets for Prevention “By identifying important genetic differences, we hope to find biomarkers of risk for the precancerous lesions—actinic keratoses—and for skin cancer progression,” Dr. Tsai said. “We ultimately aim to identify targets for chemoprevention at all stages and

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

develop therapies for them.” In addition to identifying and effectively treating those at the greatest risk, another benefit would be identification of those who don’t need intensive treatment or surveillance. Working with fellow dermatologists at MD Anderson and several other Houston practices, Dr. Tsai is collect-

placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose. Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)1 or ≥ 2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0

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Awards

ing samples of all three types of tissue—normal, precancerous, and carcinomatous—from each patient. This is a key advantage, because comparing different tissue types among different people would introduce greater variability into his results. The award, for $100,000 spread over 2 years, is one of three Landon

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

awards given annually. MD Anderson scientist Guang Peng, PhD, Assistant Professor in the Department of Cancer Prevention, won the 2012 award for cancer prevention research. “I thought of this project almost 2 years but had no resources to begin,” Dr. Tsai said “Then I received a seed grant from the Duncan Family

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

Institute for Cancer Prevention and Risk Assessment, which enabled me to get going and provided the data we needed to compete for the Landon award.” The Duncan Family Institute is part of MD Anderson’s Division of Cancer Prevention and Population Sciences. The project is a collaboration among

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]

basic scientists, bioinformatics and gene-sequencing experts, and dermatologists. n

Inflammatory Bowel Disease Raises Risk of Melanoma

atients with inflammatory bowel disease are at higher risk of melanoma, reported researchers at Mayo Clinic. Researchers found that inflammatory bowel disease is associated with a 37% greater risk for the disease. The findings were presented at the Digestive Disease Week 2013 conference in Orlando, Florida.

IBD and Melanoma ■ Inflammatory bowel disease

(including Crohn’s disease and ulcerative colitis) is associated with a 37% greater risk for melanoma.

■ Given the new data, physicians

should appropriately counsel patients with inflammatory bowel disease about the risk of melanoma.

Researchers determined this increased risk by performing a comprehensive search of all published studies on inflammatory bowel disease over the past 7 decades. They analyzed 172,837 patients with inflammatory bowel disease (92,208 with Crohn’s disease; 79,360 with ulcerative colitis) to find the 179 cases of melanoma after an inflammatory bowel disease diagnosis.

Counsel Patients about Risks “Based on this data, we are suggesting that physicians appropriately counsel patients with inflammatory bowel disease about the risk of melanoma. Sun-protective measures are very effective in preventing this cancer,” said study author Siddharth Singh, MBBS, a Mayo Clinic gastroenterologist. More than 1.5 million Americans have Crohn’s disease or ulcerative colitis, the most common forms of inflammatory bowel disease. Both conditions inflame the lining of the intestine, leading to bouts of watery diarrhea, rectal bleeding, abdominal cramps and pain, fever, and weight loss. n

The ASCO Post | JUNE 10, 2013

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In the News Breast Cancer

Women at Increased Risk for Breast Cancer Should Be Offered Medications to Reduce Risk, Draft Recommendations Advise By Charlotte Bath

linicians should engage in shared decision-making with women who are at increased risk of breast cancer about using medications, such as tamoxifen and raloxifene (Evista), to reduce risk, and should offer prescriptions to women considered at low risk for adverse effects from these medications, advises a draft recommendation statement from the U.S. Preventive Services Task Force (USPSTF).1 The statement also reaffirms the USPSTF’s 2002 recommendation against the routine use of tamoxifen or raloxifene to reduce breast cancer risk in women at low or average risk. The USPSTF updated draft recommendation statement is consistent with positions of other organizations, including ASCO, which has recommended offering tamoxifen to women at increased risk for breast cancer, or raloxifene to postmenopausal women at increased risk. (While tamoxifen has been approved by the U.S. Food and Drug Administration [FDA] for reducing breast cancer risk in women of any age, raloxifene is approved for postmenopausal women only.) The public comment period for the draft recommendation closed on May 13, and the final final statement is expected to take several months. The draft recommendation statement is based on updated evidence on the risks and benefits of these medications from seven randomized, controlled trials—four comparing tamoxifen and placebo, two comparing raloxifene and placebo, and one comparing tamoxifen and raloxifene, the Study of Tamoxifen and Raloxifene (STAR). The review and meta-analysis of these trials, published in the Annals of Internal Medicine,2 concluded that both medications reduced the incidence of invasive breast cancer and fractures and increased the risk of thromboembolic events. Tamoxifen was more effective than raloxifene in reducing breast cancer risk, but also increased the risk of endometrial cancer and cataracts.

Confidence in Results Heidi D. Nelson, MD, MPH, the lead author of the review that was conducted at the Pacific Northwest Evi-

dence-based Practice Center at Oregon Health & Science University, noted that the studies were done well, “We have confidence in the results of the trials and that they can support the recommendations.” Dr. Nelson is Research Professor of Medical Informatics and Clinical Epidemiology and Medicine at Oregon Health & Science University and Medical Director of Cancer Prevention and Screening at Providence Health & Services in Portland. In an interview with The ASCO Post, Dr. Nelson noted that it was unusual to have numerous, large, high-quality prevention trials. “When we have good data, we can make better health-care choices. It is important to critically evaluate the evidence before making practice recommendations,” Dr. Nelson said. “The placebo-controlled primary prevention trials indicate that tamoxifen and raloxifene reduce the incidence of

but not raloxifene, increased the risk of endometrial cancer and cataracts. Older women had more endometrial cancer and thromboembolic events than did women younger than 50. The most commonly reported side effects were vasomotor symptoms, vaginal discharge, itching, and dryness for tamoxifen and vasomotor symptoms and leg cramps for raloxifene. The head-to-head trial, however, found that tamoxifen users had more gynecologic problems, vasomotor symptoms, leg cramps, and bladder control symptoms, and that raloxifene users had more musculoskeletal problems, dyspareunia, and weight gain.

‘The Tricky Part’ While the evidence review provided robust estimates of the benefits and harms of tamoxifen and raloxifene, “the tricky part is finding the right candidate,”

When we have good data, we can make better health-care choices. —Heidi D. Nelson, MD, MPH

invasive breast cancer by 7 to 9 cases per 1,000 women over a 5-year period, primarily by reducing estrogen receptor– positive breast cancer. New results from STAR show that tamoxifen has a greater effect than raloxifene by reducing breast cancer [even further],” according to the evidence review. The head-to-head trial of tamoxifen and raloxifene “resolved some of the gray areas,” Dr. Nelson said, and helped “refine a more detailed description of the differences between the medications.” The evidence review found that raloxifene reduced the risk of vertebral fractures by 7 cases per 1,000 women, while tamoxifen reduced the risk of nonvertebral fractures by 3 cases per 1,000 women. Both medications increased the risk of thromboembolic events, although tamoxifen increased the risk of such events by 4 more per 1,000 than did raloxifene. Tamoxifen,

Dr. Nelson said. Finding the ideal candidate would mean determining on an individual basis who is at highest risk of invasive breast cancer and most likely to benefit from a risk-reduction medication, but is at low risk of adverse effects from the medication. The task force draft recommendation statement calls for the development of models to more precisely predict which women will not only have a high probability of developing breast cancer, but also have a low probability of thromboembolic and other medication-related events. Such models, however, do not currently exist. Current risk-stratification models are largely based on the National Cancer Institute’s Breast Cancer Risk Assessment Tool (Gail model). “The original Gail model included age, age at menarche, age of first birth, family history of breast cancer in firstdegree relatives, number of previous

breast biopsies, and history of atypical hyperplasia,” according to the evidence review. Although the Gail model has been used to define high risk in many breast cancer trials, “on a woman-towoman basis, it is not a good predictor,” Dr. Nelson said. Subsequent models include one or more of the Gail model variables in addition to factors such as race, previous false-positive mammograms or benign breast disease, body mass index or height, estrogen and progestin use, history of breastfeeding, menopause status or age, smoking, alcohol use, physical activity, education, mammographic breast density, and diet. Reviewing 19 studies that have evaluated 13 different risk-stratification models, Dr. Nelson and coauthors found that most models “performed only slightly better than age alone as a risk predictor.” She pointed out, “There are a few risk factors shown to be more important in the trials.” These include a personal history of a high-risk breast lesion, such as atypical ductal hyperplasia, and a family history with a high number of breast cancers. “A woman with a previous high-risk lesion is in a unique situation, and a model doesn’t necessarily have to be used to identify her.” According to the task force draft recommendation statement, the “models are not recommended for use in women with a personal history of breast cancer, a history of radiation treatment to the chest, or a possible family history of mutations in the BRCA1 or BRCA2 genes.”

Side Effects Are Deterrents Women who are older and have a personal or family history of thromboembolic events are at higher risk for these events, but in general, the adverse effects of tamoxifen and raloxifene are hard to predict. In addition, “when considering a medication to reduce risk rather than to treat illness, it is important to factor the potential harms into the decision, because the women are healthy and we want to avoid making them unhealthy,” Dr. Nelson said. “The equation is different from when the patient has cancer and might more readily assume certain risks in order to be treated for the disease.” In a study of women with elevated breast cancer risk scores, 77% declined tamoxifen, most citing adverse effects.

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In the News

Even side effects that are not lifethreatening, but merely unpleasant, can be a deterrent. “If you are not feeling well because of the nuisance effects, 5 years of use may be intolerable,” Dr. Nelson commented. In the primary prevention trials of tamoxifen and raloxifene reporting adherence, “at least 70% of women used the planned treatment dose,” according to the evidence review. “Part of this high adherence rate is the result of women enrolled in trials being more committed than the average patient. However, it also indicates that many patients persist with treatment, suggesting that the nuisance effects are tolerable for many women,” Dr. Nelson said.

Reluctance to Prescribe Medications Three studies found that physicians’ recommendations were important influences on patients’ decisions to use risk-reduction medications, but a survey mailed to physicians found that only 27% of responding physicians had prescribed tamoxifen for breast cancer risk reduction in the past 12 months. “There has been low usage of these medications for risk reduction,” Dr. Nelson acknowledged. Part of the reason may be “the tendency to avoid drugs if one is healthy and how women view health and prevention in general,” Dr. Nelson stated.

Other health issues may be a higher priority. Physicians may be reluctant to prescribe breast cancer risk-reduction medications to women already taking medication for hypertension and other conditions. “It all comes down to very individualized stories,” Dr. Nelson said. “I think one of the reasons raloxifene may be more acceptable in primary care practices is because it has been used for years for osteoporosis. So it already is something that primary care doctors are familiar with, whereas tamoxifen has always been a drug that primarily oncologists use.” Physicians who prescribed tamoxifen as well as those who did not mentioned the time needed to address risk and other relevant issues with patients. “It is a complex discussion that could derail an appointment, and it is hard to do well in the course of a routine visit,” Dr. Nelson acknowledged. “A good outcome of our analyses might be that our estimates are useful in these discussions.”

Unanswered Questions “Not every question is answered by the trials,” Dr. Nelson acknowledged. “For instance, we don’t know the best age for women to take the medications. We don’t have good comparisons across different age or racial groups. There is limited information about premeno-

pausal women.” Since raloxifene is approved for postmenopausal women only, premenopausal women were not included in the head-to-head trial. The task force draft recommendation statement noted that while tamoxifen and raloxifene have been shown to reduce the risk of hormone receptor–positive breast cancer, these drugs “would not prevent the type of breast cancer that is the most difficult to treat.” Dr. Nelson noted, “There are additional medications that also reduce risk, but have only been studied in one or two prevention trials so far.” Examples include tiboline, lasofoxifene, and exemestane. Although these agents are not FDA-approved for breast-cancer reduction and were therefore not included in the evidence review, “they may expand clinical options,” according to the report. Tamoxifen and raloxifene reduced the incidence of invasive breast cancer, but “noninvasive breast cancer incidence and breast cancer–specific and all-cause mortality were not statistically significantly reduced by either medication, although trials were not powered for mortality,” the reviewers reported. Part of the reason for the lack of reduction in mortality is insufficient follow-up time. “It takes a long time to accrue adequate data to determine mortality out-

comes” in cancer prevention trials, Dr. Nelson said. “In these trials, participants are healthy at the beginning of the trial and need to tracked over time to measure mortality effects.” Other “evidence gaps” include determination of optimal doses and duration. “The ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial recently reported reduced recurrence of estrogen receptor–positive breast cancer and reduced breast cancer–specific and all-cause mortality rates in women with breast cancer after 10 vs 5 years of adjuvant therapy,” the report noted. “Whether a longer course provides a more favorable benefit–harm tradeoff for risk reduction in women without breast cancer has yet to be determined.” n Disclosure: Dr. Nelson reported no potential conflicts of interest.

References 1. Medications for risk reduction of primary breast cancer in women: U.S. Preventive Services Task Force recommendation statement (draft). April 2013. Available at www.uspreventiveservicestaskforce.org/ draftrec4.htm. Accessed May 14, 2013. 2. Nelson HD, Smith MEB, Griffin JC, et al: Use of medications to reduce risk for primary breast cancer: A systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 158:604-614, 2013.

Expect Questions from Your Patients

atients reading or hearing about the updated draft recommendation statement from the U.S. Preventive Services Task Force (USPSTF) on the use of medications to reduce risk for primary breast cancer1 may ask if and how it applies to them. To help answer those questions, the information presented below was compiled from the draft recommendation statement and a supporting fact sheet,2 and a systematic review of studies on the use of medications to reduce the risk for primary breast cancer.3

Key Recommendations What are the draft recommendations? The U.S. Preventive Services Task Force recommends: Clinicians engage in shared decision-making with women at increased risk of breast cancer about medications

to reduce their risk. For women who are at increased risk for breast cancer and at low risk for adverse medication effects, clinicians should offer to prescribe risk-reducing medications such as tamoxifen or raloxifene (Evista). Women who are not at increased risk for breast cancer should not routinely use medications such as tamoxifen or raloxifene.

Systematic Review What were the major findings of the systematic review of clinical trials of tamoxifen and raloxifene? The systematic review included seven randomized, controlled trials—four with tamoxifen, two with raloxifene, and one comparing tamoxifen and raloxifene, the Study of Tamoxifen and Raloxifene (STAR). The review con-

cluded that both medications reduced the incidence of invasive breast cancer and fractures and increased the risk of thromboembolic events. Tamoxifen was more effective than raloxifene in reducing breast cancer risk but also increased the risk of endometrial cancer and cataracts.

Pertinent Population Who does the draft recommendation statement apply to? The draft recommendation statement applies to asymptomatic women between the ages of 40 and 70 who have not been diagnosed with breast cancer, ductal carcinoma in situ (DCIS), or lobular carcinoma in situ (LCIS). Because tamoxifen and raloxifene were found to increase the risk of thromboembolic events, the draft rec-

ommendation on the use of tamoxifen and raloxifene to reduce the risk of primary breast cancer does not apply to women who have a history of thromboembolic events, such as deep venous thrombosis, pulmonary embolus, stroke, or transient ischemic attack. n References 1. Medications for risk reduction of primary breast cancer in women: U.S. Preventive Services Task Force recommendation statement draft. April 2013. Available at www.uspreventiveservicestaskforce.org. 2. Commenting on Task Force Draft Recommendations: U.S. Preventive Services Task Force. April 2013. Available at www.uspreventiveservicestaskforce.org. 3. Nelson HD, Smith MEB, Griffin JC, et al: Use of medications to reduce risk for primary breast cancer: A systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 158:604-614, 2013.

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ASCOPost.com | JUNE 10, 2013

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American Society of Breast Surgeons Annual Meeting Breast Cancer

Study Clarifies Appropriate Timing of Follow-up Imaging after Benign Breast Biopsies By Caroline Helwick

ollow-up imaging for patients with benign breast biopsies can be safely done at 12 months rather than 6 months, when radiologic and pathologic findings are concordant, according to a study reported at the American Society of Breast Surgeons Annual Meeting in Chicago.1 Current guidelines from the National Comprehensive Cancer Network (NCCN) recommend that such patients undergo follow-up imaging at 6 to 12 months. However, the value of the shorter-term interval is questionable, said Demitra T. Manjoros, MD, an oncology fellow at the Comprehensive Breast Center, Bryn Mawr Hospital, Bryn Mawr, Pennsylvania, who presented the findings. “Our data do not support the routine use of short-term interval imaging following benign concordant breast biopsy,” Dr. Manjoros said.

Study Details “It’s been difficult to know what the correct interval imaging is. Our study intended to determine if there is value to imaging at 6 months when you have benign concordant find-

BI-RADS: Breast Imaging-Reporting and Data Systema 0: Incomplete 1: Negative 2: Benign finding(s) 3: Probably benign 4: Suspicious abnormality 5: Highly suggestive of malignancy 6: Known biopsy-proven malignancy Published and trademarked by the American College of Radiology.

ings, or whether we are overimaging patients,” she told The ASCO Post. Dr. Manjoros and colleagues reviewed their experience at Bryn Mawr Hospital in 2010 with image-guided breast biopsy over a 12-month period. They evaluated the cancer yield and cost associated with imaging performed less than 12 months after a benign concordant biopsy in 689 patients who underwent image-guided biopsy (stereotactic, ultrasound-guided, or magnetic resonance imaging [MRI]-guided). Of the 689 patients, 188 cases were malignant (27.3%), 3 indicated nonbreast pathology (0.4%), and 498 (72.3%) were benign. Of the 498 patients with benign findings, 44 (8.8%) underwent surgical excision secondary to atypia, papillary lesions, discordant pathology, or other benign findings. Of this patient subset, 8 lesions were discordant. Of the 454 benign biopsy patients who did not have excisions, 3 lesions were discordant. The pathologic findings for these 11 discordant lesions included benign conditions in 7, high-risk conditions in 1, and invasive cancer in 3 cases. Of the 337 concordant patients, 169 patients had a total of 204 imaging studies done in less than 12 months, and these were analyzed for this study. Of these 169 patients, biopsy findings were fibrocystic change in 39.6%, benign tissue or cyst in 37.9%, fibroadenoma in 17.8%, papillary lesion in 3.6%, atypia in 0.6%, and “other” condition in 0.6%. Of the 169 patients, 128 were BIRADS 2 while the rest were mostly BI-RADS 1 and 3 (see box). Five (3.0%) had suspicious (BI-RADS 4) findings on follow-up imaging, 2 away from the original biopsy site and 3 at the biopsy site.

Imaging following Benign Breast Biopsy ■ After benign radiologic-pathologic concordant breast biopsy, follow-up

imaging at 12 months may be preferred to imaging at 6 months in some patients.

■ Only one cancer was detected among 169 patients in this setting imaged less than 12 months after biopsy.

Only One Cancer Identified Ultimately, only one breast cancer was identified, representing 0.6% of all benign concordant patients undergoing interval imaging, Dr. Manjoros reported. This occurred in a patient imaged less than 12 months from biopsy; none occurred among patients who were imaged more than 12 months postbiopsy. “Also, no cancers were identified with interval imaging after stereotactic or ultrasound-guided biopsy,” she added. The one missed cancer occurred in a 39-year-old woman with a history of left-sided breast cancer 4 years prior who was noted to have a 6-mm area of enhancement in the left breast on screening MRI away from the lumpectomy cavity. The initial MRI-guided biopsy was benign and concordant but the 6-month followup MRI showed an increased area of enhancement; needle-localized excision demonstrated invasive cancer. “This patient was a higher-risk patient and we believe she would have been identified regardless,” she said. She said another interesting finding was the high rate of cancer detection among patients whose lesions were discordant. “We had 11 discordant lesions, and of these, 3 (27.3%) were upstaged to invasive cancer, vs 0.6% in the benign concordant group,” she noted. The cost of finding one cancer among these 169 patients with benign concordant biopsies was $192,745 (by institutional billing charges). “This is

the cost for one institution over 1 year, which if multiplied across the country amounts to a lot of health-care dollars,” said senior author Andrea V. Barrio, MD, of MLHC Breast Surgical Specialists in Bryn Mawr.

Take-home Message Dr. Manjoros said the take-home message is that routine use of interval imaging less than 12 months after biopsy is unnecessary, though the shorter interval is warranted in select cases. “We are taking away the routine recommendation for evaluation and saying that in certain conditions we don’t need to do it,” she said. “Selective use should be considered when it is difficult to confirm lesion retrieval.” Dr. Barrio emphasized the need to correlate the imaging and histologic findings. “And you need to make sure you have a system set up so radiology and pathology can communicate for every biopsy, so you can say a lesion is discordant or not,” she said. Concordance assessment, in fact, should probably be a quality measure, she added. n

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

Reference 1. Manjoros DT, Collett AE, AlbertyOller JJ, et al: The value of six-month interval imaging following benign radiologic-pathologic concordant minimally invasive breast biopsy. American Society of Breast Surgeons Annual Meeting. Abstract 125. Presented May 2, 2013.

The ASCO Post | JUNE 10, 2013

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In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Some Stage II/III HER2positive Tumors May Be Treated with Targeted Therapy without Chemotherapy Results from a multicenter phase II II study of patients with locally advanced HER2-positive breast cancer who receive targeted therapy with trastuzumab (Herceptin) and lapatinib (Tykerb) “support the hypothesis that selected patients with HER2-positive tumors may not need chemotherapy,” investigators reported in the Journal of Clinical Oncology. Women with stage II or III HER2-positive breast cancers received trastuzumab once per week (4 mg/kg loading dose, then 2 mg/ kg) and lapatinib at 1,000 mg once daily for 12 weeks. Women with estrogen receptor (ER)-positive tumors also received letrozole, plus a luteinizing hormone–releasing hormone agonist if premenopausal. The median age of the patients was 49 years, and the range was 31 to 74 years. “The study enrolled patients with large tumors, with a median tumor size of 6 cm (range, 1.5 to 30 cm), and 62% of patients had tumors that were > 5 cm,” the researchers noted.

Clinical Benefit The overall pathologic complete response, defined as disappearance of invasive cancer in the breast, among the 64 patients evaluable for response was 27%, including 21% in the ER-positive group and 36% in the ER-negative group. “Here, we show in a neoadjuvant clinical trial in patients with locally advanced HER2-positive tumors that a potent cocktail of drugs that more completely blocks the HER network causes [pathologic complete response] in the breast in a substantial percentage of patients. Achieving this rate of [pathologic complete response] with targeted therapy only and without using chemotherapy is noteworthy and clinically meaningful,” the authors wrote. While “a subset of patients derived substantial clinical benefit from the 12-week treatment de-

spite large initial tumor size,” the researchers noted, “some of them, especially those with ER-positive tumors, still had minimal residual disease at the time of surgery. The rate of low-volume residual disease was 22%, including 33% in the ERpositive group and 4% in the ERnegative group. Overall, 89% of patients proceeded to surgery after completing the study treatment, although some received additional neoadjuvant therapy before surgery. “The study treatment was generally well tolerated,” the researchers reported. “Treatment was discontinued because of toxicity in only 6% of patients. The most common toxicities were diarrhea (grades 1 to 2, 63%; grades 3 to 4, 3%) followed by rash (grades 1 to 2, 55%; grades 3 to 4, 1%), fatigue (32%), nausea (31%), and elevated liver function tests (grades 1 to 2, 18%; grade 3, 5%; grade 4, 2%). Only one grade 4 toxicity was observed in the study (elevated liver function tests), which completely normalized after 8 weeks.” The investigators noted that the study needs to be validated in a large setting but concluded that the “results raise the prospect of sparing a subset of patients in the future the toxicity and cost of chemotherapy, a worthy and meaningful goal.” Rimawi MF, et al: J Clin Oncol. April 8, 2013 (early release online).

Surgery Delays Longer Than 6 Weeks in Young Women with Breast Cancer Decrease Survival Delays of more than 6 weeks from time of diagnosis until surgical treatment of breast cancer among young women significantly decreases survival times compared to those with a shorter treatment delay time, according to a study in JAMA Surgery. “This adverse impact on survival was more pronounced in African American women, those with public or no insurance,” and those with low socioeconomic status, the authors reported. The retrospective case-only study looked at 8,860 breast cancer cases diagnosed between 1997 and 2006 and included in the California Cancer Registry, part of the National Cancer Institute Surveil-

lance, Epidemiology, and End Results (SEER) program. “In contrast to some of the previous studies, we focused only on women younger than 40 years, where breast cancer is rare but mortality is high mainly because of aggressive biologic and pathologic characteristics of tumors specific to this age group,” the authors explained. Time to treatment delay was defined as the number of weeks between pathologic diagnosis and the date of definitive treatment, either earliest definitive surgery (partial mastectomy including lumpectomy, subcutaneous mastectomy, total [simple] mastectomy, modified radical mastectomy, radical mastectomy, extended radical mastectomy, and mastectomy not otherwise specified); or definitive chemotherapy given as the first course of treatment (including neoadjuvant chemotherapy followed by surgery).

Key Finding “The 5-year survival in women who were treated by surgery and had [treatment delay time] more than 6 weeks was 80% compared with 90% (P = .005) in those with [treatment delay time] less than 2 weeks,” the investigators stated. Treatment delays of more than 6 weeks differed significantly (P < .001) between racial/ethnic groups—15.3% for Hispanics and for African Americans compared to 8.1% for non-Hispanic whites. A treatment delay greater than 6 weeks was more likely among women with public or no insurance (17.8%) than those with private insurance (9.5%), and women with low socioeconomic status (17.5%) than high socioeconomic status (7.7%). On multivariate analysis, significant risk factors for shorter survival included longer treatment delay, estrogen receptor–negative status, having public or no insurance, and late cancer stage, the researchers reported. “Our study examined surgical delay time, which is a physicianrelated delay, after the diagnosis of breast cancer was established,” the authors wrote, while noting that surgical delay “can be affected by other patient-related factors such as insurance status and [socioeco-

nomic status],” or, if the diagnosis was made during pregnancy, waiting until after the birth of the baby to start treatment. It would also be important, the authors added, “to examine physicianrelated delay prior to the diagnosis of breast cancer since there are many anecdotal stories of young women who presented to their primary care physicians on numerous occasions prior to being diagnosed with breast cancer. From our literature search, we did not find any studies examining physician-related delay prior to the diagnosis of breast cancer in a large cohort of young women.” The investigators concluded, “it is crucial to prevent further physician-related delays before and after the diagnosis of breast cancer is established to maximize the survival of these young women who are in the most productive time of their life.” Smith EC, et al: JAMA Surg. April 24, 2013 (early release online).

Black, Asian, and Younger Women at Increased Risk of PTSD after Diagnosis of Localized Breast Cancer Nearly one-quarter of women in a large prospective study of racially diverse patients with stage I to III breast cancer reported symptoms consistent with posttraumatic stress disorder (PTSD), with increased risk of PTSD among black, Asian, and younger women. “These potential risk factors can be identified at the time of diagnosis and may present an opportunity to minimize PTSD symptomatology. This approach may improve the quality of patients’ lives and may also have an indirect impact on the observed racial disparity in breast cancer survival,” the study authors concluded in their report in the Journal of the National Cancer Institute. For the study, 1,139 women participating in the Breast Cancer Quality of Care Study at sites in New York, Detroit, and northern California completed three interviews—at baseline (2 to 3 months after diagnosis but before the third cycle of chemotherapy, if administered),

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In the Literature

and again at 4 and at 6 months after diagnosis. PTSD symptoms were assessed with the Impact of Event Scale, which “is one of the most commonly used measures of PTSD among adults and has been shown to perform well as a screening tool,” the researchers noted. “At all three time points, women diagnosed at a younger age [< 50 years] had a higher likelihood of PTSD. Asian and black women were the largest groups with PTSD both at baseline (29.3% and 28.2%, respectively; P = .03) and at the second time point, although at the second time point, black women had higher PTSD than Asian women (23.6% vs 20.0%; P < .01),” the researchers reported. “Positive lymph node status was associated with increased PTSD both at baseline (28.7%; P = .01) and at the second time point (16.8%; P = .03). Both stage III (23.9%; P = .01) and HER2-positive status (19.8%; P = .03) were associated with higher PTSD only at the third time point.” The prevalence of PTSD gradually declined over time, from 23% at baseline, to 16.5% at the first time point, and to 12.6% at the third time point. Persistent PTSD, defined as having PTSD at two consecutive interviews, was observed among 12.1% of participants. “Persons with PTSD have substantially worse quality of life than those without. Thus, a higher rate of PTSD among blacks and Asians may make their survivorship experience more difficult,” the authors noted. In addition, PTSD may interfere with compliance and, through its impact on the immune system, “might contribute to cancer progression.” Vin-Raiv N, et al: J Natl Cancer Inst 105:563-572, 2013. Smoking Early in Life Is More Strongly Associated with Increased Risk of Breast Cancer Analyses of data from 73,388 women in the American Cancer Society’s Cancer Prevention Study II (CPS-II) Nutrition Cohort and from a meta-analysis including 14 other studies “support the hypothesis that active smoking increases the risk of breast cancer, especially when smoking begins at an early age.” While the potential confounding effect of alcohol use—a known risk factor for breast cancer—has

been a persistent question in studies of the relationship between smoking and breast cancer, in the CPS-II cohort, alcohol consumption “did not appreciably confound these associations.” The CPS-II analyses were based on 3,721 invasive breast cancer case patients identified during a median follow-up of 13.8 years. At the time of enrollment in the study, 8.2% of women reported current smoking, 35.6% reported former smoking, and 56.2% reported never smoking. “In multivariable-adjusted models with smoking status as a time dependent variable, breast cancer incidence was higher in current (HR = 1.24, 95% CI = 1.07 to 1.42) and former smokers (HR = 1.13, 95% CI = 1.06 to 1.21) than in never smokers,” the researchers reported in the Journal of the National Cancer Institute. Women who started smoking before menarche or after menarche but 11 or more years before giving birth to their first child had higher risk (Ptrend = .03). “In analyses that stratified an alcohol drinking status, breast cancer was associated with current smoking ... in women who reported current and former drinking, but not in women who reported never drinking. However, the test for interaction between smoking and alcohol consumption was not statistically significant (P = .11),” the investigators noted. The meta-analyses were based on 31,198 breast cancer case patients in 15 cohorts totaling 991,100 women. Current and former smoking were weakly associated with breast cancer risk, but “younger age at smoking initiation was associated with a 12% increase in breast cancer risk,” researchers reported. “The most consistent evidence supporting a causal relationship between cigarette smoking and breast cancer risk is the stronger association observed for women who initiate smoking before age at first birth,” the authors pointed out. “Mammary tissue is thought to be more susceptible to genotoxic exposures before completion of the first full-term pregnancy because the terminal ductal–lobular units of the breast are not fully differentiated until the end of gestation. The relationship with early life smoking that we and others observed, together with the lack of a consistent relationship between breast cancer risk and smok-

ing later in life, suggests that active cigarette smoking may play a greater role in the initiation than the progression of breast cancer.” Gaudet MM, et al: J Natl Cancer Inst 105:515-525, 2013.

SUPPORTIVE CARE Older Patients and Those with Comorbidities Are Less Likely to Receive Palliative Radiotherapy Older patients and those with comorbid conditions are less likely to receive palliative radiotherapy, according to an analysis of data from 51,610 patients with stage IV breast, prostate, lung, or colorectal cancer. The study also found that black patients with prostate cancer were 20% less likely than white patients to receive palliative radiotherapy (P < .001) and black patients with colorectal cancer were 28% less likely (P < .001) to receive palliative radiotherapy. “Understanding these patterns of care, along with further research into the underlying causes, will improve access and quality of palliative [radiotherapy],” the investigators stated. Patients were identified using the Surveillance, Epidemiology, and End Results–Medicare linked database. Palliative radiotherapy had been administered to 41% of the total, including 53% of patients with lung cancer, 42% of patients with breast cancer, 40% of patients with prostate cancer, and 12% of patients

with colorectal cancer. “Among those with lung, breast, or prostate cancer, there were higher rates of palliative [radiotherapy] in higher socioeconomic classes and among people who were married,” the authors noted. A significant number of patients died within 2 weeks of completing radiotherapy, including 23% of patients with lung cancer, 12% of patients with colorectal cancer, 11% of patients with breast cancer, and 8% of patients with prostate cancer. “In addition to tumor site, significant predictors (P < .05) of death within 2 weeks of receiving [radiotherapy] included increased age, increased comorbidity, and male sex,” the researchers reported. Identifying and understanding why patients sometimes receive radiotherapy within the last few weeks of their lives “poses a challenge, given that the timing of radiotherapy depends on multiple factors,” the authors wrote. “Although earlier patient identification and referral to a radiation oncologist could help, this approach may not be feasible in all patients, given their relatively short overall survival. Physicians consistently overestimate survival in patients with cancer at the end of life, and improved prognostic tools or biomarkers could lead to enhanced patient selection. In addition, improvements in the delivery of radiation therapy, such as faster times from referral to treatment or shorter courses of palliative [radiotherapy]

continued on page 122

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In the Literature

Emerging Clinical Data continued from page 121

would effectively lengthen the interval between [radiotherapy] and death. Further research is desperately needed to better understand this complicated issue.” Murphy JD, et al: J Oncol Pract. April 16, 2013 (early release online).

Patients with Cancer Can Have Cachexia-related Poor Prognostic Factors Regardless of Overall Weight

share a poor prognosis, regardless of overall body weight,” concluded a study in the Journal of Clinical Oncology. Researchers assessed 1,473 patients with lung or gastrointestinal cancers at presentation for weight loss history, lumbar skeletal muscle index, and mean muscle attenua-

“Patients with cancer who are cachexic by the conventional criterion (involuntary weight loss) and by two additional criteria (muscle depletion and low muscle attenuation)

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tion by computed tomography. By body mass index distribution, 36% were normal weight, 35% were overweight, 17% were obese, and 12% were underweight. “Patients in all [body mass index] categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival,” the investigators explained. “Patients who possessed all three of these poor prognostic variables survived 8.4 months [95% CI = 6.5– 10.3], regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months [95% CI = 24.2–32.6; P < .001],” the researchers reported. The authors noted that while the conventional view of cancer cachexia was patients who appear thin or wasted, “patients in our cohort were more commonly overweight or obese, but they often harbored occult, severe pre-existing muscle depletion.” Diagnostic imaging is important in revealing this depletion. “We feel this is of increasing importance as the world prevalence of overweight/obesity continues to climb; these patients have a survival no longer than patients who are frankly cachectic if they have simultaneous weight loss, sarcopenia, and low [muscle attenuation],” the authors wrote. n Martin L, et al: J Clin Oncol 31:1539-1547, 2013.

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Letter to the Editor

More Recollections on Emil ‘Tom’ Frei III, MD

have read with interest the recent tributes to Emil “Tom” Frei III, MD, who passed away in April. I was backstage at the ASCO Annual Meeting in 1981, when Dr. Frei was giving his Karnofsky acceptance address. I had a slide presentation at the combined ASCO/American Association for Cancer Research (AACR) meeting, which followed immediately thereafter. Back then, the ASCO and AACR meetings were held during the same week, at the same venue. The ASCO meeting was held on the first 3 days, with the AACR meeting following. On the afternoon of the final day of the ASCO meeting and on the first day of the AACR meeting, there was a combined ASCO/AACR session, which consisted of about 10 papers felt to be of interest to both ASCO and AACR membership (papers that today would be broadly considered “translational research”). This session followed immediately after the Karnofsky address. I recall the venue as having an actual stage, with a curtained-off waiting area, from where I watched the speech.

Two Types of Researchers I was thrilled in particular by a portion of Dr. Frei’s address, wherein he described two types of clinical cancer researchers, namely “investigators”

vs “discoverers.” The investigators proceed in a very orderly fashion, are esteemed by their peers, typically succeed (at least in answering the often rather ordinary question being addressed by their work), but produce, at most, single-step advances and don’t create new paradigms. Discoverers, on the other hand, follow a path of inquiry that often seems disordered, tend not to be esteemed by their peers, of-

We’ve had some breakthroughs of lesser magnitude in oncology: anti-HER2 treatment of breast cancer, anti-CD20 in lymphatic neoplasms, tyrosine kinase inhibitors, and so forth. But I think that Dr. Frei’s exhortation to be more supportive of “discoverer”-type researchers has never been acknowledged, much less embraced. When his Karnofsky address was subsequently published in the journal Cancer, there

I was thrilled in particular by a portion of Dr. Frei’s address, wherein he described two types of clinical cancer researchers, namely “investigators” vs “discoverers.” —Larry Weisenthal, MD, PhD

ten fail, but, on occasions where they do succeed, produce multistep advances and create new paradigms. Dr. Frei’s point was that the clinical oncology research establishment would be well advised to be more supportive of the work of discoverers. Since that 1981 speech, the best example of discovery-oriented clinical research of which I am aware comes from gastroenterology—the central role of bacterial infection (Helicobactor pylori) in peptic ulcer disease.

was only passing mention of the investigator vs discoverer concept, which had been a major point in the address itself, and this point didn’t even appear in the abstract.1

Encouraging Would-be Discoverers If anyone ever wished to honor Dr. Frei with some type of ASCO award to be presented in his name, it might be, for example, an award for the most creative discovery-oriented research

presented at the previous year’s ASCO Annual Meeting. This might focus more attention on the need for more out-of-the-box thinking, in a world where investigators control the peerreview pipeline, investigators beget more investigators, and there are decreasing opportunities for would-be discoverers. Note that the “Emil Frei Award” would be different from the usual awards, which require confirmation through years of follow-up work. As Dr. Frei pointed out that discoverers often fail, what is honored is a potentially breakthrough idea, supported by credible pilot data. One important purpose of the award would be to focus attention on the new idea so that it will receive scrutiny and early confirmation or refutation. The fact that the work would attract such scrutiny should serve to discourage fraud and encourage the would-be discoverer to have reasonable certainty that he or she is on a sound path.n —Larry Weisenthal, MD, PhD Huntington Beach, California Disclosure: Dr. Weisenthal reported no potential conflicts of interest.

Reference 1. Frei E 3rd: Clinical cancer research: An embattled species. Cancer 50:19791992, 1982.

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myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thrombotic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.10 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.14 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.15 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly

in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.16 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Fourteen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with STS who Received VOTRIENT

Adverse Reactions Fatigue

VOTRIENT

Placebo

(N=240)

(N=123)

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

Diarrhea

Nausea

Weight decreased

Hypertension

Appetite decreased

Hair color changes

Vomiting

Tumor pain

Dysgeusia

Headache

Musculoskeletal pain

Myalgia

Gastrointestinal pain

Dyspnea

Exfoliative rash

Cough

Peripheral edema

Mucositis

Alopecia

Dizziness

Skin disorderb

Skin hypopigmentation

Stomatitis

Chest pain

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

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

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

VOTRIENT Placebo (N=240) (N=123) All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 % % % % % % 44 43 36 33

1 10 3 4

0 0 1 0

15 36 6 7

0 9 0 0

0 2 0 0

51 46 45

5 8 <1

3 2 0

22 18 35

2 2 2

0 1 0

T:14”

B:14.25”

S:13”

Alkaline phosphatase 32 3 0 23 1 0 increased Sodium decreased 31 4 0 20 3 0 Total bilirubin 29 1 0 7 2 0 increased Potassium increased 16 1 0 11 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the STS clinical trial. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)] 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.16)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile

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

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

VOTRIENT is a registered trademark of GlaxoSmithKline.

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

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

1.6 MONTHS 4.6 MONTHS

Proportion progression-free

1.0

Median PFS

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

Median PFS

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

0.8

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

0.6 0.4 0.2 0.0 0

Months

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

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

• Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures. Treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence.

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

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In soft tissue sarcoma, a dose decrease or increase should be in 200 mg steps based on individual tolerability • In patients taking VOTRIENT, dose modifications, interruptions, and discontinuations may be required for hepatic impairment, drug interactions, and following adverse events • In the advanced STS clinical trial, 58% of patients on VOTRIENT required a dose interruption; 38% of patients on VOTRIENT had their dose reduced • Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modifications based on drug interactions, please see Section 2.2 of accompanying Brief Summary

T:14”

B:14.25”

S:13”

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

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

• Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs 0% in the placebo group). • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.

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

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. • Adverse Reactions in the Randomized STS Trial: Fifty-eight percent of patients on VOTRIENT required a dose interruption, 38% of patients on VOTRIENT had their dose reduced, and 14% of patients who received VOTRIENT discontinued therapy due to adverse reactions.

VOTRIENT.com/HCP GSKSource.com

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

LIGHTING A WAY FORWARD

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