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FEBRUARY 15, 2013

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

Gastrointestinal Cancers Symposium

Nab-paclitaxel/Gemcitabine Combination Improves Overall Survival in Pancreatic Cancer

ASCOPost.com

We Need Gemtuzumab Available Again to Treat AML

By Caroline Helwick

I

n patients with treatment-naive metastatic pancreatic cancer, the addition of nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) to gemcitabine improved overall survival vs gemcitabine alone, in an international study presented at the 2013 Gastrointestinal Cancers Symposium.1

Daniel Von Hoff, MD

New Standard “We are very proud of this study and we are confident in this result. We believe that nab-paclitaxel plus gemcitabine is a new standard for the treatment of patients with metastatic pancreatic cancer,” said Daniel Von Hoff, MD, Physician-in-Chief and Distinguished Professor at the Translational Genomics

Research Institute (TGen) in Scottsdale, Arizona.

Nab-paclitaxel is approved for the treatment of metastatic breast cancer. Studies with other taxanes in pancreatic cancer have not been encouraging.

“The past few decades have See Page 97 brought us very few treatment advances for patients with advanced pancreatic cancer. I have counted 33 phase III trials since 1990, and only 3 were positive. This has been a frustrating area,” he said in an interview with The ASCO Post.

“The fact that nab-paclitaxel plus gemcitabine demonstrated an overall survival benefit, and also did so at 1 and 2 years, is a significant step forward in offering potential new hope for our patients,” Dr. Von Hoff said.

He believes the regimen could also serve as a backbone continued on page 10

Quality Care Symposium

Integration across the Spectrum: Community Perspective on the Medical Oncology Home Model

By Ronald Piana

T

he term “patient-centered cancer care” has become ingrained in today’s health-care vernacular. However, no matter what modifications occur in clinical oncology practice, the terms value and cost-effectiveness are now a solid part of the equation. At ASCO’s Quality Care Symposium, Linda D. Bosserman, MD, FACP, President of the Wilshire Oncology Medical Group, spoke about how

to achieve value and quality in today’s challenging economic setting.

“We are in the Wild West California. A few years ago, our group was offered a capitated contract basically on a take-it-or-leave-it basis. So, we took it and fully evaluated the care we were providing and how that would fit into a monthly fixed payment with few drug carve-outs and a potential annual bonus only if the whole physician group did well. We then had to figure The takeaway message is that the out how to work within a partnership within our group and with capitated environment and still maintain the value that the payers keeps evolving. The end we pride ourselves on,” said Dr. Bosserman. result is high-quality, cost-effective The Wilshire Group care that is validated by outcomes, has seven treatment centers in Southern Califormeasurement, and reporting. nia and, in 2010, entered —Linda D. Bosserman, MD, FACP

By Farhad Ravandi, MD, Jorge Cortes, MD, and Hagop Kantarjian, MD

T

he word “revival” signifies a renewed use or acceptance after a period of inactivity; similarly, the word “resurrection” refers to the concept of an entity coming back to life after death. In the past year, these terms have been used frequently by us (and others) in articles calling for the return of gemtuzumab ozogamicin (Mylotarg).1-3 Some may wonder about the intense interest in bringing this drug back to clinical oncology. Do the available data support the assertion that gemtuzumab is an important drug in the treatment of patients with acute myeloid leukemia (AML)? Do they justify a reversal of the decision by the producers of the drug to withdraw it from the market?

Efficacy and Economics In previous commentaries, we have discussed the data supporting the role of gemcontinued on page 97

Dr. Ravandi and Dr. Cortes are Professors in the Department of Leukemia, and Dr. Kantarjian is Chair of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

MORE IN THIS ISSUE Oncology Meetings Coverage ASH Annual Meeting ��������������� 3, 18, 30 ESMO Congress ��������������������������������������� 9 San Antonio Breast Cancer Symposium �������� 23, 24, 26, 41 Quality Care Symposium ��������������������� 58 Selumetinib/Docetaxel in Lung Cancer ��������������������������������������������19 FDA Update ����������������������������������������� 28-29 Direct from ASCO �����������������������������45-48

continued on page 8

Send your comments to editor@ASCOPost.com

A Harborside Press® Publication

The ASCO Post | FEBRUARY 15, 2013

PAGE 2

Erratum

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

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

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

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

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

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

Douglas W. Blayney, MD Stanford University Medical Center

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

Philip D. Bonomi, MD Rush University Medical Center

George W. Sledge, MD Indiana University

Richard Boxer, MD University of Miami

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

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

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

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

Lynn D. Wilson, MD Yale University School of Medicine

Jay S. Cooper, MD Maimonides Medical Center

Stanley H. Winokur, MD Singer Island, Florida

John Cox, DO Texas Oncology

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

E. David Crawford, MD University of Colorado

International Editors

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

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

George D. Demetri, MD Dana-Farber Cancer Institute

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

Paul F. Engstrom, MD Fox Chase Cancer Center

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

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

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

John A. Fracchia, MD New York Urological Associates

Jacek Jassem, MD Medical University of Gdansk, Poland

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

David Khayat, MD Pitie-Salpetriere Hospital Paris, France

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

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

Michael P. Link, MD Stanford University Medical Center

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

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

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

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

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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.

T

wo of the articles published in the January 15, 2013, issue of The ASCO Post included comments from a Dr. Peter Ellis. One report, from the 2012 Quality Care Symposium referred to Peter G. Ellis, MD, of UPMC, Pittsburgh, while a second report pertained to a presentation at the 35th ESMO Congress made

by Peter Ellis, MBBS, PhD, of McMaster University, Hamilton, Ontario, Can-

Peter G. Ellis, MD

ada. Unfortunately, the same photo (of the latter Dr. Ellis) appeared in both articles.

See Page 97 The correct photo for the article, “Developing Cancer Care Pathways for the New Environment,” is shown at left below, and the correct photo for the article, “French Investigators Prospectively Test Genomically Driven Treatment in Metastatic Breast Cancer,” is shown at right.

We regret the error and apologize for the confusion.

The photos on our website (ASCOPost.com) and in the digital edition of the issue (http://issuu.com/ascopost/ docs/tap_vol_4_issue_1) Peter Ellis, MBBS, PhD have been corrected.n

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication.

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.

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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.

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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 | FEBRUARY 15, 2013

PAGE 3

ASH Annual Meeting Hematology

Chemotherapy-free Regimen Successful in Acute Promyelocytic Leukemia

By Alice Goodman

F

or the first time, a chemotherapy-free regimen was superior to conventional cytotoxic chemotherapy for the treatment of acute promyelocytic leukemia (APL). The combination of all-trans retinoic acid (ATRA) plus arsenic trioxide (Trisenox) achieved significantly superior overall survival compared to ATRA plus chemotherapy: 98.7% vs 91.1%, reSee Page 97 spectively. Patients who received ATRA plus arsenic trioxide had a 2-year event-free survival of 97% vs 86.7% for those who received ATRA plus chemotherapy (idarubicin followed by anthracycline-based consolidation and maintenance therapy).

New Strategy “APL is a rare but aggressive subtype of acute myeloid leukemia (AML). Recent research suggests that malignant cells can be transformed rather than killed, and this means that acute leukemia may be curable without chemotherapy,” stated Francesco Lo-Coco, MD, Chair of the APL subcommittee of the Italian GIMEMA group and Professor of Hematology at University Tor Vergata, Rome, Italy.

“Our results are an important step toward the further utilization of targeted therapies for other types of leukemia, as we begin to focus on improving the overall treatment experience for patients by offering new strategies that deliver the same efficacy as traditional options with considerably less toxicity,” he stated.

Intergroup Study APL 0406 was an intergroup study conducted by GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto), SAL (Study Alliance Leukemia Group), and AMSLG (German-Austrian AML Study Group), designed as a noninferiority trial to compare arsenic trioxide plus

ATRA vs ATRA plus chemotherapy (the standard of care at the time the trial was initiated). APL 0406 randomly assigned 162 patients with standard-risk APL in a 1:1 ratio to both arms.

“This was the first randomized controlled trial to compare these two regimens in APL,” Dr. Lo-Coco noted.

Patients in the ATRA/arsenic trioxide group received both drugs daily until complete remission was achieved; then arsenic trioxide 5 days per week, 4 weeks on/4 weeks off, for a total of 4 courses and ATRA 2 weeks on/2 weeks off for a total of 7 courses, for a total duration of 28 weeks. Standard treatment was ATRA/idarubicin as induction, followed by three cycles of ATRA/anthracycline and ATRA/mitoxantrone consolidation therapy, followed by ATRA plus low-dose chemotherapy maintenance therapy for 2 years.

Complete remission was achieved in 100% of the ATRA/arsenic trioxide arm vs 95% of the ATRA/chemotherapy arm.

Two-year event-free survival was achieved in 97% in the ATRA/arsenic trioxide arm (with one death and two relapses) vs 86.7% in the ATRA/chemotherapy arm (seven deaths and four relapses). Diseasefree survival rates were 97% and 90%, respectively. Cumulative incidence of relapse rates were 1.4% vs 5.6%, respectively.

Fewer side effects, including significantly less fever, neutropenia, and thrombocytopenia (P < .001 for all three effects), were reported in the chemotherapy-free arm, Dr. Lo-Coco said.

Continuous Progress “There has been continuous progress in treating APL. In the early 1990s, ATRA was found to be highly effective when combined with chemotherapy, making it the standard of care for APL. In 1996, response to arsenic trioxide was seen, creating the potential for a regimen that would avoid the toxicity of chemotherapy-based

Treating Acute Promyelocytic Leukemia ■■ A chemotherapy-free regimen of all-trans retinoic acid and arsenic trioxide achieved better outcomes compared with conventional therapy in acute promyelocytic leukemia.

■■ This is the first randomized trial to demonstrate these results.

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

regimens. Now the chemotherapy-free combination of ATRA plus arsenic trioxide has been shown to improve outcomes even further,” he commented.

“APL is still a fulminant disease that needs to be promptly diagnosed and treated; otherwise patients will die within hours or days,” he stated. “This represents success in transforming malignant cells into ‘good guys’ through ATRA, to become terminally differentiated cells that die. It represents the demolition of dogma, with a remarkable cure rate with ATRA plus arsenic trioxide.”

‘Huge’ Step Forward in APL Commenting on this study, press conference moderator William G. Woods, MD, Pediatric Hematology/ Oncology Director and the Daniel P. Amos Children’s Chair, Aflac Cancer and Blood Disorders Center, Children’s

Healthcare of Atlanta, said, “This is the first curative treatment for APL that does not include myelosuppressive chemotherapy. This is a huge step forward in the front-line treatment of APL.” n

Disclosure: Dr. Lo-Coco is a member of the advisory committee for Boehringer Ingelheim, and a member of the speakers bureau for Cephalon. Dr. Woods reported no potential conflicts of interest.

Reference 1. Lo-Coco F, Avvisati G, Orlando SM, et al: ATRA and arsenic trioxide (ATO) versus ATRA and idarubicin (AIDA) for newly diagnosed, non-high risk acute promyelocytic leukemia (APL): Results of the phase III, prospective, randomized, intergroup APL0406 study led by the Italian-German cooperative groups GIMEMA-SAL-AMLSG. 2012 ASH Annual Meeting. Abstract 6. Presented December 9, 2012.

EXPERT POINT OF VIEW

By Farhad Ravandi, MD

O

ver the past 2 decades, we have witnessed remarkable progress in the treatment of patients with acute promyelocytic leukemia (APL). The introduction of all-trans retinoic acid (ATRA) in the front-line therapy setting and arsenic trioxide in the relapse setting had already led to a significant improvement in the outcome of these patients. In this randomized trial,1 Dr. Lo-Coco and colleagues have confirmed prior phase II reports of high efficacy of the combination of these two drugs for the initial treatment of patients with low-risk disease, which constitute about two-thirds of the patients with APL. They have unequivocally proven that an acute leukemia can be more effectively treated with drugs that target the underlying pathogenic molecular events rather than with nonspecific cytotoxic chemotherapy, which is also associated with higher toxicity. Although their population was limited to patients with low-risk disease, conventional wisdom as well as prior nonrandomized clinical trials suggest that this strategy, perhaps with the addition of minimal chemotherapy, may also be effective in patients with high-risk APL. More importantly, as the author quite aptly suggests, these results are an important step toward the utilization of targeted therapies for other types of leukemia and hopefully a prelude for future strategies in cancer therapy, in general. n Disclosure: Dr. Ravandi reported no potential conflicts of interest.

Reference 1. Lo-Coco F, Avvisati G, Orlando SM, et al: ATRA and arsenic trioxide (ATO) versus ATRA and idarubicin (AIDA) for newly diagnosed, non-high risk acute promyelocytic leukemia (APL): Results of the phase III, prospective, randomized, intergroup APL0406 study led by the Italian-German cooperative groups GIMEMASAL_AMLSG. 2012 ASH Annual Meeting. Abstract 6. Presented December 9, 2012.

Dr. Ravandi is Professor of Medicine at the University of Texas-MD Anderson Cancer Center in Houston, Texas.

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.

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

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

ADT = androgen-deprivation therapy.

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women.

ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in study 1) or NYHA Class II to IV heart failure (in study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated

with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

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

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

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

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

Reference: 1. Data on file. Janssen Biotech, Inc.

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

K08Z121176

Adverse Reactions—The most common adverse reactions (≥ 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion.

The most common laboratory abnormalities (> 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index.

If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on its use with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors or inducers on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution during treatment with ZYTIGA®.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

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

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment.

Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castrationresistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥ 2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT > 5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

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

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

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

29.5 26.2

4.2 3.0

23.4 23.1

4.1 2.3

26.7

1.9

18.3

0.8

19.0 8.5

0.3 1.3

16.8 6.9

0.3 0.3

17.6 6.1

0.6 0

13.5 3.3

1.3 0

11.5 5.4

2.1 0

7.1 2.5

0.5 0

10.6

0

7.6

0

7.2 6.2

0.3 0

5.1 4.1

0.3 0

5.9

1.4

2.3

0

7.2 3.8 2.3

1.1 0.5 1.9

4.6 2.8 1.0

1.0 0 0.3

1 Adverse

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

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 2 Includes 3 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Laboratory Abnormality Hypertriglyceridemia High AST Hypokalemia Hypophosphatemia High ALT High Total Bilirubin

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

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

Study 2: Metastatic CRPC Prior to Chemotherapy Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy.

Patients were ineligible if AST and/or ALT ≥ 2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥ 2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Prednisone (N=542) Grade 3-4 System/Organ Class All Grades1 Adverse reaction % % General disorders Fatigue 39.1 2.2 Edema2 25.1 0.4 Pyrexia 8.7 0.6 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 Groin pain 6.6 0.4 Gastrointestinal disorders Constipation 23.1 0.4 Diarrhea 21.6 0.9 Dyspepsia 11.1 0.0 Vascular disorders Hot flush 22.3 0.2 Hypertension 21.6 3.9 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 Dyspnea 11.8 2.4 Psychiatric disorders Insomnia 13.5 0.2 Injury, poisoning and procedural complications Contusion 13.3 0.0 Falls 5.9 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 Nasopharyngitis 10.7 0.0 Renal and urinary disorders Hematuria 10.3 1.3 Skin and subcutaneous tissue disorders Rash 8.1 0.0 1 Adverse

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

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

1.7 1.1 0.2

25.2 4.1

2.0 0.7

19.1 17.8 5.0

0.6 0.9 0.2

18.1 13.1

0.0 3.0

13.5 9.6

0.2 0.9

11.3

0.0

9.1 3.3

0.0 0.0

8.0 8.1

0.0 0.0

5.6

0.6

3.7

0.0

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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

Storage and Handling: Store at 20oC to 25oC (68oF to 77oF); excursions permitted in the range from 15oC to 30oC (59oF to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

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

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

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

38.2

8.7

31.7

7.4

56.6 41.9 37.3 32.8 17.2

6.5 6.1 3.1 0.4 2.8

50.9 29.1 28.7 25.0 10.2

5.2 0.7 1.1 0.2 1.7

on non-fasting blood draws

Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms.

Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo.

Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE There have been no reports of overdose of ZYTIGA during clinical studies.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

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

The ASCO Post | FEBRUARY 15, 2013

PAGE 8

Quality Care Symposium Medical Oncology Home continued from page 1

into an alliance with Texas-based US Oncology, which was subsequently purchased by McKesson Corporation.

A Culture Change “Our move to patient-centered care [and the team-based “medical home” model] was a significant culture change that took leadership and a reengineering of the practice and patient experience to one in which the patient is totally engaged as a partner. We also had to be fully committed to work with the payer; this becomes a relationship more than a contract,” said Dr. Bosserman. She added, “Our patients are being driven out of the PPO [preferred provider organization] market because of high premiums and copays, so it is just as important for us to be cost-effective across the whole continuum of care.”

Dr. Bosserman noted that her group moved to customizable electronic medical records in 2005, which helped them program decision support and collect a comprehensive picture of their treatments. “Our hypothesis was that delivering cost-effective care using evidence-based guidelines, with comprehensive care coordination and management, can lower costs and improve health outcomes and satisfaction, from prevention to end of life,” commented Dr. Bosserman.

Reengineering the Practice “It is important that physicians in your practice assume leadership roles.

We partner at every level of our group’s

system; it is a cooperative model, not hierarchical. We have comprehensive monthly clinical meetings, in which we discuss pathways and review our new patients and our data. There is nothing that changes physician behavior quicker than feedback,” stressed Dr. Bosserman.

Dr. Bosserman added that reengineering the doctor-patient relationship is also a central component of the medical home model. “We make

lively series of substantive meetings. I then contacted the chief medical officer at Anthem Blue Cross, our largest payer in California, and we gradually developed an idea that wasn’t immediately “ready for prime time.” We launched the medical oncology home pilot model about a year ago,” said Dr. Bosserman.

The first step was identifying the key cost drivers in five categories: therapies, supportive care, symptom

The partnership within our group and with the payers keeps evolving. The end result is high-quality, cost-effective care that is validated by outcomes, measurement, and reporting.

—Linda D. Bosserman, MD, FACP

sure that all our patients are educated about their treatments. We encourage them to call us, which reinforces the concept that we are there for their all health-care needs. We have a proactive call service that contacts patients, with a built-in patient satisfaction survey to be added next year,” said Dr. Bosserman.

Medical Home Model Dr. Bosserman explained how her group transitioned within the fairly hostile capitation environment to the medical home model. “Several years ago I went on the board of our local individual practice association and began sharing data about our outcomes and cost savings. This generated a

management, optimizing site of care to prevent hospital visits, and endof-life care. “For instance, we saved a significant amount of money by using guidelines from ASCO and NCCN, as well as our internally identified costeffective pathways (like US Oncology Network’s Level 1 pathways) to choose drug regimens with benefits equal to those of higher-priced therapies. We also had substantial savings by providing proactive relief of seven common symptoms, any of which can also lead to unnecessary, expensive ER and hospital visits,” said Dr. Bosserman.

“We looked at whether our choices of cost-effective regimens were less than the California average and cer-

tainly less than the highest-cost option on the National Comprehensive Cancer Network [NCCN] guidelines. And we realized that our treatment planning fees made up the difference between the California costs, so we actually came in at lower than the state average, and well below the NCCN costs. Clearly, measurement and planning can be done, and we can be paid for our services in a way that is consistent with the cancer care system staying in business,” said Dr. Bosserman.

An Evolving Model “We learned that delivering highquality patient-centered care is possible as long as it is evidence-based and outcomes-driven. Our group treats patients in two counties in California that each have populations greater than those of 15 states, so broad access across the spectrum of patients is achievable. Moreover, working in partnership with the payer, we learned that some of the generic drugs we were using were more expensive than alternative generic therapies,” Dr. Bosserman continued.

“The takeaway message is that the partnership within our group and with the payers keeps evolving. The end result is high-quality, cost-effective care that is validated by outcomes, measurement, and reporting. This is really what we went into medicine for; it’s just a new way of looking at it,” concluded Dr. Bosserman. n

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

Don’t Miss These Important Reports in This Issue of The ASCO Post Farhad Ravandi, MD, and colleagues on Gemtuzumab in AML, see page 1

Charles J. Ryan, MD, on Abiraterone in Patients with Prostate Cancer, see page 37

Cyberspace and Cancer, discussed by Edward P. Ambinder, MD, see page 53

Patient Navigation in Harlem and Nationwide, with Harold P. Freeman, MD, see page 56

Hope S. Rugo, MD, on Treating HER2-positive Disease in 2013, see page 63

David A. Karnofsky, MD, and Important Contributions to Cancer Research and Medical Oncology, see page 80

Visit The ASCO Post online at ASCOPost.com

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PAGE 9

News Gastrointestinal Oncology

TH-302 plus Gemcitabine Delays Progression in Untreated Advanced Pancreatic Adenocarcinoma

By Caroline Helwick

A

novel drug that is activated under conditions of hypoxia significantly delayed progression in locally advanced or metastatic pancreatic adenocarcinoma when combined with gemcitabine in untreated patients.

The findings of the randomized phase II TH-CR-04 trial were presented at the 2012 ESMO Congress by Mitesh J. Borad, MD, Assistant Professor of Medicine at the Mayo Clinic in Scottsdale, Arizona.1 TH-302 is a tumor-selective, hypoxia-activated cytotoxic prodrug.

“Pancreatic cancer is one of the more hypoxic tumors,” he noted.

Study Details The multicenter TH-CR-04 trial randomly assigned 214 patients with previously untreated advanced pancreatic adenocarcinoma to gemcitabine plus TH-302 (240 mg/m2 or 340 mg/m2) or placebo.

Median progression-free survival was 6.0 months with gemcitabine plus TH-302 at the higher dose, 5.6 months with the lower dose of the drug, and 3.6 months with placebo, for a 41% reduction in progression with TH-302 given at 340 mg/m2 (P = .008). All subgroups showed benefit, Dr. Borad reported.

Mean nadir change in CA19-9 was –523 U/mL with placebo, –3,909 U/ mL with the lower dose of TH-302 and –5,385 U/mL with the higher dose, for a greater mean decrease with TH-302. Response rates were increased from 10% without the drug to 26% with TH-302.

Median overall survival was approximately 9 months with either active treatment arm and 6.9 months with placebo, which was not statistically significant (the study was not powered for this endpoint). In a post-hoc analysis, a significant difference was shown in 6-month survival

EXPERT POINT OF VIEW

M

ichel Ducreux, MD, PhD, of the Institut Gustave Roussy in Villejuif, France, discussed the findings at the ESMO meeting. He said that TH-302 represents a “new drug and new concept, the microenvironment.” He noted, “Pancreatic cancers are frequently hypovascularized, at least the primary tumor, and there is good rationale for the use of a drug that is cytotoxic under hypoxic conditions.”

He called the trial “a well done randomized Michel Ducreux, MD, PhD phase II trial in a well-balanced population,” but questioned the continuation of the low-dose arm and the inclusion of both advanced and metastatic patients. “We know these are different populations, and even within locally advanced disease there are two categories. This is not the way to run trials in pancreatic cancer,” he maintained.

He also had some concerns about hematologic toxicity with the higher dose, which was associated with grade 3 or 4 thrombocytopenia (63%), neutropenia (60%), and anemia (27%). “This drug is probably a little difficult to handle,” he figured.

Additional Concerns He further questioned whether gemcitabine is the “adequate drug” to combine with TH-302. “We always use gemcitabine as the standard of care and compare the new regimen with it, but we know this not so good for metastatic disease,” he said. “In the future, the backbone of treatment in advanced and metastatic pancreatic cancer will not be gemcitabine.”

Dr. Ducreux also described other novel approaches that target the microenvironment in advanced pancreatic tumors, including nab-paclitaxel (Abraxane), which has the advantage of having a predictive biological test (SPARC level). He even questioned whether targeted therapy is appropriate for this disease. Other targeted therapies, including cetuximab (Erbitux), bevacizumab (Avastin), and to some extent erlotinib (Tarceva) have “failed to change the dismal prognosis of these tumors.”

In conclusion, he said that TH-302 has shown consistent efficacy, good response rates, a clearly positive progression-free survival benefit, a marginally positive overall survival benefit, and a favorable toxicity profile, “so there is hope here.” n Disclosure: Dr. Ducreux reported no potential conflicts of interest.

between the gemcitabine arm (57%) and the high-dose TCH-302 arm (73%, P = .037), he added.

In addition, in the small group of 11 patients in the control arm who crossed over to the experimental

TH-302 plus Gemcitabine in Pancreatic Cancer ■■ The novel hypoxia-activated drug TH-302 plus gemcitabine significantly

delayed progression in previously untreated advanced pancreatic cancer.

■■ Median progression-free survival improved from 3.6 months with

gemcitabine alone to 6.0 months with gemcitabine plus high-dose TH-302.

■■ The drug is one of several emerging agents targeting the tumor microenvironment in advanced pancreatic cancer.

arms, median overall survival reached 13.4 months with gemcitabine plus TH-302 given at 340 mg/m2. While this open-label phase was not designed to estimate an overall survival treatment effect, and the number of patients is small, “this seems to be a wide disparity,” he noted.

Safety Considerations The addition of the drug to gemcitabine primarily increased rash, fatigue, and stomatitis but these were mild. Grade 3/4 hematologic toxicities were significantly increased with the addition of the drug, but overall

rates of serious adverse events were similar (54% with gemcitabine alone, 49% with gemcitabine plus the lowdose drug, and 58% with gemcitabine plus high-dose TH-302).

“There was no increase in creatinine, which is important as it distinguishes the safety profile of this drug vs ifosfamide, which has renal toxicity in high doses,” Dr. Borad noted. There was also no excess in study discontinuations among patients receiving TH-302.

A phase III study has been initiated to evaluate TH-302 at 340 mg/m2. n Disclosure: Dr. Borad received research funding pertaining to conduct of the clinical study from Threshold Pharmaceuticals.

References 1. Borad MJ, Reddy S, Bahary N, et al: TH-302 plus gemcitabine vs gemcitabine in patients with untreated advanced pancreatic adenocarcinoma. Abstract 6660.

Presented September 29, 2012.

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PAGE 10

2013 Gastrointestinal Cancers Symposium Nab-paclitaxel in Pancreatic Cancer continued from page 1

for the addition of new agents, such as monoclonal antibodies.

Study Details MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) was an international phase III open-label study in which 861 patients at 151 sites were randomly assigned to receive nabpaclitaxel at 125 mg/m2 followed by gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks, or gemcitabine at 1,000 mg/m2 weekly for 7 weeks in cycle 1, then on days 1, 8, and 15 every 4 weeks. Treatment with the combination extended median overall survival by approximately 2 months—from 6.7 months with single-agent gemcitabine to 8.5 months with the combination.

This represented a highly significant 28% reduction in the risk of dying (P = .000015), Dr. Von Hoff reported.

“Interestingly, we saw a separation of the curves at 2 to 3 months that widened and persisted,” he said. “At each time point along the curve the difference was statistically significant.”

The combination led to significant improvements in a number of outcomes: ■■ 28% reduction in mortality risk: median overall survival was 8.5 vs 6.7 months (P = .000015) ■■ 31% reduction in risk of disease progression: median progressionfree survival was 5.5 months vs 3.7 months (P = .000024) ■■ 30% improvement in time to treatment failure: median of 5.1 vs 3.6 months (P < .0001) ■■ 59% increase in survival at 12 =�������������������� ������������������� .00020) and 78% inmonths (P ��������������������� crease at 18 months (P = .00803) ■■ Improved overall response rate: 23% vs 7%

Superiority across Subgroups Nab-paclitaxel/gemcitabine was favored in all subgroups. “In fact, the poorer the prognostic factor, the more favorable the hazard ratio,” he said.

Censoring the analysis at the start

EXPERT POINT OF VIEW

P

hilip Agop Philip, MD, Head of the Multidisciplinary Team for Gastrointestinal and Neuroendocrine Oncology and Neuroendocrine at Karmanos Cancer Institute at Wayne State University, Detroit, was the formal discussant of the paper at the Gastrointestinal Cancers Symposium. He said the positive findings earn nab-paclitaxel/gemcitabine a place in the list of treatment options for metastatic pancreatic cancer, along with gemcitabine with or without erlotinib (Tarceva), and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) in modified form.

“It offers an incremental benefit in this patient population,” he said.

Immediate Question “The immediate question would be the relative role of nab-paclitaxel/gemcitabine vs FOLFIRINOX in our day-to-day practice, and in our future clinical research activities,” he said, “as well as how to sequence these regimens in a given patient.”

The general consensus among experts at this meeting was that nab-paclitaxel may be better tolerated, and therefore a better fit for elderly or frail patients, but Dr. Philip argued, “This comparison may not be as simple as we would like.” He pointed out that fatigue and diarrhea are more common with FOLFIRINOX, but neuropathy is more common with nabpaclitaxel/gemcitabine.* “The nature of the neuropathy is different, however, especially with regard to its reversibility,” he added.

In terms of efficacy, Dr. Philip judged FOLFIRINOX to be the clear winner, as overall survival in the pivotal French trial was 11.1 months, vs 6.8 months with gemcitabine alone.1 “This begs the *Editor’s note: Dr. Von Hoff’s presentation included a footnote indicating that neuropathy rates in the MPACT study were for a “grouped term”—as deemed by a Standardized MedDRA Query—which includes up to 45 terms for peripheral neuropathy.

Nab-paclitaxel plus Gemcitabine in Pancreatic Cancer ■■ In the international MPACT trial, the addition of nab-paclitaxel to

gemcitabine improved median overall survival by about 2 months vs gemcitabine alone.

■■ The combination also produced a 59% increase in survival at 12 months (P = .00020) and 78% increase at 18 months (P = .00803).

■■ More grade 3/4 adverse events were observed with the combination, most commonly neutropenia, fatigue, and neuropathy.

question as to whether the study populations may have been dissimilar,” he suggested, noting that MPACT recruited patients “from different corners of the world,” whereas the FOLFIRINOX study was from multiple centers (in one country, France) with expertise in treating this disease.

Philip Agop Philip, MD

‘Too Many Variables’ The same question struck Alan P. Venook, MD, the Madden Family Distinguished Professor of Medical Oncology and Translational Research and Chief of Gastrointestinal Oncology at the University of California, San Francisco. In an interview with The ASCO Post, Dr. Venook said the results appear to be “far superior” with FOLFIRINOX but the patients in the FOLFIROINOX study may have been healthier or had less advanced disease.

“But you can’t tell, even by looking at the baseline characteristics. There are too many variables,” he said. Given the worldwide study population, the patients in the MPACT trial may also have received less consistently good care than the FOLFIRINOX study population, who were all treated at Centers of Excellence with expertise in pancreas cancer, such that the benefits of the new regimen would be “diluted,” he said.

“I do think this will be a standard treatment, but wonder if FOLFIRINOX is just more effective than nab-paclitaxel/ gemcitabine, and I would like to know if it can match up against FOLFIRINOX,” he concluded, suggesting that a headto-head comparison could be a worthy research pursuit by the cooperative groups. The analysis of biomarker data in the study will also be important, to see if there is a way to select patients likelier to benefit from the new combination. “The biomarker SPARC has been discussed in of second-line (subsequent) therapy produced a more impressive overall survival benefit: median of 9.4 months vs 6.8, a 32% reduction in risk (P = .000072), Dr. Von Hoff reported.

More grade 3/4 adverse events were observed with the combination, most commonly neutropenia (38% vs 27%), fatigue (17% vs 7%), and neuropathy (17% vs 1%). The neuropathy was “rapidly reversible, and 44% of these pa-

Alan P. Venook, MD

this context, and there will be an analysis, but I am disappointed the information presented did not include SPARC.” While the novel regimen may be more tolerable, he observed, “it was no bargain, either, as 4% of each arm in the study died of complications related to treatment.

See Page 97 This also may reflect care received at some of the study sites,” he suggested. He further noted that an alert went out to the investigators early in the trial because of an excess of deaths in the experimental arm. While the study protocol was not amended, a number of recommendations for the management of toxicities were emphasized.

“I do believe this is better tolerated than FOLFIRINOX was in the studies, although we are exploring less intense versions of the regimen [FOLFIRINOX],” he said. “The critical question is, when you see a patient with metastatic pancreatic cancer, how will you treat him now?

With nab-paclitaxel/gemcitabine, or with FOLFIRINOX? Until proven otherwise, in the patient with a good performance status, I will still use FOLFIRINOX.” n Disclosure: Drs. Philip and Venook reported no potential conflicts of interest.

Reference 1. Conroy T, Desseigne F, Ychou M, et al: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817-1825, 2011.

tients were able to resume treatment,” he added. Treatment-related deaths occurred in 4% of each arm. n Disclosure: Dr. Von Hoff is a consultant for and has received honoraria and research funding from Celgene.

Reference 1. Von Hoff DD, Ervin T, Arena FP, et al: 2013 Gastrointestinal Cancers Symposium. Abstract LBA148. Presented January 25, 2012.

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

vs

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

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 SCCHN=squamous cell carcinoma of the head and neck; CT=platinum-based therapy with 5-FU; OR=odds ratio; CI=confidence interval; HR=hazard ratio.

The EXTREME Study was an open-label, randomized (1:1), multicenter, controlled clinical trial that compared EU-approved cetuximab + CT vs 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 inotecan in first-line therapY therapY for metaSTatic metaST STatic colorectAL 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

MONTHS

HR=0.88 (95% CI: 0.78–1.0)

Objective Response Rates (Reduced Tumor Size)‡

Median Progression-Free Survival

EXTENDED

19.6 MONTHS

46%

FOLFIRI alone (n=356)

19.5 MONTHS

(95% CI: 17–21)

HR=0.80 (95% CI: 0.67–0.94)†

57%

38%

IMPROVED

39%

PATIENTS

PATIENTS

PATIENTS

PATIENTS

(95% CI: 42–50)

(95% CI: 34–42)

(95% CI: 51–62)

(95% CI: 34–44)

8.9

8.1

9.5

MONTHS

MONTHS

(95% CI: 8.0–9.4)

(95% CI: 7.6–8.8)

PROLONGED

8.1

MONTHS

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 mCRC=metastatic colorectal cancer; CI=confidence interval; HR=hazard ratio. †

‡

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

The ERBITUX (cetuximab) Patient Support Program 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; July 2012. 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.

SCAN QR CODE for more information. By scanning the QR code, you are confirming you are a US Healthcare Professional.

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

©2012 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.

693US13BR00168-02-01 11/12

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].

• in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment,

• in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy,

• a s 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: The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

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.

Erbitux0712PBS_7x9wip6.indd 1

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 15 3 2 0 Infusion Reactionb 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 43 2 21 1 Alanine Transaminase, highc Aspartate Transaminase, highc 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, highc Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneiform Rashd 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.

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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:

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 Body System Grades Grades 3 and 4 Preferred Term 1–4b 1–4 3 and 4 % of Patients Blood and Lymphatic System Disorders Neutropenia 49 31 42 24 Eye Disorders Conjunctivitis 18 <1 3 0 Gastrointestinal Disorders Diarrhea 66 16 60 10 Stomatitis 31 3 19 1 Dyspepsia 16 0 9 0 General Disorders and Administration Site Conditions 14 2 <1 0 Infusion-related Reactionc Pyrexia 26 1 14 1 Infections and Infestations Paronychia 20 4 <1 0 Investigations Weight Decreased 15 1 9 1 Metabolism and Nutrition Disorders Anorexia 30 3 23 2 (Continued)

Erbitux0712PBS_7x9wip6.indd 2

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) Body System Grades Grades Grades Grades Preferred Term 1–4b 3 and 4 1–4 3 and 4 % 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 reaction has been identified during post-approval use of Erbitux.

Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure.

• Aseptic meningitis 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.

M Erbitux0712PBS_7x9wip6.indd 3

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

Copyright © 2004–2012 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886B1

Rev July 2012 693US12PBS11501

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The ASCO Post | FEBRUARY 15, 2013

PAGE 18

ASH Annual Meeting Hematology

Daunorubicin-free Induction Therapy for Standard-risk Childhood Acute Lymphoblastic Leukemia

By Alice Goodman

O

mitting daunorubicin from induction therapy for children with standard-risk acute B-cell lymphoblastic leukemia (ALL) does not compromise survival and at the same time reduces the risk of associated toxicities, including myelosuppression and car-

outcome. Removing harmful chemotherapy can minimize their risk of heart damage later in life,” Dr. Baruchel stated.

Standard-risk ALL is highly curable in children, with an estimated 5-year survival of 90%. Some groups use anthracyclines during induction, while

We conclude that daunorubicin is dispensable during induction therapy in children with good early response to treatment.

—André Baruchel, MD

diac damage, according to results of the large phase III FRALLE 2000-A trial, which were reported at the 54th Annual Meeting of the American Society of Hematology (ASH) in Atlanta.

Induction with or without daunorubicin achieved a 5-year event-free survival of about 93%. Overall survival was 97% in children treated with anthracycline-free induction therapy vs 98% among those who received daunorubicin during induction.

First Scientific Proof In fact, many centers in the United States and some in Europe no longer use daunorubicin as initial therapy, but this study is important because it provides the first scientific proof in the modern era for omitting this drug, See Page 97 noted lead author André Baruchel, MD, Head of the Department of Pediatric Hematology at the Robert Debr������������������� é������������������ University Hospital in Paris.

“This study shows that daunorubicin can be safely omitted from initial treatment in standard-risk B-cell lineage ALL children, who constitute the majority of ALL patients, without negatively affecting their immediate

Visit

others don’t, and no randomized trials have been published since 1991 to resolve this issue, Dr. Baruchel explained.

“Only three older studies [of anthracyclines in this setting] are included in a specific Cochrane Review, and these studies used different supportive care measures. Now we use increased doses of dexamethasone. Although daunorubicin may reduce relapses, it is not clear if it improves survival in standard-risk ALL, and causes myelosuppression and cardiac events,” he continued.

EXPERT POINT OF VIEW

P

ress conference moderator William G. Woods, MD, Pediatric Hematology/Oncology Director and the Daniel P. Amos Children’s Chair, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, called the phase III FRALLE trial “an important confirmatory step regarding the front-line treatment of childhood ALL using the most modern day therapy.”

“Reducing anthracycline exposure will not impede outcomes. We know that anthracyclines are William G. Woods, MD still needed in smaller doses, but the hope is that someday we will be able to eliminate them by substitution of other drugs, especially novel drugs that may not be invented yet,” Dr. Woods said. n Disclosure: Dr. Woods reported no potential conflicts of interest.

asparaginase [Elspar in the United States, Kidrolase in France, where the FRALLE 2000-A study was primarily conducted]) with or without daunorubicin. All patients received delayed doxorubicin-based intensification therapy, followed by 24 months of maintenance therapy.

At the ASH meeting, Dr. Baruchel reported findings at a median follow-

Daunorubicin in Pediatric ALL ■■ The first large randomized study of its kind in the modern era shows that daunorubicin can be safely omitted from induction therapy for children with standard-risk B-cell acute lymphoblastic leukemia (ALL) without reducing survival.

■■ In clinical practice, many centers no longer use daunorubicin at induction in standard-risk ALL.

■■ Anthracyclines are still needed in consolidation regimens for this disease,

but the hope is that eventually novel drugs can replace them and avoid the early and late associated toxicity.

Current Study Details In one of the largest studies to date of anthracycline-based induction therapy in childhood ALL, 1,128 patients were randomly assigned to standard induction (vincristine, dexamethasone, and native Escherichia coli

up of 69 months. Both groups were quite similar at baseline for demographic and disease characteristics.

Complete response to chemotherapy was similar between treatment arms: 99.7%. No significant difference was seen in overall survival, event-free

survival, and complete response. Fiveyear event-free survival was 92.6% with daunorubicin and 92.8% without it.

Overall survival rates were 97.3% and 98%, respectively, for the two groups.

“The number of events was almost identical in both arms. This is nearly too good to be true,” he said.

The only significant difference in grade 3 or 4 toxicity was the incidence of neutropenia, which was a median of 22 days with daunorubicin and 25 days without.

“We conclude that daunorubicin is dispensable during induction therapy in children with good early response to treatment. These children still undergo intensive treatment with a long maintenance therapy of 24 months,” he said.n Disclosure: Dr. Baruchel reported no potential conflicts of interest.

Reference 1. Baruchel A, Petit A, Leblanc T, et al: Daunorubicin or not during the induction treatment of childhood standard-risk B-cell precursor acute lymphoblastic leukemia: The randomized FRALLE 2000-A protocol. 2012 ASH Annual Meeting. Abstract 135. Presented December 9, 2012.

website at ASCOPost.com

ASCOPost.com | FEBRUARY 15, 2013

PAGE 19

Journal Spotlight Thoracic Oncology

Selumetinib/Docetaxel Shows Promising Activity in Previously Treated KRAS-mutant Non–Small Cell Lung Cancer

By Matthew Stenger

C

urrently, there are no approved therapies for KRAS-mutant non– small cell lung cancer (NSCLC), and few clinical trials have been performed specifically in this setting. In a recent article in Lancet Oncology, Pasi A. Jänne, MD, PhD, Scientific Director, Belfer Institute for Applied Cancer Science, and See Page 97 Associate Professor of Medicine, Harvard Medical School, and colleagues at the Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, reported results of a phase��������������� �������������� II study showing promising activity of the oral MEK inhibitor selumetinib plus docetaxel in patients with KRAS-mutant NSCLC.1 Selumetinib inhibits MEK1/MEK2 downstream from KRAS, with preclinical studies indicating that it inhibits KRAS-mutant tumor growth and exhibits a synergistic antitumor effect in com-

EXPERT POINT OF VIEW

I

Pasi A. Jänne, MD, PhD

75 mg/m2 on day 1 of a 21-day cycle (n = 44) or docetaxel alone (n = 43).

There were slight imbalances between the selumetinib and placebo groups in some baseline characteristics. For the selumetinib and placebo groups, 52% and 53% of patients were female, median ages were 59.5 and 59 years, 89% and 88% were current (16% and 26%) or past smokers, 52% and 51% had an ECOG performance status of 1, 68% and 53% had adenocarcinoma (14% and 23% had bronchoalveolar adenocarcinoma), and 89% and 98% had stage IV disease.

Although there was no significant difference between the two groups in median overall survival (the primary endpoint of the study), selumetinib treatment was associated with significant improvements in progression-free survival, objective response rate, and patient-reported outcomes. bination with docetaxel. A phase II study of monotherapy showed little activity of selumetinib in an unselected pretreated population of NSCLC patients.

Study Details In this study, 87 patients were randomly assigned to receive selumetinib at 75 mg twice daily plus docetaxel at

All patients had received at least one prior treatment regimen (surgery, radiotherapy, or neoadjuvant or adjuvant chemotherapy), and 11% and 14% had two or more. All had prior chemotherapy, including platinum compounds in 98% and 100%, taxanes in 39% and 30%, and vinca alkaloids/analogs in 9% continued on page 20

Selumetinib plus Docetaxel in NSCLC ■■ Although selumetinib plus docetaxel did not significantly improve overall survival in this phase II trial, significant improvements were observed in progression-free survival, response rate, and patient-reported outcomes.

■■ The apparent synergy of effect with selumetinib plus docetaxel is a

novel finding in studies examining the addition of targeted therapy to chemotherapy in non–small cell lung cancer.

■■ The combination of selumetinib plus docetaxel was associated with greater toxicity compared with docetaxel alone.

n a commentary accompanying reporting of the phase������������������������ II��������������������� study of the MEK inhibitor selumetinib by Dr. Pasi A. Jänne, MD, PhD, and colleagues, Sarah B. Goldberg, MD, MPH, Assistant Professor of Medicine, and colleagues at Yale Cancer Center, New Haven, Connecticut, noted that KRAS, a member of the RAS family of oncogenes, has remained an elusive target in cancer therapy.1 Some of the genetically defined subsets of NSCLC, including those characterized by EGFR and ALK activating mutations, are sensitive to tyrosine kinase inhibitors, which can produce sustained clinical responses in patients with these disease subtypes.

Activating KRAS mutations are implicated in the largest genetically defined subset, being found in approximately 25% of all patients with lung cancer, but until recently, there had been no reports of successful targeted therapy in such disease.

Interpreting the Results Dr. Goldberg and colleagues make several points about the phase II study that need to be taken into account in interpreting its findings. First, they note that the efficacy of the selumetinib-plus-docetaxel combination may be considered more remarkable given the poor outcome and absence of objective response in the patients receiving docetaxel alone. Outcomes in this group of patients with KRAS-mutant disease were worse than has been observed in populations of unselected patients receiving docetaxel alone for refractory disease.

Second, they note that existing data suggest that KRAS mutation subtype may be an important predictor of treatSee Page 97 ment outcome and that the presence of certain comutations (ie, p53 and Lkb1 mutations) has been found to affect the activity of the selumetinib-plus-docetaxel combination in mice. Jänne and colleagues did not analyze outcomes by KRAS mutation subtype due to the small number of patients in the trial, and did not report on the status of comutated genes. The commentators note that future trials assessing outcome in KRASmutant tumors should include information about both mutation subtype and the presence of comutations, given their potential importance.

Mechanism Unclear Finally, as stated by the commentators, “[A]lthough Jänne and colleagues showed a benefit with the addition of an MEK inhibitor to a chemotherapeutic agent in the population of patients studied, the mechanism of why these two drugs together are synergistic remains unclear in view of the modest activity with either alone. Moreover, in the absence of information about the effect of selumetinib plus docetaxel in patients with NSCLC that do not harbor an oncogenic KRAS mutation, one cannot definitively conclude that the clinical benefit of selumetinib plus docetaxel has anything to do with the status of RAS in these tumors.”

They note that although effective KRAS inhibitors are currently not available, genetic studies have identified drug targets that are essential for RAS cellular localization and function, raising the hope that novel inhibitors of KRAS and other RAS members will be discovered.

The authors conclude, “In the meantime, [this study] lays the groundwork for a regimen that could bring us one step further in the treatment of NSCLC; however, additional work is needed to confirm these findings and to determine the optimum subset of patients who will benefit from this therapy.” n Disclosure: Commentary authors Drs. Sarah B. Goldberg, Joseph Schlessinger, Julie L. Boyer, and Roy S. Herbst reported no potential conflicts of interest.

Reference 1. Goldberg SB, Schlessinger J, Boyer JL, et al: A step towards treating KRAS-mutant NSCLC (comment). Lancet Oncol 14:3-5, 2013.

The ASCO Post | FEBRUARY 15, 2013

PAGE 20

Journal Spotlight

Selumetinib in NSCLC continued from page 19

and 21%; 27% and 26% had prior surgery, and 27% and 53% had prior radiotherapy. Best response to prior chemotherapy was complete response in 2% and partial response in 36% of the selumetinib group and complete response in 2% and partial response in 16% of the placebo group.

Median treatment durations were 117 days (range, 7–435 days) in the selumetinib group and 68 days (range, 7–463 days) in the placebo group. The median numbers of docetaxel cycles were 5 (1–9) and 4 (1–12). One patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumors were not confirmed to be KRAS-mutation positive. The relative dose intensity of docetaxel was 86% in the selumetinib group and 91% in the placebo group.

Selumetinib dose reduction and dose interruption occurred in 36% and 55% of patients, respectively. Poststudy chemotherapy was used in 44% of selumetinib patients and in 55% of placebo patients.

Significant Improvements in Secondary Endpoints Although there was no significant difference between the two groups in median overall survival (the primary endpoint of the study), selumetinib treatment was associated with significant improvements in progression-free survival, objective response rate, and patient-reported outcomes.

Median overall survival was 287 days in the selumetinib group and 157 days in the placebo group, representing a nonsignificant 20% reduction in risk for death with selumetinib treatment (hazard ratio [HR] = 0.80, 80% confidence interval [CI] = 0.56–1.14, =����������������������������������� ���������������������������������� .21). Median progerssion-free surP ������������������������������������ vival was 5.3 months in the selumetinib group and 2.1 months in the placebo group, representing a significant 42% reduction in risk for progression (HR = 0.58, 80% CI = 0.42-0.79, P = .014).

Objective response was significantly more common with selumetinib plus docetaxel than with docetaxel <���������������� ��������������� .0001). All realone (37% vs 0%, P ����������������� sponses were partial responses. Median duration of response was 182 days.

Outcomes on the patient-reported Lung Cancer Specific Symptom Questionnaire—Lung Cancer Subscale (LCS) also showed benefit of selumetinib treatment. More selumetinib patients had improvement on the LCS (44% vs 24%, P = .029), and median

time to deterioration in LCS score was longer in the selumetinib group (186 vs 49 days, P = .0002).

Toxicity Increased with Combination Adverse events were more common with selumetinib treatment. The most common adverse events of any grade

in the selumetinib group were neutropenia, diarrhea, nausea, vomiting, peripheral edema, rash, and stomatitis, all of which were more common than in the placebo group. Dyspnea, exertional dyspnea, musculoskeletal chest pain, arthralgia, fatigue, and myalgia were more common in the placebo group.

Grade 3 or 4 adverse events occurred

in 82% of patients in the selumetinib group vs 67% of patients in the placebo group. The most common grade 3 or 4 adverse events were neutropenia (67% vs 55%), febrile neutropenia (18% vs 0%), dyspnea (2% vs 12%), and asthenia (9% vs 0%).

Serious adverse events occurred in 59% of selumetinib patients and 31%

Announcing: J-code

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CD30-directed therapy

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Important Safety Information BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS® (brentuximab vedotin).

CT SCANS confirmed responses in relapsed patients

Contraindication:

Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.

Warnings and Precautions:

• Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported.

ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.

• Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion.

If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted.

• Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. • Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.

Mx8000 Ex: CT080100137 Se: 8002/4 Im: 130/208 Ax: 1623.9 120.0 kV 280.0 mA 1.3 mm/-0.5:1 Tilt: 0.0 0.0s Lin:DCM/ Lin:DCM/id:ID W:200 L25

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ASCOPost.com | FEBRUARY 15, 2013

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Journal Spotlight

of placebo patients; the most common were febrile neutropenia (14% vs 0%), pneumonia (9% vs 0%), neutropenia (7% vs 7%), and respiratory failure (7% vs 5%). Serious adverse events resulted in death in 9% vs 7% of patients, with none of the events being deemed related to study drugs. Adverse events led to hospitalization in 48% of selumetinib

patients and 19% of placebo patients. In the selumetinib group, adverse events led to discontinuation of selumetinib in 18% of patients and discontinuation of docetaxel in 14%. In the placebo group, adverse events led to discontinuation of placebo in 12% of patients and discontinuation of docetaxel in 17%.

The authors concluded, “Selu-

metinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated KRASmutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRASmutant NSCLC.” They noted that the finding of ap-

After multiple failures,

single-agent response Indicated for the treatment of:

Important Safety Information (continued)

• Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

HL: 73% objective response rate (ORR) (95% CI: 65%-83%)

1

32%

complete remission (95% CI: 23%-42%)1

40%

partial remission (95% CI: 32%-49%)1

N = 102, 15-77 years (median: 31 years)1

• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1

sALCL: 86% ORR (95% CI: 77%-95%)

1

57%

complete remission (95% CI: 44%-70%)1

29%

partial remission (95% CI: 18%-41%)1

N = 58, 14-76 years (median: 52 years)1

The indications for ADCETRIS® (brentuximab vedotin) are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

2011 August 19 Acq Tm: 14:05:52

• P rogressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS® (brentuximab vedotin)– treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression.

Consider the diagnosis of PML in any patient presenting with newonset signs and symptoms of central nervous system abnormalities.

Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy.

Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

• Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

• U se in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

Adverse Reactions:

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

Drug Interactions:

Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

512x512 B

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Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad.

REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; 2012.

US/BVP/2011/0104k

855.4SEAGEN (855.473.2436) SeaGenSecure.com

parent synergy of selumetinib plus docetaxel in this setting, while consistent with preclinical findings with the combination, stands in contrast to the findings of previous studies in NSCLC indicating no additional benefit when a targeted agent is added to chemotherapy. In this regard, the aucontinued on page 22

The ASCO Post | FEBRUARY 15, 2013

PAGE 22

Journal Spotlight

Selumetinib in NSCLC continued from page 21

thors stated, “Additional studies are therefore needed to understand why the combination studied here displays synergistic activity and whether this finding will also be recorded with other agents targeting MAPK signaling or other chemotherapies.”

The authors further noted, “Our study has potential therapeutic implications for other tumors in which KRAS mutations are particularly prevalent, such as colorectal and pancreatic cancers. In both cases, selumetinib monotherapy has shown no clinical benefit versus chemotherapy.

Whether addition of selumetinib to

Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS® (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates.

ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

Contraindications Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions.

Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia

Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients.

In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression.

Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

chemotherapy agents commonly used in these diseases, which do not include docetaxel, will result in enhanced clinical benefit when combined remains to be established and should be tested in prospective clinical trials.” n

Disclosure: The phase II selumetinib study was funded by AstraZeneca. Among the study investigators, Dr. Pasi A. Jänne has received

ADCETRIS® (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks.

Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactions In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Effect of other drugs on ADCETRIS

CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

The ASCO Post

Use in specific populations Pregnancy

Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers

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

Pediatric use

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

Geriatric use

Rights & Permissions

It is not known whether brentuximab vedotin 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 ADCETRIS 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.

The safety and effectiveness of ADCETRIS have not been established in the pediatric population.

Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Renal impairment

The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment

The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Use in pregnancy

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased.

ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting.

The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

Contact

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Dosage and administration

Adverse reactions

Reference 1. Jänne PA, Shaw AT, Pereira JR, et al: Selumetinib plus docetaxel for KRASmutant advanced non-small-cell lung cancer: A randomized, multicentre, placebocontrolled, phase 2 study. Lancet Oncol 14:38-47, 2013.

Effect of ADCETRIS on other drugs

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

consultancy fees from AstraZeneca, Roche, Genentech, Pfizer, Boehringer Ingelheim, and Sanofi, and other remuneration from Lab Corp.

Dr. Alice T. Shaw has received consultancy fees from Pfizer, Ariad, Novartis, Chugi, and Daiichi-Sankyo, and received research funding from AstraZeneca and Novartis. Dr. Johan Vansteenkiste’s institute has received research funding from AstraZeneca. Dr. Carlos Barrios has received consultancy fees from Pfizer, Roche, and GlaxoSmithKline and has received research funding from AstraZeneca. Drs. Ian Smith and Paul Smith and Ms. Lynda Grinsted are employees and stockholders of AstraZeneca. Dr. Victoria Zazulina is a former employee of AstraZeneca. Drs. Jose R. Pereira, Gaëlle Jeannin, Fabio A. Franke, and Lucio Crinò reported no potential conflicts of interest.

General dosing information

Dose modification

Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued.

Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS and its logo, SeaGen Secure and its logo, Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2013 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA US/BVP/2011/0150c

e-mail: Permissions@harborsidepress.com

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Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

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

ASCOPost.com | FEBRUARY 15, 2013

PAGE 23

San Antonio Breast Cancer Symposium Breast Cancer

Chemotherapy for Breast Cancer Carries a Small, but Concerning, Risk for Leukemia

By Caroline Helwick

T

he risk for developing a secondary malignancy after chemotherapy for breast cancer is very small, but it is statistically significantly higher than for the general population, a review of the National Comprehensive Cancer Network (NCCN) database revealed in a study presented at the 2012 San Antonio Breast Cancer Symposium.1

Antonio C. Wolff, MD, FACP

Increase over Earlier Data Ten years after treatment for early breast cancer, approximately 0.5% of women developed leukemia. While this risk is small, it represents a twofold increase over earlier data from studies evaluating the risk of chemotherapyinduced malignancies, according to Antonio C. Wolff, MD, FACP, Professor of Oncology at the Johns Hopkins Kimmel Cancer Center, Baltimore.

“Adjuvant chemotherapy was associated with a cumulative 10-year incidence of leukemia of about 0.5%, which appears to be higher than previously reported,” Dr. Wolff said.

For years, there has been concern that chemotherapy may induce second cancers. A report See Page 97 from the National Surgical Adjuvant Breast and Bowel Project (NSABP) some 10 years ago found a 0.27% risk of myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) occurring 8 years after treatment with doxorubicin/cyclophosphamide.2 Patients who received radiotherapy or growth factors were at highest risk. In NSABP B-38, reported at the 2012 ASCO Annual Meeting, a 0.49% risk for MDS and AML was found 5 years after treatment for breast cancer that included growth factors.3 To further ascertain the true risk of secondary malignancies, Dr. Wolff and

colleagues analyzed prospectively collected data from 20,533 patients with breast cancer (without a prior cancer history) followed for a median of 5.1 years. Patients with stage I to III breast cancers were treated between 1997 and 2008 at eight cancer centers.

Information included patient demographics, tumor stage and phenotype, type of treatment, and patient outcomes. Data were not collected, however, on family history of cancer, use of growth factors, dose of chemotherapy, dose of radiation, or clinical characteristics and treatment related to subsequent cancer diagnoses. Women who developed a recurrence were excluded from the analysis.

51 Hematologic Cancers Diagnosed The inestigators discovered 51 cases of leukemia among the 20,533 patients, including 44 cases of myeloid leukemia and 7 cases of lymphoid leukemia.

“Leukemia risk was not limited to MDS and AML, and cases of high-risk lymphoid leukemia were observed,” he said.

Since the hazard ratios for the two types were similar, data from myeloid and lymphoid leukemia were combined in the analysis. Patients who developed leukemia differed from the noncancer group only in terms of age, with the average leukemia patients aged 60 years vs 54 years for those without leukemia (P = .02).

The systemic chemotherapy they received was largely four or six cycles of anthracycline and/or alkylating agent, with or without a taxane. “This was, for the most part, just four cycles of anthracycline and cyclophosphamide,” he emphasized. “The docetaxel/cyclophosphamide regimen was not well represented, and therefore its leukemia risk remains unknown.”

In the adjusted model, the hazard

EXPERT POINT OF VIEW

C

ommenting on the study presented by Dr. Wolff at the 2012 San Antonio Breast Cancer Symposium, ASCO President Sandra M. Swain, MD, FACP, Medical Director, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC, said she found it “disturbing” that about half the population had node-negative disease. “They were treated prior to the availability of the Oncotype DX recurrence score, when we were overtreating many patients. These findings give us another reason to be careful about unnecessary treatment,” she offered.

Eric P. Winer, MD, Professor of Medicine at Harvard Medical School, Boston, agreed, and told The ASCO Post, “Generally speaking, the risk of leukemia with chemotherapy is quite small. The absolute risk is about half a percent, and because the general population has a risk that’s greater than zero, we are talking about an excess risk of approximately 3 or 4 cases in 1,000 women. For a treatment with a big benefit, that risk is a relatively small price to pay. But if we are talking about treatment that has a smaller benefit, then the leukemia risk is something to consider. It’s among the reasons why we have to think very carefully about treating women with very early-stage disease or those whose tumors have biologic features that suggest a very limited benefit from chemotherapy. Unfortunately, we cannot dial down the toxicity based on the amount of benefit.” n Disclosure: Drs. Swain and Winer reported no potential conflicts of interest.

ratios for the risk of leukemia were 1.29 for radiation vs no radiation, which was not significant (P = .461); 2.51 for any chemotherapy vs not (P = .007); and 1.59 for chemotherapy plus radiation vs a single modality (P = .127).

Stratified Analysis In a stratified analysis that included women receiving only surgery, there was a trend toward increased risk with radiotherapy only (hazard ratio [HR] = 2.73; P = .194), chemotherapy only (HR = 5.68; P = .037), and chemotherapy plus radiation (HR = 5.64; P = .028). The risk with the combined modality was not significantly higher than was seen with chemotherapy alone, Dr. Wolff reported.

“Radiation alone appears to be a risk factor but may not add much [risk] to patients already treated with chemotherapy,” he concluded.

The analysis yielded rates of leukemia per 1,000 patient-years of 0.46 for the whole cohort, 0.16 for surgery

Leukemia Risk after Breast Cancer Treatment ■■ An analysis from the NCCN database found the risk of developing

myelodysplastic syndromes or leukemia after breast cancer treatment, especially chemotherapy, is about 0.5% over 10 years.

■■ The risk is small, but it is statistically significantly higher than was shown in previous studies.

■■ The risk underscores the need to avoid chemotherapy in women who will not benefit from it.

alone, 0.43 for radiation alone, 0.52 for chemotherapy alone, and 0.54 for chemotherapy plus radiation. The cumulative incidence for all patients was 0.25% at 5 years and 0.46% at 10 years, and for the chemotherapy/radiotherapy cohort was 0.32% and 0.51%, respectively.

While he did not report the baseline risk observed in women of similar age without breast cancer, Dr. Wolff noted that the surgery cohort was the best control group to assess the therapy risk in this data set. “Chemotherapy increased the risk,” he said, “but there are challenges in comparing this with risk in patients without cancer because other factors could be in play, like family history and possible associations with mutations in the ATM and BRCA2 genes.”

He further noted that since MDS was underreported until fairly recently, the overall leukemia frequency after breast cancer treatment likely is frequently underrepresented in the findings.

Time to Event and 10-year Incidence Interestingly, while the general belief is that leukemia develops within 5 years of chemotherapy, almost half of the events occurred beyond this time, Dr. Wolff noted. Median time to an event was 3.3 years overall. Within the myeloid group, median time was 4.9 years for patients with adverse MDS-like leucontinued on page 24

The ASCO Post | FEBRUARY 15, 2013

PAGE 24

San Antonio Breast Cancer Symposium Breast Cancer

Novel Oral Agent plus Letrozole Improves Progression-free Survival in ER-positive Advanced Breast Cancer

By Alice Goodman

T

he combination of letrozole plus a novel oral inhibitor of cyclin-dependent kinase 4/6 called PD 0332991 achieved an unprecedented improvement in progression-free survival among women with advanced estrogen receptor–positive/HER2-negative breast cancer. Median progression-free survival was 26.1 months among women treated with the combination vs 7.5 months for letrozole alone (P = .006), according to results of a randomized phase II study presented at the 2012 San Antonio Breast Cancer Symposium.1 PD 0332991 is a first-in-class oral selective inhibitor of cyclin-dependent kinase 4/6. The drug See Page 97 prevents cellular DNA synthesis.

Experts were excited about these results but agreed that further study is needed. Pfizer, marketer of PD 0332991, is planning a phase III trial of this combination.

Well Tolerated Drug “The dramatic, significant, and clinically meaningful improvement in progression-free survival with the combination is very encouraging. Importantly, this novel drug is very well tolerated,” stated Richard S. Finn, MD, Associate Professor of

Dr. Finn did not present any data on cyclin D1 amplification and loss of p16 because these biomarkers had no effect on results, based on retrospective review of the part 1 patients. The only biomarker required for selection of patients was estrogen receptor positivity, he added.

Earlier and Updated Reports Richard S. Finn, MD

Medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. “This study validates preclinical studies showing that the new compound has significant activity in breast cancer models and acts synergistically with hormonal therapy.”

The phase II study had two parts, and in both, women were randomly assigned 1:1 to receive letrozole plus PD 0332991 or letrozole alone. Part������ ����� 1 enrolled 66 postmenopausal women with estrogen receptor–positive/HER2-negative advanced breast cancer. Part������ ����� 2 enrolled 99 patients using the same eligibility criteria but also screened tumors for cyclin D1 amplification and/or loss of p16 by fluorescence in situ hybridization. For both parts of the trial, the primary endpoint was progression-free survival; secondary endpoints included response rate, overall survival, safety, and correlative biomarker studies.

PD 0332991/Letrozole in Estrogen Receptor–positive Breast Cancer ■■ A phase II study showed excellent progression-free survival with

combination of the novel oral drug PD 0332991 plus letrozole compared with letrozole alone in advanced breast cancer.

■■ PD 0332991 is a first-in-class cyclin-dependent kinase 4/6 inhibitor.

Chemotherapy and Leukemia Risk continued from page 23

kemia often seen after alkylating agents, extending to 8 years in some, and was 1.9 years for those with translocations associated with anthracycline exposure.

For the lymphoid group, median time to the event was 2.3 years for chronic lymphocytic leukemia and 1.9 years for acute lymphoblastic leukemia.

Dr. Wolff pointed out that the latency time after exposure to anthracy-

clines is 1 to 3 years but is much longer for cyclophosphamide. “Patients exposed to cyclophosphamide could be at risk at 10 years or more,” he said.

Regarding the issue of overtreatment, he added, “many times we have been in the unfortunate situation where we make decisions about giving chemotherapy ‘just in case,’” he said.

“We need to be very careful, because some of those patients will derive none of the benefit of chemotherapy but all of the harm.” n

Interim results for progression-free survival in part������������������������� ������������������������ 1 of the trial were presented at the IMPAKT Breast Cancer Conference in Brussels earlier in 2012.

The combination significantly improved progression-free survival compared with letrozole alone (P = .006).

Dr. Finn updated these results at the San Antonio Breast Cancer Symposium based on a total of 165 patients enrolled in both parts 1 and 2. In this analysis, median progression-free survival was 26.1 months with the combination vs 7.5 months with letrozole alone, representing a 63% improvement in risk of progression (P < .001).

The combination was also superior to letrozole alone for secondary endpoints of response rate (45% for the combination vs 31% for letrozole alone in patients with measurable disease), and clinical benefit rate (70% vs 44%, respectively).

Neutropenia, leukopenia, anemia, and fatigue were the most common treatment-related adverse events reported with combination therapy. The neutropenia that patients experienced was generally uncomplicated and manageable, with no cases of febrile neutropenia.

The two treatment arms were well balanced at baseline for demographic and disease characteristics. Median age was about 63 years, about 95% had stage IV disease, about 50% had visceral metastases, and about 19% Disclosure: Dr. Wolff reported no potential conflicts of interest.

References 1. Karp JE, Blackford A, Visvanathan K, et al: Myelodysplastic syndrome and/or acute myelogenous leukemia after a breast cancer diagnosis: The National Comprehensive Cancer Network experience. 2012 San Antonio Breast Cancer Symposium.

Abstract S3-5. Presented December 6, 2012.

2. André Baruchel, MD et al: Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophos-

had bone-only metastases. About 70% had a recurrence less than 12 months after adjuvant therapy or had de novo advanced disease. About 50% had no prior systemic treatment for advanced disease.

Combination to Watch Commenting on these results, Jennifer Litton, MD, breast medical oncologist at The University of Texas MD Anderson Cancer Center in Houston, said, “I can’t recall a phase II trial that has shown such significant early results with a drug that appears to be fairly well tolerated. This will be an exciting

Jennifer Litton, MD

combination to watch.” Acknowledging that not all phase II results hold up under phase III scrutiny, she said, “I am cautiously optimistic.” n Disclosure: Drs. Finn and Litten reported no potential conflicts of interest.

Reference 1. Finn RS, Crow JP, Lang I, et al: Results of a randomized phase 2 study of PD 0332991, a cyclin dependent kinase (cdk) 4/6 inhibitor in combination with letrozole alone for first-line treatment of ER+/ HER2- advanced breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract S1-6. Presented December 5, 2102.

phamide adjuvant therapy for operable breast cancer: The National Surgical Adjuvant Breast and Bowel Project Experience.

J Clin Oncol 11:1195-1204, 2003.

3. Swain SM, Tang G, Geyer CE, et al: NSABP B-38: Definitive analysis of a randomized adjuvant trial comparing dosedense AC→ paclitaxel plus gemcitabine with DD AC→P and with docetaxel, doxorubicin, and cyclophosphamide (TAC) in women with operable, node-positive breast cancer. 2012 ASCO Annual Meeting. Abstract LBA1000. Presented June 5, 2012.

This is the biologic medicine That the patient counts on That the nurse trusts That the pharmacist has confidence in That the doctor relies on Because it was manufactured knowing the patient’s treatment depends on it.

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The ASCO Post | FEBRUARY 15, 2013

PAGE 26

San Antonio Breast Cancer Symposium Breast Cancer

For Lobular Carcinoma, Letrozole Works Better Than Tamoxifen

By Caroline Helwick

I

n the treatment of postmenopausal estrogen receptor–positive women with lobular carcinoma, letrozole appears to have a greater benefit than tamoxifen, according to an analysis of this subset of patients in the Breast In-

Otto Metzger-Filho, MD

ternational Group (BIG) 1-98 trial reported at the 35th Annual San Antonio Breast Cancer Symposium.1 “The magnitude of benefit of adjuvant letrozole varies by histology and estrogen receptor subgroup,” said Otto Metzger-Filho, MD, of Dana-Farber Cancer Institute in Boston. “Letrozole is associated with statistically significant reductions in disease-free and overall survival events for both lobular and ductal carcinoma, but the magnitude of benefit is higher for patients diagnosed with lobular carcinoma.” In both histologic subtypes, patients with luminal B tumors derived more benefit than those with luminal A, he added.

Study Background BIG 1-98 was a randomized phase III study comparing 5 years of tamoxifen monotherapy, letrozole monotherapy, and two sequential treatments (tamoxifen followed by letrozole, or letrozole followed by tamoxifen) in postmenopausal women with hormone receptor– positive early breast cancer. The current analysis focused on patients randomly assigned to the monotherapy arms of BIG 1-98 study and included patients who had centrally reviewed pathology data for histologic subtypes, hormone receptors, HER2, and Ki67.

Visit

Lobular and ductal tumors centrally classified as hormone receptor–positive and HER2-negative were further subdivided into luminal A (low proliferative) or luminal B (high proliferative) subsets using a Ki67 cutoff of 14%. In the ductal carcinoma subset (n = 2,599), 45% of women were lumiSee Page 97 nal A and 56% were luminal B, while in the lobular carcinoma group (n = 324), these proportions were 73% and 27%, respectively.

Disease-free and overall survival rates were estimated using a method called inverse probability of censoring weighted analysis, which provided a better estimate of treatment benefit than intentto-treat analysis due to the high selective crossover rate (25%) from tamoxifen to letrozole after the study results were presented in 2005, he said.

Summary of Results At 8.4 years of median follow-up, patients with lobular carcinoma experienced a 52% reduction in the hazard of a disease-free survival event in favor of letrozole, whereas patients with ductal carcinoma experienced a 20% reduction.

The observed difference was significantly related to histology (interaction P value = .03). For overall survival, the magnitude of benefit of letrozole compared to tamoxifen was again higher in the subset with lobular disease than in the ductal subset, and significantly related to his-

EXPERT POINT OF VIEW

C

. Kent Osborne, MD, Professor of Medicine and Molecular and Cellular Biology at Baylor College of Medicine and Director of the Lester and Sue Smith Breast Center at Baylor told The ASCO Post that this is “brand new” data that “looks very interesting.” He noted that groups for whom letrozole is the preferred antihormonal agent have already been established: those who are HER2-positive, have high proliferation rates, or have lower estrogen receptor levels. Published studies have shown that these factors predict for better C. Kent Osborne, MD outcomes with letrozole, he noted.

While the findings suggest yet another group might be added to this list, he cautioned, “This is an unplanned subset analysis, and there’s a hazard that you are getting the wrong answers. The findings should be confirmed in another dataset,” he maintained, “but do I believe the data? I think I do.”

Known Biology Frankie A. Holmes, MD, of Texas Oncology in Houston, already foresees the information as “practice-changing,” she said. She also noted that the findings correlate with the known biology of this cancer subtype.

“We have always known that lobular patients are addicted to estrogen, especially the classic lobular type as in this study. They are not chemosensitive, and we know that letrozole is the superior means of reducing estrogen levels [among the antiestrogens]. It’s good to see some data, and it’s also good to see an orphan tumor type being addressed. Ten percent is a small proportion of patients with breast cancer, but it is a ‘significant small,’” she said. n Disclosure: Drs. Osborne and Holmes reported no potential conflicts of interest.

for lobular patients treated with letrozole and tamoxifen, respectively.

In the multivariate analysis of diseasefree survival correcting for classic clinicopathologic factors, significant interactions were observed between treatment and histology (ductal/lobular, interac-

Letrozole vs Tamoxifen in ER-positive Breast Cancer ■■ In a subset analysis of the BIG 1-98 trial, letrozole was shown to have a

greater survival benefit than tamoxifen in postmenopausal women with estrogen receptor–positive carcinoma.

■■ The effect of letrozole on disease-free survival was greatest for patients with lobular vs ductal breast cancer and for luminal B vs A disease.

tology (interaction P value = .045). At 8 years, survival rates were 88% and 84%

tion P value = .006) and treatment and subtype (luminal A/luminal B, interac-

tion P value = .01), Dr Metzger reported.

All hazard ratios favored letrozole, but the hazard ratio of 0.33 for lobular luminal B tumors was most striking, he added.

Hazard ratios for other tumor subtypes were 0.49 for lobular luminal A tumors, 0.64 for ductal luminal B tumors, and 0.95 for ductal luminal A tumors. n Disclosure: Dr. Metzger-Filho reported no potential conflicts of interest.

Reference 1. Metzger O, Giobbie-Hurder A, Mallon E, et al: Relative effectiveness of letrozole compared with tamoxifen for patients with lobular carcinoma in the BIG 1-98 trial. 2012 San Antonio Breast Cancer Symposium. Abstract S1-1. Presented December 5, 2010.

website at ASCOPost.com

NOW APPROVED for the treatment of patients with metastatic

castration-resistant prostate cancer (mCRPC) who have previouslyy received docetaxel

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

AND...

• 37% reduction in risk of death vs placebo

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

• XTANDI can be taken with or without food1 • Patients were allowed, but not required, to take glucocorticoids1

—

In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1

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

• Seven patients (0.9%) out of 800 treated AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

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

Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved.

Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial

with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1

were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs.

If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

Learn more at XtandiHCP.com Reference: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. © 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012I-076-6330 9/12 XTANDI is a registered trademark of Astellas Pharma Inc. Astellas and the flying star logo are trademarks of Astellas Pharma US, Inc.

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; FEBRUARY 15, 2013

PAGE 28

FDA Update

Bevacizumab Approved as Combination Therapy for Metastatic Colorectal Cancer after Progression on First-line Bevacizumab Therapy

O

n January 23, 2013, the FDA approved bevacizumab (Avastin) for use in combination with fluoropyrimidine-irinotecan or

fluoropyrimidine-oxaliplatin based chemotherapy for the treatment of patients with metastatic colorectal cancer whose disease has progressed

on a first-line bevacizumab-containing regimen. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to human

vascular endothelial growth factor (VEGF), preventing the interaction of VEGF to its receptors on the surface of endothelial cells.

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

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information.

------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel.

--------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@.

-------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures.

The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

--------------------------------- ADVERSE REACTIONS ------------------------------Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo.

All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4.

7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders

9.0 44.4 9.3 Asthenic Conditionsa Peripheral Edema

1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4

24.3 4.0 Arthralgia

17.3 1.8 Musculoskeletal Pain

1.3

0.3 Muscular Weakness 9.8

6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

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

Gastrointestinal Disorders Diarrhea 21.8 1.1

0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9

0.0

Dizzinessb Spinal Cord 7.4 6.6

3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0

0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0

0.3 Upper Respiratory Tract Infectiond Lower Respiratory

2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0

Anxiety

0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8

1.0 Pollakiuria 4.8 0.0

0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin

0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH

Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo.

Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms.

Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; FEBRUARY 15, 2013

PAGE 29

FDA Update

Study Details The current approval is based on the results of a randomized, open-label, multinational trial enrolling patients with metastatic colorectal cancer that progressed during or within 3 months of discontinuation of bevacizumabbased combination chemotherapy with fluoropyrimidine-oxaliplatin or

fluoropyrimidine-irinotecan in the first-line setting.

The clinical trial accrued 820 patients who were randomly allocated

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

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers.

Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ

DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @.

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @.

-------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment.

Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@.

Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

(1:1) to receive crossover chemotherapy alone (n = 411) or crossover chemotherapy in combination with bevacizumab (n = 409). Patients received either irinotecan-based therapy or oxaliplatin-based chemotherapy depending on prior treatment (ie, irinotecan-based regimen for patients who received prior treat-

Live: 7"w Ă&#x2014; 10"h

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose.

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8&

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\

XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember.

If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

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

ONCOLOGY

ment with oxaliplatin and oxaliplatin-based therapy for patients who received prior treatment with irinotecan).

The treatment cycles on both arms were repeated every 2 or 3 weeks, depending on the chemotherapy regimen used, and bevacizumab was administered at a dose of 5 mg/kg by intravenous infusion every 2 weeks or 7.5 mg/kg by intravenous infusion every 3 weeks. Â Bevacizumab was continued until disease progression or unacceptable toxicity.

The primary efficacy endpoint was overall survival. Treatment assignment was stratified by first-line treatment (irinotecan-based vs oxaliplatin-based), first-line progression-free survival (more than 9 months vs 9 months or less), time from last bevacizumab dose (more than 42 days vs 42 days or less), and ECOG performance status (0-1 vs 2).

Results The median age of the study population was 63 years, 64% were men, and 96% had an ECOG performance status of 0 or 1. A statistically significant improvement in overall survival was observed in patients receiving crossover chemotherapy plus bevacizumab compared to those receiving crossover chemotherapy alone (HR = 0.81, 95% CI = 0.69â&#x20AC;&#x201C;0.94; P = .0062, unstratified log-rank test).

Median overall survival was 11.2 and 9.8 months for patients on the crossover chemotherapy plus bevacizumab and crossover chemotherapy arms, respectively. Progression-free survival was also significantly improved in patients receiving crossover chemotherapy plus bevacizumab compared to those receiving chemotherapy alone (HR = 0.68, 95% CI = 0.59â&#x20AC;&#x201C;0.78; P < .0001). The median progression-free survival times were 5.7 and 4.0 months, respectively.

No new safety signals were observed in this trial. The safety data was consistent with the known safety profile established in previously approved indications.

The recommended dose and schedule in patients receiving bevacizumab in combination with fluoropyrimidine-irinotecan or fluoropyrimidineoxaliplatin based chemotherapy after progression on a first-line bevacizumab containing regimen is 5 mg/kg administered every 2 weeks or 7.5 mg/kg administered every 3 weeks as a 60-minute IV infusion. n

The ASCO Post | FEBRUARY 15, 2013

PAGE 30

ASH Annual Meeting Hematology

ASH Highlights Included New Data in Myeloma, Lymphoma, and Leukemia, plus Studies of Mucositis and Graft-vs-Host Disease

By Alice Goodman and Caroline Helwick

T

he 54th Annual Meeting of the American Society of Hematology (ASH) featured about 5,000 abstracts, including oral sessions and posters, as well as named lectures and symposia. In addition to our regular news coverage from the meeting, below are capsule summaries of a few news highlights that we hope you will find of interest.

Pomalidomide/Carfilzomib Promising in Relapsed/ Refractory Myeloma In a phase I/II trial in heavily pretreated multiple myeloma patients, the combination of pomalidomide, carfilzomib (Kyprolis), and dexamethasone led to high response rates and delays in progression. All 32 patients had a median of six prior lines of therapy (range, 1–15) and were relapsed/refractory to lenalidomide (Revlimid); 30 of 32 were also bortezomib (Velcade)-refractory.1 Of 30 evaluable patients, 15 (50%) responded, with 37% achieving a partial response, 13% achieving at least a very good partial response, and 67% attaining clinical benefit (minor response or better), reported Jatin Shah, MD, of The University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival was 7.4 months, and overall survival at 1 year was 90%. “The combination has encouraging preserved response rates and survival independent of FISH/cytogenetic risk status,” he commented.

The most common toxicities were neutropenia (84%), anemia (63%), and thrombocytopenia (57%). Febrile neutropenia occurred in 6%. The hematoSee Page 97 logic toxicities were “all reversible and manageable,” Dr. Shah said.

The maximum tolerated doses in the regimen were determined to be carfilzomib at 20/27 mg/m2 (initiated at 20 mg/m2 and escalated to 27 mg/m2), pomalidomide at 4 mg, and dexamethasone at 40 mg in relapsed/ refractory myeloma. Enrollment is ongoing in a phase II study of 82 patients.

A second retrospective study evaluated the impact on overall survival of

the two drugs as separate treatments in 65 dual-refractory patients, showing approximately a 50% reduction in mortality risk, vs nonreceipt of these novel agents (P = .047).2 Other predictors of poor survival, present prior to receipt of the new drugs, were low hemoglobin, prior treatment with bortezomib/ lenalidomide/dexamethasone, and advanced lytic lesions, investigators from Washington University in St. Louis reported.

Daratumumab Moving Forward in Myeloma Data continue to accumulate for the monoclonal antibody daratumumab in multiple myeloma. In a phase���������������������������������� ��������������������������������� I/II study in 32 patients, clinical benefit was achieved in almost half the heavily pretreated relapsed/ refractory population.3 Torben Plesner, MD, of Vejle Hospital in

Torben Plesner, MD

Vejle, Denmark, reported that 47% of patients demonstrated a reduction in the amount of monoclonal (M) protein in the blood or urine, which corresponded to a 13% partial response rate, 19% minor response rate, and 16% stable disease rate. A reduction in plasma cell infiltration of the bone marrow was also observed. The maximum tolerated dose of the drug has not been established.

“The infusion was surprisingly well tolerated,” Dr. Plesner noted. The investigators found a dose-dependent reduction in natural killer cells that was reversible after treatment discontinuation.

Brentuximab Vedotin Prolongs Survival in Hodgkin Lymphoma Several studies at the ASH meeting validated the use of brentuximab vedotin (Adcetris) in Hodgkin lymphoma

and suggested that indications for the drug may be expanded. Treatment with brentuximab after autologous stem cell transplant prolonged overall survival compared to standard therapy, in relapsed/refractory Hodgkin lymphoma patients in a study from The University of Texas MD Anderson Cancer Center.

The investigators took a retrospective look at 102 patients who received brentuximab and compared them to 756 treated with standard therapy (matched by age). They also performed a multivariate analysis on a smaller cohort of patients with known disease characteristics and treatment history.4 They found a highly significant overall survival benefit in patients receiving brentuximab (median, 91 months) over standard therapy (median, 28 months; P < .0001). Neither age nor sex impacted overall survival, reported Meghan S. Karuturi, MD. “There was an improvement in overall survival irrespective of the time to relapse from transplant,” she said.

Among complete responders to brentuximab, negativity by positronemission tomography (PET) after seven cycles was correlated with longer progression-free survival (P < .013).

PET status (negative vs positive) after both four and seven cycles among all patients who received brentuximab in the phase II clinical trial was significantly associated with improved progression-free and overall survival, she reported.

Several phase I studies also found encouraging activity for first-line bren-

Meghan S. Karuturi, MD

tuximab. In a study from The University of Texas MD Anderson Cancer Center, brentuximab combined with CHP (cyclophosphamide, doxorubicin, and prednisone) produced complete remissions in 23 of 26 patients with systemic anaplastic large-cell

Michelle A. Fanale, MD

lymphoma (19 patients) or a CD30positive mature T-cell or natural killer cell lymphoma (7 patients). The other three patients achieved partial remissions.5 All 7 of the mature T-cell or natural killer cell lymphoma patients had a complete remission, reported Michelle A. Fanale, MD. A phase III trial is planned for next year.

Predicting Risk for Oral Mucositis Bayesian networks based on singlenucleotide polymorphisms (SNPs), developed from saliva-sourced DNA, predicted the occurrence of oral mucositis with 81% accuracy in a study presented by Stephen Sonis, DMSc, of Harvard School of Dental Medicine, Boston.6 The assay is being developed by Inform Genomics, Inc, in Boston.

Dr. Sonis and fellow investigators noted single-nucleotide polymorphism–based Bayesian networks for risk assessment offer significant advantages over classic candidate gene and genome-wide association studies.

They are also finding single-nucleotide polymorphism networks associated with other treatment-related toxicities. Advances in bioinformatics and computational power have enabled the development of learned networks using a Bayesian methodology, which is a means of estimating probabilities.

The oral mucositis study presented at the ASH meeting included 153 patients in the discovery set (82 myeloma patients and 71 with Hodgkin disease or non-Hodgkin lymphoma) undergoing stomatotoxic conditioning regimens prior to autologous hematopoietic stem cell transplantation.

The genetic analysis revealed 82 single-nucleotide polymorphisms within the network, and these identified

ASCOPost.com | FEBRUARY 15, 2013

PAGE 31

ASH Annual Meeting patients who developed mucositis with an accuracy of 99.3%, Dr. Sonis reported.

To assist in sample size calculations for future studies, the predictive validity of the single-nucleotide polymorphism network was tested in an exploratory set of 16 demographically similar patients. The network predicted mucositis in the cohort with an accuracy of 81%. Of 8 patients without mucositis, all were accurately identified and there were no false-positives. Of 8 patients who did not develop mucositis, 5 were accurately identified and there were 3 false-negatives.

Dr. Sonis suggested that future stratification by conditioning regimen is likely to further improve the predictive accuracy of the analytical method. The clinical application of such a network could identify patients who would benefit from pro-

Stephen Sonis, DMSc

phylaxis with agents such as palifermin (Kepivance), he said.

This approach to personalized medicine could become available for routine patient care if results from these studies can be validated in a multicenter study.

Blinatumomab in Relapsed/ Refractory ALL A phase II single-arm study showed that the anti-CD19 bispecific T-cell engager (BiTE) antibody blinotumomab induced high complete remission rate and prolonged overall survival in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). 7 Blinatumomab is an orphan drug that engages T cells and tumor cells, placing the T cells within reach to inject toxins into the tumor cell, triggering apoptosis. Blinatumomab directs the T cells to target cells that express CD19, a protein on the surface of most B-cell derived leukemias and lymphomas.

The study established a dose regimen of 5 μg/m2/d for week 1, followed by 15 μg/m2/d in weeks 2, 3, and 4, and

subsequent cycles. The most common adverse events were pyrexia, fatigue, headache, tremor, and leukopenia.

Medically important but fully revers-

Max S. Topp, MD

ible adverse events included cytokine release syndrome and central nervous system events.

At the ASH meeting, Max S. Topp, MD, Wuerzburg University Medical Center, in Wuerzburg, Germany, reported “unprecedented” single-agent activity of blinatumomab with among 36 patients enrolled in the phase II trial. The complete remission rate was 69%. Molecular remission was achieved in 88% of hematologic responders. Median overall survival was 9.8 months, and median relapse-free survival was 7.6 months.

A global phase II trial has been launched in adults with relapsed/refractory B-cell ALL.

arm vs 48% of historical controls.

Compared with control data, the experimental arm had a lower rate of grade 3/4 graft-vs-host disease (4% vs 20%) and a lower incidence of transplant-related mortality at 1 year (13% vs 19%). No differences between groups were reported in infectious complications or risk of relapse, suggesting that vorinostat helped reduce the incidence of graft-vs-host disease without further compromising patients’ immune systems, Dr. Choi said.

The next step is to determine whether vorinostat improves outcomes in patients undergoing unrelated donor myeloablative hematopoietic stem cell transplant and to assess its effect in pa-

Sung W. Choi, MD

tients at high risk for grade 2-4 acute graft-vs-host disease. A phase����������� ���������� III clinical trial would be needed for confirmatory evidence.

Vorinostat plus Standard Therapy Reduces Graft-vsHost Disease

Lenalidomide in Relapsed/ Refractory Mantle Cell Lymphoma

Targeting histone deacetylases with the oral anticancer drug vorinostat (Zolinza) appears to prevent graft-vshost disease in patients undergoing hematopoietic stem cell transplantation, according to results of a first-in-human phase I/II trial presented by Sung W. Choi, MD, University of Michigan Bone Marrow Transplant and Hematologic Malignancies Program, Ann Arbor.8 The single-arm study enrolled 47 adult patients slated for matched related donor-reduced intensity conditioning hematopoietic stem cell transplantation from the University of Michigan and Washington University in St. Louis. Patients were treated with oral vorinostat from day 10 through day 100 on top of a standard regimen after stem cell transplantation and were compared with 25 historical controls for the cumulative incidence of graft-vs-host disease.

Graft-vs-host disease occurred in 21% of patients in the experimental

A large phase II trial called MCL001 EMERGE found that singleagent lenalidomide achieved rapid and durable efficacy in patients with mantle cell lymphoma (MCL) who either relapsed or were refractory to bortezomib.9 Lenalidomide shows durable efficacy in very heavily pretreated MCL patients regardless of number of prior therapies, including bortezomib, said lead author Andre Goy, MD, the John Theurer Cancer Center, Hackensack, New Jersey.

Mantle cell lymphoma comprises about 6% of all non-Hodgkin lymphomas and has only one FDA-approved treatment—bortezomib. The phase II trial included 134 MCL patients who had relapsed or experienced disease progression after bortezomib therapy, or were refractory to bortezomib; patients had a median of four previous therapies (range, 2–10).

Lenalidomide was given at 25 mg/d (21/28-day cycles), overall

response rate was 28%, complete response rate 8%, and median duration was 16.6 months according to independent central review. According to investigator assessment, the overall response rate was 32%, complete response rate was 16%, and median duration of response was 18.5 months.

As determined by central review, median progression-free survival was 4 months and median overall survival was 19 months. Response rates were consistent across subgroups, regardless of bulky disease or number of prior therapies.

Dose reduction was required in 38%, and 19% discontinued treatment, mainly due to myelosuppression, as seen in myeloma. The most common grade 3/4 adverse events were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%), and fatigue (7%). n Disclosure: Drs. Shah, Karuturi, Fanale, Sonis, Topp, Choi, and Goy reported no potential conflicts of interest. Dr. Plesner is a consultant for Genmab, on advisory boards for Janssen and Celgene, an investigator for Genmab, Janssen, Celgene, Bristol-Myers Squibb, Novartis, Roche, Nordic Myeloma Study Group, HOVON, German CLL Study Group, a teacher for Janssen, Celgene, Novartis, and Nonpharma/Mundipharma, and has received research grants from Janssen, Celgene, Roche, and Novartis.

References 1. Shah J, Orlowski R, Thomas S, et al: 2012 ASH Annual Meeting. Abstract 75.

Presented December 9, 2012.

2. Wang T-F, Fiala M, Ahluwalia R, et al: 2012 ASH Annual Meeting. Abstract 4050. Presented December 10, 2012.

3. Plesner T, Lokhorst H, Gimsing P, et al: 2012 ASH Annual Meeting. Abstract 73. Presented December 9, 2012.

4. Karuturi M, Arai S, Chen R, et al: 2012 ASH Annual Meeting. Abstract 3701. Presented December 1, 2012.

5. Fanale M, Shustov A, Forero-Torres A, et al: 2012 ASH Annual Meeting. Abstract 60. Presented December 9, 2012.

6. Sonis S, Antin J, Alterovitz G, et al: 2012 ASH Annual Meeting. Abstract 735.

Presented December 10, 2012.

7. Topp M, Goekbuget N, Zugmaier G, et al: 2012 ASH Annual Meeting. Abstract 670. Presented December 10, 2012.

8. Choi S, DiPersio J, Braun T, et al: 2012 ASH Annual Meeting. Abstract 740.

Presented December 10, 2012.

9. Goy A, Sinha R, Williams MJ, et al: 2012 ASH Annual Meeting. Abstract 905.

Presented December 11, 2012.

In Advanced Renal Cell Carcinoma (RCC)...

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

IMPORTANT SAFETY 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,” 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 well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than one week), and frequently thereafter. Treat increased blood pressure promptly with standard antihypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if 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.

Move Forward With VOTRIENT In a Phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC of clear cell or predominant clear cell histology1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 1,2

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 1,2

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 1,2

9.2 months (95% CI, 7.4-12.9)

NCCN Guidelines® Category 1 recommendation4 • 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

Once-daily oral dosing1

VOTRIENT: Summary of serious and common adverse reactions1

• The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In RCC, initial dose reduction should be 400 mg; additional 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

• Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

• Forty-two percent of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose-reduced • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

• 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.

• 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, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • Most common adverse events (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting • See below and accompanying Brief Summary for additional Important Safety Information, including warnings and precautions

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.

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.

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%).

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

References: 1. VOTRIENT® (pazopanib) Tablets [package insert].

Research Triangle Park, NC: GlaxoSmithKline; 2012. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Data on file, GlaxoSmithKline.

4. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.2.2012. ©National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed June 1, 2012. 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.

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.

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%).

VOTRIENT.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 least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period.

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 post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. 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)

(N=145)

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

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

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

B:15” T:13” S:12”

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 drug-drug 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 (5.15)]. 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 least once every 4 weeks for the first 4 months of treatment or 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.

©2012, GlaxoSmithKline. All rights reserved.

Revised 11/2012 VTR:8BRS ©2012 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. VOT391R0 December 2012

The ASCO Post | FEBRUARY 15, 2013

PAGE 36

News Hematology

ASH International Clinical Collaboration Replicates High Cure Rate of APL in Developing Countries

T

he work of an American Society of Hematology (ASH) international clinical network collaborative focused on modernizing treatment protocols for patients in the developing world with acute promyeloctyic leukemia (APL) has drastically improved cure rates in patients in Central and South America. In fact, the project has achieved comparable outcomes to those observed in patients in the United States and Europe, according to an online report in the journal Blood.1 APL can be fatal in hours or days without proper diagnosis and treatment, though it has become a highly curable disease for patients in most developed countries. This is the result of a combination regimen of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy.

Recent clinical trials conducted in the developed world have reported very high rates of complete remission and long-term disease-free survival in patients treated with this regimen (90% achieving complete response and 85% achieving disease free survival, respectively). This progress has not yet reached developing countries, however, where the reported longterm overall survival for patients with APL is below 60%.

International Consortium Founded ASH founded the International Consortium on Acute Promyelocytic Leukemia (IC-APL) in 2005. The goal of the IC-APL was to foster collaboration among researchers, clinicians, and laboratory scientists from institutions in developing countries and wellestablished international cooperative groups based in the United States and Europe. Founding members of the initiative created the program with the hope that the resulting exchange of clinical expertise and support would ultimately improve the diagnosis and treatment of patients in developing countries with this often deadly hematologic malignancy.

“We chose APL as a model disease for the initiative because of the opportunity to improve patient outcomes in the developing world by collaborating with and learning from colleagues who have already successfully made these strides against this disease,” said

Eduardo Rego, MD, PhD, founding member of the IC-APL and Professor of Hematology/Oncology at the University of Sao Paulo in Brazil. “This initiative aims to build the capacity of local clinicians in the developing world to conduct clinical trials by introducing and fostering clinical and laboratory procedures that represent the standard of care for the treatment

was the replacement of idarubicin with daunorubicin, which is less expensive and more readily available in these countries. Patients enrolled in the trial received combination therapy including oral ATRA in two daily doses until complete remission and daunorubicin given intravenously on days 2, 4, 6, and 8.

Throughout the trial, participating

Our initial success truly demonstrates that when we work closely with colleagues from around the world we can close the gap in treatment outcomes between patients in developed countries and those in developing countries.

—Eduardo Rego, MD, PhD

of acute leukemia in many countries around the world.”

Registry Study and Training As part of the IC-APL, four transitioning countries—Brazil, Chile, Mexico, and Uruguay—were chosen to participate in a registry study modeling a clinical trial evaluating the efficacy and safety of a standardof-care protocol for APL. During the registry study, which was governed by a panel of acute leukemia experts from Europe, Latin America, and the United States, medical representatives from each participating country received essential clinical trial administration training, including standard patient enrollment, data collection and reporting, administration of therapy, and outcomes reporting. Participants also attended regular face-to-face and online meetings with the expert panel to discuss progress and share data.

Following this extensive training, clinicians and scientists from the four participating countries began their registry trial, enrolling 183 adult patients with a suspected APL diagnosis between June 2006 and September 2010. An important change in the induction therapy protocol in the IC-APL registry study conducted in Brazil, Chile, Mexico, and Uruguay compared to regimens used in trials in developed countries

sites registered all cases using common clinical record forms in the Pediatric Oncology Network Database and collaborated with national clinical trial coordinators and reference laboratories to confirm the integrity and accuracy of treatment data.

Study Results After approximately 3 years of follow-up, investigators observed promising results: 80% of patients achieved 2-year overall survival and 91% achieved disease-free survival, all with a low cumulative incidence of relapse (4.5%). Early patient mortality in the trial, defined as death occurring between diagnosis and first evaluation at 30 days, was reduced by nearly half compared to historical controls, and overall survival improved by 30%. Of the 180 evaluable patients that participated in the four host countries, 153 (85%) achieved complete remission.

After 5 years of follow-up, 75.4% of all patients enrolled and 90.2% of those who achieved complete remission remained alive. Early death occurred in 27 patients (15%). These rates of death are considerably lower than other population-based studies analyzing early mortality of APL patients conducted in the United States and Sweden (17.3% and 29%, respectively), further demonstrating the safety of this treatment combination.

The most frequent hematologic toxicity was grade 4 neutropenia, which was observed in a small group (3.3%) of patients. No significant toxicities were reported during maintenance therapy, and no secondary malignancies were reported.

Improving Care in Developing Countries “In a very short time period, we observed an extraordinary increase in survival rates of our participants, who, before this trial, might not have had much hope for survival,” said Dr. Rego.

The excellent patient survival rates observed in the IC-APL trial demonstrate the efficacy of this affordable and readily available treatment protocol and are comparable to those observed in studies conducted in developed countries by both the Spanish group Programa para el Estudio de la Terapeutica en Hemopatia Maligna (PETHEMA, complete response rates of 92.5% and 90%) and the North American Leukemia Intergroup (complete response rate of 90%).

By refining and standardizing diagnostic procedures and implementing a standard-of-care treatment protocol, members of this innovative ASH collaborative have taken the first step toward significantly improving the prognosis of patients with severe and rapidly fatal diseases, such as APL, in developing countries using affordable and available treatments.

Based on the initial success of the IC-APL, its governing body voted to expand the collaborative model to address other subtypes of acute leukemias, beginning with acute myeloid leukemia. To reflect this change, the cooperative group is now called the International Consortium on Acute Leukemia (ICAL). For more information on ICAL, visit the ASH Global Programs website (www.hematology. org/global). n Reference 1. Rego EM, Kim HT, Ruiz-Argüelles GJ, et al: Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. January 14, 2013 (early release online).

ASCOPost.com | FEBRUARY 15, 2013

PAGE 37

Journal Spotlight Genitourinary Oncology

Abiraterone Benefits Patients with Metastatic Prostate Cancer Who Have Had No Previous Chemotherapy

By Matthew Stenger

T

he androgen biosynthesis inhibitor abiraterone acetate (Zytiga) has been shown to increase radiographic progression-free survival and delay clinical decline and initiation of chemotherapy in a clinical trial in castration-resistant patients with metastatic prostate cancer who have had no prior chemotherapy. A trend toward improved overall survival was also observed with abiraterone treatment.

Charles J. Ryan, MD

The trial, recently reported by Charles J. Ryan, MD, of the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, and colleagues in The New England Journal of Medicine, provided the basis for the recent expanded indication for abiraterone in patients with metastatic disease and no prior chemotherapy.1 The prior indication for abiraterone was limited to patients who had previously received chemotherapy including docetaxel.2

Study Details In this trial, 1,088 patients were randomly assigned to receive abiraterone at 1,000 mg daily plus prednisone at 5 mg twice daily (n = 546) or placebo plus prednisone (n = 542).

Patients had to have no or mild pain symptoms, prostate-specific antigen (PSA) or radiographic progression in soft tissue or bone, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and ongoing androgen deprivation with a serum testosterone level of less than 50 ng/ dL. Patients with visceral metastases who had received previous therapy with ketoconazole lasting more than 7 days were excluded.

Baseline characteristics were balanced between the two groups.

Overall, patients had a median age of

70 years, 95% were Caucasian, and ECOG performance status was 0 in 76% of patients and 1 in 24%. Treatment continued until radiographic or clinical disease progression, unacceptable toxicity, or withdrawal. The coprimary endpoints were radiographic progression-free survival and overall survival.

Benefits in Survival across Subgroups The study was unblinded after the second planned interim analysis, which occurred when 43% of the expected deaths had occurred. The median follow-up for all patients was 22.2 months.

On the first interim analysis (which occurred when 13% of expected deaths had occurred), abiraterone was associated with a significant 57% reduction in risk for radiographic progression (median radiographic progression-free survival not reached vs 8.3 months, hazard ratio [HR] = 0.43, P < .001).

At the second interim analysis, median radiographic progression-free survival was 16.6 months in the abiraterone group vs 8.3 months in the placebo group, representing a 47% reduction in risk of progression (HR = 0.53, P < .001).

At the second interim analysis, death had occurred in 27% of the abiraterone group vs 34% of the placebo

longing radiographic progression-free survival was significant across all subgroups (ECOG performance status 0 or 1, brief pain inventory-short form score 0–1 or 2–3, presence/absence of bone metastases at entry, age, region, and high or low PSA, lactate dehydrogenase, and alkaline phosphatase). Hazard ratios for overall survival favored abiraterone for all subgroups and were significant for some.

Prolonged Time to Opiate Use and Chemotherapy Abiraterone treatment was also associated with prolonged median times to decline in ECOG performance status (12.3 vs 10.9 months, HR = 0.82, P = .005), initiation of cytotoxic chemotherapy (25.2 vs 16.8 months, HR = 0.58, P < .001), opiate use for cancer-related pain (not reached vs 23.7 months, HR = 0.69, P < .001), PSA progression (11.1 vs 5.6 months, HR = 0.49, P < .001), and worsening in health-related quality of life as indicated by decline in the Functional Assessment of Cancer–Prostate total score (12.7 vs 8.3 months, HR = 0.78, P = .003).

No New Safety Signals The most common adverse events in the abiraterone group were fatigue (39% vs 34% in the prednisone-alone

Abiraterone for Prostate Cancer without Prior Chemotherapy ■■ A double-blind trial of abiraterone in metastatic prostate cancer with no previous chemotherapy was stopped after the second interim analysis, when abiraterone treatment was associated with a 57% reduction in risk for radiographic progression and a strong trend toward improved overall survival.

■■ No safety concerns were identified that are unique to the previously untreated patient population.

group. Median overall survival was not reached vs 27.2 months; the 25% reduction in risk for death in the abiraterone group (HR = 0.75, P = .01) indicated a strong trend toward mortality reduction but did not reach the prespecified boundary for significance ����������������������������������� .001). ��������������������������������� Final overall survival re(P ≤���������������������������������� sults are awaited.

The benefit of abiraterone in pro-

group), back pain (32% vs 32%), and arthralgia (28% vs 24%). Grade 3 or 4 adverse events occurred in 48% of abiraterone patients vs 42% of placebo patients, serious adverse events occurred in 33% vs 26%, and adverse events resulted in treatment discontinuation in 10% vs 9% and in dose modification or interruption in 19% vs 12%. Adverse events led to death

in 4% vs 2%, with the most common cause being events related to disease progression (0.6% of each group).

Cardiac and Mineralocorticoidrelated Toxicities With regard to adverse events of special interest based on earlier abiraterone studies, grade 3 or 4 hypertension (4% vs 3%), cardiac disorders See Page 97 (6% vs 3%, including atrial fibrillation in 1% vs < 1%), increased ALT (5% vs < 1%), and increased AST (3% vs < 1%) were more common with abiraterone.

Overall, adverse events classified as cardiac disorders occurred in 19% of abiraterone patients and 16% of placebo patients. Mineralocorticoidrelated toxicities, including hypertension (22% vs 13%), hypokalemia (17% vs 13%), and fluid retention/ edema (28% vs 24%), were more common in the abiraterone group, with most of the adverse events being grade 1 or 2.

The authors noted that safety of abiraterone in this study was similar to that observed in the study of patients who received abiraterone after docetaxel chemotherapy,2 with no toxic effects unique to the previously untreated population being detected.

They concluded, “The results show benefit from the use of abiraterone in patients with asymptomatic or mildly symptomatic metastatic castrationresistant prostate cancer who have not received previous chemotherapy. n For more on use of abiraterone in the clinic, see page 38.

Disclosure: Dr. Ryan has received grant support (via his institution) from Cougar Biotechnology/Janssen, consultancy fees from Cougar Biotechnology/Janssen, Millenium, and Sanofi-Aventis, and grants or grants pending from Novartis, Aragon, and Medivation.

References 1. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368:138-148, 2013.

2. de Bono JS, Logothetis CJ, Molina A, et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995-2005, 2011.

The ASCO Post | FEBRUARY 15, 2013

PAGE 38

In the Clinic Genitourinary Oncology

Abiraterone in Patients with Metastatic Castration-resistant Prostate Cancer and No Prior Chemotherapy

By Matthew Stenger

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

Indication On December 10, 2012, abiraterone acetate (Zytiga) received an expanded indication for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.1,2 The initial indication was limited to patients who had previously received docetaxel-containing therapy.

Approval was based on a phase III trial in which 1,088 patients with metastatic castration-resistant prostate cancer who had not received prior cytotoxic chemotherapy were randomly assigned to abiraterone at 1,000 mg daily plus prednisone at 5��������������������������������� mg �������������������������������� twice daily (n��������������� =������������� �������������� 546) ������������ or placebo plus prednisone (n = 542).2,3 (See page 37 for more on this trial.)

Patients had to have prostate-specific antigen or radiographic progression in soft tissue or bone and had to have

OF NOTE The most common adverse events with abiraterone therapy are fatigue, joint swelling/discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and bone pain. ongoing androgen deprivation with a serum testosterone level of < 50 ng/ dL. Patients with moderate to severe cancer pain or opiate use for cancer pain were excluded.

Overall, patients had a median age of 70 years, 95% were Caucasian, and ECOG performance status was 0 in 76% of patients and 1 in 24%. Treatment continued until radiographic or clinical disease progression, unacceptable toxicity, or withdrawal.

The coprimary endpoints were radiographic progression-free survival and overall survival. Median radio-

graphic progression-free survival was not reached in the abiraterone group vs 8.3 months in the placebo group, representing a significant 57% reduction in risk for radiographic progression (hazard ratio [HR] = 0.43, P < .0001). At the third prespecified interim analysis, overall survival was prolonged in the abiraterone group (median, 35.3 vs 30.1 months, HR = 0.79, 95% confidence interval = 0.66–

The starting dose of abiraterone should be reduced to 250 mg/d in patients with moderate hepatic impairment, and ALT, AST, and bilirubin must be monitored prior to the start of treatment, every week for the first month, every 2 weeks for the following 2 months, and monthly thereafter in such patients. The drug should not be used in patients with severe hepatic impairment. If hepatotoxicity

Abiraterone in Metastatic Prostate Cancer ■■ Abiraterone acetate (Zytiga) has received an expanded indication for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (regardless of prior docetaxelcontaining therapy).

■■ The drug must be given on an empty stomach at a recommended

dosage of 1,000 mg orally once daily in combination with prednisone, 5 mg twice daily.

0.96), but these results did not cross the prespecified (O’Brien-Fleming) boundary for statistical significance.

The finding of benefit was supported by statistically significant improvements in time to opiate use and time to cytotoxic chemotherapy in the abiraterone group.

How It Works Abiraterone acetate is converted to abiraterone, an androgen biosynthesis inhibitor that inhibits CYP17 (17 α-hydroxylase/C17,20-lyase).

This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for biosynthesis of the androgen precursors of testosterone.

In contrast, androgen deprivation therapies such as GnRH agonists or orchiectomy decrease androgen production in the testes but do not affect androgen production by the adrenals or in tumors.

How It Is Given The recommended dose of abiraterone is 1,000 mg orally once daily in combination with prednisone at 5 mg twice daily. Abiraterone must be taken on an empty stomach. No food should be consumed for at least 2 hours before and for at least 1 hour after a dose. Exposure to abiraterone increases up to 10-fold when abiraterone acetate is taken with food.

occurs during treatment, treatment should be interrupted and resumed after resolution of liver function abnormalities at a dose of 750 mg and at 500 mg for subsequent recurrence; treatment should be discontinued for recurrence of liver toxicity at a dose of 500 mg.

Abiraterone is a CYP2D6 inhibitor. Coadministration with drugs that are CYP2D6 substrates and that have a narrow therapeutic index should be avoided. If an alternative treatment cannot be used, caution should be exercised and a dose reduction of the concomitant CYP2D6 substrate should be considered.

Abiraterone should be used with caution in patients with a history of cardiovascular disease. In addition to being regularly monitored for hepatic function, patients should be regularly monitored for adrenocortical insufficiency and mineralocorticoid excess. Hypertension and hypokalemia should be controlled before starting treatment. Increased doses of corticosteroids may be required before, during, and after stressful situations.

Safety Profile Safety data are available from 1,333 patients with metastatic castration-resistant prostate cancer who received abiraterone plus prednisone and in

934 patients who received placebo plus prednisone in the current clinical trial and in the previous pivotal trial in patients with prior chemotherapy including docetaxel.

In this pooled analysis, adverse events that occurred in at least 10% of abiraterone recipients and more frequently (> 2% difference) than in placebo recipients were fatigue, joint swelling/discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and bone pain. The most common laboratory abnormalities (>����������������������������� 20%) ���������������������������� that occurred more frequently (≥����������������������� ���������������������� 2%) in abiraterone patients were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. Grade 3 or 4 adverse events occurred in 55% of abiraterone patients and 50% of placebo patients.

In the pooled analysis, cardiac failure occurred more frequently in abiraterone patients (2.1% vs 0.7%); grade 3 or 4 cardiac failure occurred in 1.6% of abiraterone patients, leading to five treatment discontinuations and two deaths, and in 0.2% of placebo patients, leading to no discontinuations and one death. The majority of arrhythmias detected were grade 1 or 2; there was one death associated with arrhythmia and one sudden

OF NOTE Abiraterone acetate is converted to abiraterone, an androgen biosynthesis inhibitor that inhibits CYP17, which is expressed in testicular, adrenal, and prostatic tumor tissues and is required for biosynthesis of testosterone precursors. death among abiraterone patents and no deaths in placebo patients. Adrenal insufficiency occurred in 0.5% of abiraterone patients and in 0.2% of placebo patients.

The median duration of treatment with abiraterone in the current trial was 13.8 months. In this trial, the most common adverse events continued on page 40

For the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

Start with TREANDA® (bendamustine HCI) for Injection for established front-line CLL therapy Single-agent TREANDA tripled median PFS Progression-free survival (PFS)* Survival distribution function

1.0

TREANDA (n=153)

0.9

Chlorambucil (n=148)

18 Months

0.8

median PFS

0.7 0.6 0.5 0.4

6 Months

0.3

median PFS

0.2 P<.0001 HR=0.27 (95% CI: 0.17, 0.43)

0.1 0 0

5

10

15

20

25

30

Months

*TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6).

HR=hazard ratio.

CI=confidence interval.

TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatment-naïve patients with Binet stage B or C (Rai stages I–IV) CLL who required treatment (N=301). Patients were scheduled to receive either TREANDA 100 mg/m2 intravenously on Days 1 and 2 (n=153) or chlorambucil 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles.

The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia.

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL).

Efficacy relative to first-line therapies other than chlorambucil has not been established.

• TREANDA is administered with a convenient dosing schedule – The recommended CLL dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day treatment cycle, up to 6 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 Please see accompanying brief summary of full Prescribing Information.

Learn more at TREANDAHCP.com © 2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2545a December 2012

The ASCO Post | FEBRUARY 15, 2013

PAGE 40

In the Clinic

Abiraterone in Prostate Cancer continued from page 38

of any grade in abiraterone patients (compared to those receiving placebo) were fatigue (39% vs 34%), joint swelling/discomfort (30% vs 25%), edema (25% vs 21%), constipation (23% vs 19%), hot flush (22%

vs 18%), diarrhea (22% vs 18%), and hypertension (22% vs 13%). The most common grade 3 or 4 adverse events were hypertension (4%vs 3%), dyspnea (2% vs 1%), fatigue (2% vs 2%), and joint swelling/discomfort (2% vs 2%). The most common laboratory abnormalities of any grade were hyperglycemia (57% vs

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established.

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. 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 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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 CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial.

The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

51%), elevated ALT (42% vs 29%), lymphopenia (38% vs 32%), elevated AST (37% vs 29%), and hypernatremia (33% vs 25%). The most common grade 3 or 4 abnormalities were lymphopenia (9% vs 7%), hyperglycemia (6.5% vs 5%), elevated ALT (6% vs 1%), elevated AST (3% vs 1%), and hypokalemia (3% vs 2%).

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. 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 CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.

Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of 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 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. 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 singleuse 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-2511e (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

November 2012

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

The abiraterone label carries warnings/precautions for mineralocorticoid excess, adrenocortical insufficiency, hepatotoxicity, and food effect. The safety of abiraterone was not established in patients with leftventricular ejection fraction < 50% or New York Heart Association (NYHA) class III or IV heart failure in the trial in previously treated patients or in patients with left-ventricular ejection fraction < 50% or NYHA class II to IV heart failure in the trial supporting the expanded indication. n References 1. U.S. Food and Drug Administration: Abiraterone acetate. Available at http:// www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm331628. htm. Accessed January 3, 2013.

2. ZYTIGA® (abiraterone acetate) tablets prescribing information. Janssen Biotech, Inc, December 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202379s005lbl. pdf. Accessed January 3, 2013.

3. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy.

N Engl J Med 368:138-148, 2013.

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San Antonio Breast Cancer Symposium Breast Cancer

Research Roundup from San Antonio: New Data on Triple-negative, HER2-positive, Local, and Advanced Breast Cancer

By Caroline Helwick, Alice Goodman, and Jo Cavallo

T

he 2012 San Antonio Breast Cancer Symposium featured more than 2,500 abstracts and lectures, including timely research in the field and discussions for scientists and clinicians alike. In addition to nearly two dozen in-depth reports from the meeting, The ASCO Post brings readers the following news briefs.

Bevacizumab (Avastin) did not improve outcomes when added to chemotherapy in patients with early breast cancer who have the triple-negative subtype, the results of the randomized phase III BEATRICE study showed.1 Overall, the outcomes were better than expected, but “in terms of improvement in outcomes, giving 1 year of bevacizumab isn’t the answer,” said David Cameron, MD, Professor of Oncology at Edinburgh University in Scotland.

David Cameron, MD

C. Kent Osborne, MD, Director of both the Breast Center and Cancer Center at Baylor College of Medicine, Houston, who moderated the press conference where the results were first presented, added, “It’s getting to the point where it’s going to be difficult to know the role of bevacizumab, if any, in breast cancer.”

BEATRICE included 2,591 women with triple-negative invasive early breast cancer starting adjuvant chemotherapy with a taxane, anthracycline, or both. Patients were randomly assigned to four to eight cycles of chemotherapy, alone or with the addition of bevacizumab. Treatment was continued for 1 year.

Invasive disease–free survival was achieved by 83.7% in the bevacizumab arm compared with 82.7% for chemotherapy alone, for a 13% nonsignificant reduction in risk.

C. Kent Osborne, MD

While the overall survival analysis was premature, a similar trajectory was observed. The bevacizumab arm had a 16% nonsignificant reduction in mortality. Bevacizumab was associated with more cardiovascular toxicity, but most cases were reversible after discontinuation.

Intraoperative Radiotherapy vs External-beam Radiotherapy Low-dose intraoperative radiation therapy proved comparable to wholebreast irradiation (ie, external-beam radiotherapy) for preventing breast cancer recurrence in an updated analysis of the randomized noninferiority TARGIT-A trial.2 After a median follow-up of 29 months, the 34 cases of ipsilateral breast recurrence were observed slightly but significantly more often in the targeted intraoperative radiotherapy group. Nonetheless, the absolute difference of 2.01% fell within the prespecified boundary for noninferiority of targeted intraoperative radiotherapy (2.5%), reported Jayant Vaidya, MD, FRCS, PhD, Reader and Consultant Surgeon at the University College London.

Photo Courtesy © SABCS/ Todd Buchanan 2012

Bevacizumab in Triplenegative Breast Cancer

Jayant Vaidya, MD, PhD

The study population consists of 3,451 women aged 45 and older with unifocal early invasive breast cancer (preferably < 3.5 cm). The updated results showed a hazard ratio for re-

currence of 2.05 for targeted intraoperative radiotherapy vs external-beam radiotherapy (P = .042). In addition to the recurrences, 88 deaths have occurred in the two treatment groups, but in this case there was a trend toward 30% fewer deaths overall with targeted intraoperative radiotherapy (P = .099) and a 53% reduction in non–breast cancer mortality (P = .009) vs external-beam radiotherapy.

Dr. Vaidya maintained that focusing radiation therapy on the primary tumor site, where most recurrences are observed, is a logical strategy, giving rise to the targeted intraoperative radiotherapy protocol. After surgical excision, patients receive about a 20Gy dose directly to the wound bed. Patients with high-risk features (~15%) receive supplemental external-beam radiation therapy in this “risk-adapted” approach.

Prespecified stratification by hormone receptor as a surrogate for radiation sensitivity status showed that the difference in recurrence rate owed primarily to increased locoregional recurrence in patients with progesterone receptor–negative tumors and delayed delivery of targeted intraoperative radiotherapy (necessitating reopening of the wound cavity). An analysis limited to the 1,625 progesterone receptor– positive women who received targeted intraoperative radiotherapy concurrent with lumpectomy produced a between-group difference for local recurrence of 0.18% and a reduction in overall mortality of 3.1% (P = .08) vs external-beam radiotherapy.

Dr. Vaidya emphasized the need for careful patient selection in applying targeted intraoperative radiotherapy in clinical practice. “Patients should fulfill the eligibility criteria for the TARGITA trial,” he said. “The preferred treatment option is concurrent [targeted intraoperative radiotherapy at the time of surgery] in progesterone receptor– positive patients. Add external-beam radiotherapy if adverse prognostic factors are present.”

Cognitive Impairment May Precede Chemotherapy Treatment A small study by Bernadine E. Cimprich, PhD, RN, FAAN, Emerita Professor, and colleagues at the Uni-

versity of Michigan3 found that some common neurocognitive problems associated with chemotherapy in the treatment of breast cancer, such as poor performance on verbal working memory tasks (ie, “chemobrain”), are often present before treatment begins and may be the result of fatigue and anxiety.

Bernadine E. Cimprich, PhD, RN, FAAN

The research involved testing the neurocognitive responses of 65 patients with stages 0 through IIA breast cancer and 32 age-matched healthy subjects using functional magnetic resonance imaging (MRI). The functional MRI was performed 24 to 34 days after surgery and before either adjuvant anthracycline-based combination chemotherapy (n = 28) or radiotherapy (n = 37) for localized breast cancer. The participants were asked to perform a verbal working memory task during functional MRI scanning and provide self-reported levels of fatigue both 1 month prior to treatment and 1 month following therapy.

The findings showed that the chemotherapy group had significantly greater severity of fatigue (P < .05) and performed less accurately on the verbal working memory task both 1 month pre- and 1 month post-treatment, compared with participants in the other two groups. The radiotherapy-treated patients had an intermediate cognitive function score between that of the chemotherapy and control groups.

The researchers concluded that pretreatment neurocognitive compromise and fatigue are contributors to the cognitive impact often attributed solely to chemotherapy. Moreover, they noted that early therapeutic interventions that target fatigue may improve cognicontinued on page 42

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PAGE 42

San Antonio Breast Cancer Symposium San Antonio Research Roundup continued from page 41

tive function and reduce the distress of “chemobrain” during adjuvant treatment.

According to press conference moderator C. Kent Osborne, MD, of Baylor College of Medicine, Houston, worry and stress of a breast cancer diagnosis, as well as anticipatory anxiety before chemotherapy, can affect cognitive function. This problem needs attention because cognitive effects can worsen over time, he added.

trastuzumab should remain the standard of care.”

Higher Doses of Fulvestrant in Metastatic Breast Cancer Fulvestrant (Faslodex) at 500 mg achieved superior survival vs the 250mg dose in postmenopausal women with estrogen receptor–positive metastatic breast cancer in an update of the

Duration of Trastuzumab in HER2-positive Early Breast Cancer Two years of trastuzumab (Herceptin) is not better than the standard 1 year of trastuzumab therapy for HER2-positive breast cancer, according to 8-year follow-up of the HERA trial reported by Martine Piccart, MD, President of the European Society for Medical Oncology and Chair of the Breast International

Martine Piccart, MD

Group, Institut Jules Bordet, Brussels, Belgium.4 HERA accrued 5,102 women with early HER2-positive breast cancer who were treated with neoadjuvant or adjuvant therapy according to the investigators’ choice and then randomly assigned to 1 or 2 years of trastuzumab following chemotherapy.

At 8 years, no difference in diseasefree survival was observed between the two arms and both were significantly better than observation. No difference in the cumulative incidence of severe cardiac endpoints was observed between the two arms.

“We were concerned that there would be a progressively smaller effect of 1 year of treatment with trastuzumab over time. Now with 8 years of follow-up, there is no further attenuation of benefit as was seen at 1 year, and a very robust effect with 1 year of trastuzumab,” she said. “One year of

Angelo Di Leo, MD, PhD

randomized CONFIRM trial.5 The higher dose did not increase toxicity.

The standard of care in this setting has been fulvestrant at 250 mg. “Our results indicate that this should be modified to 500 mg,” said lead author Angelo Di Leo, MD, PhD, Head of the Department of Medical Oncology at the Hospital of Prato, Istituto Toscano Tumoria, Prato, Italy.

The multinational phase��������� III����� CONFIRM trial randomly assigned 736 women to 250 mg of fulvestrant vs 500 mg. An analysis performed after 75% of the women died showed that the 500-mg dose achieved a clinically relevant 4.1-month difference in median overall survival compared with 250 mg: 26.4 months and 22.3 months, respectively. The relative risk reduction in death was 19% for those taking the higher dose of fulvestrant.

Serious adverse events were reported in 8.9% of the 500 mg-dose group and 6.7% of those on the lower dose.

Peter Dubsky, MD

ceptor–positive breast cancer, even beyond 15 years of follow-up. This is in sharp contrast to estrogen receptor–negative breast cancer. Thus, a multigene assay that assesses not only a short-term, but also long-term, prognosis meets an unmet medical need” he noted.

Unlike other multigene tests that are based largely on genes with a role in tumor proliferation, the EndoPredict score also factors in genes involved in estrogen receptor regulation and genes with a role in tumor differentiation.

These biologic motifs are contained in the eight genes of the test; three reference genes are also included. Furthermore, data derived from tumor size and nodal status factor into the final test result.

Among 1,702 women with estrogen receptor–positive/HER2-negative breast cancer, the EndoPredict score defined about two-thirds with an excellent prognosis; 98.2% with a low risk score were free of distant metastasis at 10 years. One-third of women with higher risk scores had a five times higher risk of late recurrence than the low-risk group, Dr. Dubsky explained.

Expanded studies are ongoing. EndoPredict is currently available for diagnostic use in Austria, Germany, and Switzerland.

EndoPredict Identifies Women at Risk for Distant Metastases

Breast Cancer Index and Late Recurrences in ER-positive Patients

The EndoPredict score identifies women with estrogen receptor (ER)positive /HER2-negative breast cancer at risk for late distant metastases, according to Peter Dubsky, MD, Associate Professor of Surgery at the Medical University of Vienna in Austria.6 Other predictive tests, including Oncotype DX and MammaPrint, have been trained and validated to predict recurrence within the first 5 years, Dr. Dubsky explained. The good news about the EndoPredict score is that it predicts late metastases. “Risk of recurrence persists for estrogen re-

The polymerase chain reaction– based Breast Cancer Index (BCI) assay, performed on primary tumors in node-negative estrogen receptor–positive patients traditionally considered at good risk, identifies groups of patients with a high risk of recurrence, and performs independently of clinical characteristics, such as number of nodes, tumor grade, and age.7 “The residual risk of recurrence remains a substantial concern for estrogen receptor–positive patients with breast cancer. Current multigene signatures have significant prognostic

performance in predicting early recurrences, ie, 0 to 5 years postdiagnosis.

However, such signatures have limited performance in predicting the risk of late recurrence, ie, beyond 5 years,” said Dennis Sgroi, MD, Associate Professor of Pathology at Harvard Medical School, Boston.

The Breast Cancer Index consists of two independently developed biomarkers: the HOXB13:IL17BR gene expression ratio and the molecular grade index, a set of cell cycle–related genes. Investigators examined the prognostic performance of the Breast Cancer Index as compared to the 21gene Recurrence Score and IHC4 test with regard to early and late recurrences.

The population included 665 patients from the translational arm of

Dennis Sgroi, MD

the Arimidex, Tamoxifen, Alone or in Combination trial (TransATAC), followed for a median of 10 years. Prognostic evaluation for early recurrences was done by censoring survival time to 5 years, and for late recurrences, by analyzing patients who had remained recurrence-free for at least 5 years.

The index distinguished three risk groups: BCI-low (58%), BCI-intermediate (25%), and BCI-high (17%).

With BCI-low as a reference, the BCI-intermediate group had nearly a threefold risk for distant recurrence at 10 years and the BCI-high group had nearly a fivefold risk (P < .001). The BCI-high group also had more than an eightfold risk of early recurrence, with disease recurring in 18% within 5 years.

“As it relates to late recurrence, BCI demonstrated sustained significant prognostic performance in a multivariate analysis, while IHC4 and Oncotype DX Recurrence Score lost their prognostic ability,” Dr. Sgroi noted.

“At the point of diagnosis, BCI identified two groups: those at low risk of early recurrence who are adequately treated with endocrine therapy alone.

And those at high risk of early recurrence who do not benefit adequately

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PAGE 43

San Antonio Breast Cancer Symposium from simple endocrine therapy and who should be considered for additional therapy,” he said.“ “At the point of 5-year follow-up among patients who are disease-free, the BCI identified two groups as well: those at low risk of late recurrence who do not need subsequent therapy and those at significant risk of late recurrence who should be considered for additional or alternative systemic adjuvant therapy,” he concluded.

vival (HR = 5.6; P < .001), whereas HER2-positive status determined by local testing only trended toward an overall survival association (HR = 1.78; P = .098). The observed discrepancy in survival based on different HER2 classification methods appeared to be due to the misclassification of HER2 status determined by

local testing, Dr. Yardley said.

Interestingly, of the 24 triple-negative cases that were reported via the local testing, 4 were reclassified as HER2-positive by HERmark testing.

Quantitative HER2 total protein expression determined via the HERmark assay may enrich the identification of both HER2-positive and HER2-nega-

tive breast cancers and thus may provide added clinical value to real-world local HER2 testing, she said.

Vitamin D Levels and Breast Cancer Outcome Postmenopausal women with sufficient levels of vitamin D were much continued on page 44

HER2 Status by Central Laboratory Testing HER2 status is more reliably determined with novel central laboratory testing techniques than routine local HER2 testing such as immunohistochemistry and in situ hybridization, a multicenter retrospective biomarker study showed.8 The finding could have implications for patients with HER2-negative breast cancer as well, said ­Denise A. Yardley, MD, Senior Investigator, Breast Cancer Research Program, at Sarah Cannon Research Institute, Nashville, Tennessee.

For men with metastatic prostate cancer, a major threat lives in their bones.

A SIGNIFICANT THREAT IN mCRPC

90%

Bone metastases are the leading cause of death in patients with mCRPC.1

Her team evaluated the HERmark assay, a novel method for quantitatively measuring HER2 total protein expression in breast cancer. They compared results obtained with the HERmark assay to those obtained by local (“real-world,” site-reported) HER2 testing and by central laboratory HER2 retesting of formalinfixed, paraffin-embedded breast cancer tissues. They correlated the results with tumor histopathologic characteristics and overall survival in a cohort of 192 formalin-fixed, paraffin-embedded breast cancer samples from patients, 90% of whom had not received HER2-targeted therapy.

Study sites were instructed to identify approximately 50% HER2-positive and 50% HER2-negative breast cancer cases.

High HER2 total protein expression levels (> 13.8) determined by the HERmark assay significantly correlated with poor overall sur-

Skeletal-related events (SREs) increase mortality associated with bone metastases in mCRPC.2 Bone metastases often lead to pathologic fractures, spinal cord compression, hypercalcemia, and bone marrow insufficiency—events that can cause intense pain from bone deconstruction and nerve compromise.3 Moreover, SREs are a key driver of mortality in prostate cancer.4 Prostate cancer tumor cells are uniquely suited to proliferate within the bone microenvironment.1 As a result, bone represents the earliest and most common site of prostate cancer metastasis.5 In fact, 84% to 92% of patients with mCRPC show evidence of bone metastases.6,7

BONE METASTASES SIGNIFICANTLY DECREASE SURVIVAL2 100

Bone metastases No bone metastases

90 80

Survival probability (%)

Denise A. Yardley, MD

In a large cohort study of patients with prostate cancer, mortality at year 1 was nearly 5 times higher in the subgroup of patients who had bone metastases.2 At year 5, survival fell from 56% in patients without bone metastases to just 3% in patients with bone metastases.2

OF PATIENTS WITH mCRPC SHOW EVIDENCE OF BONE METASTASES6,7

70

56% alive at 5 years

60 50 40 30 20

3% alive at 5 years

10 0

0

1

2

3

4

5

6

7

8

9

10

Years after initial prostate cancer diagnosis Adapted from Nørgaard et al.

CONFRONTING THE THREAT Extending survival in mCRPC patients remains a significant challenge. Recognizing the impact of bone metastases on mortality is an important step towards improving treatment of patients with mCRPC.8 mCRPC: metastatic castration-resistant prostate cancer.

References: 1. Jin J-K, Dayyani F, Gallick GE. Steps in prostate cancer progression that lead to bone metastasis. Int J Cancer. 2011;128(11):2545-2561. 2. Nørgaard M, Jensen AØ, Jacobsen JB, Cetin K, Fryzek JP, Sørensen HT. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol. 2010;184(1):162-167. 3. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94(19):1458-1468. 4. DePuy V, Anstrom KJ, Castel LD, Schulman KA, Weinfurt KP, Saad F. Effects of skeletal morbidities on longitudinal patient-reported outcomes and survival in patients with metastatic prostate cancer. Support Care Cancer. 2007;15(7):869-876. 5. Bubendorf L, Schöpfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31(5):578-583. 6. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512. 7. Petrylak DP, Tangen CM, Hussain MHA, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513-1520. 8. Aljumaily R, Mathew P. Optimal management of bone metastases in prostate cancer. Curr Oncol Rep. 2011;13(3):222-230.

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PAGE 44

San Antonio Breast Cancer Symposium San Antonio Research Roundup continued from page 43

less likely to have breast cancer recur in their bones and in distant recurrence to any tissue when their standard chemotherapy was combined with zoledronic acid (Zometa), found researchers from the University of Sheffield in the United Kingdom.9 The finding was based on the analysis of stored blood samples taken from a subgroup of participants in the Adjuvant Zoledronic

Robert Coleman, MD

Acid to Reduce Recurrence (AZURE) trial before they began treatment. The subgroup included 606 premenopausal women and 266 postmenopausal women.

The researchers looked at the baseline serum levels of two markers of bone turnover—beta C-terminal telopeptide type 1 collagen (βCTX) and N-terminal propeptide type 1 procollagen (P1NP)—and baseline measurements of 25-hydroxyvitamin D (25-OHD) as a marker of bone and general health.

Although neither of the two bone turnover markers predicted outcomes, the investigators found that 25-OHD levels > 30 ng/mL were significantly associated with lower risk for bone relapse (hazard ratio [HR] = 0.11, 95% confidence interval [CI] = 0.02–0.76, P = .0257). A similar trend was seen for any site of distant recurrence (HR = 0.56, 95% CI = 0.31–1.01, P = .0519).

Only 10.3% of the women in the subgroup had vitamin D levels above this cutoff.

“We should be measuring vitamin D and replenishing it appropriately….

[But] whether vitamin D as an intervention will change outcome, I don’t know,” said lead researcher Robert Coleman, MD, Professor of Medical

Oncology at the University of Sheffield, United Kingdom, at the San Antonio meeting.

Age and Likelihood of Complete Response to Neoadjuvant Chemotherapy According to the results of a metaanalysis of 8,949 women with breast cancer by researchers from the German Breast Group,10 women aged 35 years or younger more often achieved a pathologic complete response with neoadjuvant chemotherapy than older women, especially in the subgroups of luminal and triple-negative tumors.

The researchers determined that 23.6% of the subgroup of 704 younger women in the study were able to achieve a pathologic complete response following neoadjuvant chemotherapy, compared with 17.5% of the 4,167 women in the 35- to 50-year-old age range and 13.5% of the 4,078 older women (P < .001).

The subgroup of younger women included a greater proportion of triple-negative breast cancer cases and a smaller proportion of luminal A– type breast cancer cases, compared with the group of women over age 35 (26% vs 19% for triple-negative disease and 21% vs 27% for luminal A–type disease). The study results found no difference in disease-free survival according to age among patients who achieved a pathologic complete response. However, disease-free survival was significantly worse among younger women who did not achieve a pathologic complete response.

Tumor biology, especially in young women, also seemed to play a role in predicting pathologic complete response and disease-free survival. Researchers found that pathologic complete response was able to predict disease-free survival in luminal A patients only among the younger women. The worst diseasefree survival rate among women with luminal A–type cancer was seen in those who were younger than 35 and did not achieve a pathologic complete response. The best disease-free survival rate in this group was found among women younger than 35 who

Sibylle Loibl, MD

did achieve a pathologic complete response.

“The most surprising finding was that young women with a luminal A–type tumor—hormone receptor–positive and HER2-negative— who achieved a pathologic complete response had a better survival rate than the patients with nonpathologic complete response. This is not true for other age groups, which indicates that breast cancer in the young—even with a luminal-type breast cancer—is chemosensitive,” Sibylle Loibl, MD, Associate Professor of Gynecology at the University of Frankfurt and lead author of the study, said at the San Antonio meeting. n

Disclosure: Drs. Cameron, Osborne, Cimprich, Dubsky, Sjroi, Yardley, and Loibl reported no potential conflicts of interest. Dr. Vaidya received support for ISC meetings/ conferences and honoraria from Carl Zeiss.

Dr. Piccart is a consultant for and receives honoraria from Sanofi-Aventis, Amgen, Bayer, Roche-Genentech, PharmaMar, and AstraZeneca; and receives honoraria from Novartis. Dr. Di Leo received honoraria from AstraZeneca, Novartis, and Pfizer for participation in advisory boards and as a speaker at sponsored symposia. Dr. Coleman received research support and provided expert testimony for Novartis, and was on the speakers bureau for Amgen.

References 1. Cameron D, Brown J, Dent R, et al: Primary results of BEATRICE, a randomized phase III trial evaluating adjuvant bevacizumab-containing therapy in triplenegative breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract S6-5.

Presented December 7, 2012.

2. Vaidya JS, Wenz F, Bulsara M, et al: Targeted intraoperative radiotherapy for early breast cancer: TARGIT-A trial—updated analysis of local recurrence and first analysis of survival. 2012 San Antonio Breast Cancer Symposium. Abstract S4-2.

Presented December 6, 2012.

3. Cimprich B, Hayes DF, Askren MK, et al: Neurocognitive impact in adjuvant chemotherapy for breast cancer linked to fatigue: A prospective functional MRI study. 2012 San Antonio Breast Cancer Symposium. Abstract S6-3. Presented December 7, 2012.

4. Goldhirsch A, Piccart-Gebhart MJ, Procter M, et al: HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow-up. 2012 San Antonio Breast Cancer Symposium. Abstract S5-2. Presented December 7, 2012.

5. DiLeo A, Jerusalem G, Petruzelka L, et al: Final analysis of overall survival for the phase III CONFIRM trial: Fulvestrant 500 mg versus 250 mg. 2012 San Antonio Breast Cancer Symposium. Abstract S1-4. Presented December 5, 2012.

6. Dubsky P, Brase JC, Fisch K, et al: The EndoPredict score identifies late distant metastases in ER+/HER2- breast cancer patients. 2012 San Antonio Breast Cancer Symposium. Abstract S4-3. Presented December 6, 2012.

7. Sgroi DC, Sestak I, Cuzick J, et al: Comparative performance of Brest Cancer Index vs. Oncotype Dx and IHC4 in the prediction of late recurrences in hormonal receptor-positive lymph node-negative breast cancer patients: A TransATAC study. 2012 San Antonio Breast Cancer Symposium. Abstract S1-9. Presented December 5, 2012.

8. Yardley D, Kaufman P, Adams J, et al: Quantitative measurement of HER2 expression in breast cancers: Comparison with “real world” HER2 testing in a multicenter Collaborative Biomarkers Study and correlation with clinicopathological features. 2012 San Antonio Breast Cancer Symposium. Abstract P2-05-06. Presented December 6, 2012.

9. Coleman RE, Rathbone EJ, Marshall HC, et al: Vitamin D, but not bone turnover markers, predict relapse in women with early breast cancer: An AZURE translational study. 2012 San Antonio Breast Cancer Symposium. Abstract S6-4. Presented December 7, 2012.

10. Loibl S, Jackisch C, Gade S, et al: Neoadjuvant chemotherapy in the very young, 35 years of age or younger. 2012 San Antonio Breast Cancer Symposium.

Abstract S3-1. Presented December 6, 2012.

ASCOPost.com | FEBRUARY 15, 2013

PAGE 45

Direct from ASCO

International Members Cite Networking, Enhanced Patient Care Among Benefits of ASCO Membership

Discounts on meeting registrations, educational resources are additional plusses

T

hanks to the membership category ASCO designed for physicians in developing countries, Brazilian oncologist Milena Mak, MD, can greatly enhance the care she delivers in the very busy 580bed Instituto do Cancer do Estado de Sao Paulo.

Pooja Nandwani Patel, MD

And radiation oncologist Pooja Nandwani Patel, MD, can use the experience of others from around the world in the cancer treatment she provides at the 650-bed Gujarat Cancer & Research Institute in Ahmedabad, Gujarat, India, which sees 800 to 900 cancer patients per day.

Drs. Mak and Patel are just two

of the oncologists who belong to ASCO’s International Corresponding membership category, an online-focused category that offers an affordable membership option for experienced licensed physicians who are eligible for ASCO’s Full membership and who reside in a developing nation, as defined by the World Bank as one whose economy is low, lower-middle, or upper-middle income. This membership category is open to oncologists from every specialty.

The membership fee for the International Corresponding category is significantly discounted.

Although it provides a lowercost ASCO membership option to those in developing countries, where cancer is most prevalent, all membership categories are available to international prospective members depending upon eligibility.

The International Corresponding category delivers the numerous benefits of ASCO membership in an online-only format. The

CONQUERING

and awards, including the International Development and Education Award (IDEA), which pays for international members to come to the ASCO Annual Meeting and afterward shadow a mentor.

Milena Mak, MD

reduced fee gives members access to ASCO’s premier oncology journals, Journal of Clinical Oncology and Journal of Oncology Practice, and includes savings of 20% off all ASCO Educational Products and Resources.

International Corresponding members also receive significant savings off the nonmember registration rate for the ASCO Annual Meeting and Symposia as well as advance access to members-only housing and registration for each ASCO Annual Meeting. In addition, international members have the opportunity to apply for Conquer Cancer Foundation grants

Connecting to Other Oncologists Is ‘LifeChanging’ But it’s the ability to communicate with colleagues—using ASCO’s online membership directory, the ASCO LinkedIn group, ASCOConnection.org, and other networking tools—that many international members find most exciting.

“Being able to access all of the ASCO benefits, like ASCO University and meetings sponsored

by ASCO, has been just amazing,” said Dr. Mak. “But what has been really life-changing has been connecting with other ASCO members in other developing countries, and learning how they overcome some of the obstacles and barriers that we face.”

One of the cornerstones of ASCO membership is networking, which can and often does lead to collaboration on research, patient care, and other initiatives. International Corresponding members enjoy networking opportunities with

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 supporting the 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

Jose Duarte, MD,

other ASCO members around the world.

Jose Duarte, MD, a surgical oncologist who focuses on breast cancer at the Instituto Del Cancer in Paraguay, said he most appreciates how the International Corresponding category has unified oncologists continued on page 46

The ASCO Post | FEBRUARY 15, 2013

PAGE 46

Direct from ASCO

International Corresponding Membership continued from page 45

of various subspecialties in his country. Now they connect in ways they never had before.

“My experience with this membership category is strongly positive because it provides a local umbrella for doctors to get together and share knowledge,” said Dr. Duarte. “We knew each other before, but we never worked together in ways that were multidisciplinary. ASCO’s message is all about being multidisciplinary, and that has really helped us and our patients.”

Dr. Duarte, president of the Paraguayan Society of Surgical Oncol-

Volume 7, Issue 3

May 2011

Journal of oncology Practice

As cancer has no language and knows no borders, ASCO resolved to make the science, programs, and products it offers accessible to every corner of the world. The idea for the International Corresponding category came from Margaret A. Tempero, MD, 2003–2004 ASCO Past President, who charged the Membership Committee with determining the feasibility of cre-

What’s Hot in

Subspecialization in Community Oncology: Option or Necessity?

By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists

By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials

By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice

By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

JCO.org Overcoming Obstacles in Accessing Unfunded Oral Chemotherapy: Physician Experience and Challenges

By Dolly Han, et al

There are two main Conquer Cancer Foundation grants geared toward early-career ASCO members who reside in a country that is in the low, lower-middle, or upper-middle income category on the World Bank List. They are IDEA and the Long-term International Fellowship (LIFe) award.

For IDEA recipients, ASCO pays for travel to the Annual Meeting and pairs each recipient with an ASCO

Margaret A. Tempero, MD

ating a category for physicians in countries with limited resources who may be unable to afford Full membership.

ASCO membership is popular among those in who focus on cancer care in countries outside the United States; international members make up approximately 30% of

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY

5 most-accessed Top 10Top most-accessed articles published 2012 articles published in in 2011 in in Journal of Clinical Oncology Journal of Clinical Oncology

Official Journal of the American Society of Clinical Oncology

What’s Hot in

JCO

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

www.jco.org

2012

JOP

Report on the ASCO 2010 Provider-Payer Initiative Meeting

By Michael N. Neuss, MD, et al

Conquer Cancer Foundation Grants

A Growing Membership Category

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

The Authoritative Resource for Oncology Practices

ASCO’s membership. International Corresponding members make up about 2.34% of ASCO’s membership, and the category grows on average 48% each year.

ogy, is one of only 50 oncologists in Paraguay and has been an International Corresponding member since 2005. He is now a member of ASCO’s International Affairs Committee.

JCO.org Choosing the Best Trastuzumab-Based Adjuvant Chemotherapy Regimen: Should We Abandon Anthracyclines?

By Harold J. Burstein, et al

Early-Phase Clinical Trials In The Community: Results From the National Cancer Institute Community Cancer Centers Program Early-Phase Working Group Baseline Assessment

Progression-Free Survival: Meaningful or Simply Measurable?

If Palliative Care Is the Answer, What Is the Question?

By J. Russell Hoverman

Reasons Why Physicians Do Not Have Discussions About Poor Prognosis, Why It Matters, and What Can Be Improved

What Currently Defines a Breast Center? Initial Data From the National Accreditation Program for Breast Centers

Caring for the Whole Patient: The Science of Psychosocial Care

Inpatient Hospitalization of Oncology Patients: Are We Missing an Opportunity for End-of-Life Care?

ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers

By Howard A. Zaren, et al

By Meena S. Moran, et al

By Gabrielle B. Rocque et al

By Christopher M. Booth, et al

By Jennifer W. Mack, et al

By Paul B. Jacobsen, et al

By Kristin Bergethon, et al

ASCOPost.com | FEBRUARY 15, 2013

PAGE 47

Direct from ASCO

member mentor. After the meeting, recipients travel to their mentor’s institution for three days in order to shadow them and learn directly from their work. In 2011, ASCO launched the IDEA in Palliative Care award, which uses the same application criteria but is targeted specifically to those who focus on palliative care.

The LIFe Award is geared toward early-career oncologists and allows recipients to spend a year with a mentor at their institution in the United States or Canada.

Dr. Patel, from Ahmedabad, India, was thrilled to be an IDEA award recipient this year. “Training under my mentor, Dr. Brian’O Sullivan at Princess Margaret Hospital in Toronto, Canada, was one of the best things I’ve ever done,” said Dr. Patel. “And that way of learning continues. Through my ASCO membership I get an ongoing opportunity to interact with other ASCO members with whom I can share my views and gain from their experience regarding their attitude towards cancer management in different countries of world.”

Those outside the United States

Help Your Patients Find the Latest Research on GU Cancers

who have become ASCO members say they find that the value of ASCO membership becomes apparent very soon after joining. Dr. Mak, for one, says she expects her ASCO membership to continue broadening the scope of her practice and thus improving the level of

care that she’s able to bring to her patients.

“I’ve only been a member for a few months, but already I’ve benefitted so much,” said Dr. Mak. “And I believe many more benefits are to come, which will certainly help me to be a better doctor and

he 2013 Genitourinary Cancers Symposium is taking place now, from February 14–16 in Orlando, Florida. Direct your patients to www. cancer.net/GUsymposium to find written summaries for patients and a podcast that highlights the research presented at the meeting. Also on Cancer.Net, your patients can find detailed sections of many types of GU cancers at www.cancer.net/cancer, as well as shorter, introductory fact sheets at www.cancer.net/factsheets. n © 2013. American Society of Clinical Oncology. All rights reserved.

© 2013. American Society of Clinical Oncology. All rights reserved.

FOR A DIFFERENT PERSPECTIVE IN RENAL CELL CARCINOMA, DISCOVER…

ANOTHER SIDE OF RCC

In the United States, RCC is the 9th most common malignancy and accounts for 2% to 3% of all adult cancers.1,2 Incidence rates continue to rise; however, the reason for this increase is unknown. 2 The American Cancer Society estimates that there will be 64,770 new cases of RCC and 13,570 RCCrelated deaths in 2012. 3

Studies have demonstrated the importance of sustained drug levels; however, these levels can be compromised when toxicities lead to dose modifications, interruptions, or discontinuations. 5,8,9 In the Phase 3 trials of targeted agents, 30% to 40% of patients required dose modifications, and in the community setting this percentage may be higher.7 Treatment modifications require significant monitoring by healthcare professionals, and may potentially compromise treatment exposure and patients’ daily living. 5,8

Is good enough, enough?

Today’s RCC patients are often active, with busy lifestyles and families. With a median age at diagnosis of only 64, quality of daily living on therapy is critical. 3 While the introduction of targeted therapy has improved the management of advanced disease and the outlook for patients, new challenges and existing unmet needs may compromise not only patients’ everyday life, but overall outcomes.4,5

Furthermore, patients themselves may choose not to adhere to their dosing regimen due to discomfort or dissatisfaction with the toxicity of therapy. 8 Other factors that may affect adherence include misinterpretation of physician instructions, polypharmacy syndrome and lifestyle distractions (e.g., demands of work and family, lack of support).10

Therapy for advanced RCC has evolved…

T

clinical investigator, but will also allow me to bring knowledge to the medical community here in Sao Paulo, and to better help the people of Brazil.” n

There may be opportunities to improve patient care

Each therapeutic class of agents is associated with distinct adverse events. Despite recent advances in treatment, side effects remain an important issue in patient management.6

Proactive monitoring, early detection, and prompt management of side effects are important for optimal patient management. Additionally, open communication between patients and healthcare professionals can be crucial to try to avoid premature treatment discontinuations or adverse impacts on patients’ everyday lives. 5,8

Research has shown that a substantial proportion of patients—both in clinical trials and everyday clinical practice—may not receive the full dose of their therapy due to adverse event management.7,8

Go behind the scenes to learn more at www.AnotherSideOfRCC.com.

AVEO and Astellas are uncompromising in their commitment to RCC References: 1. Centers for Disease Control and Prevention. http://apps.nccd. cdc.gov/uscs/toptencancers.aspx. Accessed January 27, 2012. 2. National Comprehensive Cancer Network. http://www.nccn.org. Published October 18, 2011. Accessed January 27, 2012. 3. American Cancer Society. Atlanta: ACS; 2012.

4. Cowey CL, Hutson TE. Clin Adv Hematol Oncol. 2010;8(5):357-364. 5. Hudes GR, Carducci MA, Choueiri TK, et al. J Natl Compr Canc Netw. 2011;9(suppl 1):S-1-S-30.

6. Appleby L, Morrissey S, Bellmunt J, Rosenberg J. Hematol Oncol Clin North Am. 2011;25(4):893-915. 7. Rini BI. J Clin Oncol. 2009;27(19):3225-3234. 8. Ravaud A. Ann Oncol. 2009;20(suppl 1):i7-i12. 9. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Cancer Chemother Pharmacol. 2010;66(2):357-371. doi:10.1007/s00280-009-1170-y. 10. Moore S. Cancer Nurs. 2007;30:112-122.

An Uncompromising Commitment to RCC

AVEO ONCOLOGY is a trademark of AVEO Pharmaceuticals, Inc. Astellas and the Flying Star logo are trademarks of Astellas Pharma Inc. ©2012 AVEO Pharmaceuticals, Inc. and Astellas Pharma US, Inc.

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PAGE 48

Direct from ASCO

Young Investigator Award’s Humble Beginnings Mark the Start of Something Big

J

udith Kaur, MD, was presented with the very first Young Investigator Award (YIA) at the 1984 ASCO Annual Meeting in Toronto in what she felt was a “very prestigious event”—having breakfast with the

beginning, that there would be lots of other investigators who could be supported,” she recalls. Now, 30 years later, Dr. Kaur reflects, “That’s why it feels so good to me to have been the first one, that it led to so many more young in-

tion of the American Society of Clinical Oncology is celebrating the 30th anniversary of its Grants and Awards Program, and over 200 applications have already been received for the 30th class of Young Investigator Award recipients

vestigators, young researchers, getting a chance to do good research.”

who will be recognized at the 2013 ASCO Annual Meeting. Over 700 YIA grants have been awarded since the program’s beginning, and with the 30th anniversary, the Foundation will have distributed over $30 million of research funding through the YIA program alone. The program has trained genera-

Judith Kaur, MD

ASCO president. The purpose of the new YIA program was to provide grant funding to help a young investigator launch a research career in clinical oncology. When the director of her melanoma clinic encouraged her to apply, Dr. Kaur had no idea that she would be the inaugural YIA recipient, or that she would be the first of many impressive YIA winners to come. But this became clear at breakfast that morning. “The emphasis was that this was just the

30 Years of Grants and Awards Her feeling was correct: it was just the beginning. What started as one research grant has now become many.

In 2013, the Conquer Cancer Founda-

ASCO in

Ac t i on Your source for public policy news and information from ASCO Visit our one-stop source for the latest information on: Policy Information – get the latest news on key legislation and priorities such as access to care, clinical trials and drug shortages Advocacy Tools – take action with ASCO’s ACT Network Position Statements – see ASCO’s positions on current issues

Stay informed by visiting http://ascoaction.asco.org Follow @asco on Twitter

tions of oncologists; more than a quarter of the 2012 YIA recipients had a past YIA recipient as their mentor, and there are some YIA “families” that are already on their third generation.

In addition, the Grants and Awards Program has expanded from one single grant to multiple grants and awards that span the continuum of a researcher’s career. In 2012, the Conquer Cancer Foundation offered 12 different funding opportunities for medical students through full professors, from academic centers and community practices, and from any country throughout the world. The Grants and Awards Program supports all types of translational and clinical cancer researchfrom prevention to treatment to palliative care to outcomes and everything in between.

Growing a Pipeline for the Future Even more importantly, the Young Investigator Award program is working and meeting its goal of supporting young researchers in launching their careers and growing a pipeline of researchers for the future. Nearly 99% of the YIA alumni who responded to a recent survey from the Conquer Cancer Foundation indicated that they are still involved in oncology research. The work of current and past recipients is being presenting at major medical meetings, published in prestigious journals, and featured in publications such as ASCO’s annual Clinical Cancer Advances report, which identifies the most practice-changing research of the year. These young oncology trainees are staying in research fields, touching the lives of the patients they treat, and making an impact in the constantlyevolving field of oncology.

The Grants and Awards Program and the future of many young researchers would not be possible without support from individuals who believe in the Foundation’s vision to create a world free from the fear of cancer. Join us in our mission to support the next 30 years of cancer research by visiting www.conquercancerfoundation.org/ donate. n © 2013. American Society of Clinical Oncology. All rights reserved.

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Catch hemoglobin levels before they fall too far Reduce RBC transfusions and achieve a gradual and steady Hb rise with Aranesp

®1-4

• In untreated patients whose Hb fell below 10 g/dL, 1 in 3 required an RBC transfusion within 6 weeks*5 • Aranesp® significantly reduced the need for RBC transfusions by 48% compared to placebo†2,3 • Aranesp® can be synchronized with the majority of chemotherapy regimens, including Q3W6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa CIA trials. Patients had baseline Hb ≥ 10 g/dL and decline to Hb < 10 g/dL at least once during the study-treatment period. Kaplan-Meier (K-M) estimates were calculated for the incidence of patients with transfusions by Weeks 0, 3, 6, and 9 after Hb < 10 g/dL was reached. Seventy-two percent of patients had lung cancer.5 †Data from a randomized, double-blind, placebo-controlled trial of 314 anemic (Hb ≤ 11 g/dL) patients with lung cancer receiving platinum-containing chemotherapy. Patients received once-weekly treatment with either Aranesp® (2.25 mcg/kg) or placebo, administered by subcutaneous injection, for up to 12 weeks. Per the pivotal trial protocol, doses were withheld if Hb exceeded 14 g/dL for women or 15 g/dL for men.3

INDICATION and LIMITATIONS OF USE Aranesp® (darbepoetin alfa) is for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

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

References: 1. Vansteenkiste J, Hedenus M, Gascon P, et al. BMC Cancer. 2009;9:311. doi:10.1186/1471-2407-9-311. 2. Aranesp® (darbepoetin alfa) Prescribing Information, Amgen.

3. Vansteenkiste J, Pirker R, Massuti B, et al. J Natl Cancer Inst. 2002;94:1211-1220. 4. Canon JL, Vansteenkiste J, Bodoky G, et al. J Natl Cancer Inst. 2006;98:273-284. 5. Pirker R, Collins H, Legg J, et al. J Clin Oncol. 2011;29(suppl). Abstract e19637. 6. Data on file, Amgen; [Tandem Anti-cancer and Tumor Audit].

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799

©2012 Amgen Inc. All rights reserved. Not for Reproduction.

G69514-R1-V2 68701-R1-V2

RBC = red blood cell

Hb = hemoglobin

Q3W = once every three weeks

Important Safety Information including Boxed WARNINGS for Aranesp® (darbepoetin alfa) WARNING: ESAs Increase the Risk of Death, Myocardial Infarction, Stroke, Venous Thromboembolism, Thrombosis of Vascular Access and Tumor Progression or Recurrence Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL • No trial has identified a hemoglobin target level, Aranesp® dose, or dosing strategy that does not increase these risks • Use the lowest Aranesp® dose sufficient to reduce the need for red blood cell (RBC) transfusions Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions • Use ESAs only for anemia from myelosuppressive chemotherapy, and discontinue upon completion of a chemotherapy course

• ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure • Prescribers and hospitals must enroll in the ESA APPRISE Oncology Program to prescribe or dispense Aranesp® to patients with cancer; to enroll, visit www.esa-apprise.com or call 1-866-284-8089 for assistance Do not use Aranesp® in patients with uncontrolled hypertension; control blood pressure prior to and during treatment.

Do not use Aranesp® in patients with pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other erythropoietin protein drugs. If severe anemia and low reticulocyte count develop during treatment, withhold Aranesp® and evaluate for PRCA. Do not use Aranesp® in patients with history of serious allergic reactions to the product, which may include anaphylaxis, angioedema, bronchospasm, skin rash, and urticaria. Immediately discontinue Aranesp® if such a reaction occurs.

Adverse reactions in ≥ 1% of patients treated with Aranesp® in clinical studies were abdominal pain, edema, and thrombovascular events.

Please see Aranesp® brief summary on following page for additional safety information, including Boxed WARNINGS. Visit Aranesp.com for more information.

BRIEF SUMMARY: Consult package insert for complete prescribing information.

Aranesp┬о (darbepoetin alfa) Injection, for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: t *O DPOUSPMMFE USJBMT QBUJFOUT FYQFSJFODFE HSFBUFS SJTLT GPS EFBUI TFSJPVT BEWFSTF DBSEJPWBTDVMBS SFBDUJPOT BOE TUSPLF XIFO BENJOJTUFSFE FSZUISPQPJFTJT TUJNVMBUJOH BHFOUT &4"T UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- t /P USJBM IBT JEFOUJmFE B IFNPHMPCJO UBSHFU MFWFM "SBOFTQ EPTF PS EPTJOH TUSBUFHZ UIBU EPFT OPU JODSFBTF UIFTF SJTLT t 6TF UIF MPXFTU "SBOFTQ EPTF TVGmDJFOU UP SFEVDF UIF OFFE GPS SFE CMPPE cell (RBC) transfusions.

Cancer: t &4"T TIPSUFOFE PWFSBMM TVSWJWBM BOE PS JODSFBTFE UIF SJTL PG UVNPS QSPHSFTTJPO PS SFDVSSFODF JO DMJOJDBM TUVEJFT PG QBUJFOUT XJUI CSFBTU OPO TNBMM DFMM MVOH IFBE BOE OFDL MZNQIPJE BOE DFSWJDBM DBODFST t #FDBVTF PG UIFTF SJTLT QSFTDSJCFST BOE IPTQJUBMT NVTU FOSPMM JO BOE DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS 5P FOSPMM JO UIF &4" "113*4& 0ODPMPHZ 1SPHSBN WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF t 5P EFDSFBTF UIFTF SJTLT BT XFMM BT UIF SJTL PG TFSJPVT DBSEJPWBTDVMBS BOE UISPNCPFNCPMJD SFBDUJPOT VTF UIF MPXFTU EPTF OFFEFE UP BWPJE RBC transfusions. t 6TF &4"T POMZ GPS BOFNJB GSPN NZFMPTVQQSFTTJWF DIFNPUIFSBQZ t &4"T BSF OPU JOEJDBUFE GPS QBUJFOUT SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF BOUJDJQBUFE PVUDPNF JT DVSF t %JTDPOUJOVF GPMMPXJOH UIF DPNQMFUJPO PG B DIFNPUIFSBQZ DPVSTF

INDICATION AND USAGE "OFNJB %VF UP $IFNPUIFSBQZ JO 1BUJFOUT 8JUI $BODFS Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being.

Aranesp is not indicated for use: t *O QBUJFOUT XJUI DBODFS SFDFJWJOH IPSNPOBM BHFOUT CJPMPHJD QSPEVDUT or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. t *O QBUJFOUT XJUI DBODFS SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF anticipated outcome is cure. t "T B TVCTUJUVUF GPS 3#$ USBOTGVTJPOT JO QBUJFOUT XIP SFRVJSF JNNFEJBUF correction of anemia.

CONTRAINDICATIONS

Aranesp is contraindicated in patients with: t 6ODPOUSPMMFE IZQFSUFOTJPO t 1VSF SFE DFMM BQMBTJB 13$" UIBU CFHJOT BGUFS USFBUNFOU XJUI "SBOFTQ PS PUIFS erythropoietin protein drugs. t 4FSJPVT BMMFSHJD SFBDUJPOT UP "SBOFTQ

WARNINGS AND PRECAUTIONS *ODSFBTFE .PSUBMJUZ .ZPDBSEJBM *OGBSDUJPO 4USPLF BOE 5ISPNCPFNCPMJTN *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI $,% DPNQBSJOH IJHIFS IFNPHMPCJO UBSHFUT H E- UP MPXFS UBSHFUT H E- "SBOFTQ BOE PUIFS &4"T increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.

6TJOH "SBOFTQ UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- JODSFBTFT UIF SJTL of serious adverse cardiovascular reactions and has not been shown to provide BEEJUJPOBM CFOFmU 6TF DBVUJPO JO QBUJFOUT XJUI DPFYJTUFOU DBSEJPWBTDVMBS EJTFBTF BOE TUSPLF 1BUJFOUT XJUI $,% BOE BO JOTVGmDJFOU IFNPHMPCJO SFTQPOTF UP &4" UIFSBQZ may be at even greater risk for cardiovascular reactions and mortality than other QBUJFOUT " SBUF PG IFNPHMPCJO SJTF PG HSFBUFS UIBO H E- PWFS XFFLT NBZ DPOUSJCVUF to these risks. * O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI DBODFS "SBOFTQ BOE PUIFS &4"T increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. *O DPOUSPMMFE DMJOJDBM USJBMT &4"T JODSFBTFE UIF SJTL PG EFBUI JO QBUJFOUT VOEFSHPJOH DPSPOBSZ BSUFSZ CZQBTT HSBGU TVSHFSZ $"#( BOE UIF SJTL PG EFFQ WFOPVT UISPNCPTJT %75 JO QBUJFOUT VOEFSHPJOH PSUIPQFEJD QSPDFEVSFT 1BUJFOUT XJUI $BODFS An increased incidence of thromboembolic reactions, some serious and lifeUISFBUFOJOH PDDVSSFE JO QBUJFOUT XJUI DBODFS USFBUFE XJUI &4"T *O B SBOEPNJ[FE QMBDFCP DPOUSPMMFE TUVEZ TFF 4UVEZ JO 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO PG XPNFO XJUI NFUBTUBUJD CSFBTU DBODFS SFDFJWJOH DIFNPUIFSBQZ patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered UP QSFWFOU BOFNJB NBJOUBJO IFNPHMPCJO MFWFMT CFUXFFO BOE H E- PS IFNBUPDSJU CFUXFFO BOE 5IJT TUVEZ XBT UFSNJOBUFE QSFNBUVSFMZ XIFO JOUFSJN SFTVMUT EFNPOTUSBUFE B IJHIFS NPSUBMJUZ BU NPOUIT WT BOE B IJHIFS SBUF PG GBUBM UISPNCPUJD SFBDUJPOT WT JO UIF mSTU NPOUIT PG UIF TUVEZ BNPOH QBUJFOUT USFBUFE XJUI FQPFUJO BMGB #BTFE PO ,BQMBO .FJFS FTUJNBUFT BU UIF UJNF PG TUVEZ UFSNJOBUJPO UIF NPOUI TVSWJWBM XBT MPXFS JO UIF FQPFUJO BMGB HSPVQ UIBO JO UIF QMBDFCP HSPVQ WT )3 $* Q

1SFTDSJCJOH BOE %JTUSJCVUJPO 1SPHSBN GPS "SBOFTQ JO 1BUJFOUT 8JUI $BODFS *O PSEFS UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS BOE BOFNJB due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN SFRVJSFNFOUT 5P FOSPMM WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF "EEJUJPOBMMZ QSJPS UP each new course of Aranesp in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Aranesp.

*ODSFBTFE .PSUBMJUZ BOE PS *ODSFBTFE 3JTL PG 5VNPS 1SPHSFTTJPO PS 3FDVSSFODF JO 1BUJFOUT 8JUI $BODFS &4"T SFTVMUFE JO EFDSFBTFE MPDPSFHJPOBM DPOUSPM QSPHSFTTJPO GSFF TVSWJWBM BOE PS PWFSBMM TVSWJWBM 4FF 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO 5IFTF mOEJOHT XFSF observed in studies of patients with advanced head and neck cancer receiving SBEJBUJPO UIFSBQZ 4UVEJFT BOE JO QBUJFOUT SFDFJWJOH DIFNPUIFSBQZ GPS NFUBTUBUJD CSFBTU DBODFS 4UVEZ PS MZNQIPJE NBMJHOBODZ 4UVEZ BOE JO QBUJFOUT XJUI OPO small cell lung cancer or various malignancies who were not receiving chemotherapy PS SBEJPUIFSBQZ 4UVEJFT BOE

Hypertension "SBOFTQ JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI VODPOUSPMMFE IZQFSUFOTJPO *O "SBOFTQ DMJOJDBM TUVEJFT BQQSPYJNBUFMZ PG QBUJFOUT XJUI $,% SFRVJSFE JOJUJBUJPO PS intensiямБcation of antihypertensive therapy during the early phase of treatment. )ZQFSUFOTJWF FODFQIBMPQBUIZ BOE TFJ[VSFT IBWF CFFO SFQPSUFE JO QBUJFOUT XJUI $,% receiving Aranesp.

Appropriately control hypertension prior to initiation of and during treatment with "SBOFTQ 3FEVDF PS XJUIIPME "SBOFTQ JG CMPPE QSFTTVSF CFDPNFT EJGmDVMU UP DPOUSPM Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.

Seizures "SBOFTQ JODSFBTFT UIF SJTL PG TFJ[VSFT JO QBUJFOUT XJUI $,% %VSJOH UIF mSTU TFWFSBM months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for OFX POTFU TFJ[VSFT QSFNPOJUPSZ TZNQUPNT PS DIBOHF JO TFJ[VSF GSFRVFODZ Lack or Loss of Hemoglobin Response to Aranesp For lack or loss of hemoglobin response to Aranesp, initiate a search for causative GBDUPST F H JSPO EFmDJFODZ JOGFDUJPO JOnBNNBUJPO CMFFEJOH *G UZQJDBM DBVTFT PG MBDL PS MPTT PG IFNPHMPCJO SFTQPOTF BSF FYDMVEFE FWBMVBUF GPS 13$" *O UIF BCTFODF PG 13$" GPMMPX EPTJOH SFDPNNFOEBUJPOT GPS NBOBHFNFOU PG QBUJFOUT XJUI BO insufямБcient hemoglobin response to Aranesp therapy.

Pure Red Cell Aplasia $BTFT PG 13$" BOE PG TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT UIBU BSJTF GPMMPXJOH UIF EFWFMPQNFOU PG OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO IBWF CFFO reported in patients treated with Aranesp. This has been reported predominantly in QBUJFOUT XJUI $,% SFDFJWJOH &4"T CZ TVCDVUBOFPVT BENJOJTUSBUJPO 13$" IBT BMTP CFFO SFQPSUFE JO QBUJFOUT SFDFJWJOH &4"T GPS BOFNJB SFMBUFE UP IFQBUJUJT $ USFBUNFOU BO JOEJDBUJPO GPS XIJDI "SBOFTQ JT OPU BQQSPWFE

*G TFWFSF BOFNJB BOE MPX SFUJDVMPDZUF DPVOU EFWFMPQ EVSJOH USFBUNFOU XJUI "SBOFTQ XJUIIPME "SBOFTQ BOE FWBMVBUF QBUJFOUT GPS OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO $POUBDU "NHFO ".(&/ UP QFSGPSN BTTBZT GPS CJOEJOH BOE OFVUSBMJ[JOH BOUJCPEJFT 1FSNBOFOUMZ EJTDPOUJOVF "SBOFTQ JO QBUJFOUT XIP EFWFMPQ 13$" GPMMPXJOH USFBUNFOU XJUI "SBOFTQ PS PUIFS FSZUISPQPJFUJO QSPUFJO ESVHT %P OPU TXJUDI QBUJFOUT UP PUIFS &4"T Serious Allergic Reactions 4FSJPVT BMMFSHJD SFBDUJPOT JODMVEJOH BOBQIZMBDUJD SFBDUJPOT BOHJPFEFNB CSPODIPTQBTN TLJO SBTI BOE VSUJDBSJB NBZ PDDVS XJUI "SBOFTQ *NNFEJBUFMZ BOE permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.

Dialysis Management 1BUJFOUT NBZ SFRVJSF BEKVTUNFOUT JO UIFJS EJBMZTJT QSFTDSJQUJPOT BGUFS JOJUJBUJPO PG "SBOFTQ 1BUJFOUT SFDFJWJOH "SBOFTQ NBZ SFRVJSF JODSFBTFE BOUJDPBHVMBUJPO XJUI IFQBSJO UP QSFWFOU DMPUUJOH PG UIF FYUSBDPSQPSFBM DJSDVJU EVSJOH IFNPEJBMZTJT Laboratory Monitoring &WBMVBUF USBOTGFSSJO TBUVSBUJPO BOE TFSVN GFSSJUJO QSJPS UP BOE EVSJOH "SBOFTQ treatment. Administer supplemental iron therapy when serum ferritin is less than NDH - PS XIFO TFSVN USBOTGFSSJO TBUVSBUJPO JT MFTT UIBO 5IF NBKPSJUZ PG QBUJFOUT XJUI $,% XJMM SFRVJSF TVQQMFNFOUBM JSPO EVSJOH UIF DPVSTF PG &4" UIFSBQZ 'PMMPXJOH JOJUJBUJPO PG UIFSBQZ BOE BGUFS FBDI EPTF BEKVTUNFOU NPOJUPS IFNPHMPCJO XFFLMZ VOUJM UIF IFNPHMPCJO JT TUBCMF BOE TVGmDJFOU UP NJOJNJ[F UIF OFFE GPS 3#$ transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

ADVERSE REACTIONS $MJOJDBM 5SJBM &YQFSJFODF #FDBVTF DMJOJDBM USJBMT BSF DPOEVDUFE VOEFS XJEFMZ WBSZJOH DPOEJUJPOT BEWFSTF reaction rates observed in the clinical trials of a drug cannot be directly compared UP SBUFT JO UIF DMJOJDBM USJBMT PG PUIFS ESVHT BOE NBZ OPU SFnFDU UIF SBUFT PCTFSWFE in practice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

"EWFSTF SFBDUJPOT XFSF BMTP CBTFE PO EBUB GSPN SBOEPNJ[FE EPVCMF CMJOE QMBDFCP DPOUSPMMFE TUVEJFT JODMVEJOH UIF 4$-$ TUVEZ EFTDSJCFE BCPWF UIBU FOSPMMFE QBUJFOUT "SBOFTQ QMBDFCP XJUI OPO NZFMPJE NBMJHOBODJFT .PTU QBUJFOUT XFSF XIJUF NBMF BOE UIF NFEJBO BHF XBT ZFBST SBOHF UP ZFBST PG UIF TUVEZ QPQVMBUJPO XFSF GSPN /PSUI "NFSJDB 8FTUFSO &VSPQF BOE "VTUSBMJB %PTJOH BOE TDIFEVMFT WBSJFE CZ TUVEZ GSPN PODF XFFLMZ UP PODF FWFSZ XFFLT BOE UIF NFEJBO EVSBUJPO PG FYQPTVSF XBT XFFLT SBOHF UP XFFLT

5ISPNCPWBTDVMBS "EWFSTF 3FBDUJPOT JO 1BUJFOUT 3FDFJWJOH $IFNPUIFSBQZ SCLC Study 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.

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ASCOPost.com | FEBRUARY 15, 2013

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Expert’s Corner Technology

As Computers Learn to ‘Talk’ to Each Other, Patient Care Will Improve A Conversation with Edward P. Ambinder, MD

By Jo Cavallo

Edward P. Ambinder, MD

L

T:14”

B:14.25”

S:13”

ast fall, Edward P. Ambinder, MD, Clinical Professor of Medicine, Hematology, and Medical Oncology at the Icahn School of Medicine at Mount Sinai in New York, and a member of ASCO’s Health Information Technology Work Group, spoke about “The Information Age: Cyberspace and Cancer,” at the Chemotherapy Foundation Symposium in New York. During his presentation, Dr. Ambinder discussed how advances in information technology are changing the way cancer care is delivered.

Improvements continue to be made in software functionalities and in terms of interoperability between computer systems. Nevertheless, more work needs to be done to make health information technology more seamless and universally used, said Dr. Ambinder.

The ASCO Post talked with Dr. Ambinder about the importance of developing computer-compatible electronic health records, advances in DNA sequencing, and the implementation of ASCO’s CancerLinQ rapid learning system.

Technology-based Changes Is technology making it easier for physicians to care for patients with cancer, and is it making it easier for patients to understand their disease and treatment?

Mobile hardware and operating systems that use touch and voice (eg, voice-to-text, voice-to-text-to-data, voice-directed navigation, and conversation—think Apple’s Siri) and incorporate user educational tools are beginning to transform how physicians interact with computers. They require a fraction of the time to learn, are much less costly to buy and use, can be easily updated using cloud-

computing technology, and improve our office workflow compared to the older Mac or PC systems. These older programs are good for documenting patient information, capturing charges for billing, and helping with administrative tasks, but they are far from ideal to meet the current needs of the practitioner, office staff, and patient.

For patients, technology is making it easier to access information about their disease and find clinical trials. But the problem is the overwhelming amount of information available online and the difficulty of not having good guidance about where to get reliable, accurate information. Patients really have to rely on their physicians and nurses for help; clinical decision-support tools and links from the electronic health record to appropriate websites will encourage this trend.

Computational Genomics How is using technology to decipher a person’s genetic mutations in cancer cells improving cancer care?

There are 3.2 billion base pairs or genetic “letters” and over 20,000 expressed genes present in our DNA. What we are learning is that most cancers that we treat have gene mutations and we can now collate these mutations, giving us diagnostic, prognostic, and predictive information about the cancer. By predictive, I mean we are beginning to be able to predict which medications, chemotherapy drugs, or monoclonal antibodies will be a specific and effective treatment for the cancer.

As the price of utilizing this technology falls and dramatic advances in DNA sequencing continue to be made possible by computational genomics, most patients with cancer will automatically get a complete genomic analysis of their disease, and we will be able to provide more targeted therapy.

We will be overwhelmed with data and must rely on computers to maintain this patient information and help guide us in choosing the best cancer treatment.

If we were asked to stage a patient with cancer 9 or 10 years ago, we would basically use the TNM staging system. We would look at the size

of the tumor, whether or not lymph nodes were involved, and whether there was metastatic disease. Now, in addition to all that, we are beginning to get significant amounts of genomic, proteomic, and other molecular data that will begin to guide us in better staging the patient with cancer and more precisely choosing the patient’s therapy.

Communication between Systems At the Chemotherapy Foundation Symposium, you talked about the need for developing an electronic health record that would contain common data fields for different cancer types and treatments and that could be used universally across different computer platforms. Is that happening now?

Because cancer is so data-intensive, oncologists need software that captures and automatically presents key data about patients in a standardized report or template, which can be

dardized reports and have templates shared by the various cancer registries. ASCO’s Oncology Standards Summit, which took place in January, will bring together 21 of these groups to begin this process.

Right now all this information is captured manually or in an electronically proprietary way. If we can use the computer to do this for us automatically, it will save a lot of time and effort and make a major contribution to significantly improving the workflow and efficiency in all our offices.

Ultimately, we will have a health-care system with a continuously learning feedback process.

Future of the Electronic Health Record Do you envision that the electronic health record would be a complete document that holds the patient’s medical history as well as information about clinical trials and survivorship care plans?

No. The way I envision the elec-

Because cancer is so data-intensive, oncologists need software that captures and automatically presents key data about patients in a standardized report or template, which can be sent to and understood by computers in other hospitals, office practices, patient homes, cooperative research groups, and registries.

This requires agreed-upon standards between the data generators and recipients.

—Edward P. Ambinder, MD

sent to and understood by computers in other hospitals, office practices, patient homes, cooperative research groups, and registries. This requires agreed-upon standards between the data generators and recipients.

That’s what we are beginning to do with ASCO’s Health Information Technology Work Group and ASCO’s CancerLinQ rapid learning system (asco.org/cancerlinq). Hopefully, with the assistance of electronic health record vendors, the office and hospital data from our electronic health records will be shared with CancerLinQ and other cancer stakeholders, permitting us to create stan-

tronic health record is that it will keep the data on patients, document our encounters, and assist with billing and other administrative tasks.

But it will need to be electronically interoperable with other sites for obtaining clinical decision support data, providing registry reporting, and other information sharing with all health-care stakeholders including the patient.

Some people are looking at the Apple app model, by which different apps could work with other apps with the electronic health record database. For example, you might have continued on page 54

The ASCO Post | FEBRUARY 15, 2013

PAGE 54

News Melanoma

Gene in Eye Melanomas Linked to Good Prognosis

M

elanomas that develop in the eye often are fatal. Now, researchers at Washington University School of Medicine and the Siteman Cancer Center, St. Louis, Missouri, report they have identified a mutated gene in melanoma tumors of the eye that appears to predict a good outcome. The research was published in the advance online edition of Nature Genetics.1 “We found mutations in a gene called SF3B1,” said senior author Anne Bowcock, PhD, Professor of Genetics. “The good news is that these mutations develop in a distinct subtype of melanomas in the eye that are unlikely to spread and become deadly.”

Uveal melanomas occur in about 2,000 patients a year, making up about 5% of all melanomas. In many patients, there are no symptoms, and the tumors become fatal when they spread to the liver.

Study Background Several years ago, Dr. Bowcock and the study’s lead author, J. William Harbour, MD, a former Washington University eye surgeon who is now at the University of Miami, identified a commonly mutated gene, BAP1, in patients with uveal melanomas. They found BAP1 alterations in about 80% of uveal melanomas with a poor prognosis, called class���������������������������� ��������������������������� II tumors. About 75% of patients with these tumors die within 5 years, a sharp contrast to the generally favorable outcomes of patients whose tumors don’t have BAP1 mu-

Edward P. Ambinder, MD continued from page 53

apps that are easily updated with the ability to query the electronic health record and capture the data necessary for the electronic prescription app, the clinical and genomic staging app, the cancer guidelines and care plan app, the clinical trial app, the cancer registry app, and ASCO’s CancerLinQ app.

Thus, the raw patient data resides in the electronic health record, but the software to use that data for a specific purpose will reside at an external site. The app would act as an intermediary to get the data from the electronic health record, bring

tations, called class I. For the new study, Dr. Bowcock and her colleagues initially sequenced the DNA of uveal melanomas from 18 patients whose BAP1 status was already known. Seven had no BAP1 mutations, and 11 had BAP1 mutations. The researchers’ analysis uncovered alterations in the SF3B1 gene in three of the patients.

“This is the first time mutations in this gene have been found in uveal melanoma,” said Dr. Bowcock, who

genes may represent alternative pathways in tumor progression,” Dr. Bowcock said.

The SF3B1 gene also has been reported recently by other researchers to be mutated in myelodysplastic syndrome. For these patients, SF3B1 mutations mean the condition is less likely to develop into a full-blown leukemia. Changes in the SF3B1 gene also have been found in chronic lymphocytic leukemia and less frequently in breast cancer

A complete understanding of the molecular basis of this tumor will be invaluable in predicting prognosis and in the identification and development of novel treatments for this cancer.

—Anne Bowcock, PhD

also is a Professor of Pediatrics and of Medicine.

As part of the current study, the researchers also looked for SF3B1 mutations in uveal melanoma tumors from 102 patients, finding it in nearly 20% of them. Mutations in the gene were linked to favorable features, including a younger age at diagnosis and a far lower metastasis rate.

Mutually Exclusive Mutations Interestingly, SF3B1 mutations always occurred at the same site of the gene. And the SF3B1 and BAP1 mutations were found to be almost mutually exclusive.

“This suggests mutations in these it to the site that needs the data for analysis, and then come back to the electronic health record with information that is appropriate for the particular patient.

Information for Patients Could there also be an app for patients to maintain their own health records, including their treatment and survivorship care plans?

Sure. At ASCO a few years ago we began to define a chemotherapy treatment plan based on specific cancer types that we could give patients before they started their chemotherapy.

It would give patients information about the chemotherapy drugs they

and other solid tumors. The gene’s link to prognosis is unclear for these cancers.

Next Step Normally, the SF3B1 gene is involved in converting RNA into messenger RNA. The researchers don’t yet understand how mutations in this gene are involved in cancer but it’s the next step of their research.

“We want to understand the functional consequences of mutations in SF3B1,” Dr. Bowcock said. “How are changes in this gene linked to cancer development? This is the fourth gene known to be mutated in uveal melanoma along with BAP1 and the genes GNAQ and GNA11. A comwould be getting, their treatment schedule, and the side effects they could expect.

We also developed a treatment summary report for the cancer survivor. This would give the patient all the basic information we had already created for the chemotherapy treatment plan and also have information about the current state of the cancer, what the response was to treatment, what significant adverse events occurred during treatment, and how patients should be monitored after finishing treatment.

These plans are now combined in the Chemotherapy Treatment Plan and Summary templates (asco.org/

Anne Bowcock, PhD

plete understanding of the molecular basis of this tumor will be invaluable in predicting prognosis and in the identification and development of novel treatments for this cancer.”

This research was supported by grants from the National Institutes of Health (NIH), the Melanoma Research Alliance, the Melanoma Research Foundation, the Tumori Foundation, Research to Prevent Blindness, Inc, and awards to the Department of Ophthalmology and Visual Sciences at Washington University from a Research to Prevent Blindness, Inc, unrestricted grant and also the NIH Vision Core grant and an NIH training grant. n Disclosure: Drs. Harbour and Bowcock reported that they and Washington University may receive income from the licensing of related technology by Washington University to Castle Biosciences, Inc. This work was not supported by Castle Biosciences.

Reference 1. Harbour JW, Roberson EDO, Anbunathan H, et al. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nature Genetics. January 13, 2013.

treatmentsummary). This information is helpful for both the patient and the medical team caring for the patient post-treatment.

One of the big criticisms of cancer care today is that there is this disconnect between the time a patient completes treatment and his transition back to the primary care physician.

Without a seamless way to electronically communicate the patient’s medical record to all the necessary parties, it makes it very difficult to maintain continuous, coordinated care, and that is one of the major goals of our health-care system. n

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

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The ASCO Post | FEBRUARY 15, 2013

PAGE 56

Expert’s Corner Health Disparities

The Doctor Who Championed Patient Navigation in Harlem A Conversation with Harold P. Freeman, MD

By Ronald Piana ondary prevention, the idea of awareness needs to be connected to the larger issue of access to care. To achieve goals in secondary prevention in poor communities, such as timely mammograms and colonoscopies, the challenge is to educate people and create access opportunities.

Patient Navigation

Harold P. Freeman, MD

A

fter completing his residency at Memorial Sloan-Kettering Cancer Center, Harold P. Freeman, MD, arrived at Harlem Hospital Center in 1967, where the overwhelming majority of his patients presented with late-stage disease. That early experience with underserved patients would shape his career as one of the nation’s most preeminent oncologists on the subject of poverty and cancer. Dr. Freeman recently shared some of his experiences with The ASCO Post.

Ongoing Disparities What progress has been made to diminish disparities in cancer care for economically challenged populations?

People today of every economic level are doing better overall in terms of cancer outcomes compared with 25 years ago, but the relative disparity of access and care between the poor and other populations has remained constant. There is more awareness of the problem today, which is important particularly when focused on primary prevention, such as lifestyle drivers of cancer.

However, when considering sec-

The Patient Navigator Program was born of your early experience in Harlem.

What inspired the program?

In 1979, I was the Director of Surgery at Harlem Hospital Center, and I was shocked that the overwhelming majority of our patients presented with advanced disease. In response, I

We all need to use our health-care resources wisely, but no patient in America with cancer should go untreated, no matter what his or her economic status.

—Harold P. Freeman, MD

set up free breast- and cervical cancer– screening centers in the community.

Although these programs helped accelerate the rate of early detection, we still had the overriding problem, in a population of poor women, of ensuring that abnormal findings on cancer screening examinations were rapidly resolved by timely diagnosis and treatment.

The concept of patient navigation came to me when I was the National President of the American Cancer Society from 1988 to 1989. I had the opportunity to hold national hearings on cancer in the poor, from which the published document Report to the Na-

Findings from the 1989 Hearings on Cancer in the Poor, Which Remain Persistent Today ■■ Poor people face substantial barriers to obtaining cancer care and often do not seek care for which they cannot pay.

■■ Poor people endure greater pain and suffering from cancer.

■■ Poor people and their families often make extraordinary sacrifices to pay for care.

■■ Fatalism about cancer is prevalent among the poor and may prevent them from seeking care.

■■ Current cancer education programs are often culturally insensitive and irrelevant to many poor people.

tion on Cancer in the Poor was developed (see sidebar). The hearings were conducted in seven American cities; the testimony was primarily from poor people of all ethnic groups who had been diagnosed with cancer.

The testimonials, which had a unifying theme across ethnic and racial lines, opened my eyes a bit wider to the depth of the access challenge. One universal problem that the poor articulated were the barriers they faced simply trying to enter the health-care system.

Prior to the national hearings, I was centered on the Harlem experience; the hearings elevated my thinking to a universal level. It was during that exciting time that I coined the term “patient

navigation.” Soon after returning to Harlem, I initiated the nation’s first patient navigator program in 1990.

Evolving Program How did the patient navigator program evolve?

When we began the program, we were looking at the window of opportunity from the point of abnormal findings to the clinical point of resolution. Data from the Harlem breast cancer experience showed that the patient navigator program dramatically improved outcomes. Looking at a 22year period ending in 1986, 606 poor women with breast cancer were treated at Harlem Hospital Center, half of whom were without health insurance: 6% had stage I disease, 49% presented with stages III and IV, and the 5-year survival rate was 39%.

Our intervention consisted of two key elements: providing free or lowcost examinations and mammograms, along with patient navigation services.

Our subsequent study of 325 patients with breast cancer found that 41% had early stages 0 and I, whereas 21% had stages III and IV. The 5-year survival was 70%. Not surprisingly, we discovered that the major reasons for the

significantly better outcomes were free breast examinations and patient navigation, which led to early diagnosis and treatment.

The first model, which initially focused on the interval between detecting the disease and its resolution, expanded into navigation across the whole health-care continuum—all the way to survivorship.

National Recognition What events took the Harlem experience to the national level?

The Harlem experience generated quite a bit of interest. Based on that program, the Patient Navigator Outreach and Chronic Disease Prevention Act (HR 1812) was signed into law by President Bush in 2005. To date, more than 20 patient navigation demonstration sites have been funded by government agencies.

For a 5-year period, I was the Director of the Center to Reduce Cancer Health Disparities at the NCI. During my tenure, I suggested that the Harlem model be tested. Consequently, the NCI launched a 5-year study that involved nine sites around the nation.

The study results—published in a

A History of Success

D

r. Harold P. Freeman is the descendant of a slave who bought his freedom and changed his name—hence, “Freeman.” Dr. Freeman is a great-grandnephew of Robert Freeman, the first African-American dentist, and a cousin of Robert Weaver, former Secretary of the Department of Housing and Urban Development under President Lyndon Johnson, and the first African-American presidential cabinet member.

In his early days, Dr. Freeman was a nationally ranked tennis player, winning doubles championships on the African-American tennis circuit with his brother Clyde as his partner. They played briefly in the U.S. Open, when the tournament was desegregated in the early 1950s. n

ASCOPost.com | FEBRUARY 15, 2013

PAGE 57

Expert’s Corner

series of articles in the October 2012 issue of Cancer Epidemiology, Biomarkers & Prevention—gave scientific validity to the work in disparities and patient navigation that I had begun years before in Harlem. In short, the study showed definitively that patient navigation shortens the critical time from abnormal findings to diagnosis and treatment in poor populations. Navigation has also been shown to increase the number of people coming to a center for screening.

Since the law passed in 2005, has patient navigation been involved in any other political activity?

The Patient Protection and Affordable Care Act signed into law by President Obama actually mentions patient navigation in several sections, requiring that patient navigators be used to assist uninsured people access to health-care exchanges.

Also, the American College of Surgeons (ACoS) has mandated that before a cancer center can be granted the coveted approval by the ACoS Commission on Cancer, it must have a navigator program in place by the year 2015. I am very pleased that an early initiative of mine that was first designed to solve local health-care challenges has gained universal acceptance.

Related Costs In today’s fiscally challenged time, does the cost of initiating patient navigation programs pose a challenge?

Patient navigation is actually costeffective. A highly regarded epidemiologist, Dr. Tim Byers, has studied this issue and has concluded that the upfront costs of initiating patient navigation will be justified by the downstream cost benefits of early diagnosis and treatment.1 More studies are beginning to show the cost-effectiveness of navigation.

It’s important to note that patient navigation focuses on eliminating barriers to timely movements of individual patients through an often fragmented health-care continuum. This focus is different from the necessary energy used to make those health-care systems larger and more specialized.

On a larger scale, today’s medical care system has shifted more toward a business model. Such a shift, unfortunately in my opinion, may lead to a tendency to provide health care as a commodity rather than as human service. We live in a free-market, capi-

talist society, which is good because it provides an atmosphere in which researchers can flourish and produce wonderful health-care tools. We all need to use our health-care resources wisely, but no patient in America with cancer should go untreated, no matter what his or her economic status. n

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

Reference 1. Byers T: Assessing the value of patient navigation for completing cancer screening. Cancer Epidemiol Biomarkers Prev 21:1618-1619, 2012.

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Patient Navigation in Breast Cancer See report on

page 58

The ASCO Post | FEBRUARY 15, 2013

PAGE 58

2012 Quality Care Symposium Breast Cancer

A Look at the Patient Navigator Program in Breast Cancer

By Ronald Piana

I

n 1990, Harold P. Freeman, MD, established the nation’s first patient navigation program at Harlem Hospital Center in New York (see accompanying article beginning on page 56).

Since then, Dr. Freeman’s vision has gained national attention and is cur-

Naomi Ko, MD, MPH

rently being looked at in a demonstration project across multiple healthcare settings. At ASCO’s Quality Care Symposium, Naomi Ko, MD, MPH, discussed a study that looked at the impact of patient navigation on the delivery of breast cancer treatment.

Cancer Care Disparity “The background that drove this research is the knowledge that low-income, racial and ethnic minorities have significantly higher mortality from breast cancer. Naturally, the goal of our research is to try to eliminate healthcare disparities, which is an important component for lessening the cancer burden on vulnerable patient populations,” said Dr. Ko. “One approach to attack this issue in the cancer disparity setting is to look

at this as a paradigm in which there is a critical disconnect between cancer discoveries and the delivery of cuttingedge cancer care to patients of all economic backgrounds,” said Dr. Ko. Dr. Ko explained that the patient navigation model was originally devised to create a system in which a navigator assists and coordinates all aspects of cancer care, trying ultimately to have things done in an orderly and timely way. “Navigators were first engaged to deal with the challenging issues that poor people from minority communities face, which are exacerbated by low literacy rates and language barriers. However, up until now there is little data on the actual effect on the quality of care that patient navigation has on its intended patient populations,” said Dr. Ko.

across the country,” said Dr. Ko. Using data from 2006 to 2011, Dr. Ko and the PNRP co-investigator team a logistic regression model to determine the proportion of navigated and control patients with breast cancer whose care met National Comprehensive Cancer Network (NCCN) quality metrics, which were adjusted for age, race, language, marital status, insurance status, tumor size, and number of nodes. The investigators looked at NCCN category���������������������� ��������������������� 1 breast cancer quality measures in three settings: (1)����� ���� hormonal therapy among women with hormone receptor–positive disease, (2)������������������������������ radiation ����������������������������� therapy postlumpectomy, and (3) chemotherapy in triplenegative disease for women less than 70 years of age whose tumors were greater than 1 cm in size.

Patient navigation programs can have a positive effect on the quality of care in challenged populations, but we need more research to determine which navigation models work and on what aspects of care.

—Naomi Ko, MD, MPH

Study Objective “Our study asked the basic question: Are navigated patients with breast cancer more likely to meet quality measures of care? To answer this we did a secondary analysis of pooled data from the Patient Navigation Research Program (PNRP), which is a National Cancer Institute–funded study with nine sites

“We looked at 1,004 breast cancer cases and we broke that down into three cohorts: those eligible for hormone therapy (n = 668), radiation therapy (n = 572), or chemotherapy (n = 211). Some of these patients could overlap, so the treatment cohorts were not mutually exclusive; therefore, we had varying sample siz-

es for each of the three eligibility categories,” said Dr. Ko, adding that the study had several limitations in that it was a hypothesis-generating, secondary analysis that ultimately left certain variables unaccounted for.

“Our preliminary results showed that the odds of receiving these quality metrics—comparing navigated and nonnavigated groups differed in each category. Women eligible for hormone therapy who had a patient navigator were more likely to receive recommended treatment. Similarly, women with a patient navigator were also more likely to receive radiation after lumpectomy. However, among the chemotherapy group, we saw an opposite trend. Patients in the control group who weren’t navigated were actually more likely to receive guideline-driven adjuvant chemotherapy,” noted Dr. Ko.

Overall Conclusions The researchers found that while navigation did have a positive effect in hormonal therapy, the effect in radiation was statistically insignificant and, surprisingly, more nonnavigated patients received chemotherapy.

“So although we feel that patient navigation programs can have a positive effect on the quality of care in challenged populations, we need more research to determine which navigation models work and on what aspects of care,” said Dr. Ko. n

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

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Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ.

• Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

• Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®.

• Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

©2012 Amgen Inc. All rights reserved. 7/12 64000-R6-V1 G69095-R1-V1

www.XGEVA.com

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

PERCENTAGE OF PATIENTS WITHOUT SRE

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

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: 19.4 months

40 30

17%

Median time: 27.7 months

20 10

RISK REDUCTION

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

0 0

3

6

9

12

15

18

21

24

27

30

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

STUDY MONTH Data from three international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046), castration-resistant prostate cancer (N = 1,901), and solid tumors (other than breast or prostate) or multiple myeloma (N = 1,776). Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information. XGEVA® was administered subcutaneously 120 mg, once every 4 weeks. The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.3

SUBCUTANEOUS INJECTION

NO DOSE ADJUSTMENTS

PRECISE ACTION

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

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

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

Pregnancy • Women should be advised not to become pregnant when taking XGEVA®. If the patient is pregnant or becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

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

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

REFERENCES: 1. Lipton A, Siena S, Rader M, et al. Comparison of denosumab versus zoledronic acid for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials. Ann Oncol. 2010;21(suppl 8):viii380. Abstract 1249P and poster. 2. Data on file, Amgen. 3. XGEVA® (denosumab) prescribing information, Amgen. 4. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women.

J Bone Miner Res. 2004;19:1059-1066. 5. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis.

Biologics. 2008;2:645-653. 6. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies.

Clin Pharmacokinet. 2010;49:493-507. 7. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs. 2010;24:23-39. 8. Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50:793-807.

T:9.5â&#x20AC;?

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information).

DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions).

Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment.

Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva.

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

ADVERSE REACTIONS: The following adverse reactions are discussed below DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted and elsewhere in the labeling: with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva t )ZQPDBMDFNJB TFF 8BSOJOHT BOE 1SFDBVUJPOT

was administered in combination with standard anticancer treatment. Serum t 0TUFPOFDSPTJT PG UIF +BX TFF 8BSOJOHT BOE 1SFDBVUJPOT) denosumab concentrations at 1 and 3 months and reductions in the bone turnover The most common adverse reactions in patients receiving Xgeva (per-patient marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, were similar in patients with and without prior intravenous bisphosphonate therapy. and nausea (see Table 1). The most common serious adverse reaction in patients There was no evidence that various anticancer treatments affected denosumab receiving Xgeva was dyspnea. The most common adverse reactions resulting in systemic exposure and pharmacodynamic effect. Serum denosumab concentrations discontinuation of Xgeva were osteonecrosis and hypocalcemia. at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone Clinical Trials Experience. Because clinical trials are conducted under widely therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar varying conditions, adverse reaction rates observed in the clinical trials of a drug between patients receiving concomitant chemotherapy and/or hormone cannot be directly compared to rates in other clinical trials and may not reďŹ&#x201A;ect the therapy (see Clinical Pharmacology [12.2] in full Prescribing Information). rates observed in practice. The safety of Xgeva was evaluated in three randomized, USE IN SPECIFIC POPULATIONS: double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Information) in which a total of 2841 patients with bone metastasis from prostate Xgeva can cause fetal harm when administered to a pregnant woman based cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple on ďŹ ndings in animals. In utero denosumab exposure in cynomolgus monkeys myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were resulted in increased fetal loss, stillbirths, and postnatal mortality, along with randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid evidence of absent lymph nodes, abnormal bone growth and decreased every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium neonatal growth. There are no adequate and well-controlled studies with Xgeva (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance in pregnant women. Women should be advised not to become pregnant when 30 mL/min or greater. Patients who had received IV bisphosphonates were taking Xgeva. If this drug is used during pregnancy, or if the patient becomes excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an pregnant while taking this drug, the patient should be apprised of the potential active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, hazard to the fetus. Women who become pregnant during Xgeva treatment are or any planned invasive dental procedure. During the study, serum chemistries encouraged to enroll in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or including calcium and phosphorus were monitored every 4 weeks. Calcium and their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

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

DOUS2X0319_T_4Pg Tabloid_Update_Aug_12_BS_r8.indd 1

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and beneďŹ ts in continuing or discontinuing treatment with Xgeva.

Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information).

OVERDOSAGE: There is no experience with overdosage of Xgeva.

HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat.

Avoid vigorous shaking of Xgeva.

PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: t 4ZNQUPNT PG IZQPDBMDFNJB JODMVEJOH QBSFTUIFTJBT PS NVTDMF TUJGGOFTT twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) t 4ZNQUPNT PG 0/+ JODMVEJOH QBJO OVNCOFTT TXFMMJOH PG PS ESBJOBHF GSPN UIF jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) t 1FSTJTUFOU QBJO PS TMPX IFBMJOH PG UIF NPVUI PS KBX BGUFS EFOUBM TVSHFSZ (see Warnings and Precautions) t 1SFHOBODZ PS OVSTJOH (see Warnings and Precautions and Use in SpeciďŹ c Populations) Advise patients of the need for: t 1SPQFS PSBM IZHJFOF BOE SPVUJOF EFOUBM DBSF t *OGPSNJOH UIFJS EFOUJTU UIBU UIFZ BSF SFDFJWJOH 9HFWB t "WPJEJOH JOWBTJWF EFOUBM QSPDFEVSFT EVSJOH USFBUNFOU XJUI 9HFWB Advise patients that denosumab is also marketed as ProliaÂŽ. Patients should inform their healthcare provider if they are taking Prolia.

Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 Š2012 Amgen Inc. All rights reserved. Printed in USA.

68257-R1-V3

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T:13â&#x20AC;?

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Animal Data: The effects of denosumab on prenatal development have been studied Severity (Trials 1, 2, and 3) in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?).

Xgeva Zoledronic Acid In cynomolgus monkeys dosed subcutaneously with denosumab throughout Body System n = 2841 n = 2836 pregnancy at a pharmacologically active dose, there was increased fetal loss during % % gestation, stillbirths, and postnatal mortality. Other ďŹ ndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal GASTROINTESTINAL bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and Nausea 31 32 tooth malalignment; and decreased neonatal growth. At birth out to one month of Diarrhea 20 19 age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects GENERAL on bone quality and strength returned to normal; there were no adverse effects Fatigue/ Asthenia 45 46 on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes INVESTIGATIONS were present, though small; and minimal to moderate mineralization in multiple )ZQPDBMDFNJBb 18 9 tissues was seen in one recovery animal. There was no evidence of maternal 32 20 )ZQPQIPTQIBUFNJBb harm prior to labor; adverse maternal effects occurred infrequently during labor.

NEUROLOGICAL Maternal mammary gland development was normal. There was no fetal NOAEL (no )FBEBDIF 13 14 observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of RESPIRATORY denosumab) also caused fetal lymph node agenesis and led to postnatal impairment Dyspnea 21 18 of dentition and bone growth. Pregnant RANKL knockout mice showed altered Cough 15 15 maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information). a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials Nursing Mothers. It is not known whether Xgeva is excreted into human milk.

1, 2, and 3, and meeting one of the following criteria: Measurable concentrations of denosumab were present in the maternal milk t "U MFBTU HSFBUFS JODJEFODF JO 9HFWB USFBUFE QBUJFOUT PS of cynomolgus monkeys up to 1 month after the last dose of denosumab t #FUXFFO HSPVQ EJGGFSFODF FJUIFS EJSFDUJPO PG MFTT UIBO BOE NPSF UIBO (â&#x2030;¤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and 5% greater incidence in patients treated with zoledronic acid compared to because of the potential for serious adverse reactions in nursing infants from placebo (US Prescribing Information for zoledronic acid) Xgeva, a decision should be made whether to discontinue nursing or discontinue b Laboratory-derived and below the central laboratory lower limit of normal the drug, taking into account the importance of the drug to the mother. Maternal [8.3 â&#x20AC;&#x201C; 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL (0.71 â&#x20AC;&#x201C; 0.9 mmol/L) for phosphorus] signaling pathway that have shown altered maturation of the maternal mammary Severe Mineral/Electrolyte Abnormalities HMBOE MFBEJOH UP JNQBJSFE MBDUBUJPO QPTUQBSUVN )PXFWFS JO DZOPNPMHVT t 4FWFSF IZQPDBMDFNJB DPSSFDUFE TFSVN DBMDJVN MFTT UIBO NH E- PS MFTT monkeys treated with denosumab throughout pregnancy, maternal mammary than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% gland development was normal, with no impaired lactation. Mammary gland of patients treated with zoledronic acid. Of patients who experienced severe histopathology at 6 months of age was normal in female offspring exposed to hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia denosumab in utero; however, development and lactation have not been fully and 16% experienced 3 or more episodes (see Warnings and Precautions and evaluated (see Nonclinical Toxicology [13.2] in Full Prescribing Information).

Use in SpeciďŹ c Populations).

Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and t 4FWFSF IZQPQIPTQIBUFNJB TFSVN QIPTQIPSVT MFTT UIBO NH E- PS MFTT UIBO effectiveness of Xgeva in pediatric patients have not been established. Treatment 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of with Xgeva may impair bone growth in children with open growth plates and patients treated with zoledronic acid. may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target Osteonecrosis of the Jaw of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in at doses â&#x2030;¤ 10 mg/kg was associated with inhibition of bone growth and tooth 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic eruption. Adolescent primates treated with denosumab at doses 5 and 25 times acid group (see Warnings and Precautions). When events occurring during an (10 and 50 mg/kg dose) higher than the recommended human dose of extended treatment phase of approximately 4 months in each trial are included, 120 mg administered once every 4 weeks, based on body weight (mg/kg), had the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Postmarketing Experience. Because postmarketing reactions are reported decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and voluntarily from a population of uncertain size, it is not always possible to reliably mesenteric lymph nodes. Some bone abnormalities recovered once exposure estimate their frequency or establish a causal relationship to drug exposure. was ceased following birth; however, axillary and inguinal lymph nodes remained The following adverse reactions have been identiďŹ ed during post approval absent 6 months post-birth (see Use in Pregnancy). use of Xgeva: Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) t )ZQPDBMDFNJB Severe symptomatic hypocalcemia, including fatal cases. were 65 years of age or older. No overall differences in safety or efďŹ cacy were Immunogenicity. As with all therapeutic proteins, there is potential for observed between these patients and younger patients.

ASCOPost.com | FEBRUARY 15, 2013

PAGE 63

Expert’s Corner Breast Cancer

Treatment of HER2-positive Disease in 2013 A Conversation with Hope S. Rugo, MD

By Caroline Helwick

Hope S. Rugo, MD

F

rom the initial discovery of the HER2 family of receptors in the mid-1980s to the present, a “wealth of riches” has been uncovered in terms of agents that can target pathways relevant to this aggressive breast cancer type, notes Hope S. Rugo, MD, Director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco. “We have seen HER2-positive breast cancer go from being the worst type of breast cancer to one in which we can offer a lot of hope to our patients.”

Elaborating on this theme, Dr. Rugo described the emerging landscape of HER2-positive breast cancer and what this means for oncologists.

HER2-positive Breast Cancer Today What are the main “truths” about HER2-positive breast cancer in 2013?

The addition of trastuzumab (Herceptin) to taxane-based first-line chemotherapy for metastatic breast cancer improves response rate, progression-free survival, and overall survival, and we should continue HER2-directed therapy through progression. In early-stage disease, the addition of trastuzumab to adjuvant chemotherapy results in remarkably early and sustained improvement in disease-free survival and overall survival. Most recently, we have learned that trastuzumab is as effective when combined with a non–anthracyclinebased regimen as it is when combined with anthracycline-containing therapy.

The optimal duration of therapy for early-stage disease continues to be evaluated, but at the 2012 European Society for Medial Oncology (ESMO) Congress and San Antonio Breast Cancer Symposium we learned from the HERA1 and PHARE2 trials that 1 year

is as effective as 2 years of therapy and more effective than 6 months. So 1 year is the standard of care unless future studies prove otherwise.

We have also seen approval of an exciting new agent, pertuzumab (Perjeta), when added to standard first-line therapy for metastatic breast cancer. Pertuzumab is an antibody similar to trastuzumab that blocks heterodimerization of HER2 to HER3, and is able to overcome at least some pathways of resistance to standard trastuzumab-based therapy.

Interestingly, pertuzumab is most effective when given with trastuzumab. The combination (plus docetaxel) proved very promising in the CLEOPATRA study,3 which treated patients not previously exposed to trastuzumab.

Progression-free survival reached 1.5 years—the longest duration we have

in combination with any taxane.

Ongoing and future studies will help to determine how best to utilize pertuzumab. The phase��������������������� �������������������� II PERTAIN study includes 250 women with HER2-positive, estrogen receptor–positive previously untreated metastatic disease, randomly assigning them to trastuzumab/taxane or trastuzumab plus an aromatase inhibitor, with or without pertuzumab.

The phase���������������������������� ��������������������������� II VELVET trial of 210 previously untreated patients evaluates pertuzumab/trastuzumab plus vinorelbine; sequential cohorts will test sequential vs combination antibody administration.

In the neoadjuvant setting, pertuzumab added to trastuzumab in the Neosphere trial resulted in pathologic complete response rates of 40% to 52%.5 The APHINITY trial randomly assigns patients with early-stage disease who

We have learned that we can improve outcomes by overcoming resistance through combined signal blockade targeting different parts of the HER pathway. We are already doing so by adding lapatinib to trastuzumab, and have seen that pathologic complete response rates are high … though lapatanib does add toxicity.

—Hope S. Rugo, MD

seen in any metastatic trial treating HER2-positive disease.

Updated CLEOPATRA data presented at San Antonio 20124 demonstrated a significant improvement in survival in patients receiving the triplet compared to those receiving trastuzumab and docetaxel alone. These benefits were achieved with little additional toxicity, an advantage seen with many antibodies used in targeted therapy for cancer and a striking difference from the unpredictable toxicity seen with oral small-molecule tyrosine kinase inhibitors.

The survival impact achieved with pertuzumab/trastuzumab/docetaxel is practice-changing, and this regimen is now FDA-approved as firstline treatment for advanced breast cancer. National Comprehensive Cancer Network (NCCN) guidelines support using the combination in either the first- or second-line settings

have completed primary surgery to chemotherapy plus trastuzumab alone or trastuzumab plus pertuzumab for 1 year.

Metastatic HER2-positive Disease How can anti-HER2 treatment be improved for patients with metastatic disease?

Despite high response rates, the majority of patients eventually develop progressive disease, though the occasional patient has long-term stability on HER2-directed therapy—appearing to be cured of what we previously thought was incurable disease. We would like to know how to improve upon our upfront therapies to create the long remissions we see in this small minority of patients.

We have learned that we can improve outcomes by overcoming resistance through combined signal blockade targeting different parts of the HER pathway. We are already doing so by adding lapatinib (Tykerb) to trastuzumab, and

have seen that pathologic complete response rates are high—47% to 60%— though lapatanib does add toxicity. As a single agent (combined with chemotherapy) lapatanib is inferior to trastuzumab, probably because it is difficult to administer easily (due to unpredictable toxicity, especially diarrhea).

In addition to the data seen in the neoadjuvant setting, the single-agent lapatinib arm in the eagerly awaited adjuvant ALTTO study was closed due to futility, meaning that lapatinib with chemotherapy in the adjuvant setting was inferior to trastuzumab or the combination of trastuzumab and lapatinib. This is in keeping with other studies showing that lapatinib by itself is inferior, though it can be an important partner to trastuzumab. Other means of combined HER family blockade are needed.

Early-stage HER2-positive Disease Will it be possible to predict which patients with early breast cancer will benefit from certain anti-HER2 treatments?

We want to be able to define not only prognostic factors but also predictive factors in early-stage disease. In the recent NeoSphere trial,5 which evaluated various combinations of trastuzumab, pertuzumab, and docetaxel, we identified markers (PI3K mutations, PTEN loss) that we thought indicated resistance to trastuzumab. But while these predicted worse outcomes, they did not help us select patients who would benefit from novel targeted therapy. At this point, we have to give all drugs to all patients. We are not able to select the ones who will benefit from a specific strategy.

We also want to confirm that treatment benefits observed in the neoadjuvant setting will translate into benefits later. This would allow us to cure patients more easily, with less exposure to drugs, and to study these drugs in smaller patient populations.

Emerging HER2-directed Therapies Trastuzumab emtansine (T-DM1) is an exciting investigational anti-HER2 agent. How will it impact the treatment of HER2-positive disease?

T-DM1 has proven superior to capecitabine (Xeloda)/lapatinib in continued on page 64

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Expert’s Corner

terms of response rates, progression-free survival, overall survival, and safety. At the 2012 ESMO meeting, we heard updated results of the EMILIA trial,6 which showed a 6-month improvement in overall survival, including a 32% reduction in mortality risk at a median followup of about 20 months, from treatment with T-DM1 compared to lapatinib/ capecitabine in patients whose cancer had progressed on trastuzumab and chemotherapy. T-DM1 will clearly become a new standard in the metastatic setting, and we expect FDA approval early in 2013.

We look forward to results from the MARIANNE trial, which is evaluating T-DM1 in 1,092 untreated patients with metastatic disease. The three arms of the study are trastuzumab plus taxane, T-DM1 plus placebo, and T-DM1 plus pertuzumab. This is a fascinating design because patients receiving T-DM1 will not receive a taxane and thus will not experience hair loss.

T-DM1 will also be studied in the late-line THERESA trial, which includes 795 women with prior exposure to trastuzumab, lapatanib, anthracyclines, taxanes, and capecitabine. The drug is also moving into trials in the neoadjuvant and adjuvant setting.

it has remarkable efficacy and modest toxicity and is likely to become FDAapproved early in 2013.

Pertuzumab is approved in the firstline setting in combination with trastuzumab and docetaxel and is a new standard of care.

Lapatinib is associated with more toxicity and less efficacy than trastu-

zumab in the first-line metastatic setting.

Lapatinib plus capecitabine is still an option for later-line therapy or in special settings, such as for patients with low ejection fractions or brain metastases.

These drugs might best be used in the following sequence: pertuzumab/ trastuzumab/taxane first-line, then drop the chemotherapy after best re-

sponse and continue the dual antibodies; then move to T-DM1 as a single agent; and as late-line therapy, give lapatinib plus capecitabine. n Disclosure: Dr. Rugo reported no potential conflicts of interest.

References 1. Gelber RD, Goldhirsch A, Piccart M,

Further Overcoming Resistance How is resistance to HER2-directed treatment being addressed clinically and as a research question?

Many drugs are being evaluated for their potential to overcome trastuzumab resistance, including the mTOR inhibitor everolimus (Afinitor). The phase�������� ������� III BOLERO-1 trial will compare trastuzumab and paclitaxel with and without everolimus, while the phase III BOLERO-3 trial will compare trastuzumab and vinorelbine with and without everolimus.

Other experimental approaches to overcoming resistance are evaluating HER1/2 inhibitors such as afatinib, panHER inhibitors, PI3K and other combined inhibitors, heat shock protein 90 inhibitors, insulin-like growth factor 1 receptor inhibitors, HER3 monoclonal antibodies, and vaccines. We can expect steep competition among new agents that might fulfill this role.

Clinical Context Can you distill all the data into a useful clinical context?

Here’s what the data mean for clinical practice: T-DM1 is a new and effective treatment for HER2-positive metastatic patients who progress on trastuzumab;

Simulated image based on locally advanced BCC patient at Week 24.

Indication

Erivedge (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. ®

Boxed Warning and Additional Important Safety Information • Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen

• Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant • Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555

Blood Donation

• Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge

Nursing Mothers

• Inform female patients of the potential for serious adverse reactions in nursing infants from Erivedge, taking into account the importance of the drug to the mother

Trim:

:15.5”

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Expert’s Corner

et al: HERA trial: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. 2012 ESMO Congress. Abstract LBA6. Presented October 1, 2012.

2. Pivot X, Romieu G, Bonnefoi H, et al: PHARE trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer. 2012 ESMO Congress. Ab-

stract LBA5. Presented October 1, 2012.

3. Baselga J, Cortes J, Kim S-B, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-111, 2012.

4. Swain SM, Kim S-B, Cortes J, et al: Confirmatory overall survival analysis of CLEOPATRA: A randomized, doubleblind, placebo-controlled Phase III study with pertuzumab, trastuzumab, and docetax-

el in patients with HER2-positive first-line metastatic breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract P5-1826. Presented December 7, 2012.

5. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-

label, phase 2 trial. Lancet Oncol 13:25– 32, 2012.

6. Verma S, Miles D, Gianni L: Updated overall survival results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer. 2012 ESMO Congress. Abstract LBA12. Presented October 1, 2012.

ORAL, ONCE-DAILY THERAPY1

TRANSFORM THE TREATMENT OF ADVANCED BCC Erivedge— a unique treatment option • Systemic therapy that targets dysregulated Hedgehog pathway signaling, a known driver of BCC1,2 • One 150-mg capsule a day until disease progression or unacceptable toxicity1 • Erivedge reduced lesions in patients with advanced BCC1,3 Objective response rates (ORR) by IRF from ERIVANCE1,3* laBCC (n=63)

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

ORR (95% CI)

Median response duration (months) (95% CI)

*Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. Response in laBCC: absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on sampling biopsy.

Response in mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.

IRF=Independent Review Facility. laBCC=locally advanced BCC. mBCC=metastatic BCC. CI=confidence interval. NE=not estimable.

Adverse Reactions

• The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) Please see Brief Summary of Prescribing Information on following page.

© 2012 Genentech USA, Inc. All rights reserved. HED0001559500 Printed in USA.

See what you can offer your patients with advanced BCC at www.Erivedge.com References: 1. Erivedge® (vismodegib) capsule Prescribing Information.

Genentech, Inc. January 2012. 2. Epstein EH. Nat Rev Cancer. 2008; 8:743-754. 3. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012;366:2171-2179.

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Complete response

43% (n=27) (30.5-56.0) 21% (n=13)

mBCC (n=33) 30% (n=10) (15.6-48.2) 0%

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Journal Spotlight Breast Cancer

Subcutaneous Trastuzumab a Potential Alternative to Intravenous Administration in Breast Cancer

By Matthew Stenger

S

ubcutaneous administration of trastuzumab might offer improvements in patient convenience and resource use compared with con-

ventional intravenous administration (Herceptin). A new subcutaneous trastuzumab formulation containing a fixed dose of 600 mg and recombinant T:7”

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont) All aBCC Patients (N = 138) Grade 3 Grade 4 All Grades 3 (%) (%) (%) 1

MedDRA Preferred Term

Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information.

WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations.

Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].

All aBCC1 Patients (N = 138) MedDRA Preferred Term

2

Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

-

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

-

35 (25.4%)

3 (2.2%)

-

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

-

76 (55.1%) 15 (10.9%)

-

-

88 (63.8%)

-

-

aBCC = Advanced Basal Cell Carcinoma.

2 MedDRA = Medical Dictionary for Regulatory Activities.

3 Grading according to NCI-CTCAE v3.0.

Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)].

Laboratory Abnormalities: Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%).

1

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole).

Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased.

Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown.

7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib.

In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits.

Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE 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 embryo or fetus.

Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)].

In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws).

8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, 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 ERIVEDGE capsule have not been established in pediatric patients.

In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose).

8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555.

Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus.

Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)].

Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib.

8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). t "EWJTF QBUJFOUT UIBU &3*7&%(& FYQPTVSF EVSJOH QSFHOBODZ DBO cause embryo-fetal death or severe birth defects. t *OTUSVDU GFNBMF QBUJFOUT PG SFQSPEVDUJWF QPUFOUJBM UP VTF B IJHIMZ effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t *OTUSVDU BMM NBMF QBUJFOUT FWFO UIPTF XJUI QSJPS WBTFDUPNZ UP VTF condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. t *OTUSVDU QBUJFOUT UP JNNFEJBUFMZ DPOUBDU UIFJS IFBMUIDBSF QSPWJEFS if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. t *OTUSVDU QBUJFOUT UP JNNFEJBUFMZ SFQPSU BOZ QSFHOBODZ FYQPTVSF UP ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. t *OGPSN GFNBMF QBUJFOUT PG UIF QPUFOUJBM GPS TFSJPVT BEWFSTF reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. t "EWJTF QBUJFOUT OPU UP EPOBUF CMPPE PS CMPPE QSPEVDUT XIJMF UBLJOH ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t "EWJTF QBUJFOUT UP TXBMMPX &3*7&%(& DBQTVMFT XIPMF BOE OPU UP crush or open the capsules.

ERIVEDGE ® [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0001559500 HED0000832301

The trial showed that subcutaneous trastuzumab given in the neoadjuvant and adjuvant settings resulted in noninferior trough drug levels and pathologic complete response rates compared with intravenous trastuzumab and had a similar safety profile.

Study Design

T:10”

1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)].

ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules.

If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed.

Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)].

5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 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 clinical practice.

ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer.

The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1).

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients

2

human hyaluronidase PH-20 (rHuPH-20) as excipient has been evaluated in the recently reported phase III, open-label, multicenter HannaH trial.1

In HannaH, 596 patients with HER2positive stage I to III locally advanced or inflammatory breast See Page 97 cancer were randomly assigned to subcutaneous trastuzumab (n = 297) or intravenous trastuzumab (n����������� ���������� =��������� �������� 299) every 3 weeks as neoadjuvant treatment in combination with chemotherapy consisting of four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide.

The subcutaneous dose of 600 mg was given over approximately 5 minutes; the intravenous dose was an 8-mg/kg loading dose followed by a 6-mg/kg maintenance dose.

After surgery, trastuzumab was continued to complete 1��������������� �������������� year of treatment. The primary endpoints of the study were trough serum trastuzumab concentration prior to dosing in cycle 8 before surgery, with a noninferiority margin of 0.80 for the ratio between the two groups, and pathologic complete response rate, with a noninferiority margin for difference between the two groups of –12.5%.

Locoregional radiation therapy was given to 71.0% of patients in the subcutaneous arm and 68.8% of patients in the intravenous arm after surgery.

Hormonal therapy after surgery consisted of tamoxifen in 30.3%, anastrozole in 5.7%, and letrozole in 4.4% of patients in the subcutaenous group compared with 25.5%, 6.7%, and 7.0%, respectively, in the intravenous group.

Noninferior Trough Drug Levels, Complete Response Rates The geometric mean presurgery trastuzumab trough concentration was 69.0 µg/mL in the subcutaneous group and 51.8 µg/mL in the intravenous group; the geometric mean ratio of subcutaneous trough level to intravenous trough level of 1.3 (90% confi-

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Journal Spotlight

dence interval [CI] = 1.24–1.44) met the noninferiority requirement. Presurgery trough drug levels exceeded the target therapeutic level of 20 µg/ mL in 97.0% of patients in the subcutaneous group and in 98.7% of those in the intravenous group.

Although the trough drug level was approximately 30% higher in the subcutaneous group, overall exposure as indicated by the geometric mean area under the concentration-time curve from 0 to 21 days (AUC0-21d) was very similar in the two groups (2,108 µg/mL day for the subcutaneous group vs 1,978 µg/mL day for the intravenous group, geometric mean ratio = 1.07). The similarity in AUC despite the higher trough level in the subcutaneous group was related to a higher maximum concentration in the intravenous group (mean at cycle 7 before surgery of 149 µg/mL in the subcutaneous group vs 221 µg/mL in the intravenous group, geometric mean ratio = 0.67).

Pathologic complete response was observed in 118 (45.4%) of 260 evaluable patients in the subcutaneous group and in 107 (40.7%) of 263 evaluable patients in the intravenous group; the difference between groups was 4.7% (95% CI = –4.0 to 13.4%), thus satisfying the noninferiority requirement. No association between body weight and pathologic complete response was observed. Overall response rates were similar in the subcutaneous and intravenous groups (87.2% and 88.8%), as were median times to response (6 weeks in both groups). Study patients continue to be followed to substantiate the study’s efficacy findings.

More Serious Adverse Events?

The safety profile of the subcutaneous formulation was consistent with the known profile of intravenous trastuzumab. The incidence of adverse events of grades 3 to 5 in the

Visit

subcutaneous group was similar to that in the intravenous group (51.9% vs 52.0%), with the most common being neutropenia (29.0% vs 33.2%), leukopenia (4.0% vs 5.7%), and febrile neutropenia (5.7% vs 3.4%).

Serious adverse events were more common in the subcutaneous group (20.9% vs 12.4%), with the difference being mainly attributable to a higher incidence of infection/infestation adverse events in subcutaneous patients (8.1% vs 4.4%).

No specific clinical explanation for the imbalance in serious adverse events was identified; multiple regres-

treatment-related. The authors stated that these deaths did not appear to be causally related to trastuzumab per se.

Causality assessment in one intravenous patient dying from pneumonia and the subcutaneous patient dying from septic shock were confounded by underlying pulmonary fibrosis and febrile neutropenia, respectively, and deaths attributed to myocardial infarction and sudden death in the subcutaneous group occurred in patients with recognized concurrent cardiovascular risk factors.

Cardiac safety profiles were similar in the two groups. No cases of New

Subcutaneous Trastuzumab ■■ A novel subcutaneous formulation of trastuzumab consists of a fixed dose of 600 mg given over approximately 5 minutes.

■■ Trastuzumab trough concentrations and pathologic complete response rates with subcutaneous administration were noninferior to those with intravenous administration.

■■ An excess of serious adverse events in the subcutaneous group may reflect a more conservative attitude of investigators toward adverse events in subcutaneous patients in the open-label study.

sion analysis did not show any association between trastuzumab AUC or body weight and rates of serious adverse events. It was noted, however, that the proportion of both grade 3 (18.1% vs 7.7%) and grade 2 (1.5% vs 0.5%) adverse events classified as serious was higher in the subcutaneous group; the authors speculated that this imbalance may reflect a more conservative attitude on the part of investigators toward adverse events in the subcutaneous group in this openlabel trial.

Adverse events led to three deaths in the subcutaneous group and one in the intravenous group, with all deaths occurring during neoadjuvant treatment; two deaths in the subcutaneous group, due to myocardial infarction and septic shock, were considered

York Heart Association (NYHA) class III or IV congestive heart failure were observed. Two patients in the subcutaneous group (both obese with a history of hypertension) and none in the intravenous group had class II heart failure. Reductions in left-ventricular ejection fraction of 10% or more to below 50% occurred in 2.4% of subcutaneous patients and 2.1% of intravenous patients.

Injection-site reactions, most commonly pain, occurred in 11.1% of the subcutaneous group, with almost all being grade 1. Irrespective of baseline antibody status, antidrug antibody was found in 6.8% of subcutaneous patients and 3.4% of intravenous patients, and anti-rHuPH-20 antibodies were found in 11.5% of subcutaneous patients. No neutralizing antibodies

to either protein were detected, and the presence of antibodies had no effect on trastuzumab trough concentrations, pathologic complete response rate, or infusion-related reactions.

The authors concluded, “[Subcutaneous] trastuzumab at a fixed dose of 600 mg administered every 3 weeks in about 5 minutes could … provide an alternative to the [intravenous] regimen given every 3 weeks for HER2positive breast cancer. The shortened duration of administration … suggests the potential for substantial time-saving for patients, physicians, and nursing staff.”

The Pref Her trial (NCT01344863) is examining patient convenience, patient preference for route of administration, and medical resource use with the subcutaneous formulation. n Disclosure: TheHannaH study was funded

by Hoffman-La Roche. Among the HannaH investigators, Dr. Gustavo Ismael has received honoraria from F Hoffmann-La Roche for participation in conferences. Dr. Tadeusz Pienkowski has received travel grants from Hoffmann-La Roche. Dr. Bohuslav Melichar has received speakers honoraria and honoraria from Hoffman-La Roche for participation in advisory board meetings. Dr. Christian Jackisch has received speakers honoraria from HoffmannLa Roche. Dr. Bert Lum is an employee of Genentech and a stockholder in Roche Holding AG. Drs. Susanne Muehlbauer and Dominik Heinzmann are employees of and have stock ownership in Hoffmann-La Roche. Drs. Roberto Hegg, Sung-Bae Kim, Mikhail Lichinitser, and Vladimir Semiglazov reported no potential conflicts of interest.

Reference 1. Ismael G, Hegg R, Muehlbauer S, et al: Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): A phase 3, open-label, multicentre, randomized trial. Lancet Oncol 13:869878, 2012.

website at ASCOPost.com

The ASCO Post | FEBRUARY 15, 2013

PAGE 68

In the Clinic Hematology

Ponatinib in Chronic Myeloid Leukemia and Philadelphia Chromosome–positive Acute Lymphoblastic Leukemia

By Matthew Stenger

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

Indication

O

n December 14, 2012, ponatinib (Iclusig) was granted accelerated approval for the treatment of adult patients with chronic-phase, acceleratedphase, or blast-phase chronic myeloid leukemia (CML) with resistance or intolerance to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior tyrosine kinase inhibitor therapy.1 Approval was based on rates of major cytogenetic response in patients with chronic-phase CML and major hematologic response in patients with accelerated-phase CML, blastphase CML, or Philadelphia chromosome–positive ALL in a single-arm trial (PACE) in patients with intolerance of or disease resistant to prior tyrosine kinase inhibitor treatment, including patients with the BCR-ABL T315I mutation.2 Currently, there are no data verifying an improvement in disease-related symptoms or increased survival with ponatinib. Submission of 24-month follow up data was a condition for accelerated approval.

In the trial,2 449 patients received a ponatinib starting dose of 45 mg daily.

Patients had a median age of 59 years, 53% were male, 79% were white, 92% had ECOG performance status 0 or 1,

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

88% had resistance to prior tyrosine kinase inhibitor therapy, and 56% had received three or more prior approved tyrosine kinase inhibitors. At the time of analysis, the median durations of ponatinib treatment were 281 days in patients with chronic-phase CML, 286 days in those with accelerated-phase CML, 89 days in those with blastphase CML, and 81 days in those with Philadelphia chromosome–positive ALL. The median dose was 37 mg.

Major cytogenetic response occurred in 54% of 267 chronic-phase CML patients, including 49% of 203 with resistance/intolerance and 70% of 64 with the T315I mutation. Major hematologic response occurred in 52% of 83 patients with accelerated-

tinib inhibited the viability of cells expressing native or mutant BCR-ABL, including T315I and reduced the size of tumors expressing native or T315Imutant BCR-ABL.

How It Is Given The recommended dose of ponatinib is 45 mg orally once daily with or without food. Treatment is continued until evidence of disease progression or unacceptable toxicity.

Treatment interruption and sequential dose reduction to 30 mg and 15 mg are recommended for neutropenia and thrombocytopenia, grade 2 or higher liver transaminase elevations, grade 3 lipase elevations, and grade 2 or 3 pancreatitis. Discon-

Ponatinib in CML and Ph+ ALL ■■ FDA has approved ponatinib (Iclusig) to treat chronic myeloid leukemia

(CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior tyrosine kinase inhibitor therapy.

■■ The recommended dose of ponatinib is 45 mg orally once daily, continued until evidence of disease progression or unacceptable toxicity.

phase CML (complete hematologic response in 47%), 31% of 62 patients with blast-phase CML (complete hematologic response in 21%), and 41% of 32 patients with Philadelphia chromosome–positive ALL (complete hematologic response in 34%).

Median time to major cytogenetic response in chronic-phase CML patients was 84 days, and median duration of major cytogenetic response had not been reached at the time of analysis. Median times to major hematologic response were 21, 29, and 20 days in patients with accelerated-phase CML, blast-phase CML, and Philadelphia chromosome–positive ALL, respectively, and median durations of response were 9.5, 4.7, and 3.2 months.

How It Works Ponatinib is a kinase inhibitor that blocks activity of ABL and T315Imutant ABL kinases, members of the VEGFR, PDGFR, FGFR, EPH receptor, and SRC families of kinases, and KIT, RET, TIE2, and FLT3 kinases. In preclinical studies, pona-

tinuation is recommended for elevation of AST or ALT to greater than or equal to three times the upper limit of normal concurrent with an elevation of bilirubin to greater than two times the upper limit of normal and alkaline phosphatase to greater than two times the upper limit of

OF NOTE Ponatinib carries boxed warnings for arterial thrombosis and hepatotoxicity. normal, grade 4 pancreatitis, and for liver abnormalities and lower-grade pancreatitis persisting at the lowest ponatinib dose (15 mg).

The ponatinib dose should be reduced to 30 mg daily in patients receiving strong CYP3A inhibitors (for example, protease inhibitors [ritonavir, idinavir], some macrolide antibiotics [clarithromycin], and some antifungals [ketoconazole, itraconazole]).

OF NOTE Ponatinib blocks activity of ABL, T315I-mutant ABL, and multiple other kinases, thereby inhibiting targeted-cell viability and reducing the size of tumors expressing native or T315I-mutant BCRABL

Safety Profile The most common grade 3 or 4 nonhematologic adverse events by patient group were: hypertension (39%), abdominal pain (10%), and rash (5%) in patients with chronic-phase CML; hypertension (36%), pneumonia (9%), abdominal pain (8%), and rash (8%) in accelerated-phase CML patients; hypertension (26%), cardiac failure (11%), febrile neutropenia (11%), and pneumonia (11%) in blast-phase CML patients; and hypertension (31%), febrile neutropenia (25%), and sepsis (22%) in Philadelphia chromosome– positive ALL patients. Among all patients, the most common serious adverse events were arterial ischemic events (8%, including myocardial infarction or worsenSee Page 97 ing coronary artery disease in 5%) and pancreatitis (5%).

Grade 3 or 4 hematologic abnormalities by treatment group included thrombocytopenia, neutropenia, and anemia in 36%, 24%, and 14% of chronic-phase CML patients; 47%, 51%, and 26% of accelerated-phase CML patients; 57%, 55%, and 55% of blast-phase CML patients; and 47%, 63%, and 34% of Philadelphia chromosome–positive ALL patients. Among all patients, the most common grade 3 or 4 nonhematologic abnormalities were increased lipase (15%), increased ALT (8%), and decreased phosphorus (8%).

Adverse events resulted in discontinuation of treatment in 13% of chronicphase CML patients, 11% of acceleratedphase CML patients, 15% of blast-phase CML patients, and 9% of Philadelphia chromosome–positive ALL patients, with the most common causes consisting of thrombocytopenia (4%) and infections (1%). Overall, adverse events caused dose delays or reductions in continued on page 70

The dual role that integrins play on both tumor and endothelial cells may contribute to the aggressive nature of glioblastoma PRESENTING

THE

ROLE

OF

I N T E G R I N S

in Glioblastoma

• Gliomas account for approxiately 80% of all malignant brain and central nervous system tumors in adults.1 Glioblastoma is the most aggressive form of gliomas.2 • Integrins are a family of at least 24 distinct cell surface heterodimer receptors. As cell surface receptors, integrins regulate cellular behavior by way of signal transmission between extracellular and intracellular spaces through interactions with extracellular ligands.3, 4, 5 • Integrins are overexpressed on tumor cells and vasculature but not widely expressed on normal tissues and blood vessels.3, 5 • The overexpression and activity of integrins are important for proliferation, migration, invasion, and survival of glioblastoma cells.3 Integrins also support tumor growth and progression by promoting tumor-associated angiogenesis.6 References 1. Central Brain Tumor Registry of the United States. http://www.cbtrus.org/2011-NPCR-SEER/ WEB-0407-Report-3-3-2011.pdf. Accessed October 6, 2011. 2. Louis DN, et al.

Acta Neuropathol. 2007;114:97-109. 3. Desgrosellier JS, et al. Nat Rev Cancer. 2010;10:9-22. 4.

Hynes RO. Cell. 2002;110:673-87. 5. Lu X, et al. Perspect Medicin Chem. 2008;2:57-73.

6. Tabatabai G, et al. Target Oncol. 2010;5:175-81.

To view an informative animation on the role of integrins in GBM, please visit our website at www.emdserono.integrins.com

111020-160332

EMD Serono, Inc. is a subsidiary of Merck KGaA, Darmstadt, Germany

The ASCO Post | FEBRUARY 15, 2013

PAGE 70

Announcements

Hematology/Oncology Team Joins NewYork-Presbyterian Hospital/Columbia University Medical Center

T

he Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian Hospital/Columbia University Medical Center has welcomed five new clinician-scientists specializing in leukemia. These practitioners joined the HICCC faculty in early January 2013.

The new staff members are Mark G. Frattini, MD, PhD; Mark L. Heaney, MD, PhD; Joseph G. Jurcic, MD; Nicole Lamanna, MD; and Todd Rosenblat, MD. They will all see patients in the Irving Pavilion of NewYork-Presbyterian/Columbia University Medical Center. Dr. Lamanna will also see patients at ColumbiaDoctors Midtown, the new Columbia outpatient facility.

“I am pleased to welcome these wonderful physicians—who combined have more than 60 years of experience treating leukemia—as members of the Herbert Irving Comprehensive Cancer Center,” said Stephen Emerson, MD, PhD, Director of the HICCC. “We are looking forward to supporting their clinical and translational research, and patients will benefit greatly from their expertise in leukemia and related diseases.”

Their recruitment is one of a number of strategic initiatives made possible by a $40 million donation to the HICCC from Herbert and Florence Irving, which was announced in June 2012.

Comprehensive Coverage “This spectacular team provides comprehensive coverage across the whole spectrum of acute and chronic leukemias,” said Donald W. Landry, MD, PhD, the Samuel Bard Chair of the Department of Medicine at the Columbia University College of Physicians and Surgeons and Chief of Medicine at NewYork-Presbyterian/ Columbia. “They were drawn to each other in the past by a shared commitment to excellence—and this same

Ponatinib in CLL, AML continued from page 68

74% of patients, with the most common causes consisting of thrombocytopenia (30%), neutropenia (13%), increased lipase (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and increased ALT, AST, or GGT (6%).

Ponatinib carries boxed warnings for arterial thrombosis (cardiovascular, cerebrovascular, and peripheral

Mark G. Frattini, MD, PhD

Mark L. Heaney, MD, PhD

Joseph G. Jurcic, MD

lowship in medical oncology/hematology at Memorial Sloan-Kettering Cancer Center.

Dr. Nicole Lamanna will join the faculty as Associate Clinical Professor of Medicine. Dr. Lamanna is a medical oncologist who specializes in the treatment of adult patients with acute and chronic leukemias, with a focus on lymphoid leukemia and expertise in chronic lymphocytic leukemia. Her clinical research interests include the development of combination therapies that include chemoimmunotherapy, immunomodulatory drugs, novel kinase inhibitors, and monoclonal antibodies. She also is working to find active, safer therapies for older patients. She received her MD from Albert Einstein College of Medicine and completed her fellowship in medical oncology/hematology at Memorial SloanKettering Cancer Center.

commitment now draws them to a resurgent heme malignancy program at NewYork-Presbyterian/Columbia, with Dr. Owen O’Connor directing the Center for Lymphoid Malignancies, Dr. Marcus Mapara directing the Bone Marrow Transplant (BMT) unit, Dr. Azra Raza directing the Myelodysplastic Syndromes (MDS) Center, Dr. Suzanne Lentzsch directing the Multiple Myeloma and Amyloidosis Service, and Dr. Megan Sykes, Director of the Columbia Center for Translational Immunology, heading research for the BMT unit.”

Dr. Mark Frattini will join the faculty as Associate Professor of Clinical Medicine and Director of Research for the Hematologic Malignancies Section.

Dr. Frattini is a medical oncologist who specializes in the treatment of adult patients with acute and chronic leukemias, myeloproliferative disorders, and myelodysplastic syndrome. Dr. Frattini’s research focuses on new drug development for acute and chronic leukemias, with a special interest in small-molecule inhibitors of cell cycle-regulated kinases. He received his MD and PhD from The University of Chicago and his fellowship training in medical oncology at The Johns Hopkins Hospital.

Dr. Mark Heaney will join the faculty as Associate Clinical Professor of Medicine. Dr. Heaney is a hematologist/ oncologist with a particular interest in myeloproliferative neoplasms, including

myelofibrosis, polycythemia vera, essential thrombocythemia, and chronic myelogenous leukemia. He also has expertise in several rare hematologic malignancies, including hairy cell leukemia, large granular lymphocyte leukemia, hypereosinophilic syndromes, mastocytosis, and histiocytic diseases. His laboratory research focuses on metabolic differences between normal and leukemic cells. He received his MD and PhD from the University of Virginia and completed his fellowship in medical oncology/hematology at Memorial Sloan-Kettering Cancer Center.

Dr. Joseph Jurcic will join the faculty as Professor of Clinical Medicine and Director of the Hematologic Malignancies Section of the Hematology/OncolNicole Lamanna, MD Todd Rosenblat, MD ogy Division. Dr. Jurcic is a hematologist/oncologist focusing on Dr. Todd Rosenblat will join the the treatment of acute and chronic leufaculty as Assistant Clinical Professor of kemias, myeloproliferative neoplasms, Medicine. Dr. Rosenblat is a hematoloand myelodysplastic syndrome. His gist/oncologist whose research focuses research interests include acute myon developing new and more effective eloid leukemia, radioimmunotherapy treatments for patients with acute mywith alpha and beta particle-emitting eloid leukemia. This includes the develradioisotopes, monoclonal antibody opment of novel drugs and drug comtherapy for leukemia, development of binations, as well as immunotherapy novel small-molecule inhibitors for for myeloid leukemias. He received his leukemia, and molecular monitoring MD from Stony Brook University and of minimal residual disease. He recompleted his fellowship in medical onceived his MD from the University of cology/hematology at Memorial SloanPennsylvania and completed his felKettering Cancer Center. n

vascular thrombosis, including fatal myocardial infarction and stroke) and hepatotoxicity (including liver failure and death). Ponatinib also carries warnings/precautions for congestive heart failure, hypertension, pancreatitis, hemorrhage, fluid retention, cardiac arrhythmias, myelosuppression, tumor lysis syndrome, compromised wound healing and gastrointestinal perforation, and embryo-fetal toxicity.

Patients should be monitored monthly for serum lipase and every 2 weeks for 3 months and then monthly as clinically indicated for complete blood counts.

Adequate hydration should be ensured and high uric acid levels corrected before starting ponatinib treatment.

Cost The estimated wholesale cost of ponatinib is $115,000 per year. n

References 1. U.S. Food and Drug Administration: Ponatinib. Available at http://www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm332368.htm. Accessed January 21, 2013.

2. ICLUSIG® (ponatinib) tablets prescribing information, ARIAD Pharmaceuticals, Inc, December 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf.

Accessed January 21, 2013.

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 (%)

80

60

Median PFS: 3.2 months

55%

Median PFS: 7.8 months

reduction in risk of progression or death2

40

20 AFINITOR plus exemestane (n/N=310/485) Placebo plus exemestane (n/N=200/239)

0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

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

© 2012 Novartis

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

T:14”

B:14.25”

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.

T:14”

B:14.25”

S:13”

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

The ASCO Post | FEBRUARY 15, 2013

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Integrative Oncology Barrie R. Cassileth, MS, PhD, Guest Editor

Turmeric Scientific Name: Curcuma longa Common Names: Indian saffron, curcumin, jiang huang.

T

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 complementary therapies commonly used by patients with cancer. We chose turmeric for this issue because of the growing interest in its anticancer potential.

Integrative Oncology is compiled by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine, and Jyothirmai Gubili, MS, Editor of About Herbs, Memorial Sloan-Kettering Cancer Center. The free About Herbs website and the free About Herbs application are managed

by K. Simon Yeung, PharmD, LAc, Memorial Sloan-Kettering Cancer Center.

Overview

Believed to have originated in India, turmeric is a perennial herb cultivated extensively in Southeast Asia

and in many warm regions of the world, with a medicinal history that dates back 5,000 years. It is used in traditional medicine for wound healing, to treat stomach ailments, and to “purify” blood. The rhizome is used as a spice in regional cuisines, and as a coloring agent in food and cosmetics.

In addition to its role as a culinary agent and as a component in Ayurvedic formulations and traditional Chinese medicine, turmeric is under investigation for its therapeutic potential.

Following discovery of a wide spectrum of biological effects, turmeric’s potential value in the treatment of several diseases, including cancer, has been widely studied.

Turmeric was the center of a controversy in 1995, when the U.S. Patent and Trademark Office granted a patent to the University of Mississippi Medical Center for use of turmeric as a wound-healing agent.1 The patent, however, was revoked after the Council for Agricultural Research in India disputed the novelty of the work and provided evidence of turmeric’s medicinal use in India since ancient times.

Extracts of turmeric are marketed as dietary supplements to improve memory, for arthritis, and for cancer prevention. Turmeric is also available in the form of ointments and creams

for topical use.

It is generally considered safe to consume turmeric. However, data on its interactions with chemotherapy agents are conflicting. Cancer patients should discuss use of turmeric supplements with their physicians.

The Science

Several bioactive compounds from turmeric extracts have been studied in the past few decades. Much of the current investigation centers on curcumin, a watersoluble bioactive constituent.

In vitro studies suggest that curcumin acts as a weak phytoestrogen2 and exhibits 3 neuroprotective, anti-inflammatory,4 immunomodulatory,5 and chemopreventive effects.6 Curcumin, its analogs, and liposomal formulations also produce chemo- and radiosensitizing effects.7,8 Epidemiologic data suggest improved cognitive performance in elderly Asians who consume turmeric in the form of curry powder.9 However, curcumin supplementation did not confer the same benefit in patients with Alzheimer’s disease.10 Turmeric may help alleviate the symptoms of irritable bowel syndrome11 and quiescent ulcerative colitis.12 It is safe and equally effective to

a nonsteroidal anti-inflammatory drug for the treatment of osteoarthritis of the knee.13 In patients with colorectal cancer, oral curcumin administered during the presurgery waiting period improved cachexia and general health of patients.14 In a phase II trial of oral curcumin in patients with advanced pancreatic cancer, there were no treatment-related toxic effects, and clinically relevant biological activity was seen in two patients despite limited absorption.15 In other early-phase studies, combined administration of curcumin with docetaxel16 and gemcitabine17 was shown to be safe.

Curcumin has estrogenic activity,2 but its effects on breast cancer patients remain unclear. Overall, the use of turmeric for clinical purposes requires further investigation due to its inherent poor absorption, rapid metabolism, complex mechanistic profile, and the current availability of only preliminary, preclinical data.

Adverse Effects

Allergic dermatitis,18 contact urticaria,19 and transient atrioventricular block20 have been reported following intake of curcumin.

Herb-Drug Interactions

Anticoagulants/antiplatelets: Turmeric may increase the risk of bleeding due to its antiplatelet properties.21 Drugs metabolized by cytochrome P450 enzymes: Curcumin inhibits CYP3A4 and CYP1A2 but en-

Learn More About

Herbs, Botanicals, & Other Products Visit the About Herbs website at

www.mskcc.org/aboutherbs

ASCOPost.com | FEBRUARY 15, 2013

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Integrative Oncology hances CYP2A6 enzymes,22,23 altering the metabolism of some prescription drugs.

Camptothecin: Turmeric inhibits camptothecin-induced apoptosis of breast cancer cell lines in vitro.24 Mechlorethamine: Turmeric inhibits mechlorethamine-induced apoptosis of breast cancer cell lines in vitro.24 Doxorubicin: Turmeric inhibits doxorubicin-induced apoptosis of breast cancer cell lines in vitro.24 Cyclophosphamide: Dietary turmeric inhibits cyclophosphamideinduced tumor regression in animal studies.24 Norfloxacin: Pretreatment with curcumin results in increased plasma elimination half-life, thereby reducing the dosage of norfloxacin.25

OF NOTE Turmeric is gaining popularity among patients with cancer. Oncologists should be aware of its anticoagulant and estrogenic effects, as well as its potential to interact with several prescription medicines, including some chemotherapeutic agents.

Amphotericin B: Curcumin may enhance the effect and decrease the toxicity of amphotericin B.26 Midazolam: Curcumin downregulates intestinal P-glycoprotein levels, thereby increasing the concentration of midazolam.27 Verapamil: Curcumin inhibits intestinal P-glycoprotein expression and function, thereby increasing the concentration of verapamil.28 n

Disclosure: Drs. Cassileth and Yeung and Ms. Gubili reported no potential conflicts of interest.

References 1. Kumar S: India wins battle with USA over turmeric patent. Lancet 350:724, 1997.

2. Bachmeier BE, Mirisola V, Romeo F, et al: Reference profile correlation reveals estrogen-like trancriptional activity of Curcumin. Cell Physiol Biochem 26:471482, 2010.

3. Cemil B, Topuz K, Demircan MN, et al: Curcumin improves early functional re-

sults after experimental spinal cord injury.

Acta Neurochir (Wien) 152:1583-1590, 2010.

4. Yun JM, Jialal I, Devaraj S: Epigenetic regulation of high glucose-induced proinflammatory cytokine production in monocytes by curcumin. J Nutr Biochem 22:450-458, 2011.

5. Jantan I, Bukhari SN, Lajis NH, et al: Effects of diarylpentanoid analogues of curcumin on chemiluminescence and chemotactic activities of phagocytes. J Pharm Pharmacol 64:404-412, 2012.

6. Chang KW, Hung PS, Lin IY, et al: Curcumin upregulates insulin-like growth factor binding protein-5 (IGFBP-5) and C/EBPalpha during oral cancer suppression. Int J Cancer 127:9-20, 2010.

7. Selvendiran K, Ahmed S, Dayton A, et al: HO-3867, a curcumin analog, sensitizes cisplatin-resistant ovarian carcinoma, leading to therapeutic synergy through STAT3 inhibition. Cancer Biol Ther 12:837-845, 2011.

8. Qiao Q, Jiang Y, Li G: Curcumin improves the antitumor effect of X-ray irradiation by blocking the NF-kappaB pathway: An in-vitro study of lymphoma.

Anticancer Drugs 23:597-605, 2012.

9. Ng TP, Chiam PC, Lee T, et al: Curry consumption and cognitive function in the elderly. Am J Epidemiol 164:898-906, 2006.

10. Baum L, Lam CW, Cheung SK, et al: Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol 28:110-113, 2008.

11. Bundy R, Walker AF, Middleton RW, et al: Turmeric extract may improve irritable bowel syndrome symptomology in otherwise healthy adults: A pilot study.

J Altern Complement Med 10:1015-1018, 2004.

12. Hanai H, Iida T, Takeuchi K, et al: Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial.

Clinical Gastroenterol Hepatol 4:15021506, 2006.

13. Kuptniratsaikul V, Thanakhumtorn S, Chinswangwatanakul P, et al: Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. J Altern Complement Med 15:891-897, 2009.

14. He ZY, Shi CB, Wen H, et al: Upregulation of p53 expression in patients with colorectal cancer by administration

I

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial SloanKettering Cancer Center, New York.

The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, Barrie R. Cassileth, MS, PhD minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.

In addition, the About Herbs app, Memorial Sloan-Kettering Cancer Center’s very first mobile application, was launched last fall. In the week following its release on September 21, the app was downloaded more than 6,300 times, making it #4 on the top new medical apps chart. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be See Page 97 downloaded at http://itunes.apple.com/us/app/aboutherbs/id554267162?mt=8. of curcumin. Cancer Invest 29:208-213, 2011.

15. Dhillon N, Aggarwal BB, Newman RA, et al: Phase II trial of curcumin in patients with advanced pancreatic cancer.

Clin Cancer Res 14:4491-4499, 2008.

16. Bayet-Robert M, Kwiatkowski F, Leheurteur M, et al: Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Cancer Biol Ther 9:8-14, 2010.

17. Epelbaum R, Schaffer M, Vizel B, et al: Curcumin and gemcitabine in patients with advanced pancreatic cancer. Nutr Cancer 62:1137-1141, 2010.

18. Lamb SR, Wilkinson SM: Contact allergy to tetrahydrocurcumin. Contact Dermatitis 48:227, 2003.

19. Liddle M, Hull C, Liu C, et al: Contact urticaria from curcumin. Dermatitis 17:196-197, 2006.

20. Lee SW, Nah SS, Byon JS, et al: Transient complete atrioventricular block associated with curcumin intake. Int J Cardiol 150(2):e50-2, 2011.

21. Prakash P, Misra A, Surin WR, et al: Anti-platelet effects of Curcuma oil in experimental models of myocardial ischemia-reperfusion and thrombosis.

Thromb Res 127:111-118, 2011.

22. Zhang W, Lim LY: Effects of spice constituents on P-glycoprotein-mediated transport and CYP3A4-mediated metabo-

lism in vitro. Drug Metab Dispos 36:12831290, 2008.

23. Chen Y, Liu WH, Chen BL, et al: Plant polyphenol curcumin significantly affects CYP1A2 and CYP2A6 activity in healthy, male Chinese volunteers. Ann Pharmacother 44:1038-1045, 2010.

24. Somasundaram S, Edmund NA, Moore DT, et al: Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res 62:3868-3875, 2002.

25. Pavithra BH, Prakash N, Jayakumar K: Modification of pharmacokinetics of norfloxacin following oral administration of curcumin in rabbits. J Vet Sci 10:293297, 2009.

26. Kudva AK, Manoj MN, Swamy, BM, et al: Complexation of amphotericin B and curcumin with serum albumins: Solubility and effect on erythrocyte membrane damage. J Exp Pharmacol 3:1-6, 2011.

27. Zhang W, Tan TM, Lim LY: Impact of curcumin-induced changes in P-glycoprotein and CYP3A expression on the pharmacokinetics of peroral celiprolol and midazolam in rats. Drug Metab Dispos 35:110-115, 2007.

28. Hou XL, Takahashi K, Tanaka K, et al: Curcuma drugs and curcumin regulate the expression and function of P-gp in Caco-2 cells in completely opposite ways.

Int J Pharm 358(1-2):224-229, 2008.

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Pioneers in Oncology David A. Karnofsky’s Early Contributions to Cancer Research Helped Establish Oncology as a Medical Discipline

By Jo Cavallo

David A. Karnofsky, MD

F

or nearly 30 years, from the time he was a young resident at the Collis P. Huntington Memorial Hospital for Cancer Research of Harvard University, until his death from lung cancer on August 31, 1969, David A. Karnofsky, MD, dedicated himself to the pursuit of scientific excellence and the investigation of more effective therapies for cancer.

Dr. Karnofsky’s early research discoveries at Memorial Hospital–SloanKettering Institute (now Memorial Sloan-Kettering Cancer Center) in New York led to the development of numerous chemotherapeutics, including the first oral alkylating agent triethylenemelamine, the glutamine antagonists azaserine (NSC 742) and 6-diazo5-oxo-L-norleucine (DON), and two breakthrough agents widely used today in the treatment of childhood leukemias, daunorubicin and asparaginase (Elspar). In fact, his early clinical trials of asparaginase on 400 cancer patients proved so effective, especially in the treatment of acute lymphoblastic leukemia (ALL), it has been in common use in pediatric ALL for over 30 years.

Disciplined Approach to Oncology Dr. Karnofsky’s meticulous attention to the clinical evaluation of drugs, which brought hard-data reliant objectivity and discipline to cancer research, is one reason he is credited with helping establish the field of oncology as a specific medical discipline. His creation in 1949 of the Karnofsky Performance Scale (along with another early pioneer

of cancer chemotherapeutics, Joseph H. Burchenal, MD) is another.

“The relevant matter in examining any form of treatment is not the reputation of its proponent, the persuasiveness of his theory, the eminence of its lay supporters, the testimony of patients, or the existence of public controversy, but simply … does the treatment work?” said Dr. Karnofsky in 1959.

“Dr. Karnofsky brought a very disciplined approach to the field of oncology,” said Michael Link, MD, Immediate Past President of ASCO and the Lydia J. Lee Professor of Pediatrics at Stanford University School of Medicine. “The Karnofsky Performance Scale not only provided physicians with the first tool to evaluate a patient’s clinical status, it also enabled them to objectively quantify the effectiveness of treatment and establish whether a drug was beneficial or not.

That is the sort of real-science approach we want in the development of anticancer agents, and Dr. Karnofsky was the driving force behind that approach.”

Modern Age of Chemotherapy In 1942, Dr. Karnofsky began studying the biological activities of mustard gas, a chemical warfare agent, at the Mount Desert Island Biological Laboratory in Maine. He continued that re-

the first organized clinical chemotherapy program in the country, and continued studies of nitrogen mustard and other antitumor cancer drugs.

“It was these experiences, many of us believe, that initiated the modern era of cancer chemotherapy,” said Irwin H. Krakoff, MD, in his remarks at the 24th Annual David A. Karnofsky Memorial Lecture, which were later published in the Journal of Clinical Oncology.1 In addition to being a researcher, clinician, and teacher, designing a course in chemotherapeutics for medical students, Dr. Karnofsky also traveled the world giving lectures on cancer research and was the recipient of numerous awards, including the Shabanu Medal for Cancer Research from the Empress Farah of Iran in 1968.2

Honoring the Early Cancer Pioneers After Dr. Karnofsky’s death, a group of his friends donated money to ASCO to fund a yearly lecture at ASCO’s Annual Meeting, and in 1970, ASCO launched a permanent memorial to honor Dr. Karnofsky’s body of work with the David A. Karnofsky Memorial Award and Lecture. The Award, which is presented at ASCO’s Annual Meeting, recognizes oncologists who have made outstanding contributions in the areas of cancer re-

Dave was a fountain of ideas, stimulating all those around him to new and better research while constantly helping them with wise counsel to be critical of their own results.

—Joseph H. Burchenal, MD

search after joining the Army Chemical Warfare Service, then a branch of the U.S. Army. It was while in the Army that Dr. Karnofsky became interested in the antineoplastic activity of nitrogen mustard (mechlorethamine [Mustargen]), which had been found to be effective, albeit briefly, against lymphoma.

His commanding officer at the time was C.P. Rhodes, MD, on leave as Medical Director of the Memorial Hospital for Cancer. At the end of World War II, in 1945, Dr. Karnofsky joined Dr. Rhodes at Memorial Hospital and, with Dr. Burchenal, launched

search, diagnosis, and/or treatment and is the Society’s highest scientific honor.

The first Award recipient was Sir Alexander Haddow, FRS, whose lecture, “Thoughts on Chemical Therapy,” addressed his concern that scientists would never be able to develop drugs that can discriminate cancer cells from normal cells, making it impossible, he thought, to develop targeted therapies to kill malignant cells. The 2012 recipient of the Karnofsky Award is Kanti R. Rai, MD, the creator of the Rai clinical staging system for chronic lymphocytic leukemia.

“The list of recipients of the David A. Karnofsky Memorial Award reads like a Who’s Who in oncology,” said Dr. Link.

“It is important to acknowledge our forbearers. Sometimes we forget the important work done by our earlier cancer pioneers and take for granted their struggles and the progress that has been made. So much of the early studies in chemotherapy were done in childhood cancers. If we hadn’t had the kind of successes we’ve had in treating pediatric cancers, I’m not sure there would be the kind of interest we see in the field of oncology and in chemotherapy, because it is success that encourages more scientific work and optimism,” said Dr. Link.

‘A Great and Dedicated Physician’ At the time of his death, Dr. Karnofsky was Chief of the Medical Oncology Service and Head of the Division of Chemotherapy Research at the SloanKettering Institute for Cancer Research, Professor of Medicine at Cornell University Medical Center, and a physician at The New York Hospital.

Dr. Karnofsky’s contributions as a scientist, physician, and teacher in the fledgling field of oncology were summed up in an obituary written by Dr. Burchenal, Dr. Karnofsky’s friend and colleague at the Sloan-Kettering Institute. “Dave was a fountain of ideas, stimulating all those around him to new and better research while constantly helping them with wise counsel to be critical of their own results.… We at Memorial have been immensely fortunate to have had more than 2 decades of association with him as a friend, a distinguished and truly creative scientist, a careful and exact clinical investigator, a wise counselor, and, most important of all, a great and dedicated physician,” wrote Dr. Burchenal.2 The 2013 Karnofsky lecture will be presented on June 1 at the ASCO Annual Meeting. n References 1. Krakoff IH: The 24th annual David A. Karnofsky memorial lecture. Progress and prospects in cancer treatment: The Karnofsky legacy. J Clin Oncol 12:432438, 1994.

2. Burchenal JH: Obituary: David A. Karnofsky. Cancer Res 30:549-550, 1970.

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PAGE 81

News Pediatric Oncology

Genetic Basis of High-risk Childhood Cancer Points to Possible New Drug Treatment Strategy

R

esearch led by scientists at St. Jude Children’s Research Hospital, Memphis, Tennessee, has identified a possible lead in treatment of two childhood leukemia subtypes known for their dramatic loss of chromosomes and poor treatment outcomes. The findings also provide the first evidence of the genetic basis for this high-risk leukemia, hypodiploid acute lymphoblastic leukemia (ALL). The research appears online in Nature Genetics.1 The study, the largest ever focused on hypodiploid ALL, confirmed that this tumor has distinct subtypes distinguished by the number of chromosomes lost and the submicroscopic genetic alterations they harbor.

Researchers found evidence suggesting more than one-third of patients with a subtype known as low hypodiploid ALL have Li-Fraumeni syndrome. Families with Li-Fraumeni syndrome harbor inherited mutations in the TP53 tumor-suppressor gene and have a high risk of a range of cancers. Hypodiploid ALL had not previously been recognized as a common manifestation of Li-Fraumeni syndrome.

with low hypodiploid ALL. Investigators also checked white blood cells collected when 89 of the 124 patients were in remission. The study included whole-genome sequencing of the en-

tire cancer and normal genomes of 20 patients with near haploid or low hypodiploid subtypes. For another 20 patients, investigators deciphered just DNA involved in protein production.

Researchers also screened cancer cells from 117 adult ALL patients, including 11 with the low hypodiploid subtype. continued on page 82

INHIBIT ANDROGEN PRODUCTION

Drug Sensitivity Researchers reported that the major hypodiploid subtypes are both sensitive to a family of compounds that block the proliferation of cancer cells. The compounds include drugs already used to treat other cancers.

The subtypes are low hypodiploid ALL, characterized by 32 to 39 chromosomes, and near haploid ALL, which has 24 to 31 chromosomes.

“This study is a good example of the important insights that can be gained by studying the largest possible number of patients in as much detail as possible. This approach led us to key insights about these leukemia subtypes that we would otherwise have missed,” said the study’s senior and corresponding author, Charles Mullighan, MBBS(Hons), MSc, MD, an Associate Member of the St. Jude Pathology Department.

Researchers used a variety of laboratory techniques to look for genetic abnormalities in cancer cells from 124 pediatric patients missing at least one chromosome. The patients included 68 with near haploid ALL and 34

BLOCK THE ANDROGEN RECEPTOR

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. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. 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. 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.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 08Z12191

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PAGE 82

Book Review

Important Messages about Palliative Care and Hospice at the Heart of New End-of-life Memoir

By Ronald Piana

T

he illness memoir’s appeal proves enduring in a very crowded genre, perhaps because illness is a tie that binds us all. As Susan Sontag wrote in her classic work, Illness as a Metaphor, “Illness is the night-side of life, a more onerous citizenship. Everyone who is born holds dual citizenship, in the kingdom of the well and in the kingdom of the sick.” Will Schwalbe’s new book, The End of Your Life Book Club, opens in the kingdom of the sick—the outpatient waiting room of Memorial Sloan-Kettering Cancer Center.

The Drama Unfolds The author is at Memorial SloanKettering to support his mother, Mary Anne—she is being treated for pancreatic cancer. Both devoted bibliophiles, they share cups of mocha and begin an ad hoc book club that will serve as the emotional braid as the drama unfolds. To Mr. Schwalbe’s credit, he draws his mother’s zest for life and save-theworld passions in a way that deftly captures the arc of her disease as she bravely struggles against her fading horizons. She’s a big presence in her son’s life, making her decline all the more painful.

For years, Mary Anne worked tirelessly for myriad international humanitarian organizations that kept her traveling to war-torn regions of the world—Afghanistan, Liberia, Sudan, Laos, and Gaza, to name a few. After one particularly exhausting trip she presented with an illness that was first diagnosed as hepatitis. However, Mary Anne progressively got sicker and, at the urging of her family, went to another doctor. Mr. Schwalbe, a book editor and journalist, was in Germany at the annual Frankfurt Book Fair when his

New Treatment Strategy for High-risk Childhood Cancer continued from page 81

Key Findings

Near haploid ALL was characterized by alterations in six genes and increased activity in key pathways that help regulate cell division and development. Disruption of these pathways, known as Ras and PI3K, has been linked to other cancers.

mother called and relayed the news that her malady was not hepatitis; she had pancreatic cancer. Stalwart as ever, she urged her son not to cut his trip short.

“I can’t remember much of what I said, or what she replied,” the author writes, underscoring the mindnumbing reaction to a cancer diagnosis. From this point on, Mr. Schwalbe’s rendition of his mother’s battle with cancer becomes a son’s heartfelt tale of a death foretold and how he used the power of the printed word to assuage and at times make sense of the existential realities of terminal illness.

Short on Clinical Realities The intimate and often difficult bonding process between cancer pa-

Sloan-Kettering, Eileen M. O’Reilly, MD, who “thankfully was all over this. She understood, in a way that many doctors don’t, that a dreadful mouth sore or needing to go to the bathroom five or ten times in a morning needs treatment just as the cancer itself does.” Another Sloan-Kettering doctor, Kathleen Foley, MD, comes into the palliative care picture. But perhaps for readers of The ASCO Post, the role of the oncologist, the therapeutic details, and the decision-

The lesson the book leaves the oncology community with is one that has already taken root, but still needs to be reinforced: Quality care begins and ends with meaningful doctor-patient discussions. tient and caregiver is a familiar story, but Mr. Schwalbe weaves it in a way that let’s the reader become a voyeur to his relationship with his mother, which blossoms in the face of death.

Although the author focuses on his mother—“the person, not the disease,” which has become a mantra in today’s oncology culture—his story might have had more pathos had he brought the reader a little deeper into the clinical realities of pancreatic cancer.

Moreover, her doctors could have been fleshed out a bit more—for one, her medical oncologist at Memorial

making discussions are given too little attention.

Some of the most compelling parts of the book are when Mr. Schwalbe relates the end-of-life discussions that his mother initiated, truly understanding that ignoring the inevitable shortchanges the patient and her family of precious time to properly prepare for the final transition. “Plenty of people are willing to talk about death but very few about dying,” he writes. Noting that some people continued to ignore the way his mother talked about her cancer, he points out that she “occasionally expressed frustration. People

The changes were found in 71% of near haploid ALL patients and included deletion of the NF1 gene.

The gene had not previously been linked to high-risk leukemia. Other alterations involved the genes NRAS, KRAS, MAPK1, FLT3, and PTPN11.

Low hypodiploid ALL in both adults and children was linked to mutations in the TP53 tumor-suppressor

gene. The gene was altered in 91% of pediatric patients with the low hypodiploid ALL subtype and in 10 of the 11 adults with low hypodiploid ALL included in the study. Other common alterations involved RB1, another tumor-suppressor gene.

About 38% of children with low hypodiploid ALL also carried TP53 abnormalities in noncancerous blood cells. The mutations included many

Title: The End of Your Life Book Club Author: Will Schwalbe Publisher: Knopf Publication date: October 2, 2012 Price: $25.00; Hardcover, 352 pages

weren’t listening. She wasn’t going to get better.”

Underlying Themes In the end, Mr. Schwalbe’s mother passed with grace and dignity, despite the cruel ravages of pancreatic cancer.

She was fortunate to have a skilled palliative care team and a loving and supportive family. This was textbook end-of-life care, and a large part was due to what the author describes as his parents’ introduction to the hospice movement and the concept of palliative care many years before her own diagnosis. “Perhaps this helped explain why Mom was so comfortable discussing all aspects of her death and what needed to be done.”

In the epilogue, Mr. Schwalbe comments that the mother-son book club “help[ed] Mom on her journey toward death and me on mine to life without her.” The lesson the book leaves the oncology community with is one that has already taken root, but still needs to be reinforced: Quality care begins and ends with meaningful doctor-patient discussions. The book runs a bit long and chatty at times, but its overall humanity and important messages about palliative care and hospice make it a worthwhile read. n previously linked to Li-Fraumeni syndrome, which is characterized by changes in TP53. n Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Holmfeldt L, Wei L, Diaz-Flores E, et al: The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet.

January 20, 2013 (early release online).

ASCOPost.com | FEBRUARY 15, 2013

PAGE 83

News Breast Cancer

Researchers Develop Automated Breast Density Test Linked to Cancer Risk

R

esearchers at Moffitt Cancer Center in Tampa, Florida, and colleagues at the Mayo Clinic in Rochester, Minnesota, have developed a novel computer algorithm to quantify breast density based on analysis of a screening mammogram.

Increased levels of mammographic breast density have been shown in multiple studies to be correlated with elevated risk of breast cancer, but the approach to quantifying it has been limited to the laboratory setting where measurement requires highly skilled technicians. This new discovery opens the door for translation to the clinic where it can be used to identify high-risk women for tailored treatment.

“We recently developed an automated method to estimate mammographic breast density that assesses the variation in grayscale values in mammograms,” explained study lead author J. Heine, PhD, Associate Member of the Cancer Epidemiology Program and Cancer Imaging and Metabolism Department at Moffitt.

Using their new method, the researchers compared the accuracy and reliability of their measurements of variation in breast density with the performance of tests that use the degree of dense breast tissue in a mammogram to assess breast cancer risk. A study describing their novel method and its utility was published in the Journal of the National Cancer Institute.1

the ability to standardize and automate the measure across sites, could hold promise for clinicians and their patients if the measurements were incorporated into clinical risk assessment practices.

This work was supported with grants by the U.S. Department of Defense and National Cancer Institute. n

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

Reference 1. Heine JJ, Scott CG, Sellers TA, et al: A novel automated mammographic density measure and breast cancer risk.

J Natl Cancer Inst 104:1028-1037, 2012.

Potential Use in Risk Assessment According to Dr. Heine, they found that the variation measure was a “viable, automated mammographic density measure that is consistent across film and digital imaging platforms” and “may be useful in the clinical setting for risk assessment.”

In addition, they found that the association between variation and the risk of breast cancer was strong for mammograms carried out 4 years prior to diagnosis. The automated method also made clearer distinctions between breast cancer case subjects and controls who did not have breast cancer.

The researchers concluded that the simplicity of the measure, 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.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 8/12 08Z12235

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Patient’s Corner Breast Cancer

Betting Against the Odds

The 5-year survival rate associated with my incurable breast cancer is just 23%. I believe I’ll make it.

By Sharon K. Barger, as told to Jo Cavallo

I

knew the two tumors in my left breast were cancerous even before I got the pathology results back on my biopsy. I could clearly see the tumors on the digital mammogram my doctor ordered, and when the radiologist pointed out that they had spikes radiating from the edges and that he was scheduling a biopsy and an appointment with a surgical oncologist, I was pretty sure the news wasn’t going to be good. So I wasn’t surprised when the doctor called to tell me that I did, in fact, have cancer and that it was invasive ductal carcinoma.

I had been preparing myself for the call and decided that I would undergo every treatment that he recommended, including a mastectomy with reconstructive breast surgery. If all went well, I would be back to normal in a year or two. What I wasn’t expecting was the news that the cancer had metastasized to my bones, including my spinal column, and that there were suspicious spots on my lungs. Further tests have confirmed seven malignant lymph nodes near my heart and lungs as well as several cancerous nodules in my lungs. I have stage IV breast cancer, and there is no cure.

When the doctor told my husband, sister, and me that I wouldn’t need a mastectomy or chemotherapy because I wouldn’t benefit from those therapies,

my husband and sister were relieved almost to the point of being excited because what they heard was I didn’t have to have disfiguring treatment. All I heard was that I have incurable cancer, and it has taken a while for the full impact of the diagnosis to sink in.

Because my cancer is incurable, it is critically important to me to know exactly how the cancer is reacting to treatment, so having to wait several weeks until my next medical appointment to get my latest test results is very difficult. I would prefer that my

Because my cancer is incurable, it is critically important to me to know exactly how the cancer is reacting to treatment, so having to wait several weeks to get my latest test results is very difficult.

—Sharon K. Barger

Coping with Incurable Cancer My doctor has reassured me that my cancer is treatable, and since my diagnosis last April, I’ve been taking tamoxifen daily and getting monthly injections of denosumab (Xgeva) to preserve my bones. In August, a PET scan showed that the tumors in my breast have shrunk by 25% and that the tumors in my bones and lungs are no longer active. My oncologist tells me that when tamoxifen stops working, there are at least 25 other chemotherapies and combinations of drugs he can prescribe.

physicians inform me of my test results as soon as they have that information and not make me wait. Not knowing what is going on with my breast cancer is the hardest part of coping with this disease.

Prognosis I’ve accepted the fact that I have a chronic cancer that is not curable but that is treatable. There are times, however, when I struggle with my prognosis.

I’ve seen the long-term survival rate for my breast cancer and it is pretty grim.

According to the American Cancer So-

ciety, there’s just a 15% chance that I will survive 5 years. I’ve chosen to believe that I’ll be among those lucky 15%.

Recently, I read on Cancer.net that the 5-year survival rate for stage IV breast cancer has jumped to 23%. I was so happy when I saw that statistic I cried. Others may think a 23% chance doesn’t sound that good, but it’s a lot better than 15%.

Quality of Time I have three children, ages 22, 20, and 17, and I desperately want to see my youngest son graduate high school and college and my other children start their careers and families. I’ll do whatever it takes to accomplish that goal.

I have tremendous faith and believe that advances in treatment will increase my long-term survival. But if I reach the point when active treatment fails to stop progression of my cancer and continuing therapy interferes with my quality of life, I’ll stop. More than anything else, what is important to me is quality of time with my family, not quantity of time. If I reach that point, I’ll make that wish known to my medical team. n Sharon K. Barger is a business specialist for a global chemical company and lives in Kingsport, Tennessee.

News and Views from the World of Clinical Oncology and Hematology

Visit The ASCO Post website at

www.ASCOPost.com

ASCOPost.com | FEBRUARY 15, 2013

PAGE 85

Announcements

University of Michigan Cancer Center Names Kathleen Cooney, MD, to Head Clinical Operations

T

he University of Michigan (UM) Comprehensive Cancer Center in Ann Arbor has named Kathleen Cooney, MD, as Deputy Director for Clinical Services.

gree at the University of Pennsylvania School of Medicine and completed residency training and a fellowship at the University of Michigan Medical School.

She joined the U-M faculty in 1991,

where her clinical interests focus in the treatment of men with prostate cancer.

Dr. Cooney’s research focuses on identifying genetic defects in in hereditary prostate cancer. Her work led

to the recent identification of a novel prostate cancer susceptibility gene, HOXB13 on chromosome 17.

Dr. Cooney’s appointment was effective January 1. n

Kathleen Cooney, MD

Dr. Cooney is Frances and Victor Ginsberg Professor of Hematology/ Oncology and Chief of the Division of Hematology/Oncology at the U-M Medical School and has been serving as interim Medical Director for the Cancer Center since 2011.

This newly created position will encompass overseeing and coordinating clinical activities throughout the spectrum of cancer care at U-M. This includes outpatient facilities, inpatient cancer units, cancer clinical programs at satellite locations, and the development of a network of community partners.

Expanded Role “Dr. Cooney’s outstanding leadership and administrative skills and knowledge of cancer clinical operations make her eminently qualified to assume this expanded role. Under her leadership, the University of Michigan and the Cancer Center have the opportunity to create programs of clinical excellence, which will serve as a model for cancer programs nationally,” said Max S. ­Wicha, MD, Director of the U-M Comprehensive ­ Cancer Center.

As Deputy Director, Dr. Cooney will look broadly at cancer care across the entire University of Michigan Health System, with a goal of incorporating best clinical practices at all locations and integrating support services for all patients.

“The Cancer Center has grown tremendously in the 25 years since it was founded,” Dr. Cooney said. “Patients with cancer are seen at many locations throughout our institution and we need to make sure our patients receive the best treatment and care regardless of where we’re seeing them.”

Dr. Cooney received her medical de-

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. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. 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. 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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2013 Oncology Meetings February Scripps Cancer Center’s 33rd Annual Clinical Hematology and Oncology Conference February 16-19 • San Diego, California For more information: www.scripps.org/events/clinicalhematology-and-oncologyfebruary-16-2013 2013 Translational Research Cancer Centers Consortium: The Power of Negative Thinking: Inhibiting the Inhibitors of Tumor Immunity February 20-22 • Seven Springs, Pennsylvania For more information: www.trccc.org/ Best of Oncology 2013 – West February 22 • Vancouver, British Columbia, Canada For more information: www.oncologyeducation.com NCOA & SCOS Joint Membership Conference February 22-23 • Greenville, South Carolina For more information: www.ncoa-northcarolina.com 2013 Multidisciplinary Head and Neck Cancer Update February 22-23 • Weston, Florida For more information: www.clevelandclinicmeded.com 2nd Novel Cancer Therapeutics Summit February 25-26 • Las Vegas, Nevada For more information: www.gtcbio.com

March Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial Sloan-Kettering Cancer Center March 1-5, 2013 • New York, New York For more information: www.mskcc.org/hemoncreviewcourse International Congress on Targeted Anticancer Therapies March 4-6 • Paris, France For more information: www.tatcongress.org/tat13-home.html

24th Annual Cancer Progress Conference March 5-6 • New York, New York For more information: www.cancerprogressbyDH.com Inaugural Prostate Cancer Research and Translation Symposium March 6-7 • Winston-Salem, North Carolina For more information: northwestahec.wfubmc.edu NCCN 18th Annual Conference: Advancing the Standard of Cancer Care March 14-17 • Hollywood, Florida For more information: www.nccn.org 5th Thyroid Neoplasms Conference March 21-23 • Houston, Texas For more information: www.mdanderson.org/conferences Community Oncology Journal’s 8th Annual Oncology Practice Summit March 21-23 • Las Vegas, Nevada For more information: onc.globalacademycme.com/ conferences/oncology-practicesummit-2013/conference-overview.html ASTRO Spring Refresher Course March 22-24 • Chicago, Illinois For more information: www.astro.org/springrefresher Highlights of ASH® in Asia March 23-24 • Shanghai, China For more information: www. hematology.org/meetings 23rd Annual National Interdisciplinary Breast Cancer Conference March 23-27 • Las Vegas, Nevada For more information: www.breastcare.org/

66th Urological Society of Australia and New Zealand Annual Scientific Meeting April 13-16 • Melbourne, Australia For more information: www.usanz2013.com/ International Society for Extracellular Vesicles 2013 Conference April 17-20 • Boston, MA For more information: www.isevmeeting.org 3rd ITLT Essen 2013 Interdisciplinary Treatment of Liver Tumors April 18-20 • Essen, Germany For more information: www.itlt.org Ultrasound in the New Millennium: The Cancer Patient April 19-20 • Houston, Texas For more information: www.mdanderson.org/conferences 7th Conference on Experimental and Translational Oncology April 20-24 • Portoroz, Slovenia For more information: www.ceto.si Highlights of ASH® in Latin America April 25-26 • Santiago, Chile For more information: www.hematology.org/meetings

May 5th IMPAKT Breast Cancer Conference May 2-4 • Brussels, Belgium For more information: www.esmo.org

April

Precision Medicines in Breast Cancer May 9-10 • London, United Kingdom For more information: www.precisionmedicines.com

IGCS Regional Meeting on Gynecologic Cancers April 11-13 • Bali, Indonesia For more information: www2.kenes.com/igcs2013

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

The Psychological Impact of Cancer for Patients, Carers, and Families May 15 • Milton Keynes, United Kingdom For more information: www8.open.ac.uk/health-and-socialcare/main/research/research-events/ psychological-impact-of-cancer Iowa Oncology Society Spring Membership Conference May 17-18 • West Des Moines, Iowa For more information: www.ios-iowa.com State of the Art Techniques Symposium May 17-19 • San Antonio, Texas For more information: www.astro.org/ stateofthearttechniques Targeting Cancer Drug Resistance May 28-30 • Chicago, Illinois For more information: www.cancer-drugresistance.com/ The Bone Marrow Niche, Stem Cells, and Leukemia: Impact of Drugs, Chemicals, and the Environment May 29-31 • New York, New York For more information: www.nyas.org/bonemarrow Interventional Oncology Sans Frontières May 29-June 1 • Cernobbio, Italy For more information: www.iosfc2013.org 13th World Congress of the European Association for Palliative Care May 30-June 2 • Prague, Czech Republic For more information: www.eapc-2013.org 2013 ASCO Annual Meeting May 31-June 4 • Chicago, Illinois For more information: www.asco.org

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2013 Oncology Meetings June 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

MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes.com

Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org 11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

September 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

Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences

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

15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

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/

Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

October

Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org

Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/About+ASCO/ International+Affairs/International+Cli nical+Trials+Workshops 4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in 18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18

July Up Close and Personalized: The 2nd International Congress on Personalized Medicine July 25-28 • Paris, France For more information: www.upcp.org

ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu

ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13 Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences

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

November

EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de 9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: http://www. ncri.org.uk/ncriconference/ Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro

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

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

6.1-Month Improvement in Median IRF†-Assessed PFS1 Placebo + Herceptin + docetaxel 100

• Consistent PFS results were observed across a broad range of patient subgroups • At the time of analysis, there were 191 (47.5%)

90

1

•

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

80 70

18.5 MONTHS

60 PFS (%)

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

PERJETA + Herceptin + docetaxel

50

12.4 MONTHS

40 30 20 10 0

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

0

5

10

15

402 406

345 311

267 209

139 93

20

25

30

35

40

32 17

10 7

0 0

0 0

MONTHS P+H+D Pl+H+D

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.

For more information, scan the QR code or visit www.PERJETA.com.

• •

© 2012 Genentech USA, Inc.

All rights reserved.

PER0001010501

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.

(09/12)

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

PERJETA is a trademark of Genentech, Inc. 6/12 PER0000999400 © 2012 Genentech, Inc. 10139000

ASCOPost.com | FEBRUARY 15, 2013

PAGE 91

In the News Physician-Patient Communication

Keeping Diabetes under Control Is Critical to Good Outcomes for Patients Who Also Have Cancer

By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit.

This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

C

ancer and diabetes can be comorbid diseases, but often they are not comanaged. Patients may “put their diabetes on the back burner” and focus on what they perceive as the most immediate and lethal threat of cancer, according to June M. McKoy, MD, MPH, JD, MBA, Director of Geriatric Oncology for Robert H. Lurie Comprehensive Cancer Center and Associate Professor of Medicine at Northwestern University Feinberg School of Medicine in Chicago. Patients with cancer need to know “that keeping their diabetes under control is critical to a good outcome on both fronts,” Dr. McKoy told The ASCO Post.

June M. McKoy, MD, MPH, JD, MBA

“Patients also need to be educated that cancer is not the killer that some people think it is,” Dr. McKoy said. “We have so many survivors of cancer, but especially older persons still labor under the belief that cancer is very bad, and once you say the word cancer, their lives stop right at that second. It takes a while for them to refocus, but even when they refocus, if you do not start educating them, patients just don’t do that well.”

Education Underutilized Dr. McKoy was recently interviewed for an article in The New York Times1 about a study looking at the effects of diabetes education on individuals with diabetes-cancer comorbidity.

“Individuals who received diabetes education were more likely to have regular outpatient follow-up (HbA1c

testing), which resulted in fewer hospitalizations, lower health-care expenditures, and fewer [emergency department] visits,” according to the study, published by Population Health Management.2 Dr. McKoy, supported by a grant from the National Institutes of Health/National Cancer Institute, was the senior author of that study, and Lauren Irizarry, a 4th-year medical student working with Dr. McKoy and supported by the Northwestern University Feinberg Medical Student Summer Research Program, was the lead author.

Despite the potential benefits of diabetes education, it is often underutilized. In the study described above, which included members of commercial and Medicare Advantage health plans from a private national database of payer data, only 3.5% of individuals with diabetes-cancer comorbidity participated in diabetes education.

The Cancer-Diabetes Connection “Cancer and diabetes are diagnosed within the same individual more frequently than would be expected by chance, even after adjusting for age,” according to a consensus report of experts jointly assembled by the American Cancer Society and the American Diabetes Association and published in Diabetes Care.3 The report cites evidence suggesting that people with diabetes have a significantly higher risk of developing some forms of cancer, particularly cancers of the liver, pancreas, and endometrium, and to a lesser degree of the colon and rectum, breast, and bladder. “Results of some, but not all, epidemiological studies suggest that diabetes may significantly increase mortality in patients with cancer,” according to the consensus report.

“Diabetes itself causes certain changes at the cellular level that we believe actually makes one prone to cancer,” Dr. McKoy said. “Oftentimes diabetes is a precursor to pancreatic cancer, and since pancreatic cancer is more common in older persons (the majority of cases being diagnosed between ages 65 and 79), for select older patients with no family history of cancer who present with diabetes, I often will do a screening ultrasound See Page 97 of the pancreas to

Expect Questions from Patients with Diabetes and Cancer

P

atients with diabetes and cancer need to know that some chemotherapy drugs and adjuvant agents may require modifications in how they manage their diabetes. For example, patients who are receiving steroids might have to further restrict their diet to keep blood sugar levels under control.

“You might have to increase the dose of your insulin. You might have to increase the dose of any oral drug you’re taking for diabetes,” said June McKoy, MD, MPH, JD, MBA, Director of Geriatric Oncology for Robert H. Lurie Comprehensive Cancer Center and Associate Professor of Medicine at Northwestern University Feinberg School of Medicine in Chicago.

Insulin Advice Patients who are on insulin while receiving chemotherapy should also be advised that if they are not feeling well, eating well, or keeping their food down, they should be cutting their insulin dose, or holding it for a day if they are not eating at all. “There are patients who don’t know that,” Dr. McKoy said, “so they continue to take the medication, and they end up in the hospital almost in a coma because their glucose has dropped to 30 mg/dL.” Once a patient with diabetes receives a diagnosis of cancer, it is critical that the patient be referred back to a diabetes educator for “a refresher course, but in the context of cancer,” Dr. McKoy said. “The diabetes educator will remind patients that when they are throwing up, they shouldn’t take the medication, or when they are doing well and taking a steroid, they need to check their sugars more often. If they think it is out of control, they can call their doctor and say, ‘You have me on 20 units of insulin; I want to let you know that I have increased my insulin to 22 units because my sugars are running higher since my cancer doctor has me on a steroid.’”

Need for Partnership Dr. McKoy added, “There needs to be a partnership, and I think diabetes educators are critical to care in these circumstances. They will give directions to patients and tell them that they have to have close contact with their primary care doctor, because many times patients don’t see their primary care doctor once they are diagnosed with cancer. They stick with their oncologist only,” she said.

“To be fair, we want the oncologist to do a lot of things, but it is very difficult,” she continued. “We are trying to get oncologists to start thinking, ‘When I have a patient with diabetes and cancer, I have to give her guidance.’ That guidance may not be specific advice on how to treat the diabetes, but it might be that the patient needs to follow it closely with her primary care doctor.” n make sure that they have no existing mass.

Nevertheless, I am not advocating routine ultrasound screening for pancreatic cancer in a­ symptomatic persons.”

Concern about Chemotherapy Oncologists and their patients should be aware of the effects of some chemotherapy agents on diabetes. “I think it is a major concern because chemotherapy is toxic by its very nature,” Dr. McKoy said. “One of the side effects of many of these toxic therapies is that they can affect the kidney. Carboplatin can cause kidney damage,” she said. “A very popular, very good drug for diabetes is metformin, which is metabolized through the

kidney,” Dr. McKoy noted. “So you have two drugs competing, going through the kidney, and you can have further kidney damage to patients. That is certainly a problem,” Dr. McKoy said.

“Carboplatin is a drug commonly used for ovarian and lung cancers,” she continued. “Carboplatin causes so much renal toxicity and one has to be careful, especially in older populations, how it is dosed. Older people tend to have decreased lean muscle mass, and if you dose it using creatinine, you’re going to overdose a patient, so you have to dose it using creatinine clearance. But I think oncologists today are doing a much betcontinued on page 93

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PAGE 93

In the News

Diabetes and Cancer continued from page 91

ter job with how they dose carboplatin.”

Cancer and diabetes drugs can also “compete for metabolic space” in the liver, leading to serious liver problems, Dr. McKoy said.

“Doxorubicin is cardiotoxic,” she noted. “So patients with diabetes— which affects the vascular system, including the heart, so terribly—who don’t keep their diabetes under control are not going to have a heart that is strong enough to endure treatment with a drug like doxorubicin.”

Steroids can also cause problems.

High-dose dexamethasone for patients with brain cancer and premedication with prednisone for patients receiving chemotherapy can “send blood sugar levels through the roof if somebody isn’t keeping an eye on that,” Dr. McKoy said.

She noted that she did not know of any diabetes drugs that interfere with cancer treatment.

Who Is Watching Out for the Diabetes?

“When a patient gets cancer, the oncologist becomes the perceived primary care doctor,” Dr. McKoy said. “Patients will spend most of their time in the cancer clinic seeing an oncologist or an advanced practice nurse whose specialty is oncology. They rarely will see their primary care doctor. The oncologist is extremely busy. Who is watching out for the diabetes? You can see where we need someone else to step in.”

At Northwestern, that person is a certified diabetes educator. “If you educate patients, they know what to look for,” Dr. McKoy said. “Diabetes should be seen as a self-management disease. Patients

should be trained to manage their own diabetes. The doctor is just a facilitator.

Patients need to know how and when to check their sugars, and when to call in when something isn’t right. They need to know how to regulate their diet.”

For patients who have diabetes and then get cancer, Dr. McKoy refers them to a refresher course. It may have been 1, 2, or even 10 years since the patient was first diagnosed with diabetes and seen by a diabetes educator.

“The oncologist who diagnoses them or even the primary care doctor often does not send them back for diabetes education,” Dr. McKoy said. “But I do.

Patients with a comorbid illness are grappling with two important diseases, and if they don’t get that refresher to remind them that this one is as critical as the one that you have just been told about, they are going to ignore the diabetes.”

Double-front Approach Like other patients with diabetes, those who also have cancer are referred

Shout-out to Policymakers on Diabetes Education

“I

f we could just give a shout-out to policymakers to understand that in the long term,” when patients who have diabetes and cancer receive adequate diabetes education, “we are cutting our length of stay, we are decreasing hospital costs, we are decreasing readmission rates,” June McKoy, MD, MPH, JD, MBA, Director of Geriatric Oncology for Robert H. Lurie Comprehensive Cancer Center in Chicago, said in an interview with The ASCO Post.

Patients with cancer and diabetes, whether they have Medicare or other health insurance, should be covered for diabetes education, she said. While it is sometimes covered now for a short period of time, Dr. McKoy said that insurers “should be more liberal with diabetes education. In the long run, it is much cheaper than the morbidity and mortality you get when patients don’t take care of their diabetes and cancer. Alternatively, you have increased costs to the system in terms of hospitalizations, increased readmission rates, and all the downstream drugs needed to get someone well in the hospital.” n talk about is the fact that diabetes does suppress the immune system, so patients with diabetes are prone to getting certain infections, like pneumococcal pneumonias, and that is why we always give patients with diabetes the pneumococcal

Patients with a comorbid illness are grappling with two important diseases, and if they don’t get that refresher to remind them that [diabetes] is as critical as [cancer], they are going to ignore the diabetes.

—June McKoy, MD, MPH, JD, MBA

to a dietitian for help with diet modifications. “What our dietitians do is a double-front approach. They are helping patients modify their diet not only to keep their sugars controlled, but also to boost their immune system to fight this cancer,” Dr. McKoy said.

“One thing that many people never

IMPORTANT VIDEO HIGHLIGHTS FROM

vaccine. So you have two suppressive actions going on—one with cancer, one with diabetes,” Dr. McKoy stated.

“We try to let our patients know that while they are not feeling anything with their diabetes, it is slowly destroying their bodies, and they need to really fight to survive both the diabetes and the

new-onset cancer,” Dr. McKoy said. “I have seen the light bulb go off when you tell them that diabetes is a silent killer and that cancer can often be cured or turned into a chronic disease with which you can live for a long, long time. We tell them, “Don’t give up; you can do this.

We are here. We are partnering with you.

Call us.” You can see the relief on patients’ faces, and they tend to do well.” n

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

References 1. O’Connor A: Juggling diabetes and cancer. New York Times, December 31, 2012.

2. Irizarry L, Li QE, Duncan I: Effects of Cancer Comorbidity on Disease Management: Making the Case for Diabetes Education (A Report from the SOAR Program). Population Health Management.

October 31, 2012 (early release online).

3. Giovannucci E, Harlan DM, Archer MC: Diabetes and cancer: A consensus report. Diabetes Care 33:1674-1685, 2010.

ASH 2012

Dr. James Armitage, Editor-in-chief of The ASCO Post, interviews leading experts:

Dr. Richard Fisher on lymphomas

Dr. Hagop Kantarjian on leukemias

Presented by The ASCO Post. Recorded at ASH 2012 in Atlanta, Georgia Visit ASCOPost.com to view webcast program

Dr. Sagar Lonial on multiple myelomas

The ASCO Post | FEBRUARY 15, 2013

PAGE 94

In the Literature

Emerging Clinical Data on Cancer Management RECTAL CANCER Even at NCCN Institutions, a ‘Sizable Minority’ of Patients with Rectal Cancer Are Not Treated per NCCN Guidelines

Even at the eight cancer centers participating in the National Comprehensive Cancer Network (NCCN) Colorectal Cancer Outcomes project, a “sizable minority” of patients with stage II/III rectal cancer treated with curative

intent neoadjuvant chemoradiotherapy did not complete postoperative chemotherapy, according to a study published in the Journal of Clinical Oncology.

“Current NCCN Colorectal Cancer Guidelines recommend completion of

a 6-month course of adjuvant chemotherapy for patients with stage II/III rectal cancer,” noted Polina Khrizman, MD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, and coauthors.

Underlying Reasons

Read the Expert’s Guide to the

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How can your patients navigate these changes while staying on treatment and maintaining some quality of life?

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The study analyzed data for 1,193 patients with stage II/III rectal cancer receiving neoadjuvant chemoradiotherapy.

Among the 203 patients (17%) not receiving any adjuvant chemotherapy, 67% were seen by a medical oncologist postoperatively, 20% were not, and it was unknown whether the remaining 13% were or were not seen by a medical oncologist.

The most frequent reason chemotherapy was not recommended for patients seen by a medical oncologist was comorbid illness (25 of 50 patients, 50%). Other reasons cited were therapy not indicated, older age, disease recurrence, and death.

The most frequent reason chemotherapy was not received when recommended or discussed was patient refusal (54 of 74, 73%). Other reasons were recurrence before treatment was administered, no treatment documented at 12-month assessment, death, and transfer to another center. Factors significantly associated with not receiving adjuvant chemotherapy were age, Eastern Cooperative Oncology Group performance status ≥ 1, on Medicaid or indigent, complete pathologic response, reoperation/wound infection, and no closure of ileostomy/colostomy.

Khrizman P, et al: J Clin Oncol 31:3038, 2013.

NEUROBLASTOMA Surgery of Primary Tumor Site Has No Impact on Local Control and Outcome in Patients ≥ 18 Months with Stage IV Disease

Available at:

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drlacoutureskincare.com

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.

“In intensively treated patients with stage IV neuroblastoma age 18 months or older at diagnosis, surgery of the primary tumor site has no impact on local control rate and outcome,” according to findings from the German prospective clinical trial NB97. “The results of the study,” the researchers concluded in an article in the Journal of Clinical Oncology, “do not justify aggressive surgery in patients undergoing high-intensity multimodal treatment for metastatic neuroblastoma. Thus, the concept of accepting incomplete resection to avoid serious complications proved suc-

ASCOPost.com | FEBRUARY 15, 2013

PAGE 95

In the Literature

cessful, as evidenced by analyses of the data from the NB97 trial.”

Study Details NB97 was a randomized trial comparing autologous stem-cell transplantation and oral maintenance therapy.

Data on extent and complications of resection were collected prospectively.

The researchers distinguished between two types of operations: “first operation was the tumor operation performed before induction chemotherapy, and best operation was the most extensive removal of primary tumor tissue done at any time during first-line therapy.”

The data from 278 patients who had stage IV neuroblastoma and were 18 months or older showed that whether patients had complete resection, incomplete resection, biopsy, or no surgery before chemotherapy, the “extent of first operation had no impact on event-free survival (P = .207), local progression–free survival (P = .195), and overall survival (P = .351),” the researchers reported. “After induction chemotherapy, 54.7% of patients underwent complete resection of the primary tumor, 30.6% underwent incomplete resection, and 13.3% had only biopsy or no surgery of the primary tumor,” they continued.

The most extensive removal of primary tumor tissue was done during the first operation in 61 patients (21.9%) and later in 212 patients (76.3%). “The extent of best operation also had no impact on [event-free survival] (P = .877), [local progression–free survival] (P = .299), and [overall survival] (P = .778),” the investigators stated. “Moreover, multivariate analyses showed that surgery did not affect [event-free, local progression–free, and overall] survival.”

Adverse Events Complications during surgery occurred among 64 patients (23%). “At first operation, 16 patients developed relevant intraoperative bleeding (5.8%), nine patients had intestinal obstruction after resection of abdominal neuroblastoma (3.2%), and nine patients experienced postoperative local or systemic infections (3.2%),” the researchers reported. Although the trial protocol discouraged nephrectomy, it was performed in eight patients during first operation (2.9%) and in 18 patients (6.5%) during best operation. “During best operation, relevant bleeding occurred in 26 patients (9.4%), postoperative intestinal obstruction occurred in 14 patients (5.0%), and postoperative local or systemic infec-

tions occurred in 17 patients (6.1%). Nephrectomy was performed in 18 patients (6.5%),” the investigators wrote.

“Combining the results of this study with those from the literature clearly shows that aggressive surgery has a limited impact, if any, on the outcome of high-risk neuroblastoma,” the researchers concluded. “However, future trials are required to determine whether even less surgery might be adequate in highintensity multimodal treatment of metastatic neuroblastoma and if biologic factors are correlated with the resectability of the primary tumor.”

Simon T, et al: J Clin Oncol. January 2, 2013 (early release online).

CHEMOTHERAPY COMPLICATIONS Failure to Screen Patients for Hepatitis B Virus Could Result in Fatal Complications Although hepatitis B virus (HBV) reactivation is a potentially fatal complication of chemotherapy, “provided that HBV carriers are recognized, HBV reactivation can be largely prevented through the administration of oral antinucleoside analogs,” researchers at the University of Toronto noted in an article in the Journal of Oncology Practice. However, a survey they conducted among practicing hematologists/oncologists in Canada revealed that many respondents often underestimated the risk of HBV reactivation, and their “knowledge regarding risk factors for HBV carriage seems to be low, potentially undermining the success of a selective screening strategy,” the researchers reported.

“Current guidelines recommend HBV screening before chemotherapy, although there are some discrepancies among published recommendations,” the investigators wrote. “Infectious disease and hepatology bodies recommend universal screening, whereas the lead oncology society recommends consideration of targeted testing of high-risk individuals. Targeted testing is predicated on the assumption that physicians are aware of the risks of HBV reactivation and able to identify those at highest risk of HBV carriage.” The survey results showed, however, that only 33% identified the major risk factor for HBV—birth in an endemic area—and only 2% correctly identified all continents having HBV endemic regions.

The authors estimated that approximately 0.3% to 0.5% of the population in the United States and 2% of the popu-

lation in Canada are affected by HBV. “Reactivation hepatitis is associated with substantial morbidity and mortality,” they reported. “Estimates of the risk of reactivation in asymptomatic HBV carriers range from 20% to more than 70% depending on tumor type and chemotherapy administered. Risk factors for HBV reactivation include high HBV viral load before treatment, HBeAg positivity, young age, treatment of hematologic malignancies, use of glucocorticoids, use of rituximab [Rituxan], and bone marrow/ hemapoeitic stem-cell transplantation.”

Contributors to Low Screening Levels Physicians responding to the survey “tended to underestimate the risk of HBV reactivation in both solid and hematologic tumors. For instance, most respondents estimated the risk of HBV reactivation in patients receiving chemotherapy for a hematologic malignancy as being less than 30%, whereas the literature suggests that the actual risk is greater than 50% in this population,” the researchers noted.

“Slightly more than half of respondents (58%) reported screening for HBV before chemotherapy (36% employed selective screening; 22% employed universal screening). Forty percent of respondents never or rarely screened their patients,” the authors wrote. “The most commonly cited reasons for not testing were a perception that HBV incidence was low in the

respondent’s practice, and a perceived absence of guidelines or evidence recommending HBV testing. Only 27% of respondents indicated that they were aware of existing guidelines regarding HBV screening before chemotherapy,” the researchers stated.

“A similar study was conducted in the United States involving oncologists registered with the American Medical Association,” the researchers reported. “Although limited by a low response rate (5%), it showed similar findings: 20% of respondents reported never screening patients for HBV before chemotherapy, 38% reported only screening in the presence of abnormal liver biochemistry results, and 30% reported screening in the presence of risk factors or a known history of hepatitis.

Lee RSM, et al: J Oncol Pract 8:325-328, 2012.

MELANOMA Tremelimumab Not Better Than Standard-of-care Chemotherapy in Patients with Advanced Melanoma Tremelimumab did not produce a statistically significant advantage in overall survival compared to first-line standard-of-care chemotherapy in a phase III randomized trial reported in the Journal of Clinical Oncology. At final analysis, median overall survival by intent to treat was 12.6 months (95% con-

© Joe Dator/The New Yorker Collection/www.cartoonbank.com

continued on page 96

The ASCO Post | FEBRUARY 15, 2013

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In the Literature

Emerging Clinical Data continued from page 95

fidence interval [CI] = 10.8–14.3) for tremelimumab vs 10.7 months (95% CI = 9.36–11.96) for chemotherapy (hazard ratio [HR] = 0.88, P = .127).

“Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the che-

motherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 vs 13.7 months; P = .0011),” the researchers reported.

“The durable responses seen in this trial confirm that a subset of patients may derive benefit from treatment with tremelimumab,” the authors added.

“Prolonged responses in a minority of patients were consistent with the effect of other types of immunotherapy, such as high-dose interleukin-2 [Proleukin].

Subset analysis by predefined baseline demographic and disease factors did not identify a factor that selects for benefit from tremelimumab compared with chemotherapy.”

All of your

Oncology News...

Novel Agent Tremelimumab (CP-675206) is a cytotoxic T lymphocyte–associated antigen-4–blocking monoclonal antibody that induced durable responses in a subset of patients with advanced melanoma in phase I/II trials. In this phase III study, patients ≥ 18 years of age with treatmentnaive, unresectable stage IIIC or IV melanoma were enrolled at 114 sites in 24 countries and randomly assigned to receive tremelimumab at 15 mg/kg once every 90 days, or physician’s choice of standard-of-care chemotherapy with temozolomide (Temodar) or dacarbazine.

The most common treatment-related adverse events related to tremelimumab were diarrhea, pruritus, and rash. The only grade 3 or higher treatment-related adverse events occurring in ≥ 10% of patients were diarrhea, reported in 14% of those taking tremilumumab, and neutropenia, reported in 10% of those receiving chemotherapy. Seven deaths occurring among patients taking tremelimumab and one death of a patient receiving chemotherapy were considered treatment-related.

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“Since the trial described in this report was initiated, the standard of care for melanoma has changed,” the authors noted. Ipilimumab (Yervoy), a CTLA4blocking IgG1 monoclonal antibody, and the BRAF inhibitor vemurafenib (Zelboraf) “have recently been approved in several countries, including the United States, the European Union, and Australia,” the investigators wrote.

Two phase III trials have also demonstrated a survival advantage for patients with metastatic melanoma who took ipilimumab. The tremelimumab study investigators pointed out that during the conduct of their trial, ipilimumab became widely available to patients in the comparator group, both in clinical trials and through a worldwide expanded-access program.

“Use of CTLA4 blockade in both arms of this study could have decreased the power of the study to demonstrate a statistically significant difference in survival and biased the estimates of survival in the control arm,” they asserted.

“Patient selection, dosing regimen, and use of another CTLA4-blocking agent (ipilimumab) as salvage therapy for patients in the comparator arm may explain the differences between the results of this phase III trial and those of two positive phase�������������������������� ������������������������� III trials with ipilimumab,” the authors concluded. n Ribas A, et al: J Clin Oncol. January 7, 2012 (early release online)

ASCOPost.com | FEBRUARY 15, 2013

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Perspective

Gemtuzumab for AML continued from page 1

tuzumab in the treatment of patients with acute promyelocytic leukemia (APL).1 A significant number of clinical trials have clearly established the activity of gemtuzumab in patients with APL, both in the front-line and relapse settings.

The argument against its use is that APL is now highly curable using all-trans retinoic acid, arsenic trioxide (Trisenox), and anthracyclines, and we can do without gemtuzumab.4 However, the advantages of a “chemotherapy-free” regimen are becoming more apparent, with recent trials demonstrating the superiority of such regimens in low-risk APL and the effectiveness of gemtuzumab in replacing anthracyclines in high-risk patients, thereby avoiding the well described risk of late cardiomyopathy.5,6 Several recent large prospective randomized clinical trials have shown that the addition of a small dose of gemtuzumab to cytarabine and anthracycline-based induction and consolidation provides a survival advantage to patients with core-binding factor leukemias. In randomized trials by the Southwest Oncology Group (SWOG) and the UK’s Medical Research Council (MRC) analyzing the subset of core-binding factor AML, the addition of gemtuzumab was associated with significantly improved survival.7,8 Furthermore, accumulating data have shown the benefit of gemtuzumab in intermediate-risk AML, both in younger patients (MRC study7) and older patients (French

study9), when added to chemotherapy. Thus, in an era of personalized and targeted therapy, it seems illogical to withdraw gemtuzumab, the only agent newly approved for the treatment of AML in the past 15 years.

This is particularly of concern when many new agents in various solid tumors have been approved with only limited benefits in progression-free survival with or without survival benefits. In renal cell cancer alone, the FDA approved seven agents between 2005 and 2012 based on improvements in progression-free survival, with survival improvement for only one of those drugs, temsirolimus (Torisel).

Also, in contrast to solid tumors, where the market share of new targeted agents can represent billions of dollars, the total market share of gem-

Farhad Ravandi, MD

zumab in AML subsets, does it justify the reversal of the decision in a relatively uncommon disease with a relatively favorable prognosis? The answer is a resounding yes.

In the past century, we have witnessed significant progress in medicine leading to a gradual but steady rise in life expectancy and quality of life in the industrialized world. With the exception of a few notable giant leaps, such progress has been accomplished

In an era of personalized and targeted therapy, it seems illogical to withdraw gemtuzumab, the only agent newly approved for the treatment of AML in the past 15 years.

—Farhad Ravandi, MD, Jorge Cortes, MD, and Hagop Kantarjian, MD

tuzumab at the time of its withdrawal was only $20 million annually. This raises the question of whether economic considerations dominated the decision, discouraging Pfizer from stronger efforts to keep gemtuzumab available in the U.S. market.

Important Step Forward The question that arises then is, even if we accept the benefit of gemtu-

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

mainly through incremental steps.

What may be considered minimal progress in clinical trials, such as improvements in survival of a few months, can lead, over the long haul, to meaningful improvements in life expectancy. The reintroduction of gemtuzumab would likely benefit only a subset of patients with AML, but it remains an important step toward curing leukemia.

Jorge Cortes, MD

Hagop Kantarjian, MD

Resurrected Agents In the history of medicine, few drugs have been worthy of the label ”Lazarus-like,” having been resurrected from obscurity to full FDA approval, usually for indications unrelated to the ones for which they were previously used. Thalidomide (Thalomid), a drug originally developed and used as a sedative, was withdrawn by the FDA, only to be re-introduced for a variety of indications such as mouth ulcers, leprosy, and, most recently, multiple myeloma.10 Arsenic trioxide was used at the turn of the 20th century for a variety of ailments as a component of Fowler’s solution. Its reappearance in Western medicine was largely due to the demonstration of its significant activity in relapsed APL by Chinese investigators.11 The recent approval of omacetaxine mepesuccinate (aka homoharringtonine [Synribo]) in advanced chronic myelogenous leukemia is another example of a drug abandoned after prior significant enthusiasm, only to be resurrected for special indications.12

Closing Thoughts Clearly, we are making progress in continued on page 98

1

When you see a code that you would like to scan, start your code-reading application.

2

The code will scan automatically.

3

Position your device in front of the code so that it fills about half your screen.

4

If the scan is successful, you will be rerouted to the targeted link.

T:10.25" S:9.5" PAGE 98

The ASCO Post | FEBRUARY 15, 2013

Perspective

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Gemtuzumab for AML continued from page 97

treating various cancers through better understanding of the mechanisms of carcinogenesis and identification of targets for drug development. A great deal of enthusiasm has been generated in favor of targeted and personalized therapies for increasingly smaller subsets of patients with different cancers. Such examples are numerous and include the use of RAF inhibitors in BRAF-mutated melanoma, monoclonal antibodies in various lymphoid malignancies, ALK inhibitors in ALK-positive lymphomas and lung cancer, and so forth.

In this exciting era, it seems anachronic that gemtuzumab would be withdrawn from the United States as a treatment for AML. We therefore renew our call for restoration of gemtuzumab ozogamicin as a treatment option for patients with AML. n Disclosure: Drs. Ravandi, Cortes, and Kantarjian reported no potential conflicts of interest.

References 1. Ravandi F, Estey EH, Appelbaum FR, et al: Gemtuzumab ozogamicin: Time to resurrect? J Clin Oncol 30:3921-3923, 2012.

2. Ravandi F, Kantarjian H: Haematological cancer: Gemtuzumab ozogamicin in acute myeloid leukaemia. Nat Rev Clin Oncol 9:310-311, 2012.

3. Estey E: Treatment of AML: Resurrection for gemtuzumab ozogamicin? Lancet 379:1468-1469, 2012.

4. Iland HJ, Bradstock K, Supple SG, et al: All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 120:1570-1580, 2012.

5. Lo-Coco F, Avvisati G, Orlando SM, et al: ATRA and arsenic trioxide (ATO) versus ATRA and idarubicin (AIDA) for newly diagnosed, non high-risk acute promyelocytic leukemia (APL): Results of the phase III, prospective, randomized,

intergroup APL0406 study by the ItalianGerman Cooperative Groups GimemaSAL-AMLSG. 2012 ASH Annual Meeting. Abstract 6. Presented December 9, 2012.

6. Ravandi F, Estey E, Jones D, et al: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin.

J Clin Oncol 27:504-510, 2009.

7. Burnett AK, Hills RK, Milligan D, et al: Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: Results of the MRC AML15 trial. J Clin Oncol 29:369-377, 2010.

8. Petersdorf S, Kopecky K, Stuart RK, et al: Preliminary results of Southwest Oncology Group Study S0106: An international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia. Blood (ASH Annual Meeting Abstracts) 114:Abstract 790, 2009.

9. Castaigne S, Pautas C, Terre C, et al: Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): A randomised, open-label, phase 3 study. Lancet 379:1508-1516, 2012.

10. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999.

11. Shen ZX, Chen GQ, Ni JH, et al: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89:3354-3360, 1997.

12. Cortes J, Lipton JH, Rea D, et al: Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 120:2573-2580, 2012.

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Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy.

Avastin in combination with fluoropyrimidine‑irinotecan or fluoropyrimidine‑ oxaliplatin based chemotherapy is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).]

1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls.

The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).

[See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

• Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin.

Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.

"

T:10.25" S:9.5" AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.

In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3.

Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

(approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs.

19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients).

The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.

In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone.

The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%).

Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs.

5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs.

1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs.

13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs.

3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs.

2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

a

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown.

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

In Study 2, patients aged ≥65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥65 years (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility.

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations.

Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

01/13 AVA0000765904 10136665 Initial U.S. Approval: February 2004 Code Revision Date: January 2013 Avastin® is a registered trademark of Genentech, Inc. © 2013 Genentech, Inc.

S:12.5"

Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8.

The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8).

[See Warnings and Precautions (5.8).]

Arm 2 IFL+ + Avastin (n = 392) 87%

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Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%).

Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

a

Arm 1 IFL+ + Placebo (n = 396) 74%

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

NOW APPROVED: Avastin continued beyond first progression in MCRC In combination with fluoropyrimidine-based chemotherapy following a first-line Avastin-containing regimen...

Think Avastin

Continuing to deliver proven overall survival The only biologic to prospectively demonstrate significant overall survival (OS) in a Phase III MCRC trial after treatment with a first-line Avastin-containing regimen1 Median OS:

Percentage Surviving

100

11.2 vs 9.8 months

(HR=0.81 [95% CI, 0.69–0.94], P=0.0057)

80 60

Avastin + fluoropyrimidine-based chemotherapy* (n=409) Fluoropyrimidine-based chemotherapy* alone (n=411)

40 20 0

12

24 OS (Months)

36

48

*Chemotherapy combinations included both irinotecan- and oxaliplatin-containing regimens.

At first progression, chemotherapy was switched: oxaliplatin→irinotecan or irinotecan→oxaliplatin.1

1.7-month increase in median PFS beyond first progression with Avastin plus fluoropyrimidine-based chemotherapy*: 5.7 vs 4.0 months with fluoropyrimidine-based chemotherapy* alone (HR=0.68 [95% CI, 0.59–0.78], P<0.0001)1 There was no significant difference in response rate1

MCRC=metastatic colorectal cancer; HR=hazard ratio; CI=confidence interval; PFS=progression-free survival.

Indications

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidineoxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%)

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Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Across all studies, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

When continued beyond first progression in MCRC, no new safety signals were observed in Study ML18147 when Avastin was administered in second-line MCRC patients who progressed on an Avastin-containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at (888) 835-2555.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Reference: 1. Avastin Prescribing Information. Genentech, Inc. January 2013.

(01/13)

www.avastin.com