TAP Vol 3 Issue 17 by Harborside Press LLC

Nab-paclitaxel for NSCLC

44, 47

| Affordable Cancer Care

| Obesity and Cancer

VOLUME 3, ISSUE 17

102

NOVEMBER 15, 2012

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

35th ESMO Congress

Updated Results from T-DM1 and Regorafenib Trials, plus Other Highlights from ESMO 2012

ASCOPost.com

Who Should Receive First-line BEACOPP Therapy for Hodgkin Lymphoma?

By Alice Goodman and Caroline Helwick

By Andreas Engert, MD

he 35th European Society for Medical Oncology (ESMO) Congress in Vienna broke all records for attendance, with about 16,000 attendees from all over the world. Some sessions were standing room only, including the Presidential Symposia, the Sunil Verma, MD ESMO-ASCO Joint Symposium on genomics in breast cancer, and the Special Session on melanoma. To complement our more comprehensive news coverage of key ESMO presentations, additional studies of interest are summarized below.

New Data from EMILIA The novel drug-antibody conjugate T-DM1 ex-

tended survival compared with chemotherapy in women with advanced HER2-positive breast cancer in an updated analysis of the phase III EMILIA trial presented by lead author, Sunil Verma, MD, Sunnybrook Odette Cancer Center, Toronto, Canada.1 Women randomly assigned to T-DM1 were 32% less likely to die, compared with the group randomly assigned to lapaSee Page 108 tinib (Tykerb) plus capecitabine (Xeloda), the reference arm. Median overall survival was 30.9 months in the T-DM1 arm vs 25.1 months in the lapatinib/ capecitabine arm. The absolute 6-month difference in survival between the two arms was highly statistically significant (P < .0001). “These are some of the best survival data reported continued on page 8

Issues in Oncology

Seeking Solutions to the Dilemmas of Overdiagnosis and Overtreatment

odgkin lymphoma has become one of the most curable malignancies, due to substantial improvements in radiotherapy and the introduction of multiagent chemotherapy. Hodgkin lymphoma survivors constitute one of the largest groups of cancer survivors in Western countries. Depending on the choice and dose of treatment, these patients face some risk of treatment-related toxicities, including secondary neoplasia, organ damage, infertility, and psychosocial problems. Thus, there is an ongoing discussion on the best choice of treatment for these patients. continued on page 86

Dr. Engert is Professor of Internal Medicine, Hematology and Oncology, Department of Internal Medicine I, Cologne University Hospital, Cologne, Germany.

MORE IN THIS ISSUE

By Ronald Piana

idespread use of screening technologies has markedly increased early detection rates of cancer, saving countless lives. However, while screening technologies have remarkable sensitivity, their inability to identify which tumors will progress and which will not has created the phenomenon of overdiagnosing cancers that might otherwise not go on to cause symptoms or deaths, resulting in potentially

unnecessary treatments and burgeoning costs. Over the past several years, due in part to increased scrutiny over rising health-care expenditures; the value of certain cancer screening methods is increasingly being questioned. Laura Esserman, MD, MBA, examined the overdiagnosis dilemma at the ASCO Annual Meeting and offered a prescription for change.1 “Overdiagnosis by itself isn’t the problem; the problem is that we often overtreat cancer, As clinicians, we need to recognize and by doing so, we cause harm and psychological that overdiagnosis occurs, which distress over risk of recurcan lead to overtreatment if rence that is extremely ununrecognized…. [W]e should try doing likely to our patients,” said Dr. Esserman. less and learn from that restrained Dr. Esserman noted that part of the problem clinical behavior. is rooted in the old para— Laura Esserman, MD, MBA

Oncology Meetings Coverage 2012 Breast Cancer Symposium ��18 9th International SIO Conference �� 30 35th ESMO Congress �� 34, 40 11th International Kidney Cancer Symposium ��53 Adjuvant Chemotherapy for Breast Cancer �� 42 Direct from ASCO ��51 FDA Update �� 2, 20, 58, 61 Androgen Suppression for Prostate Cancer �� 62 Getting into an Oncology Fellowship �� 94 In Memoriam: E. Donnall Thomas, MD �� 115

continued on page 12

November is Lung Cancer Awareness Month

A Harborside Press® Publication

The ASCO Post | NOVEMBER 15, 2012

PAGE 2

FDA Update

FDA Approves Omacetaxine for Chronic Myeloid Leukemia

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

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

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

Philip D. Bonomi, MD Rush University Medical Center

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

Richard Boxer, MD University of Miami

George W. Sledge, MD Indiana University

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

he FDA has approved omacetaxine mepesuccinate (Synribo) to treat adults with chronic myelogenous leukemia (CML) whose cancer has progressed after treatment with at least two tyrosine kinase inhibitors.

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

Douglas W. Blayney, MD Stanford University Medical Center

Robert W. Carlson, MD Stanford University Medical Center

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

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

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

Omacetaxine is injected subcutaneously twice daily for 14 consecutive days over a 28-day cycle until hematologic response is achieved. The agent is then administered twice daily for 7 consecutive days over a 28-day cycle as long as patients continue to clinically benefit from therapy. “Today’s approval provides a new treatment option for patients who are resistant to or cannot tolerate other FDA-approved drugs for chronic or accelerated phases of CML,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research. Omacetaxine is approved under the FDA’s accelerated approval program. The drug also received orphan-product designation by the FDA.

Study Details The effectiveness of omacetaxine was evaluated using a combined cohort of patients whose cancer progressed after previous treatment with two or more tyrosine kinase inhibitors. All participants were treated with omacetaxine. The drug’s effectiveness in chronicphase CML was demonstrated by a reduction in the percentage of cells expressing the Philadelphia chromosome mutation found in most CML patients. Fourteen out of 76 patients (18.4%) achieved a reduction in an average time of 3.5 months. The median length of the reduction was 12.5 months. In the setting of accelerated-phase CML, omacetaxine’s effectiveness was determined by the number of patients who achieved major hematologic response. Results showed 5 out of 35 patients (14.3%) achieved major hematologic response in an average time of 2.3 months. The median duration of major hematologic response in these patients was 4.7 months. The most common side effects reported during clinical studies include thrombocytopenia, anemia, neutropenia, diarrhea, nausea, weakness and fatigue, injection site reaction, and lymphopenia. Omacetaxine is marketed by Teva Pharmaceuticals.

■

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2012 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 26,000 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: $235; Individual International: $290; Institutional Domestic: $290; Institutional International $370. Contact subscriptions@harborsidepress.com.

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PAGE 3

JCO Spotlight Gastrointestinal Oncology

No Survival Benefit for Oxaliplatin Added to Adjuvant Therapy in Stage II or Elderly Patients with Colon Cancer By Matthew Stenger

xaliplatin plus fluorouracil (5FU)/leucovorin or capecitabine (Xeloda) is a standard of care in adjuvant therapy for stage III colorectal cancer. There is ongoing debate about whether any adjuvant therapy is of benefit in patients with stage II disease, and it is not routinely recommended in this patient population. There is also ongoing debate about the role of adjuvant therapy in elderly patients, with some data suggesting that such patients do as well on 5-FU–based therapy as younger patients and do not derive additional benefit from the addition of oxaliplatin to treatment. A post hoc analysis of outcomes in the MOSAIC trial, reported in Journal of Clinical Oncology by Tournigand and colleagues,1 suggests that there

is no benefit in overall or disease-free survival with the addition of oxaliplatin to 5-FU/leucovorin in patients with stage II disease or patients aged 70 to 75 years.

Study Details In the MOSAIC study, a pivotal trial for regulatory approval of oxaliplatin in adjuvant therapy, 2,246 patients were randomly assigned to 5-FU/leucovorin with oxaliplatin (FOLFOX4) or without oxaliplatin. The trial included 889 patients with stage�� II �� disease, including 451 in the FOLFOX4 group and 448 in the 5-FU/leucovorin group. Of these, 569 were high-risk patients, including 282 in the FOLFOX4 group and 287 in the 5-FU/leucovorin group.

Of a total of 315 patients aged 70 to 75 years, 155 were in the FOLFOX4 group and 160 in the 5-FU/leucovorin group. Of the 155 in the FOLFOX4 group, 96 had stage III disease and 59 had stage II disease (18 low-risk, 41 high-risk). Of the 160 in the 5-FU/ leucovorin group, 94 had stage�� III �� disease and 66 had stage II disease (22 low-risk, 44 high-risk). There was no imbalance in baseline characteristics or comorbidities between the stage II or elderly subgroups in the two treatment groups. There was no difference between FOLFOX4 and 5-FU/leucovorin treatment with regard to incidence of serious adverse events in patients with stage�� II disease; among elderly patients, serious adverse events were significantly more

common with FOLFOX4 (P = .018). Median follow-up durations were 63 months for disease-free survival and 80 months for overall survival.

Stage II Disease For all stage II patients, FOLFOX4 was associated with a nonsignificant 16% reduction in risk for recurrence or death from any cause (disease-free survival hazard ratio [HR] = 0.84, P = .26). The interaction test between treatment and risk was not significant (P = .066). Among low-risk stage II patients, 5-year disease-free survival was 86.0% with FOLFOX4 vs 89.3% with 5-FU/leucovorin, representing a nonsignificant 36% increase in risk with FOLFOX4 (HR = 1.36, continued on page 4

EXPERT POINT OF VIEW By John L. Marshall, MD Professor of Oncology and Medicine, Associate Director of Clinical Research, and Director, Experimental Therapeutics and GI Oncology at Georgetown University, Washington, DC

he pendulum continues to swing in the treatment of stage II and III colon cancer. Not 5 years ago, our party line was that essentially all patients should receive 6 months of adjuvant FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin): patients with stage II or III disease, whether rectal or colon cancer, old or young—treat them all the same. And why not? They were all considered to be the same disease, with the same relative risk reduction. If it were not for the neuropathy, the regimen was well tolerated. Might as well offer it, right?

This new report from Tournigand and colleagues is incredibly important and, in my opinion, it is immediately practice-changing. — John L. Marshall, MD

cause the elderly that entered the trials from which we obtained the results were the well elderly, and not the poor performance status patients. So, as the data continue to mature, our enthusiasm falls further.

Analysis of Outcomes Is Practice-changing This new report from Tournigand and colleagues1 is incredibly important and, in my opinion, it is immediately practice-changing. We give too much oxaliplatin relative to its benefit. I interpret these data such that we should no longer give oxaliplatin in patients with stage II disease or the elderly. And, I am hopeful that the current trial comparing 3 months to 6 months of treatment will accrue quickly and give us further support to reduce our treatment duration, further reducing the risk of neuropathy. Oncologists are incredibly enthusiastic about adjuvant therapy. We love to give it, we love to push doses, thinking this will increase cure rates. But, frankly, we must first remember that 5-FU remains the most important drug, that oxaliplatin adds little even in the middle-aged stage III patients, and that we need to look to new strategies to improve outcomes.

■

Disclosure: Dr. Marshall has served as a consultant for and has received honoraria from Genentech and Amgen.

Then things started to shift. The stage II subsets failed to show survival advantages from the addition of oxaliplatin, but many “thought leaders” still insisted that our patients with high-risk stage II cancers and certainly T4 tumors “needed” oxaliplatin. As data in the elderly population began to emerge, thought leaders claimed that we should only avoid oxaliplatin in the poor performance status elderly, and that the well elderly should still get oxaliplatin. Of course, this position does not make sense be-

Reference 1. Tournigand C, André T, Bonnetain F, et al: Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: Subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer Trial. J Clin Oncol 30:3353-3360, 2012.

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

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

The ASCO Post | NOVEMBER 15, 2012

PAGE 4

JCO Spotlight

Oxaliplatin in Stage II Colon Cancer continued from page 3

P = .305). Among high-risk patients, 5-year disease-free survival rates were 82.3% with FOLFOX4 vs 74.6% with 5-FU/leucovorin, representing a nonsignificant 28% reduction in risk (HR = 0.72, P = .063).

leucovorin in overall survival (HR = 1.00, P = .986) and the interaction test between treatment and risk was not significant (P = .343). Sixyear overall survival was 90.2% with FOLFOX4 vs 93.0% with 5-FU/leucovorin in low-risk patients, representing a nonsignificant 36% increase in risk of death with FOLFOX4

Adjuvant Therapy for Colon Cancer ■■ The addition of oxaliplatin to 5-FU/leucovorin improved time to recurrence but not disease-free or overall survival in patients with high-risk stage II colon cancer.

■■ No significant benefit of the addition of oxaliplatin to 5-FU/leucovorin was

observed for disease-free survival, time to recurrence, or overall survival in patients with low-risk stage II disease or patients aged 70 to 75 years.

FOLFOX4 was associated with a significant 30% reduction in risk of recurrence (time to recurrence HR = =�� .045). The interaction test be0.70, P �� tween treatment and risk was not significant (P = .235). FOLFOX4 was not associated with a significantly reduced risk for recurrence in low-risk patients (5-year time to recurrence = 90.8% vs 90.5%, HR = 1.01, P = .972), but was associated with a significant 38% reduction in risk in high-risk patients (5-year time to recurrence = 86.8% vs 78.8%, HR = 0.62, P = .020). There was no significant difference between FOLFOX4 and 5-FU/

(HR = 1.36, P = .399), and 85.0% vs 83.3% in high-risk patients, representing a nonsignificant 9% decrease in risk (HR = 0.91, P = .48).

Elderly Patients Among elderly patients, 5-year disease-free survival was 69.1% with FOLFOX4 vs 65.8% with 5-FU/leucovorin, representing a nonsignificant 9% decrease in risk for recurrence or death with FOLFOX4 (HR = 0.91, =�� .71). Risk of recurrence was nonP �� significantly reduced by 32% (5-year time to recurrence = 78.8% vs 69.9%, HR = 0.68, P = .089). Five-year overall

survival was 75.8% with FOLFOX4 vs 76.1% with 5-FU/leucovorin, representing a nonsignificant 10% increase in risk of death (HR = 1.10, P = .661). Tests for interaction between treatment and age for disease-free survival, time to recurrence, and overall survival were not significant (P = .418, 0.719, and 0.180, respectively). As stated by the authors, “[These] results show that patients with lowrisk stage II colorectal cancer do not benefit from oxaliplatin; in high-risk stage�� II �� patients, oxaliplatin significantly improved time to recurrence without benefit in disease-free survival or overall survival. However, these subgroup analyses should be cautiously considered as exploratory results only. In elderly patients, there was no benefit from oxaliplatin for [time to recurrence], disease-free survival, or overall survival, but the subgroup was small and restricted to patients younger than 76 years. The lack of interaction between treatment and stage or age suggests that the effect of FOLFOX4 compared with 5-FU/leucovorin does not differ according to high vs low risk in stage II patients or according to age.” The investigators also noted that similarities in survival estimates for high-risk stage II patients and elderly patients are in part explained by the overlap in the subgroups, with 40% of

elderly patients having stage II disease and 15% of the stage II patients being older than 70 years.

Conclusions The authors concluded: “The administration of fluoropyrimidines alone remains the standard option for both elderly and selected low-risk stage II patients. According to the MOSAIC subgroup analyses…, the addition of oxaliplatin to infusional 5-FU/leucovorin has not been shown to be beneficial in low-risk or high-risk stage II patients or for patients between 70 and 75 years. The identification of a See Page 108 patient population for which adjuvant therapy is necessary, safe, and effective continues to be challenging, especially for highrisk stage II patients and for elderly patients.”

■

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

Stage II or Elderly Patients with Colon Cancer, by John L. Marshall, MD, see page 3

Donald I. Abrams, MD, on Integrative Medicine and Cancer Management, see page 29

Prophylaxis in Catheterrelated Thrombosis, by Fausto Roila, MD, see page 40

Explaining Research to Patients, by John F. Smyth, MD, see page 83

Getting into an Oncology Fellowship, by Bishoy Faltas, MD see page 94

Rachel Ballard-Barbash, MD, MPH, on Obesity and Cancer Incidence/Prognosis, see page 102

Visit The ASCO Post online at ASCOPost.com

A N E W I N D I C ATI O N

COMING SOON Please see adjacent pages for current indication, Important Safety Information, and brief summary of full Prescribing Information.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 8/12 08Z12244A

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) 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 hypertension, hypokalemia, and 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 because these patients were excluded from the randomized clinical trial. 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 has been reported in clinical trials 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—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. 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. Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. 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.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration 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. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution. Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

www.zytiga.com Please see brief summary of full Prescribing Information on the following pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 8/12 08Z12244A

08Z11121R3

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castrationresistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. 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, the patient should be apprised of the potential hazard to the fetus. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. 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. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. 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: Adrenocortical insufficiency has been reported in clinical trials 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: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. 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. Food Effect: 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]. Food effect [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. In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months. The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA). Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions]. Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities). Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Prednisone (N=791) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % Musculoskeletal and connective tissue disorders 29.5 4.2 Joint swelling/discomfort2 26.2 3.0 Muscle discomfort3 General disorders 26.7 1.9 Edema4 Vascular disorders Hot flush 19.0 0.3 Hypertension 8.5 1.3 Gastrointestinal disorders Diarrhea 17.6 0.6 Dyspepsia 6.1 0 Infections and infestations Urinary tract infection 11.5 2.1 Upper respiratory tract infection 5.4 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 Nocturia 6.2 0 Injury, poisoning and procedural complications 5 5.9 1.4 Fractures Cardiac disorders 6 Arrhythmia 7.2 1.1 Chest pain or chest discomfort 7 3.8 0.5 Cardiac failure8 2.3 1.9 1 2 3

Placebo with Prednisone (N=394) All Grades Grade 3-4 % % 23.4 23.1

4.1 2.3

18.3

0.8

16.8 6.9

0.3 0.3

13.5 3.3

1.3 0

7.1 2.5

0.5 0

7.6

5.1 4.1

0.3 0

2.3

4.6 2.8 1.0

1.0 0 0.3

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness

ZYTIGA® (abiraterone acetate) Tablets 4 5 6

Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture 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 Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms. Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations. In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated. Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%). Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebocontrolled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 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 was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. 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 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, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. 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: ZYTIGA is not indicated in children. Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. 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. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F 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]. Manufactured by: Patheon Inc. Mississauga, Canada

Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044

Revised: July 2012

08Z12237B

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35th ESMO Congress T-DM1 Results continued from page 1

to date in metastatic breast cancer,” Dr. Verma stated. “These findings suggest that T-DM1 should be an important therapeutic option in the treatment of HER2-positive breast cancer.” The results he presented were based on the second interim overall survival analysis of EMILIA, now with a median follow-up of about 19 months, and these updated results were also published in The New England Journal of Medicine2 on the day of the presentation (see page 10). Final overall survival findings will be presented in 2014. However, these will be descriptive only, as patients in the reference arm are now allowed to cross over to receive T-DM1. Secondary endpoints in the trial were all significantly improved with T-DM1 vs lapatinib/ capecitabine, he said. The overall rate of grade 3 or more severe adverse events was higher in the lapatinib/capecitabine arm (57%) compared with T-DM1 (41%). T-DM1 was associated with higher rates of thrombocytopenia and elevated serum aminotransferase levels, whereas the lapatinib/capecitabine regimen was associated with higher rates of diarrhea, nausea, vomiting, and hand-foot syndrome. The rate of cardiac toxicity, a concern with trastuzumab (Herceptin), was low in both treatment arms. EMILIA enrolled 991 patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Baseline demographic and disease characteristics were well balanced. About 61% had prior anthracycline treatment.

CORRECT Trial Update Regorafenib (Stivarga) produced a sustained survival benefit in patients with heavily pretreated metastatic colorectal cancer, according to an update of the phase III CORRECT trial.3 The benefit of regorafenib was seen across all prespecified subgroups. With longer follow-up, no new safety concerns were identified. During the ESMO meeting, regorafenib was approved by FDA for treatment of metastatic colorectal cancer in the salvage setting (see page 22). The final updated analysis of overall survival presented at ESMO by Eric Van Cutsem, MD, University Hospitals Gasthuisberg/Leuven, Belgium, followed on the heels of the first preplanned interim overall survival analysis presented at the 2012 ASCO Annual Meeting, dem-

Eric Van Cutsem, MD

onstrating a significant survival benefit (P < .0052). The updated analysis showed that median overall survival was 6.4 months for regorafenib vs 5 months for placebo (P = .0038), representing a 21% reduced risk of death for the mul-

disease … as long as the patients are in good condition.” In the CORRECT trial, 760 patients from 14 countries whose disease had progressed on several lines of standard treatment were randomly assigned to oral regorafenib or placebo for 2 weeks on and 1 week off. Randomization was carried out in a 2:1 ratio. Both groups also received best supportive care. Adverse events associated with regorafenib included hand-foot syndrome (46%), fatigue (47.6%), hypertension (27.8%), diarrhea (38%), and rash or skin desquamation (26%). Translational studies are planned to identify a biomarker for response to regorafenib based on serum and tis-

Regorafenib represents a new potential standard of care for patients with chemorefractory metastatic disease … as long as the patients are in good condition. —Eric Van Cutsem, MD

tikinase inhibitor. At 6 months, 52.2% of those who received regorafenib were alive vs 43% of the placebo group. At 1 year, 24% and 17%, respectively, were alive. Dr. Van Cutsem noted that patients included in CORRECT all had good

sue samples from patients enrolled in CORRECT.

Maintenance Bevacizumab More support for the continuation of bevacizumab (Avastin) beyond disease progression in metastatic colorectal

Important Presentations at the 2012 ESMO Congress ■■ Updated analysis of the phase III EMILIA trial showed extended survival with T-DM1 vs lapatinib/capecitabine in patients with advanced HER2-positive breast cancer.

■■ Updated analysis of the phase III CORRECT trial confirmed the survival benefit of regorafenib in patients with heavily pretreated metastatic colorectal cancer.

■■ In patients with metastatic colorectal cancer, bevacizumab continued

after first-line chemotherapy reduced the risk of progression by 35% in a phase III Italian trial.

■■ In patients with GIST refractory to imatinib and sunitinib, regorafenib

delayed progression in all subgroups; benefits appeared to be sustained when the drug was continued beyond progression.

■■ In patients with advanced pancreatic neuroendocrine tumors, soluble

VEGFR1 and placental growth factor were significant prognostic markers, with lower baseline levels associated with longer progression-free survival. No markers proved predictive of benefit with everolimus.

■■ Correcting for the confounding effect of crossover, investigators showed an approximate 50% reduction in mortality among patients receiving sunitinib (vs placebo) for advanced pancreatic neuroendocrine tumors.

performance status despite the failure of standard treatments. “Results show that the benefit of treatment is sustained over time, with manageable side effects. Regorafenib represents a new potential standard of care for patients with chemorefractory metastatic

cancer came from the phase III BEBYP trial by the Gruppo Oncologico Nord Ovest.4 The study randomized patients who had received bevacizumab plus first-line chemotherapy with a fluoropyrimidine monotherapy, or FOLFIRI (leucovorin, fluorouracil [5-FU], iri-

notecan), FOLFOX (leucovorin, 5-FU, oxaliplatin), or FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, irinotecan) to receive a second line of chemotherapy using either FOLFOX or FOLFIRI alone or with bevacizumab. Among 184 patients followed for 18 months, median progression-free survival was 4.97 months without bevacizumab and 6.77 months with main-

Gianluca Masi, MD

tenance bevacizumab, representing a 35% reduction in risk (P = .0062), reported Gianluca Masi, MD, of the University Hospital of Pisa. Overall survival data are immature, but 52 deaths have occurred among controls and 46 among bevacizumab recipients.

Regorafenib in Refractory GIST The multi–tyrosine kinase inhibitor regorafenib significantly delayed disease progression in all subgroups of patients with gastrointestinal stromal tumor (GIST) refractory to both imatinib (Gleevec) and sunitinib (Sutent), and appeared to confer benefits when continued after progression, according to subgroup and postprogression analyses of the phase III GRID trial.5 Upon progression, the study was unblinded and placebo recipients could cross over to receive regorafenib, while those whose disease progressed on regorafenib could continue the drug, if desired. Previous analyses of the 199-patient trial found a 4-month improvement in progression-free survival with regorafenib (hazard ratio [HR] = 0.27; P < .0001). The drug conferred benefits regardless of the number of prior systemic therapies, geographic region, age, baseline ECOG performance score, duration of prior treatment with imatinib, or presence of KIT/PDGFRA mutations, reported Peter Reichardt, MD, PhD, of HELIOS Klinikum in Bad Saarow, Germany. When continued after progression (n = 41), regorafenib was associated with an additional 4.5 months of remission; when given upon crossover (n = 56), it

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35th ESMO Congress

Peter Reichardt, MD, PhD

delayed progression for an additional 5.0 months. “This suggests that continuous kinase inhibition after progression may benefit patients by slowing tumor progression,” Dr. Reichardt suggested.

lower baseline levels associated with longer progression-free survival. This means that patients with high sVEGFR1 and high PlGF are likely to have a worse prognosis. None of the markers, however, proved predictive of a benefit with everolimus, Dr. Yao reported. In a separate presentation, an updated overall survival analysis of the phase III sunitinib trial was reported by Sandrine Faivre, MD, PhD, of Assistance Publique–H�� ô�� pitaux de Paris, Uni-

Neuroendocrine Data Since pancreatic neuroendocrine tumors are highly vascular, and since the mTOR inhibitor everolimus (Afinitor) has antiangiogenic activity, RADIANT-3 investigators evaluated potential tumor markers in the vascular endothelial growth factor (VEGF) pathway. The results were presented by James C. Yao, MD, of The University of Texas MD Anderson Cancer Center in Houston.6 Pretreatment plasma samples were assessed for levels of the angiogenic cytokines VEGF-A, soluble receptors sVEGFR1 and sVEGFR2, and placental growth factor (PlGF). The multivariate analysis showed that sVEGFR1 and PlGF were significant prognostic markers, with

Sandrine Faivre, MD, PhD

versité Paris Diderot, Hôpital Beaujon, Clichy, France.6,7 The trial closed early and 69% of patients on the placebo arm eventually crossed over to sunitinib, potentially confounding the overall survival analysis. Dr. Faivre presented overall survival data 2 years after study closure and after adjusting for crossover using four different statistical methods. The intent-to-treat analysis without

adjustment for crossover showed median survival to be 33 months with sunitinib and 26.7 months with placebo (HR = 0.71). Adjusted for crossover, median survival with sunitinib ranged from 16.4 months (HR = 0.43) to 26.7 months (HR = 0.49), depending on the model employed. This yielded an overall survival benefit of 6.3 to 16.7 months, Dr. Faivre reported.

■

Disclosure: Dr. Verna has received honoraria from Roche/Genentech and GlaxoSmithKline, and research grants from Roche and Sanofi-Aventis. Dr. Reichardt is on the advisory board of Bayer. Dr. Masi reported no potential conflicts of interest. Dr. Van Cutsem has received research funding (via his institution) from Bayer. Dr. Faivre has received honoraria from Pfizer and Novartis. Dr. Yao has been a paid consultant for and has received research support (via his institution) from Novartis.

References 1. Verma S, Miles D, Gianni L, et al: Updated overall survival results from EMILIA, a phase 3 study of trastuzumab emtansine (TDM1) vs capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC). 2012 ESMO Congress. Abstract LBA12. Presented October 1, 2012. 2. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. Oct 1, 2012 (early release online). 3. Van Cutsem EJD, Grothey A, Sobrero A, et al: Phase 3 CORRECT trial of

regorafenib in metastatic colorectal cancer (mCRC): Overall survival updated. 2012 ESMO Congress. Abstract LBA18. Presented October 1, 2012. 4. Masi G, Loupakis F, Salvatore L, et al: A randomized phase III study evaluating the continuation of bevacizumab beyond progression in metastatic colorectal cancer patients who received bevacizumab as part of first-line treatment: Results of the BEBYP trial by the Gruppo Oncologico Nord Ovest. 2012 ESMO Congress. Abstract LBA17. Presented October 1, 2012. 5. Reichardt P, Casali PG, Kang Y-K, et al: Clinical benefit with regorafenib across subgroups and post-progression in patients with advanced gastrointestinal stromal tumor after progression on imatinib and sunitinib: Phase 3 GRID trial update. 2012 ESMO Congress. Abstract 14780. Presented September 30, 2012. 6. Yao JC, Shah M, Panneerselvam A, et al: The VEGF pathway in patients with pancreatic neuroendocrine tumors: Efficacy of everolimus by baseline marker level, and prognostic and predictive effect analyses from RADIANT-3. 2012 ESMO Congress. Abstract 11540. Presented September 29, 2012. 7. Faivre S, Niccoli P, Raoul JL, et al: Updated overall survival analysis from a phase III study of sunitinib vs placebo in patients with advanced, unresectable pancreatic neuroendocrine tumor. 2012 ESMO Congress. Abstract 11550. Presented September 29, 2012.

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Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

The ASCO Post | NOVEMBER 15, 2012

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Journal Spotlight Breast Cancer

Trastuzumab Emtansine Improves Survival vs Capecitabine plus Lapatinib in Second-line HER2-positive Breast Cancer By Matthew Stenger

rastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab bound to the cytotoxic microtubule inhibitor emtan-

sine (DM1, derivative of maytansine) by a stable linker. Trastuzumab targets the conjugate to HER2 receptors, and the linker releases the cytotoxic agent

when the compound is internalized via receptor endocytosis. Trastuzumab emtansine has been found to be active in trastuzumab (Herceptin)- and lapa-

tinib (Tykerb)-resistant disease, as well as in trastuzumab-naive tumors, and the conjugate appears to maintain the antitumor activity of trastuzumab. Results of the international, openlabel phase III EMILIA trial, recently reported by Velma and colleagues in The New England Journal of Medicine,1 indicate that trastuzumab emtansine improves survival compared with capecitabine (Xeloda)/lapatinib in patients with advanced HER2-positive breast cancer who had previously received trastuzumab.

Study Design In the EMILIA trial, 991 patients with advanced breast cancer who had previously been treated with trastuzumab and a taxane were randomly assigned to trastuzumab emtansine, 3.6 mg/kg IV every 21 days (n = 495), or oral lapatinib, 1,250 mg/d and oral capecitabine 1,000 mg/m2 twice daily on days 1 to 14 of each 21-day treatment cycle (n = 496). Patients had to have progressive disease during or See Page 108 after the most recent treatment for locally advanced or metastatic disease or within 6 months after treatment for early disease. Patients also had to have a left-ventricular ejection fraction ≥ 50% and ECOG performance status of 0 or 1 and could have measurable or nonmeasurable disease. The trastuzumab emtansine and lapatinib/capecitabine groups were well matched for age (median 53 years in both; ranges, 25–84 and 24–83 years), race (white in 72% and 75%), ECOG performance status (0 in 60% and 63%), site of disease involvement (visceral in 67% and 68%), hormone receptor status (both estrogen receptor–negative and progesterone receptor–negative in 41% and 45%), and number of prior chemotherapy regimens for locally advanced or metastatic disease (> 1 in 39% of both groups). Prior therapy included an anthracycline in 61% of both groups and endocrine therapy in 41% of both groups; 3% of trastuzumab emtansine patients and 4% of lapatinib/capecitabine patients had received a biologic agent other than trastuzumab. The trial was initially designed with progression-free survival on indepen-

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Journal Spotlight

dent review as the primary endpoint, but the protocol was amended while data were still blinded to include overall survival as a coprimary endpoint and to increase enrollment to adequately power the study to detect an overall survival difference. The first interim analysis of overall survival occurred at the time of the primary progressionfree survival analysis; a second interim overall survival analysis was performed when 50% of projected events for the final overall survival analysis had occurred. Median follow-up to the first data cutoff date was approximately 13 months; median follow-up to the second interim analysis of overall survival was approximately 19 months.

Improved Survival Median progression-free survival on independent review was 9.6 months in the trastuzumab emtansine group vs 6.4 months in the lapatinib/ capecitabine group, yielding a significant 35% reduction in risk for progression or death with trastuzumab emtansine (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.55–0.77, P < .001). There was consistent benefit across most clinical subgroups, with a less definitive benefit in patients aged 75 years or older and in those with nonvisceral or nonmeasurable disease. At the first interim analysis of overall survival, trastuzumab emtansine was associated with a 38% reduction in risk of death (HR = 0.62, 95% CI �� .0005), but the dif= 0.48–0.81, P = ference did not meet the criterion for significance according to the prespeci-

fied stopping boundary (P = .0003). At the second interim analysis, median overall survival was 30.9 months in the trastuzumab emtansine group vs 25.1 months in the lapatinib/capecitabine group, representing a significant 32% reduction in risk of death (HR = 0.68, < .001). Esti95% CI = 0.55–0.85, P �� mated survival rates were 85.2% in the trastuzumab emtansine group vs 78.4% in the lapatinib/capecitabine group at 1 year and 64.7% vs 51.8% at 2 years.

erythrodysesthesia was more common in the lapatinib/capecitabine group (58.0% vs 1.2%), as was hyperbilirubinemia (8.2% vs 1.2%). Grade 3 or 4 adverse events were less common in the trastuzumab emtansine group (40.8% vs 57.0%), with the most frequent being thrombocytopenia (12.9% vs 0.2%) and elevated AST (4.3% vs 0.8%). Grade 3 or 4 adverse events that were more common in the lapatinib/capecitabine group

T-DM1 vs Capecitabine/Lapatinib in Breast Cancer ■■ In patients with HER2-positive breast cancer previously treated with

trastuzumab and a taxane, trastuzumab emtansine (T-DM1) improved progression-free and overall survival compared with lapatinib/ capecitabine.

■■ Overall, trastuzumab emtansine was associated with reduced toxicity. The objective response rate was higher in the trastuzumab emtansine group (43.6% vs 30.8%, P < .001), and the median duration of response was longer (12.6 vs 6.5 months).

Reduced Overall Toxicity The most frequent adverse events of any grade in trastuzumab emtansine– treated patients were nausea (39.2% vs 44.7% with lapatinib/capecitabine), fatigue (35.1% vs 27.9%), thrombocytopenia (28.0% vs 2.5%), diarrhea (23.3% vs 79.7%), and elevated AST (22.4% vs 9.4%). The overall incidence of bleeding events was higher with trastuzumab emtansine (29.8% vs 15.8%, including grade 3 or 4 events in 1.4% vs 0.8%). In addition to diarrhea, palmar-plantar

included diarrhea (20.7% vs 1.6%) and palmar-plantar erythrodysesthesia (16.4% vs 0%). Serious adverse events occurred in 15.5% of trastuzumab emtansine patients and in 18.0% of lapatinib/ capecitabine patients. Dose reductions occurred more frequently in the lapatinib/capecitabine group (27.3% for lapatinib and 53.4% for capecitabine) than in the trastuzumab emtansine group (16.3%), as did discontinuation of treatment due to adverse events (7.6% for lapatinib and 9.4% for capecitabine compared with 5.9% for trastuzumab emtansine). Left-ventricular ejection fraction ≥ 45% was maintained in 97.1% of the trastuzumab emtansine group and

93.0% of the lapatinib/capecitabine group; 1.7% and 1.6%, respectively, had left-ventricular ejection fraction < 50% and ≥ 15% below baseline value, and three patients in each group developed left-ventricular ejection fraction < 40%. One trastuzumab emtansine recipient developed grade 3 left-ventricular systolic dysfunction. Four deaths in the lapatinib/ capecitabine group (due to coronary artery disease, multiorgan failure, coma, and hydrocephalus) and one death in the trastuzumab emtansine group (due to metabolic encephalopathy after CNS progression) were attributed to adverse events occurring within 30 days of the last dose of study medication. As concluded by the investigators, “The safety profile of T-DM1 and the improved progression-free and overall survival with this agent, as compared with standard HER2-directed therapy, provide clinical evidence that intracellular delivery of the cytotoxic agent specifically to HER2-overexpressing cells improves the therapeutic index by minimizing exposure to normal tissue.… [Our] study shows that T-DM1 has therapeutic potential, across a heterogeneous population of patients, for the treatment of advanced, HER2-positive breast cancer that has progressed during or after treatment with trastuzumab and a taxane.”

■

Reference 1. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med October 1, 2012 (early release online).

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The ASCO Post | NOVEMBER 15, 2012

PAGE 12

Issues in Oncology

Overdiagnosis and Overtreatment continued from page 1

digm. “Patients assume that cancer left untreated will kill them, and so do most doctors who are still operating under the premise that stage determines outcome in a disease that inexorably progresses in an orderly manner through a discrete set of stages,” said Dr. Esserman. This system dictates that early detection should result in reducing mortality, but this is not always going to be true, she added. “Some of the lesions we detect would not necessarily progress, so early detection would lead to overtreatment, and some would spread early despite being small. So early detection is not necessarily the road to cure.” Dr. Esserman explained that cancer is heterogeneous and varies by subtype, which in turn determines fate, rate of growth, and response to therapy. “Biology, as it turns out, trumps the size of the tumor. Clearly there are very small cancers that are lethal because of their capacity to metastasize. But we now have longitudinal studies that challenge the notion that all cancers will grow and progress. Moreover, screening can reveal indolent disease, in which intervention is a net negative. We know that the more we look, the more we find. The question becomes: What is the value of the finding?” said Dr. Esserman.

Is New Terminology Needed? Dr. Esserman pointed out that some tumors do well in spite of multiple positive nodes, using thyroid cancer as one example. “This is an opportunity to use some of our evolving molecular markers to put tumor biology into a better clinical context, and in the process adjust cancer taxonomy and change the terminology. For example, precancerous, indolent lesions need a renaming convention without the word “cancer” in the label. Maybe we need to look for a critical threshold before a disease is labeled cancer, ” said Dr. Esserman. She continued, “I don’t think that a disease that if excised is associated with a 98% chance of survival should be labeled cancer. Lesions with a low risk of progression, that are suitable for active surveillance, and have a 90%-plus chance of never progressing should perhaps be relabeled indolent lesions. Again, the impact of early intervention will be minimal if the disease that develops is indolent.”

Risk vs Reward in Screening Dr. Esserman stressed that it was important to fully understand the clinical benefits of screening and treatments. “Early detection from screening is likely to have the most benefit in slower-growing disease that is potentially lethal. However, for disease that is lethal and rapidly

growing, the chance of hitting it at the right time is low. In those cases, early detection with screening is not likely to have much value. It is equally important for women not to ignore a new mass if they had a normal mammogram 6 months ago; the more rapidly growing cancers often show up between normal scans,

as they can grow quickly,” said Dr. Esserman, commenting that in indolent disease, especially when not clinically apparent, screening is of no value and often leads to unnecessary treatment. Using breast cancer screening—a $10 billion per year expenditure—as a model, Dr. Esserman focused on

CD30-directed therapy 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).

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.

CT SCANS confirmed responses in relapsed patients 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

ASCOPost.com | NOVEMBER 15, 2012

PAGE 13

Issues in Oncology

Gauging the Need for Surgery in Ductal Carcinoma in Situ ■■ For patients whose DCIS recedes or disappears, perhaps no surgical therapy is needed.

■■ For patients whose DCIS does not change, close follow-up may be appropriate.

■■ For patients whose DCIS progresses, the need for more aggressive intervention is clear.

ductal carcinoma in situ (DCIS), a disease state she feels offers the best example for change. “Everyone understands the prostate cancer screening story, but breast cancer screening is part of a similar narrative. In in situ disease, the detection rate has increased about 500-fold since the advent of mammographic screening.

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%)

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%)

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

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

A R

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

L Vp

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/2011/0104f

855.4SEAGEN (855.473.2436) SeaGenSecure.com

So, we have to ask, have we identified the right precursor lesions? Because it is unlikely that the majority of DCIS detected on screening will develop into significant cancers,” she said. “The detection rate has increased 500-fold since the advent of mammography screening. And decontinued on page 14

The ASCO Post | NOVEMBER 15, 2012

PAGE 14

Issues in Oncology

Overdiagnosis and Overtreatment continued from page 13

spite taking out more than 50,000 in situ cases per year for well over 10 years, we have not seen a concomitant drop in the incidence of invasive cancers. In fact, the rate of new cancers has risen over time.”

Dr. Esserman posed the question: If the goal of breast cancer screening is to reduce morbidity and mortality, how did DCIS become the focus of that effort? “I submit that we need to back off the model of assuming that all cases of DCIS are cancers and should be treated as we do stage I cancer. First, low- and intermediate-grade DCIS

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

should not be a target of screening. And lesions with a 20% to 35% risk of progression to invasive cancer should be considered high-risk lesions, not cancer,” said Dr. Esserman.

Prescription for Change “The data indicate that all cases of DCIS are not the same, so I am sug-

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%.

Effect of ADCETRIS on other drugs

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.

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

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.

Geriatric use

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.

The ASCO Post

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.

Dosage and administration 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%).

Reference 1. Esserman L: Avoiding overdiagnosis and overtreatment of common cancers: Ductal carcinoma in situ. 2012 ASCO Annual Meeting. Education Session. Presented June 2, 2012.

Pediatric use

Use in pregnancy

Adverse reactions

■

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

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.

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.

gesting that we rename low- to intermediate-grade DCIS to better reflect their clinical path. We should also participate in trials that change our treatment approaches in low-grade lesions. Time can be used as a discriminator to determine which women do indeed need surgical intervention. And in high-grade lesions, there’s no reason to rush into surgery,” commented Dr. Esserman (see sidebar on page 13). “We can use a period of time (1 to 2 months) prior to surgical excision as an opportunity to test new approaches to prevention for highgrade cancers,” she said. The central message moving forward is that DCIS is neither an emergency, nor a life-threatening cancer, and we must enable an approach that allows us to learn and better inform our patients. “As clinicians, we need to recognize that overdiagnosis occurs, which can lead to overtreatment if unrecognized. We shouldn’t look so hard for DCIS, especially in older women. In short, we should try doing less and learn from that restrained clinical behavior,” concluded Dr. Esserman.

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, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA

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PAGE 15

Issues in Oncology

Mammography Study Stokes Overdiagnosis Debate By Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center, New York

verdiagnosis and the harms associated with unnecessary procedures is becoming a vibrant subject in today’s health-care dialogue, with serious implications for providers and patients alike. A new study from the Norwegian Screening Program concluded that 15% to 25% of breast cancers identified on mammography would never have been clinically significant in a woman’s lifetime.1 What are the implications of these findings, particularly within the larger discussion of overdiagnosis?

sensitive and predictive tests in a cost-effective manner. For instance, I recently saw a woman who had been getting mammograms every 6 months because of her family history. Shortly after her last normal mammogram, she presented with invasive lobular breast cancer that had spread to 20 of 37 lymph nodes. This illustrates that mammography can fail More Confusion Than Clarity? even those women who are hypervigilant about their Clearly, this is an area of ongoing controversy, not only within the oncology breast health. Lobular breast cancer, which repreAndrew D. Seidman, MD community, but also in the overall health-care dialogue. It is an important dissents about 15% of all breast disease, is only one of cussion; however, I’m not convinced that the recent study out of Norway sheds several breast cancers that are frequently missed on significant light on the issue of overdiagnosis. It was a laudable effort, but it may screening mammography. add more confusion than clarity to the dispute. We can, of course, increase the sensitivity of mammography by compleFor one, so many clinicians and statisticians have argued publically in menting the test with ultrasonography, and in selected populations, adding numerous letters to the editor about the study, which calls attention to pobreast MRI. However, this increased sensitivity also increases the number tential problems with the Norweof potential false-positives, so again, gian report. This was essentially a I believe that we must continue to cohort-controlled study, which used wisely use our current screening The focus in the United States is based on recognition historical comparison groups that technologies and intensify our efthat although mammography is an imperfect screening forts to develop more accurate tests. were screened in disparate counties around Norway, leading to a lot of test, it does save lives. Proper Context statistical assumptions, corrections —Andrew D. Seidman, MD The Norwegian investigators, and for lead-time bias, and other issues others pursuing the same path, try to that proved problematic. Also, many make the case that many of the cancers found on screening will not end up to be of the patients in this study were screened before the advent of digital mamlife-threatening. Consequently—as a public health-care policy— we can safely mography, which is a higher-contrast and more sensitive test than film mamlimit the amount of screening mammography, and by doing so, reduce waste and mography. the associated harms such as unnecessary biopsies and lumpectomies. The debate Different Perspective over cost-effective screening will continue, but this study does not make a conThat said, I’m not a statistician, so I would address the public-health issue vincing case that the potential harms of mammography outweigh the benefits. of overdiagnosis from a different perspective. First and foremost, dying of The issue of overdiagnosis is a complicated and nuanced challenge. We, breast cancer is a serious public health issue, and any pursuit to reduce overthe doctors who order and provide these tests, debate among ourselves about treatment needs to be balanced within the context of that what is the best and most cost-effective way to screen and treat our patients. clinical reality. We all strive to get more accurate screening But when studies make headlines in the lay press, without proper context and data and reduce the harms associated with potential overanalysis, they can do disservice to patients who are seeking information to diagnosis. help them make educated decisions about their health care. Disclosure: Dr. Seidman reported no potential conflicts of interest. The focus in the United States is based on recognition that although mammography is an imperfect See Page 108 Reference screening test, it does save lives. For me, the more com1. Kalager M, Adami HO, Bretthauer M, et al: Overdiagnosis of invasive breast pelling challenge is not to analyze mammography studcancer due to mammography screening: Results from the Norwegian screening ies that looked at populations from 20 years ago, but to try to develop program. Ann Intern Med 156:491-499, 2012. better technologies to improve our ability to screen patients with more

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

www.ASCOPost.com

Soft Tissue Sarcoma... Most common primary sites of soft tissue sarcoma.1

HEAD AND NECK

[9%]

TRUNK

[19%] RETROPERITONEUM

[15%]

EXTREMITIES

[60%]

Raising Awareness of a Challenging Disease Soft tissue sarcomas are a heterogeneous group of more than 50 distinct histological subtypes with an estimated incidence of more than 10,000 cases per year in the United States.1 They can originate from connective tissue, including fat, muscle, nerve and nerve sheath, vasculature, and other connective tissues.1 They most commonly arise in the extremities, trunk and retroperitoneum. 1 The presentation of soft tissue sarcomas is variable, but patients often present with a painless mass that is increasing in size.2 Guidelines recommend a biopsy for diagnosis and histopathological classification of soft tissue sarcomas. The biopsy should be performed by an experienced surgeon or radiologist and assessed by a pathologist with sarcoma expertise.1 Guidelines also recommend that magnetic resonance imaging with or without computed tomography be performed for all masses with a chance of being malignant.1 1.

NCCN Guidelines®: Soft Tissue Sarcoma, V.1.2012. NCCN.org. http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed 05/01/2012. NCCN® and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc.

Ilaslan H, Schils J, Nageotte W, Lietman SA, Sundaram M. Clinical presentation and imaging of bone and soft-tissue sarcomas. Cleveland Clinic Journal of Medicine. 2010;77:S2-7.

The ASCO Post | NOVEMBER 15, 2012

PAGE 18

2012 Breast Cancer Symposium Contralateral Breast Cancer Risk Is Highly Overestimated By Caroline Helwick

reast cancer is highly unlikely to develop in the contralateral breast of women treated for primary breast cancer, yet many women continue to fear it and undergo prophylactic mastectomies. “Regardless, the perceived risk of developing and dying from a contralateral breast cancer is highly overestimated, and this has been shown to be a driving force for aggressive surgical intervention,” said Lori Uyeno, MD, MPH. Dr. Uyeno and colleagues documented the incidence of contralateral breast cancer and its impact on overall survival after mastectomy for unilateral breast cancer. They presented their findings at the 2012 Breast Cancer Symposium.1

Lori Uyeno, MD, MPH

While contralateral breast cancer is the most common malignancy among breast cancer survivors, it is still incredibly rare. The risk figure usually quoted is 0.5% to 1.0% per year, said senior author Courtney Vito, MD. “But our study found the risk to be less than 1% at 51 months, and this is a very big difference,” she noted. Previous estimates may be higher because they originated during an era of less effective systemic therapies. “We also found that when a contralateral breast cancer does occur, the only patients with a decrease in overall survival are those with a latestage presentation (stage IIB/III/ IV),” Dr. Vito added.

SEER Database Explored Investigators used the Surveillance, Epidemiology and End Results (SEER) database of 109,411 women (median age, 54 years) with a primary diagnosis of unilateral breast cancer

IIB to IV increased mortality. Earlystage contralateral breast cancer had no effect on overall survival,” Dr. Uyeno reported. The survival analysis was adjusted for primary tumor characteristics and

When they see the risk, compared to the small benefit, patients start to change their decisions. — Courtney Vito, MD

between 1998 and 2006. Patients underwent mastectomy, and about 10% also had a contralateral prophylactic mastectomy. The median follow-up was 51 months beyond the 1-year survival landmark. The researchers divided the population into two similar groups: a test sample (n = 54,706) and a validation sample (n = 54,705). The patients’ primary tumors were mostly early stage (1–IIA, 63%), moderately or poorly differentiated (78%), and hormone receptor–positive (52%).

Low Incidence of Contralateral Cancer After 51 months’ follow-up, contralateral breast cancer was diagnosed in 867 women (0.79%) at a median age of 61 years after a median observation time of about 2 years. The majority of these (66.2%) were detected at an early stage (0–IIA) and were moderately/poorly differentiated and estrogen receptor–positive. The analysis showed a stage-specific effect on overall survival. “Only contralateral tumors that were stage

Contralateral Breast Cancer Risk ■■ The risk of contralateral breast cancer after a primary diagnosis of unilateral breast cancer was 0.79% at 51 months, in an analysis of the SEER database.

■■ Women who did develop contralateral breast cancer had no decrease in

overall survival, compared with breast cancer survivors not developing these tumors, unless they were diagnosed at a late stage (stage IIB/III/IV).

treatment (including contralateral prophylactic mastectomy), patient demographics, and aging. The adjusted hazard ratios were 3.04 for stage IIB/III/IV on the test sample (P < .0001) and 2.72 (P < .0001) on the validation sample. Stage I/I/IIA and tumors of unknown stage carried hazard ratios of 0.73 (P = .05) and 1.20 (P = 0.21), respectively.

having a contralateral tumor of an advanced stage. Efforts to improve survival after unilateral breast cancer should emphasize early detection of contralateral breast cancer, the researchers advised. Intensive monitorSee Page 108 ing should begin early after treatment of the primary tumor, and any barriers to follow-up should be addressed. Dr. Vito said she counsels patients by “giving them the true numbers,” which come as a surprise to many women, she said. She also informs them that their risk for a surgical complication is at least 20%, for prophylactic mastectomy with reconstruction, according to series from Mayo Clinic and The University of Texas MD Anderson Cancer Center.

Factors Linked to Later-stage Tumors “We then wanted to know which patients are most at risk. This is not information we generally have when we see the patient upfront and are making decisions about treatment,” Dr. Vito said. The 247 cases of stage IIB/III/IV contralateral tumors were compared with 559 cases of stage 0/I/IIA tumors. The likelihood of having an advanced-stage contralateral tumor was greater when the patient’s original tumor was aggressive (extensive disease, large size, positive nodes) and when the patient was African American. Although African-American race is a risk factor nationwide (twofold risk compared to other races), it was much greater for patients living in the Southeast (sixfold risk compared to other races), which the investigators attributed to the possibility of reduced access to health care or cultural biases. Shorter time since the primary diagnosis was also associated with

Cornelia Liedtke, MD

“When they see the risk, compared to the small benefit, patients start to change their decisions,” she said. Cornelia Liedtke, MD, of the University of Muenster, Germany, commented on the study. “Patients tend to opt for more safe therapies because of their anxiety, but several analyses of contralateral breast cancer risk show that risk is only really increased in families with known mutations. I advise against prophylactic mastectomies unless the patient has a proven mutation,” she told The ASCO Post.

■

Disclosure: Drs. Uyeno, Vito, and Liedtke reported no potential conflicts of interest.

Reference 1. Uyeno L, Behrendt, Vito C: Contralateral breast cancer: Impact on survival after unilateral breast cancer is stage-dependent. 2012 Breast Cancer Symposium. Abstract 69. Presented September 14, 2012.

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 Post | NOVEMBER 15, 2012

PAGE 20

FDA Update

New Drug Application for Tivozanib for the Treatment of Advanced Renal Cell Carcinoma

VEO Oncology and Astellas Pharma, Inc, recently announced that AVEO has submitted a New Drug Application (NDA) to the FDA for tivozanib, in patients

with advanced renal cell carcinoma (RCC). Tivozanib is a potent, selective, long half-life inhibitor of all three vascular endothelial growth factor (VEGF) receptors

that is designed to optimize VEGF blockade while minimizing off-target toxicities. The drug is an oral, once-daily, investigational tyrosine kinase inhibitor.

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

XTANDI® (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 6SHFL¿F 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 UHÀHFW 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 UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW ÀXVK 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 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 XQGH¿QHG

ASCOPost.com | NOVEMBER 15, 2012

PAGE 21

FDA Update

Phase III Trial The NDA submission is based on results of the global phase III TIVO-1 trial, a randomized superiority-designed pivotal trial evaluating the efficacy and safety of tivozanib compared to sorafenib (Nexavar) in 517 patients with advanced RCC who had no prior

treatment with a systemic therapy, as well as data from 17 clinical studies involving over 1,000 subjects who received tivozanib. In the TIVO-1 investigation, tivozanib demonstrated a statistically significant improvement in progression-free survival vs sorafenib, an approved targeted agent, and a favor-

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

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHP¿EUR]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 PRGD¿QLO QDIFLOOLQ DQG 6W -RKQ¶V :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 LGHQWL¿HG 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 VLJQL¿FDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ FUHDWLQLQH FOHDUDQFH >&U&/@ P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ 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\@

able tolerability profile. Results from the study were first presented at the 2012 ASCO Annual Meeting in Chicago. Tivozanib is also under evaluation across a broad range of solid tumors, including metastatic colorectal cancer and metastatic breast cancer.

■

Live: 7"w × 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 ¿QGLQJV 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 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 PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8& PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). ,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. ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. ,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. ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ¿UVW 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. $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW ÀXVK 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. ,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 © 2012 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

FDA Approves Noninvasive Radiation Therapy to Treat Pain from Bone Metastases

nSightec Ltd announced that the FDA has approved ExAblate MRIguided focused ultrasound as a therapy to treat pain from bone metastases in patients who do not respond or cannot undergo radiation treatment for their pain. This is the second FDA approval for ExAblate since it was approved in 2004 as a noninvasive outpatient therapy for uterine fibroids.

Improved Quality of Life ExAblate combines therapeutic acoustic ultrasound waves and continuous guidance and treatment monitoring with an MRI. Physicians use the MRI to plan and guide the therapy and monitor treatment outcome. The focused ultrasound acoustic energy destroys the nerves causing the pain, resulting in rapid reduction in pain. The second FDA approval for ExAblate was based on the results of an international, multicenter, randomized clinical study comparing patients with painful bone metastases undergoing palliative therapy with ExAblate to a similar group undergoing a placebo therapy. Patients who underwent the ExAblate therapy reported clinically significant pain relief and improvement of quality-of-life during followup three months after treatment. Over 15 centers participated in the clinical trial including Fox Chase Cancer Canter, Stanford University, UCSD, UVA, Moffitt Cancer Center, and Brigham and Women’s Hospital in the United States as well as University of Toronto, La Sapienza University in Rome, Sheba and Rambam Medical Centers in Israel, and Petrov Research Institute of Oncology and Rostov Medical University in Russia.

■

FDA Update For more on newly approved drugs and indications,

see pages 2, 58, and 61 in this issue of The ASCO Post ONCOLOGY

The ASCO Post | NOVEMBER 15, 2012

PAGE 22

In the Clinic Gastrointestinal Oncology

Regorafenib, Multikinase Inhibitor, for Previously Treated Metastatic Colorectal Cancer By Matthew Stenger

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

Indication On September 27, 2012, regorafenib (Stivarga) was approved for the treatment of patients with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if they had wild-type KRAS tumors, anti-EGFR therapy.1,2 Approval was based on results of an international, multicenter, double-blind trial (Study 14387) in which 760 patients with previously treated metastatic colorectal cancer were randomly assigned to receive regorafenib at 160 mg orally once daily (n�� =�� 505) �� plus best supportive care or placebo (n = 255) plus best supportive care for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.2 Regorafenib was administered with a low-fat breakfast containing less than 30% fat. All patients had received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and bevacizumab. Of the 96% of patients who had been evaluated for KRAS mutation status, 59% had mutant KRAS; all but one patient with wild-type KRAS had received panitumumab (Vectibix) or cetuximab (Erbitux). In the total population, patients had a median age of 61 years, 61% were men, 78% were white, and all had a baseline ECOG performance status of 0 or 1. The primary site of disease was the colon in 65% of patients, rectum in 29%, and both in 6%. Patients had a median of three prior lines of therapy for metastatic disease.

OF NOTE Regorafenib is an oral small-molecule inhibitor of multiple kinases involved in normal cell function and oncogenesis, tumor angiogenesis, and maintenance of tumor microenvironment.

The mean duration of treatment was 12 weeks in regorafenib patients and 8 weeks in placebo patients. Median overall survival was 6.4 months in the regorafenib group vs 5.0 months in the placebo group, representing a significant 23% reduction in risk of death (hazard ratio [HR]�� = 0.77, �� 95% confidence interval [CI] = 0.64–0.94, P = .0102). Median progression-free survival was also significantly prolonged with regorafenib (2.0 vs 1.7 months, HR = 0.49, 95% CI = 0.42–0.58, P < .0001). Partial response was observed in 1% of regorafenib patients and in 0.4% of placebo patients.

How It Works Regorafenib is an oral small-molecule inhibitor of multiple membranebound and intracellular kinases involved in normal cell function and in oncogenesis, tumor angiogenesis, and maintenance of tumor microenvironment.2,3 In in vitro testing, regorafenib or its two major active metabolites inhibited the activity of RET, VEGFR1,

hand-foot skin reaction (palmar-plantar erythrodysesthesia), after recovery from any grade 3 or 4 adverse event, and for grade 3 AST or ALT elevations.

OF NOTE Regorafenib carries a boxed warning for severe and fatal hepatotoxicity; liver function tests must be performed before and during treatment. Interruption of treatment is recommended for grade 3 or recurrent grade 2 hand-foot skin reaction, symptomatic grade 2 hypertension, and any grade 3 or 4 adverse event. Regorafenib should be discontinued for failure to tolerate a dose of 80 mg/d after dose reductions, any occurrence of AST or ALT more than 20 times the upper limit of normal, and any occurrence of AST or ALT more than 3 times the upper limit of normal with bilirubin more than 2 times the upper limit of normal. Con-

Regorafenib in Colorectal Cancer ■■ Regorafenib (Stivarga) has been approved to treat metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy, an anti-VEGF therapy, or, if KRAS wildtype, an anti-EGFR therapy.

■■ The drug is given at 160 mg once daily for the first 21 days of each

28-day treatment cycle; treatment is continued until progression or unacceptable toxicity.

VEGFR2, VEGFR3, KIT, PDGFR-α, PDGFR-β, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl kinases at clinically achievable concentrations. The drug has shown antiangiogenic activity in experimental models and inhibition of tumor growth and antimetastatic activity in xenograft models including colorectal cancer models.

How It Is Given The recommended dose of regorafenib is 160 mg once daily for the first 21 days of each 28-day treatment cycle, with treatment continued until disease progression or unacceptable toxicity. It should be taken with a lowfat breakfast (<�� 30% �� fat). Dose reductions are recommended for grade 2

comitant use of strong CYP3A4 inducers or inhibitors should be avoided (eg, carbamazepine, dexamethasone, phenobarbital). Liver function tests must be performed before starting regorafenib, at least every 2 weeks during the first 2 months of treatment, and monthly or more frequently thereafter as clinically indicated. Tests should be performed weekly in patients experiencing elevated liver function tests.

Safety Profile The most frequent adverse events of any grade in regorafenib patients (> 40%) that occurred more frequently than in placebo patients were asthenia/ fatigue (64% vs 46%), decreased appetite and food intake (47% vs 28%),

hand-foot skin reaction (45% vs 7%), and diarrhea (43% vs 17%).2 The most frequent grade ≥ 3 adverse events were hand-foot skin reaction (17% vs 0%), asthenia/fatigue (15% vs 9%), infection (9% vs 6%), diarrhea (8% vs 2%), hypertension (8% vs < 1%), and rash (6% vs < 1%). The most common laboratory abnormalities of any grade in regorafenib patients (> 50%) were anemia (79% vs 66%), increased AST (65% vs 46%), proteinuria (60% vs 34%), hypocalcemia (59% vs 18%), hypophosphatemia (57% vs 11%), and lymphopenia (54% vs 34%). The most frequent (> 10%) grade 3 or 4 abnormalities were hypophosphatemia See Page 108 (32% vs 4%), hyperbilirubinemia (13% vs 8%), and increased lipase (11% vs 5%). Keratocanthoma/squamous cell carcinoma of the skin has been observed in 0.09% of 1,100 patients receiving regorafenib in clinical trials.

■

References 1. U.S. Food and Drug Administration: Regorafenib. Available at http://www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm321378.htm. Accessed October 8, 2012. 2. STIVARGA® (regorafenib) tablets prescribing information. Bayer HealthCare Pharmaceuticals Inc, September 2012. Available at http://www.accessdata.fda.gov/ drugsatfda_docs/label/2012/203085lbl. pdf. Accessed October 8, 2012. 3. Mross K, Frost A, Steinbild S, et al: A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res 18:2658-2667, 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).

FOR ADULT PATIENTS NEWLY DIAGNOSED WITH Ph+ CML IN CHRONIC PHASE (CP)

Choose TASIGNA first

TASIGNA provides superior MMR* rates vs imatinib at 12 months and <1% progression to AP/BC1† (44% [95% CI, 38%-50%] vs 22% [95% CI, 18%-28%], P<0.0001)1 *Major molecular response (MMR)=≥3 logs below baseline (≤0.1% international scale [IS]).1 †

Progression to accelerated phase or blast crisis (AP/BC) includes patients with clonal evolution and CML-related death.2

INDICATION AND BOXED WARNING TASIGNA (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA is based on major molecular response and cytogenetic response rates. The study is ongoing and further data will be required to determine long-term outcome. WARNING: QT PROLONGATION AND SUDDEN DEATHS ■ TASIGNA prolongs the QT interval. Prior to TASIGNA administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, and follow any dose adjustments ■ Sudden deaths have been reported in patients receiving nilotinib. Do not administer TASIGNA to patients with hypokalemia, hypomagnesemia, or long QT syndrome ■ Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors ■ Patients should avoid food 2 hours before and 1 hour after taking dose Please see Important Safety Information, including Boxed WARNING, and brief summary of Prescribing Information on the following pages.

IN THE TREATMENT OF ADULT PATIENTS NEWLY DIAGNOSED WITH Ph+ CML-CP Less than 1% of TASIGNA patients progressed to AP/BC1 Progression to AP/BC at 24 months

0.7%

■

17 6%

TASIGNA 300 mg bid (n=282)

Imatinib 400 mg qd (n=283)

TASIGNA

Imatinib

(n=282)

(n=283)

TASIGNA significantly improved the rate of MMR compared with imatinib at 12 months—the primary end point of the ENESTnd (44% [95% CI, 38%-50%] vs 22% [95% CI, 18%-28%], 300trial mg bid 400 P<0.0001) mg qd1

ENESTnd study design: A randomized, controlled, open-label, multicenter Phase III trial of 846 patients with newly diagnosed Ph+ CML-CP. Patients were randomized to receive either TASIGNA 400 mg bid (n=281), TASIGNA 300 mg bid (n=282), or imatinib 400 mg qd (n=283). The daily dose of imatinib could be escalated to 800 mg (400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for RQ-PCR testing. The primary end point was MMR at 12 months.1,2

IMPORTANT SAFETY INFORMATION ■

■

Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter

■

Caution is recommended in patients with a history of pancreatitis The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase

■

TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia (see Boxed WARNING) ■ ■

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. Grapefruit products should also be avoided The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s wort) TASIGNA must not be taken with food TASIGNA exposure is increased in patients with impaired hepatic function 3/12

AM7-1033710

TASIGNA maintained the difference in MMR rates through 24 months1,2 At 12 months

■

Cases of tumor lysis syndrome have been reported in TASIGNA-treated patients with resistant or intolerant CML. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA The exposure of TASIGNA is reduced in patients with total gastrectomy Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do. The safety and effectiveness of TASIGNA in pediatric patients have not been established

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

At 24 months

■

In newly diagnosed Ph+ CML-chronic phase, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, headache, nausea, fatigue, and myalgia TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors References: 1. TASIGNA® (nilotinib) capsules prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; November 2011. 2. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12(9):841-851.

Tasigna® (nilotinib) Capsules Initial U.S. Approval: 2007 BRIEF SUMMARY: Please see package insert for full prescribing information. WARNING: QT PROLONGATION AND SUDDEN DEATHS • Tasigna prolongs the QT interval. Prior to Tasigna administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies (5.2). Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and follow any dose adjustments (5.2, 5.3, 5.6, 5.12). • Sudden deaths have been reported in patients receiving nilotinib (5.3). Do not administer Tasigna to patients with hypokalemia, hypomagnesemia, or long QT syndrome (4, 5.2). • Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors (5.7). • Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). 1 INDICATIONS AND USAGE 1.1 Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1) in the full prescribing information]. The study is ongoing and further data will be required to determine long-term outcome. 1.2 Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [see Clinical Studies (14.2) in the full prescribing information]. 4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning]. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction [see Dosage and Administration (2.2) in the full prescribing information]. 5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments [see Warnings and Precautions (5.12)]. Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [see Warnings and Precautions (5.7, 5.8)]. The presence of hypokalemia and hypomagnesemia may further enhance this effect [see Warnings and Precautions (5.6, 5.12)]. 5.3 Sudden Deaths Sudden deaths have been reported in patients with CML treated with nilotinib in clinical studies (n= 5,661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence. 5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated. 5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated [see Warnings and Precautions (5.12)]. 5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. 5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning, Dosage and Administration (2.2), Drug Interactions (7.2) in the full prescribing information]. 5.8 Food Effects The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided [see Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information]. 5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment (at baseline) and QT interval should be monitored closely [see Dosage and Administration (2.2) and Use in Specific Populations (8.7) in the full prescribing information]. 5.10 Tumor Lysis Syndrome Cases of tumor lysis syndrome have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna. 5.11 Total Gastrectomy The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy [see Clinical Pharmacology 12.3) in the full prescribing information]. 5.12 Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactosecontaining products or of glucose-galactose malabsorption.

5.13 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels, including the lipid profile, should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments [see Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion. 5.14 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib. 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 child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations (8.1) in the full prescribing information]. 6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert [see Boxed Warning, Warnings and Precautions (5)]. Myelosuppression [see Warnings and Precautions (5.1)] QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)] Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)] Elevated serum lipase [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)] 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. Newly diagnosed Ph+ CML-CP The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 25 months (range 0.1 – 35.4 months). The median actual dose intensity was 594 mg/day in the nilotinib 300 mg twice daily group. The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 2.5% of patients. Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec while on study drug. The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (17%), neutropenia (15%) and anemia (7%). See Table 7 for Grade 3/4 laboratory abnormalities. Discontinuation due to adverse events regardless of causality was observed in 9% of patients. Resistant or intolerant Ph+ CML-CP and CML-AP In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1-1096) and 264 (range 2-1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151–1110) and 780 mg/day (range 150-1149), respectively and corresponded to the planned 400 mg twice daily dosing. The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1-345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1–234). In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (≥1% and <10%) were thrombocytopenia, neutropenia and anemia. In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (≥1% and <10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.4) in the full prescribing information]. Discontinuation due to drug-related adverse reactions was observed in 16% of CML-CP and 10% of CML-AP patients. Most Frequently Reported Adverse Reactions Tables 5 and 6 show the percentage of patients experiencing non-hematologic adverse drug reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least one dose of Tasigna are listed. Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Imatinib 400 mg once daily groups)a Patients with Newly Diagnosed Ph+ CML-CP TASIGNA Imatinib TASIGNA Imatinib 300 mg 400 mg 300 mg 400 mg twice daily once daily twice daily once daily N=279 N=280 N=279 N=280 Body System and Preferred Term All Grades (%) CTC Gradesb 3 / 4 (%) Skin and subcutaneous Rash 37 18 <1 2 tissue disorders Pruritus 20 7 <1 0 Alopecia 11 6 0 0 Periorbital edema <1 15 0 0 Gastrointestinal Nausea 20 39 1 1 disorders Constipation 17 6 0 0 Diarrhea 14 40 <1 2 Vomiting 11 24 0 <1 Abdominal pain upper 15 11 <1 <1 Abdominal pain 14 10 1 0 (continued)

Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Imatinib 400 mg once daily groups)a Patients with Newly Diagnosed Ph+ CML-CP TASIGNA Imatinib TASIGNA Imatinib 300 mg 400 mg 300 mg 400 mg twice daily once daily twice daily once daily N=279 N=280 N=279 N=280 Body System and Preferred Term All Grades (%) CTC Gradesb 3 / 4 (%) Nervous system Headache 30 18 3 <1 disorders General disorders Fatigue 21 16 1 1 and administration Pyrexia 11 12 <1 0 site conditions Asthenia 11 10 <1 0 Edema, peripheral 8 18 0 0 Face edema <1 11 0 <1 Musculoskeletal and Myalgia 14 18 <1 0 connective tissue Arthralgia 17 13 <1 <1 disorders Muscle spasms 11 31 0 <1 Pain in extremity 11 13 <1 <1 Back pain 14 11 <1 1 Respiratory, thoracic Cough 14 9 0 0 and mediastinal disorders Infections and Nasopharyngitis 22 17 0 0 infestations Upper respiratory tract infection 14 10 <1 0 Eye disorders Eyelid edema 1 16 0 <1 aExcluding laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP CML-AP N=321 N=137 All CTC All CTC Grades Gradesb Grades Gradesb Body System and Preferred Term (%) 3 / 4 (%) (%) 3 / 4 (%) Skin and subcutaneous Rash 36 2 29 0 tissue disorders Pruritus 32 <1 20 0 Night sweat 12 <1 27 0 Alopecia 11 0 12 0 Gastrointestinal Nausea 37 1 22 <1 disorders Constipation 26 <1 19 0 Diarrhea 28 3 24 2 Vomiting 29 <1 13 0 Abdominal pain 15 2 16 3 Abdominal pain upper 14 <1 12 <1 Dyspepsia 10 <1 4 0 Nervous system Headache 35 2 20 1 disorders General disorders and administration site conditions

Fatigue Pyrexia Asthenia Edema, peripheral Myalgia

32 22 16 15 19

3 <1 0 <1 2

23 28 14 12 16

<1 2 1 0 <1

Musculoskeletal and connective tissue disorders

Arthralgia Muscle spasms Bone pain Pain in extremity Back pain Musculoskeletal pain

26 13 14 20 17 11

2 <1 <1 2 2 <1

16 15 15 18 15 12

0 0 2 1 <1 1

Respiratory, thoracic and mediastinal disorders

Cough Dyspnea Oropharyngeal pain

27 15 11

<1 2 0

18 9 7

0 2 0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

Metabolism and nutritional disorders

Anorexia

Psychiatric disorders

Insomnia

Vascular disorders

Hypertension

aExcluding bNCI

laboratory abnormalities Common Terminology Criteria for Adverse Events, Version 3.0

Laboratory Abnormalities Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.

Table 7: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities Patient Population Resistant or Intolerant Ph+ Newly Diagnosed Ph+ CML-CP

Hematologic Parameters Thrombocytopenia Neutropenia Anemia Biochemistry Parameters Elevated lipase Hyperglycemia Hypophosphatemia Elevated bilirubin (total) Elevated SGPT (ALT) Hyperkalemia Hyponatremia Hypokalemia Elevated SGOT (AST) Decreased albumin Hypocalcemia Elevated alkaline phosphatase Elevated creatinine

CML-CP

CML-AP

TASIGNA 300 mg twice daily N=279 (%)

Imatinib 400 mg once daily N=280 (%)

TASIGNA 400 mg twice daily N=321 (%)

TASIGNA 400 mg twice daily N=137 (%)

10 12 4

9 21 5

301 312 11

423 424 27

7 6 5 4 4 2 1 <1 1 0 <1

3 0 8 <1 3 1 <1 2 1 0 0

18 12 17 7 4 6 7 2 3 4 2

18 6 15 9 4 4 7 9 2 3 5

0 0

<1 <1

1 <1

*NCI Common Terminology Criteria for Adverse Events, version 3.0 1CML-CP: Thrombocytopenia: 12% were grade 3, 18% were grade 4 2CML-CP: Neutropenia: 16% were grade 3, 15% were grade 4 3CML-AP: Thrombocytopenia: 11% were grade 3, 32% were grade 4 4CML-AP: Neutropenia: 16% were grade 3, 26% were grade 4 6.2 Additional Data from Clinical Trials The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (≥1% and <10%), uncommon (≥0.1% and <1%), and unknown frequency (single events). For adverse drug reactions listed under “Investigations”, very common events (≥10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Infections and Infestations: Common: folliculitis. Uncommon: upper respiratory tract infection (including nasopharyngitis, pharyngitis, rhinitis), pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis), gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis. Neoplasms Benign, Malignant and Unspecified: Common: Skin papilloma. Unknown frequency: oral papilloma. Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythaemia, leukocytosis, eosinophilia. Immune System Disorders: Unknown frequency: hypersensitivity. Endocrine Disorders: Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis. Metabolism and Nutrition Disorders: Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, decreased appetite. Uncommon: dehydration, increased appetite. Unknown frequency: hyperuricemia, gout, hypoglycemia, dyslipidemia. Psychiatric Disorders: Common: depression, insomnia, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria. Nervous System Disorders: Common: dizziness, peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome. Eye Disorders: Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye. Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctival hemorrhage, conjunctivitis allergic, ocular surface disease. Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus. Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease. Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis. Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing.

Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, gastritis, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis. Hepatobiliary Disorders: Common: hepatic function abnormal. Uncommon: hepatotoxicity, hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly. Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic and acneiform), dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy. Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis. Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia. Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling. General Disorders and Administration Site Conditions: Common: pyrexia, chest pain (including noncardiac chest pain), pain (including neck pain and back pain), chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema.

Investigations: Common: hemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased. Uncommon: blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, blood insulin increased, lipoprotein increased (including very low density and high density), blood parathyroid hormone increased. 10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2011-126 November 2011

ASCOPost.com | NOVEMBER 15, 2012

PAGE 29

Expert’s Corner Integrative Oncology

Integrative Medicine Showing Benefits in Cancer Management A Conversation With Donald I. Abrams, MD By Jo Cavallo “complementary” therapies are used in conjunction with conventional care. The ASCO Post spoke with Dr. Abrams about the benefits of integrative medicine in the treatment of cancer and how the practice is slowly gaining legitimacy and greater acceptance in the field of oncology.

Foundations of Integrative Medicine Donald I. Abrams, MD, Chief of Hematology-Oncology at San Francisco General Hospital and Integrative Oncologist at the University of California, San Francisco, Osher Center for Integrative Medicine, has been investigating and incorporating integrative medicine approaches in his clinical treatment of diseases like HIV/AIDS and cancer for nearly 3 decades. For example, while assembling information for a study of cannabis to combat AIDS-wasting syndrome in patients with HIV/AIDS, he became convinced of the medicinal potential of marijuana in relieving the side effects of conventional cancer therapy, including anorexia, nausea, vomiting, pain, and insomnia. (The use of medicinal marijuana is currently legal in 17 states, including California, and in the District of Columbia, although it remains illegal under federal law. Seven more states have pending legislation to legalize medical cannabis.) In 2004, Dr. Abrams completed a 2-year distance-learning fellowship in Integrative Medicine from the University of Arizona and today enlists a variety of complementary therapies in his clinical practice. Among the tools and approaches he employs are nutrition, physical activity, supplements including cannabis, acupuncture, and stressrelieving methods like massage, meditation, guided imagery, and yoga. Dr. Abrams is Past President of the Society for Integrative Oncology and is currently a member of the NCI’s PDQ Cancer Complementary and Alternative Medicine (CAM) Editorial Board. Like other integrative medicine specialists, Dr. Abrams objects to the acronym CAM and the confusion it causes for patients, since “alternative” medicine refers to treatments used in place of conventional cancer therapy, whereas

What is the definition of integrative medicine and how is the practice used in oncology? Integrative medicine refers to more than just complementary therapies to chemotherapy, radiation therapy, and surgery. The Consortium of Academic Health Centers for Integrative Medicine defines integrative medicine as the practice of medicine that reaffirms the importance of the relationship between practitioner and patient, focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic approaches, health-care profes-

treatment and, more importantly, how to reduce their risk of recurrence and prolong their survival. My main areas of focus are lifestyle choices, especially diet and the importance of eating nutritious foods and physical activity. The World Cancer Research Fund/American Institute for Cancer Research has affirmed that preventable malignancies are caused as often by obesity, poor nutrition, and lack of physical exercise as by tobacco use. Recently, the American Cancer Society updated its lifestyle recommendations based on evidence showing a correlation between obesity, high caloric intake, and lack of physical activity and cancer incidence/recurrence. Clearly, we are in the midst of an obesity epidemic in this country, so at the beginning of my consultation I talk about nutrition and advise patients to consume—as much as possible—an organic, plant-based, antioxidant-rich, anti-inflammatory whole foods diet. Then I talk about physical activity.

Clearly, we are in the midst of an obesity epidemic in this country, so at the beginning of my consultation I talk about nutrition and advise patients to consume— as much as possible—an organic, plant-based, antioxidant-rich, anti-inflammatory whole foods diet. — Donald I. Abrams, MD

sionals, and disciplines to achieve optimal health and healing. I like to say that at San Francisco General Hospital I treat cancer using conventional therapies, and at the Osher Center for Integrative Medicine I treat people living with cancer with an array of complementary interventions. I always start my consultations by asking patients to tell me their story, so I understand how their cancer diagnosis and treatment have impacted their lives.

Clinical Focus Are patients coming to you because they are having side effects from their treatment and are looking for some relief? Not exclusively. I see people who are undergoing acute treatment and want to prevent or ameliorate side effects, but I also see survivors who want to know how to handle long-term side effects of

Regular physical activity is something that can decrease the risk of cancer. Increasing evidence shows the benefits of exercise on reducing cancer recurrence as well. The final topic I discuss is stress reduction through different modalities, such as massage, meditation, and yoga.

Patient Empowerment How else is integrative medicine important in cancer care? It empowers the patient. When people get a diagnosis of cancer, their internal locus of control is removed. Now they are at the mercy of their surgeon, their radiation oncologist, their medical oncologist, their nurse, and often a seemingly uncaring health-care system. My goal is to return some sense of control to patients by giving them things during their treatment or in their

survivorship that they can do themselves. They can eat better, they can be physically active, they can take judicious supplements, and they can learn how to cope with and manage their stress.

Increasing Evidence of Efficacy How much scientific evidence is there that complementary medicine enhances conventional cancer care? There is an increasing amount of data from controlled clinical trials supporting the use of complementary interventions, especially in symptom management. For example, studies suggest that acupuncture is useful for chemotherapy-induced nausea and vomiting, as well as in reducing hot flashes in both men and women taking hormonal therapy and may relieve xerostomia in patients undergoing radiation for head and neck cancer. My patients who are getting acupuncture while undergoing conventional chemotherapy or radiation therapy seem to have an easier time coping with symptoms than my patients who aren’t getting acupuncture. Can I prove that my integrative intervention is better than conventional care alone? That is difficult to do. As an oncologist, when I prescribe a specific chemotherapy agent to a patient, I can cite the evidence showing risk and benefit. But I can’t show scientific proof of the health benefits of getting a massage once or twice a month or of eating more blueberries and broccoli. How do I do a placebo-controlled, randomized trial to study the effects of broccoli and blueberries or even physical activity in cancer care? Some of these strategies are just not amenable to our gold standard modality of investigation: the randomized double-blind, placebo-controlled trial that evidencedbased medicine requires.

Marijuana as Medicine How effective is medicinal marijuana in the treatment of people with cancer? Medical cannabis has been legal in California since 1996, and I have conducted clinical trials using cannabis in patients with HIV/AIDS and in patients with chronic pain. I’m also an editor of the NCI’s website on Cannabis and Cannabinoids (cancer.gov/cancertopics/pdq/cam/cannabis/healthprocontinued on page 30

The ASCO Post | NOVEMBER 15, 2012

PAGE 30

Ninth International SIO Conference Highlights From the Ninth International Conference of the Society for Integrative Oncology By Jo Cavallo

he theme of this year’s International Conference of the Society for Integrative Oncology (SIO) was “Honoring Diversity in Cancer Prevention and Control.” The conference was held October 8–10, 2012, in Albuquerque, New Mexico, and examined such varied topics as health-care disparities, novel perspectives on cancer prevention and control, and diet and exercise. The conference included workshops on conducting research in integrative cancer symptomology; evaluation of herbal medicine; and early career development. There were also clinical science abstracts presented on herbs and supplements and attitudes on complementary care among patients with cancer. Three of the abstracts presented are summarized below. (To access all the clinical and basic science abstracts presented at the SIO International Conference, go to the Society of Integrative Oncology website at integrativeonc.org.)

Flaxseed Study Lilian U. Thompson, PhD, of the University of Toronto, addressed Flaxseed/Lignans and the Risk Reduction and Treatment of Breast Cancer. This presentation summarized data from various animal, epidemiologic, and clinical studies on the use of flaxseed, which is rich in phytoestrogen lignans and may have anticancer effects. In all studies, flaxseed was shown to provide some benefit. In rat and mouse models with human breast cancer xenografts, flaxseed was found to reduce

Donald I. Abrams, MD continued from page 29

fessional), which outlines information available on the use of cannabis in symptom management. In addition to clinical trials, an increasing body of evidence from in vitro studies and animal models suggests that cannabinoids might have direct anticancer activity. I believe that cannabis is a medicine and that this medicine has significant utility in addressing a number of concerns of patients with cancer, including nausea related to chemotherapy, anorexia, pain, insomnia, and depression. Those are five common side effects from cancer and its treatments, and instead of writing prescriptions for five drugs that may all interact with each other or with

Lilian U. Thompson, PhD

the development, growth, and metastasis of both estrogen receptor–positive and estrogen receptor–negative breast tumors and improved the effectiveness of tamoxifen. A review of clinical studies of postmenopausal patients with breast cancer also found that flaxseed intake can reduce tumor cell proliferation. Epidemiologic studies showed that high lignan intake or high serum levels of lignans are associated with reduced risk of breast cancer and tumors with more favorable prognostic factors. However, the effect of flaxseed intake on HER2-overexpressing tumors is unclear.

Medication Interactions Richard T. Lee, MD, of The University of Texas MD Anderson Cancer Center, Houston, spoke about The Incidence of Potential Medication Interactions Including Herbs and Supplements Among Breast and Prostate Cancer Patients During and After Systemic Anticancer Therapy. This study surveyed 68 patients with breast or prostate cancer about the medications they take, inthe chemotherapy that my patient is receiving, I can recommend one medicine that won’t adversely interfere with my patient’s cancer treatment.

Incorporating Integrative Care Are you seeing an increase in the number of oncologists incorporating integrative medicine into their practices? A number of my colleagues at the UCSF Helen Diller Comprehensive Cancer Center have worked with me over the years and have learned some of my methods. They can answer their patients’ questions and make recommendations regarding integrative care. But the reality is, if oncologists have only 20 minutes during an office visit to examine their patients, hear how they are

cluding chemotherapies, prescription and over-the-counter medicines and herbs, and supplements, to identify the prevalence of potential medication interactions and the impact they may have on clinical outcomes. Micromedex interactive software was used to identify potential interactions. On average, the respondents took 5.8 medicines during chemotherapy treatment and 5.4 medicines afterward. The use of herbs and supplements increased from 37% while on active treatment to 51% after finishing chemotherapy. The study found 104 potential interactions during chemo-

Richard T. Lee, MD

therapy and 22 after treatment was completed. Overall, 10% of the interactions were considered major, 57% were moderate, and 33% were minor. The study investigators found that one out of three patients with breast or prostate cancer given chemotherapy were at risk for interactions from overthe-counter medications and herbs and supplements. They urged oncologists to be aware of these interactions and to doing on their chemotherapy regimen, and discuss plans for the next phase of treatment, it’s a lot to ask that they also talk to patients about their diet or which supplements they take, or whether they are practicing yoga for stress reduction. Moreover, many conventional organbased oncologists might not have the knowledge to do that, so the default reflex is to say to patients, “Don’t take any supplements” or “Eat whatever you want; it doesn’t matter.”

Mainstreaming Integrative Oncology What has to happen to increase the inclusion of complementary modalities in traditional cancer care? What standards have to be met?

Lorenzo Cohen, PhD

discuss them with their patients.

Expressive Writing Lorenzo Cohen, PhD, of The University of Texas MD Anderson Cancer Center, discussed A Randomized Controlled Trial of Expressive Writing for Patients with Renal Cell Carcinoma. Over 200 patients with renal cell carcinoma were randomly assigned to either write about their deepest thoughts and feelings about their cancer (“expressive writing”) or write about neutral topics such as their diet, on four occasions over 10 days. They were followed for 10 months. At the end of 1 month, the expressive writing group had decreased scores on the Impact of Event Scale (a measure of subjective stress), and after 10 months, the expressive writing group demonstrated decreased levels of intrusive thoughts, avoidance behaviors, cancer-related symptoms, and sleep disturbances.

■

Disclosure: Drs. Thompson, Lee, and Cohen reported no potential conflicts of interest.

The field of integrative oncology is not as mainstreamed as we want it to be. I conducted a workshop at the Ninth International Conference of the Society for Integrative Oncology (SIO) in October on Integrative Oncology Education for the Physician, to begin the dialogue to establish better guidelines for recognizing and accrediting physicians who want to practice integrative oncology. In the meantime, the SIO has published clinical practice guidelines for conventional oncologists interested in increasing their knowledge base of this promising field (integrativeonc.org/siopublishes-2009-practice-guidelines).

■

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

In metastatic melanoma

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

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

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

Indication and Usage: ZELBORAF® (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Please see Brief Summary of Prescribing Information and next page for Important Safety Information.

dEcodE metastatic melanoma.

ExtEnd

Significant improvement in OS vs dacarbazine in a randomized Phase III trial of BRAFV600E(+) patients (N=675)* OS at FDA approval (August 2011)†‡ 100

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

Percentage surviving

80 60

Not reached

7.9

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

20 0

At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine.

‡

There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

OS (months) ZELBORAF (n=337)

†

Dacarbazine (n=338)

Median OS was not reached (NR) for ZELBORAF vs 7.9 months for dacarbazine (95% CI, 9.6 months-NR vs 7.3-9.6 months) The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash Indication and Usage ZELBORAF® (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information Cutaneous squamous cell carcinoma (cuSCC) The incidence of cuSCC, including both SCCs of the skin and keratoacanthomas, was 24%. Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months after therapy. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, generalized rash and erythema, or hypotension, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT prolongation Exposure-dependent QT prolongation has been reported, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes. Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval.

Monitor ECG and electrolytes before treatment and after dose modification. Monitor ECGs at day 15, monthly during the first 3 months of treatment, every 3 months thereafter, or more often as clinically indicated. If the QTc exceeds 500 ms, temporarily interrupt ZELBORAF, correct electrolyte abnormalities, and control cardiac risk factors for QT prolongation. Re-initiate treatment at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values. Liver laboratory abnormalities Liver laboratory abnormalities have occurred. Monitor liver enzymes and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity has been reported. Advise patients to avoid sun exposure and use adequate sun protection. For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions Serious ophthalmologic reactions, including uveitis and retinal vein occlusion, have been reported. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Routinely monitor patients for uveitis.

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

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

Percentage surviving

80 60

13.6 9.7

ASCO=American Society of Clinical Oncology

20 0

Patients crossing over to ZELBORAF were censored.3

At the time of updated analysis, median follow-up was 12.45 months (range, 0.4-24.0 months) for ZELBORAF patients vs 9.45 months (range, 0.0-22.5 months) for those taking dacarbazine.3,4

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

OS (months) Updated analysis of ZELBORAF

Updated analysis of dacarbazine

Median OS reached at 13.6 months with ZELBORAF: ~4-month improvement over dacarbazine median OS of 9.7 months (95% CI, 12.0-15.2 months vs 7.9-12.8 months)3,4

Additionally, blurry vision, iritis, and photophobia were observed. New Primary Malignant Melanoma New primary melanomas were reported in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitor for skin lesions as outlined on previous page [see cuSCC]. Use in Pregnancy: Pregnancy Category D Apprise patients who are pregnant or who may become pregnant that ZELBORAF may cause fetal harm. BRAF Testing Confirmation of BRAFV600E(+) melanoma is required for appropriate patient selection. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was predefined as a grade 3 event. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information.

References: 1. cobas® 4800 BRAF V600 Mutation Test Package Insert. Roche Molecular Systems, Inc. August 2011. 2. Center for Drug Evaluation and Research. Clinical review—NDA 202429: ZelborafTM (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/ 202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed July 23, 2012. 3. Chapman PB, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. Presented at: the 48th Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 8502. 4. Data on file. Genentech, Inc.

zelboraf.com

The ASCO Post | NOVEMBER 15, 2012

PAGE 34

35th ESMO Congress Novel Agents for Breast Cancer and Prostate Cancer Impressive in Early Trials By Alice Goodman and Caroline Helwick

everal sessions at the 2012 European Society for Medical Oncology (ESMO) Congress in Vienna focused on novel targeted therapies in various stages of development. Summarized here are

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

data on two promising drugs for breast cancer and two for prostate cancer.

E-3810 in Breast Cancer Two experimental agents look very

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

promising in early-phase studies. A global trial evaluated E-3810, a novel small-molecule equipotent inhibitor of the fibroblast growth factor receptor (FGFR) and vascular endothelial

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

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

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

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

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

growth factor receptor (VEGFR), in patients with FGFR1-amplified breast cancer.1 Aberrant fibroblast growth factor signaling can promote tumor development by directly driving cancer cell proliferation and survival and by supporting tumor angiogenesis, explained Rodrigo Dienstmann, MD, of Vall d’Hebron University Hospital in Barcelona. FGFR1 (8p 11-12) amplification is observed in 10% of breast tumors, predominantly those of the luminal subtype, and is often associated with resistance to endocrine treatment and poor prognosis. Additionally, fibroblast growth factor 3 (11q 12-14) amplification is seen in 15% to 30% of breast tumors and is associated with aggressiveness.

Investigational Drugs for Breast and Prostate Cancers ■■ In heavily pretreated patients

with FGFR1-amplified breast cancer, E-3810, a novel inhibitor of the fibroblast growth factor receptor and vascular endothelial growth factor receptor, achieved an 80% clinical benefit rate.

■■ In HER2-positive patients

resistant to trastuzumab, BKM120 was associated with a response rate of 10%.

■■ Two novel agents, ODM-210

and OGX-427, had promising preliminary results in phase I/II trials in castration-resistant prostate cancer.

The study evaluated E-3810 (15 and 20 mg) in 15 patients with breast cancer who had received a median of four prior lines of therapy. Among them, 12 patients had fibroblast growth factor– positive tumors with FGFR1 or 11q amplifications while the other three had previous treatment with antiangiogenics. Among 10 fibroblast growth factor–positive patients, 7 partial responses were observed and 1 patient had stable disease, for an 80% clinical benefit rate. Among 2 patients deemed to have antiangiogenic-sensitive tumors, 1 achieved stable disease, Dr. Dienstmann reported. “Many of these responses have been

ASCOPost.com | NOVEMBER 15, 2012

PAGE 35

35th ESMO Congress long-lasting, with patients remaining on treatment for 20-plus weeks,” he said. Several patients have received the drug for 1 year, including a complete responder who had received 14 prior lines of treatment (Fig. 1). One patient with triple-negative breast cancer responded dramatically after 10 prior lines of treatment (Fig. 2). Toxicities of E-3810 were mostly related to antiangiogenic effects, and these were manageable and reversible upon dose reductions. “E-3810 showed significant activity in heavily pretreated breast cancer with FGF aberrations, producing durable responses. This suggests we may have a new subcategory of breast cancer with a targetable aberration,” he concluded.

BKM120 Plus Trastuzumab in HER2-positive Disease In another global phase Ib/II study,

patients with HER2-positive advanced breast cancer resistant to trastuzumab (Herceptin) received the pan-PI3 kinase inhibitor BKM120 in combination with trastuzumab.2 PI3K/mTOR pathway signaling is important for the oncogenic function of HER2. Activating alterations of this pathway are frequently observed in HER2positive breast cancer and generally herald a poor response and resistance to trastuzumab, explained Barbara Pistilli, MD, of the Macerata Hospital in Macerata, Italy, who presented the findings. Among the 50 patients, who had received a median of 2.5 prior lines of HER2-directed therapy, the experimental combination yielded an overall response rate of 10%, including 1 complete response (2%) and 4 partial responses (8%); stable disease was observed in 21 patients (42%), for a dis-

Fig. 1: FGFR1 gene amplification by fluorescence in situ hybridization and array-comparative genomic hybridization in patient receiving E-3810 (20 mg/d). First restaging shows almost complete response in target lung/pleural disease. Patient had FGFR1-amplified, hormone receptor–positive, HER2-negative disease with bone, lung, and pleural metastases. She had received 14 prior lines of treatment, including five phase I trials. Courtesy of Rodrigo Dienstmann, MD.

Fig. 2: Tumor regression with E-3810 (20 mg/d) in Patient 18028. Patient had FGFR1-amplified, locally advanced triple-negative breast cancer with lymph node metastasis. She had received 10 prior lines of treatment. Photos courtesy of Rodrigo Dienstmann, MD.

EXPERT POINT OF VIEW

ommenting on the studies evaluating novel agents in breast cancer, Nicholas Turner, MD, PhD, of the Royal Marsden Hospital in London, observed that for BKM120 plus trastuzumab (Herceptin), the “benefit appears to be in only a relatively small proportion of patients, but in those patients there is an impressive level of activity.” He said the response rates were similar to those seen with everolimus plus trastuzumab, which suggests this drug might be targeting the same subset. Nicholas Turner, MD, PhD There is a clear need to find biomarkers to guide future development of BKM120 in HER2-positive breast cancer, Dr. Turner said, including full analysis of PIK3CA mutations. Regarding E-3810, Dr. Turner called the study results “highly impressive,” suggesting, “It’s hard to imagine a phase�� I trial that has generated more positive data than this one in breast cancer.” He noted that nearly half the patients receiving the 15-mg dose required dose reductions during the first two cycles. Therefore, further work must be done to identify a “chronically tolerable” dose and schedule, he suggested.

■

ease control rate of 52%, she reported. Preliminary evidence of clinical activity in the brain was also observed, as all three patients with target brain lesions at baseline achieved stable disease. “One such patient is still on the drug at 30-plus weeks,” Dr. Pistilli noted. Adverse events were generally manageable and reversible. Mood alterations have been observed, but it is unclear whether these are drug-related, she said. Investigators are currently exploring the relationship between PI3 kinase pathway activation status and clinical response.

ODM-201 in Castrate-resistant Prostate Cancer ODM-201 is a novel androgen receptor antagonist currently in phase I/ II development. Preclinical data suggested that the drug does not penetrate the blood-brain barrier and does not exert partial agonist activity, as does bicalutamide. At the ESMO meeting, a proof-of-concept, first-in-man, doseescalation study showed promising results with the new agent. ODM-201 reduced the levels of prostate-specific antigen (PSA) in men with progressive metastatic castration-resistant prostate cancer.3 Among 15 evaluable patients, 13 (87%) had a decrease of 50% or more in PSA level at 12 weeks; all 6 patients pretreated with docetaxel achieved a PSA decline at 12 weeks. At 12 weeks, partial response or stable disease was seen in all patients, and stable disease in bone was observed in 90% of patients.

In 21 treated patients, ODM-201 has been well tolerated, with no major treatment-emergent adverse events. No dose-limiting toxicities were identified. The most common adverse events were grades 1 and 2 gastrointestinal problems, such as diarrhea and nausea. Although these preliminary results are promising, confirmation will be needed in larger trials, stated lead author Christophe Massard, MD, Senior Consultant, Institut Gustave Roussy, SITEP, Villejuif, France. ODM-201 compares favorably with enzalutamide (Xtandi) and MDV3100, two other new drugs for castration-resistant prostate cancer. ODM-201 achieved stronger PSA responses with less diarrhea and asthenia than enzalutamide, and the novel agent had an improved toxicity profile compared with MDV3100, said formal discussant of this trial, Joan Carles, MD, PhD, Vall d’Hebron University Hospital, Barcelona, Spain. “The numbers of patients are few, and it is not clear what the recommended dose should be for phase II and III trials,” Dr. Carles commented.

OGX-427 Data Encouraging OGX-427 is an investigational heat shock protein (HSP) inhibitor currently in phase I/II trials. A phase I/II study reported at ESMO validated HSP27 as a therapeutic target for prostate cancer. OGX-427 demonstrated antitumor activity in patients with metastatic castration-resistant prostate cancer, achieving objective responses, PSA declines, and continued on page 38

For chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab

EXPAND YOUR OPTIONS A study population in need of additional treatment options1,2

median prior therapies

59%

of patients received prior rituximab

93%

of patients received prior alkylating agents

100%

of patients received prior fludarabine and alemtuzumab

The following serious adverse events (AEs) are discussed in greater detail below: Infusion reactions, cytopenias, progressive multifocal leukoencephalopathy, hepatitis B infection and reactivation, and intestinal obstruction.

To learn more, please visit www.ARZERRA.com. Indication ARZERRA (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Important Safety Information Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina, or other signs and symptoms of myocardial ischemia. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. Infusion reactions occurred in 44% of patients on the day of the first infusion

(300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture. Hepatitis B Infection and Reactivation Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers

When treated with ARZERRA monotherapy, 42% of patients with CLL refractory to fludarabine and alemtuzumab achieved a partial response1 Patients had received a median of 5 prior therapies

Overall response rate with ARZERRA 60 50 40

42%

The investigator-determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) There were no complete responses The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses

30 20 10

FLUDARABINE AND ALEMTUZUMAB REFRACTORY (n=59)

of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insuﬃcient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis. Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected. Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the pivotal study (total population, n=154) the most common adverse reactions (≥10%, all grades) were neutropenia, followed by pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%).

No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA 6.5 months—median duration of response (95% CI: 5.8, 8.3)

Most Common Serious Adverse Reactions In the pivotal study (total population, n=154), where ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses, the most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Please see Brief Summary of Prescribing Information on adjacent pages. How Supplied: Available as 2 different single-use glass vials for dilution and intravenous administration. Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution. References: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Tam CS, O’Brien S, Lerner S, et al. Leuk Lymph. 2007;48(10):1931-1939.

PAGE 38

35th ESMO Congress Novel Agents for Breast Cancer and Prostate Cancer continued from page 35

delay in disease progression. Treatment with OGX-427 was well tolerated.4 “These finding support continued clinical evaluation,” said lead author Kim N. Chi, MD, BC Cancer Agency and Vancouver Prostate Centre, Brit-

ish Columbia, Canada. Patients with metastatic castration-resistant prostate cancer were randomly assigned to OGX-427 plus prednisone (n�� =�� 32) or prednisone alone (n = 33). Crossover was allowed at disease progression; 45% of the prednisone arm crossed over to active treatment during the

The ASCO Post | NOVEMBER 15, 2012 B:22.5” T:21” S:19”

study. OGX-427 had antitumor activity, with a complete and partial response rate of 25%, compared with 12% for prednisone alone. Fortyseven percent of patients treated with OGX-427 had PSA declines of 50% or greater vs 21% with prednisone alone. Any PSA decline was observed in 75% of OGX-427–treated

patients vs 52% of those given prednisone alone. Adverse events were mainly grade 1/2 infusion-related reactions. Grade 1/2 diarrhea, fatigue, and nausea were also reported. Most adverse events occurred during the first or second administration of the drug, Dr. Chi noted.

Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients BRIEF SUMMARY BRIEF SUMMARY Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients Study 1 and inInjection, the Fludarabineand Alemtuzumab-Refractory Subset ARZERRA® (ofatumumab) Injection, for intravenous infusion ARZERRA®in(ofatumumab) in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset for intravenous infusion of Study 1 (MedDRA 9.0) of Study 1 (MedDRA 9.0) The following is a brief summary only; see full prescribing information for The following is a brief summary only; see full prescribing information for complete product information. complete product information. Fludarabine- and Fludarabine- and AlemtuzumabAlemtuzumabTotal Population Total Population 1 INDICATIONS AND USAGE 1 INDICATIONS AND USAGE Refractory (n = 154) of patients Refractory (n = 154) ARZERRA® (ofatumumab) is indicated for the treatment of patients ARZERRA® (ofatumumab) is indicated for the treatment (n = 59) with chronic lymphocytic leukemia (CLL) refractory to fludarabine and with chronic lymphocytic leukemia (CLL) refractory to fludarabine and (n = 59) Grade Grade All All Grade All is basedGrade All alemtuzumab. The effectiveness of ARZERRA is based on the demonstration alemtuzumab. The effectiveness of ARZERRA on the demonstration ≥3Body System/ ≥3 Grades Grades ≥3 Grades Grades Body System/ of durable objective responses [see Clinical Studies (14) of full prescribing of durable objective responses [see Clinical Studies (14)≥3of full prescribing information]. No data demonstrate an improvement in disease-related information]. No dataEvent demonstrate an improvement in disease-related % Adverse Event % % % % % % % Adverse symptoms or increased survival with ARZERRA. symptoms or increased with ARZERRA. Infections andsurvival infestations Infections and infestations Pneumoniaa 23 14 25 15 Pneumoniaa 23 14 25 15 4 CONTRAINDICATIONS 4 CONTRAINDICATIONS Upper respiratory tract Upper respiratory tract None. None. 11 0 3 0 11 0 3 0 infection infection 5 WARNINGS AND PRECAUTIONS 5 WARNINGS AND PRECAUTIONS Bronchitis 11 <1 19 2 Bronchitis 11 <1 19 2 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions5.1 Infusion Reactions ARZERRA can cause serious infusion reactions b 8 8 pulmonary 10edema, 10 Sepsisb 8 8 10 10 manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, manifesting as Sepsis bronchospasm, dyspnea, laryngeal edema, Nasopharyngitis 8 cardiac ischemia/infarction, 0 8 0 Nasopharyngitis 8 0 8 0 flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, flushing, hypertension, hypotension, syncope, Herpes pain, zosterpyrexia, rash, urticaria, 6 1 7Infusion 2 Herpes zoster 6 1 7 2 back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion back pain, abdominal and angioedema. 2 Sinusitis 5 2 3 2 reactions occur more frequently with the first 2 infusions [see Adverse reactions occurSinusitis more frequently with the first5 2 infusions2[see Adverse3 BloodPremedicate and lymphatic Blood and lymphatic Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and Reactions a (6.1)]. with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing corticosteroid [see disorders Dosage and Administration (2.1, 2.4) of full prescribing system system disorders information]. Interrupt infusion for infusion reactions of any severity. Institute information]. Interrupt reactions of any Institute 8 Anemia infusion for infusion 16 5 severity.17 Anemia 16 5 17 8 medical management for severe infusion reactions including angina or medical other management severe infusion reactions including angina or other Psychiatric for disorders Psychiatric disorders signs and symptoms of myocardial ischemia [see Dosage and Administration signs and symptoms of myocardial ischemia7 [see Dosage Insomnia 0 and Administration 10 0 Insomnia 7 0 10 0 (2.3) of full prescribing information]. In a study of patients with moderate (2.3) of full prescribing information]. In a study of patients with moderate Nervous system disorders Nervous system disorders to severe chronic obstructive pulmonary disease, an indication for which to severe chronic obstructive pulmonary disease, an indication for which 6 0 3 bronchospasm 7 0 Headache 6 0 7 0 ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm ARZERRA is notHeadache approved, 2 of 5 patients developed Grade Cardiovascular disorders Cardiovascular disorders during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia during and infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and Hypertension 0 0 Hypertension 5 0 8 0 thrombocytopenia can occur with ARZERRA. Monitor complete blood counts thrombocytopenia can occur with ARZERRA.5Monitor complete blood8counts Hypotension 0 and increase 3 0 Hypotension 5 0 3 0 (CBC) and platelet counts at regular intervals during therapy, and increase (CBC) and platelet counts at regular intervals5 during therapy, Tachycardia <1 3 or 4 cytopenias. 7 2 Tachycardia 5 <1 7 2 the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. the frequency of monitoring in patients who5develop Grade 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal Respiratory, thoracic, and Respiratory, thoracic, and leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. leukoencephalopathy including fatal PML, can occur with ARZERRA. mediastinal(PML), disorders mediastinal disorders Consider PML in any patient with new onset of or changes in pre-existing Consider PML in any patient with new onset19of or changes Cough 0 in pre-existing 19 0 Cough 19 0 19 0 neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, Dyspnea 14 2 19 5 Dyspnea 14 2 19 5 and initiate evaluation for PML including consultation with a neurologist,and initiate Gastrointestinal evaluation for PML including consultation with a neurologist, disorders Gastrointestinal disorders brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation Diarrhea 18 0 19 0 Diarrhea 18 0 19 0 Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can Nausea 11 0 patients12at high 0 Nausea 11 0 12 0 occur in patients following treatment with ARZERRA. Screen patients atoccur high in patients following treatment with ARZERRA. Screen and subcutaneous Skin and subcutaneous risk of HBV infection before initiation of ARZERRA. Closely monitor carriers risk of HBV Skin infection before initiation of ARZERRA. Closely monitor carriers disorders tissue disorders of hepatitis B for clinical and laboratory signs of active HBV infection during of hepatitis tissue B for clinical and laboratory signs of active HBV infection during c Rashc 14 following <1 the last infusion 17 2 14 <1 17 2 treatment with ARZERRA and for 6 to 12 months following the last infusion treatment withRash ARZERRA and for 6 to 12 months Urticaria ARZERRA in patients 8 who develop 0 viral hepatitis 5 0 Urticaria 8 0 5 0 of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis of ARZERRA. or Discontinue or reactivation of viral hepatitis, and institute appropriate treatment. Insufficient reactivation of Hyperhidrosis viral hepatitis, and institute appropriate treatment. Insufficient 5 0 5 0 Hyperhidrosis 5 0 5 0 data exist regarding the safety of administration of ARZERRA in patientsdata withexist regarding the safety Musculoskeletal andof administration of ARZERRA in patients with Musculoskeletal and active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine connective tissue disorders connective tissue disorders can occur in patients receiving ARZERRA. Perform a diagnostic evaluation can occur in patients receiving ARZERRA. Perform a diagnostic evaluation Back pain 8 1 12 2 Back pain 8 1 12 2 if obstruction is suspected. 5.6 Immunizations The safety of immunization if obstruction isMuscle suspected. 5.6 Immunizations The safety of immunization spasms 5 0 3 0 Muscle spasms 5 0 3 0 with live viral vaccines during or following administration of ARZERRA has with live viral vaccines during or following administration of ARZERRA has General disorders and General disorders and not been studied. Do not administer live viral vaccines to patients who have not been studied. Do not administer live viral vaccines to patients who have administration site administration site recently received ARZERRA. The ability to generate an immune response recently to received ARZERRA. The ability to generate an immune response to conditions any vaccine following administration of ARZERRA has not been studied.any vaccineconditions following administration of ARZERRA has not been studied. Pyrexia 20 3 25 5 Pyrexia 20 3 25 5 6 ADVERSE REACTIONS 6 ADVERSE REACTIONS Fatigue 15 0 15 0 Fatigue 15 0 15 0 The following serious adverse reactions are discussed in greater detail The in following serious reactions are9discussed in Edema adverse peripheral <1greater detail 8 in 2 Edema peripheral 9 <1 8 2 other sections of the labeling: other sections of the labeling: Chills 8 0 10 0 Chills 8 0 10 0 • Infusion Reactions [see Warnings and Precautions (5.1)] • Infusiona Reactions [see Warnings and Precautions (5.1)] a Pneumonia includes pneumonia, lung infection, lobar pneumonia, and Pneumonia includes pneumonia, lung infection, lobar pneumonia, and • Cytopenias [see Warnings and Precautions (5.2)] • Cytopenias [see Warnings and Precautions (5.2)] bronchopneumonia. bronchopneumonia. • Progressive Multifocal Leukoencephalopathy [see Warnings and • Progressive Multifocal Leukoencephalopathy [see Warnings and b b Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. Precautions (5.3)] Precautions (5.3)] c c includes rash, macular, rash vesicular. Rash includes rash, rash macular, and rash vesicular. • Hepatitis B Reactivation [see Warnings and Precautions (5.4)] • HepatitisRash B Reactivation [seerash Warnings andand Precautions (5.4)] • Intestinal Obstruction [see Warnings and Precautions (5.5)] • Intestinal Obstruction [see Warnings and Precautions Infusion Reactions: Infusion reactions occurred(5.5)] in 44% of patients on the Infusion Reactions: Infusion reactions occurred in 44% of patients on the The most common adverse reactions (≥10%) in Study 1 were neutropenia, The most common reactions in Study 1 were day of theadverse first infusion (300(≥10%) mg), 29% on the day ofneutropenia, the second infusion day of the first infusion (300 mg), 29% on the day of the second infusion pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, pneumonia,(2,000 pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, Infections:(2,000 mg), and less frequently during subsequent infusions. A mg), and less frequently during subsequent infusions. Infections: A nausea, bronchitis, and upper respiratory tract infections. The most common nausea, bronchitis, andpatients upper respiratory tract infections. Theviral, mostorcommon total of 108 (70%) experienced bacterial, fungal infections. total of 108 patients (70%) experienced bacterial, viral, or fungal infections. serious adverse reactions in Study 1 were infections (including pneumonia serious adverse reactions in Study 1 were infections (including pneumonia A total of 45 patients (29%) experienced ≥Grade 3 infections, of which A19total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 and sepsis), neutropenia, and pyrexia. Infections were the most common and sepsis), neutropenia, andThe pyrexia. Infections were the most (12%) were fatal. proportion of fatal infections in common the fludarabine- and (12%) were fatal. The proportion of fatal infections in the fludarabine- and adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical adverse reactions leading to drug discontinuation in Neutropenia: Study 1. 6.1 Clinical alemtuzumab-refractory group was 17%. Of 108 patients alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients Trials Experience Because clinical trials are conducted under widely varying Trials Experience Because clinical trialsatare conducted underdeveloped widely varying with normal neutrophil counts baseline, 45 (42%) ≥Grade 3with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 conditions, adverse reaction rates observed in the clinical trials of a drug conditions,neutropenia. adverse reaction rates(18%) observed in theGrade clinical trials of a drug Nineteen developed 4 neutropenia. Some patients neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients cannot be directly compared to rates in the clinical trials of another drug cannot and be experienced directly compared to rates in the clinical trials>2 of weeks anotherindrug and new onset Grade 4 neutropenia duration. experienced new onset Grade 4 neutropenia >2 weeks in duration. may not reflect the rates observed in practice. The safety of monotherapy may not reflect the rates observed in practice. The for safety of monotherapy 6.2 Immunogenicity There is a potential immunogenicity with therapeutic 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic with ARZERRA was evaluated in 181 patients with relapsed or refractorywith ARZERRA wassuch evaluated in 181 patients with relapsed or patients refractory proteins as ofatumumab. Serum samples from with CLL in proteins such as ofatumumab. Serum samples from patients with CLL in CLL in 2 open-label, non-randomized, single-arm studies. In these studies, CLL in 2 open-label, non-randomized, single-armimmunosorbent studies. In theseassay studies, Study 1 were tested by enzyme-linked (ELISA) for Study 1 were tested by enzyme-linked immunosorbent assay (ELISA) for ARZERRA was administered at 2,000 mg beginning with the second dose ARZERRA was administered antibodies at 2,000 mg beginning withthe the24-week second treatment dose anti-ofatumumab during and after period. anti-ofatumumab antibodies during and after the 24-week treatment period. for 11 doses (Study 1 [n = 154]) or 3 doses (Study 2 [n = 27]). The datafor 11 doses (Studywere 1 [nnegative = 154]) in or 46 3 doses (Study [n 8=th27]). Theand datain 33 patients Results patients after2the Results were negative in 46 patients after the 8th infusion and in 33 patients infusion th described in Table 1 and other sections below are derived from 154 patients described in Table other sections below areassay derived fromare 154 patients after the112and infusion. Immunogenicity results highly dependentafter on the 12th infusion. Immunogenicity assay results are highly dependent on in Study 1. All patients received 2,000 mg weekly from the second dosein Study 1.several All patients received 2,000 mgsensitivity weekly from secondassay dose methodology, factors including assay and the specificity, several factors including assay sensitivity and specificity, assay methodology, onward. Ninety percent of patients received at least 8 infusions of ARZERRA onward. Ninety percent of patients at least 8 infusions of ARZERRA sample handling, timing ofreceived sample collection, concomitant medications, and sample handling, timing of sample collection, concomitant medications, and and 55% received all 12 infusions. The median age was 63 years (range: and4155% received alldisease. 12 infusions. The reasons, median age was 63 years (range:of41antibodies underlying underlying disease. For these reasons, comparison of incidence of antibodies to For these comparison of incidence to to 86 years), 72% were male, and 97% were White. to 86 years), 72% were and 97%ofwere White.to other products may be misleading. ARZERRA withmale, the incidence antibodies ARZERRA with the incidence of antibodies to other products may be misleading.

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35th ESMO Congress

hibitor, in patients with FGFR1 amplified breast cancer. 2012 ESMO Congress. Abstract 3190. Presented October 1, 2012. 2. Pistilli B, Urruticoechea A, Chan S, et al: Ph IB/II study of BKM120 plus trastuzumab in patients with trastuzumab-resisReferences tant HER2+ advanced breast cancer. 2012 1. Dienstmann R, Andre F, Soria J-C, ESMO Congress. Abstract 3180. Presented et al: Significant antitumor activity of October 1, 2012. E-3810, a novel FGFR and VEGFR in3. Massard C, James N, Culine S, et al: ARADES trial: A first-in-man, open-label, phase I and II safety, pharmacokinetic, and proof-of-concept study of ODM-201 in patients progressiveantibody metastatic casFetuses from treated dams exhibiting anti-ofatumumab antibody responses Fetuses from treated dams exhibitingwith anti-ofatumumab responses 7 DRUG INTERACTIONS 7 DRUG INTERACTIONS had higherinteraction B cell counts and higher spleen weights compared to the fetuses had higher B cell counts and higher spleen weights compared to the(CRPC). fetuses No formal drug-drug interaction studies have been conducted with ARZERRA. No formal drug-drug studies have been conducted with ARZERRA. tration-resistant prostate cancer from other treated dams, indicating partial recovery in those animals from other treated dams, indicating partial recovery in those animals 8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS 2012 ESMOWhen Congress. LBA25. developing anti-ofatumumab antibodies. When compared to control animals, developing anti-ofatumumab antibodies. comparedAbstract to control animals, 8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled 8.1 Pregnancy Pregnancy Category C: There aredose no adequate or well-controlled fetuses from treated dams in both groups had a 10% decrease in fetuses mean from treated dams in both dose groups had a30, 10% decrease in mean Presented September 2012. studies of ofatumumab in pregnant women. A reproductive study in pregnant studies of ofatumumab in pregnant women. A reproductive study in pregnant placental weights. A 15% decrease in mean thymus weight compared to placental weights. A 15% decrease in mean thymus weight compared to cynomolgus monkeys that received ofatumumab at doses up to 3.5 timescynomolgus the monkeys that received ofatumumab at doses updams to 3.5treated times the 4. inChi K, Yu Ellard et al: A ranthe controls was also observed in fetuses from with 3.5 times the controls was also observed fetuses fromEY, dams treatedS,with 3.5 times recommended human dose of ofatumumab did not demonstrate maternalrecommended didThe notbiological demonstrate maternal of decreased the human humandose doseofofofatumumab ofatumumab. significance the human dose of ofatumumab. Thephase biological significance of decreasedplus domized II study of OGX-427 toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses toxicity or teratogenicity. crossed the placental barrier, and fetuses placental andOfatumumab thymic weights is unknown. The kinetics of B-lymphocyte placental and thymic weights is unknown. The kinetics of B-lymphocyte exhibited depletion of peripheral B cells and decreased spleen and placental exhibited depletion peripheral B cells long-term and decreased spleen and placental (P) vs. P aloneB-cell in patients recoveryofand the potential effects of perinatal B-cell depletion recovery in and the potentialprednisone long-term effects of perinatal depletion with in weights. ARZERRA should be used during pregnancy only if the potential benefit weights. ARZERRA should be used during pregnancy only if the potential benefit offspring from ofatumumab-treated dams have not been studied in animals. offspring from ofatumumab-treated dams have not resistant been studied in animals. metastatic castration prostate canto the mother justifies the potential risk to the fetus. There are no human orto the mother justifies the potential risk to the fetus. There are no human or COUNSELING INFORMATION 17 PATIENT COUNSELING animal data on the potential short- and long-term effects of perinatal B-cell animal data17 on PATIENT the potential short- and long-term effects of perinatal B-cell cerINFORMATION (CRPC). 2012 ESMO Congress. Abpatients to contact healthcare professional Ofatumumab for any of the following: Advise patients to contact a healthcare professional for any of the following: depletion in offspring following in utero exposure to ofatumumab. Ofatumumab depletion inAdvise offspring following in utero aexposure to ofatumumab. stract 900. Presented September 30,rash, 2012. • normal Signs and symptoms of infusion including fever, chills, rash, • Signs and symptoms of infusion reactions including fever, chills, does not bind normal human tissues other than B lymphocytes. It is not known does not bind human tissues other than Breactions lymphocytes. It is not known

Ongoing development includes two randomized phase II studies of OGX-427 in combination with abiraterone acetate (Zytiga) for patients with metastatic castration-resistant prostate cancer and in combination with gemcitabine/cisplatin in patients with bladder cancer. Speaking about ODM-201 and

OGX-427, Dr. Carles said that both drugs represent potential new agents for the treatment of castration-resistant prostate cancer. If these drugs are approved, the challenge will be how to integrate them with other newly approved drugs in this setting to identify the best combinations and optimal sequencing.

Disclosure: Dr. Turner has consulted for and received honoraria from Novartis and EOS. Dr. Chi has received research funding from OncoGeneX. Drs. Dienstmann, Pistilli, and Carles reported no potential conflicts of interest.

■

or to breathing problems or within hours of infusion [see Warnings and or breathing problems within 24 hours of infusion [see Warnings and if binding occurs to unique embryonic or fetal tissue targets. In addition, the if binding occurs unique embryonic fetal 24 tissue targets. In addition, the Precautions (5.1) and (6.1)] Precautions (5.1) and Adverse Reactions (6.1)] kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion kinetics of B-lymphocyte recovery areAdverse unknownReactions in offspring with B-cell depletion • Bleeding, easy bruising, petechiae, pallor,Itworsening weakness, • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers is not known whether or fatigue Warnings and Precautions (5.2)] [see Warnings and Precautions (5.2)] ofatumumab is secreted in human milk; however, human IgG is secreted inofatumumab is[see secreted in human milk; however, human IgG is secreted in Signs of data infections including fever and infant coughconsumption [see Warnings human milk. Published data suggest that neonatal and infant consumptionhuman of milk.•Published suggest that neonatal of and • Signs of infections including fever and cough [see Warnings and Precautions and Adverse Reactions (6.1)] Precautions (5.2) and Adverse Reactions (6.1)] breast milk does not result in substantial absorption of these maternal antibodies breast milk does not result in(5.2) substantial absorption of these maternal antibodies • New neurological symptoms such as confusion, or loss of • New neurological symptoms such as confusion, dizziness or loss of into circulation. Because the effects of local gastrointestinal and limited systemic into circulation. Because the effects of local gastrointestinal anddizziness limited systemic balance, difficulty talking or walking, or vision problemswhen [see Warnings and balance, difficulty talking or walking, or vision problems [see Warnings and exposure to ofatumumab are unknown, caution should be exercised when exposure to ofatumumab are unknown, caution should be exercised Precautionsto(5.3)] Precautions (5.3)] ARZERRA is administered to a nursing woman. 8.4 Pediatric Use SafetyARZERRA and is administered a nursing woman. 8.4 Pediatric Use Safety and • ofSymptoms hepatitis including worsening fatigue8.5 or Geriatric yellow discoloration • Symptoms of hepatitis including worsening fatigue or yellow discoloration effectiveness of ARZERRA have not been established in children. 8.5 Geriatric effectiveness ARZERRA of have not been established in children. of skinoforARZERRA eyes [see andsufficient Precautions (5.4)] of subjects of skin or eyes [see Warnings and Precautions (5.4)] Use Clinical studies of ARZERRA did not include sufficient numbers of subjects Use Clinical studies didWarnings not include numbers Newtoordetermine worsening abdominal or nausea [seefrom Warnings and • New or worsening abdominal pain or nausea [see Warnings and aged 65 and over to determine whether they respond differently from younger aged 65 and• over whether they pain respond differently younger Precautions (5.5)] Precautions (5.5)] subjects [see Clinical Pharmacology (12.3) of full prescribing information]. subjects [see Clinical Pharmacology (12.3) of full prescribing information]. • PregnancyNoorformal nursing [see Use in Specificin Populations 8.3)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal 8.6 Renal Impairment studies of ARZERRA patients with(8.1, renal Advise patients of the need for: Advise patients of the need for: impairment have been conducted [see Clinical Pharmacology (12.3) of impairment full have been conducted [see Clinical Pharmacology (12.3) of full Editorial Periodic monitoring forImpairment blood counts Warnings Precautions •(5.2)] Periodic monitoring for blood counts [see Warnings and Precautions (5.2)] prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA prescribing •information]. 8.7 Hepatic No[see formal studiesand of ARZERRA Correspondence • Avoiding vaccinationhave with been live viral vaccines [see Warnings and • Avoiding vaccination with live viral vaccines [see Warnings and in patients with hepatic impairment have been conducted. in patients with hepatic impairment conducted. Precautions (5.6)] Precautions (5.6)] James O. Armitage, MD 10 OVERDOSAGE 10 OVERDOSAGE by: overdosage with ARZERRA. Manufactured by: No data are available regarding overdosage with ARZERRA. No data areManufactured available regarding Editor-in-Chief GLAXO GROUP LIMITED GLAXO GROUP LIMITED e-mail: Editor@ASCOPost.com 13 NONCLINICAL TOXICOLOGY 13 NONCLINICAL TOXICOLOGY Greenford, Middlesex, UB6 0NN, United Kingdom Greenford, Middlesex, UB6 0NN, United Kingdom 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity Cara H. Glynn U.S. Lic. 1809 U.S. Lic. 1809 or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose Director of Editorial Distributed by: or unexpected mitogenic responses were noted in Distributed by: toxicity study, no tumorigenic or unexpected mitogenic responses were noted toxicity in study, no tumorigenic e-mail: Cara@harborsidepress.com cynomolgus monkeys treated for 7 months with up to 3.5 times the humancynomolgus dose monkeys treated for 7 months with up to 3.5 times the human dose Phone: 631.935.7654 of ofatumumab. Effects on male and female fertility have not been evaluated of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies. 13.3 Reproductive and Developmental Toxicology in animal studies. 13.3 Reproductive and Developmental Toxicology Andrew Nash Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose GlaxoSmithKline GlaxoSmithKline Assoc. Director of Editorial of ofatumumab weekly during the period of organogenesis (gestation days of ofatumumab weekly during the period of organogenesis (gestation days Research Triangle Park,orNCteratogenicity. 27709 Research Triangle Park, NC 27709 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of 20 to 50) had no maternal toxicity Both dose levels of e-mail: Andrew@harborsidepress.com ofatumumab depleted circulating B cells in the dams, with signs of initial ofatumumab depleted circulating B cells in thereserved. dams, with signs of initial Phone: 631.935.7657 ©2011, GlaxoSmithKline. All rights ©2011, GlaxoSmithKline. All rights reserved. B cell recovery 50 days after the final dose. Following Caesarean section B cell recovery 50 days after the final dose. Following Caesarean section September September 2011 at gestational day 100, fetuses from ofatumumab-treated dams exhibited at gestational day 100,2011 fetuses from ofatumumab-treated dams exhibited ARZ:6BRS ARZ:6BRS decreases in mean peripheral B-cell counts (decreased to approximately decreases in mean peripheral B-cell counts (decreased to approximately Rights & Permissions 10% of control values), splenic B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15 to 20% of control values), and spleen weights (decreased by 15% for 15 theto 20% of control values), and spleenGroup weights ©2011 The GlaxoSmithKline of (decreased Companies by 15% for the ©2011 The GlaxoSmithKline Group of Companies e-mail: 2011 low-dose and by 30% for the high-dose group, compared to control values). low-dose and 30%reserved. for the high-dose compared to control values). All by rights Printed in group, USA. AZA295R0 September 2011 All rights reserved. Printed in USA. AZA295R0 September Permissions@harborsidepress.com

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The ASCO Post | NOVEMBER 15, 2012

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35th ESMO Congress Supportive Care

Does Prophylaxis Prevent Catheter-related Thrombosis? By Caroline Helwick

n ambulatory patients with cancer, the risk of catheter-related deepvein thrombosis can be reduced by almost half with anticoagulation prophylaxis, according to a single-center French study presented at the 2012 European Society for Medical Oncology (ESMO) Congress in Vienna.1 Catheters implanted for chemotherapy delivery create a risk for deepvein thrombosis that ranges from 0.3% to 28.3% for symptomatic events, rising to 27% to 66% when asymptomatic episodes are included, said Sandrine Lavau-Denes, MD, of the University Hospital Limoges in France. “But the current guidelines of ASCO, the American College of Chest Physicians, and the French

National Federation of the League of Centers Against Cancer do not recommend prophylactic anticoagulant treatment for cancer outpatients,” Dr. Lavau-Denes noted. “In recent studies and meta-analyses, the results are still contradictory, perhaps because of the heterogeneity of the screened patients.”

Randomized Trial To help resolve the controversy, Dr. Lavau-Denes and colleagues conducted a phase� �� III �� prospective, randomized, open-label trial spanning a 10-year period at their center (1999– 2010), comparing a prophylactic strategy to no prophylaxis during 3 months of chemotherapy among

Prophylaxis for Catheter-related Thrombosis ■■ The risk of catheter-related deep-vein thrombosis was reduced by 45% with warfarin or low-molecular-weight heparin in a large single-center French study.

■■ The overall incidence of catheter-related deep-vein thrombosis was 10%; symptomatic catheter-related deep-vein thrombosis occurred in 3%.

■■ Risk of major bleeding was not increased with prophylaxis. ■■ The study results need to be confirmed in a double-blind, randomized trial. 420 patients with advanced solid tumors. “We found that prophylaxis with either warfarin or low-molecularweight heparin was effective in preventing thrombotic events, and there was no increase in bleeding with prophylaxis,” Dr. Lavau-Denes reported.

The primary endpoint was the rate of symptomatic and asymptomatic catheter-related deep-vein thrombosis of the ipsilateral upper limbs and cervical veins of patients, excluding intraluminal thrombosis. The study randomly assigned patients starting a first line of treat-

EXPERT POINT OF VIEW By Fausto Roila, MD Director, Medical Oncology Division, Santa Maria Hospital Terni, Italy

Fausto Roila, MD

hromboprophylaxis for patients with a central venous catheter is at present not recommended by the international oncologic associations. This is based on the results of four recent randomized controlled trials, three of them double-blind, in which there was no statistically significant difference between patients undergoing and not undergoing prophylaxis.1-4 In these studies, the incidence of symptomatic catheter-related venous thromboembolism was generally low, about 3% to 4%, compared with about 12% to 18% when asymptomatic patients were evaluated. On the other hand, two old, open-label, randomized studies suggested a role for prophylaxis with warfarin or low-molecular-weight heparin.5,6 Dr. Lavau-Denes evalu-

ated the efficacy of these two anticoagulant drugs vs no treatment in a study carried out in 407 patients. The incidence of central venous catheter–related thrombosis was significantly lower in patients receiving prophylaxis with the two anticoagulant drugs (8.1% [22/272] vs 14.8% [20/135], respectively). No difference was shown between warfarin and low-molecular-weight heparin. The anticoagulant prophylaxis did not significantly increase bleeding.

Study Limitations The study by Dr. Lavau-Denes and her colleagues is important, but it has some limitations. It is not a blinded study, which is necessary to avoid selection bias. In fact, knowing the treatment received by the patients, the investigators might have performed more systematic Doppler ultrasound of the upper limbs and cervical veins or venography in the asymptomatic patients not submitted to anticoagulant prophylaxis, thus identifying in this subgroup of patients more catheter-related thrombosis. As a consequence, a possible statistically significant difference between patients undergoing and not undergoing thrombo-

prophylaxis would be observed. Furthermore, the incidence of thrombosis among symptomatic patients in the control arm—about 7%—is higher than the generally observed incidence of 3% to 4%. This could also be responsible for the significant difference observed in the study between patients receiving and not receiving anticoagulant prophylaxis. The study is a single-center study that required 11 years to be completed. In this long period, many things could have changed—for example, the assessment of the response to anticoagulant therapy could have improved due to more advanced instrumentation. Finally, if we compare warfarin vs no treatment and low-molecular-weight heparin vs no treatment (as the authors have done for the evaluation of adverse events), the differences are not statistically significant. Therefore, I think that the results of the study by Dr. LavauDenes should be confirmed by other double-blind, randomized clinical trials before the recommendations on thromboprophylaxis are changed.

■

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

References 1. Heaton DC, Han DY, Inder A: Minidose (1 mg) warfarin as prophylaxis for central vein catheSee Page 108 ter thrombosis. Intern Med J 32:84-88, 2002. 2. Couban S, Goodyear M, Burnell M, et al: Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis in patients with cancer. J Clin Oncol 23:4063-4069, 2005. 3. Karthaus M, Kretzschmar A, Kroning H, et al: Dalteparin for prevention of catheter-related complications in cancer patients with central venous catheters: Final results of a double-blind, placebo–controlled phase III trial. Ann Oncol 17:289-296, 2006. 4. Verso M, Agnelli G, Bertoglio S, et al: Enoxaparin for the prevention of venous thromboembolism associated with central vein catheter: A double-blind, placebocontrolled, randomized studies in cancer patients. J Clin Oncol 23:4057-4062, 2005. 5. Bern MM, Lokich JJ, Wallach SR, et al: Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomised prospective trial. Ann Intern Med 112:423-428, 1990. 6. Monreal M, Alastrue A, Rull M, et al: Upper extremity deep venous thrombosis in cancer patients with venous access device-prophylaxis with a low molecular weight heparin (Fragmin). Thromb Haemost 75:251-253, 1996.

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35th ESMO Congress Approximately one-quarter of patients discontinued prophylaxis, with no difference among the arms. For 12.5% of the control arm, the reason for discontinuation was the occurrence of a thrombotic event, compared to 2.2% of the warfarin arm and 2.2% of the low-molecular-weight heparin arm.

Overall, these results suggest that thromboprophylaxis can benefit patients with cancer receiving chemotherapy. “We think that these new results should lead to a new [consideration] of the guidelines,” said Dr. Lavau-Denes.

■

Disclosure: Dr. Lavau-Denes reported no potential conflicts of interest.

Reference 1. Tubiana-Mathieu N, Lavau-Denes S, Lacroix P, et al: Prophylaxis of catheter-related deep vein thrombosis in cancer patients with low-dose warfarin, low molecular weight heparin, or control: A randomized, controlled, phase III study. 2012 ESMO Congress. Abstract 15460. Presented October 1, 2012.

Sandrine Lavau-Denes, MD

ment—142 to low-molecular-weight heparin, 138 to warfarin, and 140 to a control arm. Patients were evaluated at baseline and on day 90 (sooner, in the case of symptoms), using Doppler ultrasound of the upper limbs and cervical veins, and venography.

FOR A DIFFERENT PERSPECTIVE IN RENAL CELL CARCINOMA, DISCOVER…

ANOTHER SIDE OF RCC

Effectiveness of Prophylaxis Among 407 evaluable patients, catheter-related deep-vein thrombosis occurred in 42 patients (10.3%), 30 of whom were asymptomatic. This included 20 (14.8%) of 135 patients in the control arm and 22 (8.1%) of 272 patients receiving either warfarin or low-molecular-weight heparin. Warfarin and low-molecular-weight heparin had no difference in efficacy. Thromboprophylaxis was associated with a 45% reduction in risk that was statistically significant (P = .0357), Dr. Lavau-Denes reported. The events were symptomatic in 6.7% of the control arm, and in 1.1% of the combined-intervention arm. Asymptomatic events occurred in 8.1% and 7.0% of the two groups, respectively. Unrelated deep-vein thromboses were also prevented, occurring in 5.1% of the control arm and 0.7% of the intervention arm. For all but one of these 9 patients, the episode was symptomatic.

Adverse Events The preventive effect was achieved without a significant increase in adverse events. Bleeding occurred in 0.7% of controls, 2.2% of the low-molecular-weight heparin arm, and 4.5% of the warfarin arm (P = .1361). However, there was an increase in thrombopenia among patients receiving t h ro m b o p ro p hylaxis (P < .0001), See Page 108 particularly with low-molecular-weight heparin; this effect was grade 3/4 in only 12 (8.8%), 4 (3.0%), and 7 (5.0%), respectively, with no significant difference among the arms (P = .1039).

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…

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

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PAGE 42

JCO Spotlight

Adjuvant Chemotherapy for Breast Cancer Predicted by Disease, Age, and Insurance Type, but Not by Race By Matthew Stenger

reast cancer mortality has been found to be higher among black and Hispanic women than among white women, with the differences in outcome being attributed in part to more advanced disease stage and greater frequency of unfavorable tumor biology among black and Hispanic women. Studies to date have not yielded a consistent picture of potential differences in chemotherapy use by race/ethnicity.

Jennifer J. Griggs, MD, MPH

In a study reported in Journal of Clinical Oncology, Jennifer J. Griggs, MD, MPH, and colleagues from the University of Michigan in Ann Arbor, Robert Woods Johnson Medical School in New Jersey, University of Southern California in Los Angeles, and University of California at Berkeley, found that adjuvant chemotherapy use in women with breast cancer was strongly determined by disease characteristics, as well as by age and insurance status, and that white women were not more likely to receive chemotherapy than were black or Hispanic women.1

Study Design The study consisted of analysis of survey responses from women (N = 3,252) diagnosed with breast cancer between August 2005 and May 2007 and reported to the Detroit or Los Angeles SEER (Surveillance, Epidemiology, and End Results) registry. All eligible black patients in Los Angeles and Detroit and Hispanic patients in Los Angeles were recruited, as was a

Visit

random sample of white patients. To clarify the role of acculturation, outcomes in Hispanic women were assessed by acculturation group; acculturation was measured by the Short Acculturation Scale for Hispanics (SASH), which assesses language preference (English or Spanish) on a numbered scale. The investigators hypothesized that Hispanics with low levels of acculturation would be at higher risk for not receiving adjuvant chemotherapy. The survey was sent to 3,133 patients and completed by 2,290 (73%). Of these, 1,403 constituted the final study population, with 458 women being excluded because they had ductal carcinoma in situ and 305 being excluded due to missing information on any of the covariates assessed in the study. There was a significant difference in proportion of women by race/ ethnicity who returned a completed questionnaire (57% of black women, 61% of Hispanic women, and 69% of

Adjuvant Chemotherapy in Breast Cancer ■■ A population-based study found that disease characteristics, age, and insurance status were strongly associated with the use of adjuvant chemotherapy in patients with breast cancer.

■■ The investigators found no data suggesting that race and ethnicity had a direct impact on likelihood of chemotherapy use.

women. Black women were more likely than white or Hispanic women to have two or more comorbid conditions.

Multivariate Predictors of Adjuvant Therapy Adjuvant chemotherapy was received by 65% of black women, 71% of low-acculturated Hispanic women, 65% of high-acculturated Hispanic women, and 57% of white women <� �� .001 across groups). On multi(P �� variate analysis, being Hispanic, tumor characteristics, younger age, and having health insurance other than Medicaid were predictors of receipt

[I]t seems that race and ethnicity need not pose barriers to receipt of adjuvant chemotherapy. Such a finding is encouraging as we continue to address racial and ethnic disparities in the receipt of quality cancer care. white women; P < .001). Response rates did not differ by age. The study population included 673 white women, 186 low-acculturated Hispanic women, 183 highacculturated Hispanic women, and 361 black women. As had been found in prior studies, black and Hispanic women were significantly more likely to have been diagnosed at a younger age (P = .002) and to have stage II or III disease (vs stage I, P = .001), hormone receptor–negative disease <� �� .001), and higher grade histol(P �� ogy (P < .001) compared with white

of adjuvant chemotherapy. Number of comorbid conditions, education level, income level, and marital status were not independently associated with receipt of chemotherapy. Key data included the following: ■■ Compared with white women (referent category), low-acculturated Hispanic women (odds ratio [OR]� = �� 2.00, �� 95% confidence interval [CI] = 1.31–3.04) and highacculturated Hispanic women (OR = 1.43, 95% CI = 1.03–1.98) were both significantly more likely to receive chemotherapy. In black

women, this difference was not significant. ■■ Patients with stage II (OR = 17.3, 95% CI = 13.7–21.7) or stage III disease (OR = 52.3, 95% CI = 33.7–81.2) were significantly more likely to receive chemotherapy compared with women with stage I disease, as were estrogen receptor–negative or progesterone receptor–negative patients (OR =3.34, 95% CI = 2.51–4.44) vs hormone receptor–positive patients, and patients with histologic grade 2 (OR = 2.91, 95% CI = 2.24–3.78) or grade 3 tumors (OR = 4.39, 95% CI = 3.27–5.88) vs patients with grade 1 tumors. ■■ For each increasing year of age, patients were significantly less likely to receive chemotherapy (OR = 0.91, 95% CI = 0.90–0.92). Nearly all patients aged 30 years or less received chemotherapy, as did more than 90% of those aged 30 to 39 years; chemotherapy was received by approximately 80% of patients in the 40 to 49 year age group, 70% of the 50 to 59 year group, 55% of the 60 to 69 year group, 35% of the 70 to 79 year group, and 30% of the 80 year or older group. The authors noted that while an association of chemotherapy with age is consistent with previous findings, the finding of reduced use in patients younger than 50 years was particularly surprising. ■■ Compared with Medicare (referent category), patients with Medicaid were significantly less likely (OR = 0.59, 95% CI = 0.37–0.95)

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PAGE 43

JCO Spotlight

and patients with other insurance were significantly more likely to receive adjuvant chemotherapy (OR = 1.50, 95% CI = 1.09–2.08), whereas patients with no insurance were more likely to receive chemotherapy (OR = 1.77, 95% CI = 0.98–3.19).

Patient-reported Reasons Among reasons for not receiving adjuvant chemotherapy reported by patients (n = 633), physician-related reasons included “physician said I did not need it” in 74% of cases and “physician did not discuss it with me” in 3%. Patient-related reasons included “physician left it up to See Page 108 me and I chose not to” in 16% of cases, “worried about side effects or complications” in 9%, “did not want to lose my hair” in 3%, and “would have been too much of a burden on me/my family” in 3%. The investigators acknowledge that response bias may have played a role in study findings, since receipt of chemotherapy and the covariates assessed may have differed in the substantial and unequal proportions of women

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who did not respond to the survey. Further, the study could not ascertain whether the quality of chemotherapy in those receiving it was equivalent across patient subgroups. As concluded by the investigators, “[I]t seems that race and ethnicity need not pose barriers to receipt of adjuvant chemotherapy. Such a finding is

encouraging as we continue to address racial and ethnic disparities in the receipt of quality cancer care. Nonetheless, differences and disparities do exist in receipt of chemotherapy according to age [and] insurance status.… These findings identify opportunities to continue to improve the quality of breast cancer care.”

■

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

Reference 1. Griggs JJ, Hawley ST, Graff JJ, et al: Factors associated with receipt of breast cancer adjuvant chemotherapy in a diverse population-based sample. J Clin Oncol 30:3058-3064, 2012.

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

Trials Now Enrolling

TRINOVA-1: A Phase 3, Randomized, Double-Blind Trial of Weekly Paclitaxel Plus Trebananib (AMG 386) or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant, Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

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

Primary Endpoint: • Progression-free survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

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

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

Trebananib IV QW + Paclitaxel IV QW (3 on/1 off)

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + Paclitaxel IV QW (3 on/1 off)

Trebananib IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Trebananib IV QW Monotherapy

Primary

PFS

2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

ENDPOINTS

Placebo IV QW Monotherapy

Key Secondary

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

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

@ASCOPost

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

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com (20090508) • www.ClinicalTrials.gov (NCT01204749)

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

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com (20101129) • www.ClinicalTrials.gov (NCT01493505)

The ASCO Post | NOVEMBER 15, 2012

PAGE 44

Journal Spotlight Thoracic Oncology

Nab-paclitaxel vs Solvent-based Paclitaxel in First-line Treatment of Advanced Non–Small Cell Lung Cancer: Final Results By Matthew Stenger

anoparticle albumin-bound (nab)-paclitaxel (Abraxane) is a solvent-free paclitaxel formulation intended to reduce solvent-related adverse reactions and improve tumor penetration via the physiologic transport properties of albumin. The final results of a phase III trial comparing nab-paclitaxel and solvent-based paclitaxel injection in combination with carboplatin as first-line treatment of advanced non–small cell lung cancer (NSCLC) were reported by Socinski and colleagues in Journal of Clinical Oncology.1 The study showed a significantly greater overall response rate and reduced neuropathy with nabpaclitaxel. The improved response rate demonstrated in the study supported the recent approval of nab-paclitaxel combined with carboplatin as first-line treatment of advanced NSCLC. (For more on using nab-paclitaxel in this setting, see page 47.) Subset analyses in the trial also suggested potential response and survival advantages with nab-paclitaxel treatment.

Study Design In this trial,2,3 1,052 patients with nonresectable stage IIIB or stage IV NSCLC received nab-paclitaxel at 100 mg/m2 via weekly infusion (n = 521) or solvent-based paclitaxel at 200 mg/ �� =� �� 531). All pam2 every 3 weeks (n� �� tients received carboplatin at area under the curve (AUC) 6 mg • min/ mL every 3 weeks. Steroid/antihistamine premedication was required in the solvent-based paclitaxel group and used at investigator discretion in the nab-paclitaxel group. Patients were to receive at least six cycles of treatment. The primary endpoint was overall response rate. The nab-paclitaxel and conventional paclitaxel groups were well matched for age (median = 60 years in both groups, 14% and 15% aged ≥ 70 years), sex (75% male in both), race (80% and 82% white), region, ECOG performance status (1 in 74% and 78%), histology (adenocarcinoma in 49% and 50%, and squamous cell carcinoma in 44% and 42%), disease stage (IV in 79% of both), and smoking status (never smoked in 26% and 27%, still smokes in 41% and 44%). Prior thera-

py included radiation therapy in 7% of nab-paclitaxel patients and 9% of solvent-based paclitaxel patients and chemotherapy in 3% and 2%, respectively.

Improved Overall Response Rates Patients in both groups received a median of six cycles of treatment. On independent radiology assessment, overall response rate was 33% in the nab-paclitaxel group vs 25% in the solvent-based paclitaxel group (response rate ratio = 1.313, P = .005). All responses were partial responses, except for one complete response in the conventional paclitaxel group. Overall response rate was significantly greater with nab-paclitaxel among patients with squamous cell histology (41% vs 24%, response rate ratio = 1.680, P < .001); there was no difference between treatments in pa-

in Russia/Ukraine (44%). As in the analysis in the intent-to-treat population, the nab-paclitaxel group had a nonsignificant increase in overall survival among patients receiving secondline therapy.

<�� .001). Medi0%, P �� an time to improvement of grade 3 or 4 sensory neuropathy to grade 1 was See Page 108 38 days in the nabpaclitaxel group and 104 days in the conventional paclitaxel group. Grade 3 myalgia (2% vs <1%, P = .011) and arthralgia (2% vs 0%, P = .008) were more common in the conventional paclitaxel group. One treatment-related death occurred in each group. Treatment was discontinued due to unacceptable toxicity without progressive disease in 12% of both groups and due to adverse events in 4% of nab-paclitaxel patients and 5% of conventional paclitaxel patients. Paclitaxel dose reductions occurred in 46% of nab-paclitaxel patients vs 23% of conventional paclitaxel patients, primarily due to neutropenia (29% vs 10%), thrombocytopenia (13% vs 4%), anemia (6% vs <1%), and sensory neuropathy (2% vs 6%). Still, paclitaxel dose intensity was 26% higher and cumulative dose was 18% greater in the nab-paclitaxel group. Dose delays occurred in 82% vs 54% of patients. On the patient-reported Functional Assessment of Cancer Therapy (FACT)-Taxane scale, assessed on day� �� 1�� of each treatment cycle, significant improvements in mean change from baseline were reported for the neuropathy subscale, pain subscale, and hearing loss subscale for the nabpaclitaxel group vs the solvent-based paclitaxel group.

Reduced Sensory Neuropathy

Study Implications

Safety data were reported as treatment-related adverse events. Grade 3 and 4 thrombocytopenia (13% and 5% vs 7% and 2%, P < .001) and anemia (22% and 5% vs 6% and < 1%, P < .001) were significantly more common in nab-paclitaxel patients and grade 3 and 4 neutropenia (32% and 26% vs 33% and 14%, P < .001) was significantly more common in conventional paclitaxel patients. Febrile neutropenia occurred in 1% of both treatment groups. Sensory neuropathy of all grades was significantly more common in the conventional paclitaxel group (62% vs 46%, P < .001), as was grade 3 and 4 neuropathy (11% and < 1% vs 3% and

The investigators noted that the treatment differences in survival observed in the North American subpopulation may reflect regional differences in baseline characteristics and standards of care. They also noted that the intriguing finding of pronged median overall survival in nab-paclitaxel–treated patients aged ≥ 70 years could have been related to better tolerability of the weekly nabpaclitaxel schedule and should be confirmed in an additional study. Although the significantly higher overall response rate in nab-paclitaxel patients with squamous cell histology did not translate into significantly great-

significantly prolonged with nab-paclitaxel treatment in North American patients (12.7 vs 9.8 months, P = .008) and in patients aged ≥ 70 years (19.9 vs 10.4 months, P = .009); no differences between treatments were observed among the 724 patients from Russia/ Ukraine or 149 patients from Japan or among patients aged < 70 years. By histology subtype, median overall survival was 10.7 months in the nab-paclitaxel group and 9.5 months in the solvent-based paclitaxel group among patients with squamous cell histology and 13.1 and 13.0 months, respectively, among those with nonsquamous histology. Second-line therapy was used in 53% of the nab-paclitaxel group and 54% of the conventional paclitaxel group. It was most commonly used in Japan (85%), Australia (79%), and North America (69%) and used least

Albumin-bound vs Conventional Paclitaxel ■■ In the final results of a phase III trial, nab-paclitaxel produced a significantly increased overall response rate and noninferior progression-free and overall survival, compared with a solvent-based paclitaxel group.

■■ Thrombocytopenia and anemia were more common with nab-paclitaxel, whereas neutropenia and sensory neuropathy were more common with conventional paclitaxel.

tients with nonsquamous histology (26% vs 25%) or with adenocarcinoma (26% vs 27%). There were no significant differences between the nab-paclitaxel and conventional paclitaxel groups in progression-free survival (median = 6.3 vs 5.8 months) or overall survival (median = 12.1 vs 11.2 months). The progression-free and overall survival comparisons met criteria for noninferiority of nab-paclitaxel.

Survival Benefit in Older Patients? Subgroup analyses suggested potential differences in survival according to geographic region and age. Median progression-free survival was nonsignificantly prolonged with nabpaclitaxel treatment among the 165 patients from the United States and Canada (7.0 vs 5.4 months) and among patients aged ≥ 70 years (8.0 vs 6.8 months). Median overall survival was

continued on page 46

NOW ENROLLING

ACUTE LYMPHOBLASTIC LEUKEMIA

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

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

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

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

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

STW00067B

April 2012

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

The ASCO Post | NOVEMBER 15, 2012

PAGE 46

Journal Spotlight

Nab-paclitaxel vs Solventbased Paclitaxel in NSCLC continued from page 44

er overall survival in this subgroup, the investigators observed that there was some separation of the survival curves from 6 months to the end of the study. They speculated that this late separation might indicate the presence of a subset

of such patients who preferentially benefit from nab-paclitaxel. In the context of the significant improvement in overall response rate and absence of differences in progressionfree and overall survival in the total population, the authors concluded, “The [nab-paclitaxel] regimen produced less severe neuropathy, neutropenia, myal-

gia, and arthralgia compared with [solvent-based paclitaxel]. The increased risk of thrombocytopenia and anemia in the [nab-paclitaxel] regimen was readily manageable. Taken together, the [nab-paclitaxel] regimen has a favorable risk-benefit profile compared with that of [solvent-based paclitaxel] as first-line therapy for all patients with NSCLC.”

■

Reference 1. Socinski MA, Bondarenko I, Karaseva NA, et al: Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: Final results of a phase III trial. J Clin Oncol 30:20552062, 2012.

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PAGE 47

In the Clinic Thoracic Oncology

Albumin-bound Paclitaxel in First-line Treatment of Advanced NSCLC By Matthew Stenger

Indication

n October 11, 2012, paclitaxel protein-bound particles for injectable suspension, albumin-bound (nab-paclitaxel, Abraxane) was approved for use in combination with carboplatin for the initial treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) who are not candidates for curative surgery or radiation therapy. Nab-paclitaxel has a prior indication in metastatic breast cancer. Approval in NSCLC was based on the prior approval of conventional paclitaxel injection for this indication and support from a randomized, openlabel, multinational trial showing that nab-paclitaxel was at least as active as solvent-based paclitaxel injection when each was used in combination with carboplatin.2,3 For further discussion of this pivotal trial, see page 44.

How It Works Conventional paclitaxel preparations are formulated with solvents to overcome poor aqueous solubility. Solvent-based paclitaxel is associated with risk of hypersensitivity reactions requiring premedication with steroids and antihistamines, as well as increased risk of other toxicities. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel, is a solvent-free colloidal suspension of paclitaxel and human serum albumin that exploits the physiologic

transport properties of albumin. In addition to avoiding hypersensitivity reactions and adverse reactions associated with taxane solvents, nab-paclitaxel may exhibit increased antitumor activity by reaching the tumor microenvironment more efficiently than solventbased paclitaxel via caveolae-mediated transcytosis and by exhibiting preferential uptake by cancer cells.

Nab-paclitaxel for Non–Small Cell Lung Cancer ■■ Previously approved in metastatic breast cancer, nab-paclitaxel (Abraxane) was recently approved for use with carboplatin in locally advanced or metastatic non–small cell lung cancer when curative surgery or radiotherapy is not an option.

■■ Nab-paclitaxel is given at 100 mg/m2 via 30-minute infusion on days 1, 8,

and 15 of each 21-day cycle. Carboplatin (AUC 6 mg • min/mL) is given on day 1 of each 21-day cycle, beginning immediately after the completion of nab-paclitaxel administration.

How It Is Given The recommended dose of nabpaclitaxel is 100 mg/m2 via 30-minute infusion on days 1, 8, and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC 6 mg • min/mL on day 1 of each 21-day cycle, begin-

OF NOTE Nanoparticle albumin-bound (nab)-paclitaxel exploits transport properties of albumin, avoids adverse reactions associated with taxane solvents, and may show increased antitumor activity by reaching the tumor microenvironment more efficiently than solvent-based paclitaxel. ning immediately after the completion of nab-paclitaxel administration. Premedication to prevent hypersensitivity reactions is generally not needed prior to nab-paclitaxel administration. Premedication may be needed in patients with prior hypersensitivity reactions to nab-paclitaxel, and patients with a severe hypersensitivity reaction should not be rechallenged with the agent. The nab-paclitaxel dose must be reduced for patients with moderate and severe hepatic impairment. The drug should not be administered on day�� 1 of a treatment cycle until the absolute neutrophil count is ≥ 1,500/µL and platelet count is ≥ 100,000/µL. In patients developing severe neutropenia or thrombocytopenia, treatment should be withheld until recovery (to ≥ 500/µL or ≥ 50,000 µL on days 8 or 15) and then resumed at a permanently reduced dose. Nab-paclitaxel should also be withheld for grade 3 or 4 peripheral neuropathy and resumed at a permanently reduced dose upon recovery to grade 1 or resolution. Metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4.

Therefore, nab-paclitaxel should be used with caution in patients receiving inhibitors (eg, ketoconazole, gemfibrozil) or inducers (eg, rifampin, carbamazepine) of either isoenzyme.

Safety Profile The following (≥ 10% incidence) adverse events occurred with a similar incidence in the nab-paclitaxel (incidence shown) and paclitaxel injection groups: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%). Select adverse events of any grade that were more common (≥ 5% difference) with nabpaclitaxel were peripheral edema (10% vs 4%) and epistaxis (7% vs 2%), and those that were more common with paclitaxel injection were peripheral neuropathy (64% vs 48%), arthralgia (25% vs 13%), and myalgia (19% vs 10%). Grade 3 or 4 peripheral neuropathy occurred in 3% of nab-paclitaxel recipients (grade 3 only) and in 12% of paclitaxel injection recipients; grade 3 neuropathy improved to grade�� 1 or resolved in 10 (59%) of 17 nab-paclitaxel patients following interruption or discontinuation of the drug. Grade 3 or 4 hematologic toxicity included anemia in 28% of nab-paclitaxel patients vs 7% of paclitaxel injection patients, neutropenia in 47% vs 58%, and thrombocytopenia in 18% vs 9%. Serious adverse events occurred in 18% of both treatment groups, with the most common events in nab-paclitaxel patients being anemia (4%) and thrombocytopenia (3%). Nab-paclitaxel carries a boxed warning for neutropenia; it is recommended that peripheral blood counts be monitored frequently for the occurrence of bone marrow suppression. In addition, there is a boxed warning against substitution of nab-paclitaxel for or with

other paclitaxel formulations. Nab-paclitaxel has additional warnings/precautions for myelosuppression, sensory neuropathy, severe hypersensitivity reactions (including fatality), use in paSee Page 108 tients with hepatic impairment, theoretical risk of viral transmission (since the formulation contains albumin derived from human blood), and fetal harm. Women should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving nab-paclitaxel.

■

OF NOTE The nab-paclitaxel label includes boxed warnings for neutropenia and against substitution of nabpaclitaxel for or with other paclitaxel formulations. References 1. U.S. Food and Drug Administration: Hematology/oncology approvals & safety notifications: Paclitaxel (Abraxane). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm323668. htm. Accessed October 22, 2012. 2. ABRAXANE® for injectable suspension (paclitaxel protein-bound particles for injectable suspension) (albuminbound) prescribing information, Abraxis BioScience, LLC, October 2012. Available at www.accessdata.fda.gov/drugsatfda_ docs/label/2012/021660s031lbl.pdf. Accessed October 22, 2012. 3. Socinski MA, Bondarenko I, Karaseva NA, et al: Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: Final results of a phase III trial. J Clin Oncol 30:20552062, 2012.

The median age of patients in the VISTA‡ trial was 71 years (range: 48-91).

LEARN MORE AT THE 2012 AMERICAN SOCIETY OF HEMATOLOGY ANNUAL MEETING AND EXPOSITION

Survival never gets old VELCADE® (bortezomib) delivered >13-month overall survival advantage in combination with MP* vs MP alone for previously untreated multiple myeloma (median 56.4 vs 43.1 months†; 60.1-month median follow-up‡)

Approved for subcutaneous and IV administration§ VELCADE (bortezomib) Indication and Important Safety Information INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Closely monitor patients with risk factors for, or existing heart disease ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

▼ Women should avoid becoming pregnant while being treated with VELCADE (bortezomib). Pregnant women should be apprised of the potential harm to the fetus ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

Please see Brief Summary for VELCADE on next page. *Melphalan+prednisone. † HR=0.695 (95% CI, 0.57-0.85); p<0.05. ‡ VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma (MM). The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed. § The reconstituted concentration for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL).

Living Proof

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib 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 VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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Direct from ASCO

A New Gift to Add to Your List—One to Conquer Cancer

onquering cancer requires the faith, talent, and resources of all members of our community. It requires the innovation of researchers and the insight of clinicians. It requires the courage of our worldwide community of patients and survivors, and it requires the generosity of everyone who believes in a world free from the fear of cancer. This year, as you plan your yearend giving, consider making a taxdeductible gift to the Conquer Cancer Foundation. With your support, we can make a difference in the lives of people living with cancer and those who care for and about them.

Volume 29, Issue 15

May 20, 2011

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

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

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Together, we can: ■■ Fund breakthrough research and advance new discoveries in cancer care and treatment ■■ Put up-to-the minute, accurate cancer information directly into the hands of patients and caregivers, so that they can be empowered in their care and survivorship ■■ Improve the standard of care worldwide—particularly in developing nations—by promoting international communication, collaboration, and education among cancer practitioners As the end of the year approaches, be bold: join us and make a tax-

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

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he Conquer Cancer Foundation funds research focused on finding new therapeutics to conquer cancer and is also committed to funding research that other organizations may not, such as in palliative care, rare cancers, pediatric cancers, and high-risk areas. With donations from supporters like you, the Foundation is able to fund innovative research being conducted by ambitious investigators like Leslie Doros, Irene Ghobrial, Richard White, and Alexi Wright, featured in the “Touching Patients by Funding Innovative Research” video at www.conquercancerfoundation. org/innovate.

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News Genitourinary Oncology

Stereotactic Radiosurgery May Offer Therapeutic Option for Patients with Primary Renal Cancer, Early Study Indicates

tereotactic radiosurgery may hold potential as a therapeutic option for patients with localized primary renal cancer who are considered poor

surgical candidates and who do not have a prior history of pelvic or abdominal radiation, according to data from a safety and toxicity study recent-

For newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer

Oncotype DX reveals the underlying biology that changes treatment decisions 37% of the time ®

37%

gery presented results of patients from 2 to 41 months posttreatment using a four-part dose escalation schema. Across all four groups, tumors remained stable or decreased on post-treatment imaging in 94% of patients. For patients who underwent a posttreatment biopsy, incomplete or refractory treatment was found in 91%. Acute toxicity included grade 1 fatigue in two See Page 108 patients in the highest dose treatment group. Late toxicity included worsening of preexisting chronic renal disease in two patients.

Phase I Study Details

changed

63% confirmed

Even when treatment decisions based on traditional measures seem conclusive, Oncotype DX can lead to a different approach • In a meta-analysis, treatment decisions were changed even when definitive treatment decisions had already been made*†1

▸ 33% switched from CT + HT to HT alone ▸ 4% switched from HT only to CT + HT

‡

• Only assay incorporated into major clinical practice guidelines to predict chemotherapy benefit www.oncotypeDX.com *This analysis included 912 patients with node-negative, ER-positive, early-stage invasive breast cancer. †Patients with unclear treatment decisions were excluded from this meta-analysis. Additionally, patients who did not want CT, those with poor performance status, and those who could not tolerate CT were excluded. ‡CT=chemotherapy; HT=hormone therapy. Reference: 1. Hornberger J, et al. Poster P2-09-06. Presented at: San Antonio Breast Cancer Symposium; 2010.

Now available for patients with ductal carcinoma in situ (DCIS) Genomic Health, Oncotype DX, Recurrence Score, and Uncover the Unexpected are trademarks of Genomic Health, Inc. © 2012 Genomic Health, Inc. All rights reserved. GHI10100_0712

ly presented at the American Society for Radiation Oncology’s (ASTRO’s) 54th Annual Meeting. This study of stereotactic radiosur-

Twenty patients ranging from 58 to 92 years old received initial doses of 600 cGy per fraction, followed by increments of 200 cGy per fraction to total doses of 24 Gy, 32 Gy, and 48 Gy. Doses were escalated after patients showed non-prohibitive levels of toxicity within 180 days from the date of treatment. Limiting levels of toxicity were defined as any grade 3 or higher gastrointestinal/genitourinary acute radiation toxicity, according to the NCI common toxicity criteria. Imaging and post-treatment biopsy results were evaluated for tumor response and treatment efficacy. Rodney J. Ellis, MD, lead author of the study, commented, “Our first trial shows that low to moderate doses of stereotactic radiosurgery is a safe and viable option for renal cancer patients who typically do not have surgical options.” Dr. Ellis is Clinical Director and Vice Chair for Clinical Affairs of the Department of Radiation Oncology at University Hospitals Case Medical Center Seidman Cancer Center, and an Associate Professor in Radiation Oncology and Urology at Case Western Reserve University School of Medicine in Cleveland. Dr. Ellis added, “Further studies are needed to determine safe levels for the maximum dosage.”

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Reference 1. Ellis RJ, Patel RB, Kunos C, et al: Stereotactic radiosurgery for renal cancer: Phase I safety and toxicity. 54th Annual Meeting of the American Society for Radiation Oncology. Abstract 294. Presented October 31, 2012. .

ASCOPost.com | NOVEMBER 15, 2012

PAGE 53

11th International Kidney Cancer Symposium Options Shifting for First-line Treatment of Renal Cell Carcinoma By Charlotte Bath

rials with pazopanib (Votrient) have “provided significant efficacy, toxicity, and tolerability data for pazopanib to be established as a first-line standard of care” for renal cell carcinoma,” Tim Eisen, PhD, of the University of Cambridge, United Kingdom, stated at the 11th International Kidney Cancer Symposium in Chicago. He noted that the pazopanib trials show noninferiority relative to sunitinib (Sutent) for progression-free survival, although the “safety profile favors pazopanib,” with the exception of liver function test abnormalities.

Tim Eisen, PhD

“In the future, tivozanib may be a first-line standard of care, but for me, this is a premature conclusion right now. We do need comparative data with sunitinib, pazopanib, or axitinib [Inlyta],” Dr. Eisen added. Moving axitinib into front-line treatment for renal cell carcinoma also depends on data from phase III trials. In addition, “there is no way yet of targeting therapy, and that is something we

continue to work on,” Dr. Eisen said. Dr. Eisen’s conclusions followed presentations on recent trials of tyrosine kinase inhibitors of vascular endothelial growth factor (VEGF)1, -2, and -3. used to treat renal cell carcinoma. “First-generation agents include pazopanib, sunitinib, and sorafenib [Nexavar],” Dr. Eisen said. The second-generation agents, which he listed as tivozanib and axitinib, “are both more specific in targeting VEGF receptors preferentially and also more potent,” he added (see Fig. 1). “Kidney cancer is fundamentally a VEGF-driven disease,” noted Brian R. Rini, MD, of the Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, and Glickman Urologic and Kidney Institute. “It follows that precise and potent inhibition of VEGF will produce the most robust clinical effects, and that this really should be applied as early as possible in the course of treatment before other alternative pathways have a chance to emerge.”

Axitinib Trials Axitinib “is the most biochemically potent agent and selective secondgeneration inhibitor of the VEGF family of receptors, [with] demonstrated efficacy as second-line treatment for metastatic renal cell carcinoma,” Dr. Rini said. In the phase II 1046 trial (reported at this year’s ASCO An-

VEGFR-1 More potent

VEGFR-2

VEGFR-3

0.1

Sunitinib3

1 Tivozanib1,2 (AV-951)

Pazopanib3 (GW-786034)

Sorafenib3

Axitiniba,3 (AG13736)

10 Less potent

100

*Approximate: adjustment in consideration of 2.3% Body Surface Area

Note: Reported potenciesa are either biochemical- or cell-based IC50s (nM); cell-based data are shown when available. a Axitinib data for VEGFR-2 are from an ELISA assay; all other axitinib data are from an immunoprecipitation assay. In addition, Chow LQM, Eckhardt SG reported an axitinib IC50 of 1.2, 0.25, and 0.29 nM for VEGFR-1, -2, and -3 (J Clin Oncol. 2007;25[7]:884-895). 1. Eskens FALM, et al. In: Proceedings of the 99th Annual Meeting of the AACR. San Diego, CA: AACR; 2008 (abstr LB-201). 2. Nakamura K, et al. Cancer Res. 2006;66(18):9134-9142. 3. Axitinib FDA Oncologic Drugs Advisory Committee briefing document. 12.07.2011

Fig. 1: Reported potencies of tyrosine kinase inhibitors. Courtesy of Tim Eisen, PhD.

Rising Expectations for Tivozanib

lthough the data on new first-line treatment options for renal cell carcinoma are still immature, those data were convincing enough to change the minds of many, according to expert testimony presented at the 11th International Kidney Cancer Symposium. Both before and after the session, “Options for the Treatment of the Naive Patient,” participants were asked, “Which drug do you expect to be your preferred option for treatment of a fit naive patient in 3 years?” The percentages opting for sunitinib (Sutent) decreased from 36.4% to 19%. The percentages choosing pazopanib (Votrient) remained the same at 25%. The percentages preferring tivozanib increased from 31.8% to 54%.

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nual Meeting1), axitinib was shown to produce a median progression-free survival of 14.5 months in the entire cohort of 213 patients with metastatic disease with clear cell histology and a median progression-free survival of 16.4 months in a subset of 91 patients who did not meet criteria for dose titration, mainly due to hypertension. “These patients had the best outcomes, not surprisingly, because they had adequate drug levels. Overall response rates were 48% in the total cohort and 59% in the subset. “If a patient doesn’t meet criteria for titration, he will likely have adequate levels. This isn’t true for every single patient, but for a group of patients, it is going to be true. In contrast, patients who are eligible for titration generally have inadequate levels,” Dr. Rini explained. “So titration upward is not to achieve superhigh drug levels…. It is to achieve adequate drug levels and give patients a chance to respond.” Patients who did meet criteria for titration were either titrated stepwise to 7 mg twice daily (to a maximum of 10 mg twice daily) or received placebo dose titration (blinded therapy).

Hypertension Connection Hypertension is not only associated with higher drug levels and advantages in progression-free survival and response rate, but “is the dominant adverse event,” Dr. Rini said. Hypertension of all grades occurred in 135 patients (63%) and of grade 3/4 in 61 patients (29%). “The numbers are higher than have been reported for axitinib previously, mostly because there was more intensive blood pressure monitoring and there was also more aggressive dose titration in this trial.” Dr. Rini said. Other common adverse

events included diarrhea (all grades occurring in 58% of patients and grades 3/4 in 7%), fatigue (all grades occurring in 48% of patients and grades 3/4 in 6%), and dysphonia (all grades occurring in 40% of patients, but grades 3/4 in only 1%). “It is my belief that axitinib is the most effective first-line treatment for metastatic renal cell carcinoma, as evidenced by a very long

Brian R. Rini, MD

progression-free survival and a high objective response rate based on preliminary data,” Dr. Rini concluded. “When optimally titrated, axitinib can produce a progression-free survival of over 16 months and a response rate of nearly 60%” in previously untreated clear cell renal cell carcinoma, he continued. “I think many other oral drugs, including the tyrosine kinase inhibitors we use in kidney cancer, are being underdosed in many patients and probably not being optimally used, resulting in suboptimal efficacy,” he said. “We are waiting for the phase III trial to be ready soon, which is a front-line trial of axitinib compared to sorafenib,” Dr. Rini said. “The primary endpoint is progression-free survival and along with the unblinding of the 1046 data, it will provide a more precise and more robust estimate of the continued on page 55

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11th International Kidney Cancer Symposium continued from page 53

activity of axitinib in the front-line setting, which I believe is substantial.”

The Case for Panozanib Taken together, the results of the PISCES2 and COMPARZ3 trials make a strong case for the use of panozanib as first-line treatment for advanced renal cell carcinoma, according to Camillo Porta, MD, of the Istituto di Ricovero e Cura a Carattere Scientifico, San Matteo University Hospital Foundation, Pavia, Italy. He cautioned, however, that “we should wait for the final publication of the two studies to really go deeply through the data.” The double-blind PISCES study evaluated patient preference of two different sequences of treatment: pazopanib given for 10 weeks and then after a 2-week washout, sunitinib for 10 more weeks, or the reverse sequence. Both drugs were given at the standard doses and schedules, 800 mg once daily for pazopanib, and for sunitinib, 50 mg once daily, 4 weeks on treatment, followed by 2 weeks matching placebo, then 4 weeks on treatment. “Significantly more patients preferred pazopanib vs sunitinib due to better general quality of life and less fatigue,” Dr. Porta said. “There was a consistency between patient and physician preference and health-related quality of life that statistically favored pazopanib for fatigue, foot/hand soreness, and mouth/throat soreness. Furthermore, fewer dose modifications were observed in patients taking pazopanib,” he said. “The PISCES study is actually very important,” Dr. Eisen noted, because patient preference cannot easily be measured. “This is an abstract concept, and the patient that has been on both agents is in a hugely better position than a patient that has been on one agent and has nothing with which

was less than 10%. For me, this is convincing” (see Fig. 2). “This innovative trial clearly demonstrated the better tolerability of pazopanib over sunitinib, despite the more modest difference in reported adverse events,” Dr. Porta stated. “This

Completed while patient still blinded 70%

Physician preference

60%

Patient preference

50%

to compare that experience,” he continued. “The number of patients who were not able to express a preference

for 2 weeks, and there is a possibility that that would make a difference to the disease assessment and the progression-free survival assessment,” Dr. Eisen said. “It would not, in my view, make any difference at all to the overall survival assessment, and I also expect it to have less of an impact on diseasefree survival for patients who got a large number of cycles,” he continued. “We are seeing 28- to 29-month overall survival. Compare that with what we were achieving 11 or 12 years ago with interferon, when it was around 8.5 months, and I think we have made significant progress.”

40% 30%

61%

Adverse Effects

70%

20% 22%

10%

22%

0% Pazopanib Preferred

Sunitinib Preferred

17%

No Preference

Fig. 2: PISCES: Physician and patient preferences: primary analysis population. Courtesy of Tim Eisen, PhD. Data from Escudier BJ, et al.2

study design does not allow an efficacy comparison, but a comparison between the two drugs has just been reported, with the presentation of the results of the phase III COMPARZ trial at [the 35th European Society for Medical Oncology (ESMO) Congress].” Using the same dosing and schedule as the PISCES trial, the COMPARZ trial, reported in the November 1 issue of The ASCO Post,4 demonstrated that pazopanib is not inferior to sunitinib. “Progression-free survival was 8.4 months for pazopanib vs 9.5 months for sunitinib. The 95% confidence interval of the two progressionfree survivals clearly overlap, with a hazard ratio of 1.047, meaning that the trial demonstrated pazopanib is not inferior compared to sunitinib in terms of progression-free survival,” Dr. Porta stated. Quality of life, a secondary endpoint of the study, was superior in the pazopanib arm, “thus corroborating the results of the PISCES study,” according to Dr. Porta.

Timing of Assessments

Camillo Porta, MD

ment of patients’ preference clearly [did not favor] sunitinib” in both the PISCES and COMPARZ trials. “Compared with baseline, patients reported worse fatigue during the first cycle of sunitinib treatment; however, less fatigue was reported in all con-

80%

Physician/Patient Preference

First-line Treatment of RCC

“We now have two recent analyses that examine the impact of sunitinib dosing schedule on measurement of patient-reported fatigue and health-related quality of life,” Dr. Porta said.“ He noted that presentations at the ESMO genitourinary poster discussions questioned whether “the timing of assess-

secutive treatment cycles.” In addition, the sunitinib schedule “was associated with a clear-cut on/off effect,” Dr. Porta noted, with patients reporting more fatigue at the end of the 4-weekon period and less fatigue on day 1 after the 2-week rest period. “This effect should be accounted for when collecting health-related quality-of-life data,” he said. Another relevant question raised at the ESMO genitourinary poster discussion was whether patients in the PISCES study were informed that some side effects, such as hypertension and hand-foot skin reaction, are considered predictive of efficacy and how that might have influenced patient preference. “Nobody can answer this question, but it could make a lot of difference,” Dr. Porta said. Dr. Eisen concurred that the study assessments for the COMPARZ trial “are not entirely acceptable in that the timing definitely favored (or would be expected to definitely favor) pazopanib” for the reasons presented by Dr. Porta. “Baseline assessment and then every 28th day of every cycle assessment for quality of life certainly will have had an impact for the reasons you’ve heard. Patients on sunitinib treatment on day 28 of each cycle are feeling at their worst.” In addition,“disease assessments were taken when patients were still on pazopanib but had been off sunitinib

One of the two most important reasons for pazopanib preference by patients in the primary analyses of the PISCES study was less fatigue, Dr. Porta said. “The other most important reason was ‘no single reason,’ meaning that patients were simply not able to explain the exact reason for their choice, which is realistically multifactorial.” Dr. Eisen characterized the adverse effects as either on target—hypertension, hypothyroidism, and dysphonia—or off target. “The off-target effects vary between agents, and they are largely due to kinase inhibitor properties other than the main ones we are interested in.” Off-target effects include fatigue, hand-foot syndrome, diarrhea, rash, liver function test changes, peripheral edema, myelosuppression, stomatitis, and hair color change. “Differences between sunitinib and pazopanib are basically offtarget effects. Pazopanib did worse for liver function test abnormalities and for weight decrease. Those two things could be of importance to patients. The liver function tests are definitely of importance to the doctor who needs to assess those, but they would be of importance to patients if they [showed rapid increases], because you need to interrupt treatment and modify it. But in terms of everyday side effects, pazopanib seemed to cause less of the three things that in my practice matter most to patients—fatigue, skin toxicity, and stomatitis.”

‘New Kid on the Block’ “Tivozanib is the new kid on the block, but it is a very exciting, promising drug that I think is going to play a major role in first-line treatment of renal cell carcinoma in the next few continued on page 57

NOW FDA APPROVED new phase III trial data

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

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

ASCOPost.com | NOVEMBER 15, 2012

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First-line Treatment of RCC continued from page 55

years,” noted Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York. “When we think about tivozanib, we should think of three words: efficacy, safety, and tolerability.”

Robert J. Motzer, MD

A highly potent inhibitor of VEGF receptors 1, 2, and 3, tivozanib is also selective, with “fewer off-target kinase activities than some of the earlier developed tyrosine kinase inhibitors. It has a favorable pharmacokinetic profile, with a half-life of about 4 days, which allows a once daily dosing schedule, 3 weeks on and 1 week off,” Dr. Motzer said. He stressed that the schedule with the week off was based on the pharmacokinetic profile, “and not symptoms developing on treatment, as in the case of sunitinib. The sunitinib holiday was built in because of the intolerability around day 28. Not so with tivozanib. This was based on the pharmacokinetic profile, and patients don’t feel poorly around day 21.” A phase II trial of tivozanib in 272 patients with advanced renal cell carcinoma “showed a high level of efficacy and good safety profile, and that led to the TIVO-1 trial, which we presented at ASCO,”5 Dr. Motzer said. This is a phase III superiority trial of tivozanib vs sorafenib as firstline targeted therapy for metastatic renal cell carcinoma. Patients could have received no or one prior therapy, but no prior VEGF or mTOR therapy. Tivozanib was given orally at 1.5 mg, in a 3-week-on, 1-weekoff schedule, and sorafenib was given orally at 400�� mg twice daily, continuously. “One of the unique features that was built into this study was that patients who were on sorafenib, at time of progression, were offered

tivozanib on a second separate extension protocol,” Dr. Motzer said.

Impact of Subsequent Treatment “The efficacy of tivozanib was demonstrated both in the overall population as well as the treatmentnaive population, with those patients receiving tivozanib as first-line therapy. And all patients receive it as the first-line targeted therapy.” Cautioning that “this is a work in progress,” Dr. Motzer noted that the study showed median progressionfree survival rates, according to an independent review, of 12.7 months for tivozanib vs 9.1 months for sorafenib. “The median progressionfree survival for currently approved treatment-naive therapies “has been 11 months or less, so certainly there is room for improvement,” Dr. Motzer said (see Fig. 3). Adding that he expected overall survival data to be available at the 2013 Genitourinary Cancers Symposium, Dr. Motzer noted that “overall survival is pretty much comparable at 1 year to the other agents”—77% for tivozanib

Median Progression-free Survival, Months

11th International Kidney Cancer Symposium 14 12

12.7

11.1

Sunitinib

Pazopanib

9.1

8 6 4 2 0 Tivozanib

Sorafenib

TIVO-11

Sunitinib Pivotal2

Pazopanib Pivotal3

1. Motzer RJ, et al. Presented at: ASCO. 2012 (abstr 4501). 2. Sutent [prescribing information]. New York, NY: Pfizer Labs; May 2011. 3. Votrient [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; January 2012.

Fig. 3: TIVO-1: Median progression-free survival for treatment-naive patients. Courtesy of Robert J. Motzer, MD.

to provide further data to check that this is the case.”

‘Not Long to Wait’ “With regard to adverse events, tivozanib is a very safe drug, very tolerable in my own experience, which I think is well reflected from the TIVO-1 trial,” Dr. Motzer reported. All-grade adverse events occurred in 67.6% of patients receiving tivozanib

With regard to adverse events, tivozanib is a very safe drug, very tolerable in my own experience, which I think is well reflected from the TIVO-1 trial. —Robert J. Motzer, MD

vs 81% for sorafenib. Very few of the patients on tivozanib received subsequent second-line therapy, largely due to the patient’s geographic distribution. According to immature data cited by Dr. Eisen, the percentage of patients receiving second-line treatment was 53% for sorafenib, “so it is really a sequential trial to a large extent— sorafenib, then tivozanib vs tivozanib alone, for the majority of patients, only 17% of whom went on to get any further treatment, which could have included agents other than tyrosine kinase inhibitors. The overall survival difference is worth noting. A plausible explanation would be that there is a difference in the second-line therapies, but plausible doesn’t necessarily mean correct. I think the onus is on us

11.0

vs 83.3% of those receiving sorafenib. Grade 3/4 adverse events were 36.3% vs 51.0%. For those receiving tivozanib, “the predominant side effects are hypertension and dysphonia,” Dr. Motzer said. “Other than that, it is a pretty well tolerated agent, and I think [physicians] will agree as [they] gain more experience with it.” Tivozanib also demonstrated tolerability, “with a relatively low proportion of patients that require dose reductions or dose discontinuation on the study,” Dr. Motzer added. Dose reduction rates were 11.6% in the tivozanib group vs 42.8% in the sorafenib group, and dose discontinuation rates were 4.2% vs 5.4%. Dr. Motzer “has made an excellent case for tivozanib,” Dr. Eisen said, noting that we shouldn’t use the phase II

data to inform standard of care right now. Nevertheless, he added, “we don’t have long to wait.”

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Disclosure: Dr. Rini has received research funding from and has been a consultant for Pfizer. Dr. Motzer has received research fundng from AVEO Oncology. Drs. Eisen and Porta reported no potential conflicts of interest.

References 1. Rini BI, Grünwald V, Fishman MN, et al: Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study. 2012 ASCO Annual Meeting. Abstract 4503. Presented June 2012. 2. Escudier BJ, Porta C, Bono P, et al: Patient preference between pazopanib (Paz) and sunitinib: Results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310. 2012 ASCO Annual Meeting. Abstract CRA4502. Presented June 2, 2012. 3. Motzer RJ, Hutson TE, Reeves J, et al: Randomized open-label phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (MRCC): Results of the COMPARZ trial. 2012 ESMO Congress. Abstract LBA8. Presented October 1, 2012. 4. Goodman A: Pazopanib noninferior to sunitinib as front-line therapy for metastatic renal cell carcinoma. The ASCO Post. November 1, 2012. 5. Motzer RJ, Nosov D, Eisen T, et al: Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter trial. 2012 ASCO Annual Meeting. Abstract 4501. Presented June 2012.

The ASCO Post | NOVEMBER 15, 2012

PAGE 58

FDA Update

FDA Approves New Use of Pemetrexed in the Maintenance Setting for NSCLC

he FDA has expanded labeling to include the results of an additional trial evaluating the safety and efficacy of pemetrexed (Alimta) for the initial treatment of patients with locally advanced or metastatic, nonsquamous, non–small cell lung cancer (NSCLC)

Rituximab Infusion Approved for NHL

he FDA recently approved a 90-minute infusion for rituximab (Rituxan) starting at cycle 2 for patients with nonHodgkin lymphoma (NHL) who did not experience a grade 3 or 4 infusion-related adverse reaction during cycle 1. Patients with clinically significant cardiovascular disease and high circulating lymphocyte counts (≥ 5,000/µL) are not recommended to receive the faster infusion.

Phase III Trial The approval was based on an open-label, single-arm, multicenter, phase III trial (RATE). The evaluable patient population was comprised of 363 previously untreated patients with follicular NHL or diffuse large B-cell lymphoma who had not experienced a grade 3 or 4 infusion-related reaction to rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) chemotherapy during cycle 1. Patients received the faster infusion in cycle 2 and, if tolerated, in all subsequent cycles. The faster infusion regimen consisted of rituximab administered over 90 minutes with 20% of the total dose given in the first 30 minutes, and remaining 80% of the total dose administered over the subsequent 60 minutes. The trial’s primary endpoint was the incidence of grade 3 and 4 infusion-related reactions in patients who received rituximab by faster infusion at cycle 2. The incidence of grade 3 infusion-related reactions at cycle 2 was 1.1% (95% CI = 0.3–2.8), with no grade 4 or 5 infusion-related reactions reported. The RATE trial results are comparable to the results of infusion-related reactions during cycle 2 reported from trials using the standard infusion regimen.

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followed by pemetrexed maintenance in patients whose disease has not progressed after four cycles of platinum and pemetrexed as firstline chemotherapy. Pemetrexed is currently approved,

in combination with cisplatin therapy, for the initial treatment of patients with locally advanced or metastatic nonsquamous NSCLC and for the maintenance treatment of patients

Important Safety Information WARNINGS AND PRECAUTIONS: • Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%). Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%),

with locally advanced or metastatic nonsquamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Pemetrexed is not indicated for the treatment of patients with squamous cell lung cancer.

thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%). Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%). DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution

Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

ASCOPost.com | NOVEMBER 15, 2012

PAGE 59

FDA Update

Study Design The additional trial described in product labeling is a multicenter, randomized (2:1), double-blind, placebo-controlled trial evaluating pemetrexed maintenance in patients with stage IIIB/IV nonsquamous NSCLC whose initial treatment was four cycles of pemetrexed plus cisplatin.

Patients with ECOG performance status 0 or 1 who completed four cycles of pemetrexed plus cisplatin with a best response of either stable disease, partial response, or complete response were randomly assigned to receive either pemetrexed 500 mg/m2 intravenously on day 1 of each 21-day cycle or matching placebo until disease pro-

gression. Patients in both study arms also received folic acid and vitamin B12 supplementation for the duration of maintenance treatment and dexamethasone prior to, on the day of, and the day following pemetrexed administration. The primary efficacy outcome was investigator-assessed progressionfree survival.

INDICATIONS THE FIRST AND ONLY • Treatment of peripheral T-cell lymphoma (PTCL) in patients DRUG APPROVED IN BOTH who have received at least one prior therapy PTCL AND CTCL • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy These indications are based on response rate. Clinical beneﬁt such as improvement in overall survival has not been demonstrated.

RECHARGE THE POSSIBILITIES

www.istodax.com Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

Results A significant improvement in investigator-assessed progression-free survival was observed in patients randomly assigned to receive pemetrexed maintenance compared to those receiving placebo (HR = 0.62 [95% CI = 0.49–0.79]; P < .0001). The mecontinued on page 60

The ASCO Post | NOVEMBER 15, 2012

PAGE 60

FDA Update

Expanded Labeling for Pemetrexed continued from page 59

dian progression-free survival was 4.1 and 2.8 months for patients receiving pemetrexed and placebo, respectively. A significant improvement in overall survival, a key secondary endpoint, was also observed for patients

randomly assigned to pemetrexed maintenance compared to those on the placebo arm (HR = 0.78 [95% CI = 0.64–0.96] P = .02). The median survival times were 13.9 and 11.0 months for patients receiving pemetrexed and placebo, respectively. Patients received a median of 4 cycles of maintenance in both

arms. Treatment was reduced or delayed in approximately 25% of patients in the pemetrexed arm due to toxicity. The most common adverse reactions in patients receiving pemetrexed maintenance in this trial were neutropenia, anemia, fatigue, nausea, vomiting, stomatitis, and edema. The most common severe adverse reactions were anemia

Only

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug. 2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2. • Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2. • Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction. Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2. • Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2. 2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)]. 5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)]. 5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)]. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)]. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients

and neutropenia; 13% of patients received red blood cell transfusions, 12% erythropoiesis-stimulating agents, 6% granulocyte colony–stimulating factors, and 1.5% platelet transfusions. Full prescribing information is available at: http://www.accessdata .fda .gov/dr ugsatfda_doc s/ label/2012/021462s039lbl.pdf.

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with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate. 5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [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. Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1. Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8) Cosmos Communications 718.482.1800

ASCOPost.com | NOVEMBER 15, 2012

PAGE 61

FDA Update

CyberKnife M6 Series Gets FDA 510(k) Clearance

ccuray Incorporated has announced that the company received 510(k) clearance from the FDA for its new CyberKnife M6 Series. The CyberKnife M6 Series features expanded clinical capabilities and reduced treatment times. The new CyberKnife

M6 FIM and FM Systems, featuring the InCise Multileaf Collimator combines the benefits of beam-shaping with the flexibility of nonisocentric, noncoplanar delivery, offering unmatched clinical capabilities and expanding the number of patients eligible for treatment.

Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%). Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome. Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesmia. Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles. Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2. Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

The new InCise Multileaf Collimator was designed specifically for stereotactic radiosurgery and stereotactic body radiation therapy treatments, giving the system the capability to extend its radiosurgical accuracy into a broader field of applications, meeting radiosurgery and

Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 of patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%). Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause. Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%). 6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience. 7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)]. 7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors. Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital) may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort. 7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)]. There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus. Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures Cosmos Communications 718.482.1800

radiotherapy needs. With the InCise Multileaf Collimator, the CyberKnife M6 Series can be used to treat large and irregular tumors with more efficient dose gradients. This added flexibility expands the number of patients eligible for treatment with the CyberKnife M6 Series.

■

The ASCO Post | NOVEMBER 15, 2012

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Journal Spotlight Genitourinary Oncology

Intermittent Androgen Suppression in Prostate Cancer Noninferior to Continuous Suppression, Associated with Some QOL Benefit By Matthew Stenger

recently reported National Cancer Institute of Canada (NCIC) Clinical Trials Group study, reported by Crook and colleagues in The New

England Journal of Medicine, showed that intermittent androgen suppression was associated with noninferior overall survival when compared

(AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification. 8.3 Nursing Mothers It is not known whether romidepsin 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 ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established. 8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

with continuous suppression in patients with prostate cancer and rising prostate-specific antigen (PSA) levels after radiotherapy. Intermittent

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-4 [See References (15)]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. 17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)]. • Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)]. • Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)]. • Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)]. • Use in Pregnancy If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling. [See Warnings and Precautions (5.5)]. • Patients should be instructed to read the patient insert carefully. Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBVPI.003/PPI.003 09/11

Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

Cosmos Communications 718.482.1800

therapy is of interest because it may improve quality of life (QOL) and delay hormone resistance. Experimental models have shown that successive castration and reexposure to androgens resulted in multiple apoptotic regressions and increased time to androgen indeSee Page 108 pendence, and early-phase trials have provided proof of principle of an intermittent suppression approach in humans.

Study Design In the NCIC study, 1386 patients with PSA level > 3 ng/mL more than 1 year after definitive primary or salvage radiotherapy for localized prostate cancer were randomly assigned to intermittent (n� �� =� �� 690) or continuous (n = 696) androgen-deprivation therapy. Prior androgen suppression for up to 12 months in association with definitive treatment was permitted if it had been completed ≥�� 12 months before enrollment. Patients had to have a serum testosterone level > 5 nmol/L and life expectancy of > 5 years. The primary endpoint was median overall survival. Continuous androgen suppression consisted of a luteinizing hormonereleasing hormone agonist (LHRHa) plus a nonsteroidal antiandrogen or orchiectomy. Intermittent androgen suppression consisted of 8-month treatment cycles with a LHRHa plus a nonsteroidal antiandrogen followed by a nontreatment period if there was no evidence of clinical progression and PSA level was < 4 ng/mL and ≤ 1 ng/ mL above the prior value obtained in monitoring during the treatment cycle. The nontreatment period continued, in the absence of clinical progression, until PSA level reached 10 ng/mL, with PSA levels being measured every 2 months. Castration-resistant disease was defined as three increases in PSA level at least 1 month apart or evidence of new clinical disease while patients were receiving androgen-deprivation therapy and testosterone was at castrate levels. At baseline, the intermittent group and continuous group were well matched for median age (74 vs

ASCOPost.com | NOVEMBER 15, 2012

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Journal Spotlight

74 years), ECOG performance status (0 in 79% vs 82%), baseline PSA (> 15 ng/mL in 23% vs 23%), prior radical prostatectomy (11% vs 11%), time since radiotherapy (> 3 years in 79% vs 78%), and proportion without prior hormone therapy (61% vs 61%). Median follow-up was 6.9 years (range, 2.8–11.2 years). Patients in the intermittent group completed 1 to 9 treatment cycles; 95% entered the first nontreatment interval, 58% a second, and 32% a third, with median durations of the nontreatment intervals progressively decreasing from 20.1 months to 13.2 months and 9.1 months over the first three intervals, and to 4 to 5 months in intervals 4 to 7. The median cumulative nontreatment period for patients in the intermittent group was 37.6 months. Patients in the continuous group had a median of 43.9 months of LHRHa treatment compared with 15.4 months of LHRHa treatment in patients in the intermittent group.

Noninferior Overall Survival On intent-to-treat analysis, median overall survival was 8.8 years in the intermittent group vs 9.1 years in the continuous group, a nonsignificant difference (hazard ratio [HR] = 1.02, 95% confidence interval [CI] = 0.86–1.21). The P value for noninferiority (HR >�� 1.25) was .009, supporting the hypothesis that intermittent androgen-deprivation therapy was not inferior to continuous treatment. A per-protocol analysis yielded similar results. Multivariate analysis including age, ECOG performance status, time since completion of radiotherapy, baseline PSA level, and neoadjuvant androgen suppression also yielded similar results (HR = 1.03, 95% CI = 0.86–1.22). No differential treatment effect was observed in analysis by Gleason score categories of ≤ 6, 7, and 8 to 10. In total, 59% of deaths were not related to prostate cancer. Thus, an unplanned retrospective analysis was performed to determine disease-specific survival. Risk of prostate cancer–related death was comparable with intermittent androgen-deprivation therapy (HR = 1.18, P = .24), with a similar finding after adjustment for stratification and confounding factors (HR = 1.23, P = .13). Estimated 7-year cumulative disease-related death rates were 18% in the intermittent group and 15% in

the continuous group. Factors that were significantly associated with increased risk of prostate cancer–related death in the entire population on this analysis were age ≥ 75 vs < 75 years (HR = 1.58, P = .001), baseline PSA > 15 vs 3 to 15 ng/mL (HR = 1.98, P < .001), and prior hormone therapy (HR = 1.66, P < .001). Time since radiotherapy of > 3 vs 1 to 3 years was associated with a significantly decreased risk (HR = 0.41, P < .001).

Castration-resistant Disease Castration-resistant disease developed in 202 patients in the intermittent group and 243 in the continuous group, yielding a significant 20% reduction in risk in the intermittent group (HR = 0.80, P = .02), with

Androgen Deprivation in Prostate Cancer ■■ No difference in overall survival or disease-specific mortality was observed between intermittent and continuous androgen-deprivation therapy for prostate cancer associated with rising prostate-specific antigen levels after radiotherapy.

■■ Testosterone recovery was not universal with intermittent androgen

suppression, but the strategy was associated with some quality-of-life benefits.

functional domains (physical, role, and general health), the intermittent group had scores that were slightly but nonsignificantly better than those in the continuous group. For symptom items, the intermittent group had significantly better scores for hot flashes (P < .001), desire for <� �� .001), and urisexual activity (P �� nary symptoms (P = .006), with a

An intermittent approach to androgen deprivation for men with a rising PSA level after definitive radiotherapy does not result in inferior survival…. Although testosterone recovery was not universal, benefits in some aspects of quality of life were observed. the reduction remaining significant after adjustment for prognostic factors (HR = 0.81, P = .03). A 4-month survival gain after diagnosis of castration-resistant disease observed in the intermittent group likely reflected the inherent delay in identification of such disease in this group (ie, treatment had to be restarted in these patients, who then had to satisfy testosterone and PSA criteria for diagnosis). A return to pretreatment testosterone levels occurred in 35% of intermittent group patients within 2 years of completing the first treatment period, and 79% had a level of ≥ 5 nmol/L (the required entry level). Return to pretreatment levels was significantly less likely in patients aged 75 years or older compared with younger patients =� �� .001). Recovery of potency oc(P �� curred in 29% of patients who were potent at baseline.

trend toward improvement in fatigue (P = .07). A safety analysis showed no significant between-group differences in adverse events. The investigators noted that the improvements in QOL were not as marked as might be expected in the intermittent group and suggested that this finding likely reflects the fact that, over time, intermittent group patients were increasingly distributed between treatment and

■

Reference 1. Crook JM, O’Callaghan CJ, Duncan G, et al: Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med 367:895-903, 2012.

View Our Special Webcast

Case Studies in Rare Lymphomas Supplement • Volume 3, Issue 14 • September 15, 2012

Case Studies in Rare Lymphomas: Hodgkin Lymphoma and Systemic Anaplastic Large Cell Lymphoma INTRODUCTION

The ASCO Post announces availability of a special online program featuring cases in Hodgkin lymphoma and systemic anaplastic large cell lymphoma.

James O. Armitage, MD University of Nebraska Medical Center Omaha, Nebraska

HODGKIN LYMPHOMA Management Following Failure of Autologous Stem Cell Transplant Joseph M. Connors, MD James O. Armitage, MD

Joseph M. Connors, MD

HODGKIN LYMPHOMA Management of Relapsed and Refractory Disease Andreas Engert, MD

Some QOL Improvement Quality of life was assessed at fixed time points, irrespective of treatment phase, using the EORTC QLQ-C30. Assessment occurred at baseline, every 4 months for 2 years, and then every 8 months until diagnosis of castration-resistant disease and annually thereafter. For

nontreatment intervals at the times of QOL assessment. The observed difference in QOL between the two groups was greatest during the first nontreatment interval, entered at the same time point by the majority of intermittent group patients, and diminished thereafter. For an individual patient receiving intermittent androgen-deprivation therapy, differences in QOL might be more striking between treatment and nontreatment phases, with benefits also expected to be affected by such factors as testosterone recovery and age. The authors concluded: “An intermittent approach to androgen deprivation for men with a rising PSA level after definitive radiotherapy does not result in inferior survival…. Although testosterone recovery was not universal, benefits in some aspects of quality of life were observed. These results cannot be extrapolated to other intermittent-treatment schedules or disease characteristics.”

SYSTEMIC ANAPLASTIC LARGE CELL LYMPHOMA Management Following Failure of One or More Combination Regimens Steven M. Horwitz, MD

Andreas Engert, MD

Steven M. Horwitz, MD

Webcast available at ASCOPost.com/lymphomaweb/

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

ASCOPost.com

An expert panel includes moderator James O. Armitage, MD, with faculty Joseph M. Connors, MD, Andreas Engert, MD, and Steven M. Horwitz, MD.

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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%)

•

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

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.

402 406

345 311

267 209

139 93

32 17

10 7

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.

• •

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

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2012-2013 Oncology Meetings November 2012 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org Connective Tissue Oncology Society 17th Annual Meeting November 14-17 • Prague, Czech Republic For more information: www.ctos.org Controversies in the Management of DCIS of the Breast November 15 • Wilmington, Delaware For more information: www.dsco-delawareoncology.org Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org Iowa Oncology Society Fall Membership Conference: New Directions in Healthcare and Cancer Management November 16 • West Des Moines, Iowa For more information: www.ios-iowa.com/ Washington State Medical Oncology Society Fall Conference 2012 November 16 • SeaTac, Washington For more information: www.wsmos.org 17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com

2nd Symposium Targeted Cancer Therapy November 19-20 • Heidelberg, Germany For more information: www.dfkz.de/en/symposiumTCT/ RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/ 5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp 13th Annual Congress of the Asia Pacific Association for Gynecological Endoscopy & Minimally Invasive Therapy November 28-30 • Pattaya, Thailand For more information: www.apage2012.org 2nd Annual Best of Oncology Conference November 30 • Toronto, Ontario For more information: www.oncologyeducation.com/ conferences/best-of-oncology-2012. html ASCO’s Quality Care Symposium November 30-December 1 • San Diego, California For more information: quality2012.asco.org Global Conference on Perioperative Medicine: Care of the Elderly and the Cancer Patient November 28-December 2 • Houston, Texas For more information: www.mdanderson.org/conferences Oklahoma Society of Clinical Oncology November 30-December 1 • Grapevine, Texas For more information: www.oscook.org

December 2012 Cancer Survivorship: Advancements in Research and Care November 17 • Honolulu, Hawaii For more information: www.hsco-hawaii.com/

35th Annual San Antonio Breast Cancer Symposium December 4-8 • San Antonio, Texas For more information: www.sabcs.org

IDIBELL Cancer Conference on Personalized Cancer Medicine December 3-4 • Barcelona, Spain For more information: www.bocemtium.com/icc2012

The Second Montréal Conference on Focal Therapy for Prostate Cancer December 7-8 • Montreal, Canada For more information: www.focaltherapymontreal.com 2012 ASH Annual Meeting December 8-11 • Atlanta, Georgia For more information: www.hematology.org Recent Advances in Biomarker Research in Lung Cancer with Special Reference to New Targeted Therapies December 11 • Honolulu, Hawaii For more information: www.hsco-hawaii.com

January 2013 Breast-Gynecological International Cancer Congress January 17-18 • Cairo, Egypt For more information: www.bgicc.eg.net/ Case-based Clinical Hematology and Oncology 2013: The 10th Annual Review January 18-20 • Scottsdale, Arizona For more information: www.mayo.edu/cme 11th Oncology Update: Advances and Controversies January 18-21 • Steamboat Springs, Colorado For more information: www.mdanderson.org/conferences 2013 Gastrointestinal Cancers Symposium January 24-26 • San Francisco, California For more information: www.gicasymposium.org

T-cell Lymphoma Forum January 24-26 • San Francisco, California For more information: www.tcellforum.com 3rd Annual San Antonio Breast Cancer Symposium Review January 26 • Omaha, Nebraska For more information: www.nebraskaoncology.org The 15th International Symposium on Anti-Angiogenic Therapy: Recent Advances and Future Directions in Basic and Clinical Cancer Research January 31-February 2 • San Diego, California For more information: www.mdanderson.org/conferences

February 2013 Interventional Pulmonology in Cancer Patients: An Intensive Hands-on Course February 7-9 • Houston, Texas For more information: www.mdanderson.org/conferences Advances in Orbital Oncology and Oculofacial Plastic Surgery February 8-9 • Houston, Texas For more information: www.mdanderson.org/conferences Integrative Medicine Program’s 1st Annual Integrative Oncology Healthcare Professional Training Conference February 8-9 • Houston, Texas For more information: www.mdanderson.org/conferences Methods in Cancer Research Workshop February 9-13 • Al Ahsa, Saudi Arabia For more information: mcrw.kacst.edu.sa ASCO-MECC Palliative Care Workshop February 10-13 • Muscat, Oman For more information: www.asco.org/palliativecare Genomics in Medicine: Individualized Care for Improved Outcomes February 11-12 • San Francisco, California For more information: www.triconference.com/genomicspersonalized-medicine continued on page 68

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2012-2013 Oncology Meetings continued from page 67

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

March 2013 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

Quantitative Real-time PCR: Applications for Molecular Diagnostics February 11-12 • San Francisco, California For more information: www.triconference.com/ Quantitative-Pcr/

Inaugural Prostate Cancer Research and Translation Symposium March 6-7 • Winston-Salem, North Carolina For more information: northwestahec.wfubmc.edu

Molecular Med Tri-Con 2013 February 11-15 • San Francisco, California For more information: www.triconference.com

NCCN 18th Annual Conference: Advancing the Standard of Cancer Care March 14-17 • Hollywood, Florida For more information: www.nccn.org

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

23rd Annual National Interdisciplinary Breast Cancer Conference March 23-27 • Las Vegas, Nevada For more information: www.breastcare.org/

April 2013 3rd ITLT Essen 2013 Interdisciplinary Treatment of Liver Tumors April 18-20 • Essen, Germany For more information: www.itlt.org The Arizona Clinical Oncology Society Spring Membership Conference April 19 • Phoenix, Arizona For more information: www.tacos-oncology.com

May 2013 Precision Medicines in Breast Cancer May 9-10 • London, United Kingdom For more information: www.precisionmedicines.com

European Multidisciplinary Conference in Thoracic Oncology May 9-11 • Lugano, Switzerland For more information: www.esmo.org Interventional Oncology Sans Frontières May 29-June 1 • Cernobbio, Italy For more information: www.iosfc2013.org 2013 ASCO Annual Meeting May 31-June 4 • Chicago, Illinois For more information: www.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 2013 Breast Cancer Symposium 2013

June 2013 12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes.com

July 2013 Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences

September 7-9 • San Francisco, California For more information: www.breastcasym.org Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu

August 2013 Best of ASCO® Chicago August 9-10 • Chicago, Illinois For more information: boa.asco.org Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org

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

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The ASCO Post | NOVEMBER 15, 2012

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Health-care Policy Cost of Care

Delivering Affordable Cancer Care: Is It Possible and What Will It Entail? By Margot J. Fromer

“M

any experts agree that at 18% of gross domestic product, health care (to paraphrase Shakespeare) is eating the country out of house and home. “The average cost of treating the most common cancers has increased, and as more expensive targeted therapies and other new technologies become the standard, things will escalate more rapidly. But despite high expenditures, disparities in outcomes persist,” said Patricia A. Ganz, MD, Professor, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, and Co-Chair of the National Cancer Policy Forum Workshop Planning Committee, as she opened the recent meeting on Delivering Affordable Cancer Care in the 21st Century at the Institute of Medicine (IOM) in Washington, DC.

Critical Considerations IOM President Harvey V. Fineberg, MD, PhD, went on to say that three critical points have to be part of cost-containment considerations:

Patricia A. Ganz, MD

Challenges Are Many and Diverse Scott Ramsey, MD, PhD, Director of Research and Economic Assessment in Cancer and Healthcare, Fred Hutchinson Cancer Research Center, Seattle, said that the United States spends at least twice as much on health care as other developed countries, but life expectancy and other critical measures lag behind many of them. He noted that the population is growing and aging; obesity and other risk factors increase the likelihood of cancer; and the public doesn’t understand treatment and consequently makes unrealistic demands. Moreover, there is poor reimbursement for cognitive care (but it is better for chemotherapy and procedures); providers are stressed and burning out; and the value of care is significantly affected by the presence and type of insurance. Mark B. McClellan, MD, Senior Fellow, The Brookings Institution, Washington, DC, added that there is a misalignment between what matters most to patients (availability of 24hour response from physician offices

Harvey V. Fineberg, MD, PhD

First, Quality of care must be maintained. Second, the kinds of costs involved must be examined, including personal out-of-pocket expenses, insurance reimbursement, the public purse, and other types of payment. He noted that cancer care is a major cause of personal bankruptcy and that shifting costs from one pocket to another doesn’t necessarily lower them. Finally, policymakers must be willing to look at many strategies at once: cheaper drugs, efficiency of care delivery, prevention, research. “We must be prepared to use every tool in the toolbox, and it is ethically imperative that we involve patients in the endeavor.”

Scott Ramsey, MD, PhD

and phone consultation, for instance) and what is reimbursed. He listed key elements of real reform: ■■ Data measurement and evidence of benefit and harm ■■ Changes in the way benefits are paid to providers in the accountable care system and performancebased payment for drug reimbursement ■■ Patients’ ability to make real choices in health insurance plans “The era of providing high-cost interventions with little benefit must end. A 600% increase in cancer care over the past 30 years—with inconsistent outcomes—is unsustainable,” said Jeffrey Peppercorn, MD, MPH,

Jeffrey Peppercorn, MD, MPH

Veena Shankaran, MD

Associate Professor of Medicine, Duke University Medical Center, Durham, North Carolina.

Parameters of Value Dr. Peppercorn addressed some of the factors that contribute to high costs for cancer care: high costs for development of new therapy, lack of clinical and economic studies to guide evidence-based care, lack of awareness or willingness to follow evidencebased practice when data is available, and lack of adequate sociopolitical debate on the real choices we face. In addition, he noted that we need to recognize distinct aspects of this challenge. “We must differentiate between costs to society and costs to individual patients, and in the United States, the challenge of dealing with costs to patients is compounded by the fact that almost 50 million are currently uninsured and an additional 29 million are underinsured,” Dr. Peppercorn continued. “On a societal level, we must find the resources to provide interventions that have high value to everyone in need, while at the same time finding ways to reduce or eliminate practices that do no have proven benefit.” But what are the parameters of value? And who defines value: the state, physicians, patients, insurers, a panel of experts? Dr. Peppercorn enumerated several of the challenges we face in seeking to control costs and preserve or improve quality and access: ■■ How can they be most efficiently, ethically, and equitably allocated? ■■ To what extent do we view health care as a commodity? ■■ How do we curb overutilization? ■■ How do we balance cost control and clinical freedom and discretion? ■■ How do we incentivize best care? ■■ How and when should physicians consider the cost of care, and

Mark B. McClellan, MD

when should they discuss it with patients?

Patients Are Vulnerable Veena Shankaran, MD, Assistant Professor of Medical Oncology, Fred Hutchinson Cancer Research Center, added that not only is the patient’s share of costs increasing, but insurance premiums have gone up significantly, sometimes by 100%. Deductibles, copayments, and outof-pocket expenses for off-label diagnostics and treatments also are on the rise. “Patients are financially vulnerable,” she said. “They are inundated with nonmedical costs, and often they’re too sick to work. Sometimes financial hardships lead to noncompliance, and sometimes patients are so scared that they accept any treatment at any price, regardless of potential benefit.” More spending is not necessarily the answer. “We need better outcomes and better value,” Dr. Shankaran said. She thinks it is imperative for oncologists to discuss cost with patients and families (including convenience, distance from the cancer center, transportation expenses, and the like) and make it part of the treatment decision. Therefore, physicians need to know what various treatments cost, both reimbursed and out-of-pocket. It is true, she added, that these discussions are time-consuming (and mostly unreimbursed), and many physicians don’t know how to conduct them. “But the bottom line is if there is no evidence of benefit, regardless of cost, we shouldn’t recommend it,” she concluded.

What the Problem Is and What It Isn’t Ezekiel J. Emanuel, MD, PhD, Diane v.S. Levy and Robert M. Levy

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Health-care Policy

University Professor, Perelman School of Medicine, University of Pennsylvania, Philadelphia, threw out another giant number: $2.8 trillion spent on health care in 2012— the same as the entire gross domestic product of France. “The United States is on a different planet [compared to other countries] when it comes to health-care spending,” said Dr. Emanuel. “And it is by no means benign.” It affects: ■■ Who can be covered by health insurance (Medicare and Medicaid will rise from 4.5% of the economy today to 20% by 2050.)

Ezekiel J. Emanuel, MD, PhD

■■ State budgets and support of education, in some states escalating tuition at colleges and universities ■■ Middle-class wages. For instance, over the past 30 years, health insurance premiums have increased by 300% after inflation, corporate profits increased 200% after taxes, and net worker income in private industries declined by 4%. ■■ America’s long-term fiscal stability and status as a world power He added that 50% of the population uses 3% of total health-care cost, while 10% uses 63%. “And the quality of care is equally uneven.” Many ideas about cost control aren’t real, Dr. Emanuel commented. “Physicians often ignore their own role and fail to change the way they practice. They blame medical malpractice and defensive medicine costs, insurance company profits, drug costs, and demanding patients.” These factors exist, he said, but for example, medical malpractice costs $35 billion, 2% of total cost. Defensive medicine comes in at $66 billion: 3% of the total. And yes, insurance companies are profitable ($11.7 billion in 2010), but he said this represents only a drop in the bucket. And there is no evidence that demanding patients are culprits. People who use more than $1 million in care use 0.5% of the total, and those who use $250,000 use 6.5% of the total.

Nevertheless, all these drops in the bucket and small percentages of the total add up to far more than small change.

Screening, Diagnosis, and Value Otis W. Brawley, MD, Chief Medical Officer, American Cancer Society,

said that some people consume too much (unnecessary) health care, and some do not receive what is necessary. But despite the negative connotation of the word, health care is indeed being rationed. “A substantial portion of people Bleed:7.875” do not get adequate care—up to 30% of Trim:7.625” breast cancer patients and 20% of those Live:7” with colon cancer, for instance. ”

Many of the problems stem from screening issues, such as: ■■ A perception that all cancer is bad and must be found early and treated aggressively ■■ The belief that there is no such thing as overdiagnosis ■■ Thinking that increases in 5-year continued on page 72

NOW AVAILABLE ZALTRAP®, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatincontaining regimen. IMPORTANT SAFETY INFORMATION FOR ZALTRAP WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage. GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation. Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. WARNINGS AND PRECAUTIONS • Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events — Monitor patients for signs and symptoms of bleeding — Do not initiate ZALTRAP in patients with severe hemorrhage — Discontinue ZALTRAP in patients who develop severe hemorrhage Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

Visit www.ZALTRAP.com to learn more. For more information about ZALTRAP, call 1-855-ZALTRAP (1-855-925-8727).

FPO

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Health-care Policy

Delivering Affordable Cancer Care continued from page 71

survival are evidence that screening is beneficial ■■ Confusion of relative risk and absolute risk ■■ Nonconformity with established screening and treatment guidelines,

many of which are flawed to begin with Dr. Brawley also listed areas of overuse: imaging, expensive drugs (brand name vs generic), and screening for lung, breast, cervical, and prostate cancers. This results from ig-

Otis W. Brawley, MD

noring known science and the “greedy feeding the gluttonous.” He added, “We are tolerating a subtle form of corruption.” True health-care reBleed:7.875” form will involve evidenceTrim:7.625” based care and prevention Live:7” for everyone. “It is possible

to decrease costs, improve outcomes, and reduce disparities by using science to guide our policies,” said Dr. Brawley. “However, a plan that would truly lower costs, maintain quality, and be fair to everyone would involve significant changes in the ways we currently do health-care business. ” For disclosures, visit ASCOPost.com.

■

NOW AVAILABLE

IMPORTANT SAFETY INFORMATION FOR ZALTRAP® (cont’d) • GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP — Monitor patients for signs and symptoms of GI perforation — Discontinue ZALTRAP in patients who experience GI perforation • Discontinue ZALTRAP in patients with compromised wound healing — Suspend ZALTRAP for at least 4 weeks prior to elective surgery — Do not initiate/resume ZALTRAP until at least 4 weeks after surgery and surgical wound is fully healed • Fistula formation involving GI and non-GI sites occurs at a higher incidence in patients treated with ZALTRAP. Discontinue ZALTRAP therapy in patients who develop ﬁstula • An increased risk of Grade 3-4 hypertension has been observed in patients receiving ZALTRAP — Monitor blood pressure every two weeks or more frequently and treat with appropriate anti-hypertensive therapy during treatment with ZALTRAP — Temporarily suspend ZALTRAP until hypertension is controlled, and reduce ZALTRAP dose to 2 mg/kg for subsequent cycles — Discontinue ZALTRAP in patients with hypertensive crisis • Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. Discontinue ZALTRAP in patients who experience an ATE • Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP — Suspend ZALTRAP when proteinuria ×2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours — If recurrent, suspend until proteinuria <2 grams/24 hours and then reduce ZALTRAP dose to 2 mg/kg — Discontinue ZALTRAP if nephrotic syndrome or TMA develops • A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP — Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ×1.5 x 109/L • Incidence of severe diarrhea and dehydration is increased in patients treated with ZALTRAP/FOLFIRI — The incidence of diarrhea is increased in patients ×65 years of age. Monitor closely • Discontinue ZALTRAP in patients who develop reversible posterior leukoencephalopathy syndrome

ADVERSE REACTIONS • The most common adverse reactions (all grades, ×20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache • The most common Grade 3-4 adverse reactions (×5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia • Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection • In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI Please see accompanying Brief Summary of full Prescribing Information, including Boxed WARNING. In the U.S., ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2012 sanoﬁ-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.

US.AFL.12.07.046

8/12

Printed in U.S.A.

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In the Literature

Emerging Clinical Data on Cancer Management SECOND NEOPLASMS Risk Reduction for Patients with Multiple Primary Cancers The number of patients with multiple primary cancers is increasing

ZALTRAP® (ziv-aﬂibercept) Injection for Intravenous Infusion

so that second malignant neoplasms now represent approximately 16%, or 1 in 6 cancers reported to the Surveillance, Epidemiology, and End Results Bleed:7.875” (SEER) Program. While some second Trim:7.625” malignant neoplasms are treatmentLive:7” related, others are due to genetic sus-

Rx Only

Brief Summary of Prescribing Information WARNING:

HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Hemorrhage: Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage [see Dosage and Administration (2.2), Warnings and Precautions (5.1)]. Gastrointestinal Perforation: Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Compromised Wound Healing: Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

continued on page 74

Bleed:10.75”

Live:10”

Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line. Administer ZALTRAP using an infusion set made of one of the following materials: • PVC containing DEHP • DEHP free PVC containing trioctyl-trimellitate (TOTM) • polypropylene • polyethylene lined PVC • polyurethane 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/ hemorrhage (all grades) were reported in 38% of patients treated with ZALTRAP/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3–4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and post-procedural hemorrhage, were reported in 3% of patients receiving ZALTRAP/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving ZALTRAP. Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage [see Dosage and Administration (2.2)]. 5.2 Gastrointestinal Perforation Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three Phase 3 placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation events occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo. Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2)]. 5.3 Compromised Wound Healing ZALTRAP impairs wound healing in animal models [see Nonclinical Toxicology (13.2) in the full prescribing information]. Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI regimen and in none of the patients treated with placebo/ FOLFIRI regimen. Suspend ZALTRAP for at least 4 weeks prior to elective surgery. Do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with compromised wound healing [see Dosage and Administration (2.2)]. 5.4 Fistula Formation Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with ZALTRAP. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and in 1 placebo-treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula [see Dosage and Administration (2.2)]. 5.5 Hypertension ZALTRAP increases the risk of Grade 3–4 hypertension. There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% of patients treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Among those patients treated with ZALTRAP/FOLFIRI developing Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment. Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with ZALTRAP. Treat with appropriate anti-hypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend ZALTRAP in patients with uncontrolled hypertension until controlled, and permanently reduce ZALTRAP dose to 2 mg per kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.2)]. 5.6 Arterial Thromboembolic Events Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. In patients with mCRC, ATE was reported in 2.6% of patients treated with ZALTRAP/FOLFIRI and 1.7% of patients treated with placebo/ FOLFIRI. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE [see Dosage and Administration (2.2)]. 5.7 Proteinuria Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. In patients with mCRC,

cers mandates that we also further probe etiologic influences and genetic variants that heighten risk, and that we better define high-risk groups for targeted preventive and interventional clinical strategies,” the authors wrote.

Trim:10.5”

Bleed:10.75”

Live:10”

1 INDICATIONS AND USAGE ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen [see Clinical Studies (14) in the full prescribing information]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule Administer ZALTRAP 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment [see Clinical Studies (14) in the full prescribing information]. Continue ZALTRAP until disease progression or unacceptable toxicity. 2.2 Dose Modification / Treatment Delay Recommendations Discontinue ZALTRAP for: • Severe hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised wound healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula formation [see Warnings and Precautions (5.4)] • Hypertensive crisis or hypertensive encephalopathy [see Warnings and Precautions (5.5)] • Arterial thromboembolic events [see Warnings and Precautions (5.6)] • Nephrotic syndrome or thrombotic microangiopathy (TMA) [see Warnings and Precautions (5.7)] • Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.10)] Temporarily suspend ZALTRAP: • At least 4 weeks prior to elective surgery [see Warnings and Precautions (5.3)] • For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.5)]. • For proteinuria of 2 grams per 24 hours. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.7)]. For toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information. 2.3 Preparation for Administration Inspect vials visually prior to use. ZALTRAP is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles. Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial. Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP to achieve a final concentration of 0.6–8 mg/mL. Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags. Store diluted ZALTRAP at 2–8°C (36–46°F) for up to 4 hours. Discard any unused portion left in the infusion bag. 2.4 Administration Administer the diluted ZALTRAP solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon. Do not administer as an intravenous (IV) push or bolus.

ceptibility, lifestyle and environmental exposures, or a combination of factors, according to a review article in a special series on adult cancer survivorship in the Journal of Clinical Oncology. ”The growing number of patients with second (and higher-order) can-

The ASCO Post | NOVEMBER 15, 2012

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In the Literature

Emerging Clinical Data continued from page 73

Treatment-related Cancers Both radiotherapy and chemotherapy have been associated with second malignant neoplasms. “Hallmarks of radiotherapy-associated cancers include a long latency period of at least 5 to 10 years and a tendency to arise

within or at the edges of prior treatment fields,” the authors stated. This could affect survivors of Hodgkin lymphoma and cancers of the testes, breast, cervix, and prostate. Chemotherapy with alkylating agents has been associated with increased risk of acute leukemia and solid tumors, including lung cancer, gastrointestinal cancer, sarco-

ma, and bladder cancer. Topoisomerase II inhibitors and rituximab (Rituxan) have also been associated with increased risk of second malignant neoplasms.

Genetic Susceptibility

Bleed:7.875”

“Cancer survivors with a family hisTrim:7.625” tory of cancer may be at above average Live:7” risk of [a second malignant neoplasm],”

proteinuria was reported in 62% patients treated with ZALTRAP/FOLFIRI compared to 41% patients treated with placebo/FOLFIRI. Grade 3–4 proteinuria occurred in 8% of patients treated with ZALTRAP/FOLFIRI to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies. Monitor proteinuria by urine dipstick analysis and urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during ZALTRAP therapy. Obtain a 24-hour urine collection in patients with a UPCR greater than 1. Suspend ZALTRAP administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg. Discontinue ZALTRAP in patients who develop nephrotic syndrome or TMA [see Dosage and Administration (2.2)]. 5.8 Neutropenia and Neutropenic Complications A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. In patients with mCRC, Grade 3–4 neutropenia occurred in 37% of patients treated with ZALTRAP/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Grade 3–4 febrile neutropenia occurred in 4% of patients treated with ZALTRAP/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of patients treated with ZALTRAP/FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI. Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay ZALTRAP/FOLFIRI until neutrophil count is at or above 1.5 × 109/L. 5.9 Diarrhea and Dehydration The incidence of severe diarrhea is increased in patients treated with ZALTRAP/FOLFIRI. In patients with mCRC, Grade 3–4 diarrhea was reported in 19% of patients treated with ZALTRAP/FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3–4 dehydration was reported in 4% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/ FOLFIRI [see Adverse Reactions (6.1)]. The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age [see Geriatric Use (8.5)]. Monitor elderly patients closely for diarrhea. 5.10 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Conﬁrm the diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death [see Dosage and Administration (2.2)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal Perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised Wound Healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula Formation [see Warnings and Precautions (5.4)] • Hypertension [see Warnings and Precautions (5.5)] • Arterial Thromboembolic Events [see Warnings and Precautions (5.6)] • Proteinuria [see Warnings and Precautions (5.7)] • Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8)] • Diarrhea and Dehydration [see Warnings and Precautions (5.9)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.10)] 6.1 Clinical Trial Experience Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reﬂect the rates actually observed in clinical practice. The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1216 previously treated patients with metastatic colorectal cancer (Study 1) who were treated with ZALTRAP 4 mg per kg intravenous (N=611) or placebo (N=605) every two weeks (one cycle) in a randomized (1:1), double-blind, placebo-controlled Phase 3 study. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI or 8 cycles of placebo/FOLFIRI. The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm , in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache (see Table 1). The most common Grade 3–4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1). The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.

the authors wrote. “Individuals with a family history suggestive of a cancer family syndrome (eg, autosomal dominant inheritance, early onset cancer, and clustering of cancer types) may be candidates for genetic testing and should be referred for genetic counseling.” If a germ-line mutation in a cancer-causing gene is identified in a cancer survivor,

ZALTRAP® (ziv-aﬂibercept) Injection for Intravenous Infusion The ZALTRAP dose was reduced and/or omitted in 17% of patients compared to placebo-dose modiﬁcation in 5% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI compared with 43% of patients treated with placebo/FOLFIRI. The most common adverse reactions and laboratory abnormalities during study treatment in Study 1 where the incidence was ≥5% (all grades) in patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients treated with ZALTRAP/FOLFIRI compared to placebo/FOLFIRI are shown in Table 1. Table 1 – Selected Adverse Reactions and Laboratory Findings in Study 1: Placebo/FOLFIRI ZALTRAP/FOLFIRI (N=605) (N=611) Primary System Organ Class All grades Grades All grades Grades Preferred Term (%) 3–4 3–4 Infections and infestations Urinary Tract Infection 6% 0.8% 9% 0.8% Blood and lymphatic system disorders Leukopenia 72% 12% 78% 16% Neutropenia 57% 30% 67% 37% Thrombocytopenia 35% 2% 48% 3% Metabolism and nutrition disorders Decreased Appetite 24% 2% 32% 3% Dehydration 3% 1% 9% 4% Nervous system disorders Headache 9% 0.3% 22% 2% Vascular disorders Hypertension 11% 1.5% 41% 19% Respiratory, thoracic and mediastinal disorders Epistaxis 7% 0 28% 0.2% Dysphonia 3% 0 25% 0.5% Dyspnea 9% 0.8% 12% 0.8% Oropharyngeal Pain 3% 0 8% 0.2% Rhinorrhea 2% 0 6% 0 Gastrointestinal disorders Diarrhea 57% 8% 69% 19% Stomatitis 33% 5% 50% 13% Abdominal Pain 24% 2% 27% 4% Abdominal Pain Upper 8% 1% 11% 1% Hemorrhoids 2% 0 6% 0 Rectal Hemorrhage 2% 0.5% 5% 0.7% Proctalgia 2% 0.3% 5% 0.3% Skin and subcutaneous tissue disorders Palmar-Plantar 4% 0.5% 11% 3% Erythrodysesthesia Syndrome Skin Hyperpigmentation 3% 0 8% 0 Renal and urinary disorders Proteinuria* 41% 1% 62% 8% Serum creatinine increased 19% 0.5% 23% 0 General disorders and administration site conditions Fatigue 39% 8% 48% 13% Asthenia 13% 3% 18% 5% Investigations AST increased 54% 2% 62% 3% ALT increased 39% 2% 50% 3% Weight decreased 14% 0.8% 32% 3% Note: Adverse Reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0 *Compilation of clinical and laboratory data Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection. In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%). In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients

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In the Literature

that individual may be eligible for highrisk screening and prevention strategies. The variability of effects of radiotherapy and chemotherapy on individual patients “points to an important role of genetic susceptibility,” the authors stated. “Although much of this research is not yet ready for routine clinical application, oncologists should be

aware of a few key points,” the authors noted. For example, patients with “genetic mutations in highly penetrant genes such as RB (associated with retinoblastoma) or TP53 (associated with Li-Fraumeni syndrome) would Bleed:7.875” be well-advised to avoid radiotherapy, Trim:7.625” if possible, because of the high rate of Live:7” [second malignant neoplasms] in irra-

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion 8.8 Females and Males of Reproductive Potential Male and female reproductive function and fertility may be compromised during treatment with ZALTRAP, as suggested by findings in monkeys [see Nonclinical Toxicology (13.1) in the full prescribing information]. These animal findings were reversible within 18 weeks after cessation of treatment. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment. 10 OVERDOSAGE There have been no cases of overdose reported with ZALTRAP. There is no information on the safety of ZALTRAP given at doses exceeding 7 mg per kg every 2 weeks or 9 mg per kg every 3 weeks. Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807, A SANOFI COMPANY U.S. License # 1752 ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2012 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC ZIV-BPLR-SA-AUG12

Revised: August 2012

low-penetrance genes have been associated with increased risks of therapy-related [second malignant neoplasms], to the best of our knowledge, identification of these genetic alterations in individual patients has not yet resulted in changes in clinical management.”

Environment and Lifestyle Along with therapy-related considerations and genetic susceptibility, the third group of factors associated with increased risk of second malignant neoplasms relates to shared environmental and lifestyle influences, such as smoking, excess drinking of alcohol, and dietary patterns. “In terms of absolute excess risk, tobacco- and alcohol-related cancer sites are estimated to account for more than 35% of all subsequent malignancies,” the authors stated. While there are few data on the interaction of risk factors and the development of second malignant neoplasms, based on reports to date, “it is synergistic relationships between lifestyle decisions (such as tobacco use) and treatment that may be associated with the highest risks of [second malignant neoplasms],” the authors added.

Risk Reduction

Bleed:10.75”

Live:10”

Several risk reduction strategies were proposed in the report. These include evaluating the second malignant neoplasm risk for any cancer survivor, taking into account family history, cancer treatment, and environmental factors such as obesity and smoking. The authors include accompanying tables to suggest how patients might be categorized as average, moderate, or high risk for second malignant neoplasms. “In general, all cancer survivors should follow applicable national guidelines for cancer screening, such as those provided by the American Cancer Society (ACS), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), and the U.S. Preventive Services Task Force (USPSTF),” the authors continued. In addition, they highlighted randomized controlled data for consideration in the prevention of second malignant neoplasms. These include data from observational studies showing that intentional weight loss and physical activity have been associated with reductions in cancer risk. Trim:10.5”

Bleed:10.75”

Live:10”

Trim:10.5”

treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo. The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay 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 ZALTRAP with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic drug-drug interactions were found between ziv-aflibercept and irinotecan/SN-38 or 5-FU, based on cross-study comparisons and population pharmacokinetic analyses. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with ZALTRAP in pregnant women. ZALTRAP was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ziv-aflibercept produced embryo-fetal toxicity when administered every 3 days during organogenesis in pregnant rabbits at all intravenous doses tested, ≥ 3 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation losses and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (in the heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). Administration of the 3 mg per kg dose to rabbits resulted in systemic exposure (AUC) that was approximately 30% of the AUC in patients at the recommended dose. The incidence and severity of fetal anomalies increased with increasing dose. 8.3 Nursing Mothers It is not known whether ZALTRAP 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 ZALTRAP, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the 611 patients with mCRC, patients treated with ZALTRAP/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9)]. The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI. No dose adjustment of ZALTRAP is recommended for patients greater than or equal to 65 years of age. 8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function [see Clinical Pharmacology (12.3) in the full prescribing information]. There are no data available for patients with severe hepatic impairment. 8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function [see Clinical Pharmacology (12.3) in the full prescribing information].

diated tissues,” the authors stated. “Genes associated with an increased risk of therapy-related [second malignant neoplasms] have also been related to drug metabolism (such as glutathione transferase [eg, GSTP1]) or the repair of DNA damage (such as mismatch repair gene MLH1),” they continued. “Although genetic changes (polymorphisms) in these

Wood ME, et al: J Clin Oncol 30:37343745, 2012. For more “In the Literature” see page 113

The ASCO Post | NOVEMBER 15, 2012

PAGE 76

In the Clinic

Ruxolitinib: Novel Drug for Myelofibrosis By Matthew Stenger

Indication

n November 2011, ruxolitinib ( Jakafi) was approved for treatment of patients with intermediate- or highrisk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.1,2 Approval was based on two phase III trials in patients with intermediate- or high-risk myelofibrosis: a double-blind trial comparing ruxolitinib (n = 155; 15–20 mg orally twice daily based on baseline platelet counts) vs placebo (n = 154) and an open-label trial comparing ruxolitinib (n = 146; same dosage) vs best available therapy (n = 73). Ruxolitinib treatment was continued as long as patients continued to benefit or until unacceptable toxicity was seen. In the two studies, 50% and 53% of patients had primary myelofibrosis, 31% and 31% had post–polycythemia vera myelofibrosis, and 18% and 16% had post–essential thrombocythemia myelofibrosis. In the first study, 35% or greater reduction in spleen volume at 24 weeks (the primary endpoint) occurred in 42% of ruxolitinib patients vs 1% of placebo patients (P < .0001). In the second study, 35% or greater reduction in spleen volume at 48 weeks (the primary endpoint) occurred in 29% of ruxolitinib patients vs 0% of patients in the best available care group (P < .0001). A 50% or greater reduction in symptom score at 24 weeks (key secondary endpoint) occurred in 46% of ruxoli-

OF NOTE Loss or lack of response and disease progression have resulted in high ruxolitinib discontinuation rates; most patients experience acute relapse of symptoms and splenomegaly during ruxolitinib withdrawal. Discontinuation should be closely supervised, in a tapering schedule.

tinib patients vs 5% of placebo patients (P < .0001) in the first study. In the second study, a 35% or greater reduction in spleen volume at 24 weeks (key secondary endpoint) occurred in 32% vs 0% (P < .0001). At the time of approval, 75% of the patients in the first study and 67% of those in the second who had a reduction in spleen volume of at least 35% had maintained this reduction.

How It Works Ruxolitinib inhibits JAK1 and JAK2 kinases, which mediate signaling of cytokines and growth factors important to hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors and activation and localization of STATs to the nucleus, resulting in modulation of gene expression. Myelofibrosis is associated with dysregulation of JAK signaling.

How It Is Given The starting dose of ruxolitinib is based on platelet count: 20 mg twice daily for counts greater than 200 × 109/L and 15 mg twice daily for counts of 100 to 200 × 109/L. Treatment should be interrupted for counts less than 50 × 109/L and can be restarted at full or reduced doses depending on the magnitude of recovery of platelet count. Dose adjustments can also be made based on platelet count (see prescribing information). Complete blood counts and platelet counts must be performed prior to starting treatment, every 2 to 4 weeks until dose is stabilized, and as clinically indicated thereafter.

Safety Profile In the phase III trials, the most common hematologic adverse events (> 20%) in patients receiving ruxolitinib were thrombocytopenia and anemia. The most common nonhematologic adverse events (> 10%) were bruising, dizziness, and headache. Adverse events of grade 3 or greater that occurred more frequently with ruxolitinib vs placebo in the double-blind trial were thrombocytopenia (13% vs 1%) and anemia (45% vs 19%). Similar results were observed in the second study. Ruxolitinib carries warnings/precautions for thrombocytopenia, anemia, neutropenia, and infections.

Ruxolitinib in Myelofibrosis ■■ Ruxolitinib (Jakafi) is approved for treatment of patients with intermediateor high-risk myelofibrosis, including primary myelofibrosis, post– polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.

■■ The starting dose of ruxolitinib is based on platelet count: 20 mg twice

daily for counts greater than 200 × 109/L and 15 mg twice daily for counts of 100 to 200 × 109/L, with dose adjustments made based on ongoing platelet counts.

Important Long-term Observations Tefferi and colleagues3,4 have reported on unfavorable long-term outcomes of ruxolitinib treatment in the 51 patients treated at their institution (Mayo Clinic) from among a total of 153 participating in a phase I/II trial in myelofibrosis.5 The 51 Mayo Clinic patients were enrolled from October 2007 through February 2009 and followed through July 2011 at

OF NOTE The most common hematologic adverse events associated with ruxolitinib are thrombocytopenia and anemia; the most common nonhematologic adverse events are bruising, dizziness, and headache. the most recent reporting. Of these patients, 47 (92%) have discontinued treatment. The median time on treatment was 9.2 months. Discontinuation rates at 1, 2, and 3 years were 51%, 72%, and 89%, respectively. Reasons for discontinuation included loss or lack of response/disease progression (~34%), toxicity with/without lack of response/disease progression (~34%), patient/physician choice, often associated with lack of response (~13%), and death during the study (~4%). Most patients experienced acute relapse of their symptoms and splenomegaly during treatment discontinuation. In 5 patients (11%), hospitalization following emergency department visits was required for acute relapse, rapid and painful enlargement of the spleen, and acute hemodynamic decompensation, which occasionally led to a septic shock-like syndrome. At the time of reporting, 18 patients (35%) had died and 5 (10%) had leukemic transformations. There was no significant difference in survival rate between the 51 ruxolitinib-treated pa-

tients and a cohort of 410 patients with primary myelofibrosis who were treated with standard therapy at the Mayo Clinic in the most recent 10-year period. Tefferi and colleagues stated: “Our experience calls for full disclosure of the ruxolitinib withdrawal syndrome to patients with [myelofibrosis] before initiating ruxolitinib therapy, and treatment discontinuation must be done under close physician supervision and preferably in a tapering schedule.”4

■

References 1. U.S. Food and Drug Administration: Ruxolitinib. Available at http://www.fda. gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ ucm280155.htm. Accessed September 28, 2012. 2. JAKAFITM (ruxolitinib) tablets prescribing information. InCyte Corporation, November 2011. Available at http:// www.accessdata.fda.gov/drugsatfda_docs/ label/2011/202192lbl.pdf. Accessed September 28, 2012. 3. Tefferi A, Litzow MR, Pardanani A: Long-term outcome of treatment with ruxolitinib in myelofibrosis. Correspondence. N Engl J Med 365:1455-1457, 2011. 4. Tefferi A, Pardanani A: Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 86:1188-1191, 2011. 5. Verstovsek S, Kantarjian H, Mesa RA, et al: Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 363:1117-1127, 2010.

ASCOPost.com | JULY 15, 2012

PAGE 77

Announcements

IOM Elects New Members, Foreign Associates

he Institute of Medicine (IOM) recently announced the names of 70 new members and 10 foreign associates during its 42nd Annual Meeting, in Washington, DC. Election to the IOM is considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service. “The Institute of Medicine is greatly enriched by the addition of our newly elected colleagues, each of whom has significantly advanced health and medicine,” said IOM President Harvey V. Fineberg, MD, PhD. The newly elected members raise IOM’s total active membership to 1,732 and the number of foreign associates to 112.

Paula M. Lantz, PhD, George Washington University, Washington, DC Terry R. Magnuson, PhD, School of Medicine, University of North Carolina, Chapel Hill Andrew I. Schafer, MD, Weill

Cornell Medical College and New York Presbyterian Hospital, New York Mitchell D. Schnall, MD, PhD, Perelman School of Medicine, University of Pennsylvania, Philadelphia Gregg L. Semenza, MD, PhD,

Johns Hopkins University School of Medicine, Baltimore Diana J. Wilkie, RN, PhD, FAAN, Center for Excellence for End-of-Life Transition Research and College of Nursing, University of Illinois, Chicago

■

Comprehensive

reporting.

New Members Active in Cancer-related Pursuits Newly elected IOM members working in oncology/hematology and other cancer-related fields include: R. Daniel Beauchamp, MD, FACS, Vanderbilt University Medical Center, Nashville, Tennessee Shelley L. Berger, PhD, University of Pennsylvania, Philadelphia Bruce R. Blazar, MD, University of Minnesota, Minneapolis John M. Carethers, MD, University of Michigan Health System, Ann Arbor Lynda Chin, MD, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston Don W. Cleveland, PhD, Ludwig Institute for Cancer Research, La Jolla, California, and University of California, San Diego Lisa DeAngelis, MD, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York Vishva M. Dixit, MD, Genentech Inc, San Francisco Jennifer R. Grandis, MD, FACS, University of Pittsburgh School of Medicine, Pittsburgh Donald E. Ingber, MD, PhD, Harvard Medical School and Children’s Hospital, Boston Carl H. June, MD, Perelman School of Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia Daniel L. Kastner, MD, PhD, National Human Genome Research Institute and National Institutes of Health, Bethesda, Maryland

Timely results. Confident decisions. At Clarient Diagnostic Services, we specialize in molecular and cellular diagnostic, prognostic and predictive cancer laboratory testing–including leukemia and lymphoma. We have a team of expert pathologists who collaborate with community pathologists, oncologists, and other clinicians to deliver our services 24/7/365—less wait time for your patients and their families. Our services provide you with the confidence to make the right individual treatment decisions for your patients’ care. Learn more. Visit us at SABCS, Booth #225 and ASH, Booth #3657. Together, we help you find the difference that makes a difference.

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The ASCO Post | NOVEMBER 15, 2012

PAGE 78

35th ESMO Congress Thoracic Oncology

Sorafenib Fails to Improve Survival as Third- or Fourth-line Treatment of Advanced Non–Small Cell Lung Cancer By Alice Goodman

hird- or fourth-line therapy with sorafenib (Nexavar) failed to extend overall survival in patients with advanced non–small cell lung cancer (NSCLC), according to the main results of the phase� �� III MISSION trial. However, a post hoc biomarker analysis of MISSION suggested that patients with EGFR-mutant tumors may benefit from sorafenib in this setting. Both studies were presented at the 2012 European Society for Medical Oncology (ESMO) Congress in Vienna.

Luis Paz-Ares, MD

MISSION Trial MISSION was a phase III, doubleblind, placebo-controlled study conducted in 33 countries that randomly assigned 703 patients with advanced, relapsed/refractory, heavily pretreated NSCLC to third- or fourth-line therapy with either oral sorafenib monotherapy at 400 mg twice daily or placebo. All patients got best supportive care. The study did not meet its primary

endpoint of improved overall survival, which was similar in both groups: 248 days for sorafenib vs 253 days for placebo. However, median progression-free survival, time to disease progression, overall response rate, and disease control rate were significantly improved by the addition of sorafenib. Median progression-free survival was 84 days for sorafenib vs 43 <� �� .0001). �� Medays for placebo (P �� dian time to progression was 89 vs 43 days, respectively (P < .0001). Overall response rate was 4.9% vs 0.9 (P < .001), and disease control rate (response plus stable disease) was 47% vs 25% (P < .0001). At baseline, demographic factors and prior treatments were well balanced in the two arms. Minor differences were more females in the sorafenib group (47% vs 41%) and more never-smokers (46% vs 38%). Fewer patients in the sorafenib arm were treated with additional therapies postprogression (44% vs 56%). A higher rate of adverse events was reported in the sorafenib arm: 99% vs 91%. Serious adverse events were reported in 39% vs 32%, respectively. Although sorafenib had relevant antitumor activity, lead author Luis Paz-Ares, MD, Virgen del Rocio University Hospital, Seville, Spain, said, “The fact that there is no significant overall survival highlights the increasing importance of poststudy therapies. In addition, one cannot exclude a po-

EXPERT POINT OF VIEW

Jean-Yves Pierga, MD

ormal discussant of the MISSION trial, Jean-Yves Pierga, MD, Institut Curie, Paris, said that it is one of several studies to show no clear benefit in overall survival for the addition of a tyrosine kinase inhibitor targeting angiogenesis in advanced non–small cell lung cancer. Dr. Pierga noted that findings of the biomarker study from MISSION are not in line with other studies. He commented, “In fact, clinical results [of studies of sorafenib and EGFR as a biomarker] are puzzling. There is no clear confirmation that EGFR status is relevant,” he said.

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

■

Sorafenib in Advanced Non–Small Cell Lung Cancer ■■ The addition of sorafenib as third- or fourth-line therapy did not extend overall survival in advanced NSCLC.

■■ A biomarker analysis suggested that EGFR mutations predict for response to sorafenib, but this is a preliminary finding that needs to be validated.

tential overall survival benefit in some patient populations.”

Biomarker Analysis A post hoc companion biomarker analysis of MISSION explored the effect of EGFR and KRAS mutation status on progression-free and overall survival, and findings suggested that EGFR-mutated status may be a predictive factor for sorafenib response. This conclusion was based on a positive interaction analysis for

Tony Mok, MD

both progression-free and overall survival, explained lead author Tony Mok, MD, Chinese University of Hong Kong. Median overall survival was twice as long in patients with mutated EGFR receiving sorafenib vs placebo (423 vs 197 days, hazard ratio [HR] = 0.48, P = .002). In contrast, there was no significant difference in overall survival between patients with wild-type EGFR receiving sorafenib or placebo (253 vs 256 days, HR = 0.92, P = .559). That said, Dr. Mok noted, “In the EGFR analysis, overall survival outcome could be biased by much greater use of poststudy EGFR tyrosine kinase inhibitors [43% in the sorafenib arm vs 18% in the placebo arm].” KRAS mutation status did not appear to predict response to sorafenib, based on a negative interaction analy-

sis for both progression-free and overall survival. Sorafenib treatment had a more favorable effect on progressionfree survival than placebo in patients with both mutated and wild-type KRAS tumors. “We do not see KRAS as having a predictive value for sorafenib as thirdor fourth-line therapy,” Dr. Mok stated. Samples were obtained from 357 patients; 107 provided tissue samples and 346 provided plasma samples. Samples were positive for EGFR mutations in 26% and for KRAS mutations, in 20%. “This is a retrospective exploratory analysis with a small sample size. It is hypothesis-generating, and results should be interpreted with caution,” Dr. Mok said. During the question-and-answer session, he said that it is not clear why EGFRpositive patients appeared to benefit from sorafenib. “We need to learn more,” he concluded.

■

Disclosure: Dr. Mok has been a consultant to and speaker for AstraZeneca, Roche, Pfizer, Boehringer Ingelheim, Lilly, Merck Serono, Taiho, BeiGene, and Eisai. Dr. Paz-Ares has been an advisor for Lilly.

References 1. Paz-Ares L, Hirsh V, Zhang L, et al: Monotherapy administration of sorafenib in patients with non-small cell lung cancer: Phase III, randomized, double-blind, placebo-controlled MISSION trial. 2012 ESMO Congress. Abstract LBA33. Presented September 29, 2012. 2. Mok TSK, Paz-Ares L, Wu Y-L, et al: Association between tumor EGFR and KRas mutation status and clinical outcomes in NSCLC patients randomized to sorafenib plus best supportive care (BSC) or BSC alone: Subanalysis of the phase III MISSION trial. 2012 ESMO Congress. Abstract LBA9. Presented September 29, 2012.

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

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

INDICATION XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

IMPORTANT SAFETY INFORMATION Hypocalcemia

Osteonecrosis of the Jaw (ONJ)

• XGEVA® can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to XGEVA® treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ.

• Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

• Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. • Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

www.XGEVA.com

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

PERCENTAGE OF PATIENTS WITHOUT SRE

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

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: 19.4 months

40 30

17%

Median time: 27.7 months

20 10

RISK REDUCTION

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

0 0

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

STUDY MONTH Data from three international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046), castration-resistant prostate cancer (N = 1,901), and solid tumors (other than breast or prostate) or multiple myeloma (N = 1,776). Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information. XGEVA® was administered subcutaneously 120 mg, once every 4 weeks. The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.3

SUBCUTANEOUS INJECTION

NO DOSE ADJUSTMENTS

PRECISE ACTION

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

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

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

Pregnancy • Women should be advised not to become pregnant when taking XGEVA®. If the patient is pregnant or becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia. During post approval use, severe symptomatic hypocalcemia, including fatal cases has been identiﬁed.

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

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

T:9.5”

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 – 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 findings 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 profile, toxicity profile, 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 Specific Populations). There are no highly dependent on the sensitivity and specificity 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 influenced 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 reflect 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 findings 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 Amgen’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 – 41) and median duration on-study was 13 months (range: 0.1 – 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 – 93). Seventyﬁve 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 beneﬁts 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 Speciﬁc 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 Prolia®. 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 ©2012 Amgen Inc. All rights reserved. Printed in USA.

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Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Animal Data: The effects of denosumab on prenatal development have been studied Severity (Trials 1, 2, and 3) in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). 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 findings 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 (≤ 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 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 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 – 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 Specific 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 confirmed in at doses ≤ 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 confirmed 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 – 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 identified 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 efficacy were Immunogenicity. As with all therapeutic proteins, there is potential for observed between these patients and younger patients.

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Perspective

Explaining Research to Patients By John F. Smyth, MD

John F. Smyth, MD

veryone understands the need for medical research, especially regarding cancer. However, only a minority of the public understand what is actually involved in taking part in a clinical trial. As professionals, we are responsible for designing relevant studies, for their conduct and analysis, and as part of this process, for selecting appropriate patients to whom participation may be relevant—all very obvious. However, the concept of obtaining and giving “informed consent” is worth a little reflection.

‘Informed Consent’ vs True Understanding In the days when protocols were 4 to 6 pages long, ethics committees trusted their medical colleagues, and patients only asked the questions to which they really wanted answers— life was simple. Now the protocols are very lengthy, ethics committees expect consent forms to highlight every possible disaster that could occur, and time pressures result in potential participants being given lengthy written explanations of trials, with sometimes little time for a real explanation of what is involved. Instead, the patient is given a handout and invited to return for questions and answers—not necessarily with the same clinician—if there is anything that is not clear. Not good. I have recent personal experience

of this. A family member (an ex-nurse) was diagnosed with multiple myeloma. Despite being referred to a well-recognized cancer center, she was given little explanation of what the diagnosis actually meant, but was offered participation in a national trial. Very little information was given about the reasons for this specific trial, but she was given an 8-page document of explanations prior to potential consent. I had to read this document twice before I understood the trial, there being no fewer than three consecutive randomizations depending on progress, and very little detail of what was actually involved.

tients that we know how to help them. This reassurance is inestimable to an anxious patient, but when introducing the concept of a clinical trial, we run the risk of undermining the very confidence that we wish to convey. We have to introduce the uncertainty that something new may be better—or may not. We do not know the answer or we would not be asking the question. The way that such information is explained is key to retaining confidence for patients. It is well established that participation in clinical trials is good for patients—the additional quality assurance of adhering to

It is imperative that we as oncologists take the time to explain what a trial is for, why it is scientifically and ethically justified, and to assure patients that their total care is not being abandoned to a computerized, randomization process selected over the Internet. — John F. Smyth, MD

She has agreed to participate, but her signature does not in truth represent “informed” consent.

Important Responsibility The reason that we should try to explain research is that the very nature of a clinical trial introduces the concept of uncertainty. One of the most important responsibilities that we have as oncologists is to help patients with their anxiety over the uncertain future that their diagnosis implies. Now that we have treatment for most cancers that offers some measure of benefit, the issue of life expectancy is less certain than in the days when we did not have such therapies. Without being patronizing or creating false hope, we seek to reassure pa-

trial protocols, the extra contact time with medical and nursing staff, etc. My point is simply that it is imperative that we as oncologists take the time to explain what a trial is for, why it is scientifically and ethically justified, and to assure patients that their total care is not being abandoned to a computerized, randomization process selected over the Internet. I have found it particularly challenging to explain placebo-controlled trials to patients, where so often it has been clear that they are desperate to have the experimental drug. This can take a little longer to explain, but then it is even more important to emphasize the benefits of trial participation, the extra care involved and so forth, regardless of study arm.

In Memoriam

E. Donnall Thomas, MD 1920 - 2012 See page 115

Phase I Studies To the surprise of some of my referring colleagues, I have found it easier to explain phase I trials or first-in-man studies. Patient selection is particularly important in this setting, and patients will usually have exhausted established treatments, or possibly already have taken part in trials comparing potentially therapeutic medicines. The explanation of participation in a phase I trial has to include the fact that this is potentially of very little if any clinical benefit to the individual patient. In this setting, I have emphasized that participation can be of significant benefit to science, and for this reason alone I have found that patients are usually more than willing to take part. I emphasize that in phase�� I studies, patients are regarded as partners in such research. If they are well selected, they can experience genuine comfort in feeling that they are making a contribution, and not being “abandoned” by their doctors now that the active phase of treatment is over.

Finding Time Handouts and written explanations have their place in this process. They ensure that details are explained, and they are a resource to return to as required. However, they are no substitute for compassionate, real-time communication with the doctor. All this takes time—that most precious of all commodities, especially when life expectancy is short. We have to find the time to ensure that a patient’s consent is as “informed” as possible.

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

Dr. Smyth is Emeritus Professor of Medical Oncology at the University of Edinburgh, Scotland, United Kingdom.

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Pioneers in Oncology Organizer of First Support Group for Young Adults with Cancer, Ellen Stovall Is Still Championing Cancer Survivors’ Rights By Jo Cavallo

tainty and fear of recurrence,” said Ms. Stovall. “I wanted to be prepared to have my fears managed in a way that was realistic and not delude myself. As far as I know, I’m the only person still alive out of the eight people in that original group.”

Fighting the Stigma of Cancer

Ellen Stovall

n 1971, just 1 month after giving birth to her son, Ellen Stovall was diagnosed with stage IV Hodgkin lymphoma. She was ineligible for a clinical trial of MOPP (mechlorethamine [mustargen], vincristine, procarbazine [Matulane], prednisone)—the first combination chemotherapy regimen developed for the treatment of Hodgkin lymphoma—because of her weakened condition from recently giving birth. Instead, she was treated with high-dose radiation to shrink a huge inoperable tumor sandwiched between her lungs and attached to her heart. Told by her oncologist at Georgetown University Hospital in Washington, DC, that she had a 20% chance of surviving 2 years, Ms. Stovall, then 24, asked her social worker at the hospital if there were other Hodgkin lymphoma patients with whom she could talk for support. After being told that most of the other patients that had been treated for the disease were either no longer alive or not in her age range, Stovall decided to start a cancer support group for young adults, the first of its kind at the hospital. That decision turned out to be the catalyst for her life’s work in cancer survivorship advocacy. “I wanted to talk to people my age with any kind of cancer so I could understand how they were managing the adjustment of living with uncer-

The support group gave Ms. Stovall a first-hand look into the issues patients with cancer have to contend with on a daily basis, from health insurance coverage to the stigma of having cancer. “One young man in the group had to drop out of his junior year in college and go back home so his family could take care of him. His mother had purchased an autoclave so she could sterilize everything he touched and wore a mask because she was terrified that he could spread the disease to other people. I thought, how awful it would be for him, on top of having cancer, to think that he

“I had seen an NCCS newsletter and it had a banner headline that read, ‘From the Moment of Diagnosis and for the Remainder of Life, a Person Diagnosed With Cancer Is a Survivor.’ And I thought that was so empowering, because I didn’t know what to call myself,” said Ms. Stovall. For 16 years, from 1992 until 2008, Ms. Stovall served as President and CEO of NCCS, she is currently its Senior Health Policy Advisor, and has been a national voice for cancer survivors, advocating for the adoption of a universal survivorship care plan to provide adult survivors with a blueprint to manage the long-term medical ramifications of their disease and helping to shape cancer health-care policy. As Vice-Chair of the Institute of Medicine (IOM) Committee on Cancer Survivorship, Ms. Stovall coedited the report, From Cancer Patient to Cancer Survivor: Lost in

Having the medical care delivery system, payment system, and patient care planning process all aligned would serve the best interest of patients. That’s what I wish for all people diagnosed with cancer; it’s what I’m working on now, and it’s probably how I will end my career. — Ellen Stovall

was a pariah,” said Ms. Stovall. The experience made her even more determined to help other patients with cancer cope with their illness. With her cancer in remission, Ms. Stovall became a volunteer for the American Cancer Society (ACS), going doorto-door raising money and educating people about the disease. Twelve years later, when her Hodgkin lymphoma recurred, ACS policy prevented her from continuing as a volunteer while she was undergoing active treatment (the policy is no longer in place) and she quickly found another home for her advocacy work with the then fledgling organization, the National Coalition for Cancer Survivorship (NCCS).

Transition and most recently was a participant on the IOM’s Committee for the Development of Trustworthy Clinical Practice Guidelines. She has also served on several advisory panels of the National Cancer Institute, the American Association for Cancer Research, and ASCO.

Ensuring Patient-centered Care Five years ago, Ms. Stovall was diagnosed with bilateral breast cancer, the likely result of her radiation treatment for her initial bout of Hodgkin lymphoma. Because of the radiation therapy and subsequent MOPP chemotherapy to treat the cancer recurrence, her doctors recommended a double

mastectomy rather than subjecting her to additional radiation and chemotherapy to treat the breast cancer. The secondary cancer wasn’t Ms. Stovall’s only long-term treatment side effect. The high-dose radiation therapy has also left her with a weakened heart. But her latest health problems aren’t slowing down her efforts to keep progress in cancer survivorship care moving forward. “The Lost in Transition report has moved the needle in the post-treatment setting, and the next step for NCCS is to move the needle in the decision-making and care planning and in the early stage of cancer diagnosis and treatment,” she said. “We’ve worked with ASCO to come up with a set of templates to use in care planning in the post-treatment setting, and we would like to work with ASCO to establish measures of quality care in the diagnostic and prognostic stages, as well as in setting goals of treatment, whether in the curative or palliative treatment setting.” With estimates from the NCI of 18 million cancers survivors by 2022, developing and instituting measurements for determining better quality of life, more efficient use of health-care services, and slowing escalating healthcare costs is imperative. And there is a lot more work to do to accomplish those goals, said Ms. Stovall. “A cancer diagnosis presents an opportunity for you to deal with yourself as a mortal person. Perhaps for the first time, after you get that diagnosis, you can envision how your life might end and decide how you want to deal with that,” she noted. Putting patient-centered cancer treatment plans in place in institutions and private practices is Ms. Stovall’s focus now. “Having the medical care delivery system, payment system, and patient care planning process all aligned would serve the best interest of patients. That’s what I wish for all people diagnosed with cancer; it’s what I’m working on now, and it’s probably how I will end my career.”

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Journal Spotlight Immunotherapy

PD-1 Blockade Increases Transferred T-cell Migration to Tumors By Matthew Stenger

ne reason that adoptive cell transfer has met with limited clinical success is that approaches based on this strategy have not fully taken into account the role of the tumor microenvironment as a limiting factor in immunotherapy. Recently reported studies by Peng and colleagues1 from The University of Texas MD Anderson Cancer Center in Houston and Juntendo University School of Medicine in Tokyo, Japan, indicate that blockade of the immunosuppressive receptor programmed cell death (PD)1 on transferred T cells increases T-cell migration to tumors and enhances the activity of adoptive cell transfer. The investigators found that in a murine model of adoptive cell transfer, PD-1 expressed on transferred T cells at the tumor site was upregulated compared with expression on transferred T See Page 108 cells in the peripheral blood or spleen. Since PD-1 can attenuate T-cell–mediated antitumor activity, the investigators tested whether use of an anti–PD-1 antibody could enhance activity of adoptive cell transfer. Concomitant adoptive cell transfer and administration of anti–PD-1 antibody increased the number of transferred T cells at the tumor site and resulted in greater tumor regression compared with either treatment alone. Although anti-PD-1 antibody did not reduce levels of immunosuppressive regulatory T cells or myeloid-derived suppressor cells, it was associated with increased expression of IFN-γ and the IFN-γ inducible chemokine CXCL10 in the tumor. Bone marrow transplant experiments in

IFN-γ receptor knockout mice showed that IFN-γ was crucial in controlling T cell tumor infiltration mediated by PD-1. As concluded by the investigators, “Taken together, our results imply that

blocking the PD-1 pathway can increase IFN-γ at the tumor site, thereby increasing chemokine-dependent trafficking of immune cells into malignant disease sites.”

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Reference 1. Peng W, Liu C, Xu C, et al: PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res 72:5209-5218, 2012.

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Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered.

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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.

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Perspective

Hodgkin Lymphoma continued from page 1

The combination chemotherapy ABVD (doxorubicin, bleomycin, �� vinblastine, dacarbazine) is regarded as standard of care for Hodgkin lymphoma patients in many countries. While this is not disputed for most earlystage patients, those in advanced stages have a poorer prognosis when treated with ABVD, with a reported failure-free survival at 5 years ranging from 63% to 66% in multicenter trials.1,2 In contrast, the more-recently developed multiagent regimen BEACOPP in its escalated-dose version (BEACOPPesc) has given more impressive results, with tumor control rates at 5 years of 87% and overall survival rates of 91%.3 Since BEACOPPesc is associated with more treatment-related toxicity, there is an ongoing discussion as to which patients should be treated with BEACOPPesc when diagnosed with Hodgkin lymphoma in advanced stages.

Escalated BEACOPP The BEACOPP regimen was developed by the German Hodgkin Study Group (GHSG) to increase dose density of chemotherapy as compared with ABVD and other regimens used in advanced-stage Hodgkin lymphoma. The pivotal GHSG HD9 trial compared the alternating regimen COPP (cyclophosphamide, vincristine, procarbazine, prednisone)/ ABVD with BEACOPP using baseline doses (BEACOPPbase) and escalated doses. This trial showed a significant advantage in terms of tumor control and overall survival for BEACOPPesc over both BEACOPPbase and COPP/ ABVD at 5 years.3 These results were confirmed in the follow-up analysis at 10 years.4 BEACOPPesc was associated with higher hematologic toxicity compared with BEACOPPbase or COPP/ABVD and induced more infertility in both male and female patients. In addition, the rate of secondary acute myeloid leukemia (AML) was higher with BEACOPPesc. The GHSG follow-up studies for patients with advanced-stage Hodgkin lymphoma thus focused on reducing intensity of treatment while maintaining efficacy. Although the GHSG HD12 trial failed to demonstrate that four cycles of BEACOPPesc followed by four cy-

cles of BEACOPPbase were less toxic than eight cycles of BEACOPPesc, this trial gave a clear signal that additional radiotherapy might not be needed in the majority of patients.5 In the GHSG HD15 followup trial for this group of patients, the old standard of eight cycles of BEACOPPesc was thus compared with just six cycles of BEACOPPesc or eight cycles of BEACOPPbase (BEACOPP-14). Only responding patients with a persistent mass after chemotherapy measuring 2.5 cm or larger and positive on PET scan received additional radiotherapy. A total of 2,182 patients were enrolled between January 2003 and April 2008; 408 hospitals and practices in Germany, Czech Republic, Switzerland, The Netherlands, and Austria recruited and treated patients in the study. The 5-year freedom from treatment failure rates were 84% for eight cycles of BEACOPPesc, 89.3% for six cycles of BEACOPPesc, and 85.4% for B EACOPP-14. The difference between eight and six cycles of BEACOPPesc was significant (P = .009). In addition, overall survival was better with six cycles compared with eight cycles of BEACOPPesc (95.3% vs 91.9%, P = .02). Importantly, six cycles of BEACOPPesc were also less toxic compared with eight cycles: the treatment-related mortality was 0.8% vs 2.1%, and mortality related to secondary neoplasia was 0.7% vs 1.8%. Overall, 0.3% of patients treated with six cycles of BEACOPPesc experienced secondary AML/myelodysplastic syndrome, compared with 2.7% of patients treated with eight cycles of BEACOPPesc. Thus, six cycles of BEACOPPesc constitutes the new standard of care in most European countries, and this regimen has been incorporated in morerecently initiated studies by the European Organisation for Research and Treatment of Cancer (H11 trial) and the Groupe d’Etude des Lymphomes de l’Adulte (GELA)/Nordic group.

PET-driven Trials The metabolic activity of tissue affected with Hodgkin lymphoma can be measured by PET. Initial retrospective studies such as the one by Hutchings and coworkers6 suggest that the metabolic activity as measured by PET after two cycles of ABVD has prognostic impact for Hodgkin lymphoma patients. Thus, most current clinical trials

use PET in order to identify good- or poor-risk patients early in the course of treatment. It is not surprising that most of the ongoing randomized clinical trials in patients with advanced-stage Hodgkin lymphoma are risk-adapted—ie, PET-negative patients receive less treatment, and PET-positive patients are being escalated. Possible designs include one or two initial cycles of BEACOPPesc followed by ABVD (Kairos Principle) in PET-negative patients, with PET-positive patients continuing on BEACOPPesc. There are indications, however, that the capacity of PET to correctly predict outcome might have been overestimated in smaller retrospective studies. We still have to wait for the results of ongoing randomized trials in order to more precisely tailor treatment for advanced-stage Hodgkin lymphoma patients. In addition, a number of clinical risk factors and other biomarkers are being evaluated for their role in monitoring treatment outcome in this population.

Which Patients Are the Best Candidates for BEACOPP? In the pivotal GHSG HD9 study, patients with an International Prognostic Index score of 2 to 3, constituting the largest cohort of advanced-stage Hodgkin lymphoma patients, were those with significant advantages in both tumor control and overall survival.3 More-recent retrospective analyses of the treatment-related mortality associated with BEACOPPesc show an overall mortality of 1.8% (64 of 3,565), which compares favorably with treatment-related mortality reported from more-recent randomized trials of ABVD regimens.7 BEACOPPesc is more toxic in patients aged over 40 years, particularly if they have a poorer performance status (Eastern Cooperative Oncology Group score of 2 or Karnofsky score < 80%). Thus, these patients are not good candidates for treatment with six cycles of BEACOPPesc. In addition, there are clear guidelines as to BEACOPPesc dose reductions based on the toxicity observed in prior cycles. Groups having no experience with this treatment need to follow these predefined guidelines for dose reduction of BEACOPPesc in order to avoid unnecessary toxicity.8

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

At the Pan Pacific Lymphoma Conference, held this year in Maui, Hawaii, Andreas Engert, MD, Chairman of the German Hodgkin Study Group, University Hospital of Cologne, Germany, led off the Hodgkin lymphoma section of the conference with a presentation on optimizing the use of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], prednisone) in Hodgkin lymphoma patients. The ASCO Post invited Prof. Engert to elaborate on the selection of patients for first-line BEACOPP. References 1. Duggan DB, Petroni GR, Johnson JL, et al: Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: Report of an intergroup trial. J Clin Oncol 21:607-614, 2003. 2. Gordon LI, Hong F, Fisher RI, et al: A randomized phase III trial of ABVD vs Stanford V ± radiation therapy in locally extensive and advanced stage Hodgkin’s lymphoma: An intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). 52nd �� ASH Annual Meeting. Abstract 415. Presented December 6, 2010. 3. Diehl V, Franklin J, Pfreundschuh M, et al: Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 348:2386-2395, 2003. 4. Engert A, Diehl V, Franklin J, et al: Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of followup of the GHSG HD9 study. J Clin Oncol 27:4548-4554, 2009. 5. Borchmann P, Haverkamp H, Diehl V, et al: Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin’s lymphoma: Final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol 29:4234-4242, 2011. 6. Hutchings M, Loft A, Hansen M, et al: FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107:52-59, 2006. 7. Wongso D, et al: In preparation, 2012. 8. Engert A, Diehl V, Franklin J, et al: Escalated-dose BEACOPP in the treatment of patient with advanced-stage Hodgkin’s lymphoma: 10 years of followup of the GHSG HD9 Study. J Clin Oncol 27:4548-4544, 2009.

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News

Effects of LKB1 Mutation and mTOR Inhibition on IGFR1 Pathway in NSCLC By Matthew Stenger

KB1 is a serine/threonine kinase that has been found to be mutated in approximately 20% to 30% of patients with non–small cell lung cancer (NSCLC). LKB1 acts as a tumor suppressor by activating AMPK, and loss of LKB1 by point mutation or deletion suppresses AMPK, leading to increased mTOR signaling.

target in LKB1 mutant tumors. In addition, inhibition of the mTOR pathway upregulates the IGFR pathway, possibly as a feedback mechanism. These results support the investigation of IGFR in-

hibitors in combination with drugs targeting the mTOR pathway, particularly for tumors bearing LKB1 mutations.”

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Disclosure: The investigators reported no potential conflicts of interest.

Reference 1. Yilmaz E, Byers LA, Diao L, et al: 2012 ASCO Annual Meeting. Abstract 10612. Presented June 4, 2012.

Role of LKB1 Mutation Emrullah Yilmaz, MD, in collaboration with John V. Heymach, MD, PhD, at The University of Texas MD Anderson Cancer Center, investigated the effects of LKB1 mutation and mTOR inhibition on cell signaling pathways, measuring protein expression in NSCLC cell lines by reverse phase protein array.1 They found that LKB1 mutant cell lines had significantly lower expression of phosphorylated AMPK and tuberous sclerosis complex compared with LKB1 wild-type cell lines < .01), consistent with prior obser(P �� vations. In addition, mutant cell lines expressed higher levels of proteins in the insulin-like growth factor 1 receptor (IGFR1) pathway, including IGFR1b (P �� < .0001), amplified in breast cancer-1 (AIB1)—which is known to upregulate IGF1 (P < .0001), and IGF binding protein 2 (IGFBP2) (P = .016).

AMPK Activation LKB1 mutant cell lines were 1.5-fold more sensitive to the AMPK activator metformin than wild-type LKB1 cell lines, but the difference was not significant (P = .10). Expression levels of IGFR1 pathway proteins increased significantly after 48 hours of treatment with metformin, the mTOR inhibitor temsirolimus (Torisel), and the dual PI3K/mTOR inhibitor PI103, with the modulation of the IGFR1 pathway by these drugs being independent of LKB1 mutation status. IGFBP2 and AIB1 were elevated after metformin treatment (P = .02 and �� .005, respectively), and insulin recepP= tor substrate-1 and IGFR1 were elevated after temsirolimus or PI-103 treatment �� .05 for both). Treatment with met(P < formin and temsirolimus (P < .01 for both) also increased expression of phosphorylated Akt, which is a downstream target of IGFR1 and an mTOR activator. The investigators stated, “LKB1 mutant cell lines have increased IGFR activity with higher baseline IGFR1, IGFBP2, and AIB1, suggesting that IGFR may be a potential therapeutic

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

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Integrative Oncology Barrie R. Cassileth, MS, PhD, Guest Editor

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 alternative and complementary therapies commonly used by patients with cancer. For this installment, we chose dong quai, an herb widely used in traditional Chinese medicine, because of its increasing popularity among patients with breast cancer.

important remedy in traditional Chinese medicine for treating menstrual disorders and menopausal symptoms, for anemia, and to improve blood circulation. It is thought to “tonify” and “invigorate” the blood and is often used in formulations with other herbs. Dong quai is widely promoted as a “woman’s herb” and is sometimes referred to as “female ginseng” because Asian ginseng is used as a tonic for men. It is sought by many patients with breast cancer to relieve hot flashes and other adverse effects related to cancer treatments, despite the fact that current evidence of its efficacy is limited and inconclusive. The agent has estrogenic effects; patients with hormone-sensitive cancers should avoid its use. Other concerns include lack of standardization and

Dong Quai Scientific Name: Angelica sinensis Common Names: Chinese angelica, dang gui, tang kuei, tan kue

Overview

Dong quai is a perennial herb indigenous to China, Japan, and Korea. Its root has been used for centuries as a spice, tonic, and medicine. Dong quai is mentioned in Shen Nong Ben Cao Jing, the second-century Chinese herbal treatise, as a treatment for gynecologic disorders. Today, dong quai continues to be an

adulteration with plants that are morphologically similar. Dong quai is sold in Asian grocery markets, in health food stores, and on the Internet. The dried root is boiled or soaked in wine for consumption, whereas the powdered root is available in the form of tablets, capsules, and tinctures.

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 Sloan-Kettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective Barrie R. Cassileth, MS, PhD and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 260 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.

The Science

Dong quai has been studied in vitro and in animal models, but human data are limited. Z-ligustilide and ferulic acid, the main components, are the agent’s biologically active compounds. In vitro studies using dong quai extracts suggest antitumor,1 antituberculosis,2 neuroprotective,3 and hematopoietic4 properties. Polysaccharides isolated from dong quai root exhibited protective effects against cyclophosphamide-induced toxicity,5 doxorubicin-induced cardiotoxicity,6 and radiation-induced pneumonitis7 in animal models. Data from clinical trials of dong quai for menopausal symptoms are inconclusive.8 A small study failed to find efficacy of dong quai against hot flashes in men.9 Dong quai acts as a phytoestrogen in vitro,10 and stimulates proliferation of MCF-7 cells.11

Adverse Effects

Gynecomastia has been reported

with use of dong quai.12 Case report: A 53-year-old woman suffered subarachnoid hemorrhage following use of a supplement containing red clover, dong quai, and See Page 108 Siberian ginseng for perimenopausal hot flashes. Her symptoms resolved after discontinuing use of the supplement.13

Contraindications

Dong quai can potentiate the effects of anticoagulants.14 Patients with hormone-sensitive cancers should avoid dong quai because it has estrogenic effects.11

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Integrative Oncology is compiled by Barrie R. Cassileth, MS, PhD, and Jyothirmai Gubili, MS, Memorial Sloan-Kettering Cancer Center. The About Herbs website is managed by K. Simon Yeung, PharmD, Lac, Memorial Sloan-Kettering Cancer Center.

Learn More About

Herbs, Botanicals, & Other Products Visit the About Herbs website at

www.mskcc.org/aboutherbs

ASCOPost.com | NOVEMBER 15, 2012

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Integrative Oncology OF NOTE Dong quai is popular among patients with breast cancer. Oncologists should be aware of its estrogenic effects and its potential for interaction with anticoagulants. Disclosure: Drs. Cassileth and Yeung and Ms. Gubili reported no potential conflicts of interest.

rent alternative and complementary therapies used in menopause. Gynecol Endocrinol 25:166-174, 2009. 9. Al-Bareeq RJ, Ray AA, Nott L, et al: Dong Quai (angelica sinensis) in the treatment of hot flashes for men on androgen deprivation therapy: Results of a randomized double-blind placebo controlled trial. Can Urol Assoc J 4:49-53, 2010. 10. Liu J, Burdette JE, Xu H, et al: Evalu-

ation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 49:24722479, 2001. 11. Lau CB, Ho TC, Chan TW, et al: Use of dong quai (Angelica sinensis) to treat peri- or postmenopausal symptoms in women with breast cancer: Is it appropriate? Menopause 12:734-740, 2005. 12. Goh SY, Loh KC: Gynaecomastia

and the herbal tonic “Dong Quai.” Singapore Med J 42(3):115-116, 2001. 13. Friedman JA, Taylor SA, McDermott W, et al: Multifocal and recurrent subarachnoid hemorrhage due to an herbal supplement containing natural coumarins. Neurocrit Care 7:76-80, 2007. 14. Page RL 2nd, Lawrence JD: Potentiation of warfarin by dong quai. Pharmacotherapy 19:870-876, 1999.

References 1. Tsai NM, Lin SZ, Lee CC, et al: The antitumor effects of Angelica sinensis on malignant brain tumors in vitro and in vivo. Clin Cancer Res 11:3475-3484, 2005. 2. Deng S, Wang Y, Inui T, et al: AntiTB polyynes from the roots of Angelica sinensis. Phytother Res 22:878-882, 2008. 3. Bu Y, Kwon S, Kim YT, et al: Neuroprotective effect of HT008-1, a prescription of traditional Korean medicine, on transient focal cerebral ischemia model in rats. Phytother Res 24:1207-1212, 2010. 4. Liu PJ, Hsieh WT, Huang SH, et al: Hematopoietic effect of water-soluble polysaccharides from Angelica sinensis on mice with acute blood loss. Exp Hematol 38:437-445, 2010. 5. Hui MK, Wu WK, Shin VY, et al: Polysaccharides from the root of Angelica sinensis protect bone marrow and gastrointestinal tissues against the cytotoxicity of cyclophosphamide in mice. Int J Med Sci 3(1):1-6, 2006. 6. Xin YF, Zhou GL, Shen M, et al: Angelica sinensis: a novel adjunct to prevent doxorubicin-induced chronic cardiotoxicity. Basic Clin Pharmacol Toxicol Dec 101:421-426, 2007. 7. Xie CH, Zhang MS, Zhou YF, et al: Chinese medicine Angelica sinensis suppresses radiation-induced expression of TNF-alpha and TGF-beta1 in mice. Oncol Rep 15:1429-1436, 2006. 8. Wong VC, Lim CE, Luo X, et al: Cur-

The ASCO Post Wants to Hear from You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com. Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

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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Awards

Conquer Cancer Foundation of ASCO Honors Researchers for Work in Measuring and Improving Quality of Cancer Care

he Conquer Cancer Foundation of the American Society of Clinical Oncology (ASCO) recently announced the first-ever recipients of its Quality Care Symposium Merit Awards. This year’s recipients will be recognized at ASCO’s inaugural Quality Care Symposium, taking place November 30 and December 1 in San Diego. “The Conquer Cancer Foundation is thrilled to honor these researchers for their work in identifying solutions and strategies to improve the quality of cancer care,” said Martin J. Murphy, DMedSc, PhD, Chair of the Foundation Board of Directors. “The rapidly changing environment in oncology practice has created a unique opportunity for the Conquer Cancer Foundation to support research examining quality of care, which has a tremendous impact on improving outcomes and patient care.” The Conquer Cancer Foundation of ASCO Merit Awards are designed to promote clinical cancer research by young investigators and provide them with the opportunity to present their research at ASCO’s Quality Care Symposium. The Symposium brings together researchers, patient advocates, health system administrators, and practicing physicians to share results in measuring and improving the quality of cancer care. Merit Award recipients are selected based on the scientific merit of their abstracts and receive funding to help with travel expenses to attend the meeting. This year’s awardees include: ■■ Jeffrey Cao, MD, MBA, FRCPC, London Health Sciences Center: Categorization of measures of quality in radiation treatment ■■ Laura Chin-Lenn, MBBS, Uni-

versity of Calgary: Using quality indicators to monitor changes in adherence to clinical practice guidelines for treatment of ductal carcinoma in situ (DCIS) of the breast ■■ Nathan Connell, MD, Brown University Oncology Group: Assessment of the effectiveness of a pre-chemotherapy teaching session: A Brown University Oncology Group study ■■ Sinead Cuffe, MD, Princess Margaret Hospital, University

therapy for stage III colon cancer ■■ Maria Ho, MD, BC Cancer Agency – Vancouver Centre: Improving the quality of abstract reporting for economic analyses in oncology ■■ Joseph Klink, MD, Glickman Urological and Kidney Institute, Cleveland Clinic: Nomogram predicting treatment-related urinary incontinence for men with localized prostate cancer treated by radical prostatectomy (RP), external-beam

The Conquer Cancer Foundation is thrilled to honor these researchers for their work in identifying solutions and strategies to improve the quality of cancer care. — Martin J. Murphy, DMedSc, PhD

of Toronto: Cancer patients’ and physicians’ preferences for decision making regarding pharmacogenomic testing (PGT) ■■ Brendan Curley, DO, MPH, Mary Babb Randolph Cancer Center at West Virginia University: Patient understanding and impression of hematology/oncology fellows ■■ Isabella Glitza, MD, PhD, The University of Texas MD Anderson Cancer Center: Attrition rates, reasons and predictive factors in supportive/palliative oncology clinical trials at a comprehensive cancer center ■■ Alex Haynes, MD, MPH, The University of Texas MD Anderson Cancer Center: Socioeconomic and clinical factors associated with delayed initiation of adjuvant chemo-

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radiotherapy (EBRT), or brachytherapy (PI) Naomi Ko, MD, MPH, Boston University Medical Center: The impact of patient navigation on receipt of quality breast cancer treatment in the national patient navigation research program Aaron Mansfield, MD, Mayo Clinic: Skin cancer surveillance and malignancies in patients with chronic lymphocytic leukemia (CLL) Petra Martin, MD, St. Vincent’s University Hospital: Use of iPad technology to determine cancer patient- reported preferences for and understanding of pharmacogenetic testing (PGT) Mark Mishra, MD, Kimmel Cancer Center, Thomas Jefferson University: Natural language pro-

cessing (NLP) of Internet conversations to evaluate prostate cancer (PC) patients’ perceptions of active surveillance (AS) ■■ Andrew Moore, MD, Vanderbilt University Medical Center: Morbidity, mortality, and improvement (MM&I) conference leading to change ■■ Sarah Mougalian, MD, The University of Texas MD Anderson Cancer Center: Feasibility and savings of a suspicion of cancer clinic at a large county hospital ■■ Manali Patel, MD, Stanford University Medical Center: Can equitable care eliminate colon cancer disparities? ■■ Anjana Ranganathan, MD, University of Pennsylvania: Documentation of code status at an outpatient academic cancer center: A marker of discussing end-of-life preferences ■■ Sonia Reichert, MD, Mount Sinai School of Medicine: Compliance to select quality measures in a non-QOPI subspecialty academic practice: A pilot quality improvement initiative ■■ Rakesh Roy, MD, ECMO, Dip Pall Med (UK): Information technology transforming quality of cancer care in developing nation ■■ Yvonne Sada, MD, Michael E. DeBakey Veterans Affairs Medical Center: The effect of gaps in chemotherapy on survival in patients with high-risk stage II and stage III colon cancer The Quality of Care Symposium Merit Awards are supported by Amgen, Astellas, AVEO Pharmaceuticals, Inc, Bristol-Myers Squibb, Celgene Corporation, Lilly USA, LLC, Millennium: The Takeda Oncology Company, Novartis Oncology, Onyx Pharmaceuticals, and Susan G. Komen for the Cure.

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NOW

APPRO ED For Patients With Advanced HR+ BC 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

There have been reports of non-infectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR® (everolimus), 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 to patients <65 years of age. Oral ulceration is the most frequently occurring adverse event and occurred at an incidence ranging from 44% to 86% of AFINITOR-treated patients across the clinical trials experience. Most of these events were Grade 1 or 2. Grade 3 or 4 stomatitis was reported in 4%-8% 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. 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. Please see Brief Summary of Prescribing Information on adjacent pages. For more information, please visit www.AFINITOR.com.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

7/12

AFB-1039129

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 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 receptorpositive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS 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 4-8% 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- or peroxide-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, 2.4) 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, 2.4) 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, 2.4) 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 SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy. 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 an 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 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 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 Median Duration of Treatmente 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 c 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

Key observed laboratory abnormalities are presented in Table 4. Table 4: 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 grades Grade 3 Grade 4 All grades Grade 3 Grade 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.

T:14”

B:14.25”

S:13”

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, 2.4) 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, 2.4) 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, 2.4) in the full prescribing information]. Agents whose Plasma Concentrations may be 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. 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 a fetus. Women of childbearing potential should be advised to use an 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 AFINITOR is recommended for use only in patients with SEGA who are aged ≥ 3 years. A prospective, open-label, single-arm trial was conducted to evaluate the safety and efficacy of AFINITOR in patients with SEGA associated with TSC. In total, 28 patients received treatment with AFINITOR; median age was 11 years (range 3-34). AFINITOR has not been studied in patients with SEGA < 3 years of age. 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 AFINITORtreated 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 SEGA patients with severe hepatic impairment (Child-Pugh class C), AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however, subsequent dosing should be individualized 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 were 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: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2012-132 July 2012

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Fellow’s Corner

The Nuts and Bolts of Getting into an Oncology Fellowship By Bishoy Faltas, MD

Bishoy Faltas, MD

ncology continues to be one of the most sought-after specialties. Because of a shortage of oncologists and the accelerating pace of developments in the diagnosis and treatment of cancer, oncology has become an increasingly competitive field. Accreditation Council for Graduate Medical Education (ACGME)-accredited training in oncology can be pursued in 2-year oncology-only programs or, more commonly, in 3-year combined hematology-oncology programs. Starting this year, the application cycle for oncology fellowships began in July, when the post office of the electronic residency application service (ERAS) opened. Over subsequent months, programs review applications and invite selected applicants for interviews. Both interviewees and programs then rank each other in certified lists submitted to the National Residency Match Program. The match occurs in mid-December, and fellowships begin on the first of July. The competitive nature of the match process makes it crucial for applicants to identify factors that would make them stand out. The main elements of fellowship application include a curriculum vitae, letters of recommendation, and a personal statement. The CV should be inclusive within reasonable limits. It is important not to neglect hobbies or areas of interest, especially those that help the applicant show consistent dedication, perseverance, and discipline. A demonstrated interest in research naturally strengthens an application but is not the most important selection factor. Publications, research projects, national presentations, and advanced degrees in research could all serve as evidence of such interest and are likely to be viewed favorably.

Letters of Recommendation The importance of letters of recom-

mendation from oncologists cannot be overstated. In a study examining selection factors for subspecialty training, the importance of recommendation letters was ranked by fellowship program directors only second to the importance of the fellowship interview.1 Oncologists naturally trust other oncologists because they share a unique perspective. In general, letters of recommendation should reflect personal knowledge of the applicant and an honest evaluation of the applicant’s residency performance and suitability for fellowship training. A letter from a nationally known oncologist who marginally knows the applicant will be almost uniformly weaker than a letter from a lesser-known oncologist with intimate knowledge of the applicant’s qualifications. Applicants should always waive rights to view the letter; anything else makes applicants appear untrusting. “Be certain that your program director has your back by reviewing the letters of recommendation before they are uploaded. I routinely reject faculty letters that are poorly composed or show no commitment to the applicant. This is part of the job description of your program director, even if you have graduated, so do not hesitate to ask” said Paul L. Bernstein, MD, former internal medicine residency Program Director at Rochester General Hospital, Rochester, New York and coauthor of a study on selection criteria for fellowships.1 According to the study, the third most important factor is the letter of recommendation from the internal medicine program director. The program director’s letter should reflect personal knowledge of the applicant as well as specific examples of his or her performance. “When writing a letter of recommendation, I usually review all of the applicant’s evaluations and include quotes about his most impressive qualities. I conclude with a detailed summative evaluation with my own assessment of the applicant’s personality, performance, and academic potential,” said Dr. Bernstein. A well-written personal statement is an integral part of the fellowship application despite its relative unimportance compared to the CV or letters of

Interview Tips for Fellowship Applicants 1. Do your homework. Know the program, the faculty, and their mission. There is no substitute for this step.

2. The key is to stick out, not blend in. Consider not wearing charcoal grey or black outfits.

3. Do not focus inward. Talk with everybody in the office, including the secretary, the coordinator, and the section manager.

4. Let the interviewer come to you. Sit back, be confident, and remain

interactive but not overzealous. If you are lucky enough to be kept waiting, look around and garner hints about the interviewer. Is there a topic you can share?

5. Follow up with at least an e-mail. Strive to find topics during the

interview that can help to maintain a thread of conversation afterward, such as updates on posters or projects.

recommendation. The key to a strong personal statement is to have a theme, a common thread that ties together the applicant’s background and formative experiences to show that she would be a “good fit” for oncology training. Applicants should be careful not to be overly influenced by personal statements of colleagues. Program directors do Google lines of text from personal statements; any plagiarism is grounds for immediate rejection and worse.

Program Goals Applicants are advised to do some soul-searching before applying for a fellowship and to review aspirations and expectations with the residency program director and other mentors. Applicants should also be mindful of the different goals of different programs to which they apply. Programs typically come in three different flavors: community-based, universitybased, or university-affiliated. University programs typically aspire to train academic oncologists who will become leaders in the field. Programs that aim to train physician-scientists offer both clinical and basic science research training. “In our program, the second year of training is typically dedicated to a translational research project of the fellow’s choosing, with intensive faculty mentorship and support. Up to 18 months of training may be devoted to this project, while the fellow also continues seeing patients in a weekly continuity clinic. The fellowship applicants we favor are the ones most likely

to thrive in this type of research environment ” said Ronald Scheff, MD, fellowship Program Director at the Weill Cornell Medical College hematology-oncology program.

First-hand Knowledge An “away” elective at the fellowship site can offer the applicant and the program a valuable opportunity to gain first-hand knowledge of one another. It can also help the applicant obtain letters of recommendation from faculty at the program. However, an away elective can also be a double-edged sword if the applicant underperforms, so the risks and benefits of such an undertaking should be weighed carefully beforehand. The interview is consistently ranked as the most important fellowship selection factor.1 Program directors trust their instincts and reach conclusions rapidly. The interview is also an opportunity for applicants to learn about the relative strengths and weaknesses of each program and its educational philosophy. At the end of the day, the best possible outcome of the match is producing a good fit that achieves both the applicant’s and the program’s goals.

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

Reference 1. Mikhail S, Bernstein P: Selection criteria for fellowships: Are we all on the same page? Academic Internal Medicine Insight. 5(1), 2007. Dr. Faltas is a hematology-oncology fellow at Weill Cornell Medical College, New York.

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News

American Society of Hematology Elects New Leadership

he American Society of Hematology (ASH) recently announced the election of four new members to its Executive Committee, the governing body of the organization, for terms to begin in January 2013. At the same time, ASH President-elect and Vice President will begin their tenures as ASH President and ASH Vice President, respectively.

David A. Williams, MD

Margaret A. Shipp, MD

Margaret Hospital in Toronto. “I have every confidence in these newly elected Society leaders to further ASH’s commitment to move hematology forward during this very exciting time.”

Wide-ranging Credentials Dr. Williams is Chief of Hematology/Oncology and Director of Translational Research at Boston Children’s

Stephanie J. Lee, MD, MPH

Armand Keating, MD

David A. Williams, MD, will serve a 1-year term as Vice President, followed by successive terms as Presidentelect and President. Stephanie J. Lee, MD, MPH, will serve a 4-year term as Secretary. Jonathan D. Licht, MD, and Margaret A. Shipp, MD, will both serve 4-year terms as Councillors. “Each of these individuals is extremely well-respected in our field and has already contributed a great deal to the Society,” said 2012 ASH President Armand Keating, MD, of Princess

Jonathan D. Licht, MD

Hospital, Associate Chairman of the Department of Pediatric Oncology at Dana-Farber Cancer Institute, Leland Fikes Professor of Pediatrics at Harvard Medical School, and Director of the Pediatric Hematology/Oncology Fellowship Program at Dana-Farber/ Children’s Hospital Cancer

Center. Dr. Lee is a member of the Fred Hutchinson Cancer Research Center and Professor of Medical Oncology at the University of Washington School of Medicine in Seattle. She is an Attending Physician in the Hematopoietic Cell Transplantation Program at Fred Hutchinson and the Seattle Cancer Care Alliance. Dr. Licht is the Johanna Dobe Professor of Medicine and Chief of the Division of Hematology/Oncology

at Northwestern University Feinberg School of Medicine in Chicago. He also serves as the Associate Director of Clinical Sciences at Northwestern’s Robert H. Lurie Comprehensive Cancer Center, where he is also an Attending Physician in the cancer center’s Leukemia Program. Dr. Shipp is Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School, Chief of the Division of Hematologic Neoplasia in the Department of Medical Oncology at Dana-Farber Cancer Institute, Director of the Lymphoma Program at Dana-Farber/Harvard Comprehensive Cancer Center, and Attending Physician in the Stem Cell Transplantation Program at Dana-Farber/ Brigham and Women’s Cancer Center in Boston.

2013 ASH President and President-elect In addition to the newly elected leaders, current ASH President-elect Janis L. Abkowitz, MD, will become ASH President in 2013, succeeding Dr. Keating. Linda J. Burns, MD, currently ASH Vice President, will become 2013 President-elect. Dr. Abkowitz is the Hematology Division Head, Clement A. Finch Professor of Medicine, and Adjunct Professor of Genome Sciences at the University of Washington. She is also Director of the Hematology Clinic at Seattle Cancer Care Alliance and an attending physician at the University of Washington Medical Center. She earned her medical degree at Harvard University before completing her Internal Medicine residency at Beth Israel Hospital in Boston and Hematology/Oncology Fellowship at the University of Washington. Dr. Burns is Professor of Medicine,

Janis L. Abkowitz, MD

Linda J. Burns, MD

Division of Hematology, Oncology, and Transplantation at the University of Minnesota, Minneapolis. She earned her medical degree at the University of Missouri, Columbia, where she was elected to Alpha Omega Alpha, and completed an internal medicine residency, chief residency, and hematology/oncology fellowship at the University of Iowa.

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2013 ASH

Executive Committee PRESIDENT Janis L. Abkowitz, MD PRESIDENT-ELECT Linda Burns, MD VICE PRESIDENT David A. Williams, MD SECRETARY Stephanie J. Lee, MD, MPH

Coming in Future Issues of The ASCO Post Watch future issues for comprehensive coverage of the 2012 ASH Annual Meeting and Exposition

Visit The ASCO Post online at ASCOPost.com

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

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) 1,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 1,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 1,3

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: Adverse events profile included1:

• The recommended starting dose of VOTRIENT is 800 mg once daily without food (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 • Dose modifications, interruptions, and discontinuations may be required in patients with 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

randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions.

• 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, hypertension, wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, 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

• 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.

• 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.

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.

• 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.

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.

• Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients.

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

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Announcements

ASTRO Elects New Officers

he American Society for Radiation Oncology (ASTRO) recently announced the election of new leaders of its Board of Directors. These five new officers started their terms at the Annual Business Meeting at ASTRO’s

54th Annual Meeting in Boston, which was held October 28-31, 2012. “Exceptional leadership is one of the key components of a successful organization,” said Leonard L. Gunderson, MD, MS, FASTRO, of the Mayo

Clinic in Scottsdale, Arizona, and Chairman of the ASTRO Board. “I am certain that these newly elected officers will continue to uphold the Society’s integrity and dedicated service to our members and our profession.

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

Congratulations to my esteemed colleagues.” The new Board of Directors members are: President-elect: Bruce G. Haffty, MD, FASTRO, The Cancer Institute of

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 studies. 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 antihypertensive 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

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Leonard L. Gunderson, MD, MS, FASTRO

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New Jersey at Robert Wood Johnson Medical School Clinical Affairs and Quality Council Chairman: Carol A. Hahn, MD, Duke University Medical Center Clinical Affairs and Quality Council Vice-chairman: Lawrence B. Marks, MD, FASTRO, University of

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 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 wellcontrolled 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)].

Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290)

(N=145)

All All Gradesa Grade 3 Grade 4 Gradesa 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.

Also at the ASTRO Annual Meeting, Colleen A. Lawton, MD, of the Medical College of Wisconsin in Milwaukee, Wisconsin, assumed the role of ASTRO President, following the term of Michael L. Steinberg, MD, of the David Geffen School of Medicine at UCLA, Los Angeles.

■

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)

Parameters

Placebo (N=145)

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

Hematologic Leukopenia 37 0 0 6 0 0 Neutropenia 34 1 <1 6 0 0 Thrombocytopenia 32 <1 <1 5 0 <1 Lymphocytopenia 31 4 <1 24 1 0 Chemistry ALT increased 53 10 2 22 1 0 AST increased 53 7 <1 19 <1 0 Glucose 41 <1 0 33 1 0 increased Total bilirubin 36 3 <1 10 1 <1 increased Phosphorus 34 4 0 11 0 0 decreased Sodium 31 4 1 24 4 0 decreased Magnesium 26 <1 1 14 0 0 decreased Glucose 17 0 <1 3 0 0 decreased a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a 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.

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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 (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT.

North Carolina School of Medicine Education Vice-chairman: Paul M. Harari, MD, FASTRO, University of Wisconsin School of Medicine and Public Health Government Relations Vicechairman: Geraldine M. Jacobson, MD, MBA, MPH, West Virginia University School of Medicine.

PAGE 100

Awards

The ASCO Post | NOVEMBER 15, 2012

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Researchers Honored at 2012 San Antonio Breast Cancer Symposium

he Susan G. Komen for the Cure® Brinker Awards for Scientific Distinction in Basic Science and Clinical Research will be presented to Hyman B. Muss, MD, Professor of Medicine and the Director of the

Geriatric Oncology Program at University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, and Yosef Yarden, PhD, of the Harold and Zelda Goldenberg Professor of Molecular Cell Biology

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.

Hyman B. Muss, MD

Yosef Yarden, PhD

cancer, in particular the treatment of breast cancer in older women. His work on clinical trials specifically targeted to older women has provided the foundation for offering geriatric patients state-of-the art treatments and has had a significant impact on the standard of care and quality of life for elderly women with breast cancer. Professor Yarden is receiving the Brinker Award for Scientific Distinction in Basic Science for his extensive contributions to breast cancer research, which have been instrumental in advancing our understanding of the biology of growth factors and their receptors, and their role in human cancers. His research has been crucial to establishing growth factor receptors— particularly the HER2 receptor—as prime targets for cancer drugs. Dr. Muss and Dr. Yarden will deliver keynote lectures on December 5 at the 35th annual San Antonio Breast Cancer Symposium. Watch for coverage of this important symposium in the next issue of The ASCO Post.

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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 preand 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 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 with rats. Body weight loss and morbidity were observed at these doses. 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 ≥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. 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 studies 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.

at the Weizmann Institute of Science in Rehovot, Israel. Dr. Muss is receiving the Brinker Award for Scientific Distinction in Clinical Research for his critical contributions to the treatment of breast

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Write to editor@ASCOPost.com. ©2012, GlaxoSmithKline. All rights reserved. Revised 04/2012 VTR:7BRS ©2012 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. VOT319R0 August 2012

All submissions will be considered for publication.

ASCOPost.com | NOVEMBER 15, 2012

PAGE 101

Appointments

Richard L. Schilsky, MD, Chosen to Serve in New ASCO Leadership Position, Chief Medical Officer

ichard L. Schilsky, MD, Chief of Hematology/Oncology in the Department of Medicine and Deputy Director of the University of Chicago Comprehensive Cancer Center, has been named to the newly created position of Chief Medical Officer (CMO) of ASCO. A former ASCO President and Fellow of the American Society of Clinical Oncology (FASCO), Dr. Schilsky is a highly respected leader in the field of clinical oncology, specializing in new drug development and treatment of gastrointestinal cancers. He will begin his new position on February 28, 2013.

Cancer Foundation Board, Dr. Schilsky brings with him a firm grasp of the organization including its history, mission, structure and operations. “Throughout my career I have tried

to remain focused on improving the treatment and outcomes of people with cancer,” said Dr. Schilsky. “I’ve been an ASCO member for 32 years and I admire the organization tremen-

dously. It’s made an enormous difference in my work and in the care of my patients and it has provided countless opportunities for my younger colleagues and trainees.”

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ASCO in

Acti o n

Richard L. Schilsky, MD

“Rich has that rare combination of clinical expertise, a formidable research track record, and a warmth and humanity that make him perfect for this role,” said Sandra M. Swain, MD, President of ASCO and Chair of the CMO Search Committee. “Having led many of ASCO’s most important efforts and committees over the years, he is also intimately familiar with ASCO’s programs, staff, and member needs. As President, I look forward to working with him. I am sure he will provide wise counsel as we advance ASCO’s mission.”

Senior Leadership and Support The Chief Medical Officer position was created by the Board of Directors to provide additional senior leadership and support to ASCO’s fast-growing quality programs, public policy and communications efforts, as well as fundraising for ASCO’s affiliated Conquer Cancer Foundation. The position will report to the Chief Executive Officer (CEO), Allen S. Lichter, MD. As a past president of ASCO (20082009), former Chair of ASCO’s Cancer Research, Communications, and Government Relations Committees, and a current member of ASCO’s Conquer

Stay informed by visiting http://ascoaction.asco.org Follow @ascoaction on Twitter

The ASCO Post | NOVEMBER 15, 2012

PAGE 102

In the News Risk Factors

Strong Association Increasingly Recognized Between Obesity and Cancer Incidence/Poor Prognosis By Charlotte Bath

Rachel Ballard-Barbash MD, MPH

he rise in obesity in the United States coincides with greater recognition of the role of obesity in cancer and other diseases.1 While decades of research have indicated a strong association between obesity and cancer, “several forces have made that association increasingly recognized,” according to Rachel Ballard-Barbash, MD, MPH, Associate Director of the Applied Research Program, Division of Cancer Control and Population Science, at the National Cancer Institute.

Convincing Evidence Contributors to this greater recognition include “larger, better designed studies that have shown the association of obesity not just with the development of cancer, but also with adverse prognosis and shorter survival in people who have some types of cancer,” Dr. Ballard-Barbash told The ASCO Post. Other studies have resulted in greater understanding of the “underlying

metabolic and physiologic characteristics that we think might contribute to cancer,” Dr. Ballard-Barbash said, and some intervention studies related to weight loss are showing positive results. “The consistency of all of those factors combined have made people both more aware of the association between obesity and cancer and more confident that the association is real and not something that is confounded by another characteristic of people who are overweight or obese,” she said. While the association between obesity and cancer is considered strong, it is not at the intensity level of smoking and lung cancer. “The relative risk for tobacoo use and lung cancer is maybe 14fold or more. That was very strong association,” Dr. Ballard-Barbash explained. “The relative risk or odds ratio that we see for many of the obesity and cancerrelated associations are more comparable to hypertension, heart disease, osteoporosis, and osteoarthritis, and physicians are very sure that those disorders are related to obesity,” she added.

Associated Cancers According to the 2012 update of the American Cancer Society’s Cancer Facts & Figures,2 “overweight and obesity are clearly associated with increased risk for developing many cancers, including cancers of the breast in postmenopausal women, colon and rectum, endometrium, adenocarci-

Randomized Trial of Weight Loss and Cancer Risk Not Feasible

“W

e have not had a randomized controlled trial of weight loss among people at risk for cancer who don’t yet have the disease, where we can show that weight loss reduces the risk for cancer. And we never will,” Rachel Ballard-Barbash, MD, MPH, told The ASCO Post. “We know from a number of very large trials, such as the Women’s Health Initiative, that we need a very large sample of people to test that association, because cancer is still a rare condition compared to heart disease, high blood pressure, or diabetes,” she said. “If we put people just at risk for cancer on a weight loss intervention, they would first show improvements in conditions like diabetes, heart disease, and hypertension, and the trial would have to be stopped before we would actually get the answer for cancer. Once you demonstrate a significant benefit for the overall population in some other disease endpoint, it is no longer ethical to continue such a trial.” Dr. Ballard-Barbash is Associate Director of the Applied Research Program, Division of Cancer Control and Population Science, at the National Cancer Institute.

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Expect Questions from Patients about Impact of Weight on Prognosis

ncreased awareness of the strong association between obesity and higher rates of cancer recurrence and mortality needs to be transmitted from oncologists to patients, but the message needs to concern more than just weight, according to Rachel Ballard-Barbash, MD, MPH, Associate Director of the Applied Research Program, Division of Cancer Control and Population Science, at the National Cancer Institute. Issues of weight, physical activity, and other health lifestyle habits are all interrelated, and should be considered along with improvements in cancer screening and treatment that have resulted in “cancer shifting for many people to a chronic condition,” she said in an interview with The ASCO Post. “We have very good evidence that the health behaviors related to reducing risk for many chronic diseases—like not smoking, having a healthy weight, being active on a daily basis, and eating properly—are all things that actually lead to much better overall health as we get older. This is a very important message for people with cancer as well. Twenty years ago, people didn’t think it was so relevant because patients with cancer tended to die much more quickly; that is just not the case anymore.”

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noma of the esophagus, kidney, and pancreas. Overweight and obesity may also be associated with increased risk of cancers of the liver, non-Hodgkin lymphoma, multiple myeloma, cervix, ovary, and aggressive prostate cancer, and obesity also likely increases the risk of cancer of the gallbladder. In addition, abdominal fatness is convincingly associated with colorectal cancer, and probably related to higher risk of pancreatic, endometrial, and postmenopausal breast cancers.” Cancer Facts & Figures also notes that in the United States, “it has been estimated that overweight and obesity contribute to 14% to 20% of all cancerrelated mortality.” That is the same estimate given in an article about obesity and cancer published in The New England Journal of Medicine in 2003.3 Based on a prospective study, the authors of that report noted that excess weight was implicated in deaths from endometrial cancer, adenocarcinoma of the esophagus, renal cancer, colon cancer, and postmenopausal breast cancer. Background material in the U.S. Preventive Services Task Force Recommendation Statement, Screening for and Management of Obesity in Adults,4 added that cancers of the liver and prostate are among the leading causes of death in obese adults. “We are seeing a shift in the United States,” said Dr. Ballard-Barbash. “Early on, one of the more common causes for

cirrhosis of the liver was due to alcohol or viral infections, like hepatitis. Today, we are seeing that obesity is becoming a more common cause of cirrhotic liver disease and that it is a major risk factor for liver cancer,” she explained. “Most of the studies don’t find a very strong association between obesity and prostate cancer incidence, but there is some suggestion with more recent studies that obesity may be associated with more aggressive prostate cancer,” she continued. “And some studies among prostate cancer patients and survivors suggest that obesity may be associated with a greater risk of recurrence and poorer prognosis.” More data now link obesity and pancreatic cancer, and “a number of studies have suggested that—particularly among women—being overweight or obese may increase the risk for some types of thyroid cancers,” Dr. BallardBarbash added. Possible associations between weight and some of the hematopoietic cancers are also being explored.

Screening for Obese Patients? A study in Archives of Surgery5 found that obese patients present with more aggressive and advanced forms of papillary thyroid cancer and suggested that obese patients should be screened for thyroid cancer. Although obesity may increase the risk of thyroid cancer, “I do not believe that would be a continued on page 106

FOR PATIENTS WITH ADVANCED BCC

IS IT TIME FOR A CHANGE? The first and only FDA-approved Hedgehog pathway inhibitor

Turn the page to see more...

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. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS See full prescribing information for complete boxed warning. Erivedge can result in embryo-fetal death or severe birth defects. Verify pregnancy status prior to initiation of Erivedge. Advise male and female patients of these risks. Advise females of the need for contraception and advise males of the potential risk of Erivedge exposure through semen. Please see additional Important Safety Information, including BOXED WARNING, on following page and Brief Summary of Prescribing Information on back.

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 Embryo-Fetal Death and Severe Birth Defects • 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

Adverse Reactions • The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea,

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)

mBCC (n=33)

43% (n=27) (30.5-56.0)

30% (n=10) (15.6-48.2)

Complete response

21% (n=13)

Partial response

22% (n=14)

30% (n=10)

7.6 months (5.7-9.7)

7.6 months (5.6-NE)

ORR (95% CI)

Median response duration (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.

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. 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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The ASCO Post | NOVEMBER 15, 2012

PAGE 106

In the News

Obesity and Cancer Risk

such as breast and colon cancers,” she said. “But we have evidence that obese patients tend to be less likely to undergo screening according to guidelines.” In addition, some forms of screening may not be as effective for obese patients. For example, breast cancer screening can be problematic in women with very large breasts associated with obesity.

continued from page 102

rationale for initiating screening,” Dr. Ballard-Barbash said, noting that no groups currently recommend screening for thyroid cancer. “It is particularly important that obese patients be screened for types of cancer we already routinely screen for,

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)

MedDRA Preferred Term2 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)]. 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 All aBCC1 Patients (N = 138) MedDRA Preferred Term2 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%)

All aBCC1 Patients (N = 138) All Grades 3 Grade 3 Grade 4 (%) (%) (%)

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. 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 2

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

‘Murky’ Recurrence Data Obese women treated for breast cancer were more likely to have recurrences and inferior outcomes for overall survival, according to a study in the journal Cancer.6 The study evaluated the relationship between body mass index in three adjuvant breast cancer trials coordinated by the Eastern Co-

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). • Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. • Instruct female patients of reproductive potential to use a highly 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. • Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. • Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. • Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. • 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. • Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Advise patients to swallow ERIVEDGE capsules whole and not to 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 HED0000832300

operative Oncology Group (ECOG). The investigators reported, “obesity was associated with inferior outcomes specifically in patients with hormone receptor–positive operable breast cancer treated with standard chemohormonal therapy.” In general, however, “we don’t currently have very good data on recurrence at the national level,” Dr. Ballard-Barbash said. “Outside of randomized controlled trials, where they are actively ascertaining whether people have recurrence on an ongoing basis, our cancer registry data is very murky in terms of capturing recurrence. It captures new breast primaries and deaths very well, but it doesn’t capture recurrence.”

Benefits of Physical Activity Several published studies have suggested that patients with cancer who regularly engage in physical activity “may experience better survival,” Dr. Ballard-Barbash said. “I just published a review in the Journal of the National Cancer Institute7 this year, summarizing the data from a number of observational studies on how physical activity is associated with cancer survival,” she said. That review about physical activity and breast cancer, described in a previous article in The ASCO Post,8 found “consistent evidence” that physical activity is associated with reduced mortality from breast cancer. Although there have been randomized controlled trials demonstrating that physical activity can improve quality of life for patients with cancer, there have not yet been randomized controlled trials demonstrating improved survival, Dr. Barbash-Ballard noted. So physicians may be hesitant to tell patients, “you definitely will do better in terms of survival if you control your weight or are physically active.” Several randomized controlled trials have been designed to understand how physical activity can impact cancer recurrence and survival, Dr. Ballard-Barbash said, but these trials are still enrolling patients and have not yet reported results. Patients undergoing cancer treatment may find it challenging to stay physically active, Dr. Ballard-Barbash acknowledged, “but a number of studies have shown that it is possible to help people initiate a physical activity program even during active treatment” and that as a result, quality of life is improved, she said. “In fact, there is some evidence that they are better able to tolerate a full

ASCOPost.com | NOVEMBER 15, 2012

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In the News

Role of High Birth Weight “A limited number of studies indicate that birth weight may be associated with cancer risk,” Dr. BallardBarbash said. “For many years, studies have suggested that babies with a very low birth weight are at increased risk for heart disease and diabetes.” For some cancers, however, studies have found an increased risk for babies with high birth weights. “That has been shown, for example, in breast cancer,” Dr. Ballard-Barbash said. Studies have also shown associations between high birth weight and testicular, brain, and some hematologic cancers.

cer.org. Accessed October 17, 2012. 3. Calle EE, Rodriguez C, Walker-Thurmond K, et al: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625-1638, 2003. 4. Moyer VA, on behalf of the U.S. Preventive Services Task Force: Screening for and management of obesity in adults: U.S. Preventive Services Task Force recom-

August 27, 2012 (early release online). 7. Ballard-Barbash R, Friedenreich CM, Courneya KS, et al: Physical activity, biomarkers, and disease outcomes in cancer survivors: A systematic review. J Natl Cancer Inst 104:815-840, 2012. 8. Bath C: Physical activity benefits breast cancer survivors, but role in reducing breast cancer risk is less clear. The ASCO Post, September 15, 2012.

INSIGHT

JNCCN

NEW

Read the November Issue of JNCCN: • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Prevention and Treatment of Cancer-Related Infections NCCN Guidelines® Insights: Ovarian Cancer In this new section, Panel members shed light on the process behind the creation of the NCCN Guidelines, clarifying why and how these important decisions are made.

• Update on Emerging Technologies in Breast Imaging • A Randomized Phase II Study of Cetuximab Every 2 Weeks at Either 500 or 750 mg/m2 for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Cancer • Current Issues in Vaccines for Adult Patients With Hematologic Malignancies

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Disclosure: Dr. Ballard-Barbash reported no potential conflicts of interest.

References 1. Trust for America’s Health/Robert Wood Johnson Foundation: F as in fat: How obesity threatens America’s future. September 2012. Available at www. healthyamericans.org/report/100. Accessed October 17, 2012. 2. American Cancer Society: Cancer facts & figures 2012. Available at www.can-

mendation statement. Ann Intern Med 157:373-378, 2012. 5. Harari A, Endo B, Nishimoto S, et al: Risk of advanced papillary thyroid cancer in obese patients. Arch Surg 147:805-811, 2012. 6. Sparano JA, Wang M, Zhao F, et al: Obesity at diagnosis is associated with inferior outcomes in hormone receptorpositive operable breast cancer. Cancer.

NEW IN EVERY ISSUE OF

NEW

dose of chemotherapy,” she added. The benefits of physical activity can come from the activity itself and its effect on weight reduction. “I don’t think we know for sure,” Dr. Ballard-Barbash said. “The studies have been a little bit inconsistent. A few studies have demonstrated that the reduced risk for women who are physically active is found predominantly in those of normal weight, suggesting that a major mechanism in breast cancer may be related to reduction in fat mass. Other studies have found the benefit even among women See Page 108 who are overweight. And some studies in colorectal cancer have shown a benefit of physical activity across all body mass index categories. So it varies somewhat by cancer site,” she added. “There is no question that reduction of fat mass is one mechanism by which physical activity may be beneficial, but there are many other mechanisms being examined, including improvements in insulin, glucose metabolism, and reductions in inflammation,” she continued. “Inflammation may increase risk for cancer as well as be associated with worse prognoses. So there are multiple mechanisms by which physical activity may be operating.”

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The ASCO Post | NOVEMBER 15, 2012

PAGE 108

Lab Notes

Ongoing Molecular Research in the Science of Oncology NOVEL MECHANISMS HIV Protease Inhibitor Nelfinavir Selectively Inhibits HER2-positive Breast Cancer Cells Shim and colleagues from Johns Hopkins School of Medicine in Baltimore, the National Cancer Institute in Bethesda, and Emory University School of Medicine in Atlanta have recently shown that the HIV protease inhibitor nelfinavir (Viracept) is a selective inhibitor of HER2-positive breast cancer cells. After nelfinavir was identified as a selective inhibitor of HER2-positive cells in pharmacologic profiling of seven genotypically distinct breast cancer cell lines from a screen of the Johns Hopkins Drug Library, a genome-wide screen of a haploinsufficiency yeast mutant collection was performed to identify the molecular targets of nelfinavir. It was found that nelfinavir inhibited heat shock protein (HSP)90 function in breast cancer cells through a novSee Page 108 el mechanism. Evaluation of the antitumor activity of nelfinavir in xenografts in athymic nude mouse models of breast cancer showed significant inhibitory effects: The mean tumor volume index of HCC1954 cells on day 29 was 14.42 for vehicle and 5.16 for nelfinavir (P < .001), and the mean tumor volume index of BT474 cells on day 26 was 2.21 vs 0.90 (P < .001). In addition, nelfinavir inhibited the growth of

trastuzumab (Herceptin)- and/or lapatinib (Tykerb)-resistant HER2positive breast cancer cells in vitro at clinically achievable concentrations. As concluded by the investigators, “Nelfinavir was found to be a new class of HSP90 inhibitor and can be brought to HER2-breast cancer treatment trials with the same dosage regimen as that used among HIV patients.” Shim JS, et al: J Natl Cancer Inst 104:1576-1590, 2012.

TREATMENT RESISTANCE Mutational Activation of PI3K-AKT Pathway and Change in HER2 Expression in Trastuzumabresistant Breast Cancer Insensitivity of HER2-amplified breast cancer to trastuzumab (Herceptin) has been associated with both changes in HER2 expression and activation of the PI3KAKT pathway in laboratory studies. Chandarlapaty and colleagues from Memorial- Sloan Kettering Cancer Center in New York and Fox Chase Cancer Center in Philadelphia recently reported that the predominant alterations found in prospectively collected trastuzumab-refractory breast tumors were loss of PTEN or PIK3CA mutation. In 60 tumor samples from patients with recurrence after adjuvant trastuzumab or progression of metastatic disease during trastuzumab, HER2 expression persisted in 53 (88%) after trastuzumab exposure; in the 7 cases without HER2 over-

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.

expression, repeat analysis of pretreatment samples showed no HER2 overexpression in 5. Absent or significantly diminished PTEN expression was found in 33 (59%) of 56 evaluable cases and activating mutations in PIK3CA were found in 13 (29%) of 45 evaluable cases. The combined rate of PTEN loss and PIK3CA mutation in these trastuzumab-refractory tumors was 71%, �� .007) in a cocompared with 44% (P = hort of 73 HER2-amplified tumors in patients not exposed to trastuzumab. As concluded by the investigators, “In this series of prospectively collected trastuzumab-refractory human breast cancers, loss of HER2 overexpression was rare while activation of the PI3KAKT pathway through loss of PTEN or PIK3CA mutation was frequently observed.” Chandarlapaty S, et al: Clin Cancer Res. October 23, 2012 (early release online).

OUTCOME PREDICTORS Impaired Plasmacytoid Dendritic Cell IFN-α Production May Contribute to Breast Cancer Progression Infiltration and dysfunction of immune cells has been observed in numerous cancers. After finding that plasmacytoid dendritic cells (pDC) in primary breast tumors correlated with unfavorable prognosis, Sisirak and colleagues from INSERM (Institut National de la Santé et de la Recherche Médicale) and Centre Léon Bérard in Lyon, France, hypothesized that these cells may interfere with antitumor immune response

and favor immune tolerance. In studies to ascertain the potential mechanisms by which plasmacytoid dendritic cells may mediate poorer outcome, the investigators found that tumor-associated plasmacytoid dendritic cells were increased in aggressive breast tumors—ie, those with a high mitotic index and triple-negative tumors. The tumorassociated plasmacytoid dendritic cells expressed a partially activated phenotype and produced very small amounts of interferon (IFN)-α after toll-like receptor activation in vitro compared with patient blood plasmacytoid dendritic cells. Within the breast tumors, the tumor-associated plasmacytoid dendritic cells co-localized with and were strongly correlated with tumorassociated regulatory T cells (Treg), especially in triple-negative tumors. When IFN-α production was selectively suppressed, the tumor-associated plasmacytoid dendritic cells exhibited a unique capacity to sustain FOXP3-positive Treg expansion, with this activity being reversed when exogenous IFN-α was added. As stated by the investigators, “These findings indicate that IFN-α– deficient [tumor-associated] pDC accumulating in aggressive tumors are involved in the expansion of tumorassociated Treg in vivo, contributing to tumor immune tolerance and poor clinical outcome. Thus, targeting pDC to restore their IFN-α production may represent an attractive therapeutic strategy to overcome immune tolerance in breast cancer.”

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Sisirak V, et al: Cancer Res 72:51885197, 2012.

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Help Your Patients Quit Tobacco Use with New ASCO Resources In an effort to improve the quality of patient care, ASCO has developed two new tobacco cessation resources, one for cancer providers and another for patients and families.

Get these Resources for Your Office and Waiting Room Today.

asco.org/store Learn More About This Initiative

Tobacco Cessation Guide for Oncology Providers A resource for oncology providers at all levels to use to educate patients about the negative effects of tobacco on treatment outcomes and how to integrate tobacco cessation strategies into your practice.

1. Talking to Patients Abo ut Tobacco Use

Key Points

• Patients with cancer who continue to outcomes compa use tobacco red to their have poorer counterparts whether the treatment cancer was tobacco related who do not use tobacco, • Tobacco use regardless of . is a serious concern survivors and those with late-st for all patients at all stages • Blame should age disease. of disease, includ not be placed ing • Relapse is on patients for common and should be viewed their tobacco use and/or addiction to cancer. as a reflection nicotine. of the individ • Tobacco use ual’s should be assess ed for every patient at every clinic visit.

Why Do I Need

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Tobacco Cessation Guide For Oncology Providers

Stopping Tobacco Use After a Cancer Diagnosis Clear, practical information about the benefits of stopping tobacco use, and tips for how patients can talk with providers.

to Talk to My

“Continued co Use? smoking negati vely affects survival in my —Roy Herbst, MD, PhD, Chair cancer patien of Medical Oncolog ts.” y, Smilow Cancer Although there Hospital, Yale is no disputing University many patien ts wonder wheth that tobacco use is the cause of severa er it is too late been diagno l kinds of cancer sed with cancer to worry about s, , a common alike. In fact, tobacco use misconceptio evidence shows n held by oncolo once they have that patients have poorer gists and patien treatment outcom with cancer who continue ts tobacco, a finding es compared to use tobacc to their counte that seems to o rparts who stop occur in patien using ts with many 4 different types TALKING TO PATIENTS ABOUT of cancer, TOBACC

How to Quit

Smoking and Using Tobacc o

A variety of treatments and resources want to stop are available using for people chances of succe tobacco, including medic ations and couns who ssfully quittin plan that includ g are greater eling. Your if you use a es steps such comprehensive as setting a to deal with quit date, devel triggers (situa tions that cause oping strate and building gies a network of you to want to support. Talk approach may with your docto use tobacco), work best for r about which you.

Medications

Using medic ation can at least double your chances of quitting smok U.S. Food and ing. The Drug Admin istration (FDA) has appro ved three types of medications to treat nicoti ne dependence : Nicotine replac ement thera py (NRT). NRT is the most widely used medication. It has mild side effects and is available over the count er and by presc various forms ription in (gum, a lozen ge, a patch that you place on the skin, symptoms of an and inhale a nasal spray r, nicotine withd ). NRT reduc rawal and cravin the best dose es the for you based gs. Your docto on your curre r nt smoking habits will help find Bupropion (Wellb . be used to reduc utrin, Zyban). This antide pressant medic e withdrawal Common side ation may symptoms, even effects includ if you are not e dry mouth asleep or stayin depressed. and insomnia g asleep). (difficulty falling Varenicline (Chantix). This medication and keeps you reduces withd from enjoying rawal symptoms nicotine if you Common side effects includ start smoking e nausea, vivid again. drowsiness. dreams, const ipation, and

HOW TO QUIT

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Stopping Tobacco Use After a Cancer Diagnosis Resources and Guidance for Patients and Families

The ASCO Post | NOVEMBER 15, 2012

PAGE 110

Letters to the Editor

Origins of PSA Testing: The Conversation Continues

s Drs. James Mohler and Donald Trump noted in their September 15 letter to The ASCO Post (“More Thoughts on PSA,” 3[14]:2, 2012), Richard Ablin, PhD, discovered a “prostate-specific antigen” of unknown properties, but his PSA is not the antigen in the PSA test we know today. Since Dr. Ablin has not published a new peer-reviewed paper on PSA since the early 1970s, a letter by Papsidero et al1 published in the Journal of the National Cancer Institute in 1981—which addressed all claims raised in Dr. Ablin’s letter and the references cited there—remains valid. My colleagues and I wrote, “We have also endeavored to provide substantial biochemical and biophysical characteristics of the prostate antigen in order to augment its immunologic identity as a distinct prostate antigen. Although not available for the See Page 108 studies of Dr. Ablin and his colleagues, modern methods of physicochemical characterization are now necessary to avoid equivocal interpretations of data between laboratories pursuing common goals.” This is especially true in light of

the fact that, in reply to Dr. Ablin’s request for a PSA sample from Roswell Park Cancer Institute in 1979, my effort to exchange PSA reagents between the two laboratories was met with silence. Further, the purified PSA and anti-PSA antibody prepared by Roswell Park researchers have been available in the public domain since 1986; to date, Dr. Ablin has not made his PSA accessible to the scientific community.

Key Point Dr. Ablin’s reading misses a key point. The “initial report by Chu” that he referred to in his September 15 reply letter was an abstract posted at the Federation Meetings in 1977.2 Two years later, in our peer-reviewed full-length paper, my colleagues and I clearly stated that “[a] preliminary report has been previously presented,” citing this abstract. As explained and discussed at length by Wang et al,3 purification of PSA was a complex task. Since posting the abstract, we had vastly revised, refined, and improved the procedure to obtain purified and homogeneous PSA with a molecular weight of 33-34 kDa. The contaminant proteins initially copurified with PSA

that may have masked and protected the glycoprotein nature of PSA had been removed. This was not a surprising observation at all. We trust that Dr. Ablin is quite aware of the well-known paper in which Papsidero et al reported that the molecular weight of serum-borne PSA is detected as 100 kDa, instead of 33-34 kDa.4 Refined techniques were needed to ascertain the antigen’s true molecular weight after removal of other serum protein complexed with circulating PSA.

Stated Goal The development of a simple blood test for early detection of prostate cancer was the stated goal of my National Institutes of Health–funded research project.5 The prevailing view then was that most tumor-specific antigens, prostate tumor–specific antigen included, were membrane-bound and nonsecretory, and thus would not be good candidates for in vitro blood tests but were instead more suitable for therapeutic purposes. In addition, as the promising results on PSA and PSA testing kept coming from our laboratories, my colleagues and I were focused on these fascinating new findings. Some of our Roswell Park

colleagues further pursued the investigation of prostate tumor–specific antigen. Dr. Ablin’s criticisms are unwarranted. Readers should base their judgment of his work solely on science and evidence and not on unsupported claims. —T. Ming Chu, PhD, DSc Chair Emeritus, Diagnostic Immunology Research Roswell Park Cancer Institute

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References 1. Papsidero LD, Kuriyama M, Wang MC, et al: Prostate antigen(s): Reply. J Natl Cancer Inst 67(5):992-993, 1981. 2. Wang MC, Valenzuela LA, Murphy GP, et al: Tissue specific and tumor specific antigens in human prostate. Fed Proc 36:1254, 1977. 3. Wang MC, Valenzuela LA, Murphy GP, et al: Purification of a human prostate specific antigen. Invest Urol 17:159-163, 1979. 4. Papsidero LD, Wang MC, Valenzuela LA, et al: A prostate antigen in sera of prostatic cancer patients. Cancer Res 40:24282432, 1980. 5. Kuriyama M, Wang MC, Papsidero LD, et al: Quantitation of prostate-specific antigen in serum by a sensitive enzyme immunoassay. Cancer Res 40:4658-4662, 1980.

The University of Tennessee Medical Center Opens New Cancer Institute

he University of Tennessee Medical Center officially opened its new Cancer Institute in Knoxville at a ceremony attended by hundreds of patients, physicians, staff, and community leaders. At 108,000 square-feet, the new building nearly triples the size of the medical center’s previous cancer care facility (Fig. 1). The growth is in response to the increase in cancer cases treated at the medical center as well as the projected rise in new cancer cases in the next 2 decades. “We believe the new Cancer Institute represents the evolution of care and provides the best possible healing environment for our patients and their families facing a cancer diagnosis,” said Joe Landsman, President and CEO of The University of Tennessee Medical Center. “Our patients and their families joined our

dedicated and highly trained physicians, nurses and staff of the Cancer Institute in the planning of the building. As a result, we’ve incorporated elements of design and functionality that are important to those receiving and delivering care.” Construction of the $23 million facility took about a year to complete. The new center brings the full scope of the medical center’s outpatient cancer treatment capabilities under one roof, thus making access to care during the cancer journey more convenient for patients and their family members, said John L. Bell, MD, Director of The University of Tennessee Medical Center Cancer Institute. The new facility will be a hub for cancer research for physicians and researchers at The University of Tennessee Medical Center and UT Graduate School of Medicine. The research and

Fig. 1: The new Cancer Institute at The University of Tennessee Medical Center is designed to accommodate growth in patient volumes as well as expanded cancer treatment options at the academic medical center in Knoxville.

clinical trials area will continue to offer studies for cancers such as breast, pros-

tate, colorectal, lung, pancreas, melanoma, hepatobiliary, and others.

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Patient’s Corner

Surrounded by Breast Cancer

I thought I could escape the fate of four generations of my family because I tested negative for the BRCA mutation. I got breast cancer anyway. By Norma E. Roth, as told to Jo Cavallo lumpectomy with radiation or a complete mastectomy, but I chose the most radical of all treatments, a bilateral

Norma E. Roth

ine women on my mother’s side of the family have been diagnosed with breast cancer, and nearly half have died from their disease, including my mother. With odds like these, I was determined to do what I could to stay ahead of this dreaded monster I thought was surely coming for me.

First Tests Negative In 1997, I underwent genetic testing for the BRCA gene mutation and was relieved when it came back negative. Then 3 years later, at age 36—as soon as I could after having given

In [women with strong family histories of breast cancer], I believe it’s okay for oncologists to push for more aggressive treatment. — Norma E. Roth

birth—I had a baseline mammogram, and it too showed no sign of cancer. So, despite my family history, when a routine mammogram in 2004 picked up a small, nonpalpable tumor with one or two suspicious-looking calcifications in my right breast, I wasn’t expecting it to be cancerous—and neither was my surgeon. When the pathology report from the biopsy came back positive for medium- to high-grade ductal carcinoma in situ (DCIS), the news was shocking. Even worse, although my surgeon was certain that he had gotten clear margins when he excised the tissue, the pathology report showed that the margins also contained malignant cells. My treatment options included a

mastectomy with breast recronstruction. Given my family history, I just didn’t think a lumpectomy with radia-

tion or even a mastectomy was enough to ensure that the cancer wouldn’t recontinued on page 112

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cur, and I was proven right.

Facing Mortality Even though the pathology report found that my left breast was healthy, one quadrant of my right breast contained microscopic medium- to high-

grade lobular and ductal carcinoma in situ cells. I was a ticking time bomb. After the diagnosis, both my gynecologist and my oncologist treated me as if I had tested positive for the BRCA mutation and advised me to have a prophylactic oophorectomy. At the time, I just wasn’t emotionally ready to take such a radical step,

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% INDICATIONS AND USAGE Hispanic, 2% Black, and < 1% Asian, Native American or other. Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated malignancies receiving myelosuppressive anticancer drugs patients. associated with a clinically significant incidence of febrile Table 1. Adverse Reactions With ≥ 5% Higher Incidence neutropenia. Neulasta is not indicated for the mobilization of peripheral blood in Neulasta Patients Compared to Placebo in Study 3 progenitor cells for hematopoietic stem cell transplantation. System Organ Class Placebo Neulasta 6 mg CONTRAINDICATIONS Preferred Term (N = 461) SC on Day 2 Do not administer Neulasta to patients with a history of serious (N = 467) allergic reactions to pegfilgrastim or filgrastim. Musculoskeletal and connective tissue disorders WARNINGS AND PRECAUTIONS Bone pain 26% 31% Splenic Rupture Pain in extremity 4% 9% Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen Leukocytosis or splenic rupture in patients who report left upper abdominal In clinical studies, leukocytosis (WBC counts > 100 x 109/L) or shoulder pain after receiving Neulasta. was observed in less than 1% of 932 patients with nonmyeloid Acute Respiratory Distress Syndrome malignancies receiving Neulasta. No complications attributable Acute respiratory distress syndrome (ARDS) can occur in patients to leukocytosis were reported in clinical studies. receiving Neulasta. Evaluate patients who develop fever and Immunogenicity lung infiltrates or respiratory distress after receiving Neulasta, for As with all therapeutic proteins, there is a potential for ARDS. Discontinue Neulasta in patients with ARDS. immunogenicity. Binding antibodies to pegfilgrastim were Serious Allergic Reactions detected using a BIAcore assay. The approximate limit of Serious allergic reactions, including anaphylaxis, can occur in detection for this assay is 500 ng/mL. Pre-existing binding patients receiving Neulasta. The majority of reported events antibodies were detected in approximately 6% (51/849) occurred upon initial exposure. Allergic reactions, including of patients with metastatic breast cancer. Four of 521 anaphylaxis, can recur within days after the discontinuation of pegfilgrastim-treated subjects who were negative at baseline initial anti-allergic treatment. Permanently discontinue Neulasta developed binding antibodies to pegfilgrastim following in patients with serious allergic reactions. Do not administer treatment. None of these 4 patients had evidence of Neulasta to patients with a history of serious allergic reactions neutralizing antibodies detected using a cell-based bioassay. to pegfilgrastim or filgrastim. The detection of antibody formation is highly dependent on Use in Patients With Sickle Cell Disorders the sensitivity and specificity of the assay, and the observed Severe sickle cell crises can occur in patients with sickle cell incidence of antibody positivity in an assay may be influenced disorders receiving Neulasta. Severe and sometimes fatal sickle by several factors, including assay methodology, sample cell crises can occur in patients with sickle cell disorders handling, timing of sample collection, concomitant medications, receiving filgrastim, the parent compound of pegfilgrastim. and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence Potential for Tumor Growth Stimulatory Effects on of antibodies to other products may be misleading. Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor Postmarketing Experience through which pegfilgrastim and filgrastim act has been found The following adverse reactions have been identified during on tumor cell lines. The possibility that pegfilgrastim acts post approval use of Neulasta. Because these reactions are as a growth factor for any tumor type, including myeloid reported voluntarily from a population of uncertain size, it is not malignancies and myelodysplasia, diseases for which always possible to reliably estimate their frequency or establish pegfilgrastim is not approved, cannot be excluded. a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more ADVERSE REACTIONS of the following factors: (1) seriousness of the reaction, (2) The following serious adverse reactions are discussed in reported frequency of the reaction, or (3) strength of causal greater detail in other sections of the Brief Summary: relationship to Neulasta. • Splenic Rupture [See Warnings and Precautions] Gastro-intestinal disorders: Splenic rupture [see Warnings • Acute Respiratory Distress Syndrome [See Warnings and Precautions] and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions] • Use in Patients with Sickle Cell Disorders [See Warnings Hypersensitivity reactions: Allergic reactions/hypersensitivity, and Precautions] including anaphylaxis, skin rash, and urticaria, generalized • Potential for Tumor Growth Stimulatory Effects on Malignant erythema and flushing [see Warnings and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity. Skin and subcutaneous tissue disorders: Sweet’s syndrome, Clinical Trials Experience Cutaneous vasculitis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials DRUG INTERACTIONS of a drug cannot be directly compared with rates in the clinical No formal drug interaction studies between Neulasta and other trials of another drug and may not reflect the rates observed in drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may clinical practice. Neulasta clinical trials safety data are based upon 932 patients result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The USE IN SPECIFIC POPULATIONS ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy Category C tumors (n = 53) and lymphoma (n = 56) received Neulasta There are no adequate and well-controlled studies in pregnant after nonmyeloablative cytotoxic chemotherapy. Most patients women. Pegfilgrastim was embryotoxic and increased received a single 100 mcg/kg (n = 259) or a single 6 mg pregnancy loss in pregnant rabbits that received cumulative (n = 546) dose per chemotherapy cycle over 4 cycles. doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies with metastatic or non-metastatic breast cancer receiving the potential risk to the fetus. docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use

but a year ago, I went through with the surgery. I don’t think anyone who hasn’t gone through these surgical procedures can understand what it’s like for a person to consciously decide to remove healthy body parts to prevent cancer. It was a very difficult choice, but my anxiety about developing additional cancers overrode everything

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary.

else. It’s one thing to have cancer come knocking on your mother’s door, taking her away. It’s quite another when it comes knocking on your own door and you are staring mortality in the face. Most of all, I didn’t want my three young children to be raised without their mother.

Advocating Aggressive Treatment Having this experience has taught me that doctors need to offer women with strong family histories of breast cancer more aggressive treatment options. Three mammograms leading up to my breast surgery had only picked up the one tiny tumor, so it always troubles me when I hear about other women at high risk being given the option of lumpectomy plus radiation. In these situations, I believe it’s okay for oncologists to push for more aggressive treatment, including bilateral mastectomy, because until you can actually examine the tissue, you can’t know for certain what’s growing in there. I also now understand that being genetically screened for the BRCA gene mutation and testing negative does not obliterate the chances for developing breast cancer. In addition to me, two cousins also tested negative for the BRCA mutation, and we were diagnosed with breast cancer within 6 months of each other. Today, I try to live life to the fullest and plan for the unexpected.

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Norma E. Roth is the author of Pink Ribbon Journey: Stories from the Heart and lives in Cherry Hill, New Jersey.

DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Supplement to

The ASCO Post Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2012 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

65481-R1-V1

Don’t miss the special supplement “Monitoring, Treatment Resistance, and Treatment Failure in Chronic Myeloid Leukemia,” mailed with this issue of The ASCO Post and available online at

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In the Literature

Emerging Clinical Data on Cancer Management LYMPHOMA Novel Mechlorethamine Gel Considered Safe and Effective for Treatment of Mycosis Fungoides A novel mechlorethamine, 0.02%, gel produced comparable or higher response rates (depending on the measurement used) than did mechlorethamine, 0.02%, compounded ointment, in a randomized controlled, multicenter study among 260 patients with stage IA to IIA mycosis fungoides, the most common form of cutaneous T-cell lymphoma. The patients had not used topical mechlorethamine within 2 years and were naive to prior use of topical carmustine (BiCNU) therapy. The mechlorethamine was applied once daily to either specific lesions or to the total skin surface, depending on the T classification, for up to 12 months. Based on the Composite Assessment of Index Lesion Severity, the primary efficacy endpoint, which identified up to five index lesions as baseline and assessed them throughout the study, response rates were 58.5% for the gel vs 47.7% for the ointment. Using the Composite Assessment of Index Lesion Severity, the ratio of gel response rate to ointment response rate was 1.23 (95% CI = 0.97–1.55), “which met the prespecified criterion for noninferiority. Time-to-response analyses demonstrated superiority of mechlorethamine gel to ointment (P < .01),” the investigators reported in the Archives of Dermatology. Because regional and total skin surface applications were also included in the study, the investigators used the Modified Severity-Weighted Assessment Tool as a secondary efficacy endpoint. “A determination of the percentage involvement of total body surface area and, if applicable, an assessment of clinically abnormal lymph nodes (>�� 1.5�� cm �� in diameter) were completed at baseline and throughout the 12-month study,” the authors explained. By this measure, response rates were 46.9% for the gel vs 46.2% for the ointment.

Adverse Events While no drug-related severe adverse events were reported during the trial, “61.7% of patients who received gel and 50.4% of patients who received ointment reported at least 1 [adverse event] that was considered related to the study drug,” the researchers noted. “Most [ad-

verse events] in both treatment arms were skin related, characterized mainly as local dermatitis (skin irritation). The incidence of skin irritation was higher in the gel arm (P = .04). No statistically significant differences were observed in the overall incidence of [adverse events] or any other subcategory between the gel and ointment arms.” Drug-related skin adverse events were responsible for withdrawal from the trial by 20.3% of patients using gel and 17.3% using ointment. In an assertion that takes on added significance with recent reports of people dying from meningitis caused by a contaminated drug from a compounding pharmacy, the authors noted that the lack of a topical mechlorethamine formulation approved by the FDA “has become problematic for physicians and patients for several reasons.” Among the reasons cited is: “Pharmacy-compounded mechlorethamine formulations are not subject to rigorous quality assurance, such as evaluations of potency and stability.” The authors concluded, “A manufactured mechlorethamine, 0.02%, gel [would address] the unmet need for good manufacturing product quality assurance that will improve drug availability for patients with [mycosis fungoides].” Lessin SR, et al: Arch Dermatol October 15, 2012 (online first).

ANTISMOKING EFFORTS Media Campaign with Real Smokers a Success Real smokers sharing in graphic terms what it is like to live with disfiguring or disabling tobacco-related diseases were the featured spokespersons for the Centers for Disease Control and Prevention (CDC) national media campaign to encourage smokers to quit. Based on shortterm response, the CDC has deemed the campaign a success. “It far exceeded our expectations,” said Tim McAfee, MD, MPH, Director of the CDC’s Office on Smoking and Health, who is quoted in an article published online first in the Annals of Internal Medicine. Calls to the toll-free quit line more than doubled during the 12- week campaign, according to Dr. McAfee, and website hits tripled. “The quit line received 207,519 additional calls in 2012 compared with the same 12-week period in 2011, and the website recorded 510,571 additional unique visitors, suggesting a substantial untapped public interest in information about quitting

smoking,” the authors noted. “Whether the short-term positive response will translate into higher rates of smoking cessation and lower smoking prevalence is the key question.… Good empirical evidence shows that public education campaigns delivered by mass media influence health behaviors, especially tobacco smoking,” the authors pointed out. “Recent reviews find strong evidence that mass media campaigns increase quitting and reduce smoking prevalence when implemented within the context of a comprehensive tobacco control program.”

Federal Investment The Tips from Former Smokers campaign was “a $54 million national mass media campaign for public education supported by the Affordable Care Act’s Prevention and Public Health Fund” and “the first federally funded, nationwide mass media effort to encourage smokers to quit,” the authors explained. “The $54 million investment of federal funds is unprecedented in U.S. tobacco control, although it pales in comparison to the $27 million spent daily by the tobacco industry to market its products,” the authors added. While paid advertising ended in June 2012, campaign materials such as videos, podcasts, and links remain accessible on the Tips website (www.cdc. gov/tobacco/campaign/tips). The authors noted, “the CDC plans to use funds from the Affordable Care Act to run another 3-month campaign during the first quarter of 2013 and hopes to do so in future years.” The CDC also might extend the campaign’s effect by partnering with states and private-

sector organizations that could reuse the campaign spots. The campaign featured graphic images, including a man with bilateral below-knee amputations and three people who talk about daily life with a stoma, as well as tips from former smokers about how they quit. “It is definitely a program to watch—and to recommend to your patients who smoke,” the authors concluded. Rigotti NA, Wakefield M: Ann Intern Med. September 25, 2012 (early release online).

KIDNEY CANCER Pulmonary Radiotherapy Can Usually Be Omitted for Nephroblastoma and Pulmonary Metastases For the majority of patients with nephroblastoma and pulmonary metastases, pulmonary radiotherapy can be omitted and the patients will still have a relatively good outcome, according to a study published in the Journal of Clinical Oncology. “The rationale of omitting pulmonary [radiotherapy] for the majority of the patients is prevention of midterm and long-term morbidity, such as exercise-induced dyspnea, interstitial pneumonia, diminished lung volumes, and other respiratory disorders,” the researchers explained. The current treatment strategy for nephroblastoma, the most frequent common renal tumor of childhood, consists of neoadjuvant chemotherapy, nephrectomy, postoperative chemotherapy, and sometimes radiotherapy, according to the

continued on page 114

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Emerging Clinical Data continued from page 113

International Society of Pediatric Oncology. Different strategies have been used for treating pulmonary metastases, ranging from the routine use of pulmonary radiotherapy for metastases detected on conventional pulmonary x-ray to using radiotherapy only in cases of persistent

nodules or high-risk histology.

Study Details The current study involved 1,170 patients (aged 6 months to 18 years), including 234 with pulmonary metastases. Patients were treated with preoperative chemotherapy consisting of 6 weeks of vincristine, dactinomycin,

and epirubicin or doxorubicin. “Chest CT was repeated at the time of nephrectomy to assess the response of the pulmonary nodules, and postoperative chemotherapy was adapted according to the results of CT,” the authors noted. Patients who achieved complete remission received three-drug postoperative chemotherapy. In cases of persisting

pulmonary nodules, metastasectomy was performed if feasible, and if complete remission was achieved, See Page 108 followed by the same three-drug regimen. Patients who did not achieve complete remission were switched to a high-risk regimen and assessed at week 11. Radiotherapy was mandatory for those not obtaining complete remission. “Of the 220 patients with [pulmonary metastases] and complete data, 185 patients (84%) were in [complete remission] postoperatively,” the authors stated. In addition, 148 patients (67%) were in complete remission after preoperative chemotherapy only and 37 patients (17%) were considered for metastasectomy. The high-risk protocol was required for 35 patients (16%) who had multiple inoperable pulmonary metastases. “Only 14% of patients received pulmonary [radiotherapy] during firstline treatment,” the authors noted.

Key Results The 5-year event-free survival rate for patients with pulmonary metastases was 73% (95% CI = 68%–79%), and the 5-year overall survival rate was 82% (95% CI = 77%–88%). “Five-year [overall survival] was similar for patients with local stage I and II disease (92% and 90%, respectively) but lower for patients with local stage III disease (68%; P < .001). Patients in [complete remission] after chemotherapy only and patients in [complete remission] after chemotherapy and metastasectomy had a better outcome than patients with multiple unresectable [pulmonary metastases] (5-year [overall survival], 88%, 92%, and 48%, respectively; P < .001),” the researchers reported. “Given the current results, we conclude that the majority of patients with nephroblastoma and [pulmonary metastases] can obtain a long-term [complete remission] without pulmonary [radiotherapy],” the authors stated. “By adopting this strategy, we observed a 5-year [event-free survival] of 73% and a 5-year [overall survival] of 82%. These survival data are similar to the 4-year recurrence-free survival rate of 77% and [overall survival] rate of 81% reported in patients with lung metastases only and treated with regimen DD-RT (a combination of vincristine, dactinomycin, doxorubicin, and radiotherapy).”

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Verschuur A, et al: J Clin Oncol 30:35333539, 2012.

In the Literature is compiled and written by Charlotte Bath.

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In Memoriam

Nobel Laureate E. Donnall Thomas, MD, Dies at 92 By Ronald Piana

E. Donnall Thomas, MD, 1920–2012

n his 1990 Nobel Prize Lecture, Eduard Donnall Thomas, MD, with characteristic humility, acknowledged that the success he celebrated “was made possible by the work of many others in this and related fields.” Dr. Thomas, whose groundbreaking work in bone marrow transplantation marked a new era in the treatment of leukemia and other blood malignancies, died at the age of 92 on October 20, 2012. Dr. Thomas was born in 1920 in the dusty farm town of Mart, Texas. His father, a family practitioner, spent long hours driving rural roads to see patients during the smallpox epidemic. “My father took me on house calls, and I decided to go into medicine when I was about 5,” Dr. Thomas told The ASCO Post during an interview earlier this year. Mart was a dot on the vast rural map, and Dr. Thomas attended grade school in a one-room structure with about 20 classmates, most of whom were children of nearby farms and ranches. He relished the unvarnished but sturdy education he received on his way through high school, leading him in 1937 to The University of Texas at Austin, where he majored in chemistry.

Staring Down Challenges Tragedy struck during Dr. Thomas’s second year at The University of Texas—his father was killed in a car crash while retuning from nighttime house calls. Overnight, Dr. Thomas was dealt a double blow, losing both his beloved father and any viable financial support for his education. Adding to the dilemma, the nation was in the grip

of the Great Depression and even the lowest of jobs were scarce. This, however, would be one of many challenges that Dr. Thomas stared down with the resolve and good humor of his pioneer forebears. He scraped up a job on campus waiting tables and washing dishes at the cafeteria in the girl’s dormitory. During a serendipitous Austin snowstorm, a prepossessing journalism major named Dorothy Martin playfully pelted him with a snowball. She married Dr. Thomas 2 years later and shortly thereafter revised her career goals, working next to her husband in the research lab throughout his career. Dr. Thomas received a BA in chemistry in 1941 and an MA in chemical engineering in 1943. Medical school was next in line, but the steep tuition daunted the young couple. World War II was still raging and to fill a dire need for doctors, the U.S. military launched the Army Specialized Training Program. Dr. Thomas already had an army reserve commission, so he decided to remain in the service and go to medical school. “Dottie and I decided that as long as Uncle Sam was paying for my education, why not try for a famous school. I applied to Johns Hopkins and Harvard and lo and behold I received an acceptance telegram from Harvard 2 weeks later,” Dr. Thomas said. There was one catch—the first class started in 10 days. The Thomases sold their few possessions and hopped a train to Boston; the two underdressed Texans arrived in a blinding snowstorm wearing sneakers.

Busy Career Path After graduating from Harvard Medical School in 1946, Dr. Thomas did a hematology internship with Clement Finch, MD, at the Brigham Hospital. He credited Dr. Finch as a first-class mentor who accelerated his interest in all aspects of clinical medicine. But working on the ward with several patients with acute leukemia ultimately fixed his research interests on the mechanisms that stimulate bone marrow. “As for pivotal things that steered my career path, well, I really just followed my nose; there’s a certain amount of luck that goes with success,” Dr. Thomas commented.

A dizzyingly busy period ensued. A year completing his army medical requirements in post-war Germany, a year of postdoctoral work at the Massachusetts Institute of Technology, and 2 years of medical residency (the last as Chief Resident at Peter Bent Hospital in Boston). In 1955, he was Physicianin-Chief at the Columbia University

Dr. Thomas’s subsequent work demonstrated that some patients with advanced leukemia, aplastic anemia, or genetic diseases could be cured with bone marrow transplant. “The story seems a bit short in retrospect. That said, my work and philosophy over the years was heavily influenced by a wonderful group

In the course of one generation Dr. Thomas and his father journeyed from horse-and-buggy house calls to lifesaving bone marrow transplants—a scientific contribution that ranks among the most significant medical advances of the 20th century. branch in Cooperstown, New York, where his marrow transplant studies began to blossom into full-time clinical research. “We first did marrow transplants on dogs, and later in human patients. We quickly learned that except for the occasional identical twin, allogeneic transplant in humans was going to be very difficult,” Dr. Thomas said. In 1963, the famous endocrinologist Robert Williams, MD, invited Dr. Thomas to join the faculty of the University of Washington School of Medicine. Realizing an opportunity to fast-forward his research, the Thomases packed up and moved to the Pacific Northwest, where in short time he established his own research program in an affiliate institution, the Seattle Public Health Hospital.

of dedicated colleagues,” Dr. Thomas said, repeatedly. Dr. Thomas’s father moved to frontier Texas with his family in a covered wagon in 1874. In the course of one generation Dr. Thomas and his father journeyed from horse-andbuggy house calls to lifesaving bone marrow transplants—a scientific contribution that ranks among the most significant medical advances of the 20th century.

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Cutting-edge Research After the Seattle program was fully equipped, Dr. Thomas recruited a host of brilliant young researchers eager to be at the cutting edge of scientific discovery.

Dr. E. Donnall Thomas. Photo courtesy of Nobel Foundation.

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Exploring uncharted territories — bringing advances in oncology to light

At Genentech BioOncology, we’re transforming the way cancer is treated by gaining a broad understanding of cancer biology and following a comprehensive approach to drug discovery. A robust pipeline — We currently have more than 40 new molecules in clinical development across a range of pathways, from angiogenesis to apoptosis. Innovative molecules — Our new molecular entities target the fundamental mechanisms of cancer growth and include antibody-drug conjugates, a HER2 dimerization inhibitor, a type II glycoengineered anti-CD20 antibody, and a one-arm antibody targeting Met. Extensive clinical trial program — We and our partners are currently enrolling patients in over 600 ongoing trials for both postapproval and pipeline products in more than a dozen tumor types. Our goal is to fundamentally change the way that cancer is treated — not just with incremental advances, but with new standards of care.