TAP Vol 3 Issue 10 by Harborside Press LLC

Brentuximab in ALCL 34

Circulating Tumor Cells in Breast Cancer

42 |

VOLUME 3, ISSUE 10

Scanning for Colon Cancer Recurrence 45

JULY 1, 2012

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

ASCOPost.com

Breast Cancer and Noncommunicable Diseases: Where in the World Do We Start?

2012 ASCO Annual Meeting

PD-1 Immune Checkpoint Inhibitors Look Promising in Multiple Solid Tumors By Caroline Helwick

nt i body-mediated PD-1 Immune Checkpoint Blockade blockade of the programmed death 1 protein ■■ Antibody-mediated blockade of the PD-1 protein and its ligand, PD-L1, (PD-1) and its ligand (PDproduces durable tumor regression or stabilization. L1) induces durable tumor ■■ Phase I studies of PD-1 and PD-L1 inhibitors have shown response rates as regression and prolonged high as 28% among patients with various solid tumors, and the drugs are stabilization of disease in well tolerated. patients with advanced solid tumors, according to of Johns Hopkins University School of Medicine, data presented at the 2012 ASCO Annual Meeting.1,2 Although the studies reported were only phase I inBaltimore, noted that the drug “induces very durable vestigations, and the drugs are known only as BMSresponses in patients who are otherwise treatment936558 and BMS-936559, the findings earned the refractory, which is a remarkable feature, and while investigators an appearance at an these are very preliminary data they give us an imporASCO press briefing and were contant lead for further investigations.” currently published in The New EngAnti–PD-1 and Anti–PD-L1 Antibodies land Journal of Medicine.3,4 Presenting data on the anti–PD-1 The first clinically validated target of “immune See Page 50 continued on page 7 agent, Suzanne L. Topalian, MD, Issues in Oncology

New PSA Recommendations: The Debate over Prostate Cancer Screening Continues

By Benjamin O. Anderson, MD, FACS

s the world’s most common cancer among women, and the most likely reason around the globe that a woman will die of cancer, breast cancer affects countries at all economic levels. Despite the common misconception that breast cancer is primarily a problem of high-income countries, the majority of the 425,000 breast cancer deaths in 2010 occurred in developing (not developed) nations. The number of young lives lost is even more disproportionate: In 2010, breast cancer killed 68,000 women aged 15 to 49 years in developing countries vs 26,000 in developed countries. If cancer will seriously be addressed as a global health issue, then breast cancer in low- and middle-income countries cannot be ignored.1 continued on page 36

Dr. Anderson is Director, Breast Health Global Initiative, Fred Hutchinson Cancer Research Center, and Professor of Surgery and Global Health-Medicine, University of Washington, Seattle.

By Ronald Piana

he U.S. Preventive Services Task Force (USPSTF) recently issued a recommendation statement advising against the use of prostate-specific antigen (PSA)-based testing for prostate cancer,1 leaving many in the oncology community concerned that decades of clinical progress will be stalled, and setting the stage for another contentious debate in the ongoing controversy over the clinical value of PSA testing. To bring clarity to this important issue, The ASCO Post spoke with sev-

eral prostate cancer experts and with the Chair and CoChair of the Task Force.

Trial Data Pushed Early Recommendation

The Task Force is an independent panel of federally appointed primary care providers who are experts in prevention and evidence-based medicine. After reviewing pertinent scientific data, the panel assigns one of five letter grades to its recommendations, which include “suggestions for practice.” The recent recommendation assigned PSA testing a D grade, which advises proWe found that most of the men who viders to “discourage the were treated would have lived just as long use of this practice.” Michael L. LeFevre, and as well without the diagnosis and MD, Co-Chair of the Task treatment. Force, explained that the — Michael L. LeFevre, MD recommendations are updated about every 5 years

MORE IN THIS ISSUE 2012 ASCO Annual Meeting Non-Hodgkin Lymphoma �� 3 Prostate Cancer �� 10 Neuro-oncology �� 18 Ovarian Cancer �� 19 Breast Cancer �� 24, 25 Letters to the Editor �� 2 Direct from ASCO �� 29 Rebecca Dresser on medical ethics �� 32 FDA Update �� 33,49, 50

continued on page 12

A Harborside Press® Publication

The ASCO Post | JULY 1, 2012

PAGE 2

Letters to the Editor Opinion

Prostate Cancer Management: A Day Late and A Dollar Short?

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

Douglas W. Blayney, MD Stanford University Medical Center

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

Robert W. Carlson, MD Stanford University Medical Center 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

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

n the May 15 issue, The ASCO Post reported on the relative cost-effectiveness of approaches to treating localized prostate cancer (“Advances in Prostate Cancer Accompanied by Ongoing Debates,” page 1). The article analyzed an important scientific paper presented at both urology and radiation oncology meetings, and a physician interviewed for the article described a “medical arms race” in the treatment of prostate cancer, with more side effects associated with the more expensive treatments that have

not shown improved results. Yet the latest buzz on prostate cancer, including national TV and print coverage, is “Not to Screen” for the disease. To an extent, this approach eliminates the issue of overtreatment or treatment of early (indolent) prostate cancer. It saves the already expensive and underfunded health-care system (specifically, Medicare) millions of dollars, and saves tens of thousands of patients the risks of major side effects from sometimes unnecessary yet agcontinued on page 51

The ASCO Post

Wants to Hear from You

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

The Editors 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

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

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, 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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ASCOPost.com | JULY 1, 2012

PAGE 3

2012 ASCO Annual Meeting Hematology

German Study Finds Bendamustine Improves Progression-free Survival in Patients with Non-Hodgkin Lymphoma By Caroline Helwick

pdated results of the StiL NHL1 study, presented at the 2012 ASCO Annual Meeting Plenary Session, showed that bendamustine plus rituximab (Rituxan) more than doubled the median progression-free survival, compared with the standard R-CHOP See Page 50 regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). No difference in overall survival was observed.

Developed in East Germany “We saw a huge difference favoring bendamustine/rituximab over RCHOP…. Bendamustine/rituximab is not only less toxic, but also more effective than the most-often-used first-line approach, and should be considered a preferred first-line treatment for these patients,” said lead investigator Mathias J. Rummel, MD, PhD, of the University Hospital in Giessen, Germany. Explaining the rationale for the simpler regimen, he said at a press briefing, “R-CHOP, which contains five different

Mathias J. Rummel, MD, PhD

drugs, has been standard treatment in most Western countries. It has an absolute place in diffuse large B-cell lymphoma, but there has been ongoing debate as to whether we need such an aggressive regimen in indolent lymphoma.” Bendamustine is approved in the United States for chronic lymphocytic leukemia and for second-line rituximab-refractory NHL.

StiL NHL1 Details The multicenter German study enrolled 549 patients newly diagnosed with stage III or IV indolent NHL (follicular, Waldenstrom’s macroglobulinemia, marginal zone, small lymphocytic, or mantle cell) and ran-

EXPERT POINT OF VIEW

ichard I. Fisher, MD, the Samuel E. Durand Professor of Medicine at the University of Rochester Medical Center in Rochester, New York, cautioned that it is too early to embrace the bendamustine/rituximab regimen.

Caution Advised “Bendamustine is a very active agent with moderate toxicity that will have a major role in the treatment of indolent lymphomas. The StiL trial Richard I. Fisher, MD remains unpublished, however, and we are not able to evaluate all the details of how the study was conducted, including staging evaluation, eligibility, statistical plan, follow-up evaluations, and so forth. Therefore, until it is available through peer review it should probably not be considered a standard of care,” he maintained. “Recall that we have made tremendous progress in the overall survival of patients with indolent lymphoma since the advent of rituximab,” he continued. “Before we abandon established successful front-line treatment regimens we should wait to see all the details of the study as well as perhaps a confirmatory trial. There is still no evidence of any survival difference between RCHOP and the bendamustine/rituximab regimen.”

■

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

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

domly assigned to standard treatment with R-CHOP (rituximab at 375 mg/ m2, cyclophosphamide at 750 mg/m2, doxorubicin at 50 mg/m2, vincristine at 1.4 mg/m2 [maximum dose, 2 mg], prednisone at 100 mg) or bendamustine at 90 mg/m2 on days 1-2 plus rituximab at 375 mg/m2. After a median follow-up of 45 months, median progression-free survival more than doubled with the bendamustine/rituximab regimen: 69.5 months vs 31.2 months with R-CHOP, a highly significant 42% reduction in the risk of progression (P = .0000148), Dr. Rummel reported. The significant progression-free survival benefit observed with bendamustine/rituximab extended to all risk groups irrespective of age and Follicular Lymphoma International

Prognostic Index (FLIPI) score. All histologic subtypes benefited except for marginal zone lymphoma, where progression-free survival was comparable. The biggest advantage was observed in patients with Waldenstrom’s macroglobulinemia (69.5 vs 28.1 months; P = .0033). Bendamustine/rituximab also produced a significantly higher complete response rate (39.8%) than R-CHOP (30.0%), although overall response rates were similar—approximately 92% per arm. Overall survival was also similar: 80.1% at 5 years with bendamustine/rituximab and 77.8% with R-CHOP. “So far, we have not observed differences in overall survival,” he said. “This is not surprising, since indolent continued on page 8

EXPERT POINT OF VIEW

ichael Williams, MD, the Byrd S. Leavell Professor of Medicine and Chief of Hematologic Malignancies at the University of Virginia Cancer Center, Charlottesville, commented, “Bendamustine/rituximab provides equivalent or better responses vs R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], and with less toxicity.” The study’s caveats are that progression-free survival was relatively short for follicular lymphoMichael Williams, MD ma patients treated with R-CHOP, and overall survival is not yet different. Long-term toxicities are also still unclear, as is the ability to collect stem cells following bendamustine treatment, although this did not appear problematic in the StiL study, he noted.

Next Steps to Validate Outcomes The next steps should be to validate outcomes in larger cohorts of indolent non-Hodgkin lymphoma (NHL) subtypes and verify the short- and long-term toxicities. Optimal combinations should also be determined, and the drug’s activity in other lymphomas should be explored, he suggested. Meanwhile, he said, “StiL NHL1 establishes bendamustine/rituximab as a front-line regimen for indolent B-cell and non–transplant-eligible mantle cell lymphoma patients.” The regimen is being further evaluated in U.S. Cooperative Group trials, in the StiL NHL 7-2008 trial (bendamustine/rituximab followed by rituximab maintenance), and the BRIGHT study (bendamustine/rituximab vs R-CHOP or R-CVP [rituximab plus cyclophosphamide, vincristine, and prednisone]).

■

Disclosure: Dr. Williams had disclosures for Celgene, Cephalon, Genentech, TG Therapeutics, Onyx, Calistoga Pharmaceuticals, Genentech, Gilead Sciences, Millennium, Novartis, and Pharmacyclics.

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.

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.

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

Mechanism of action

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 AUC 0-∞ (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.

KAPLAN-MEIER SURVIVAL CURVES OF PATIENTS TREATED WITH EITHER ZYTIGA® + PREDNISONE OR PLACEBO + PREDNISONE (INTERIM ANALYSIS) 100

P < 0.0001; HR = 0.646; 95% CI: 0.543, 0.768

% Survival

ZYTIGA®: 14.8 months (median) (95% CI: 14.1, 15.4)

60 Placebo: 10.9 months (median) (95% CI: 10.2, 12.0)

40 20 0 0

736 355

657 306

68 30

2 3

0 0

Time to Death (Months) ZYTIGA® 797 Placebo 398

520 210

282 105

The median duration of treatment with ZYTIGA® was 8 months.

Proven survival benefit At the interim analysis of the phase 3 study,*† ZYTIGA® in combination with prednisone showed a statistically significant improvement in overall survival compared with placebo plus prednisone and resulted in a 35% reduction in the risk of death (hazard ratio [HR] = 0.646; P < 0.0001; 95% confidence interval [CI]: 0.543, 0.768; median survival: 14.8 months vs 10.9 months, respectively) In an updated survival analysis,‡ results were consistent with those from the interim analysis (HR = 0.74; 95% CI: 0.638, 0.859; median survival: 15.8 months vs 11.2 months)

*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 3/12 08Z12066B

study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398). Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival. †552 events. ‡775 events. 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. 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®.

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

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

www.zytiga.com

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 Muscle discomfort3 26.2 3.0 General disorders 4 26.7 1.9 Edema 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 Arrhythmia6 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

Issued: May 2012

08Z12155B

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2012 ASCO Annual Meeting PD-1 Immune Checkpoint Inhibitors continued from page 1

checkpoint blockade” was cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), an inhibitory receptor that downmodulates the initial stages of T-cell activation. The anti-CTLA4 antibody ipilimumab

Suzanne L. Topalian, MD

(Yervoy) increases overall survival in patients with advanced melanoma, and is now being evaluated in a phase III non–small cell lung cancer (NSCLC) trial in 920 patients. But the newsmakers at ASCO were inhibitors of the PD-1 checkpoint. The anti–PD-1 (BMS-936558) and anti-PD-L1 (BMS-936559) antibodies potentiate immune responses by blocking the interaction between the PD-1 protein, a T-cell co-inhibitory receptor, and one of its ligands, PDL1—critical players in the ability of tumor cells to evade the host’s immune system. “Ipilimumab and the anti–PD-1 and PD-L1 antibodies are all immune checkpoint drugs, but they are distinct in how they act,” Dr. Topa-

lian explained at the press briefing. “The anti-CTLA4 agent is more global, whereas the others are more

BMS-936558 produced tumor shrinkage in approximately onequarter of patients, with response

The anti–PD-1 antibody BMS-936558 produced tumor shrinkage in approximately one-quarter of patients, with response rates of 28% in melanoma, 27% in renal cancer, and 18% in NSCLC. tissue-specific, so the toxicity is a bit less with them.” In the study she presented at the ASCO Annual Meeting, 296 patients with advanced solid tumors received intravenous BMS-936558 in escalating doses from 0.1 to 10 mg/kg every 2 weeks.

rates of 28% in melanoma, 27% in renal cancer, and 18% in NSCLC, and stable disease rates of 6% in melanoma, 27% in renal cancer, and 7% in NSCLC. A maximum tolerated dose was not reached. No responses were observed in patients with colorectal continued on page 8

EXPERT POINT OF VIEW

ncologists can expect to hear more about immune checkpoint blockade, according to two discussants of these abstracts. In fact, five PD-1 immune checkpoint compounds are already in the pipeline (Table 1), according to Giuseppe Giaccone, MD, PhD, of the National Cancer Institute, Bethesda, Maryland. James Allison, PhD, of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, New York, said immunotherapy has turned a corner to become a “compelling” means of treating cancer, thanks to better understanding of the complexity of T-cell regulation. “Antibodies to regulatory molecules take the brakes off the immune system, free T cells to proliferate, and maximize [antitumor] response,” he said. “And you are treating T cells, not tumor cells, so the tumor type should be irrelevant. Furthermore, the immune system can adapt; you don’t get resistance. And T cells can provide memory.” The effect of unleashing a memory immune response may be long-

Giuseppe Giaccone, MD, PhD

term disease stabilization, he predicted. “Once T cells are stimulated by engagement of peptides, you get long-lived memory that may last for the life of the patient…. In fact, I recently saw a patient who was on the phase I melanoma trial of ipilimumab 10 years ago. She is alive, without need for subsequent treatment…. With ipilimumab, survival at 2 years is about 25%, and it stays at this rate for 4 or 5 years, due to immunologic memory, though we see this in just a fraction of patients.” Responses lasting up to 2 years are being seen with PD-1 immune checkpoint drugs, but the question is, he said, “Can they be as long as those with ipilimumab?”

Patient Selection Will Be Key Commenting on the findings for the anti–PD-1 antibody, Dr. Giaccone noted, “BMS-936558 has promising activity in NSCLC, and appears to be better tolerated than the CTLA4 antibody, though severe pneumonitis was seen, resulting in three deaths. It is potentially more effective in squamous carcinoma histology, where we do not have effective targeted agents. Patient selection—ie, biomarkers— should be sought. Combination studies are warranted. And randomized studies will be needed to confirm these benefits.” Dr. Allison added that if efficacy is restricted to tumors expressing PD-L1, patient selection can be optimized. He agreed that combination

therapy may increase the efficacy of immune checkpoint blockade and might be achieved with vaccines, other checkpoint inhibitors, conventional therapies and targeted therapies, and through stimulation of costimulatory pathways. “As we learn to combine these drugs, we will see progress,” he predicted. “But we are already lucky. In a 2-year period, we have learned about two distinct pathways and have developed agents with clinical activity in a large number of patients.” In an editorial accompanying the New England Journal of Medicine publications, Antoni Ribas, MD, PhD, of the University of California, Los Angeles, suggested that PD-1 inhibitors may have fewer side effects and “even greater activity” than CTLA4 inhibitors.1 He said the newer agents have “broken the ceiling” of durable tumor response rates, are likely “to provide a new benchmark for antitumor activity in immunotherapy,” and Target PD-1

PD-L1

Antibody

James Allison, PhD

“may well have a major effect on cancer treatment.”

■

Disclosure: Dr. Giaccone reported no potential conflicts of interest. Dr. Allison reported that he is the inventor of intellectual property held by the University of California, Berkeley, licensed to Bristol-Myers Squibb and Pfizer, and he receives royalties from BristolMyers Squibb. Dr. Ribas has served on ad hoc advisory boards for Bristol-Myers Squibb and Merck.

Reference 1. Ribas A: Tumor immunotherapy directed at PD-1. N Engl J Med. June 2, 2012 (early release online).

Molecule

Company

Development stage

BMS-936558/ MDX-1106/ ONO-4538

Fully human IgG4 mAb

Bristol-Myers Squibb

Phase II multiple tumors

CT-011

Humanized IgG1 mAb

CureTech

Phase II multiple tumors

MK-3475

Humanized IgG4 mAb

Merck

Phase I

AMP-224

B7-DC/IgG1 fusion protein

Amplimmune

Phase I

MDX-1105/ BMS-936559

Fully human IgG4 mAb

Bristol-Myers Squibb

Phase I

Table 1: Clinical Development of Inhibitors of PD-1 Immune Checkpoint. Courtesy of Giuseppe Giaccone, MD, PhD.

The ASCO Post | JULY 1, 2012

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2012 ASCO Annual Meeting PD-1 Immune Checkpoint Inhibitors continued from page 7

or castration-resistant prostate cancer, she reported. The drug was generally well tolerated, and many side effects were immune-related. However, three treatment-related deaths occurred on study due to pneumonitis (among nine patients [3%] who developed pneumonitis). “But we have since developed better ways to identify patients at risk for this toxicity, so we can detect it early and treat it aggressively,” she said. Only 5% of patients discontinued treatment due to side effects. A subanalysis of the data hinted that the PD-L1 protein might serve as a biomarker of response. More than one-third of patients expressing PD-L1 responded to immunotherapy, whereas responses were not observed among patients lacking PD-L1 expression.

Squamous and Nonsquamous Tumors Responded Among 76 evaluable NSCLC patients, 14 (18%) responded to the drug and 5 (7%) achieved stable dis-

Bendamustine for NHL continued from page 3

lymphoma may need a longer observation period.” Subjects were also allowed to cross over upon disease progression. More patients received salvage treatment with bendamustine/rituximab than with R-CHOP, and more received transplants after R-CHOP. “Imbalances in salvage therapy may influence survival,” he suggested.

High Tolerability Observed As predicted for the simpler regimen, bendamustine/rituximab was associated with less toxicity. Only skin rash was more frequent with bendamustine/rituximab, mainly erythema and allergic reaction (all grades, 31% vs 15%), which were not

ease for ≥ 24 weeks. The progressionfree survival rate at 6 months was 26%. The drug was active against both squamous and nonsquamous histologies. Duration of response at the time of analysis ranged from 2 to more than 31 months. “Lung cancer is viewed as not being responsive to immune therapy, so we were surprised by the findings of activity in this tumor,” she said. “It’s the first time we have seen this rate of response in both squamous and nonsquamous subtypes. That makes us think that we don’t know the full spectrum of activity of this drug. In the future, we will be testing it in additional tumor types.”

Anti–PD-L1 Antibody Active as Well Activity was also observed for the anti-PD-L1 drug BMS-936559.2,4 The study included 207 patients with solid tumors, of whom 160 were evaluable for response. In this population, responses were observed in 17% with melanoma, 12% with renal cell cancer, 10% with NSCLC, and 6% with ovarian cancer. Responses lasted for 1 year or longer in 8 of 16

Bristol-Myers Squibb; her spouse is a consultant for Amplimmune. Dr. Tykodi has received research funding from Bristol-Myers Squibb.

Scott S. Tykodi, MD

patients with at least 1 year of followup, reported Scott S. Tykodi, MD, of the University of Washington and Fred Hutchinson Cancer Research Center. The Merck anti–PD-1 antibody, MK-3475, also showed activity in a small phase I study in which 3 of 17 patients responded, and the drug was well tolerated.5 Phase II trials involving immunologic and molecular marker correlates of PD-1 treatment are underway, and phase III studies of anti–PD-1 antibody in NSCLC, melanoma, and renal cell cancer are being planned.

■

Disclosure: Dr. Topalian serves as an uncompensated consultant for Bristol-Myers Squibb and receives research funding from

plications, neuropathy, and need for growth factors were also significantly less frequent with bendamustine/ rituximab. Second malignancies were observed in 20 patients on bendamustine/rituximab and 23 on R-CHOP, and transformation to aggressive disease occurred in about 2% of the total group.

Bendamustine for Non-Hodgkin Lymphoma ■■ For indolent non-Hodgkin lymphoma, front-line treatment with

bendamustine plus rituximab doubled the progression-free survival over standard R-CHOP therapy.

■■ Median progression-free survival was 69.5 vs 31.2 months (HR = 0.58; P = .0000148), but overall survival was not significantly different.

■■ Bendamustine/rituximab was better tolerated that R-CHOP. ■■ The data reported in the StiL NHL1 study establish bendamustine/

rituximab as a front-line option for indolent B-cell and selected mantle cell lymphomas.

■■ Experts cautioned that it there is no evidence of any survival difference

between R-CHOP and the bendamustine/rituximab regimen and that further evaluation of the study is needed, including publication in a peerreviewed journal where all of the study details may be reviewed.

dose-limiting. Grade 3/4 hematologic toxicity was significantly worse with R-CHOP, including neutropenia (69% vs 29%) and leukocyto-

References 1. Topalian SL, Brahmer JR, Hodi FS, et al: Anti-PD-1 (BMS-936558, MDX1106) in patients with advanced solid tumors: Clinical activity, safety, and a potential biomarker for response. 2012 ASCO Annual Meeting. Abstract CRA2509. Presented June 2, 2012. 2. Tykodi SS, Brahmer JR, Hwu W, et al: PD-1/PD-L1 pathway as a target for cancer immunotherapy: Safety and clinical activity of BMS-936559, an anti-PDL1 antibody, in paitenst with solid tumors. 2012 ASCO Annual Meeting. Abstract 2510. Presented June 2, 2012. 3. Topalian SL, Hodi S, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. June 2, 2012 (early release online). 4. Brahmer JR, Tykodi SS, Chow LQM, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. June 2, 2012 (early release online). 5. Patnaik A, Kang SP, Tolcher AW, et al: Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. 2012 ASCO Annual Meeting. Abstract 2512. Presented June 2, 2012.

penia (72% vs 37%). Alopecia was essentially universal with R-CHOP but completely lacking with bendamustine/rituximab; infectious com-

■

Disclosure: Dr. Rummel disclosed honoraria and research funding from Mundipharma and Roche.

Reference 1. Rummel MR, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment in patients with indolent and mantle cell lymphomas: Updated results from the StiL NHL1 study. 2012 ASCO Annual Meeting. Abstract 3. Presented June 3, 2012.

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PAGE 10

2012 ASCO Annual Meeting Genitourinary Cancer

Continuous Androgen Deprivation Therapy Continues to Be Standard of Care for Newly Diagnosed Metastatic Prostate Cancer By Alice Goodman

ased on a prespecified definition of survival comparability, intermittent androgen deprivation proved to be inferior to continuous androgen deprivation for men with newly diagnosed hormone-sensitive metastatic prostate cancer in the phase III SWOG 9346 intergroup trial. The data were presented at the 2012 ASCO Annual

Meeting Plenary Session,1 where lead author Maha Hussain, MD, of the University of Michigan Comprehensive Cancer Center, Ann Arbor, concluded, “continuous therapy continues to be the standard of care.” Intermittent androgen deprivation therapy is used in the United States as a first-line treatment option for newly

diagnosed metastatic prostate cancer, based on evidence suggesting that it was feasible, with no obvious harm and more tolerable than continuous androgen deprivation. SWOG 9346 suggests that men treated with intermittent androgen therapy could have a shorter survival, and the findings favoring continuous androgen

therapy were more pronounced in a subgroup analysis of men with minimal disease. ASCO See Page 50 dedicated a special session for a postplenary discussion of this abstract (see sidebar below).

SWOG 9346 Conclusions Debated in Special Post-plenary Discussion

ased on the controversial nature of the SWOG 9346 findings, presented at the 2012 Annual Meeting Plenary Session, ASCO intiated a pilot program at the meeting for a “town hall” type of discussion, where attendees could voice their concerns and questions, and where presenter Maha Hussain, MD, University of Michigan Comprehensive Cancer Center, Ann Arbor, and discussant William K. Oh, MD, Mount Sinai School of Medicine, New York, could respond. At the post-plenary discussion, Dr. Hussain recapped the results of the study and acknowledged that the study was not designed to look at extensive vs minimal disease prospectively. “I was surprised at the data. Intermittent androgen deprivation is thought to be most appropriate in patients with less metastatic disease burden, yet our results based on the secondary analysis suggest that intermittent therapy was especially inferior in the minimal disease group of patients. However, based on the primary results of the study, continuous therapy is the continued standard. Patients choosing intermittent therapy should be counseled regarding the data from this trial and the risks vs benefits of treatment,” she noted.

‘Difficult to Interpret’ Dr. Oh said, “These results are difficult to interpret. We want the best for our patients. These data from a large, well-powered, randomized controlled trial are not what we expected. But there is a risk of looking for information in a subset analysis. That guidance would be wrong.” That being said, he called these results “important,” and added, “It is clinically relevant if an option is up to

20% worse [in overall survival]. We want to balance quality of life with the primary objective: to control cancer and keep the men alive. This is the only study with sufficient power to compare these two options in this setting.” Speaking from the audience, Ian F. Tannock, MD, FRCPC, PhD, Princess Margaret Hospital, Toronto, said, “My concern is that the investigators did not show that intermittent androgen deprivation is inferior. The confidence interval clearly includes 1.0, so there is no significant difference in survival between the arms. You did not prove noninferiority, but that is not the same thing as showing inferiority. It is dangerous to conclude that intermittent therapy is inferior. I agree we should discuss this trial with patients, but in my opinion, intermittent therapy remains a valid option for metastatic prostate cancer.”

‘Not One-size-fits-all’ In response, Dr. Hussain said, “The point is that the study was designed to assess if intermittent therapy is noninferior. The data clearly show that intermittent therapy failed to meet the prespecified criteria for noninferiority, which specified that the upper bound of the confidence interval exclude 1.2. This is why we do randomized trials— so that we can use evidence in counseling patients, not our biases. Furthermore, in my presentation, I was very careful to point out that the subgroup analysis is exploratory. Patients need to hear the evidence in total to make their decisions. Prostate cancer therapy is not necessarily ‘one-size-fits-all’.” Another attendee said, “These findings could be consequences of a type 1 or type 2 error. We should not reject a treatment that improves quality of life,

decreases costs, and spares patients from frequent contact with doctors.” Another oncologist in the audience said that using an arbitrary confidence interval to call a treatment inferior does not make clinical sense. “You have to consider the Ian F. Tannock, MD, FRCPC, PhD Lawrence H. Einhorn, MD individual patient. If a pa“With any treatment in any cancer, tient wants extra survival at all costs, there are harms and benefits. You have that is one scenario. But if a patient to ask yourself whether there may be a doesn’t want to increase his frailty minimal benefit with continuous anand suffer the side effects of continudrogen deprivation, but it might be a ous therapy, that is another scenario. The longest survival is not necessarily quality-of-life issue for patients who the best outcome.” will want to go off hormonal therapy Dr. Oh, in his plenary discussion, until the PSA is rising,” Dr. Einhorn had suggested that the amount of time added. that patients spent off of hormone Dr. Oh said the discussion about therapy on the intermittent arm was this study will continue. He acknowlapproximately one-third, and that tesedged that the findings concerning tosterone recovery often takes months. extensive vs minimal disease may or The quality-of-life data presented by may not be real. “The basic issue is Moinpour et al in the poster discuswhether we have enough consensus sion session at this meeting suggested to say a treatment is standard of care,” modest improvements in sexual funche added. “I would submit that this tion, libido, and emotional functionstudy established continuous androing in the intermittent arm.1 gen deprivation as standard of care, and future studies with newer agents, ‘Artificial Designation’ such as abiraterone and MDV3100, Lawrence H. Einhorn, MD, Lance should build on that.” Disclosure: Drs. Tannock and Einhorn Armstrong Foundation Distinguished reported no potential conflicts of interest. Professor of Medicine at Indiana University School of Medicine, IndianapoReference lis, called it a “scare tactic” to say that 1. Moinpour C, Berry DL, Ely B, et patients with minimal risk will have al: Preliminary quality-of-life outcomes decreased survival on intermittent for SWOG-9346: Intermittent androgen therapy. “It would be a mistake to use deprivation in patients with hormonedata from an unplanned subset analysis sensitive metastatic prostate cancer to guide treatment decisions. Minimal(HSM1PC)—phase III. 2012 ASCO risk disease is an artificial designation. It Annual Meeting. Abstract 4571. Presentmakes no biological sense and doesn’t ed June 4, 2012. advance the discussion,” he said.

■

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 Erivedgeâ&#x201E;˘ (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 • 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

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 Objective response rates (ORR) by IRF from ERIVANCE1* laBCC (n=63) ORR (95% CI) Complete response

43% (n=27) (30.5-56.0) 21% (n=13)

mBCC (n=33) 30% (n=10) (15.6-48.2) 0%

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

Median response duration (months) (95% CI)

* Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. For laBCC, complete response was defined as objective response with no residual BCC on sampling biopsy. IRF=Independent Review Facility. CI=confidence interval. laBCC=locally advanced BCC. mBCC=metastatic BCC. NE=not estimable.

Adverse Reactions • The most common adverse reactions (≥10% were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) Please see Brief Summary of Prescribing Information on following page.

References: 1. Erivedge™ (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. 2. Epstein EH. Nat Rev Cancer. 2008; 8:743-754.

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

73858ge_a.indd 3

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. 2 MedDRA = Medical Dictionary for Regulatory Activities. 3 Grading according to NCI-CTCAE v3.0. Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)]. Laboratory Abnormalities: Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). 1

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. 7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)]. In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). 8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). • 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

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ASCOPost.com | JULY 1, 2012

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2012 ASCO Annual Meeting Study Details Between 1995 and 2008, the study enrolled 3,040 men with newly diagnosed metastatic disease and prostate-specific antigen (PSA) levels ≥ 5 ng/mL. Almost two-thirds were white, and 14% were black. All patients received hormone therapy for

survival with intermittent androgen deprivation therapy would be noninferior to continuous androgen therapy if the upper 95% confidence bound for the hazard ratio did not reach or include 1.2. This specification would rule out with high confidence the possibility of a 20% or greater increase in

Intermittent vs Continuous Hormonal Therapy in Metastatic Prostate Cancer ■■ A large international phase III trial failed to show noninferiority of

intermittent androgen deprivation vs continuous androgen deprivation in hormone-sensitive metastatic prostate cancer.

■■ Based on this study, investigators deemed continuous therapy to be the standard of care in this setting.

■■ An exploratory subgroup analysis found that continuous therapy was

associated with a 2-year survival advantage in men with minimal disease, but that intermittent and continuous therapy were basically comparable in men with extensive disease.

■■ Interpretations of these findings were debated at an official postpresentation discussion.

7 months. If PSA level fell to ≤ 4 ng/ mL (the study population was preselected for hormone sensitivity), they were randomized to either intermittent therapy (n = 770)—stopping treatment at that point until a rise in PSA level was observed (an increase to 20 ng/mL, or for those with baseline value < 20 ng/ mL, when PSA returned to baseline) or for symptoms—or continuous therapy (n = 765). Hormone therapy consisted of goserelin (Zoladex) and bicalutamide, which was in use in 1995 when the study was launched. At randomization, patients were stratified according to performance status, extent of disease, and prior exposure to hormone therapy.

the relative risk of death with intermittent androgen therapy, Dr. Hussain explained. The difference between the two treatments resulted in a hazard ratio of 1.09 in favor of continuous therapy, but the upper boundary of the 95% confidence interval was 1.24, so the conclusion was that the two treatments could not be called equivalent. “Because the confidence interval included 1.2, we conclude that survival with intermittent androgen therapy is inferior to continuous androgen therapy,” Dr. Hussain stated. “Survival in both arms was much better than expected; we expected a 3-year median overall survival,” she added.

Subgroup Analysis

Maha Hussain, MD

At a median follow-up of 9.2 years, median overall survival was 5.1 years with intermittent androgen deprivation and 5.8 years with continuous androgen deprivation, an absolute difference of slightly more than 6 months favoring continuous androgen deprivation therapy in the entire study population. The study design specified that

In all examined subgroups, continuous androgen therapy was slightly better than intermittent androgen therapy, with the exception of extensive disease (disease extent was a prespecified protocol stratification), where intermittent androgen therapy achieved comparable survival. In line with the noninferiority endpoint, Dr. Hussain said, “intermittent androgen therapy was not inferior in extensive disease.” In this subgroup analysis, patients with minimal disease had a median overall survival of 5.2 years in the intermittent androgen therapy group vs 7.1 years with continuous androgen therapy, suggesting that the loss of almost 2 years of life in the intermittent

EXPERT POINT OF VIEW

ormal discussant of the SWOG 9346 trial, William K. Oh, MD, Tisch Cancer Institute at the Mount Sinai School of Medicine, New York, said that at least 23 phase II trials have suggested that intermittent androgen deprivation therapy was safe and effective and that this practice has been broadly accepted. “But accepting phase II studies is fraught with risk. Most trials had small numbers of patients, difWilliam K. Oh, MD ferent stages of disease, and different rules for starting and stopping androgen deprivation therapy,” he noted. Several phase III trials have been completed that have suggested that intermittent androgen deprivation therapy was equally effective as continuous therapy, with fewer side effects, but all of these except one have been underpowered to look at a survival endpoint. Only the NCIC PR7 trial in nonmetastatic disease with rising PSA post–radiation therapy demonstrated equivalent survival between continuous and intermittent androgen deprivation therapy.

Questions Raised “The current study was a Herculean effort, taking more than 17 years since activation and including more than 3,000 patients. Cooperative groups undertake studies that no one else will conduct,” Dr. Oh commented. In his view, the study raised several questions. Dr. Oh said definitions of extensive and minimal disease used in the trial “were confusing and nonstandard, and it is not clear whether this distinction is biologically relevant.” “We need to be careful not to overinterpret the minimal and extensive disease results presented by Dr. Hussain. This was not a preplanned analysis,” Dr. Oh said. “I believe these [subgroup analysis] results are counterintuitive and should not be used to drive treatment decisions for patients,” he added.

Other Options He said that continuous androgen deprivation remains the only standard of care for patients with newly diagnosed metastatic prostate cancer, and that patients who request intermittent therapy should be informed about the results of this trial. Some patients might opt for intermittent therapy based on preference for avoiding hormonal side effects. “However, we should all remember that intermittent androgen deprivation remains an option for patients with nonmetastatic prostate cancer and rising PSA,” he stated. New drugs such as abiraterone (Zytiga) and MDV3100 have produced excellent results in castrate-resistant prostate cancer and will be explored earlier in the course of disease, including hormone-sensitive metastatic prostate cancer. “If studies show that these drugs are successful in metastatic hormonesensitive prostate cancer, that will prevent the need for lifelong androgen deprivation therapy,” Dr. Oh said.

■

Disclosure: Dr. Oh has served in a consulting or advisory role for Astellas Pharma, Janssen Biotech, and Medivation, and has received research funding from Millennium.

group could not be ruled out. “Continuous androgen therapy was significantly better in the minimal disease group, with a 23% relative increase in risk of death with intermittent androgen therapy, which was unexpected and quite striking,” Dr. Hussain commented. In the group with extensive disease, median overall survival was 5 years on intermittent androgen therapy vs 4.4 years on continuous androgen therapy.

■

Disclosure: Dr. Hussain has received research funding from Abbott Laboratories, Astellas Pharma, Merck Serono, Millennium, NCCN, Pfizer, and Lilly.

Reference 1. Hussain M, Tangen CM, Higano CS, et al: Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer patients: Results of S9346 (INT-0162), an international phase III trial. 2012 ASCO Annual Meeting. Abstract 4. Presented June 3, 2012.

The ASCO Post | JULY 1, 2012

PAGE 12

Issues in Oncology

New PSA Recommendations continued from page 1

unless important data points to an earlier revision. “The reason we updated the 2008 recommendation statement ahead of schedule on PSA screening was because of the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). After we saw the data, we decided it was time to take another look at PSA recommendations.” After examining the PLCO and ERSPC trials and other current literature, the Task Force concluded that although there may be benefits associated with routine screening, they were outweighed by the harms. “We found that most of the men who were treated would have lived just as long and as well without the diagnosis and treatment,” said Dr. LeFevre. Asked about the blanket “regardless of age” clause in the recommendation, Dr. LeFevre responded, “That goes back to the 2008 statement, in which we gave a D rating to screening men aged 75 years and above, recommending against it. The ‘regardless of age’ means that given the latest data, we could not find any age in which the benefits outweighed the harms in PSA screening,” he said. “The Task Force is charged with making recommendations about what preventive services are most likely to benefit the health of Americans, and the scientific evidence we reviewed sends a different message about PSA screening than the widely held belief that PSA-driven early detection of prostate cancer is a lifesaver with insignificant harms,” said Dr. LeFevre.

Decline in Mortality Misleading According to Task Force Chair Virginia A. Moyer, MD, MPH, the argument that the drop in prostate cancer mortality over the past decades is largely due to PSA-driven early detection is misleading. “We actually don’t

Virginia A. Moyer, MD, MPH

have a solid explanation for the decline in mortality. PSA advocates believe that we should be paying attention to the Göteborg study,2 which shows that if there is benefit, it begins to accrue at about 9 years. However, the decline in prostate cancer mortality began around 1993, at the same time the widespread use of PSA began. If the decline were a result of screening, you would expect to see the curve drop around 2003, but it occurred in 1993. While there may be some benefit in PSA tests, the numbers don’t bear out the theory supporting screening for the decline in mortality,” said Dr. Moyer. “The bottom line is that science tells us that at most, there is a very small benefit and a significant harm associated with routine PSA screening. Frankly, mass screening is a disaster for the U.S. health-care system, and thoughtless screening in the office is not much better,” said Dr. Moyer. She emphasized that screening should never be initiated without a thoughtful conversation that explains the po-

Anthony V. D’Amico, MD, PhD

tential benefits and harms. “Before a man goes ahead with PSA screening, he needs to be fully aware of what he’s getting into, and currently that is not how it’s being done.”

Uneven Evidence For Recommendation According to Anthony V. D’Amico, MD, PhD, Chief, Genitourinary Radiation Oncology, Brigham And Women’s Hospital, the Task Force’s analyses misread the reality of the disease. “Using the European study, the Task Force found that the absolute benefit (not a hazard ratio) of PSA screening saves only 1 life out of 1,000. That is not the statistic we should use, because screening for prostate cancer with PSA can show a signal of benefit within the first decade, but if you’re screening men in their 40s and 50s who have a life expectancy of 30 to 40 years, the benefits will be multiplied over several decades. So, to perform a risk-vs-reward analysis at a 10-year or 13-year time point

is really more of a cost-minded way of looking at the data, not a clinician’s,” said Dr. D’Amico. Dr. D’Amico continued, “The Task Force has acknowledged that PSA works, but they’re saying that the benefit isn’t large enough to justify the costs to the health-care system, along with the potential toxicities in men who undergo unnecessary screeninginduced treatments.” Commenting further on unnecessary treatment-associated toxicities, Dr. D’Amico said, “The side effects of prostate cancer treatments, such as erectile dysfunction and incontinence, can be clinically managed, but once a man dies we cannot bring him back to life, nor should we discount the suffering he and his family sustain along the road to death. More thought is needed when weighing potential toxicities against potential death.” Dr. D’Amico stressed that prostate cancers can have a protracted course, and the Task Force’s recommendation is based on studies with follow-up that is too short to make definitive statements about PSA screening benefits during a 40-, 50-, or 60-year-old man’s lifetime. In addition, longer follow-up is needed to assess overdiagnosis-associated toxicities, he asserted. “The PIVOT study of radical prostatectomy vs active surveillance has followed men for about a decade, the same as the screening studies, which is not long enough to ensure that a healthy man diagnosed and treated in his 40s, 50s, or 60s is going to escape metastasis and death from prostate cancer. Moreover, given the known sampling error associated with prostate biopsy, there is no proof that very low-risk prostate cancer has no meaningful risk for metastatic potential,” commented Dr. D’Amico. The Task Force acknowledged that the European study showed a 21% reduction in death and that the U.S. study had significant flaws, notably a high contamination rate (ie, 85%), he added. Addressing the potential impact on access, Dr. D’Amico said, “If Medicare adopts the Task Force’s recommendation and stops reimbursing for a screening PSA, large private insurers might follow, creating a health-care disparity problem among financially challenged populations and, in particular, men known to be at high risk for aggressive and life-threatening prostate cancer— namely, men of African American, Latino, or Hispanic heritage. This is an important issue, with huge downstream

Judd W. Moul, MD, FACS

consequences that need to be identified and addressed,” said Dr. D’Amico.

Stratifying Risk Judd W. Moul, MD, FACS, Director of the Duke Prostate Center, voiced concern that the Task Force’s blanket recommendation against PSA testing limits clinical flexibility in a disease with multiple biologic behaviors. “I think the new American Urological Association (AUA) guidelines that, for example, recommend a risk-stratified PSA test at age 40, make sense, because there’s evidence that baseline PSA measurements in certain age groups can predict aggressive prostate cancers, metastases, and disease-specific mortality years down the road. Over the past few years, we’ve learned how to better use PSA as a risk-assessment tool, which the Task Force didn’t consider. So, I’m concerned that this policy might harm at-risk groups of men.” Dr. Moul pointed to emerging nuances in the use of PSA testing that escaped the Task Force. “If a 40-year-old man has a baseline PSA of less than 1 ng/mL, that dictates a low future risk of prostate cancer, he can probably go on 5-year testing intervals. On the other hand, a 40-year-old with a PSA greater than 1.5–2.5 ng/mL should be followed more closely. Data from two randomized trials paint too narrow a picture of the value of PSA, especially in risk assessment,” said Dr. Moul. Experts agree that men with low-volume, low-risk disease have been aggressively overtreated, but Dr. Moul warned against unintended consequences of the recommendation. “President Obama had a screening PSA test as part of his annual physical at Walter Reed earlier in 2012. Presumably, he was counseled on the pros and cons of testing and chose to be tested. Wouldn’t it be a shame if that choice was now taken away from other American men,” said Dr. Moul. He added that using PSA as a risk-stratification tool will reduce the amount of overdiagnosis and help detect potentially aggressive cancers. continued on page 17

To confront a

Common Threat in the 2 leading causes of cancer death1...

Indications Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Think Avastin Percentage Surviving

First-line metastatic non-squamous NSCLC: 19% increase in median OS in combination with PC (Study E4599)2

100

1-year survival: 51% vs 44%2

2-year survival: 23% vs 15%2

60 40

Avastin + PC (n=434) PC alone (n=444)

20 0

OS (Months)

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; HR=hazard ratio; CI=confidence interval.

Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68–0.94], P=0.013)2 Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%)3

Boxed WARNINGS Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention

Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.4%) — Proteinuria including nephrotic syndrome (<1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Because overall survival matters Proven to extend overall survival (OS) in the 2 cancers with the highest mortalities1 First-line MCRC in combination with IV 5-FU–based chemotherapy: 30% increase in median OS in combination with IFL (Study 2107)2,4,5

Percentage Surviving

100

First-line median OS: 20.3 vs 15.6 months (HR=0.66 [95% CI, 0.54–0.81], P<0.001)

80 60 40 20

Avastin + IFL (n=402) Placebo + IFL (n=411)

0 6

18 12 OS (Months)

MCRC=metastatic colorectal cancer; IV=intravenous; 5-FU=5-fluorouracil; IFL=5-FU/leucovorin (LV)/irinotecan.

OS in second-line MCRC Study E3200: Median OS of 13.0 months with Avastin plus 5-FU/LV/oxaliplatin (FOLFOX4) vs 10.8 months with FOLFOX4 alone (HR=0.75 [95% CI, 0.63–0.89], P=0.001)2,6

Most common adverse events Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. References: 1. American Cancer Society. Cancer Facts and Figures 2010. http://www. cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. Accessed April 21, 2011. 2. Avastin Prescribing Information. Genentech, Inc. September 2011. 3. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550. 4. Data on file. Genentech, Inc. 5. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 6. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544.

www.avastin.com

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age

AVASTIN® (bevacizumab)

greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 3795 patients with CRC, non‑squamous NSCLC, MBC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] Data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, an indication for which Avastin is not approved. The population was aged 18‑88 years (median 59), 43.2% male and 85.3% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 5, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

AVASTIN® (bevacizumab) Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).] Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 5, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%. Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 7). [See Warnings and Precautions (5.8).] Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer MBC, an indication for which Avastin is not approved, the incidence of Grade 3–4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test)was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84 or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

Arm 1 IFL ++ Placebo (n = 396) 74%

Arm 2 IFL ++ Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence ( ≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥ 2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 5 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 7. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 7 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

55% 55% 19%

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 );

ASCOPost.com | JULY 1, 2012 AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected. 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 Avastin with the incidence of antibodies to other products may be misleading.

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Middle Ground Needed “The major urological associations argue that PSA plays a valuable role in early detection. However, other factions contend that mass screening does not provide adequate results

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

E. David Crawford, MD

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

New PSA Recommendations “Prostate cancer is viewed as a disease of older men, many of whom might die of other causes. However, when you factor in the human and financial costs of metastatic disease, it would be best not to return to a prePSA era,” said Dr. Moul.

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/ carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/ carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 7, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

Issues in Oncology

continued from page 12

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis,Anastomotic ulceration Hemic and lymphatic: Pancytopenia Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

PAGE 17

based on the number of tests needed to detect one cancer. Both opinions have valid points. What we need is to find common ground,” said E. David Crawford, MD, who presented a study at the recent AUA Annual Meeting on the potential implications of the USPSTF recommendations against PSA screening. Using the PLCO Cancer Screening Trial, Dr. Crawford and associates estimated the clinical and economic effects of increasing the current 1-year PSA screening interval by 1 to 4 years. They found significant financial savings, particularly for the 5-year screening interval, with an estimated national savings of $3.9�� billion. However, when factoring in the amount of missed prostate cancers, the investigators concluded that a “no screening” policy would be a bad investment on the societal level. “The ultimate goal is to detect and treat only those prostate cancers that will kill men. I began my career in an era when most men walked into the clinic with advanced disease. We simply don’t see that today and I think the Task Force is missing the precise economic impact of treating advanced prostate cancer. We should continue to screen, but in a rational manner that uses PSA to separate out high-risk from low-risk patients, and we should screen at appropriate intervals.” Dr. Crawford made it clear that policymakers should consider both the

risks and benefits of the USPTF recommendations on prostate cancer screening. “Hopefully, this study will help find common ground to employ PSA in a cost-effective and thoughtful manner that saves lives. The USPSTF findings should be used as an opportunity to begin that process,” said Dr. Crawford.

Recommendation Reconsidered After reviewing data from several randomized clinical trials, the Task Force concluded that PSA screening benefits do not outweigh the harms. Further, they resolved that mass PSA screening is deleterious to our healthcare system and should therefore be discouraged. Nevertheless, the Task Force’s recommendation begs the question: What are the societal consequences of a sea change in the detection and diagnosis of a disease with an estimated 240,000 new cases per year? Dr. D’Amico countered that prostate cancers can have a protracted course and the follow-up studies that the Task Force used for its risk-to-reward analysis were too short; he also pointed out flaws in the studies. Dr. Moul added that the data analyzed by the Task Force missed the nuanced potential of PSA, such as a risk-assessment and stratification, warning about unintended consequences of a onesize-fits-all approach to screening. Dr. Crawford concluded that a “no screening” policy would markedly decrease prostate cancer health expenditures but would be a bad investment at the societal level. He advised a more rational policy, screening appropriate men and treating only those with significant cancers, adding that the USPSTF findings should be viewed as an opportunity to help resolve the important debate over PSA screening for prostate cancer.

■

Disclosure: Drs. LeFevre, Moyer, D’Amico, and Moul reported no potential conflicts of interest. Dr. Crawford is an advisor for Felling (also an employee), Janssen, Dendreon, Bayer, and Amgen; and an investigator for Precision Biopsy.

References 1. U.S. Preventive Services Task Force: Screening for prostate cancer: Current recommendation. Available at www.uspreventiveservicestaskforce.org/prostatecancerscreening.htm. Accessed June 7, 2012. 2. Hugosson J, Carlsson S, Aus G, et al: Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 11:725732, 2010.

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2012 ASCO Annual Meeting Neuro-oncology

New Standard of Care for Anaplastic Oligodendroglial Tumors with 1p/19q Codeletions By Alice Goodman

djuvant chemotherapy with PCV (procarbazine [Matulane], lomustine [CeeNU], and vincristine) following standard radiation therapy delayed disease progression and increased survival in patients with a relatively rare type of brain tumor called anaplastic oligodendroglioma. A subgroup analysis found that the benefit of the addition of chemotherapy was largely driven by tumors with 1p/19q codeletion. Results of this randomized phase III EORTC 26951 trial, which took 17 years to complete, were reported at the Plenary Session during the 2012 ASCO AnSee Page 50 nual Meeting.1

Long-term Follow-up Although a survival difference was not observed in 2006 when results were first reported, long-term follow-up showed median overall survival of 42

months in the PCV-plus-radiotherapy arm vs 31 months in the radiotherapyalone arm, representing an improvement of 11 months in the entire intent-to-treat population. In patients with the 1p/19q codeletion, median overall survival has not yet been reached in the PCV-plusradiotherapy arm and is 112 months in the radiotherapy-alone arm. “Adjuvant PCV improves overall survival in anaplastic oligodendroglial tumors, and 1p/19q codeletion identifies patients with increased benefit after PCV. We saw no statistically significant benefit of PCV in ‘nondeleted’ tumors,” explained lead author Martin J. van den Bent, MD, Erasmus Medical College on Rotterdam, The Netherlands. A second study reported at the Annual Meeting, RTOG 9402,2 confirms these findings, he said. “These studies make adjuvant PCV a new standard of care in 1p/19q codeleted tumors,” Dr. van den Bent told the audience.

Genetics of Anaplastic Oligodendroglial Tumors ■■ Codeletion of 1p/19q represents an important prognostic factor for response to treatment of anaplastic oligodendroglial tumors.

■■ PCV chemotherapy (procarbazine, lomustine, vincristine) plus radiation is

a new standard of care for anaplastic oligodendroglial tumors with 1p/19q codeletions.

■■ Optimal care for non-codeleted tumors in this setting remains to be established.

Study Background Diffuse gliomas are the most common type of primary brain tumor in adults, and the histologic subtype of anaplastic oligodendroglial tumors accounts for about 5% to 10% of malignant brain tumors.

EXPERT POINT OF VIEW

ommending the investigators for their undertaking, Mark Gilbert, MD, of The University of Texas MD Anderson Cancer Center in Houston, said, “Perseverance and analysis of longterm outcomes lead to practice-changing findings and important insights.” He pointed out that two randomized trials conducted by cooperative groups reported at ASCO 2012 confirmed the benefit of PCV added to radiotherapy in codeleted anaplastic oligodendroglial Mark Gilbert, MD tumors: EORTC 26951 and RTOG 9402. “However, it took many years of follow-up for these differences in survival in patients with codeleted tumors to emerge. There is no significant survival difference in the non-codeleted group,” Dr. Gilbert said. “Now we have an upfront combination of radiotherapy and PCV chemotherapy that improves survival in codeleted patients, but not in non-codeleted patients. We have reached this conclusion only after an extensive time period and considerable efforts to collect tissue and follow-up. Radiotherapy alone is no longer adequate for patients harboring this codeletion. Front-line treatment for codeleted patients should be radiotherapy and PCV,” he stated.

Optimal Treatment The optimal treatment paradigm remains to be established. “Should it be sequential therapy with radiotherapy or chemotherapy first? Should the chemotherapy arm be temozolomide? These are remaining questions,” he told listeners. Dr. Gilbert cautioned that both studies are retrospective analyses of the codeletions, which were not included in the original study designs. “Despite these caveats, the two cooperative group studies mirror each other and validate the importance of chemotherapy for treatment of codeleted anaplastic oligodendroglioma. We can no longer use histology to decide on treatment for these tumors. Radiation alone is not a valid option for codeleted tumors. Codeletion and non-codeletion are two biologically separate diseases,” he stated.

■

Martin J. van den Bent, MD

Prior to this study, optimal treatment was extensive resection followed by radiation therapy (2001). The trial was initiated in 1995, after PCV was found to have good activity in these tumors. During the accrual phase, the protocol was amended without a proven role for adjuvant chemotherapy, to explore the correlation between 1p/19q deletions and response, after these deletions were found to be associated with chemosensitivity. From 1995 to 2002, 368 patients were randomly assigned to radiotherapy followed by six cycles of adjuvant PCV or to radiotherapy alone. Patients in the radiotherapy-alone arm could be treated with PCV at disease progression. Three-quarters of the patients in the radiotherapy-alone arm received PCV, so the study really compared early vs delayed chemotherapy after radiation, Dr. van den Bent explained. The treatment arms were well balanced for prognostic factors. When results were reported in 2006, adjuvant PCV was shown to increase progression-free survival but not overall survival. The survival benefit did not emerge until about 5 years

later. Median follow-up is now about 12 years, he said, noting that disease progressed in about 80% of patients enrolled in the trial, and about 25% are still alive.

Risk-adjusted Analysis A risk-adjusted analysis of survival showed that assignment to treatment remained an independent factor, reducing the risk of death by 24% in those treated with PCV plus radiotherapy. A total of 80 patients (25%) had 1p/19q deletions. In these patients with codeletions, progression-free survival increased from 50 months in the radiotherapy-alone arm to 157 months; for patients with the codeletions, median overall survival has not yet been reached in the PCVcontaining arm but was 112 months in the radiotherapy arm. There was no significant advantage to adjuvant chemotherapy in non-codeleted patients. PCV was used as chemotherapy when the trial was first initiated in 1995, but temozolomide may turn out to be a better option for treatment of non-codeleted anaplastic oligodendrogliomas, Dr. van den Bent suggested. This requires further study, he added.

■

Disclosure: Dr. van den Bent is a consultant for MSD.

References 1. Van Den Bent M, Hoang-Xuan K, Brandes AA, et al: Long-term follow-up results of EORTC 26951: A randomized phase III study on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors (AOD). 2012 ASCO Annual Meeting. Abstract 2. Presented June 3, 2012. 2. Cairncross JG, Wang M, Shaw EG, et al: Chemotherapy plus radiotherapy versus RT alone for patients with anaplastic oligodendroglioma: Long-term results of the RTOG 9402 phase III study. 2012 ASCO Annual Meeting. Abstract 2008b. Presented June 3, 2012.

ASCOPost.com | JULY 1, 2012

PAGE 19

2012 ASCO Annual Meeting Gynecologic Oncology

Bevacizumab and Olaparib Boost Progression-free Survival in Ovarian Cancer By Alice Goodman

trio of randomized, controlled trials of different molecularly targeted therapies showed variable results in ovarian cancer, as reported at the 2012 ASCO Annual Meeting in Chicago. The phase III AURELIA trial demonstrated that the addition of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Avastin) to chemotherapy achieved a doubling of progressionfree survival in patients with difficult-totreat platinum-resistant ovarian cancer. This is the first randomized trial to show a progression-free survival benefit in platinum-resistant patients. A second trial, investigating the poly (ADPribose) polymerase (PARP) inhibitor olaparib plus paclitaxel See Page 50 and carboplatin chemotherapy followed by olaparib maintenance therapy, showed a significant 2.6-month improvement in progression-free survival vs chemotherapy alone in platinum-sensitive ovarian cancer. A third trial, studying the endothelial growth factor receptor (EGFR) inhibitor erlotinib (Tarceva), showed no benefit in progression-free survival in the first-line setting when given as maintenance therapy immediately following six to nine courses of platinum-containing chemotherapy in high-risk patients.

an of 3.4 months to 6.7 months (P < .001). This is the best progression-free survival observed in this group of patients thus far, and the benefit was seen in all subgroups . “These are exciting results,” said Eric

personal opinion is that … bevacizumab plus chemotherapy should be considered a new standard of care for these patients.” Platinum-resistant ovarian cancer repcontinued on page 20

Cabozantinib (XL184) phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases CabOzantinib MET Inhibition CRPC Efficacy Trials KEY ELIGIBILITY CRITERIA •Diagnosis of CRPC •Presence of bone metastases •Prior treatment with docetaxel • Prior treatment with abiraterone and/or MDV3100 (enzalutamide) •No limit to the number of prior therapies

Shifting Focus Advocated The presenters of the AURELIA and olaparib trials were enthusiastic about improved progression-free survival in their respective studies of platinumresistant and platinum-sensitive disease. However, the formal discussant of these trials, Michael Seiden, MD, of Fox Chase Cancer Center, Philadelphia, suggested that the strategy of pursuing molecularly targeted therapy for ovarian cancer may be misguided and is likely not to improve overall survival. To move the field forward, Dr. Seiden suggested that research efforts should focus on genomic instability in ovarian cancer and therapies that target oncogenes (see sidebar).

Pujade-Lauraine, MD, PhD, of Groupe B:8.625” D’Investigateurs Nationaux T:7.625” Pour l’Etude des Cancer Ovariens S:6.75” (GINECO) and the Université Paris Descartes, France. “Next year, we will report survival results. My

COMET-1

COMET-2

PRIMARY ENDPOINT

Overall Survival

Confirmed Pain Response CRPC (N=246)

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

Cabozantinib (60 mg qd) Randomization Prednisone

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

Cabozantinib (60 mg qd) Randomization Mitoxantrone + Prednisone

Bevacizumab The randomized, phase III AURELIA trial found that treatment with standard chemotherapy plus bevacizumab doubled progression-free survival over standard chemotherapy alone in patients with platinum-resistant ovarian cancer from a medi-

Randomized, double-blind, controlled trial

The ASCO Post | JULY 1, 2012

PAGE 20

2012 ASCO Annual Meeting Bevacizumab and Olaparib continued from page 19

resents an unmet need. About 25% of patients will not respond to first-line therapy, and almost all patients with recurrent ovarian cancer will ultimately develop resistance. Previous combinations have failed to improve survival, and prior to this study, median overall survival was less than 1 year.

Eric Pujade-Lauraine, MD, PhD

Patients enrolled in the trial could have up to to two prior lines of treatment. Chemotherapy was selected by the investigator and included weekly paclitaxel, topotecan, or pegylated doxorubicin. Patients were randomized to chemotherapy plus bevacizumab (n = 179) vs chemotherapy alone (n = 182). Those whose disease progressed on chemotherapy alone could cross over to the bevacizumab-containing arm. Median follow-up was 13 months in the bevacizumab arm and 13.9 months in the chemotherapy arm. Bevacizumab was tolerable, with no unexpected side effects, and did not appear to potentiate the toxicity of chemotherapy, Dr. Pujade-Lauraine said. In the bevacizumab arm, a trend was observed toward a decrease in diseaserelated adverse events, but the incidence of grade 3 or higher peripheral neuropathy was greater. Dr. Pujade-Lauraine attributed this to higher exposure to chemotherapy in that arm, because more patients were responding and thus continued to be treated, whereas more progression occurred in the chemotherapy-alone arm, and those patients were taken off treatment.

Olaparib An

international,

randomized

phase�� II trial found that olaparib maintenance therapy after four to six cycles of olaparib plus concurrent paclitaxel and carboplatin chemotherapy significantly increased progression-free survival by a median of 2.6 months vs no further therapy in patients with recurrent platinumsensitive serous ovarian cancer (P = .0012). All subgroups appeared to benefit from olaparib maintenance therapy. “The study is still being followed for survival data, and we have an active biomarker program,” said lead author Amit Oza, MD, of Princess Margaret Hospital, Toronto. The study enrolled 152 women who had received up to 3 previous platinum-containing regimens. At baseline, groups were well balanced for demographic and disease characteristics. Progression-free survival curves began to diverge at 6 months. No separation of curves was seen during the concurrent portion of treatment. The concurrent-plus-maintenance olaparib regimen was well tolerated and deliverable, Dr. Oza said. In the maintenance phase, grade 3 or higher adverse events were reported in 28.8% of the olaparib group vs 16.4% of those with no further therapy. The next steps will be to determine the optimal patient population for olaparib maintenance therapy and to define an acceptable tablet dose and schedule for long-term treatment to enable the next generation of clinical studies.

Erlotinib The erlotinib trial recruited 835 patients with high-risk stage I or stage II–IV ovarian cancer who began treatment with erlotinib or observation after first-line platinumcontaining therapy. Median follow-up was 51 months. At baseline, the two groups had similar demographic and disease characteristics. Median progression-free survival was 12.7 months in the erlotinib group vs 12.4 months in the observation arm. Overall survival was a median of 51 vs 59 months, respectively. No difference in outcome was observed for stage and response to first-

Targeted Therapy in Ovarian Cancer ■■ Bevacizumab added to chemotherapy doubled progression-free survival in platinum-resistant ovarian cancer.

■■ Olaparib maintenance therapy after concurrent olaparib, paclitaxel, and

carboplatin extended progression-free survival by 2.6 months in platinumsensitive patients with ovarian cancer. Further study is needed to identify patients who will benefit from this drug.

■■ Erlotinib failed to extend progression-free survival when used as

maintenance therapy in patients with ovarian cancer who responded to first-line chemotherapy.

EXPERT POINT OF VIEW

“W

e are approaching the 15th year of exploring molecularly targeted therapies in ovarian cancer,” said Michael Seiden, MD, of Fox Chase Cancer Center, Philadelphia, and formal discussant of the papers presented during an oral abstract session on gynecologic cancer at the 2012 ASCO Annual Meeting. He said that there have been some successes with molecularly targeted therapy, most notably targeting chronic myelogenous leukemia with imatinib (Gleevec). But he doubted that this approach Michael Seiden, MD would improve survival in serous ovarian cancer, a disease with tremendous genomic instability. Both the olaparib trial in platinum-sensitive patients and the bevacizumab (Avastin) trial in platinum-resistant patients showed improved progression-free survival. The bevacizumab trial was hailed as the first randomized trial to show improved progression-free survival in platinum-resistant patients. Yet Dr. Seiden believes both trials will ultimately fail to improve survival.

Activation of Many Factors By way of explanation, he said, “Cancer is a concert of activation of many factors, including amplifications, translocations, and mutations. Therapeutic ‘home runs’ have all been associated with targeting activated oncogenes, such as HER2/ neu in breast cancer, ALK in lung cancer, and BRAF in melanoma. Targeting pathways that are activated secondary to the loss of tumor-suppressor genes have been dramatically less effective,” he stated. “In order to make inroads in improving survival in serous ovarian cancer, we will need to change the natural history of the disease. This cancer has had extreme genomic disruption—an unparalleled amount of deletions in chromosomes that look dramatically different from other cancers. In addition to genomic instability, there are somatic mutations within a gene,” Dr. Seiden continued. He believes that conventional phase III trials are not the answer and that new trial designs are needed that will incorporate genomic data to address the genomic complexity of this disease. Also, a powerful predictive biomarker will be needed. “We don’t even have a moderately good biomarker in ovarian cancer,” he stated. He suggested that it might be reasonable to stop all ovarian cancer trials of molecularly targeted agents. Perhaps there are small or medium-sized groups of genomically similar patients who could be studied, but this would take “deep” genomic sequencing of about 10,000 patients. The cost of genomic sequencing is going down, and it might be reasonable that trials of molecularly targeted agents be required to submit the full genome for all patients in clinical trials, he said. Disclosure: Dr. Seiden reported no potential conflicts of interest.

line therapy. Quality-of-life data will be analyzed, as will potential biomarkers using fluorescence in situ hybridization and immunohistochemistry. Toxicity associated with erlotinib was expected, mainly grade 1 or 2 diarrhea and grade 1–3 rash. About 25% of patients stopped erlotinib due to rash. No relationship between the emergence of rash and progression-free survival was observed. “Maintenance erlotinib did not increase progression-free or overall survival,” stated presenting author Ignace B. Vergote, MD, of University Hospital Leuven and KU Leuven, Belgium. “At this moment, we cannot identify a subgroup of patients that might benefit from maintenance erlotinib.”

■

Disclosure: Dr. Pujade-Lauraine disclosed advisory board and symposia honoraria from

■

Roche. Drs. Oza and Vergote reported no potential conflicts of interest.

References 1. Pujade-Lauraine E, Hilpert F, Weber B, et al: AURELIA: A randomized phase III trial evaluating bevacizumab plus chemotherapy for platinum-resistant recurrent ovarian cancer. 2012 ASCO Annual Meeting. Abstract LBA5002. Presented June 2, 2012. 2. Oza AM, Cibula D, Oaknin A, et al: Olaparib plus paclitaxel plus carboplatin followed by olaparib maintenance treatment in patients with platinum-sensitive recurrent serious ovarian cancer. 2012 ASCO Annual Meeting. Abstract 5001. Presented June 2, 2012. 3. Vergote IB, Joly F, Katsaros D, et al: Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based therapy for ovarian carcinoma. 2012 ASCO Annual Meeting. Abstract LBA5000. Presented June 2, 2012.

Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

The first and only personalized treatment for unresectable or metastatic melanoma with the BRAFV600E mutation1,2

DECODE

metastatic melanoma

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) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF. The incidence of cuSCC in ZELBORAF-treated patients in the Phase III study was 24%. The median time to first appearance of cuSCC was 7 to 8 weeks. Potential risk factors included age ≥65 years, prior skin cancer, and chronic sun exposure. All patients should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months following discontinuation of ZELBORAF. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe reactions may include generalized rash and erythema or hypotension. Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including 1 case of Stevens-Johnson syndrome and 1 case of toxic epidermal necrolysis in the Phase III study. ZELBORAF treatment should be permanently discontinued in patients who experience a severe hypersensitivity or dermatologic reaction. QT prolongation Exposure-dependent QT prolongation has been observed in patients treated with ZELBORAF, 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. ECG and electrolytes should be monitored before initiating treatment with ZELBORAF and after dose modification and routinely during treatment (15 days after treatment initiation, then monthly for first 3 months of treatment and every 3 months thereafter or as clinically indicated). If the QTc exceeds 500 ms, ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) controlled. Re-initiation of treatment should occur 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 with ZELBORAF. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Lab abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials. While taking ZELBORAF, all patients should be advised to avoid sun exposure and, when outdoors, to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30). For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions In the Phase III study, 5 cases of uveitis were reported in patients treated with ZELBORAF.

EXTEND

survival

56% reduction in risk of death from any cause with ZELBORAF (95% CI, 0.33-0.59)

P<0.0001

OS=overall survival HR=hazard ratio CI=confidence interval * Median follow-up was 6.2 months (95% CI, 0.4-13.9 mo) for ZELBORAF patients vs 4.5 months (95% CI, <0.1-11.7 mo) for those taking dacarbazine. † There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of analysis.

~4-month improvement in median progression-free survival (5.3 vs 1.6 months; HR=0.26, P<0.0001, 95% CI, 4.9-6.6 months vs 1.6-1.7 months) Significant improvement in best overall response rate (48.4% vs 5.5%; P<0.001, 95% CI, 41.6%-55.2% vs 2.8%-9.3%)3 There were 2 complete responses (1%) and 104 partial responses (PRs) (47.4%) with ZELBORAF vs 12 PRs (5.5%) with dacarbazine

0.294 inrash, alopecia, fatigue, photosensitivity The most common adverse reactions of any grade (≥30%) reported were arthralgia, reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash

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, 5 cases each of blurry vision and iritis and 6 cases of photophobia were reported in the Phase III study. One case of retinal vein occlusion was reported in the Phase II study. New Primary Malignant Melanoma Eight skin lesions in 7 patients were reported as new primary malignant melanoma in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitoring for skin lesions should occur as outlined above [see cuSCC]. 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 ZELBORAF is used during pregnancy or if the patient becomes pregnant while taking ZELBORAF, the patient should be apprised of the potential hazard to a fetus. BRAF Testing Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for the selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common adverse reactions of any grade (≥30%) 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 Brief Summary of Prescribing Information on the following page. References: 1. Smalley KS, Sondak VK. Melanoma—an unlikely poster child for personalized cancer therapy. N Engl J Med. 2010;363:876-878. 2. Flaherty KT. Next generation therapies change the landscape in melanoma. F1000 Med Reports. http://f1000.com/reports/m/3/8. Published April 1, 2011. Accessed July 14, 2011. 3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.

zelboraf.com

The ASCO Post | JULY 1, 2012

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2012 ASCO Annual Meeting Breast Cancer

Older Breast Cancer Drugs Prove Superior to Newer Ones By Caroline Helwick

n the treatment of metastatic breast cancer, established older agents outperformed newer, more expensive drugs in two studies that made news at the 2012 ASCO Annual Meeting.

In the phase III open-label CALBG 40502/NCCTG N063H trial of 799 chemotherapy-naive patients with Safety:7" metastatic breast cancer, standard treat-

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.

ment with weekly paclitaxel proved superior to nab-paclitaxel (Abraxane) and ixabepilone (Ixempra).1 Weekly ixabepilone was significantly less effective than paclitaxel, and nab-paclitaxel was no

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

Hope Rugo, MD

better than standard paclitaxel. Overall tolerability was also best with paclitaxel, reported lead investigator Hope Rugo, MD, of the University of California School of Medicine, San Francisco. The study aimed to determine if these newer microtubule inhibitors given on a weekly schedule would result in similar or superior effectiveness, and be less toxic, than standard weekly paclitaxel. One objective, she added, was to validate previous phase II results showing nab-paclitaxel at 150 mg/m2 weekly was the optimal dose.2 The regimens were paclitaxel at 90 mg/m2, nab-paclitaxel at 150 mg/m2, and ixabepilone at 16 mg/m2, each given weekly on a 3-weeks-on/1-week-off schedule. Bevacizumab (Avastin) at 10 mg/kg every 2 weeks was also administered to 98% of the patients. At the first interim analysis, the comparison of ixabepilone to weekly paclitaxel crossed the futility See Page 50 boundary for superiority, and the arm closed to accrual. At the second interim analysis, the same occurred with nab-paclitaxel, and the study was closed in November 2011. The investigators concluded that at these doses and schedules, the newer agents offer no advantage, but they do increase toxicity. At a median follow-up of 12 months, median progression-free survival was 10.6 months with weekly paclitaxel, 9.2 months with nab-paclitaxel, and 7.6 months with ixabepilone (nab-paclitaxel vs paclitaxel: HR = 1.19; P = .12; ixabepilone vs paclitaxel: HR = 1.54; P < .0001; see Fig. 1). Overall survival was not significantly different among the arms, with approximately 50% of patients alive at 2 years. “These data suggest that similar patients should be treated with paclitaxel on a weekly schedule,” Dr. Rugo said. Safety:10"

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

Microtubule Inhibitors

ASCOPost.com | JULY 1, 2012

PAGE 25

2012 ASCO Annual Meeting Toxicities and Interpretation Grade 3 or 4 hematologic and nonhematologic toxicities were also lowest with paclitaxel, including peripheral neuropathy (16% vs 25% with either experimental arm). Grade 3 or 4 hematologic toxicities were lowest with ixabepilone and highest for nab-paclitaxel (12% vs 51%), compared to paclitaxel (21%). Dose reductions by cycle 3 were

Proportion progression-free

1.0 0.8

to mandatory steroids and, perhaps, in patients whose disease recurs within a year of receiving paclitaxel, she said. “The study demonstrates,” she said, “that we should not simply assume that newer drugs are always better than the standard therapies.” Correlative studies will help determine if patients with specific tumor subsets will fare better with one regimen vs another one.

Comparison

P value

95% CI

nab vs pac

1.19

.12

0.96–1.49

ixa vs pac

1.53

< .0001

1.24 –1.90

0.6

“O

ur old friends are sometimes worth keeping, and that is certainly true for weekly paclitaxel,” said the invited discussant of CALGB 40502, Kathy Miller, MD, of Indiana University School of Medicine, Indianapolis, at the ASCO Annual Meeting. She noted that Dr. Rugo must “remain strict to the statistical analysis of the study” and cannot state that “the two novel agents were worse” than paclitaxel. But she, as the discussant, could claim “they Kathy Miller, MD were not better, they were more toxic, and they were substantially more expensive,” Dr. Miller said. “With the exception of patients with major issues with steroids, I simply don’t see any reason for [nab-paclitaxel or ixabepilone] to be a preferred choice in the first-line setting.”

CALGB 40502 Implications

0.4 Paclitaxel Nab-paclitaxel Ixabepilone

0.2 0.0

EXPERT POINT OF VIEW

Months from study entry Agent

Median PFS

Paclitaxel

283

10.6

Nab-paclitaxel

271

9.2

Ixabepilone

245

7.6

Fig. 1: CALGB 40502 progression-free survival by treatment arm. nab = nab-paclitaxel; pac = paclitaxel; ixa = ixabepilone. Courtesy of Hope S. Rugo, MD.

necessary for 45% of the nab-paclitaxel arm, compared with 15% with either paclitaxel or ixabepilone. Dr. Rugo emphasized that nab-paclitaxel still has a role in metastatic breast cancer—though perhaps a more limited one. “In situations where I already use nab-paclitaxel, I will continue to use it. In fact, I have patients who could not have received curative therapy without this as an option. But I had not jumped on the bandwagon to treat with 150 mg/m2, and now we know there is no reason to do so because it is more expensive and more toxic,” she said in an interview with The ASCO Post. The role for nab-paclitaxel is in the treatment of patients who are intolerant

Trastuzumab Bests Lapatinib In another study of metastatic breast cancer, trastuzumab (Herceptin) came out ahead of lapatinib (Tykerb). The interim results of the phase III MA.31/ GSK EGF 108919 trial were so striking, in fact, that the study was closed early.3 Canadian investigators compared lapatinib given with taxanebased treatment (weekly paclitaxel or docetaxel every 3 weeks) for 24 weeks followed by monotherapy with lapatinib until disease progression vs trastuzumab plus taxane therapy for 24 weeks followed by monotherapy with trastuzumab until progression, in 652 patients. Median progression-free survival for the lapatinib arm was 8.8

Older Drugs in Metastatic Breast Cancer ■■ In an open-label phase III comparison, weekly paclitaxel was as good as nab-paclitaxel, and better than ixabepilone, in delaying disease progression, with less overall toxicity, in a phase III trial.

■■ Newer microtubule agents should not replace weekly paclitaxel as the preferred first-line treatment option.

■■ In another phase III trial, trastuzumab delayed disease progression 2.6 months longer than lapatinib.

It is unclear why the novel microtubules do not improve activity over paclitaxel, she added. This is unlikely due to chance or to a differential interaction with bevacizumab, she said. The drugs appeared more potent, not less, in preclinical studies, and the doses used in this trial had been previously established as effective. “We saw that the toxicity of these regimens attenuates their exposure, with nearly half the nab-paclitaxel arm requiring dose reduction … and a substantially greater number discontinuing therapy…. So, in effect, this was a trial of lower-dose ixabepilone and lower-dose nab-paclitaxel,” she pointed out. “There is no reason to repeat this effort with a lower dose.” The study also suggests that preclinical potency studies can be misleading, and randomized phase II trials “get us excited but also let us down,” she added. “There is no substitute for well-done phase III trials as seen here.”

■

Disclosure: Dr. Miller has served in a consulting or advisory role for Clovis, Genentech, and Nektar, and has received research funding from Genentech, Geron, Merrimack, and Roche.

months, compared with 11.4 months with trastuzumab, indicating a 33% increased risk of progression with lapa= .01). In women with centinib (P �� trally confirmed HER2-overexpressing tumors, the difference between the arms actually approached 5 months (P = .003), although overall survival differences have not been observed, reported Karen A. Gelmon, MD, of the British Columbia Cancer Agency. Lapatinib therapy was associated with more adverse events than trastuzumab.

Further Considerations Gunter von Minckwitz, MD, PhD, of the German Breast Group and the University of Frankfurt, Germany, said the findings add to an increasing body of evidence that lapatinib is not as active as trastuzumab in a number of breast cancer settings, perhaps because of the rapid development of secondary resistance after “initial high efficacy.” Greater toxicity may also be an in issue, but he maintained, “the therapeutic window appears to be wide.” Dual blockade of the HER2 pathway appears to be the most promising approach, and studies of these combinations are eagerly awaited.

■

Disclosure: Dr. Rugo has received research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech. Dr. Gelmon has served in a consulting or advisory role for Amgen, AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, and Roche. Dr. von Minckwitz reported research grants by and advisory role for Roche, GlaxoSmithKline, and Boehringer-Ingelheim.

References 1. Rugo H, Barry WT, Mareno-Aspitia A, et al: CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel compared to weekly nanoparticle albumin bound nab-paclitaxel or ixabepilone with or without bevacizumab as firstline therapy for locally recurrent or metastatic breast cancer. 2012 ASCO Annual Meeting. Abstract CRA1002. Presented June 4, 2012. 2. Gradishar WJ, Krasnojan D, Sheporov S, et al: Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 27:3611-3619, 2009. 3. Gelmon K, Boyle F, Kaufman B, et al: Open-label phase III randomized controlled trial comparing taxane-based chemotherapy with lapatininb or trastuzumab as first-line therapy for women with HER2+ metastatic breast cancer. 2012 ASCO Annual Meeting. Abstract LBA671. Presented June 3, 2012.

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

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

INLYTA

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

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

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

Proportion progression-free

1.0 0.9

INLYTA (n=361)

6.7months (95% CI: 6.3, 8.6)

0.8

[43% longer median PFS]

0.7 0.6 0.5 0.4 0.3

Sorafenib (n=362)

4.7months (95% CI: 4.6, 5.6)

0.2 0.1 0.0

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

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

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

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

Please see brief summary on the following page.

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

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

AXU470817

Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (*20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in *10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in *10% of Patients Who Received INLYTA or Sorafenib INLYTA

Sorafenib

(N=359)

Adverse Reaction

(N=355)

All Gradesb

Grade 3/4

All Gradesb

Grade 3/4

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

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

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

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

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

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

a b

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

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

320 317 312 320

35 33 15 11

<1 3 <1 0

316 309 310 315

52 36 14 16

4 4 0 <1

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

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

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

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

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

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

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

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

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

May 2012

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Evolution of ASCO’s Quality Improvement Programs CancerLinQ represents the next major step in ASCO’s efforts to improve the quality of cancer care in the United States. It builds on ASCO’s unparalleled expertise in oncology quality programs,

of improving patient care,” Dr. Link added.

Assessment Phase: Breast Cancer CancerLinQ is now entering its assessment phase, focusing on the development of a breast cancer–specific prototype. This prototype will enable ASCO to fully assess the feasibility of a rapid learning system for oncology, and to refine its approach as needed before expanding the initiative to include other cancers. ASCO anticipates completing this

Transforming Cancer Care through Real-time Learning That is why ASCO is embarking on CancerLinQ, a multiphase initiative that promises to change the way cancer is understood and treated. This “rapid learning system” will harness technological advances to connect oncology practices, measure quality and performance, and provide physicians with decision support in real time. “At the pace that cancer science is moving today, this kind of system will not only be helpful, it will be essential. Oncology practices will see enormous benefits from such a system, and patient care will improve as a result,” said ASCO President Sandra M. Swain, MD. A rapid learning system, described by the Institute of Medicine in a 2010 report,1 is designed to draw insight from the vast, untapped pool of data on “real-world” patients. Today, we know very little about most patients with cancer—from the molecular characteristics of their tumors to the outcomes of their treatments—because these details are locked away in unconnected electronic and paper records. ASCO’s vision for CancerLinQ is to assemble and analyze all of that information in a central knowledge base, which will grow “smarter” over time. Specifically, the system will: ■■ Upload clinical data stored in electronic health records (EHRs) from patients in multiple practices

“We are now at an inflection point in health care, where scientific and technical advances are making the transformation of cancer care possible. Instead of waiting for clinical trials alone to guide patient care, we can now aggregate and learn from massive quantities of real-world data in ways that we couldn’t have conceived even 20 years ago,” said ASCO Immediate Past President Michael P. Link, MD. In practice, once the full technology platform is completed, CancerLinQ will: ■■ Improve personalized treatment decisions by cancer care teams by capturing patient information in real time at the point of care; providing real-time decision support tailored to each patient and his or her cancer; and automatically reporting on the quality of care compared with clinical guidelines and the outcomes of other patients ■■ Educate and empower patients by linking them to their cancer care teams and providing personalized treatment information at

which is being brought together with CancerLinQ in a new ASCO Institute for Quality established in 2011.

“ASCO’s intensive focus on quality improvement in oncology makes us uniquely suited to develop and offer this service,” said Dr. Link. “All of ASCO’s quality initiatives are converging to make this vision a reality.” ASCO issued its first clinical practice guideline in 1994. In 2006, ASCO launched QOPI, the first national program to help oncology practices measure and improve the quality of care. QOPI’s rigorous set of more than 90 quality measures allows oncologists to monitor and hold each other accountable to advance their quality of care together. A third of oncology practices in the United States, nearly 700, are registered in the program. “QOPI has demonstrated the power of oncologist-driven efforts to improve patient care,” said Dr. Link. “Like QOPI, CancerLinQ will be designed by and for oncologists and their patients, with the sole objective

prototype by the end of 2012. ASCO will be calling on you, our members, to help make the assessment phase a success. We will ask you to participate and move the field forward by sharing de-identified information on cases of breast cancer from your own practice. Taking a phased approach and learning from each phase, ASCO anticipates that the full system will be complete and operating in practices nationwide by the end of the decade. Regular updates will be coming in the months ahead.

■

Reference 1. National Research Council: A Foundation for evidence-driven practice: A rapid learning system for cancer care: Workshop summary. Washington, DC: The National Academies Press, 2010. Available at: http://www.iom. edu/Reports/2010/A-Foundation-forEvidence-Driven-Practice-A-RapidLearning-System-for-Cancer-Care.aspx © 2012. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | JULY 1, 2012

PAGE 30

Direct from ASCO

A Decade of Trusted Cancer Education

ay 18 marked the 10th anniible information. Well-informed paversary of Cancer.Net, the tients are their own best advocates patient information website of the and invaluable partners for physiAmerican Society of Clinical Oncians. By providing timely, comprecology (ASCO). This milestone hensive, oncologist-approved inis not only important to the more formation, Cancer.Net helps foster than 12 million canthis relationship cer survivors in the while also helpCancer.Net is the United States who ing patients have searched for and families only site for which all reliable answers to make informed medical content is peer- h e a l t h - c a r e many of the issues reviewed and approved decisions.A key they face, but also to the Conquer Cancer for accuracy, timeliness, strength of the Foundation, which website that and clarity by a highlyhas been a long-time continues today supporter of the site is the rigorous credentialed editorial and ASCO’s patient medical review board. information proprocess of its gram. Editorial Board. Cancer.Net is Invaluable Source for the only site for which all medical Patients and Their Families content is peer-reviewed and apAs technology and progress in proved for accuracy, timeliness, cancer research and treatment have and clarity by a highly-credentialed evolved in the last decade, so has editorial board comprised of physiCancer.Net. It initially launched in cians, nurses, physician assistants, May 2002 as People Living With oncology social workers, genetic Cancer (plwc.org) to provide a counselors, patient advocates, and trusted resource that oncology other experts. professionals could feel confident For 10 years Cancer.Net has referring their patients to and that provided trusted cancer education patients could rely on for credto people living with cancer and to

those who care for and about them. It is an incredibly valuable cancer resource that addresses all aspects of cancer—from prevention through diagnosis, treatment and survivorship. Cancer.Net also offers free, downloadable patient education materials for use by doctors, nurses, and other health-care professionals, as well as patients, caregivers, and patient advocates. The Conquer Cancer Foundation is proud to support Cancer.Net and is working to ensure that it will always be responsive to the needs of people with cancer. To help guarantee another 10 years of trusted cancer education, we invite you to join us by

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

www.jco.org

making a donation online at www. conquercancerfoundation.org/SupportPatientEducation. Happy birthday Cancer.Net, and many more!

■

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

What’s Hot in

JCO

JCO.org American Society of Clinical Oncology Identifies Five Key Opportunities to Improve Care and Reduce Costs: The Top Five List for Oncology

Explaining the Unexplainable: EGFR Antibodies in Colorectal Cancer

Help Your Patients Understand the Latest Research

irect your patients to www. cancer.net/podcasts to hear ASCO experts discuss the research that was presented at 2012 ASCO Annual Meeting. This series of “Research Round-up” podcasts provides the latest information on treatment and care for people with cancer and will help your patients understand how it affects them. These podcasts cover new research

Maximizing Human Epidermal Growth Factor Receptor 2 Inhibition: A New Oncologic Paradigm in the Era of Targeted Therapy

US Food and Drug Administration Approval Overview in Metastatic Breast Cancer

in breast cancer, brain tumors, gastrointestinal cancers, and gynecologic cancers, as well as other topics of interest to patients.

■

Radiotherapy in Older Women With Low-Risk Breast Cancer: Why Did Practice Not Change?

Announcing ASCOâ&#x20AC;&#x2122;s

lity M

Quality Care

SympoSium

Manchester Grand Hyatt San Diego, California

rs Key DateS July 31, 2012 11:59 pm eDt Abstract Submission Deadline

october 24, 2012 11:59 pm eDt Housing & Early Registration Deadline

at t e

November 30-December 1, 2012

Call for Abstracts

This exciting new ASCO Symposium will promote innovation and strategic planning in the expanding fields of oncology outcomes and health services research. Abstracts are currently being accepted in the following categories: - Quality Measurement - Quality Improvement - Guideline Recommendation Compliance and Its Effects on Quality - The Use of IT to Improve Quality - Involving Patients in Quality Care - Patient-Reported Outcomes - Communication and Decision-Making Merit awards are available for Fellows who apply and submit high-quality abstracts.

To submit an abstract or review guidelines, visit quality2012.asco.org This live activity has been approved for AMA PRA Category 1 Creditâ&#x201E;˘.

The ASCO Post | JULY 1, 2012

PAGE 32

Expert’s Corner Perspective

Medical Ethicists Reflect on Their Personal Cancer Experiences By Ronald Piana

more alert to ethical aspects of the cancer experience.

Book Origins

Rebecca Dresser, JD, MS

he recently published book, Malignant: Medical Ethicists Confront Cancer, takes a personal look at the cancer experience from the perspective of seven medical ethicists who were also patients with cancer or cared for spouses with cancer.1 The book’s editor, Rebecca Dresser, JD, MS, who teaches law and medical ethics at Washington University, St. Louis, recently spoke with The ASCO Post about her experience with cancer and what Malignant adds to the literature of oncology ethics and survivorship.

Out-of-body Experience What was your cancer diagnosis and treatment experience? In 2006, I was diagnosed with stage III/IV head and neck cancer. I was fortunate to teach at Washington University, which has a wonderful cancer treatment center. The program’s tumor board formulated a treatment plan beginning with 6 weeks of induction chemotherapy followed by 35�� days of chemoradiotherapy, with three rounds of chemotherapy, but I could only handle two. It was a very rough time, I felt absolutely terrible. Patients with cancer describe the numbing shock when they first hear that they have cancer. As a bioethicist, was your experience different? Well, I certainly was shocked when my doctor told me I had cancer. That is a universal experience. But as a bioethicist, at the same time I was hearing this horrible diagnosis, it was like there was an elf perched on my shoulder whispering, “Oh, he’s breaking bad news, this is a topic you teach to med students.” So there was an out-of-body experience— I was hearing my cancer diagnosis as both a professional and a patient. That duality was consistent throughout the entire process, and it certainly made me

What was the genesis of the book Malignant? During treatment, I would lie in bed and try to read, but quite often it proved too much of a strain, so I listened to the radio instead. One day, a program on National Public Radio featured doctors who were cancer survivors. They discussed how their professional experience affected the way they processed and dealt with cancer. I knew some people in my field who were going through cancer also, so I thought, why not have similar discussions, only with people from bioethics? After I felt better, I wrote a grant proposal to the Greenwall Foundation, which was accepted. I asked six colleagues who had also faced cancer to join me in the project. That was how the Malignant got off the ground.

We debated whether bioethicists could add anything of value to the many compelling personal narratives others had written about cancer. But Malignant differs from the other narratives in two ways. First, instead of a memoir that essentially relates one person’s experience, we present what happened to a group of people having a range of cancer experiences, some similar and some quite different. Second, as people who teach and write about medical ethics, we have a distinct outlook on what happened to us. Our training as bioethicists became the context for our personal experiences with cancer, and our personal experiences led us to rethink some of what we had previously read, written, and taught about serious illness.

cancer patients, wanted to maintain a modicum of control over my illness. But my short-term concerns interfered with my overall goal of completing cancer treatment. I don’t think people should be coerced into doing things against their will, but sometimes people in grave situations, like mine, need to be persuaded to reconsider an earlier choice. I still think that autonomy is important, but I also learned that I needed help in thinking through the potential consequences of my decisions. Cancer gave us all a better understanding of the challenges patients and their families face in coping with the medical and other decisions that come with life-threatening illness.

Did working with six other professional academics pose challenges? It was a collegial collaboration, but like all group projects, it included de-

As one who teaches ethics, how would you grade your doctors’ communication skills? The people in our group received very good medical care, but the communication, which is an important part of care, was variable. Frankly, some doctors are just poor communicators. But it’s also a very difficult situation. Doctors often don’t know how much information a patient can process at a particular time, especially when the news is less than good. As patients and caregivers, we sometimes wanted doctors to give us a frank picture of our situation, including worst-case scenarios. At other times, we only wanted the optimistic view. Sometimes we wanted to be involved in medical decisions; other times, we wanted someone to tell us what to do. We saw how difficult it is for clinicians to tailor conversations for each patient.

As patients and caregivers, we sometimes wanted doctors to give us a frank picture of our situation, including worst-case scenarios. We saw how difficult it is for clinicians to tailor conversations for each patient. —Rebecca Dresser, JD, MS

Methods and Content How were the discussions constructed? To get the ball rolling, each of us wrote short essays about our personal experiences that seemed to us to raise ethical questions. We then met twice for a couple of days to discuss our experiences and what we learned from them. I arranged for our talks to be taped and transcribed; our essays and meeting transcripts became the backbone of the book. What topics did your group cover? Actually, we covered quite a wide range of topics, such as breaking bad news, treatment decision-making, questionable-benefit interventions, and end-of-life issues. We also explored some issues less commonly associated with bioethics—for instance, cancer stereotypes, support groups, and life in remission.

Key Distinctions What separates Malignant from other cancer memoirs?

bate and disagreement. For instance, we argued about whether our “firstperson bioethics” approach would add something of value to the bioethics field—some were more convinced of its value than others were. We also had different opinions about issues related to cancer screening and clinical trial participation.

Autonomy Issues Please share a chapter of yours that highlights one of the larger cancer themes. I think the chapter on my needing a feeding tube addresses the vulnerability of patients with cancer, especially with respect to the issue of autonomy. I was a well-informed and medically savvy patient, but I made a bad decision about my own care. Because of the radiation to my mouth, I couldn’t eat, but for a long time I refused to have a feeding tube. Consequently, I lost 25 lb and had to be hospitalized for failure to thrive; that’s when I finally gave in. I was stubborn and, like many

Communication Skills

Unanticipated Discovery Were there any surprises during the process? We were a bit surprised at the physical burdens we were willing to endure for a better chance of survival. It was telling, because we learned why so many patients want those expensive cancer drugs that hardly ever extend life for more than a few months.

■

Disclosure: Dr. Dresser is editor of Malignant: Medical Ethicists Confront Cancer.

Reference 1. Dresser R (ed): Malignant: Medical Ethicists Confront Cancer. New York, Oxford University Press USA, 2012.

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FDA Update

Novel Agent Carfilzomib Receives Positive Vote from Oncologic Drugs Advisory Committee for Use in Multiple Myeloma

nyx Pharmaceuticals recently announced that the FDA’s Oncologic Drugs Advisory Committee (ODAC) determined by a vote of 11–0 (with 1 abstention) that, in patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent, the benefit-risk assessment is favorable for the use of carfilzomib (proposed brand name, Kyprolis). Onyx is developing carfilzomib for use in multiple myeloma across a variety of treatment lines. The Prescription Drug User Fee Act (PDUFA) date for completion of FDA review of the carfilzomib New Drug Application (NDA) for accelerated approval is July 27, 2012.

■■ A global phase III clinical trial, called ENDEAVOR, is planned to begin enrolling patients in mid-2012. This head-to-head trial will evaluate the combination of

carfilzomib and low-dose dexamethasone vs the combination of bortezomib and low-dose dexamethasone. ■■ A phase I/II study being conduct-

About Carfilzomib The carfilzomib NDA submission is based on the 003-A1 study, an open-label, single-arm phase IIb trial as well as supportive data from additional studies. The 003-A1 trial evaluated 266 heavily pretreated patients with relapsed and refractory multiple myeloma who had received at least two prior therapies, including bortezomib (Velcade) and either thalidomide (Thalomid) or lenalidomide (Revlimid). Carfilzomib is being studied in several clinical trials either as a singleagent or in combination with other therapies, including: ■■ A global phase III clinical trial, known as the ASPIRE trial, has completed enrollment and is evaluating the combination of lenalidomide and low-dose dexamethasone with or without carfilzomib in patients with relapsed multiple myeloma who have received one to three prior therapies. ■■ The phase III FOCUS trial is evaluating single-agent carfilzomib in patients with relapsed and refractory myeloma who have received three or more prior therapies. The trial is designed to facilitate regulatory approvals around the world.

Other pathways can contribute to prostate cancer promotion.5 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. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68 (15):6407-6415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5): 2815-2825. 4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

ed by Onyx’s partner Ono Pharmaceutical Co, Ltd, is evaluating carfilzomib in Japanese patients with relapsed/refractory multiple myeloma.

■

PAGE 34

The ASCO Post | JULY 1, 2012

JCO Spotlight

Multicenter Phase II Trial Supporting Approval of Brentuximab Vedotin in Anaplastic Large-cell Lymphoma By Matthew Stenger

ystemic anaplastic large-cell lymplant. The primary endpoint of the phoma (ALCL) is an aggressive study was objective response rate acT-cell lymphoma subtype charactercording to independent central review. ized by uniform expression of CD30. Response was assessed by CT scans Apart from low- to intermediate-risk at cycles 2, 4, 7, 10, 13, and 16 and by patients with ALK-positive disease, PET scans at cycles 4 and 7. patients with ALCL have a poor progPatients had a median age of 52 nosis when treated with conventional, years (range, 14–76 years), 57% were anthracycline-based front-line chemale, and 72% had ALK-negative motherapy and typically have disease disease. Overall, 50% of patients had that is resistant to multiagent chemorelapsed disease, and 50% had refractherapy after relapse. Brentuximab tory disease after their most recent vedotin (Adcetris)—a conjugate of therapy. The median number of prior an anti-CD30 antibody (brentuxchemotherapy regimens, excluding auimab) and the anti-microtubule agent tologous stem cell transplant, was two monomethylauristatin E (vedotin)— (range, 1–6), and 26% of patients had was found to produce responses in treatment failure with autologous stem CD30-positive lymphomas in a phase cell transplant; 45% of patients had I study,1 raising received radiation hope that the contherapy. The most The study results jugate approach recent treatment would represent an prior to study envalidate a CD30improvement over rollment was autoltargeted approach in the disappointogous transplant or ing efficacy results multiagent chemoa disease with uniform achieved with firsttherapy in 91% of antigen expression. generation antipatients. CD30 antibodies Key Data in early-phase studies.2 Patients received a median of sevIn a recent Journal of Clinical Oncolen cycles of treatment (range, 1–16). ogy article, Pro and colleagues reportThe objective response rate was 86%, ed the full results of the multicenter with complete remission occurring in phase II study of brentuximab vedotin 57% of patients and partial remission in relapsed/refractory ALCL that supin 29%. Reduction in tumor size was ported the drug’s approval in 2011 for observed in 97% of patients. The metreatment of patients with ALCL after dian time to objective response was failure of at least one prior multiagent 3 5.9 weeks (range, 4.3–14 weeks), and chemotherapy regimen. The trial is the largest prospective trial reported the median time to complete remisto date in patients with recurrent syssion was 11.9 weeks (range, 5.1–50.3 temic ALCL. weeks). These median times approximate the timing of the first CT and Study Design PET response assessments, respecIn this trial, 58 patients with systively. temic ALCL and recurrent disease afMedian durations of response ter at least one prior therapy received were 12.6 months in all responders brentuximab vedotin at 1.8 mg/kg IV and 13.2 months in patients with a over 30 minutes as an outpatient infucomplete response. Median durations sion every 3 weeks.3 of response were 12.6 months in paPatients had to be tients with complete remission who aged ≥ 12 years and did not undergo subsequent stem cell had to have an ECOG transplant (n = 22) and 13.2 months performance status in those undergoing allogeneic transof 0 or 1, measurable plant in complete remission (n = See Page 50 disease (> 1.5 cm), 6), with median duration not being absolute neutrophil count > 1,000/ reached in patients undergoing auµL, and platelet count > 50,000/µL. tologous transplant in complete rePatients could not have previously mission (n=5). The median time from received an allogeneic stem cell transthe last dose of brentuximab vedotin

Brentuximab in Anaplastic Large-cell Lymphoma ■■ Brentuximab vedotin produced an objective response in 86% of patients with relapsed/refractory anaplastic large-cell lymphoma, including complete response in 57%.

■■ Brentuximab vedotin was associated with a significantly prolonged

progression-free survival compared with the most recent prior treatment.

■■ Peripheral sensory neuropathy was the most common adverse event and

the most common adverse reaction resulting in study drug discontinuation and dose modification.

to initiation of stem cell transplant was 25 days. ALK protein status did not appear to affect response. Objective response occurred in 88% of patients with ALKnegative disease, including complete remission in 52%, and in 81% of patients with ALK-positive disease, including complete remission in 69%, and there were no differences in median duration of response or progression-free survival between these two subgroups. Other subgroup analyses (eg, according to relapsed vs refractory, primary refractory status, 1 vs > 1 prior treatments, prior autologous stem cell transplant, bone marrow involvement, age, sex, and ECOG performance status) showed clinically meaningful antitumor activity in all subgroups, with no subgroup having a greater likelihood of complete remission. The estimated median progression-free survival for on independent review was 13.3�� months for all patients and 14.6 months for those with complete remission. A prespecified comparison of investigator-assessed progression-free survival and progression-free survival after the most recent prior therapy showed a significant prolongation with brentuximab vedotin treatment (median, 14.3 vs 5.9 months, HR = 0.48, P = .001). Median overall survival had not been reached at the time of the analysis. The estimated 12-month overall survival was 70%.

Major Adverse Events The most common (≥�� 20%) �� adverse events of any grade were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). Adverse events of at least

grade 3 occurred in 60% of patients, with the most common being neutropenia (21%, including grade 4 in 9%), thrombocytopenia (14%, including grade 4 in 5%), peripheral sensory neuropathy (12%), and anemia (7%). Adverse events led to discontinuation of treatment in 24% of patients; peripheral sensory neuropathy led to discontinuation in 10%, with no other adverse event leading to discontinuation in more than one patient. Brentuximab vedotin doses were delayed due to adverse events in 40% of patients, most commonly due to peripheral sensory neuropathy (14%) and neutropenia (12%). Overall, 10% of doses were delayed. Doses were reduced in 12% of patients, most commonly due to peripheral sensory neuropathy (7%). Overall, 53% of patients experienced peripheral neuropathy adverse events, which were grade 3 in 14%. The median times to onset were 13.3 weeks for events of any grade, 16.9 weeks for grade 2 events, and 28.4 weeks for grade 3 events. Improvement or resolution of peripheral neuropathy occurred in 81% of patients, with complete resolution occurring in 48%. The median time to improvement or resolution was 9.9 weeks (range, 0.3–32.9 weeks). Tumor lysis syndrome occurred in one patient after the first dose of brentuximab vedotin; the patient recovered with supportive care, continued to receive study medication, and achieved complete remission. Four patients experienced palpable, painful enlargement of affected nodes with overlying erythema, which subsequently regressed. These tumor flares were considered to reflect an inflammatory process rather than disease progression. Overall, six patients (10%) died within 30 days of

ASCOPost.com | JULY 1, 2012

PAGE 35

JCO Spotlight

the last dose of brentuximab vedotin, with none of the deaths considered related to study treatment. It should be noted that early in 2012, a boxed warning for progressive multifocal leukoencephalopathy was added to brentuximab vedotin labeling, as was a contraindication for use of the drug concomitantly with bleomycin due to increased risk of pulmonary toxicity.4

strategy for aggressive, CD30-positive, T-cell lymphomas. Clinical evaluation of brentuximab vedotin in newly diagnosed patients with ALCL and other CD30-expressing lymphomas is warranted.”3

■

References 1. Younes A, Bartlett NL, Leonard JP, et

al: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363:1812-1821, 2010. 2. Forero-Torres A, Leonard JP, Younes A, et al: A phase II study of SGN-30 (antiCD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol 146:171-179, 2009. 3. Pro B, Advani R, Brice P, et al: Brentuximab vedotin (SGN-35) in patients

In Conclusion As stated by the investigators, “The study results validate a CD30-targeted approach in a disease with uniform antigen expression. The [complete remission] rate … and acceptable safety profile achieved in this study demonstrate that brentuximab vedotin could be valuable as a potential treatment

Contact

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

Rights & Permissions e-mail: Permissions@harborsidepress.com

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

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

References: 1. Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61(7):2892-2898. 2. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164(1):217-227. 3. Yu S-Q, Lai K-P, Xia S-J, Chang H-C, Chang C, Yeh S. The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer. Asian J Androl. 2009;11(1):39-48. 4. Corey E, Quinn JE, Buhler KR, et al. LuCaP 35: a new model of prostate cancer progression to androgen independence. Prostate. 2003;55(4):239-246. 5. Loberg RD, St. John LN, Day LL, Neeley CK, Pienta KJ. Development of the VCaP androgen-independent model of prostate cancer. Urol Oncol. 2006;24(2):161-168.

with relapsed or refractory systemic anaplastic large-cell lymphoma: Results of a phase II study. J Clin Oncol 30:2190-2196, 2012. 4. ADCETRISTM (brentuximab vedotin) for injection prescribing information. Seattle Genetics, Inc, January 2012. Available at http://www.adcetris.com/prescribing_information.php. Accessed June 13, 2012.

The ASCO Post | JULY 1, 2012

PAGE 36

Perspective

Breast Cancer and Noncommunicable Diseases continued from page 1

International Health Organizations and Cancer The World Health Organization (WHO) reported that in 2008, an estimated 36�� million of the 57�� million global deaths were due to noncommunicable diseases (NCDs), principally cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes, including 9 million deaths before age 60, nearly 80% of which occurred in developing countries. In response, the United Nations (UN) held a historic high-level meeting on September 19-20, 2011, to consider the prevention and control of noncommunicable diseases. The aim was to adopt “a concise, action-oriented outcome document that will shape the global agendas for generations to come.” While the UN’s political declara-

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tion on noncommunicable diseases mentions cancer generally, it provides no specific reference to breast cancer as a leading problem or to cancer treatment priorities in practice. The document promotes “increased access to cost-effective cancer screening programs, as determined by national situations,” but otherwise gives no guid-

nonetheless impractical for poorer countries, both because of implementation costs and limited feasibility of treatment in the primary care setting in low- and middle-income countries. Is this pessimistic perspective the end of the road for breast cancer in developing countries, or are there se-

As simple as it might sound, knowledge of median invasive tumor size provides a powerful indicator regarding the state of breast cancer detection. —Benjamin O. Anderson, MD, FACS

ance about how diagnosed cancers should be managed.2 Why is this UN “action-oriented outcome document” largely silent on breast cancer? The organization embraced tobacco control, arguably the lowest hanging fruit of cancer prevention, and discussed the prevention of infection-associated cancers like cervical, liver, and stomach cancer through increased access to costeffective hepatitis B virus and human papillomavirus vaccination. But UN statements have limited the discussion of common cancers that lack an infectious origin, like breast and colon cancers, to the modification of risk factors (unhealthy diet, obesity, and physical inactivity)—interventions that are unlikely to produce major shifts in outcome for these very common malignancies. Prior to the UN summit, WHO released an executive summary, “Global Status Report on Noncommunicable Diseases 2010,” which outlines the core obstacles in addressing noncommunicable diseases in low- and middle-income countries. 3 This analysis notes that biennial mammographic screening (from age 50–70 years) to downstage disease and breast cancer treatment of all stages are among the “best buys” for health-care interventions to tackle noncommunicable diseases. The report asserts that these breast cancer interventions could avert 19% of the cancer burden, and as such are “quite cost-effective.” However, the document’s editor and principal author, Ala Alwan, MD, who then served as WHO Assistant Director-General of Noncommunicable Diseases and Mental Health, concluded that breast cancer interventions are

quential steps that can be taken to address the most common cancer among women?

Breast Cancer Early-detection Strategies Breast cancer screening has been a source of heated debate among health-care policymakers. The discussion about mammographic screening’s strengths, limitations, frequency, and target age group, which has relevance to high-income countries with established healthcare infrastructures, has overshadowed more practical questions for addressing breast cancer outcomes in low- and middle-income countries. Throughout the world, women in developing countries are most often first diagnosed with locally advanced (stage III) or metastatic (stage IV) cancer. These large palpable, visible, or ulcerated cancers are easily detected on inspection and clinical examination, obviating the value of detection on screening. These advanced cancers are more expensive to treat, less likely to respond to therapy, and most often prove incurable in any health-care setting. The critical questions, then, must not revolve around mammographic availability in lowand middle-income countries, but instead should focus on interventions whereby cancers can be diagnosed at less-advanced stages—so-called “clinical downstaging”—followed by adequate locoregional and systemic treatments.

Core Indicators for Breast Cancer The 2010 WHO report on noncommunicable diseases states that countries require a surveillance

framework that monitors exposures (risk factors and determinants), outcomes (morbidity and mortality), and health-system responses (interventions and capacity). This WHO report recommends that standardized core indicators for each of the three components should be adopted and used for monitoring. So what metrics are most relevant to breast cancer in low- and middleincome countries? Simply knowing the number of breast cancer cases and deaths provides no guidance about what health system responses are most needed in a given low- or middle-income environment. Useful health system metrics, like predictive tumor markers in treatment planning, should suggest practical solutions as next steps. The Breast Health Global Initiative (BHGI) developed and published resource-stratified guidelines for breast cancer early detection, diagnosis, treatment, and health-care systems.4 Metrics recommended by that multidisciplinary international expert group include median invasive tumor size at initial diagnosis (the most basic tumor metric), and ratio of advanced-stage (stages III/IV) to early-stage (stages 0, I, II) disease at initial diagnosis (if higher-level staging information is available). As simple as it might sound, knowledge of median invasive tumor size provides a powerful indicator regarding the state of breast cancer detection and sheds light for early detection strategies in low- and middle-income countries. Regions where median tumor size exceeds 3 to 4 cm are dominated by clinically detectable disease and therefore need to improve public knowledge about breast cancer and access to health-care facilities where cancer diagnoses can be made in an accurate and timely fashion. Practical interventions include outreach and public education about the signs and symptoms of breast cancer, the importance of early detection when it is still a small palpable mass or thickening, the promotion of breast selfexamination, and the establishment of diagnostic tissue sampling and analysis to permit the accurate and timely diagnosis of clinically detectable disease. Image-detection of clinically occult cancers only becomes relevant when the median tumor size is less than 2 to 3 cm, and even then, the best methods for detection re-

ASCOPost.com | JULY 1, 2012

PAGE 37

Perspective

main an important area of investigation. One size does not fit all. It is crucial that WHO provide direct technical guidance to Member States about breast cancer as a relevant noncommunicable disease in low- and middle-income countries. Education about early detection, breast lumps, and self-examination is not a costly intervention and may help a woman seek treatment while it is still realistic, rather than waiting until the tumor is advanced and likely untreatable except through palliative care. On April 19, 2012, the Union for International Cancer Control (UICC), working through the multiorganizational NCD Alliance, submitted recommendations to WHO regarding the prevention and control of noncommunicable diseases. Contained within this consensus document is the recommendation for “policies to support national programs for early detection of breast cancer that are appropriate and feasible for the population-need and resource setting and include, at a minimum, tumor size to be collected as part of the pathological assessment at diagnosis.”5 The Breast Health Global Initiative fully supports and endorses this recommendation to WHO and hopes that other organizations and oncology health professionals mirror this support of the BHGI framework for breast cancer core indicators in low-resource settings, by proposing inclusion of this indicator for breast cancer to their own governments and ministers of health. Such proposals are especially critical now, in this most important year for setting global targets and indicators for noncommunicable diseases. The decision of how to intervene with breast cancer will be made at the individual country level, and must be adapted to existing resources. For countries to make informed decisions on breast cancer control, they need meaningful data, including median tumor size at diagnosis. This is a key first step in assessing the real burden and options for solutions in addressing the most common life-threatening female cancer on earth.

■

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

References 1. Forouzanfar MH, Foreman KJ, Delossantos AM, et al: Breast and cervical

cancer in 187 countries between 1980 and 2010: A systematic analysis. Lancet 378(9801):1461-1484, 2011. 2. Political Declaration of the High-level Meeting of the General Assembly on the Prevention and Control of Non-communicable Diseases (A/RES/66/2). United Nations General Assembly. 66th session, agenda item 117. New York, United Na-

tions, 2012. 3. Alwan A, Armstrong T, Bettcher D, et al: Global status report on noncommunicable diseases 2010. Geneva, WHO Press, 2012. 4. Anderson BO, Yip CH, Smith RA, et al: Guideline implementation for breast healthcare in low-income and middleincome countries: Overview of the Breast

References : 1. Pienta KJ, Bradley D. Mechanisms underlying the development of androgenindependent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671. 2. 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. 3. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10(1):33-39.

Health Global Initiative Global Summit 2007. Cancer 113(8 suppl):2221-2243, 2008. 5. Union for International Cancer Control: Follow-up to the UN Highlevel Meeting on NCDs. Available at http://www.uicc.org/advocacy/followun-high-level-meeting-ncds. Accessed May 7, 2012.

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2012 Oncology Meetings July 4th Asia-Pacific Gastroesophageal Cancer Congress and Singapore Gastric Cancer Consortium 5th Annual Scientific Meeting July 4-6 • Singapore For more information: www.apgcc.com

Best of ASCO® San Diego August 10-11 • San Diego, California For more information: http://boa2012.asco.org 10th International Congress on Targeted Therapies in Cancer August 10-12 • Washington, DC For more information: http://cancerlearning.onclive.com

British Gynaecological Cancer Society Annual Scientific Meeting July 5-6 • London, United Kingdom For more information: http://bgcsconference.com/ Best of ASCO® Chicago July 12-13 • Chicago, Illinois For more information: http://boa2012.asco.org

Pan Pacific Lymphoma Conference July 17-20 • Lahaina, Maui, Hawaii For more information: unmc.edu/panpacificlymphoma 13th International Lung Cancer Congress July 19-22 • Huntington Beach, California For more information: http://cancerlearning.onclive.com 5th Latin American Lung Cancer Conference July 25-27 • Rio De Janeiro, Brazil For more information: www.lalca2012.org 11th International Congress on the Future of Breast Cancer July 26-28 • Coronado, California For more information: http://cancerlearning.onclive.com

August Best of ASCO® Boston August 3-4 • Boston, Massachusetts For more information: http://boa2012.asco.org

17th International Conference on Cancer Nursing September 9–13 • Prague, Czech Republic For more information: www.isncc.org/ conference/17th_ICCN 2nd World Congress on Cancer Science & Therapy September 10-12 * San Antonio, Texas For more information: www.omicsonline.org/ cancerscience2012 9th International Symposium on Melanoma and Other Cutaneous Malignancies September 12 • Chicago, Illinois For more information: http://cancerlearning.onclive.com

Australian and New Zealand Children's Haematology/Oncology Group Annual Scientific Meeting August 24-26 • Surfers Paradise, Queensland, Australia For more information: www.anzchog2012.org ICC World Cancer Congress 2012 August 27–30 • Montreal, Quebec For more information: www.worldcancercongress.org

British Association for Cancer Research: Chasing Cancer Stem-like Cells September 12 • Harrogate, North Yorkshire, United Kingdom For more information: www.bacr.org.uk 2012 Breast Cancer Symposium September 13-15 • San Francisco, California For more information: http://breastcasym.org

Modern Principles of Treatment of Neurooncology Diseases: Prospects for Functional Neurosurgery September 15-16 • Yalta, Ukraine For more information: http://nbscience.com 1st Multidisciplinary Symposium: Molecular Oncology: From Laboratory Bench to Medicine September 17-22 • Kyiv, Ukraine For more information: http://rmd.org. ua/en Cancer Vaccines: Advances in Design, Therapy and Efficacy September 19-20 • London, United Kingdom For more information: www.smi-online.co.uk/events 32nd Congress of the European Society of Clinical Oncology September 19-21 • Valencia, Spain For more information: www.ecco-org.eu Congress of Oncologists September 20-22 • Sudak, Ukraine For more information: http://nbscience.com/congress-ofoncologists

September Health Effects of Chernobyl Catastrophe: A Quarter of a Century September 1-2 • Kiev, Ukraine For more information: www.nbscience.com/20.html Multidisciplinary Symposium in Thoracic Oncology September 6-8 • Chicago, Illinois For more information: http://thoracicsymposium.org 8th International Jordan Oncology Society Conference September 6-8 • Amman, Jordan For more information: http://jo-events.com/jos-conference 9th Asia Pacific Musculoskeletal Tumor Society Meeting September 6-9 • Kuala Lumpur, Malaysia For more information: apmsts2012.com

Pan Pacific

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Joe Joe Shapiro Shapiro Professor Professor of of Medicine Medicine Division Division of of Oncology Oncology and and Hematology Hematology Department of Internal Medicine Department of Internal Medicine University University of of Nebraska Nebraska Medical Medical Center Center

Julie Julie M. M. Vose, Vose, MD, MD, MBA MBA

Chief, Chief, Division Division of of Oncology Oncology and and Hematology Hematology Neumann Neumann M. M. and and Mildred Mildred E. E. Harris Harris Professor Professor Department Department of of Internal Internal Medicine Medicine University University of of Nebraska Nebraska Medical Medical Center Center

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ASCOPost.com | JULY 1, 2012

PAGE 39

2012 Oncology Meetings 8th Annual Symposium on Controversies and Clinical Challenges in Myeloma, Lymphoma, and Leukemia September 21-23 • Pasadena, California For more information: http://cancerlearning.onclive.com Molecular Diagnostics World Congress September 25-26 • San Diego, California For more information: http:// selectbiosciences.com/conferences Sydney Cancer Conference September 27-28 • Sydney, Australia For more information: sydney.edu.au/cancer-research/ SCC2012 European Conference of Oncology Pharmacy September 27-29 • Budapest, Hungary For more information: www.ecco-org. eu/home/conferences 37th ESMO Congress September 28-October 2 • Vienna, Austria For more information: www.esmo.org

October 27th Annual Critical Issues in Tumor Microenvironment, Angiogenesis, and Metastasis October 1-4 • Cambridge, Massachusetts For more information: http://steele.mgh.harvard.edu 10th Annual Functional Genomics Screening Strategies October 2-3 • Boston, Massachusetts For more information: www. discoveryontarget.com/RNAiScreens-Functional-Genomics ACCC National Oncology Conference October 3-6 • San Antonio, Texas For more information: http://accc-cancer.org American Society of Head and Neck Radiology 46th Annual Meeting October 3-7 • Miami Beach, Florida For more information: www.ashnr.org

14th Annual Lynn Sage Breast Cancer Symposium October 4-7 • Chicago, Illinois For more information: www.lynnsagebreastcancer

12th Meeting of the International Society of Geriatric Oncology October 25-27 • Manchester, UK For more information: www.siog.org

44th Congress of the International Society of Paediatric Oncology October 5-8 • London, United Kingdom For more information: www.siop2012.org

9th Annual School of Breast Oncology October 25-28 • Atlanta, Georgia For more information: http://cancerlearning.onclive.com 3rd International Conference on Stem Cells and Cancer October 27-30 • New Delhi, Delhi, India For more information: www.iscc.in

32nd Annual Oncology Nurses Symposium October 7-10 • San Diego, California For more information: www.scripps.org Oncology Clinical Development Congress October 10-11 • Manchester, Cheshire, United Kingdom For more information: www.oncologyclinicaldevelopmentcongress.com

IASLC 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org ASTRO’s 54th Annual Meeting October 28-31 • Boston, Massachusetts For more information: www.astro.org

American College of Gastroenterology Annual Scientific Meeting October 19-24 • Las Vegas, Nevada For more information: http://gi.org Sydney International Breast Cancer Congress October 23-26 • Sydney, Australia For more information: www.sydneybreastcancer2012.com Society for Immunotherapy of Cancer Workshop--Focus on the Target: The Tumor Microenvironment October 24-25 • North Bethesda, Maryland For more information: www.sitcancer. org/meetings/am12/workshop12

7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org 17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/

3rd International Breast Cancer Prevention Symposium October 10-12 • Lafayette, Indiana For more information: www.purdue.edu/breastcancer Western Neuroradiological Society 44th Annual Meeting October 18-21 • Sedona, Arizona For more information: www.wnrs.org

Chemotherapy Foundation Symposium XXX November 6-10 • New York, New York For more information: http://chemotherapyfoundation symposium.org

November 2012 AICR Annual Research Conference on Food, Nutrition, Physical Activity and Cancer November 1–2 • Washington, DC For more information: www.aicr.org/research/conference

5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp

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

8th Annual Multidisciplinary Symposium on Head and Neck Cancer November 3 • Chicago, Illinois For more information: http://cancerlearning.onclive.com 24th EORTC-NCI-AACR Symposium in Molecular Targets and Cancer Therapeutics November 6-9 • Dublin, Ireland For more information: www.ecco-org.edu

2012 ASH Annual Meeting December 8-11 • Atlanta, Georgia For more information: www.hematology.org

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速: Soft Tissue Sarcoma, V.1.2012. NCCN.org. http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed 05/01/2012. NCCN速 and NCCN GUIDELINES速 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.

息2012 The GlaxoSmithKline Group of Companies ONO528R0 Printed in USA. May 2012

The ASCO Post | JULY 1, 2012

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In the News

Too Soon to Know How Circulating Tumor Cells Might Be Used to Guide Treatment of Breast Cancer By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

“A

simple blood test.” These were the first words in some media reports about a study to determine if a blood test to measure circulating tumor cells could predict outcomes in patients with nonmetastatic breast cancer. In the study, 24% of women with early-stage breast cancer had one or more circulating tumor cells and those who did had decreased progression-free and overall survival rates. Although the blood test itself may be simple, determining what the results mean and how best to use them to benefit patients is not that simple and could take years.

Anthony Lucci, MD

“I think within the next 5 years, we will clearly know how we can use this data and whether it is going to be useful in clinical decision-making for those traditionally low-risk patients who may or may not benefit from systemic therapy,” the study’s lead author Anthony Lucci, MD, told The ASCO Post. Dr. Lucci is Professor of Surgery, Department of Surgical Oncology, at The University of Texas MD Anderson Cancer Center in Houston.

Circulating Cells and Risk of Recurrence The study included 302 chemonaive patients with stage I to III operable breast cancer undergoing surgery for their primary tumors between February 2005 and December 2010 at MD

Anderson. Patients who had bilateral cancer or another malignancy within 5 years of the current diagnosis were not eligible. “We don’t know if patients with hematologic malignancies or other solid tumors within the past 5 years could have spurious values that would confound the results,” Dr. Lucci said. “So we thought the safest thing was not to include patients with other tumors within the past 5 years to avoid any interference or confounding data, and the same with bilateral disease.” Circulating tumor cells were measured at the time of surgery using the CellSearch System by Veridex. “Detection of one or more circulating tumor cells predicted both decreased progression-free survival (log-rank P =·.005; HR = 4.62, 95% CI = 1.79–11.9) and overall survival (log-rank P = .01; HR = 4.04, 95% CI = 1.28–12.8),” the MD Anderson researchers reported in The Lancet Oncology.1 At 2 years, progression-free survival was 87% among the 73 patients with one or more circulating tumor cells vs 99% in the 229 patients with none. Progression-free survival was 79% among the 29 patients with two or more circulating tumor cells and 69% among the 16 patients with three or more. Overall survival was 99% in patients with no circulating tumor cells, 94% in patients with one or more circulating tumor cells, 89% in patients with two or more, and 81% in patients with three or more. “As the number of cells increased, so did the risk,” Dr. Lucci noted. “I don’t think it is a lot different than if you took a bag of seeds and you poured them into the soil. The chance of some of them taking hold is much greater than if you throw down just one seed,” he said. “We don’t know which patients will get metastatic spread and which ones will not, but I think you can clearly say that if you have more cells, the odds of developing distant metastases certainly increases. That, I feel, is very clear.” These results were similar to the SUCCESS trial data, presented at the San Antonio Breast Cancer

Expect Questions from Your Patients

“W

e have already received several calls and requests from patients who desire to participate in our research or get the test done,” Anthony Lucci, MD, said about the response to a study published in The Lancet Oncology and media coverage of the findings. Dr. Lucci is lead author of the study, which found that a blood test for circulating tumor cells predicted early recurrence and decreased overall survival in chemonaive patients with nonmetastatic breast cancer. He is also Professor of Surgery, Department of Surgical Oncology, at The University of Texas MD Anderson Cancer Center in Houston, where the study continues. Most of the callers are patients who have recently been diagnosed with breast cancer. “What we tell them,” Dr. Lucci said, “is that we are continuing to accrue patients under a clinical study here. So if the patients are eligible for the protocol, we tell them we welcome their participation, but we are still not offering it as a routine test.” Those interested in participating can learn more about the trial at www.mdanderson.org/patient-and-cancer-information/cancer-information/clinical-trials/index.html.

Uncertain Impact on Management He also tells patients that many insurance companies don’t yet cover the blood test for nonmetastatic patients, and “even if we were to receive the information from the test, it wouldn’t necessarily change their treatment, because this study wasn’t designed to see which treatments work best to get rid of those cells. We don’t really know exactly what to do with the information. That is the next step,” Dr. Lucci said. “Not every patient with these cells is going to get a recurrence,” he continued. “It is another prognostic indicator, like lymph nodes. The higher the number of cells—just like the higher the number of affected lymph nodes— the greater the chance that the disease could try to emerge somewhere else. But nothing is absolute. So just having a circulating tumor cell or cells doesn’t always mean that the patient is going to have a recurrence.” He counsels those with a breast cancer diagnosis to “be patient and participate in clinical studies, because I think in the very near future we will know how to use this information to better treat patients.”

■

Symposium in 20102 and likely to be published in the near future, Dr. Lucci said. “The SUCCESS investigators concluded that the finding of one or more circulating tumor cells was also a predictor of a worse disease-free survival and overall survival, and they have a large number of patients. Data will continue to emerge, and I think it is going to provide further support for figuring out how we can best use this in the clinic,” he added. “We didn’t find a correlation with standard tumor markers or with axillary lymph node status, which suggests that possibly these cells travel independently on different routes of spread and could even be biologically different. That is what we are looking at now,” Dr. Lucci said.

Not Routinely Recommended Dr. Lucci pointed out the CellSearch System has been approved by the FDA for evaluating patients being treated for breast, prostate, and colorectal cancers, but currently neither the ASCO guidelines for biomarker analysis nor the National Comprehensive Cancer Network (NCCN) guidelines recommend routine use of circulating tumor cell information to guide treatment for breast cancer patients. “We are not using it as a routine test, but we want to continue to gather this important data over the next several years so we can figure out how to best use it in the clinic,” Dr. Lucci said. He noted that there is already a great deal of data from several large studies to support using microscop-

ASCOPost.com | JULY 1, 2012

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In the News

ic disease in blood or bone marrow for staging algorithms. “The next big step will be to figure out how best to use that so we don’t overtreat patients or cause unnecessary anxiety,” he said. “But we would still not recommend it be used for routine treatment decisions in the clinic until we know more.”

design future trials to test the efficacy of certain agents to get rid of these cells,” he explained. “In the preliminary analysis that we have done, we can still identify circulating tumor cells in a significant number of patients even after the completion of their systemic therapy,” he reported. “I think in the

very near future, we will have additional data to show the importance of these cells when they are present after the completion of systemic therapy.” In another study, presented at this year’s ASCO Annual Meeting,3 Dr. Lucci’s team reported finding HER2positive cells in the blood of patients

with HER2-negative disease. “It is actually a parallel study,” he said, “where we take the blood sample and we look at the markers on that blood sample to see if the HER2 status of the circulating tumor cell is the same or different from the primary tumor. What we found was that in a significontinued on page 44

Less Invasive Staging More reliance on information from blood, bone marrow, or predictive gene signature analyses such as the Oncotype DX assay could mean a “move toward a less invasive type of staging and treatment protocol,” Dr. Lucci said. The study report stated that prognostic information about circulating tumor cells might be useful in identifying patients at high risk “especially since many of these patients will undergo only restricted lymph-node removal with the acceptance of the American College of Surgeons Oncology Group (ACOSOG) Z0011 data showing no reduced local control or survival for patients who had sentinel-node biopsy alone with limited axillary-nodal disease.” The article also mentions that “complete lymph-node removal results in complications for a substantial number of patients whereas drawing blood has few sequelae.” “If we can move away from taking out all of the lymph nodes to try to get prognostic information on the number of nodes, and perhaps use this blood test or bone marrow sampling or predictive gene signatures on the primary tumor to estimate risk, we will be much less likely to cause permanent morbidity than does complete lymph node removal,” Dr. Lucci said.

Read the Expert’s Guide to the

Skin Effects of Cancer For Your

Patients

More people than ever before are living with and surviving cancer. However, even the most promising cancer treatments may cause unexpected side effects to the skin, hair, and nails. How can your patients navigate these changes while staying on treatment and maintaining some quality of life? Written for people living with cancer by Dr. Mario Lacouture, an expert in the dermatologic side effects of anticancer medications, this book offers your patients clear information and practical suggestions for preventing, treating, and living through these skin, hair, and nail changes.

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

Expanded and Related Studies The MD Anderson study protocol has been amended to permit sequential circulating tumor cell measurements during routine follow-up. In addition, the cohort was expanded to nearly 600 patients. “We expanded it because we wanted to see the effect of chemotherapy on the cells,” Dr. Lucci said. “We can take a sample prior to chemotherapy or neoadjuvant chemotherapy. When patients complete their therapy, we can get another sample, and then get a sample even further down the road, because I think sequential time points would also be helpful and may be a way to

Available at:

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

The ASCO Post | JULY 1, 2012

PAGE 44

In the Clinic

Everolimus: New Indication in Renal Angiomyolipoma Associated with Tuberous Sclerosis Complex 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

n April 2012, the kinase inhibitor everolimus (Afinitor) was granted accelerated approval for the treatment of adults with renal angiomyolipoma associated with tuberous sclerosis complex who do not require immediate surgery.1,2 Everolimus is already indicated for treatment of adults and children at least 3 years of age with subependymal giant cell astrocytoma associated with tuberous sclerosis complex who require therapeutic intervention but are not candidates for curative surgical resection. It is also indicated for treatment of adults with unresectable, locally advanced, or metastatic See Page 50 progressive neuroendocrine tumors of pancreatic origin and adults with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Approval was based on durable reductions in tumor volume observed in everolimus-treated patients in a

Circulating Tumor Cells continued from page 43

cant number of patients, you can find changes in the circulating cells—either HER2 amplification or HER2 loss—that are different from the primary tumor,” he said. “This suggests that either: (1) We have to look at the primary tumors more carefully to ascertain if they are really HER2-negative or -positive; or (2) Some patients may have a change in the HER2 status of certain cells released into the circulation,” he continued. “We don't currently know exactly why these HER2See Page 50 positive cells are found in circulation, but the images

trial in which 118 patients with renal angiomyolipoma as a feature of tuberous sclerosis complex (n = 113) or sporadic lymphangioleiomyomatosis (n = 5) were randomized (2:1) to double-blind oral everolimus 10 mg once daily (n = 79) or placebo (n = 39).2 Treatment was continued until disease progression or unacceptable toxicity. Patients had to be at least 18 years of age, have at least one angiomyolipoma of ≥ 3 cm in longest diameter, and have no immediate indication for surgery. Patients had a median age of 31 years (range, 18–61 years), 66% were female, and 89% were Caucasian. At baseline, 92% of patients had at least one angiomyolipoma ≥ 3 cm in longest diameter, 29% had angiomyolipomas ≥ 8 cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions; 39% had prior renal embolization or nephrectomy, and 17% were receiving enzyme-inducing antiepileptic drugs. The major efficacy outcome mea-

OF NOTE Everolimus works by inhibiting mTOR kinase, which plays a central role in cell growth, proliferation, and survival as well as in protein synthesis and transcription. The mTOR pathway is dysregulated in a number of cancers.

are quite clear, and thus it opens up a whole new area for research. That is something that could affect treatment in the very near future, and we are continuing that study currently.”

Everolimus in Tuberous Sclerosis Complex–related Renal Angiomyolipoma ■■ Everolimus (Afinitor) was granted accelerated approval to treat renal angiomyolipoma associated with tuberous sclerosis complex, when immediate surgery is not required.

■■ Everolimus is administered orally at 10 mg once daily, with or without food. sure was angiomyolipoma response rate, with response defined as a ≥ 50% reduction in angiomyolipoma volume, absence of a new angiomyolipoma lesion ≥�� 1 cm, absence of kidney volume increase ≥ 20%, and no angiomyolipoma-related bleeding of at least grade 2. Disease was assessed by CT or MRI. Analyses of efficacy outcome measures were limited to the blinded treatment period that concluded 6 months after the last patient was randomized. The median duration of followup was 8.3 months (range, 0.7–24.8 months). Response rates were 41.8% in the everolimus group vs 0% in the placebo group (P < .0001). Median response duration was 5.3+ months (range, 2.3+ to 19.6+ months). Three everolimus patients and eight placebo patients had angiomyolipoma progression. The time to angiomyolipoma progression was significantly longer in the everolimus group, with everolimus treatment being associated with a 92% reduction in risk for progression are trying to determine which cells have the potential to grow into new tumors and which ones are likely to die and not form new metastases,” Dr. Lucci said.

■

We don't currently know exactly why these HER2-positive cells are found in circulation, but the images are quite clear, and thus it opens up a whole new area for research. —Anthony Lucci, MD

The accompanying commentary to the study report in The Lancet Oncology noted that just having circulating tumor cells doesn’t mean they will form metastases.4 Research at MD Anderson is also exploring that issue. “We

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

References 1. Lucci A, Hall CS, Lodhi AK, et al: Circulating tumour cells in non-metastatic breast cancer: A prospective study. Lancet

(HR = 0.08, 95% CI = 0.02–0.37, P < .0001). As a condition of the accelerated approval, the manufacturer (Novartis) will continue to follow study patients to more fully characterize angiomyolipoma response duration, provide additional information on the need for nephrectomy or renal embolization to control tumor hemorrhage, and provide updated information on time to angiomyolipoma progression.

How It Works Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) kinase, downstream of the PI3K/AKT pathway.2,3 mTOR kinase plays a central role in cell growth, proliferation, and survival and in protein synthesis and transcription. The mTOR pathway is dysregulated in a number of cancers. Everolimus binds to an intracellular protein (FKBP-12), resulting in formation of an inhibitory complex with mTOR complex�� 1 (mTORC1) and incontinued on page 51

Oncol. June 6, 2012 (early release online). 2. Rack BK, Schindlebeck C, Andergassen U, et al: Prognostic relevance of circulating tumor cells in the peripheral blood of primary breast cancer patients. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S6-5. Presented December 11, 2010. 3. Krishnamurthy S, Bischoff FZ, Mayer JA, et al: Detection of discordant HER2 status by FISH in circulating tumor cells and disseminated tumor cells in earlystage breast cancer using a microfluidicbased cell enrichment and extraction platform (OncoCEE). 2012 ASCO Annual Meeting. Abstract TPS10631. Presented June 4, 2012. 4. Krell J, Stebbing J: Circulating tumour cells as biomarkers in early breast cancer. Lancet Oncol. June 6, 2012 (early release online).

ASCOPost.com | JULY 1, 2012

PAGE 45

Pro/Con Gastrointestinal Oncology

To Scan or Not to Scan for Colon Cancer Recurrence?

Richard M. Goldberg, MD, and David P. Ryan, MD, discuss CT scanning in metastatic colon cancer. Over the past 2 decades, we have seen a substantial increase in the 5-year survival of patients with stage II and III colon cancer, marking an evolving oncologic success story. However, in the postoperative setting, the value of regular CT screening to monitor for recurrence has been greeted with mixed opinions.1 The ASCO Post recently asked two nationally regarded gastrointestinal cancer experts if CT scanning is appropriate in the routine follow-up of patients with colon cancer.

Improved Surgical Outcomes This characterization might seem counterintuitive because studies show circulating tumor cells in the bloodstreams of these patients, but very few

of these cells actually establish metastatic deposits. So resecting the few liver metastases in patients with so-called “oligometastatic disease” can result in cure of metastatic disease.

Liver surgery has vastly improved over the past couple of decades, in part due to better technology but also due to the training of liver surgeons as continued on page 46

PRO

Richard M. Goldberg, MD Physician-in-Chief and Professor The Klotz Family Chair in Cancer Research The Ohio State University Comprehensive Cancer Center James Cancer Hospital and Solove Research Institute Columbus, Ohio olorectal cancer is fairly unique among adult solid tumors in that recurrence generally occurs in the liver and lung or abdominal cavity, anatomic areas where metastases can be identified by scanning long before they would cause symptoms. Moreover, while we have a colon tumor marker, carcinoembryonic antigen (CEA), it is only elevated in about 60% of patients with recurrent disease and may be increased in some who never manifest recurrence, so it is a lessthan-perfect method to detect recurrence. And the natural history of colorectal cancer is such that—at least in a subset of patients with recurrent disease—there are a limited number of metastatic deposits limited to a single organ or site.

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PAGE 46

Pro/Con

To Scan or Not to Scan continued from page 45

part of a surgical oncology fellowship, leading to better and better outcomes. In fact, resecting limited liver metastases in selected patients with recurrent colorectal cancer can result in a 30% to 60% probability of long-term diseasefree survival, even when the initial surgery to resect the primary tumor and drug therapy prove not to be curative. In a smaller subpopulation, surgical specialists can also resect a limited number of lung metastases, although this clinical scenario is much less common. The liver is a large, thick organ in which physical examination through the abdominal wall muscles and liver function tests are most often useless in detection of resectable lesions. The point of performing regular CT surveillance is to detect liver metastases, many of which can be successfully resected.

Potential Harms On the other side of the equation, there are a few potential downsides to CT screening. A very small percentage of patients will have an anaphylactic reaction to the CT scan dye. That said, it’s a situation that scanning centers are adept at managing. There is also the chance that radiation exposure from CT can result in a future cancer, although large studies of Medicare data suggest that the risk is hard to quantify, and probably more theoretical than actual.2,3 The other concern, of course, is the cost of regular-interval screening, which is a value judgment that individual oncologists, their patients, and payers must make. The Cochrane Collaboration did a study on followup CT screening in stages II/III colon cancers, finding that costs per life saved were favorable according to the standard benchmarks for health-care expenditures.3 It is important to note that over the same period that we’ve seen treatment advances, the cost of CT screening has dropped considerably, and the

Visit

procedure has become faster and more streamlined, reducing the amount of radiation exposure to the patient to a much safer level.

Conclusions The decrease in deaths from recurrent colorectal cancer that we’ve seen in the management of metastatic disease is due mainly to surgical resection of limited recurrence, which can make the difference between death or cure. We’ve also seen considerable progress in the use of cytotoxic drugs and targeted therapies. I believe data provided by the Cochrane Collaboration, along with consensus-based clinical guidelines from ASCO and the National Comprehensive Cancer Network, support my opinion that CT scan surveillance for patients who have been treated for stage II or III colon cancer is sound practice in which the benefits outweigh the risks and costs.

Disclosure: Dr. Goldberg has received research funding from Pfizer.

CON

David P. Ryan, MD Associate Professor Department of Medicine Harvard Medical School Clinical Director MGH Cancer Center Massachusetts General Hospital Boston, Massachusetts verything we do in medicine should meet one of three goals: curing patients, extending life, or helping patients feel better. If an intervention is not accomplishing one of

those core elements of care, then we shouldn’t be doing it. Although generally not considered an intervention, imaging is in fact an intervention that can cause discomfort—both physical and emotional—and side effects such as contrast-induced allergic reactions and nephropathy. In addition, from the mammography literature it is apparent that imaging leads to a significant number of false-positives, which lead to unnecessary biopsies and follow-up scans.

Insufficient Data Unlike mammography, we do not have sufficient data to quantify harms associated with follow-up surveillance in the postoperative setting or the clinical value of regular-interval CT scans in stage II/III colon cancers to check for recurrence. So if we do not know for certain that scans are helping to cure these patients, it begs the question: What is our goal in this setting? Surveillance scans are not going to help people live longer or feel better. The theory behind surveillance CT scans is to detect recurrence when the disease is still small and isolated to the liver so it is still resectable, which, according to survival data, will give the patient about a 30% chance of cure. However, despite the theoretical upside to this potentially curative scenario, there is no level 1 evidence demonstrating that we are actually curing people because of surveillance scanning. All we have are several small, poorly executed studies, a few of which suggest that CT scanning may detect metastatic disease sooner than in a no-screening scenario, but there is no evidence that it translates into higher cure rates.

Small Potential Benefit If we were to design a randomized study assessing surveillance scans in the postoperative setting, how much could we reasonably expect the experimental arm of surveillance to improve survival? For every 100 patients with stage III colon cancer, 70 will be cured and 30 will develop recurrent disease.

From the beginning, we know that surveillance scans will add harm in those 70 patients. For the See Page 50 30 patients who will experience a recurrence, we expect that 20%, or 6 patients, will present with disease isolated to the liver—regardless of how they are followed postoperatively—and be offered a chance at curative resection. Therefore, we are monitoring 24 patients out of every 100 in order to detect their disease at an earlier time point, when it might be isolated to the liver or lungs and be amenable to resection. If we estimate that surveillance CTs detect 30% more patients with isolated disease amenable to resection, this will impact only 7 of 100 patients, of whom only 2 to 3 will eventually be cured with surgical resection. If we aggregate the added MRIs, PET scans, and procedures, we can assume that the practice of surveillance CT scans costs millions of dollars for every life that is theoretically saved. Given this extremely small potential benefit, it is incumbent upon the research community to prove to patients and providers that routine surveillance screening of patients after surgery for stage II/III colon cancer is worthwhile.

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Disclosure: Dr. Ryan has served as a consultant or advisor to Threshold Pharmaceuticals, Array Bioscience, and Millennium Pharmaceuticals.

References 1. Goldberg RM, Ryan DP: Scan? Cure? Sure! Oncologist 16:254-256, 2011. 2. Meer AB, Basu PA, Baker LC, et al: Exposure to ionizing radiation and estimate of secondary cancer in the era of high-speed CT scanning: projections from the Medicare population. J Am Coll Radiol 4:245-250, 2012. 3. Jeffery M, Hickey BE, Hider PN: Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev 1:CD002200, 2007. Interviews conducted and report compiled by Ronald Piana.

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PAGE 48

In the Literature

Emerging Clinical Data on Cancer Management HODGKIN LYMPHOMA After Complete Response to Chemotherapy, IFRT Improves Event-free Survival in Hodgkin Lymphoma Final data from the Children’s Cancer Group (CCG) trial evaluating low-dose involved-field radiation therapy (IFRT) for patients with Hodgkin lymphoma achieving a complete response after chemotherapy show that at a median follow-up of 7.7 years, IFRT produced a statistically significant improvement in event-free survival, but no improvement in overall survival. “For individual patients, the relative risks of relapse versus late effects of IFRT must be considered,” the researchers concluded. “Patient and disease characteristics and early response assessment will aid in deciding which patients are most likely to benefit from IFRT.” CCG 5942 randomized 498 patients achieving an initial complete response to chemotherapy to receive IFRT or no further therapy. Riskadapted initial chemotherapy was based on stage, presence or absence of “B” symptoms, presence or absence of bulk disease, hilar adenopathy, and the number of involved nodal sites. Patients received four or six cycles of cyclophosphamide, vincristine, procarbazine (Matulane), and prednisone/doxorubicin, bleomycin, and vinblastine or six cycles of intensified chemotherapy including high-dose cy-

tarabine and etoposide. “A complete response to initial chemotherapy was defined as the resolution of all disease or at least 70% mass reduction in tumor volume in conjunction with a change from positive to negative on gallium scan,” the investigators explained, Patients who achieved a partial response were assigned to IFRT.

Interpreting the Results At about 4 years, the investigators found a significant event-free survival difference favoring radiotherapy, and randomization was ended. “At that time, we could make no statements concerning any difference in survival because of the short follow-up for patients who experienced a relapse,” the investigators noted. The updated study results show that in an as-treated analysis, the 10year event-free survival rates were 91.2% for patients receiving IFRT vs 82.9% for those receiving no further therapy (P = .004), and the respective overall survival rates were 97.1% and 95.9% (P = .500). Bulk disease, B symptoms, and nodular sclerosis histology were risk factors for a lower event-free survival rate, the researchers reported in the Journal of Clinical Oncology. “There are a number of ways in which these results could be interpreted,” the authors wrote. “It seems that, for every 100 patients who achieve a complete response to initial therapy, treatment with IFRT will prevent nine relapses. If the tox-

icity of IFRT is minimal, then all patients should receive [radiotherapy]. However, when the risk of late effects from [radiotherapy] is high, the risk-benefit ratio of IFRT must be reconsidered.” The authors added that the choice of chemotherapy may also dictate the need for radiotherapy. “It has been shown that a more aggressive chemotherapy regimen may offset the potential benefit of the addition of [radiotherapy],” they wrote. “The dilemma is how to determine which treatment will yield the lowest toxicity because additional chemotherapy and low-dose [radiotherapy] are both associated with risk. These decisions will also be influenced by individual patient characteristics such as age, sex, and distribution of disease.” Wolden SL, et al: J Clin Oncol. May 29, 2012 (early release online).

HEAD AND NECK CANCER Obese Patients at Higher Risk of Aggressive Thyroid Tumors Obese patients present with more advanced and more aggressive forms of papillary thyroid cancer and should be screened for thyroid cancer with sonography, which is more sensitive in detecting thyroid cancer than physical examination alone, according to a study published online in the Archives of Surgery. “Patients more likely to benefit from screening are those who are overweight, obese, or morbidly obese and those older than 45 years, who, by AJCC stage definition, have a higher risk of stage III or IV disease,” the researchers concluded. “Our recommendation mirrors a similar proposal for breast cancer screening, where studies have suggested that a more vigilant mammogram screening regimen should be instituted for obese patients,” they noted. Researchers at the UCLA David Geffen School of Medicine reviewed the medical records of all patients older than 18 years who underwent total thyroidectomy as an initial procedure for papillary thyroid cancer or its variants from January 1, 2004, through March 31, 2011. A total of 443 patients were included in the

final analysis. Patients were grouped according to body mass index: normal (18.5–24.9 kg/ See Page 50 overweight m2), (25–29.9 kg/m2), obese (30–39.9 kg/m2), and morbidly obese (≥ 40 kg/m2). The study showed that patients with increasing body mass index have a progressively increasing risk in initially presenting with late-stage papillary thyroid cancer. “This finding is especially seen in the obese and morbidly obese populations,” the researchers noted.

Specific Findings Obese and morbidly obese patients presented more often with stage III or IV disease. The obese and morbidly obese groups also had higher prevalences of papillary thyroid cancer tall cell variant, a more aggressive tumor type. The researchers also found that increasing body mass index significantly predicted increased length of hospital stay and anesthesia induction times. Other studies have shown an increased incidence of thyroid cancer among obese populations, the authors noted, adding that their study “is novel in that it assesses the risk of presenting with both aggressive and disseminated disease. In addition, this study was performed in a multiethnic population with a large sample size,” they pointed out. “This parallel increase in the rates of obesity and thyroid cancer is intriguing, but without a much larger population study, we cannot determine whether obesity causes thyroid cancer,” according to an invited critique by Quan-Yang Duh, MD, of the University of California, San Francisco. “What is somewhat surprising is the lack of increase in surgical complications in obese patients,” he stated. “For obese patients with papillary thyroid cancer, the bad news is that the cancer is likely to be more advanced. The good news is that thyroid operation remains safe even in obese patients with advanced disease,” Dr. Duh concluded. Harari A, et al: Arch Surg. May 21, 2012 (early release online). Duh Q-Y: Arch Surg. May 21, 2012 (early release online).

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ASCOPost.com | JULY 1, 2012

PAGE 49

FDA Update

FDA Approves Pertuzumab for HER2-positive Metastatic Breast Cancer

he FDA has approved pertuzumab (Perjeta), a new antiHER2 therapy, to treat patients with HER2-positive late-stage breast cancer. Intended for patients who have not received prior treatment for metastatic breast cancer with an anti-HER2 therapy or chemotherapy, pertuzumab is combined with trastuzumab (Herceptin) and docetaxel. Pertuzumab is a humanized monoclonal antibody that is administered intravenously and is believed to work by targeting a different part of the HERprotein than trastuzumab, resulting in further reduction in growth and survival of HER2-positive breast cancer cells. Because there are production issues that potentially could affect the longterm supply of the drug, FDA limited its approval to drug product that has not been affected by those issues. Genentech, the manufacturer of pertuzumab, has committed to take steps designed to resolve these production issues in a timely manner. “Since trastuzumab was first approved more than a decade ago, continued research has allowed us to better understand the role HER2 plays in breast cancer,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This research provided the background to combine two targeted drugs—trastuzumab and [pertuzumab] with docetaxel to slow disease progression in breast cancer.”

zumab and docetaxel were diarrhea, hair loss, leukopenia, nausea, fatigue, rash, and peripheral sensory neuropathy. Pertuzumab is being approved with

a Boxed Warning alerting patients and healthcare professionals to the potential risk of death or severe effects to a fetus. Pregnancy status must be verified prior

to the start of pertuzumab treatment. The therapy was reviewed under the FDA’s priority review program, which provides for an expedited 6-month review of drugs that may offer major advances in treatment.

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Navigate the New ASCOPost.com Most Read See which articles are most popular on ASCOPost.com.

Today in Oncology Stay up to date on breaking reports from major oncology meetings, summaries of recently published research, developments in health-care policy and health information technology, and essential information on the latest drug approvals and practice guidelines.

Pivotal Trial The safety and effectiveness of pertuzumab were evaluated in a single clinical trial involving 808 patients with HER2-positive metastatic breast cancer who were tested prior to treatment to determine if the HER2 protein was increased. Patients were randomly assigned to receive pertuzumab, trastuzumab, and docetaxel, or trastuzumab and docetaxel with a placebo. The study was designed to measure progression-free survival. Those treated with the combination containing pertuzumab had a median progression-free survival of 18.5 months, while those treated with the combination containing placebo had a median progression-free survival of 12.4 months. The most common side effects observed in patients receiving pertuzumab in combination with trastu-

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PAGE 50

FDA Update

Supplemental New Drug Application Submitted for Abiraterone

anssen Research & Development, LLC, has submitted a supplemental New Drug Application (sNDA) to the FDA to extend the use of abiraterone acetate (Zytiga) administered with prednisone for the treat-

ment of patients with metastatic castration-resistant prostate cancer who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy and before chemotherapy.

The application follows the announcement of results observed from prespecified interim analyses of the international phase III, randomized, double-blind, placebocontrolled COU-AA-302 clinical

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trial. This study, which included 1,088 asymptomatic or mildly symptomatic men with metastatic castration-resistant prostate cancer who had not received chemotherapy, evaluated the effect of abiraterone plus prednisone on the coprimary endpoints of radiographic progression-free survival and overall survival compared to placebo plus prednisone. Data from this study were presented at the 48th ASCO Annual Meeting in June. The company previously announced the study was unblinded based on the unanimous recommendation of an Independent Data Monitoring Committee. Based on these results, the committee also recommended that patients in the control arm be offered treatment with abiraterone.

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In the Clinic

Everolimus for Renal Angiomyolipoma continued from page 44

hibition of mTOR kinase activity. Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, vascular-endothelial growth factor-dependent and -independent angiogenesis, and glucose uptake. The oncogene suppressors tuberin sclerosis complexes 1 and 2 (TSC1, TSC2) are regulators of mTORC1 signaling. Loss or inactivation of TSC1 or TSC2 leads to activation of downstream signaling. The majority of patients with tuberous sclerosis complex have mutations in TSC1 or TSC2, resulting in constitutive activation of mTOR.

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).

Letter: Prostate Cancer Management continued from page 2

gressive treatment. It will be a sad commentary when, a decade from now, today’s smart minds in urology and radiation oncology will be critiqued for our collective failure to identify and appropriately treat biologically active prostate cancer. Future critics will outline how early 21st century physicians took great pride in developing sophisticated, expensive surgical (robotic) techniques and radiation therapies (brachytherapy, tomotherapy, RapidArc, adaptive radiotherapy, and proton-beam therapy) to treat and cure patients with indolent prostate cancer. Clearly, they will point out, reimbursement for prostate cancer therapy rewards expensive technology and is another example of insurance and advertising driving the use of the most costly treatments for all patients at all times. Others will point to how regional business arrangements markedly changed patterns of

How It Is Given Everolimus is given at 10 mg once daily with or without food. Hepatic impairment results in increased everolimus exposure. In patients with mild and moderate hepatic impairment, recommended doses are 7.5 mg and 5 mg once daily, respectively, with dose reductions to 5 mg and 2.5 mg, respectively, in case of intolerance. In patients with severe hepatic impairment, a dose of 2.5 mg one daily may be used, but not exceeded, if desired benefits outweigh risks of treatment. If treatment with moderate CYP3A4 or P-glycoprotein inhibitors is required, the everolimus dose should be reduced to 2.5 mg once daily and, if tolerated, can be increased to 5 mg. Use with strong CYP3A4 inhibitors should be avoided. If treatment with a strong inducer of CYP3A4 is required, the everolimus dose can be increased in 5 mg increments to a maximum of 20 mg once daily.

OF NOTE The most frequent adverse event in patients being treated for renal angiomyolipoma with tuberous sclerosis complex is stomatitis. Other adverse events associated with the drug include arthralgia, acne, and headache.

The most frequent adverse event in the study was stomatitis, which occurred in 78% of everolimus patients and 23% of placebo patients.2 Grade 3 stomatitis occurred in 6% of everolimus patients. Other adverse events occurring in at least 10% of everolimus patients, all of which were grade 1 or 2, were arthralgia (22%), acne (22%), headache (20%),

nausea (16%), vomiting (15%), diarrhea (14%), peripheral edema (13%), arthralgia (13%), abdominal pain (11%), upper respiratory tract infection (11%), and eczema (10%). Amenorrhea occurred in 15% of women in the everolimus group (4% of women in the placebo group). Other adverse events involving the female reproductive system in everolimus patients were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%). The most common grade 3 or 4 adverse events (≥ 2%) in everolimus patients after stomatitis were amenorrhea and convulsion. The most common laboratory abnormalities (> 40%, any grade) in the everolimus group were hypercholesterolemia (85% vs 46% in placebo group), anemia (61% vs 49%), hypertriglyceridemia (52% vs 10%), and hypophosphatemia (49% vs 15%). The most common grade 3 abnormality in

care for localized prostate cancer. The controversy in prostate cancer is not about whether to screen or the cheapest approach to treating localized disease. The controversy is and has always been over what groups of patients warrant treatment. The answer to this question will automatically address

whom to screen and when to biopsy the prostate. Pathologists have developed biologic criteria with the Gleason scoring system and other pathological findings. It is primarily the clinicians (urologists and radiation oncologists) who have failed to adhere to actively and appropriately treating only inter-

Safety Profile

The controversy in prostate cancer is not about whether to screen or the cheapest approach to treating localized disease. The controversy is and has always been over what groups of patients warrant treatment. —Gilbert A. Lawrence, MD, DMRT, FRCR

the issue of optimum treatments for patient subsets. Patients with low-risk cancer do just as well with no treatment, since most of these cancers are inactive before treatment. Thus, for them, no treatment is the best treatment, and any treatment, including sophisticated technology, will achieve good results. Our current knowledge identifies

mediate-risk and high-risk prostate cancer, and selecting active surveillance for low-risk disease. Rather, we have collectively chosen to increase our workload (as well as our academic prestige and bank balance), pad the published data, and improve our results by actively treating low-risk disease. However, several studies have shown the outcome for

everolimus patients was hypophosphatemia (5%). Adverse events led to discontinuation of everolimus treatment in three patients (3.8%), with discontinuations being due to hypersensitivity, angioedema, and bronchospasm in one patient and convulsion and hypophosphatemia in one patient each. Dose interruption or reduction occurred in 52% of everolimus patients, most commonly due to stomatitis. Everolimus carries warnings/precautions for noninfectious pneumonitis, infections, oral ulcerations, renal failure, laboratory test alterations (elevations of serum creatinine, blood glucose, and lipids and decreases in hemoglobin, neutrophils, and platelets), vaccination with live vaccines, and use in pregnancy.

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References 1. U.S. Food and Drug Administration: Everolimus (2012). Available at www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm302081.htm. Accessed June 8, 2012. 2. AFINITOR (everolimus) tablets prescribing information. Novartis, April 2012. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/022334s017lbl. pdf. Accessed June 8, 2012. 3. Franz DN: Everolimus: An mTOR inhibitor for the treatment of tuberous sclerosis. Expert Rev Anticancer Ther 11:1181-1192, 2011.

low-risk prostate cancer (which is 50% of newly diagnosed prostate cancers) is just as good with surveillance and delayed treatment for the 20% to 30% patients who show biochemical or pathological progression to a higher risk category. It is time that leaders in our respective fields, trial designers, and journal editors show some leadership. If it takes disincentives (for patients, doctors, and institutions) to dissuade us from undertaking unnecessary treatment, many of us will consider that a blessing in the long run. This will be better than an ostrich-like approach of being reticent about screening and detecting early-stage intermediateand high-risk prostate cancer. The last thing we want to do is practice medicine dictated by trial lawyers, epidemiologists, or health-care economists. Yet if that happens, we will have only ourselves to blame. —Gilbert A. Lawrence, MD, DMRT, FRCR Radiation Oncology, Faxton Hospital Utica, New York

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Approved in 3 indications

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