TAP Vol 4 Issue 6 by Harborside Press LLC

Prostatectomy vs Radiotherapy

| CT Colonography Trials

| Gene Transfer Therapy in Leukemia

VOLUME 4, ISSUE 6

APRIL 15, 2013

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

Colorectal Cancer

Is Aspirin Protective against Colorectal Cancer?

New research will help define which individuals might benefit.

ASCOPost.com

Homoharringtonine/ Omacetaxine: The Little Drug that Could

By Caroline Helwick

growing body of evidence provides biologic and clinical evidence that nonsteroidal antiinflammatory agents are protective against colorectal cancer. “It is fascinating for me as a medical oncologist and epidemiologist to see how the worlds of colorectal cancer treatment and epidemiology are intersecting,” said Charles S. Fuchs, MD, MPH, Director of the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, Boston, at this year’s Gastrointestinal Cancers Symposium in San Francisco.

Key Research Preclinical studies established the notion that aspirin might be protective against colorectal carcinogenesis. This led to two pivotal prospective observational cohort studies in humans, including the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study, which together followed almost

200,000 individuals over decades to better understand cancer biology and its influences. In the NHS, individuals who took two or more adult aspirin tablets (325 mg) per day had a 23% or greater reduction in subsequent colorectal cancer.1 A linear association was found between dose and risk, such that those in the highest quartile (> 14 tablets per week) had a 42% relative risk reduction. “This indicated that—in contrast to cardiovascular prevention, where 81 mg/d is sufficient—325 mg/d would be the maximum recommendation for aspirin,” he said. “More aspirin does seem to be more protective.” Subsequent prospective randomized trials further established a protective effect against adenoma recurrence. In four trials of persons with adenomatous polyps, regular aspirin use significantly reduced

irst, a clarification: Homoharringtonine is a natural plant alkaloid derived from Cephalotaxus fortunei; from the 1970s until the present, it was the subject of intensive research efforts by Chinese investigators to clarify its role as an antileukemic agent.1-3 Omacetaxine mepesuccinate (Synribo) is a semisynthetic highly purified homoharringtonine compound (99.7% purity) used in recent studies in chronic myeloid leukemia (CML) and approved by the FDA on October 26, 2012, for the treatment of CML. In the authors’ historical experience, milligram for milligram, omacetaxine is more myelosuppressive than homoharringtonine. Homoharringtonine/omacetaxine probably continued on page 59

continued on page 12

Expert’s Corner

Sexual Health after Cancer: Communicating with Your Patients

A Conversation with Sage Bolte, PhD, LCSW, OSW-C

Dr. Kantarjian is Professor of Medicine and Department Chair, Dr. O’Brien is Professor of Medicine, and Dr. Cortes is Professor of Medicine and Deputy Department Chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

MORE IN THIS ISSUE

By Jo Cavallo

By Hagop Kantarjian, MD, Susan O’Brien, MD, and Jorge Cortes, MD

tudies show virtually all cancer survivors will experience some form of sexual dysfunction following a cancer diagnosis and treatment. Yet few cancer survivors seek help for physical problems they may be experiencing, such as vaginal dryness, dyspareunia, chemically induced menopause, reduced libido, erec-

tile dysfunction, or for psychological distress caused by changes in body image, depression, anxiety, and the inability to achieve arousal and orgasm. And few physicians broach the subject of how cancer treatment, including surgery, chemotherapy, hormonal therapy, bone marrow transplantation, and radiation therapy, may impact their patients’ sexual health. Sexual health is often For example, you might say, ‘Some left out of the conversation patients may experience changes in between patient and physician after a cancer diagnosis their sexual desire.... If you notice any for many reasons, includchanges, please feel free to talk to one of ing embarrassment and the primary concern of curing us about your concerns.’ the cancer. Sage Bolte, — Sage Bolte, PhD, LCSW, OSW-C PhD, LCSW, OSW-C, an oncology counselor at Life

Oncology Meetings Coverage GU Cancers Symposium �� 3, 8, 54 GI Cancers Symposium��10, 16 SSO Symposium ��32 AAD Meeting �� 40 NCCN Conference�� 42 APOS Conference �� 94–97 SGO Annual Meeting �� 117–119 FDA Update �� 20–23 Direct from ASCO �� 64–68 William T. McGivney, PhD, on Clinical Guidelines �� 78

continued on page 26

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The ASCO Post | APRIL 15, 2013

PAGE 2

Errata

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

Michael P. Link, MD Stanford University Medical Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

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

Associate Editors

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

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 Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine and Public Health Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD 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

William T. McGivney, PhD Philadelphia, Pennsylvania 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 Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lynn D. Wilson, MD Yale University School of Medicine

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

George D. Demetri, MD Dana-Farber Cancer Institute

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

Bishoy Morris Faltas, MD Weill Cornell Medical College John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

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

International Editors

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

Wants to Hear from You

Stanley H. Winokur, MD Singer Island, Florida

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

In combination with fluoropyrimidine/irinotecan- or fluoropyrimidine/oxaliplatin-based chemotherapy for the secondline treatment of patients with metastatic colorectal cancer who have progressed on a first-line bevacizumab-containing regimen In the March 15 issue of The ASCO Post, the article on page 20, “Ibrutinib Receives Two Oncology Breakthrough Therapy Designations from FDA,” erred as to the trade name of rituximab. The correct product is Rituxan. We apologize for the errors, both of which have been corrected in the online versions of these articles at ASCOPost.com. n

The ASCO Post

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

E. David Crawford, MD University of Colorado

Paul F. Engstrom, MD Fox Chase Cancer Center

n the March 1 issue of The ASCO Post, the article on page 2, “Outcomes Comparable for Panitumumab and Bevacizumab in Metastatic Colorectal Cancer,” contained an inaccuracy about the FDA-approved indications of bevacizumab (Avastin) in colorectal cancer. Specifically, the article noted that bevacizumab is approved for “first-line treatment of patients with wild-type KRAS metastatic colorectal cancer….” In fact, KRAS is not mentioned in any of the drug’s labels. Bevacizumab’s approved indications in metastatic colorectal cancer are as follows: First- or second-line treatment of metastatic colorectal cancer in combinations with intravenous fluorouracil– based chemotherapy

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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 Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press® Publishing Staff

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2013 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 27,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $259; Individual International: $499; Institutional Domestic: $319; Institutional International $559. Contact subscriptions@harborsidepress.com.

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Genitourinary Cancers Symposium Genitourinary Oncology

New Findings in Prostate and Kidney Cancers Clarify the Roles of Abiraterone, Finasteride, Bevacizumab, and Surveillance By Alice Goodman

ttendees at the 2013 Genitourinary Cancers Symposium in Orlando, Florida, were brought up to date with the latest news on cancers of the prostate, testes, bladder, and kidney. Below are selected highlights from the meeting describing findings of noteworthy abstracts to extend our regular news coverage.

Benefit of Prechemotherapy Abiraterone in Metastatic Prostate Cancer Updated results of the randomized COU-AA-302 trial showed that firstline therapy with the CYP17 inhibitor abiraterone (Zytiga) improved survival and slowed disease progression in men with metastatic castration-resistant prostate cancer.1 These updated results support the expanded FDA indication announced in December 2012 for abiraterone plus prednisone as first-line therapy in this setting. In 2011, abiraterone was approved by the FDA for treatment of metastatic castration-resistant prostate cancer following progression on docetaxel chemotherapy. Time to radiographic progression was twice as long in men who received abiraterone plus prednisone vs prednisone alone (median of 16.5 vs 8.3 months, respectively). More than twice as many men in the abiraterone group achieved at least a 50% decline in prostate-specific antigen levels vs prednisone (69% in the abiraterone group vs 29% of controls). Results favoring abiraterone were consistent across all subgroups. “Treatment with abiraterone plus prednisone delayed the time to opiate use and chemotherapy use, improves quality of life measures, and remains safe and well tolerated with longer exposures,” stated presenting author Dana E. Rathkopf, MD, medical oncologist at Memorial Sloan-Kettering Cancer Center in New York. Formal discussant of this trial, William K. Oh, MD, Chief of the Division of Hematology and Medical Oncology, Professor of Medicine and Urology, and the Ezra M. Greenspan, MD, Professor in Clini-

Dana E. Rathkopf, MD

cal Cancer Therapeutics at Icahn School of Medicine at Mount Sinai, New York, said that optimal timing of abiraterone initiation is an important issue. In his view, the overall survival benefit is about 5 months when abiraterone is given either after docetaxel or before, while the radiographic progression-free survival is about 8 months longer with abiraterone as firstline therapy. “It is likely that the maximal benefit of abiraterone is seen when used prior to chemotherapy,” Dr. Oh stated.

Finasteride Reduces Prostate Cancer Risk but Not Mortality Long-term follow-up of the Prostate Cancer Prevention Trial (PCPT) showed that 7 years of finasteride therapy reduces the risk of a prostate cancer diagnosis but does not affect mortality.2 In the PCPT, finasteride reduced the relative risk of developing prostate cancer by 24.8%, but was associated with a relative risk of 26.9% for developing high-grade

prostate cancer. Most doctors stopped recommending finasteride for prevention after results of the study regarding highgrade cancer were published. A 25% reduction in the diagnosis of prostate cancer with finasteride could have an enormous public health impact, so Phyllis Goodman, MS, Lead Statistician, and colleagues at the Southwest Oncology Group (SWOG) Statistical Center, Seattle, conducted a survival analysis of the randomized trial in the two study arms to determine if finasteride increased risk of death. They hypothesized that an increased risk of death with finasteride would be a potential indicator of a “true” increased risk of high-grade prostate cancer with lethal potential. At 18 years of follow-up, 5,128 deaths have been reported: 2,584 in the finasteride arm and 2,544 in the placebo arm. In both arms, 78% of men were alive at 15 years. No significant difference was observed in overall survival between the two arms. Ten-year survival from diagnosis for men with prostate cancer was slightly higher in the finasteride arm: 83% vs 81% for placebo. No evidence was found for poorer survival among men with high-grade prostate cancer who were randomly assigned to finasteride.

mTOR Inhibitors Increase Risk of Fatal Events Mammalian target of rapamycin

Recently Reported Data in Genitourinary Oncology ■ In an updated analysis of COU-AA-302, the improvement in radiologic progression-free survival with first-line abiraterone in metastatic castration-resistant prostate cancer remained statistically significant.

■ Long-term follow-up of the Prostate Cancer Prevention Trial showed that 7 years of finasteride therapy reduces the risk of a prostate cancer diagnosis but does not affect mortality.

■ The use of mTOR inhibitors was associated with an increased risk of fatal

events in patients with renal cell carcinoma (and other cancers), compared with controls.

■ In the BEST trial, VEGF, RAF kinase, and mTOR combination targeted therapy was not superior to single-agent bevacizumab in terms of progression-free survival among patients with advanced renal cell carcinoma.

■ For older patients with small renal masses, surveillance does not appear

to adversely affect kidney cancer–specific survival, whereas surgery may be associated with cardiovascular complications and an increased risk of death from any cause.

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

(mTOR) inhibitors were associated with more than double the number of fatal events in patients with cancer, according to a review of eight clinical trials.3 Three of the trials included patients with renal cell carcinoma, and the other five trials, patients with other types of cancer. Overall, patients randomly assigned to everolimus (Afinitor) or temsirolimus (Torisel) had a 3.4% incidence of treatment-emergent deaths compared with a cumulative fatality rate of 1% in controls. Looking at renal cell cancer vs other cancers, the fatal event rate on mTOR inhibitors was 3.2% and 3.4%, respectively. The cause of death was unspecified in 61% of fatal adverse events. Sepsis/infection was the most commonly reported cause of death (16%).

Toni K. Choueiri, MD

Presenting author Toni K. Choueiri, MD, Director of the Kidney Cancer Center at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, Boston, said that the risk of death on mTOR inhibitors found in this study was “small but significant,” and he emphasized the overall benefit of these drugs when used for renal cell carcinoma and other approved indications. “The risks associated with these drugs may be greater once they are introduced to the real-world oncology population,” he noted. A Medline search was conducted for relevant articles on prospective randomized clinical trials published between 1966 and 2012 and ASCO Annual Meeting abstracts from 2000 to 2012. Eight trials met inclusion criteria: five evaluating everolimus and three evaluating temsirolimus compared to a control drug or placecontinued on page 6

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.

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

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

median prior therapies

59%

of patients received prior rituximab

93%

of patients received prior alkylating agents

100%

of patients received prior fludarabine and alemtuzumab

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

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

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

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

Overall response rate with ARZERRA 60 50 40

42%

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

30 20 10

FLUDARABINE AND ALEMTUZUMAB REFRACTORY (n=59)

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

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

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

The ASCO Post | APRIL 15, 2013

PAGE 6

Genitourinary Cancers Symposium mTOR Inhibitors continued from page 3

bo. The three trials of renal cell carcinoma included a total of 1,213 patients. Discussant Sandy Srinivas, MD, Associate Professor of Medicine (Oncology) at Stanford University, Stanford, California, cited several limitations of the meta-analysis, including differences among the trials in

the definition and reporting of fatal events, the large number of unspecified deaths, and an incomplete understanding of the biologic mechanisms of mTOR inhibitors.

Single Agent Bests Combination Therapy in RCC Combination therapy for advanced renal cell carcinoma did not significantly

improve outcomes compared with bevacizumab (Avastin) alone and had greater toxicity in a phase II randomized trial of 340 patients with advanced/metastatic renal cell carcinoma (90% had clear cell histology).4 Median duration of progression-free survival was 8.7 months with bevacizumab compared with 7.3 months with

BRIEF SUMMARY ARZERRA® (ofatumumab) Injection, for intravenous infusion The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE ARZERRA® (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The effectiveness of ARZERRA is based on the demonstration of durable objective responses [see Clinical Studies (14) of full prescribing information]. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions [see Adverse Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing information]. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3) of full prescribing information]. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insufficient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected. 5.6 Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • I nfusion Reactions [see Warnings and Precautions (5.1)] • C ytopenias [see Warnings and Precautions (5.2)] • P rogressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)] • H epatitis B Reactivation [see Warnings and Precautions (5.4)] • I ntestinal Obstruction [see Warnings and Precautions (5.5)] The most common adverse reactions (≥10%) in Study 1 were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. The most common serious adverse reactions in Study 1 were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 1 [n = 154]) or 3 doses (Study 2 [n = 27]). The data described in Table 1 and other sections below are derived from 154 patients in Study 1. All patients received 2,000 mg weekly from the second dose onward. Ninety percent of patients received at least 8 infusions of ARZERRA and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were White.

bevacizumab/temsirolimus, 7.7 months with sorafenib (Nexavar)/temsirolimus, and 11.3 months with bevacizumab/ sorafenib. Although bevacizumab/ sorafenib produced longer progressionfree survival, the difference between that combination and bevacizumab alone was not statistically significant. Additionally, bevacizumab/sorafenib

Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset of Study 1 (MedDRA 9.0) Total Population (n = 154)

Fludarabine- and AlemtuzumabRefractory (n = 59) Grade All ≥3 Grades % %

Grade All ≥3 Grades Body System/ % % Adverse Event Infections and infestations Pneumoniaa 23 14 25 15 Upper respiratory tract 1 10 3 0 infection Bronchitis 11 <1 19 2 Sepsisb 8 8 10 10 Nasopharyngitis 8 0 8 0 Herpes zoster 6 1 7 2 Sinusitis 5 2 3 2 Blood and lymphatic system disorders Anemia 16 5 17 8 Psychiatric disorders Insomnia 7 0 1 0 Nervous system disorders Headache 6 0 7 0 Cardiovascular disorders Hypertension 5 0 8 0 Hypotension 5 0 3 0 Tachycardia 5 <1 7 2 Respiratory, thoracic, and mediastinal disorders Cough 19 0 19 0 Dyspnea 14 2 19 5 Gastrointestinal disorders Diarrhea 18 0 19 0 Nausea 11 0 12 0 Skin and subcutaneous tissue disorders Rashc 14 <1 17 2 Urticaria 8 0 5 0 Hyperhidrosis 5 0 5 0 Musculoskeletal and connective tissue disorders Back pain 8 1 1 2 Muscle spasms 5 0 3 0 General disorders and administration site conditions Pyrexia 20 3 25 5 Fatigue 15 0 15 0 Edema peripheral 9 <1 8 2 8 0 1 0 Chills a Pneumonia includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia. b Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. c Rash includes rash, rash macular, and rash vesicular.

Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from patients with CLL in Study 1 were tested by enzyme-linked immunosorbent assay (ELISA) for anti-ofatumumab antibodies during and after the 24-week treatment period. Results were negative in 46 patients after the 8th infusion and in 33 patients after the 12th infusion. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading.

ASCOPost.com | APRIL 15, 2013

PAGE 7

Genitourinary Cancers Symposium was not tolerable. Grade 3 to 5 toxicity rates were 70% to 80% in the combination arms vs 39% with bevacizumab alone. All three combinations achieved higher response rates, but this did not translate to a progression-free survival advantage, said presenting author David F. McDermott, MD, Director, Biologic Therapy Program, Beth Israel Deaconess Medical Center, and

Leader of the Kidney Cancer Program at Dana-Farber Cancer Institute, Boston. Discussant Sandy Srinivas, MD, Associate Professor of Medicine (Oncology) at Stanford University, Stanford, California, said, “We have reached a ceiling with targeted drugs [in renal cell carcinoma]. Combining drugs in the same class or combin-

ing different targeted drugs remains a challenge.”

Surveillance Safe for Small Kidney Masses in Elderly In older patients, surveillance of small kidney masses is associated with similar cancer-related mortality to that seen with surgery, and surveillance has a lower risk William C. Huang, MD

7 DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with ARZERRA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the recommended human dose of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use Clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted. 10 OVERDOSAGE No data are available regarding overdosage with ARZERRA.

17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.2)] • Signs of infections including fever and cough [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)] • New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.3)] • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.4)] • New or worsening abdominal pain or nausea [see Warnings and Precautions (5.5)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring for blood counts [see Warnings and Precautions (5.2)] • Avoiding vaccination with live viral vaccines [see Warnings and Precautions (5.6)] Manufactured by: GLAXO GROUP LIMITED Greenford, Middlesex, UB6 0NN, United Kingdom U.S. Lic. 1809 Distributed by:

GlaxoSmithKline Research Triangle Park, NC 27709 ©2011, GlaxoSmithKline. All rights reserved. September 2011 ARZ:6BRS ©2011 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. AZA295R0 September 2011

of cardiovascular complications and allcause mortality. A strategy of surveillance in this setting can spare patients from surgery, according to a retrospective analysis of more than 8,300 elderly patients with small kidney masses.5 These findings are especially important for older sicker patients who may not be able to tolerate surgery, explained presenting author William C. Huang, MD, Assistant Professor of Urologic Oncology at New York University Langone Medical Center, New York. “Physicians can comfortably tell an elderly patient, especially a patient who is not healthy enough to tolerate anesthesia and surgery, that the likelihood of dying of kidney cancer is low and that kidney surgery is unlikely to extend their lives,” he stated. However, surgery remains an option for elderly patients in excellent health with an extended life expectancy, he added. The investigators used Surveillance, Epidemiology, and End Results (SEER) registry data linked to Medicare claims for patients aged 66 years or older to identify people diagnosed with small renal masses (ie, under 1.5 inches in diameter). Of 8,317 patients, 5,706 (70%) underwent surgery and 2,611 (31%) underwent surveillance. At a median follow-up of 4.8 years, 2,078 deaths were reported (25% of the population); 277 deaths (3%) were due to kidney cancer. The rate of kidney cancer–specific death was similar between the surveillance and surgery groups. In an analysis that controlled for patient and disease characteristics, over time surveillance was associated with a significantly lower risk of death from any cause as well as a lower risk of cardiovascular events. n

B:15.125” T:14” S:12”

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the human dose of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies. 13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15 to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared to control values).

Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared to the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared to control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared to the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals.

Disclosure: Drs. Rathkopf and Huang and Ms. Goodman reported no potential conflicts of interest. Dr. Oh is a consultant for Jannsen, Medivation, and Astellas. Dr. Choueiri has served in a consulting or advisory role for AVEO, Genentech, GlaxoSmithKline, Novartis, and Pfizer. Dr. McDermott has served in a consulting or advisory role for Genentech and Pfizer.

References available at ASCOPost.com

The ASCO Post | APRIL 15, 2013

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Genitourinary Cancers Symposium Genitourinary Oncology

Clinical-Pathologic Stage Discrepancy High in Patients with Bladder Cancer Undergoing Surgery By Alice Goodman

bout 48% of all patients with bladder cancer undergoing radical cystectomy have a discrepancy between their clinical stage and pathologic stage, according to the largest study to date to examine this issue. Upstaging after sur-

Phillip Gray, MD

gery is associated with reduced survival, while downstaging after surgery was associated with improved survival only in patients with locally advanced disease. These findings were reported at the 2013 Genitourinary Cancers Symposium, held recently in Orlando.1

Study Background “Appropriate clinical staging is vital for preoperative risk stratification and selecting patients for neoadjuvant therapy or alternative therapies such as chemoradiotherapy. It is also important for clinical trial design and for cross-study comparisons. Unfortunately, few studies report outcomes by clinical stage, and several studies show a high rate of clinical-pathologic discrepancy in patients undergoing radical cystectomy for bladder cancer.

We sought to investigate this discrepancy and its relationship to survival in bladder cancer patients undergoing radical cystectomy using a large national database,” explained presenting author Phillip Gray, MD, a third-year resident in the Harvard Radiation Oncology Program, Boston, who has been working with collaborators from the American Cancer Society and senior author Jason A. Efstathious, MD, DPhil, from Massachusetts General Hospital. The study used the National Cancer Data Base to identify 16,953 patients with a new diagnosis of bladder cancer treated with radical cystectomy from 1998 to 2009. The survival analysis was limited to 7,270 of these patients for whom 5-year follow-up data were available. Patients were typical of the national bladder cancer population undergoing radical cystectomy, Dr. Gray said. About 73% were male, 82% were Caucasian, and median age was 67 years. About 50% were treated at academic centers and 50% in community centers. Clinical stage at diagnosis was as follows: T1, 16%; T2, 61%; T3, 13%; and T4, 7% (3% were stage Tis/Ta). Radical cystectomy alone was performed in 74%; 22% had adjuvant chemotherapy, and 4%, neoadjuvant chemotherapy.

Discrepancy Rates Overall, the discrepancy rate was 47.8%; 41.9% were upstaged at surgery, whereas 5.9% were downstaged. Among

EXPERT POINT OF VIEW

“T

his is the most robust and definitive study ever done to compare clinical and pathologic staging,” stated formal discussant of this study, Dean F. Bajorin, MD, Attending Physician, Memorial Sloan-Kettering Cancer Center, New York, at the Genitourinary Cancers Symposium. “The study found that 42% of patients were understaged clinically, and 46% of T2 tumors were upstaged pathologically,” he said. “The study implies that we cannot compare overDean F. Bajorin, MD all survival in surgical and nonsurgical series, and we cannot pick the favorable stage T2 tumors. Markers are needed to enhance accuracy. This presents a compelling argument for multimodality therapy and for better understanding of tumor biology,” Dr. Bajorin told listeners. n Disclosure: Dr. Bajorin reported no potential conflicts of interest.

Staging in Bladder Cancer ■ In patients with bladder cancer who undergo radical cystectomy, clinical

stage is highly likely to be discrepant with pathologic stage following surgery.

■ About 42% of patients are upstaged by pathologic assessment, and about 6% are downstaged.

■ Pathologic upstaging is associated with decreased survival, whereas

pathologic downstaging is likely to improve survival only in patients with locally advanced disease.

the 80% of patients with muscle-invasive bladder cancer, only 5% were downstaged to non–muscle-invasive disease at surgery. Clinical-pathologic discrepancy in nodal stage was less common; 93% of patients were node-negative at diagnosis;

Jason A. Efstathious, MD, DPhil

19% of these patients were upstaged at surgery; 11% of clinically node-positive patients were downstaged to node-negative at the time of surgery. “When comparing initial clinical stage to final pathologic stage, there was a reduction in the number of patients classified as stages I and II, a doubling of those classified as stage III, and a tripling of those falling into stage IV,” Dr. Gray said. Factors associated with upstaging included female gender, advanced age, high tumor grade, nonurothelial histology, and more extensive lymphadenectomy. Downstaging was less likely to occur in the elderly, in Hispanics, and with squamous or adenocarcinoma histology. Receipt of neoadjuvant chemotherapy was the strongest predictor of downstaging.

Survival Analysis In the survival analyses, upstaging was significantly associated with increased 5-year mortality for all clinical stages, whereas downstaging was associated with improved survival only in patients with locally advanced disease

(clinical stages III and IV). “In patients with pathologically positive lymph nodes, increasing T stage was still associated with worse survival regardless of the number of lymph nodes removed and examined at the time of surgery,” Dr. Gray said. In a multivariate analysis using a Cox proportional hazard model, upstaging was associated with 80% excess mortality, whereas downstaging had no significant association with survival for the entire population. More extensive lymphadenectomy was associated with decreased 5-year mortality, as was receipt of care at a National Cancer Institute–designated cancer center. Receipt of neoadjuvant or adjuvant chemotherapy was associated with decreased overall survival; however, for neoadjuvant chemotherapy recipients, Dr. Gray explained, this may have been due to the inclusion of clinically node-positive patients being treated with palliative intent. When these same patients were removed from the analysis, this effect disappeared. “This study shows that current clinical staging is inadequate, resulting in high rates of clinicalpathologic stage discrepancy. Pathologic upstaging is associated with an increased risk of death for all patients, while pathologic downstaging may only benefit those with more advanced disease,” Dr. Gray told listeners. n Disclosure: Drs. Gray and Efstathious reported no potential conflicts of interest.

Reference 1. Gray PJ, Fedewa SA, Shipley WU, et al: Clinical-pathologic stage discrepancy in patients with bladder cancer treated with radical cystectomy. 2013 Genitourinary Cancers Symposium. Abstract 248. Presented February 15, 2013.

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The ASCO Post | APRIL 15, 2013

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Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Important Data and Treatment Advances Reported in GIST and in Pancreatic and Liver Cancers By Caroline Helwick

he 10th annual Gastrointestinal Cancers Symposium, held recently in San Francisco, was jointly sponsored by ASCO, the AGA (American Gastroenterological Association), ASTRO (American Society for Radiation Oncology), and the SSO (Society of Surgical Oncology). “We seek to present the newest scientific and clinical developments in gastrointestinal cancers at this meeting, and we focus not only on treatment but also on diagnostic testing and preventive strategies,” said Daniel Chung, MD, Associate Professor of Medicine at Harvard Medical School and Chair of the Steering Committee. “The 10th anniversary of this meeting provided a unique opportunity to look back at where we have been and then define where the field should be going in the next 10 years. One of the most important changes is that tumors are now being characterized at the molecular level, and this information can be used to determine prognosis and response to treatment. This type of information will be practice-changing.” The ASCO Post covered key pre-

tinib alone or imatinib plus surgery to remove residual tumor (followed by more imatinib). Patients were eligible for the study if they responded to prior imatinib treatment for at least 6 months. Seong Joon Park, MD, a fellow in the Department of Oncology at Asan Medical Center in Seoul, reported that the median progression-free survival in the nonsurgical group was 42.8 months, but this increased to 87.7 months in the group that underwent surgery (P = .001). Median overall survival has not been reached in the surgery arm, and was 88.8 months in the imatinib-alone arm (P = .001). Surgical management reduced mortality risk fivefold. In a multivariate analysis, low initial tumor burden was associated with longer overall survival; low initial tumor burden, female gender, and a specific alteration in the KIT gene (KIT exon 11 mutation, which is associated with improved responses) were associated with delayed disease progression. Even after applying propensity score and inverse-probability-weighting adjust-

Tumors are now being characterized at the molecular level... This type of information will be practice-changing. —Daniel Chung, MD

sentations in longer articles, and offers the following news briefs about other important developments reported at the symposium. For more in-depth reports from the meeting, see pages 1 and 16.

Surgery after Imatinib Improves Survival in GIST South Korean investigators reported that surgery after imatinib (Gleevec) for the treatment of gastrointestinal stromal tumors (GIST) prolonged survival.1 The study involved 134 patients with metastatic or recurrent GIST who were treated with ima-

ment, surgical management was associated with better clinical outcomes. “It is difficult to establish treatment guidelines based on the retrospective design of this study, but it provides good evidence supporting a clinical practice that is already widely adopted,” Dr. Park said.

S-1 Superior to Gemcitabine in Pancreatic Cancer Preliminary results from a phase III trial conducted in Japan showed that patients with pancreatic cancer who received adjuvant chemotherapy with S-1, an oral fluoropyrimidine currently

used in Asia (and to some extent Europe) but not approved in the United States, had a 44% lower risk of dying, compared to standard treatment with gemcitabine.2 Although the study was designed as a noninferiority trial, the data found S-1 to be superior to gemcitabine. “Our survival data were much stronger than expected,” said Katsuhiko Uesaka, MD, PhD, Medical Deputy Director at Shizuoka Cancer Center Hospital, Shizuoka, Japan. “Our interim analysis showed S-1 to be superior to gemcitabine in overall survival, and therefore it may be considered as a new standard treatment for resected pancreatic cancer patients in Japan.”

Katsuhiko Uesaka, MD, PhD

The study included 385 patients with resected stage I to III pancreatic cancer who received gemcitabine or S-1. On interim analysis, the 2-year survival rates were 70% with S-1 vs 53% � .0001 for noninfefor gemcitabine (P � riority; P � .0001 for superiority). S-1 was well tolerated in the Asian population, with more than 70% of patients able to complete treatment. However, the drug has proven more toxic in Caucasians (primarily, diarrhea), therefore, the findings are not currently applicable to non-Asian populations, experts said. Dr. Uesaka maintained that with dose adjustments, “I expect S-1 may be applicable to all patients with pancreatic cancer.” A U.S. phase III trial is currently exploring S-1 for the treatment of stomach cancer.

Chemoradiotherapy Following Induction Chemotherapy in Pancreatic Cancer For the treatment of locally advanced pancreatic cancer following induction chemotherapy, chemora-

Somnath Mukherjee, MD, FRCP, FRCR

diotherapy with capecitabine (Xeloda) was more effective and less toxic than chemoradiotherapy with gemcitabine, in the phase II SCALOP trial presented by Somnath Mukherjee, MD, FRCP, FRCR, of the Gray Institute for Radiation Oncology & Biology at the University of Oxford in the United Kingdom.3 The study confirms what is already standard practice in the United States. Patients first received three cycles of gemcitabine and capecitabine (GEMCAP) combination chemotherapy. Patients with stable or responding disease, tumors ≤ 6 cm, and performance status 0 or 1 were randomly assigned to an additional cycle of GEMCAP followed by radiation administered at 50.4 Gy in 28 daily fractions in combination with either capecitabine on weekdays or gemcitabine weekly. The primary endpoint was proportion of patients progression-free at 9 months, which was 62.9% with capecitabine/radiotherapy and 51.4% with gemcitabine/ radiotherapy. Median overall survival was 15.2 months and 13.4 months, respectively, a 50% reduction in risk The 12-month overall sur(P = .025). The vival was 79.2% in the capecitabine group and 64.2% in the gemcitabine group. Patients treated with capecitabine/ radiotherapy also had significantly less grade 3 and 4 hematologic toxicity (0% vs 18.4%; P = .007) and nonhematologic toxicity (11.1% vs 26.3%), though the latter was not statistically significant. Dr. Mukherjee suggested their findings should establish “capecitabine/radiotherapy as a tem-

ASCOPost.com | APRIL 15, 2013

PAGE 11

Gastrointestinal Cancers Symposium plate regimen for future trials investigating radiotherapy dose escalation and combination with novel radiosensitizers.”

Statins May Reduce Mortality from Liver Cancer Patients with hepatocellular carcinoma who took statins had a 30% lower mortality rate than those who did not, in a study from The University of Texas MD Anderson Cancer Center, Houston.4 Statins were used in addition to local and systemic therapy or surgical resection in 644 patients followed over 10 years. The median overall survival for all patients was 19.2 months, and 10.7% reported

Young Kwang Chae, MD, MPH, MBA

statin use. Young Kwang Chae, MD, MPH, MBA, of MD Anderson Cancer Center, reported that median overall survival was higher among statin users, 22.2 months vs 18 months for nonusers (P = .04). For hepatocellular carcinoma patients without cirrhosis, median overall survival was 31.7 months vs 21.8 months, respectively (P = .06), and the reduction in mortality was 30%, but the protective effect was not seen in patient with cirrhosis, whose median overall survival was 17.5 months with statin use and 18.9 months without (P = .8). The positive effect on overall survival remained significant after adjusting for age, sex, race, staging, hepatitis C and B history, liver cirrhosis, treatment, alcohol use, and diabetes (P = .03). Although patients taking statins were older and had more cardiovascular disease, diabetes, and other comorbidities, they actually lived longer, the authors noted. Dr. Chae pointed out that hepatocellular cancer is a very vascular disease, and preclinical evidence supports the antitumoral activity of statins. n Disclosure: Dr. Uesaka has received honoraria from Lilly and Taiho Pharmaceutical. Dr. Mukherjee has served in a consultant or advisory role for Celgene. Drs. Chung, Park, and Chae reported no potential conflicts of interest.

References 1. Park SJ, Ryu M-H, Ryoo B-Y, et al: The role of surgical resection following imatinib treatment in patients with metastatic or recurrent GIST. 2013 Gastrointestinal Cancers Symposium. Abstract 62. Presented January 24, 2013. 2. Uesaka K, Fukutomi A, Boku N, et al: Randomized phase III trial of adjuvant

chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer ( JASPAC-01 study). 2013 Gastrointestinal Cancers Symposium. Abstract 145. Presented January 25, 2013. 3. Mukherjee S, Hurt C, Griffiths G, et al: SCALOP: Results of a randomized phase II study of induction chemotherapy followed by gemcitabine or capecitabine based chemoradiation

in locally advanced pancreatic cancer. 2013 Gastrointestinal Cancers Symposium. Abstract LBA146. Presented January 25, 2013. 4. Chae YK, Kaseb AO, Mohamed H, et al: The association between statin use and hepatocellular cancer outcome. 2013 Gastrointestinal Cancers Symposium. Abstract 165. Presented January 25, 2013.

SPECIFIC

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

It’s time to consider

IMMUNOTHERAPY

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The ASCO Post | APRIL 15, 2013

PAGE 12

Gastrointestinal Cancers Symposium Aspirin and Colorectal Cancer continued from page 1

the risk of subsequent adenomas in a dose-response manner. Aspirin doses in these trials ranged from 81 to 325 mg/d, and hazard ratios ranged from 0.61 to 0.96. Randomized trials then began to show aspirin to be as protective against colorectal cancer. The British Doctors Aspirin Trial followed more than 7,500 individuals for at least 20 years and showed that regular use of aspirin (≥ 300 300 mg/d) resulted in a 29% reduction in colorectal cancer risk.2 “We have what appears to be very compelling and consistent phase III III literature to support the use of aspirin in reducing the risk of colorectal adenomas and colorectal cancer,” Dr. Fuchs indicated.

Mechanism of Protection A theory “gaining traction” as to how aspirin influences cancer carcinogenesis is through inhibition of cyclooxygenase (COX)-1 and -2, which affect apoptosis, cell division, metastasis, and angiogenesis. Large trials of the selective COX-2 inhibitors celecoxib (Celebrex) and rofecoxib (Vioxx) after polypectomy demonstrated a 24% to 45% reduction in adenoma recurrence. Numerous studies, however, also suggested that large doses of the COX2 inhibitors raised the risk of cardiovascular events; rofecoxib was ultimately removed from the market because of these concerns. A meta-analysis was reassuring for the 400-mg/d dose of celecoxib, which was not associated with cardiovascular events.3 Furthermore, Dr. Fuchs maintained, risk of gastrointestinal bleeding should not be an overriding concern. In spite of the evidence, however, the U.S. Preventive Services Task Force has recommended against the general use of nonsteroidal antiinflammatory agents for colorectal cancer prevention,4 concluding that the potential for harm outweighs the potential for benefit in the general population.

Who Might Benefit? Dr. Fuchs acknowledged, “We understand that giving these agents to the entire population may be of some concern, so we are therefore trying to define which persons may more selectively benefit from aspirin.” The UGT1A6 genetic variant is related to impaired metabolism of aspi-

rin. Persons with this genotype had a 34% reduction in the risk of adenoma recurrence and a 39% reduction if they took seven or more aspirin tablets per week, while those with the wild-type genotype derived no benefit.5 Such findings suggest the potential to use genotype in determining preventive utility, Dr. Fuchs said. Systemic inflammation may be another marker of response. Persons with the highest quartiles of circulating inflammatory factors were found to have a 67% greater likelihood of developing colorectal cancer.6 Those with levels of inflammatory markers below the median derived little effect from aspirin, but those with levels above the median had a 60% reduction in the development of cancer. “The data suggest this may be an additional means of teasing out those who may benefit from aspirin for colorectal cancer prevention,”

colorectal cancer, aspirin use before diagnosis was not associated with colorectal cancer–specific survival or overall survival, but regular use after diagnosis reduced colorectal cancer mortality by 29% and overall mortality by 21%.9 The most robust effect was in aspirin-naive patients who initiated aspirin use after diagnosis, for whom mortality was reduced by 47%, and patients with COX2–positive tumors, whose mortality risk was reduced by 61% with postdiagnosis aspirin use. Other pathways and mutations may also be influential with regard to aspirin use, including the PIK3CA pathway, which is downstream of COX-2. Dr. Fuchs and colleagues recently found that patients with colorectal cancer and activating mutations in PIK3CA experienced a protective effect from postdiagnosis use of aspirin that was not

“We have what appears to be very compelling and consistent phase III literature to support the use of aspirin in reducing the risk of colorectal adenomas and colorectal cancer.” —Charles S. Fuchs, MD, MPH

he said. “We also want to know whether aspirin prevents all colorectal cancers or those with a particular biology,” Dr. Fuchs said. In particular, intratumoral COX-2 expression might indicate susceptibility to the influence of aspirin, according to a study in which two aspirin tablets per week did not prevent tumors that were negative for COX-2 expression but did reduce by 36% the occurrence of tumors expressing COX-2.7 This offers yet another potential biomarker for defining the use of aspirin in the future, he said. Furthermore, in persons with colorectal cancer, COX-2 expression was prognostic for survival in a study where individuals whose tumors were COX-2–positive had a 70% increase in colorectal cancer–related mortality.8 “Expression of this marker may influence the outcome, and perhaps interventions against this marker could change the natural history for these patients,” he suggested. Interestingly, in the NHS, among the 1,279 patients with stage I–III

observed in the absence of the intratumoral mutation.10 Postdiagnosis aspirin use among patients with the mutation was associated with an 82% reduction in colorectal cancer–related mortality and a 46% reduction in overall mortality. “This suggests that PIK3CA may be a potential biomarker worthy of subsequent validation,” he said.

Next Step: Intervention Studies “What’s needed now are intervention trials to test whether these strategies should enter clinical practice,” Dr. Fuchs said. The ASCOLT trial is evaluating the effect of 3 years of aspirin, vs placebo, after adjuvant therapy in 2,660 patients with stage II/III colorectal cancer. The CALGB/SWOG 80702 trial is evaluating celecoxib at 400 mg/d after after adjuvant therapy in 2,500 patients with stage III disease. Correlative studies will evaluate the influence of baseline circulating inflammatory factors, germline polymorphisms in COX-2 and inflammatory pathways, tumoral expression of COX-2, NFkB, IL-6,

PIK3CA mutations, and other somatic events, and measures of tumor angiogenesis. “We have new and exciting studies that will further investigate this intersection between aspirin and prevention, with the ultimate goal of informing our patients who are at risk for colorectal cancer or its recurrence,” Dr. Fuchs said. n

Disclosure: Dr. Fuchs is a consultant for Amgen, Genentech, Pozen, Metamark Genetics, Momenta Pharmaceuticals, and Sanofi.

References 1. Chan AT, Giovannucci EL, Meyerhardt JA, et al: Long-term use of aspirin and non-steroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 294:914-923, 2005. 2. Flossman E, Rothwell PM: Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomized and observational studies. Lancet 369:1603-1613, 2007. 3. Solomon SD, Wittes J, Finn PV, et al: Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation 117:2104-2113, 2008. 4. U.S. Preventive Services Task Force: Routine aspirin and non-steroidal antiinflammatory drugs for the primary prevention of colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 146:361-364, 2007. 5. Chan AT, Tranah GJ, Giovannucci EL, et al: Genetic variants in the UGT1A6 enzyme, aspirin use, and the risk of colorectal adenoma. J Natl Cancer Inst 97:457-460, 2005. 6. Chan AT, Ogino S, Giovannucci EL, et al: Inflammatory markers are associated with risk of colorectal cancer and chemopreventative response to anti-inflammatory drugs. Gastroenterology 140:799-808, 2011. 7. Chan AT, Ogino S, Fuchs CS, et al: Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131-2142, 2007. 8. Ogino S, Kirkner GJ, Nosho K, et al: Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin Cancer Res 14:82218227, 2008. 9. Chan AT, Ogino S, Fuchs CS: Aspirin use and survival after diagnosis of colorectal cancer. JAMA 302:649-658, 2009. 10. Liao X, Lochhead P, Nichihara R, et al: Aspirin use, tumor PIK3CA mutation, and colorectal cancer survival. N Engl J Med 367:1596-606, 2012.

ASCOPost.com | APRIL 15, 2012 2013

PAGE 13

Awards Gastrointestinal Oncology

Society of Surgical Oncology Fellow Receives Colorectal Cancer Research Scholar Award

he Colon Cancer Challenge Foundation (CCCF) and the Society of Surgical Oncology (SSO) named Karen Lo, MD, a surgical resident at the University of Colorado, as recipient of third annual Colorectal Cancer Research Scholar Award. The award was presented at the SSO Annual Cancer Symposium held recently in Washington, DC.

Karen Lo, MD

“We are very excited to be able to provide this recognition to young scientific and medical investigators who are focusing their research on colorectal cancer,” said Thomas K. Weber, MD, president and founder of the Colon Cancer Challenge Foundation. “We are delighted to be able to partner with the Society of Surgical Oncology to support colorectal cancer translational research.” The CCCF and the SSO developed the Colorectal Cancer Research Scholar Award in order to recognize excellence in translational research focused on the molecular biology of colorectal cancer. The award, which includes a $2,000 grant for travel support, is made to the presenter of the abstract that secures the highest review score from the SSO Scientific Program Committee and is focused on colorectal cancer. Dr. Lo received the award for her abstract titled: Downregulation of Intercellular Adhesion Molecule-1 (ICAM-1) Abrogates Hepatic Metastases in Murine Colon Adenocarcinoma. Dr. Lo attended medical school at the University of California, Davis, where her interest in surgery began under the mentorship of Vijay Khatri, MD. Since 2008, she has been working in the laboratory of Carlton C. Barnett, MD, studying tumor microenvironment and host immune response under an American Cancer Society grant.

“[SSO] appreciates this opportunity to recognize and support the work of young surgical oncologists interested in colorectal cancer research, and we’re thankful for the Co-

lon Cancer Challenge Foundation’s support of this award,” said SSO President Monica Morrow, MD, Chief, Breast Service, Department of Surgery, and the Anne Burnett

Windfohr Chair of Clinical Oncology at the Memorial Sloan-Kettering Cancer Center and Professor of Surgery at the Weill Medical College of Cornell University. n

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

It’s time to consider

IMMUNOTHERAPY

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

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The ASCO Post | APRIL 15, 2013

PAGE 14

Expert’s Corner Gastrointestinal Oncology

BRAF Mutations in Colorectal Cancer: The Next Frontier A Conversation with S. Gail Eckhardt, MD By Caroline Helwick

S. Gail Eckhardt, MD

ome 5% to 10% of patients with colorectal cancer harbor the BRAF mutation, placing them at risk for poor treatment response and worse outcomes. The ASCO Post interviewed S. Gail Eckhardt, MD, an expert in this area who is Professor and Head of the Division of Medical Oncology at the University of Colorado Cancer Center and holds the Stapp-Harlow Endowed Chair in Cancer Research. Dr. Eckhardt also directs the Program for the Evaluation of Targeted Therapy, a multidisciplinary effort focused on finding alternative treatments for colorectal cancer and melanoma.

Role of BRAF in Cancer What is the BRAF mutation? BRAF is a protein kinase downstream of RAS in the RAS/RAF/MEK/ ERK pathway and has been a promising target in several cancers. The predominant mutation is similar to what we see in melanoma, the classic V600E mutation. The BRAF gene was discovered in the 1980s, but it was 10 years later before we identified the downstream effectors of this pathway. Mutations in BRAF lead to constitutive activation of downstream signaling through the MAPK pathway. How does the BRAF mutation impact patients clinically? The BRAF mutant genotype impacts the molecular and phenotypic characteristics of colorectal cancer. The mutation occurs fairly early in the progression of colorectal cancer and is associated with CpG island methylation. It leads to serrated adenoma-type tissue that has defective mismatch repair. In the end, you get a distinct type of tumor that is diploid and microsatellite-unstable. The clinical characteristics associated

with this genotype are female gender, older age, right-sided tumors, highgrade features, and microsatellite instability–high status (but not hereditary nonpolyposis colon cancer). Metastatic BRAF-mutated tumors carry a poor prognosis. In a cohort of 524 patients, overall survival for patients with BRAFmutant colorectal cancer was 10.4 months compared with 34.7 months for BRAF wild-type patients.1 In early retrospective studies of both cetuximab (Erbitux) and panitumumab (Vectibix), we clearly observed worse outcomes— shorter progression-free and overall survival—in BRAF-mutant patients. Studies have been consistent in this regard.

Inhibition of BRAF How is BRAF inhibition affected by tumor type? The BRAF mutation activates the MEK/ERK pathway through its downstream effectors, where we see production and promotion of the malignant phenotype through gene expression and proliferation. However, the clinical results with BRAF inhibitors in colorectal tumors have been quite disappointing.

ing and nonresponding sites of disease to get a better sense of the resistance mechanisms.

Response and Resistance Pathways Can BRAF be considered a targetable driver mutation in colorectal cancer? As we discuss new findings regarding subsets of colorectal cancer, it is important to go back to some of our large genetic databases, such as The Cancer Genome Atlas (TCGA), which has performed an integrative analysis of genomic changes in 195 colorectal tumors. We see that within the subset of tumors that are hypermutated, 46% are mutant for BRAF. Interestingly, these tumors have mutations in genes involving the WNT and TGF-beta pathways, among others. Preclinical studies have been conducted to help us model response and resistance patterns that might translate into clinical scenarios. In colorectal cancer cell line–derived xenograft models, there was a nice dose-dependent reduction in tumor growth with BRAF inhibition by vemurafenib (Zelboraf) and no response in BRAF wild-type tumors.

What we know is that BRAF-mutated colorectal cancer is a distinct molecular phenotypic and clinical subset that is in dire need of new treatment strategies. —S. Gail Eckhardt, MD

Unlike what we observe in melanoma— an 81% response rate in patients with advanced disease—the response rate in patients with metastatic colorectal cancer is only about 5%. There is evidence that BRAF inhibition does work in some patients with colorectal cancer, as we have seen dramatic effects on metastatic disease in the liver. But in general, BRAF inhibition yields disparate effects between these two tumor types. This may reflect a more heterogeneous pattern of BRAF activation in patients with colorectal cancer, but we also observe tumor heterogeneity in melanoma as well—mixed clinical responses to vemurafenib and rapidly acquired resistance. Even when different malignancies exhibit similar mutations, the mutations may not always signify similar tumor biology. Clearly, we need to obtain tissue from respond-

These results were positive but potentially misleading in colorectal cancer. For example, in work reported by Yang et al in BRAF-mutant colorectal cell lines, a diversity of responses to vemurafenib was observed.2 Interestingly, the KRAS-mutant cells were fairly uniformly resistant, indicating the existence of resistance pathways that may operate through upstream receptor tyrosine kinases that signal via CRAF and MEK. These data provide evidence that BRAF mutation is necessary but not sufficient for the activity of vemurafenib and that colorectal cancer cells can escape though receptor tyrosine kinase bypass and activation of the PTEN/PI3K/ AKT pathway. It has also been shown that incomplete suppression of phosphorylated ERK in BRAF-mutant colorectal cancer is associated with decreased sensitiv-

ity to vemurafenib. This suggests that phosphorylated ERK could be a pharmacodynamic marker of effective BRAF inhibition.

Multiple Pathway Inhibition Why doesn’t targeting BRAF in BRAFmutant colorectal cancer work? In a study published in 2012, investigators conducted a synthetic lethal screen of BRAF-mutant colorectal cancer cells that were resistant to vemurafenib and ultimately revealed that BRAF inhibition by vemurafenib caused rapid feedback activation of epidermal growth factor receptor (EGFR), which supported continued proliferation in the presence of BRAF inhibition.3 The researchers showed that if you suppressed EGFR with cetuximab, erlotinib (Tarceva), or gefitinib (Iressa), added to vemurafanib, BRAF-mutant colorectal cancer was inhibited in both in vitro and in vivo models, suggesting that combination therapy with BRAF and EGFR inhibitors may be more effective in this patient population. This was corroborated by another group, which showed that the combination of vemurafenib and erlotinib led to tumor regression in colorectal cancer cell line xenografts and reduction of the proliferative marker Ki67.4 Data are becoming consistent, therefore, that EGFR or other receptor tyrosine kinases may mediate resistance to vemurafenib, and that combinations with an EGFR or MEK inhibitor may produce greater suppression of tumor growth. Dr. Scott Kopetz’s laboratory has demonstrated that vemurafenib-resistant colorectal cancer cell lines exhibit PI3K/AKT activation. Enhanced tumor growth inhibition was observed when vemurafenib was combined with an inhibitor of this pathway.5 They concluded that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors and suggest combinatorial approaches to improve outcomes in this poor-prognosis subset. Thus, we should regard the PI3K/AKT pathway as another potential target for leveraging the activity of BRAF inhibition in BRAF-mutant tumors. This research is telling us what we already know: In colorectal cancer, mutations have to be viewed within the context of other resistance pathways.

ASCOPost.com | APRIL 15, 2013

PAGE 15

Expert’s Corner

“Mutation targeting” in colorectal cancer is quite distinct from what we see, for example, in non–small cell lung cancer with EGFR or ALK mutations. We are just not observing the successes seen in non–small cell lung cancer by mutation targeting alone.

Future Studies What other questions must be addressed? Do we need to segregate patients into different bins of resistance (inherent or acquired) and develop combination strategies that are tailored to those? Should combination therapy approaches be used up front or at the time of progression, in the case of acquired resistance? In a xenograft model, the addition of vemurafenib to irinotecan, cetuximab, bevacizumab (Avastin), or capecitabine (Xeloda) in metastatic disease resulted in increased antitumor activity and improved survival.2 How should we prioritize testing these regimens and patient selection strategies for this small subset in colorectal cancer? We also need to learn more about the immunomodulatory effects of BRAF inhibition, which may complement some of the newer approaches augmenting Tcell activation.

Closing Thoughts Any final thoughts about BRAF-mutated colorectal cancer? What we know is that BRAF-mutated colorectal cancer is a distinct molecular, phenotypic, and clinical subset that is in dire need of new treatment strategies. The existence of the mutation does not confer sufficient sensitivity that a single agent targeting this mutation will be effective. This is probably related to both inherent and acquired resistance mechanisms. In this area, preclinical models have been used to characterize resistance mechanisms and to develop actionable strategies with the result being that we now know that resistance is heterogeneous. Finally, we must obtain tissue from nonresponding patients and conduct sophisticated bench-to-bedside studies, as is being done in melanoma, to support preclinical rationales. A proposed Intergroup trial will enroll 63 patients with BRAF-mutated colorectal cancer, who will receive one of three treatments: cetuximab plus irinotecan, cetuximab and irinotecan plus vemurafenib, or vemurafenib plus cetuximab. The endpoint is progression-free survival. n

Disclosure: Dr. Eckhardt has received research funding from Roche/Genetech.

References 1. Tran B, Kopetz S, Tie J, et al: Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 117:4623-4632, 2011. 2. Yang H, Higgins B, Kolinsky, K et al:

Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res 72:779789, 2012. 3. Prahallad A, Sun C, Huang S, et al: Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483:100-103, 2012. 4. Corcoran RB, Ebi H, Turke AB, et al:

EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discovery 3:227235, 2012. 5. Mao M, Tian F, Mariadason JM, et al: Resistance to BRAF inhibition in BRAFmutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res 19:657-667, 2012.

DURABLE

IMMUNOTHERAPY EMPOWERS THE IMMUNE SYSTEM TO FIGHT CANCER Immunotherapy activates some immune cells to become memory cells.1-4 These memory cells remain primed to rapidly induce another immune response, even after active treatment has ended.1-4

It’s time to consider

IMMUNOTHERAPY

as an important treatment in your fight against cancer. For more information go to www.FightCancerWithImmunotherapy.com References: 1. Murphy K, et al, eds. Janeway’s Immunobiology. 7th ed. Garland Science, Taylor & Francis Group, LLC. New York, NY: 2008. 2. Abbas AK, et al, eds. Basic Immunology. Functions and Disorders of the Immune System. 3rd ed. Saunders Elsevier; Philadelphia, PA: 2011. 3. Atanackovic D, et al. PNAS. 2008;105(5):1650-1655. 4. Perret R, et al. Tissue Antigens. 2008;72:187-194.

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The ASCO Post | APRIL 15, 2013

PAGE 16

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Three Molecular Subtypes of Colorectal Cancer Identified By Caroline Helwick

ntrinsic molecular subtyping in breast cancer has become clinically applicable, and the same could be happening for gastrointestinal tumors, according to an international study reported at the 2013 Gastrointestinal Cancers Symposium in San Francisco.1

Josep Tabernero, MD

While recent efforts have yielded prognostic assays such as Oncotype and ColoPrint, this study takes genomic testing further by defining molecular subtypes with different prognoses and responses to adjuvant chemotherapy, reported Josep Tabernero, MD, Director of Vall d’Hebron Institute of Oncology in Barcelona, Spain.

Single-sample Predictor “We have developed a diagnostic single-sample predictor that allows the classification of colorectal cancer tumors of different intrinsic molecular subtypes. These subtypes are potentially clinically relevant, as they differ in their underlying biology and clinical outcomes and consequently require different treatment strategies,” Dr. Tabernero said. The classification system might be especially helpful in patients with stage II disease, since clinical and pathologic factors do not reliably indicate those at greatest risk of relapse. The information might be used not only to identify patients needing aggressive treatment but in predicting a priori which particular drugs will be of most benefit in an individual patient, he said.

Study Details The researchers used gene-expression data from 188 patients with colorectal cancer (stage I–IV) to develop a molecular subtype classifica-

EXPERT POINT OF VIEW

xel Grothey, MD, Professor of Oncology at the Mayo Clinic, Rochester, Minnesota, said that classifying colorectal cancer by intrinsic subtypes is “the right route forward,” especially if subtypes can Axel Grothey, MD Paula R. Pohlmann, MD, PhD be reliably linked to therapeutic response and survival. “We will not be treating all colorectal cancers alike. We know that, but we have lacked the tools to distinguish among them.” Paula R. Pohlmann, MD, PhD, Assistant Professor of Medicine at Vanderbilt-Ingram Cancer Center, Nashville, looks forward to validation of these findings in a more contemporary patient population. “This is based on a series of patients treated with [fluorouracil (5-FU)], which was the standard of care at the time. We need to see the study repeated in patients treated with oxaliplatin,” Dr. Pohlmann said. She also questioned whether assumptions about chemotherapy benefit can be made from a study this size. “Based on P values, the investigators said that subtypes A and C did not derive benefit from chemotherapy, but I believe the sample may be too small,” she said. “Subtype A did appear to get some benefit from 5-FU according to the separation of the survival curve, so I would not want to withhold chemotherapy from them.” “I would suggest validating this in an oxaliplatin-based treatment subset and increasing the sample size to have more confidence that patients will not respond to chemotherapy,” Dr. Pohlmann said. n Disclosure: Drs. Grothey and Pohlmann reported no potential conflicts of interest.

Molecular Subtypes in Colorectal Cancer ■ Researchers are defining intrinsic molecular subtypes for colorectal cancer. ■ One group has identified three subtypes, each with its own prognosis and response to chemotherapy.

■ Once such a system becomes validated, it could be used to individualize colorectal cancer treatment.

tion system, which was subsequently validated in 543 patients with stage II or III disease. Unsupervised hierarchical clustering of the whole genome revealed three distinct patterns that were organized into patient subgroups: 21.5% of the samples were categorized as subtype A (32 genes), 62% as subtype B (53 genes), and 16.5% as subtype C (102 genes). These subtypes differed according to three biologic hallmarks of colorectal tumors: epithelial-to-mesenchymal transition (associated with aggressive tumors), deficiency in mismatch repair genes (associated with genetic alterations), and the rate of cell proliferation. These features are known to independently affect outcomes, which the findings of the current study confirmed.

Subtypes Associated with Outcomes “The subtypes were significantly associated with prognosis and significantly correlated with benefit from adjuvant [fluorouracil (5-FU)]–based treatment in patients with stage III III disease, the standard of care at the time the patients were diagnosed,” said Dr. Tabernero. Most strikingly, after 10 years of follow-up, subtype C had the worst outcome and did not benefit from adjuvant chemotherapy. Stage III, subtype A had a better prognosis. Ten-year survival rates were approximately 65% without chemotherapy and 80% with chemotherapy, although this difference has not achieved statistical significance (P = .183). Stage III, subtype B had a pronounced benefit from chemotherapy, with 10-year survival rates of approximately 55% vs 80%, respectively (P = .014). In contrast, patients with subtype C derived no benefit from adjuvant chemotherapy, with 10-year survival rates of approximately 50% with chemotherapy and 65% without chemotherapy (P = .542). The 5-year overall survival difference between types A

and B, vs type C, was statistically significant (P = .0166).

Tailoring Treatment Directing treatment according to subtype would perhaps mean giving no 5-FU–based adjuvant chemotherapy to subtype A, giving chemotherapy to subtype B, and using a targeted approach (with companion diagnostics) in subtype C patients, he said. The investigators believe that differences in proliferation between the subtypes might explain the differences in 5-FU–based adjuvant treatment benefits. For example, subtype C had significantly reduced expression of Ki67 and AURKA, compared to subtypes A and B. The subtypes also differed significantly in mutation and microsatellite instability frequency (ie, mismatch repair deficiency), in mesenchymal markers (higher in subtype C) and in epithelial markers. The subtypes are currently being evaluated in stage IV colorectal cancer. In an interview with The ASCO Post, Dr. Tabernero said the researchers will be assessing their system in other patient populations, including those treated with oxaliplatin. He noted that a number of research groups are working in this area, and considerable overlap and consistency is being observed among their findings. “Next year, I believe we will see at least four publications related to molecular subtypes in colorectal cancer,” he predicted. n

Disclosure: Dr. Tabernero has received research funding from Agendia.

Reference 1. Simon I, Roepman P, Schlicker A, et al: Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesynchymal transition. 2013 Gastrointestinal Cancers Symposium. Abstract 333. Presented January 26, 2013.

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

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

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

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

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

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity

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

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors. Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia. Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide

were excluded from studies and may be at higher risk of hypersensitivity. Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

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

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

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

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

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

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

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

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

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

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN. Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. ©2013 Celgene Corporation 02/13 US-POM120044a

The ASCO Post | APRIL 15, 2013

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FDA Update

FDA Approves New Radioactive Diagnostic Imaging Agent to Help Locate Lymph Nodes in Patients with Certain Cancers

he FDA has approved technetium Tc 99m tilmanocept (Lymphoseek Injection), a radioactive diagnostic imaging agent that helps doctors locate lymph nodes in patients with breast cancer or

melanoma who are undergoing surgery to remove tumor-draining lymph nodes. Tilmanocept is an imaging drug that helps locate lymph nodes; it is not a cancer-imaging drug. It is the first new drug

used for lymph node mapping to be approved in more than 30 years. Other FDA-approved drugs used for lymph node mapping include sulfur colloid (1974) and isosulfan blue (1981). T:7”

This brief summary does not include all the information needed to use POMALYST® safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma: POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Neutropenia • ANC* < 500 per mcL or Febrile neutropenia (fever more than or equal to 38.5°C and ANC < 1,000 per mcL)

Interrupt POMALYST treatment, follow CBC weekly.

• ANC return to more than or equal to Resume POMALYST at 3 mg daily. 500 per mcL • For each subsequent drop < 500 per Interrupt POMALYST treatment mcL • Return to more than or equal to 500 Resume POMALYST at 1 mg less per mcL than the previous dose Thrombocytopenia • Platelets < 25,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly

• Platelets return to > 50,000 per mcL Resume POMALYST treatment at 3 mg daily • For each subsequent drop < 25,000 Interrupt POMALYST treatment per mcL • Return to more than or equal to 50,000 per mcL

Resume POMALYST at 1 mg less than previous dose.

*Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. Cosmos Communications

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2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma: Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity: Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity Dose Modification

who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

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FDA Update

“Removal and pathological examination of lymph nodes draining a primary tumor is an important diagnostic evaluation for some patients with breast cancer or melanoma,” said Shaw Chen, MD, Deputy Director of the Office of Drug Evaluation IV in the FDA’s Center for Drug Evaluation and Research. “To use [tilmanocept], doctors inject the

breast cancer. All patients were injected with the agent and blue dye, another drug used to help locate lymph nodes. Surgeons subsequently removed suspected lymph nodes for pathologic examination. Confirmed lymph nodes were examined for their content of blue dye and/or tilmanocept. Results showed the agent and blue dye had

drug into the tumor area and later, using a handheld radiation detector, find lymph nodes that have taken up [the agent’s] radioactivity.”

Safety and Efficacy Tilmanocept’s safety and effectiveness were established in two clinical trials of 332 patients with melanoma or

localized most lymph nodes, although a notable number of nodes were localized only by tilmanocept. The most common side effects identified in clinical trials was pain or irritation at the injection site. Technetium Tc 99m tilmanocept is marketed by Navidea Biopharmaceuticals, Inc, based in Dublin, Ohio. n

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6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm Trial 1 POMALYSTa

System Organ Class/Preferred Term Number(%) of Patients With at Least One Treatment Emergent Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

107 (100)

112 (100)

59 (55)

70 (63)

Pyrexia

20 (19)

34 (30)

Edema peripheral

25 (23)

18 (16)

Chills

10 (9)

12 (11)

Pain

6 (6)

5 (5)

Blood and lymphatic system disorders Neutropenia

56 (52)

53 (47)

Anemia

41 (38)

44 (39)

Thrombocytopenia

27 (25)

26 (23)

Leukopenia

12 (11)

20 (18)

4 (4)

17 (15)

38 (36)

39 (35)

Gastrointestinal disorders Constipation Diarrhea

36 (34)

37 (33)

Nausea

38 (36)

25 (22)

Vomiting

15 (14)

15 (13)

Infections and infestations Pneumonia

25 (23)

32 (29)

Upper respiratory tract infection

34 (32)

28 (25)

8 (8)

18 (16)

Urinary tract infection

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

Back pain

34 (32)

34 (30)

Musculoskeletal chest pain

23 (22)

22 (20)

Muscle spasms

20 (19)

21 (19)

System Organ Class/Preferred Term Musculoskeletal and connective tissue disorders

Arthralgia

17 (16)

17 (15)

Musculoskeletal pain

12 (11)

17 (15)

Pain in extremity

5 (5)

16 (14)

Muscular weakness

13 (12)

Bone pain

13 (12)

5 (5)

Dyspnea

36 (34)

50 (45)

Cough

15 (14)

23 (21)

Epistaxis

16 (15)

12 (11)

Respiratory, thoracic and mediastinal disorders

Metabolism and nutritional disorders Decreased appetite

23 (22)

20 ( 18)

Hyperglycemia

13 ( 12)

17 ( 15)

Hyponatremia

11 ( 10)

14 ( 13)

Hypercalcemia

22 ( 21)

13 (12)

Hypocalcemia

6 (6)

13 ( 12)

Hypokalemia

11 ( 10)

12 ( 11)

6 ( 6)

18 ( 16)

23 ( 22)

18 ( 16)

Skin and subcutaneous tissue disorders Hyperhidrosis

Fatigue and asthenia

Lymphopenia

Trial 1 POMALYSTa

(continued)

Rash Night sweats

5 ( 5)

14 ( 13)

Dry skin

10 ( 9)

12 ( 11)

Pruritus

16 ( 15)

12 ( 11)

Dizziness

21 ( 20)

19 ( 17)

Tremor

10 ( 9)

14 ( 13)

Headache

14 ( 13)

9 ( 8)

Neuropathy peripheral

11 ( 10)

8 ( 7)

Nervous system disorders

Investigations Blood creatinine increased

16 ( 15)

12 ( 11)

Weight increased

1 ( 1)

12 ( 11)

Weight decreased

15 ( 14)

9 ( 8)

Psychiatric disorders Insomnia

7 ( 7)

16 ( 14)

Confusional state

11 ( 10)

15 ( 13)

Anxiety

12 ( 11)

8 ( 7)

16 ( 15)

11 ( 10)

Renal and urinary disorders Renal failure aPOMALYST

alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period

Cosmos Communications

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General disorders and administration site conditions

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm

The ASCO Post | APRIL 15, 2013

PAGE 22

FDA Update

Philips Receives FDA 510(k) Clearance for MicroDose SI Mammography System

oyal Philips Electronics recently announced that it has received 510(k) clearance from the FDA for its MicroDose SI system, a full-field digital mammography system that has the

capability to enable future single-shot spectral imaging applications.

High Breast Density High breast density is a known risk

factor for breast cancer; women with high breast density as seen on a mammogram are four to five times more likely to get breast cancer than women with low breast density. Additionally,

high breast density blocks x-rays, making it difficult for clinicians to interpret breast images. As a result, categorization of breast density has become mandatory in many countries and several

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Table 3: Grade 3/4 Adverse Reactions Reported in ≥5% of Patients in Any Treatment Arm

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1

Trial 1 POMALYSTa

System Organ Class/Preferred Term [a] Number(%) of Patients With at Least One Treatment Emergent NCI CTC Grade 3 or 4 Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

96 ( 90)

99 ( 88)

50 ( 47)

43 ( 38)

Anemia

24 ( 22)

23 ( 21)

Thrombocytopenia

24 ( 22)

21 ( 19)

Leukopenia

6 ( 6)

11 ( 10)

Lymphopenia

2 ( 2)

8 ( 7)

Infections and infestations Pneumonia

26 (23)

2 ( 2)

9 ( 8)

Sepsis

6 ( 6)

3 ( 3)

10 ( 9)

1 ( 1)

12 ( 11)

14 ( 13)

6 ( 6)

3 ( 3)

7 ( 7)

14 ( 13)

13 ( 12)

10 ( 9)

6 ( 6)

4 ( 4)

10 ( 9)

7 ( 6)

Metabolism and nutritional disorders General disorders and administration site conditions Fatigue and asthenia Investigations Blood creatinine increased Respiratory, thoracic and mediastinal disorders Dyspnea Musculoskeletal and connective tissue disorders Back pain Muscular weakness Renal and urinary disorders Renal failure a

POMALYST alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1 POMALYSTa (N = 107)

POMALYST + Low dose Dex (N=112)

System Organ Class/Preferred Term

n (%)

Number(%) of Patients With at Least One Treatment Emergent Serious Adverse Reaction

72 ( 67)

69 ( 62)

Pneumonia

15 (14)

21 (19)

Urinary tract infection

0 ( 0)

6 ( 5)

Sepsis

6 ( 6)

3 ( 3)

5 (5)

7 (6)

Pyrexia

3 (3)

5 (5)

General physical health deterioration

0 (0)

2 (2)

Atrial fibrillation

2 (2)

3 (3)

Cardiac failure congestive

0 (0)

3 (3)

Infections and infestations

Respiratory, Thoracic and mediastinal disorders Dyspnea

n (%)

9 (8)

7 (6)

1 (1)

3 (3)

5 (5)

1 (1)

Dehydration

5 (5)

3 (3)

Hypercalcemia

5 (5)

2 (2)

4 (4)

2 (2)

System Organ Class/Preferred Term Renal and urinary disorders Renal failure Gastrointestinal disorders

General disorders and administration site conditions

Cardiac Disorders

(continued)

Blood and Lymphatic system disorders Febrile neutropenia Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders Back pain

[a] POMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)] Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and Cosmos Communications

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17 ( 16)

Urinary tract infection

Hypercalcemia

POMALYST + Low dose Dex (N=112)

constipation

Blood and lymphatic system disorders Neutropenia

POMALYSTa (N = 107)

ASCOPost.com | APRIL 15, 2013

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FDA Update

states in the United States. Unfortunately, there is not yet a standardized method for assessing breast density, which has limited making use of the density categorization for clinical decisions. The most frequently used method of breast density assessment is subjective manual and visual inspection of the image.

Single-shot Spectral Imaging As in existing MicroDose systems, MicroDose SI uses unique digital photon-counting technology, which enables clinicians to conduct exams using low-dose radiation without compromising image quality. The technology powering the MicroDose SI, single-shot spectral imaging, separates

raphy systems, with an average dose reduction of 40%) ■ Short exam time (less than 5 minutes including image acquisition) ■ Patient comfort with anatomically curved and warmed breast support. “The MicroDose SI … contributes to breast cancer screening by delivering the same low dose, high image quality, and ergonomics it already offers, while supplying clinicians with spectral-ready technology,” saidLakshmi Gudapakkam, Senior Vice President & General Manager of Diagnostic X-ray and Mammography Solutions, Philips Healthcare. n

high- and low-energy x-rays within one single exposure to target different tissue types, enhancing the clarity of mammogram images. Key advantages of MicroDose SI include: ■ High image quality at low x-ray dose (18% to 50% lower radiation dose than other digital mammog-

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diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN.

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

Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved.

POMBS.001 02/13

T:9.875”

misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established. 8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom,

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

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The ASCO Post | APRIL 15, 2013

PAGE 24

Journal Spotlight Genitourinary Oncology

Similar 15-year Functional Outcomes after Prostatectomy or Radiotherapy for Localized Prostate Cancer By Matthew Stenger

omparative longer-term functional outcomes of radical prostatectomy and external-beam radiation therapy for localized prostate cancer remain undefined. In a study recently reported in The New England Journal of Medicine,1 Matthew J. Resnick, MD, and colleagues at Vanderbilt University, Nashville, compared urinary, bowel, and

Matthew J. Resnick, MD

sexual function up to 15 years after prostatectomy or external-beam radiation therapy in men from the populationbased Prostate Cancer Outcomes Study (PCOS) who had been diagnosed with localized cancer in the mid-1990s. The study showed that there is little difference in functional outcomes between the two types of treatment at 15 years, with decline in all functional domains being common over the long term.

Study Details The PCOS enrolled 3,533 men diagnosed with prostate cancer in 1994 and 1995. The cohort for the current study consisted of 1,655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (n = 1,164) or external-beam radiation therapy (n = 491) as primary therapy (with or without androgendeprivation therapy) within 1 year after diagnosis. Patients had to have completed a 2-year or 5-year follow-up survey. Disease-specific outcomes were measured using multi-item rating scales,

with each domain-specific summary scale scored from 0 to 100 (worse to better function). Odds ratios (ORs) for all outcome analyses were adjusted for age, baseline function, race/ethnic group, tumor grade, number of coexisting illnesses, education level, and propensity score. At baseline, there were significant differences between the prostatectomy group and the radiotherapy group with regard to age (median of 64 vs 69 years, P � .001) and race/ethnic group distribution (white, black, and Hispanic for 76%, 12%, and 12%, respectively, vs 82%, 10%, and 8%, respectively; P � .001). Gleason scores tended to be lower in the prostatectomy group (2–4, 5–7, and 8–10 in 64%, 18%, and 6.5%, respectively, vs 59%, 22%, and 10%, respectively; P � .001), with the prostatectomy group also having fewer coexisting illnesses (0, 1, 2, and ≥ in 42.5%, 34%, 15%, and 8%, respectively, vs 33%, 33%, 17%, and 17%, respectively; P � .001). However, none of these differences was significant on analysis adjusting for propensity scores. There was no difference between groups in prostate-specific antigen level at baseline. At the time of the 15-year survey, 27.7% of patients in the prostatectomy group and 50.3% of those in the radiotherapy group had died. Among living patients, survey response rates were 87.5% at 2 years, 83.3% at 5 years, and 60.3% at 15 years. More surviving patients in the surgery group responded to the 15-year survey (63.2% vs 51.0%).

Urinary Function Patients in the surgery group were significantly more likely to have no urinary control or frequent urinary leakage at 2 years (9.6% vs 3.2%, OR = 6.22, 95% confidence interval [CI] = 1.92– 20.29) and 5 years (13.4% vs 4.4%, OR = 5.10, 95% CI = 2.29–11.36), but not at 15 years (18.3% vs 9.4%, OR =

Prostatectomy vs Radiotherapy for Localized Prostate Cancer ■ There was little difference in urinary, sexual, and bowel function at 15 years between men undergoing prostatectomy and those undergoing radiation therapy for localized prostate cancer.

■ Both the surgery and radiotherapy groups exhibited declining function in all domains over the long term.

2.34, 95% CI = 0.88–6.23). Patients in the prostatectomy group were more likely at all time points to wear incontinence pads. The likelihood of being bothered by urinary incontinence was significantly higher in the prostatectomy group at 2 years (10.6% vs 2.4%, OR = 5.86, 95% CI = 1.93–17.64) and 5 years (12.9% vs 2.9%, OR = 7.66, 95% CI = CI = = 2.97–19.89), but no signifisignificant difference was observed between groups at 15 years (17.1% vs 18.4%, OR = 0.87, 95% CI = 0.41–1.80). Mean summary scores decreased from 100 at baseline to approximately

80 in the radiotherapy group and to less than 70 in the prostatectomy group at 15 years among patients with normal baseline urinary function. Scores were higher in the radiotherapy group at years 1, 2, and 5. Among patients with lower function at baseline, both groups had a baseline score of 70. The mean score initially increased in the radiotherapy group but then gradually declined to near baseline level by 15 years.

Two Caveats on the PCOS Follow-up By Anthony V. D’Amico, MD, PhD

r. Resnick and colleagues are to be congratulated for following men on the PCOS study out to 15 years. The main result—“At 15 years, no significant relative differences in disease-specific functional outcomes were observed among men undergoing prostatectomy or radiotherapy”—should be interpreted with the following two caveats in mind. First, there is a numerical trend for increased urinary incontinence at 15 years in men undergoing surgery (18.3%) as compared to radiation (9.4%) and, similarly, a numerical trend for increased bowel dysfunction in the radiation (35.8%) as compared to the surgical (21.9%) group. These trends may have been statistically significant if all men evaluable at 5 years were still alive at 15 years. Specifically, the authors state that “at the time of the 15-year survey, 322 of the 1,164 men in the Anthony V. D’Amico, MD, PhD prostatectomy group (27.7%) and 247 of the 491 men in the radiotherapy group (50.3%) had died.” Therefore, the power to achieve statistical significance in the numerical trends observed at 15 years is limited by intercurrent deaths. Second, the authors state at the end of the discussion that “Although we evaluated the comparative harms of prostatectomy and radiotherapy, the precise contribution of prostate cancer treatment to age-dependent changes in urinary, sexual, and bowel function remains unknown, given the absence of an untreated, age-matched control cohort.” This is a very important point, and I would add that the ideal control group would have been men with prostate cancer matched by age, baseline genitourinary and gastrointestinal function, and prostate cancer indices (prostate-specific antigen level, Gleason score, and T category) who underwent and stayed on active surveillance so an accurate assessment of the treatment effect on 15-year genitourinary and gastrointestinal function could be assessed. Without this control group, the comparative data on erectile dysfunction, which we know normally increases with age, are very hard to interpret. n Disclosure: Dr. D’Amico reported no potential conflicts of interest.

Dr. D’Amico is the Eleanor Theresa Walters Distinguished Professor of Radiation Oncology, Department of Radiation Oncology, Harvard Medical School, and Chief of Genitourinary Radiation Oncology at both Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.

ASCOPost.com | APRIL 15, 2013

PAGE 25

Journal Spotlight

Scores initially decreased in the prostatectomy group and then improved back to baseline levels by 1 year and gradually declined to a score of approximately 65 at 15 years. Scores were higher in the radiotherapy group at years 1, 2, and 5 by similar magnitudes.

Sexual Function Patients in the surgery group were significantly more likely not to have erections sufficient for intercourse at 2 years (78.8% vs 60.8%, OR = 3.46, 95% CI = 1.93–6.17) and 5 years (75.7% vs 71.9%, OR = 1.96, 95% CI = 1.05–3.63), but there was no significant difference between groups at 15 years (87.0% vs 93.9%, OR = 0.38, 95% CI = 0.12–1.22). More patients in the prostatectomy group reported being bothered by sexual dysfunction at 2 years (55.5% vs 48.2%), 5 years (46.7% vs 39.7%), and 15 years (43.5% vs 37.7%), but none of these differences was statistically significant. Among patients with higher sexual function summary scores at baseline (≥ 80), the mean score decreased from approximately 90 in both groups to approximately 20 to 25 at 15 years; scores were higher in the radiotherapy group at 1 and 2 years, nearly identical in the two groups at 5 years, and declined at a

similar rate thereafter in both. Among patients with lower baseline function, scores in the ra-

pain, or urgency at 2 years (2.9% vs 7.9%, OR = 0.37, 95% CI = 0.14–0.96) and at 15 years (5.2% vs 16.0%, OR =

Considering the often long duration of survival after treatment for prostate cancer, these data may be used to counsel men considering treatment for localized disease. —Matthew J. Resnick, MD, and colleagues

diotherapy group decreased from approximately 43 at baseline to approximately 13 at 15 years, whereas those in the prostatectomy group decreased from approximately 53 to 15. Scores were higher in the radiotherapy group at 1 and 2 years, with scores in the two groups being nearly identical at 5 years.

Bowel Function Significantly fewer patients in the prostatectomy group had bowel urgency at 2 years (13.6% vs 34.0%, OR = 0.39, 95% CI = 0.22–0.68) and 5 years (16.3% vs 31.3%, OR = 0.47, 95% CI = 0.26–0.84), with the difference no longer being significant at 15 years (21.9% vs 35.8%, OR = 0.98, 95% CI = 0.45– 2.14). Significantly fewer patients in the prostatectomy group were bothered by frequent bowel movements,

0.29, 95% CI = 0.11–0.78), but not at 5 years (4.4% vs 5.8%, OR = 0.93, 95% CI = 0.27–3.22). Among patients with normal bowel function at baseline, mean summary scores decreased from 100 to approximately 87 in the prostatectomy group and 83 in the radiotherapy group at 15 years. The difference between the two groups remained stable after 1 year, with scores being higher in the surgery group at years 1, 2, and 5. Among patients with lower function at baseline, scores improved from 72 in the prostatectomy group and 70 in the radiotherapy group to 82 and 78, respectively, at 1 year and remained fairly stable thereafter (approximately 82 and 77, respectively, at 15 years). The authors concluded, “[M]en undergoing prostatectomy or [radiotherapy] for localized prostate cancer

had declines in all functional outcomes throughout early, intermediate, and long-term follow up. Whereas shortand intermediate-term data reveal differences in functional profiles among men undergoing prostatectomy and [radiotherapy], at 15 years we observed no significant relative between-group differences. Considering the often long duration of survival after treatment for prostate cancer, these data may be used to counsel men considering treatment for localized disease. Furthermore, these data underscore the need for consideration of active surveillance in appropriately selected men with lowrisk prostate cancer.”n

Disclosure: Dr. Resnick has served as a consultant/advisor for Dendreon and Bayer Healthcare.

Reference 1. Resnick MJ, Koyama T, Fan K-H, et al: Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med 368:436-445, 2013.

Editor’s note: For more on outcomes following prostatectomy vs radiotherapy and information on what your patients may be reading in the lay press, see page 130 in this issue of The ASCO Post for an interview with study coauthor David F. Penson, MD, MBA.

Don’t Miss These Important Reports in this Issue of The ASCO Post Sage Bolte, PhD, LCSW, OSW-C, on Sexual Health After Cancer see page 1

Charles S. Fuchs, MD, MPH, on Aspirin and Colorectal Cancer Prevention see page 1

S. Gail Eckhardt, MD, on BRAF Mutations in Colorectal Cancer see page 14

Anthony V. D’Amico, MD, PhD, on Prostate Cancer Outcomes Study see page 24

Matthew L. Meyerson, MD, PhD, Discusses Genomic Analysis of Squamous Cell Lung Cancers see page 34

David H. Kim, MD, on CT Colonography and the SIGGAR Trials see page 51

Visit The ASCO Post online at ASCOPost.com

Dean F. Bajorin, MD, ClinicalPathologic Discrepancy in Patients with Bladder Cancer see page 8

Thomas B. Julian, MD, and Shelley Hwang, MD, Debate Treatment of DCIS see page 32

The ASCO Post | APRIL 15, 2013

PAGE 26

Expert’s Corner

Sexual Health after Cancer continued from page 1

With Cancer, a program of the Inova Comprehensive Cancer and Research Institute, Fairfax, Virginia, said unresolved sexual dysfunction raises levels of distress and anxiety among cancer survivors and lowers their quality of life. This is especially true in young adult survivors who may not be sexually experienced enough to recognize the signs of sexual dysfunction caused by their treatment and raise the issue with their oncology team. The ASCO Post talked with Dr. Bolte about how oncologists can better inform patients of the potential sexual health problems associated with cancer therapy and provide resources to help patients resolve or manage symptoms.

Reason for Prevalence Why is sexual dysfunction so common among cancer survivors? Limited research has revealed two major reasons why patients don’t initiate conversations about sexual health (and consequently don’t get help): They don’t want to make their health-care provider uncomfortable, and they don’t believe there is a solution to their problem. For example, a woman may be told that she will go through menopause as a result of her therapy and interpret that as, “There is nothing I can do about it.” Moreover, although we are bombarded with commercials about warming vaginal lubricants and pills for erectile dysfunction, sexual health is still a very private and personal matter. If something is wrong, we may have feelings of embarrassment and sometimes shame about being broken, or we believe the problem can’t be fixed. Also, immediately after a cancer diagnosis, sex is often the last thing on patients’ minds, because they are rightly concentrating on getting rid of their

cancer, and they think they will be able to resume their sexual life after cancer. That is why sexual dysfunction is so distressing to many of our patients— because usually they can’t return to the sexual life they had before. Of course, the main concern for oncologists is to quickly rid patients of their cancer, so unless the cancer is affecting a sex organ—such as prostate cancer, where conversations about erectile dysfunction are common because it is often a result of treatment—sexual health usually doesn’t come up. As a result, patients with head and neck and hematologic cancers, for example, are often overlooked when it comes to this issue, and the distress in those patients is higher.

cause we didn’t give them information upfront about what to expect. Older survivors typically have enough experience to recognize sexual dysfunction. Further, they may be more creative in solving the problem because they may already have been experiencing changes in sexual function before their cancer diagnosis and had time to adjust to problems like vaginal dryness or erectile dysfunction. However, this does not mean that older adults do not experience psychological distress regarding changes in their sexual health. Maintaining sexual health is an important component in quality of life, regardless of age.

Younger vs Older Survivors

What can oncologists do to raise patient awareness of potential sexual health side effects due to treatment? Sexual side effects of treatment should be part of informed consent and discussed with the same level of detail as other possible side effects. When a woman is told that there is a risk she will go through medical menopause because of her chemotherapy, she may not really understand what that means and may not have enough information to ask, “What does that mean for me?” We usually tell patients they may have hot flashes or weight gain, but we often don’t explain that there could be vaginal changes, including vaginal stenosis and vaginal dryness, low libido, and painful intercourse, so we’re not providing patients with fully informed consent. The informed consent process should include the informational component of potential side effects of treatment and normalizing language to explain them. For example, you might say, “Some patients may experience changes in their sexual desire, the way they feel about their body, changes in erectile function, or vaginal changes. If you notice any changes, please feel free to talk to one of us about your concerns.” I know it is unrealistic to think that health-care providers can do all of the education about how to manage these symptoms in the upfront setting. But it is important to acknowledge potential sexual side effects and give patients permission to talk about their sexual well-being. There is a model of sexual assessment I teach called Ex-PLISSIT (permission, limited information, specific suggestions, and intensive therapy).1 Seventy percent of oncology patients are only going to need the first three parts of that model: permission, limited information, and specific sugges-

Does sexual dysfunction caused by cancer treatment affect younger and older survivors similarly? We don’t have enough comparative data to know exactly how the problem differs in younger and older survivors of all cancers. We do know that younger patients are likely to have fewer sexual experiences or time to establish their sexual identity and may not know what is normal for them in terms of sexual health. For example, if a young woman is experiencing vaginal dryness and had not been engaged in sexual activities prior to her diagnosis, she may not realize that her vaginal dryness is abnormal and tell her physician that she is experiencing pain during intercourse. Or a young male survivor may not recognize erectile problems. If young adults aren’t aware of what is sexually normal for them, they don’t have the information to even ask about solutions. When young adults are aware of sexual function changes, their psychological distress is higher. And shame on us as health-care providers if they are left to feel more isolated and alone be-

Resources for Combating Sexual Dysfunction after Cancer ■ American Association of Sexuality Educators, Counselors and Therapists—aasect.org

■ American Cancer Society—Sexuality for the Woman with Cancer; Sexuality for the Man with Cancer—cancer.org

■ ASCO—cancer.net ■ Leukemia & Lymphoma Society—Sexuality and Intimacy Fact Sheet: lls.org

■ LIVESTRONG—Male Sexual Functioning After Cancer; Female Sexual Functioning After Cancer—livestrong.org

■ National Cancer Institute—Facing Forward: Life After Cancer Treatment—cancer.gov

■ The Institute for Sexual Medicine—sexualmed.org

Fully Informed Consent

tions. For example, in packets of treatment information given to patients, oncologists can include fact sheets on managing sexual side effects or managing body image changes (see sidebar). It is also helpful if hospitals or private practices have a specific person on staff—for example, a nurse or social worker—with some training in sexual health. This designated person should have a list of resources handy, including the names of sex therapists, pelvic floor specialists, urologists, endocrinologists, and gynecologists, to give patients. An oncology-certified social worker can also be found through the Association of Oncology Social Work (www.aosw.org). Survivorship care plans should include a sexual health component with information regarding who to see about ongoing sexual health issues, whether they are psychological or physiological.

Recommended Approach What can physicians do to make the conversation about sexual health comfortable for their patients? The most important thing is body language. Are you standing over the patient or are you sitting next to the patient (or a little bit lower) to put yourself on the same level as you begin the conversation? It’s important to be mindful of the setting. You might begin by giving general information, such as, “Patients diagnosed with cancer often experience some change in their sexual desire or sexual function because of the treatments and/or because of the emotional distress the diagnosis causes.” You can follow this with specific information, such as, “Eighty percent of patients diagnosed with ovarian cancer or cervical cancer experience some change in vaginal integrity. Here are some things you can do about it.” Alternatively, you might add, “Here is the name of a person you can talk to, or at your next appointment, I’d like you to spend time with our nurse so she can educate you about what you can do proactively to help manage your sexual side effects.” If we wait for the patient to tell us about the sexual problems he or she is having, it means the issue has already settled in. n

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

Reference 1. Taylor B, Davis S: Using the extended PLISSIT model to address sexual healthcare needs. Nurs Stand 21(11):3540, 2006.

In metastatic melanoma

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

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

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

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

dEcodE metastatic melanoma.

ExtEnd

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

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

Percentage surviving

80 60

Not reached

7.9

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

20 0

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

‡

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

OS (months) ZELBORAF (n=337)

†

Dacarbazine (n=338)

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

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

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

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

Percentage surviving

80 60

13.6 9.7

ASCO=American Society of Clinical Oncology

20 0

Patients crossing over to ZELBORAF were censored.3

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

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

OS (months) Updated analysis of ZELBORAF

Updated analysis of dacarbazine

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

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

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

zelboraf.com

The ASCO Post | APRIL 15, 2013

PAGE 30

In the Clinic Breast Cancer

Ado-Trastuzumab Emtansine in Metastatic Breast Cancer By Matthew Stenger

Indication

n February 22, 2013, adotrastuzumab emtansine (Kadcyla, previously known as TDM1) was approved for use as a single agent for the treatment of patients with

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

HER2-positive metastatic breast cancer who previously received trastuzumab (Herceptin) and a taxane separately or in combination.1 Patients should have either received prior therapy for metastatic disease

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.

or developed disease recurrence during or within 6 months of completing adjuvant therapy. Approval was based on findings in the EMILIA trial,2,3 in which 991 patients with HER2-positive advanced

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

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. breast cancer who had previously been treated with trastuzumab and a taxane were randomly assigned to ado-trastuzumab emtansine at 3.6 mg/kg IV every 21 days (n = 495) or oral lapatinib (Tykerb) at 1,250 mg/d plus oral capecitabine (Xeloda) at 1,000 mg/m2 twice daily on days 1 to 14 of each 21day treatment cycle (n = 496). Patients had to have left-ventricular ejection fraction of ≥ 50% and ECOG performance status of 0 or 1. The ado-trastuzumab emtansine and lapatinib-plus-capecitabine groups were well matched for age (median of 53 years in both), race (white in 72% and 75%), ECOG performance status (0 in 60% and 63%), site of disease involvement (visceral in 67% and 68%), hormone receptor status (estrogen receptor–negative and progesterone receptor–negative in 41% and 45%), and number of prior chemotherapy regimens for locally advanced or metastatic disease (> 11 in 39% of both groups). The primary endpoints were progressionfree survival and overall survival. Ado-trastuzumab emtansine was associated with a significant 35% reduction in risk for disease progression (median progression-free survival, 9.6 vs 6.4 months; hazard ratio [HR] = 0.65; P � .0001). At a second interim analysis, ado-trastuzumab emtansine was associated with a significant 32% reduction in risk of death (median overall survival, 30.9 vs 25.1 months; HR = 0.68; P = .0006). Estimated survival rates were 85.2% in the ado-trastuzumab emtansine group vs 78.4% in the lapatinib-pluscapecitabine group at 1 year and 64.7% vs 51.8% at 2 years.

OF NOTE Ado-trastuzumab emtansine binds to the HER2 receptor, releasing cytotoxic catabolites that cause cell-cycle arrest and apoptotic cell death.

ASCOPost.com | APRIL 15, 2013

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In the Clinic

How It Works Ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate comprising trastuzumab and the small-molecule cytotoxic microtubule inhibitor emtansine (DM1). (The “ado-“ designation has been

OF NOTE Ado-trastuzumab emtansine carries boxed warnings for avoiding substitution for or with trastuzumab; hepatotoxicity, including liver failure and death; reductions in left-ventricular ejection fraction; and fetal harm. added to avoid potential dispensing errors arising from confusion with trastuzumab.) After binding to subdomain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and lysosomal degradation, resulting in intracellular release of emtansine-containing cytotoxic catabolites. The binding of emtansine to tubulin disrupts microtubule networks in the cell, resulting in cell-cycle arrest and apoptotic cell death. In vitro studies have also shown that, similar to trastuzumab, adotrastuzumab emtansine inhibits HER2 receptor signaling, mediates antibodydependent cell-mediated cytotoxicity, and inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress HER2.

How It Is Given The recommended dose of adotrastuzumab emtansine is 3.6 mg/kg via IV infusion every 3 weeks weeks until disease progression or unacceptable toxicity. The drug should not be given at higher doses. The first infusion should be given over 90 minutes; if infusion is tolerated, subsequent infusions may be

given over 30 minutes. Infusion should be slowed or interrupted in patients with infusion-related reactions, and the drug should be permanently discontinued in those with life-threatening reactions. Left-ventricular ejection fraction must be assessed prior to treatment and monitored during treatment. Hepatic function must be assessed prior to treatment and before each dose. Emtansine is metabolized mainly by CYP3A4; thus, concomitant use of strong CYP3A4 inhibitors (eg, ritonavir, clarithromycin, ketoconazole) should be avoided. Dose reduction or interruption or discontinuation of treatment may be required for increased serum transaminases, hyperbilirubinemia, left-ventricular dysfunction, thrombocytopenia, pulmonary toxicity, or peripheral neuropathy. For dose modification,

per limit of normal and total bilirubin to two times the upper limit of normal, symptomatic congestive heart failure, persistent left-ventricular ejection fraction less than 40%, or 40% to 50% with a decrease of 10% or more from baseline, development of interstitial lung disease or pneumonitis, and nodular regenerative hyperplasia.

Safety Profile The most common adverse events of any grade (> 25% of patients) occurring in patients receiving ado-trastuzumab emtansine in the EMILIA trial were nausea (39.8%), fatigue (36.3%), musculoskeletal pain (36.1%), thrombocytopenia (31.2%), increased transaminases (28.8%), headache (28.2%), and constipation (26.5%). The most common grade 3 or 4 adverse events were thrombocytopenia (14.5%), increased transami-

Ado-Trastuzumab Emtansine in Breast Cancer ■ Ado-trastuzumab emtansine (Kadcyla) was approved for monotherapy

in patients with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination.

■ Ado-trastuzumab emtansine is given at 3.6 mg/kg via IV infusion every 3 weeks until disease progression or unacceptable toxicity.

the first reduction is to 3.0 mg/kg and the second to 2.4 mg/kg; treatment should be discontinued if any further dose reduction is required. The dose should not be re-elevated after any dose reduction. Treatment interruption is required for grade 3 increased transaminases, grade 2 or 3 hyperbilirubinemia, leftventricular ejection fraction less than 40%, or 40% to 50% with a decrease of 10% or more from baseline, grade 3 or 4 thrombocytopenia, and grade 3 or 4 peripheral neuropathy. Treatment should be discontinued for grade 4 transaminase elevation, grade 44 hyperbilirubinemia, a concomitant increase in transaminases to three times the up-

nases (8.0%), anemia (4.1%), hypokalemia (2.7%), fatigue (2.5%), and peripheral neuropathy (2.2%). The most common grade 3 or 4 laboratory abnormalities were thrombocytopenia (17%), increased aspartate aminotransferase (8%), increased alanine aminotranferease (6%), and decreased hemoglobin (5%). Adverse events led to dose reduction in 16.3% of patients (most commonly due to thrombocytopenia, increased transaminases, and peripheral neuropathy), dose delay in 23.7% (most commonly due to neutropenia, thrombocytopenia, leukopenia, fatigue, increased transaminases, and pyrexia), and treatment discontinu-

ation in 6.5% (most commonly due to thrombocytopenia and increased transaminases). Ado-trastuzumab emtansine has boxed warnings for avoiding substitution for or with trastuzumab; hepatotoxicity, including liver failure and death; reductions in left-ventricular ejection fraction; and fetal harm. It also has warnings/precautions for pulmonary toxicity, infusion-related reactions, thrombocytopenia, neurologic toxicity, and the requirement that only FDA-approved tests be used for HER2 testing.

Cost The estimated cost of ado-trastuzumab emtansine is approximately $9,800 per month. n References 1. U.S. Food and Drug Administration: Ado-trastuzumab emtansine. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm340913. htm. Accessed March 5, 2013. 2. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012. 3. KADCYLATM (ado-trastuzumab emtansine) for injection prescribing information, Genentech, Inc, February 2013. Available at http://www.accessdata.fda.gov/ drugsatfda_docs/label/2013/125427lbl. pdf. Accessed March 5, 2013.

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

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

www.ASCOPost.com

The ASCO Post | APRIL 15, 2013

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Society of Surgical Oncology Breast Cancer

Does All DCIS Need Treatment? Debaters Take Sides at Surgical Oncology Meeting By Caroline McNeil

here are a few things about ductal carcinoma in situ (DCIS) on which everyone agrees: Incidence increased dramatically with the advent of mammography screening, not all cases detected will go on to cause symptoms in the patient’s lifetime, and there’s no proven way to tell which cases will progress. But agreement often ends when it comes to clinical management. Should all cases be treated with surgery and radiation in the absence of proven markers to show which cases will progress? Or is watch-and-wait an option? Can existing tools be used to guide the decision? Experts put their views on the line in a debate at the 66th Annual Cancer Symposium of the Society of Surgical Oncology, held March 6–9 in Washington, DC.

Battle Lines Drawn “All DCIS patients benefit from standard therapy,” declared Thomas B. Julian, MD, a Professor of Surgery at Drexel and Temple Universities in Philadelphia, who took the pro-treatment position in the debate-format session. DCIS is a heterogeneous disease that is overdiagnosed and overtreated, argued Shelley Hwang, MD, Professor of Surgery and Chief of Breast Surgery at Duke University. “Not all DCIS patients benefit from standard therapy.” The increase in DCIS in the United States has been dramatic, rising from 1% in the 1970s to 25% in 2009. It now accounts for 30% to 40% of lesions found by mammography. And MRI is likely to find even more. “As our technology moves, this will be a continuing problem…. We will have to move on to a better way to interpret the taxonomy of this disease,” Dr. Julian said. The current standard of care, according to National Comprehensive Cancer Network (NCCN) guidelines, is either lumpectomy followed by radiation, or

mastectomy, or lumpectomy alone. However the level of evidence supporting the last option is considered “low-level.”

If treatment prevents invasive breast cancer, why have the rates of invasive cancer gone up in the mammography era?

It’s Cancer—Treat It as Such Dr. Julian began with the basics: DCIS shares many characteristics and biomarkers with invasive cancer. And in the many major, randomized trials of DCIS, adjuvant treatment has reduced the recurrence rate. In trials by the National Surgical Adjuvant Breast and Bowel Project, for instance, radiation therapy after lumpectomy reduced recurrence by 50% (though it had no effect on overall survival). In other trials, treatment with tamoxifen reduced recurrence rates when compared with a placebo, and radiation was superior to observation. Even participants deemed “good risk” benefited to a degree in these trials. In fact, although some indicators of risk—margin status, presence of comedo necrosis, estrogen receptor status, Ki67 status, and others—are under study, none has so far been able to predict treatment benefit. In analyses of the large randomized trials, “there was no subset that didn’t seem to benefit from use of radiation therapy, even those with free margins and no comedo necrosis,” Dr. Julian said. Biomarker trials will need to be completed, including long-term follow-up and validation, “before we start moving away completely from use of radiation therapy in a subset of patients with DCIS,” he insisted. “Certainly molecular profiling is very important and will probably help us identify where we might not have to have a draconian full-court press for this disease. But this is still a work in progress,” he said.

One Size Does Not Fit All This approach ignores some important facts, argued Dr. Hwang. First, it is uncertain whether treating DCIS prevents the incidence of invasive breast

There was no subset that didn’t seem to benefit from use of radiation therapy. —Thomas B. Julian, MD

—Shelley Hwang, MD

cancer overall. “If treatment prevents invasive breast cancer, why have the rates of invasive cancer gone up in the mammography era? This is in direct contrast to colon cancer surveillance, where colonoscopy and removal of polyps has reduced the incidence of colon cancer.” Second, treatment doesn’t come without costs—financial costs to the medical system and personal costs to the patient. Surgery and radiation leave their marks and may have complications. (On her obligatory financial disclosure slide, Dr. Hwang included what she said was the most important disclosure: “I hate overtreatment.”) Third, there are markers, even if not perfect, that can help in gauging a patient’s risk of DCIS recurring or progressing. Dr. Hwang highlighted clinical markers such as grade, tumor size, estrogen receptor status, age, comorbidities, and so forth; the Van Nuys Prospective Score, a conglomerate of clinical data and other markers such as margin status; and the newer “nomogram” from Memorial Sloan-Kettering Cancer Center that uses 10 variables to predict the likelihood of recurrence in different subsets of patients. She also pointed to emerging molecular tools, such as the “12-gene score,” and a “DCIS score,” which identifies low-, intermediate-, and high-risk patients based on the presence of cancer-related genes.

Patient’s Role in Decision-making More validation of markers is needed, Dr. Hwang said, agreeing with Dr. Julian on this point. But, she argued, what we know so far can still serve as a starting point for discussion with patients. And finally, what about the patient? “All the preceding discussion has almost assumed that we’re in the driver’s seat and patients are going to do whatever we say. But this is no longer the reality and

I think it’s essential that we consider the patient’s very important central role.” It is important that women be given the chance, and the necessary information, to choose alternatives to standard therapy, she concluded, “and it really is our responsibility to start offering them options and inform them of the possible outcomes for each option. Every patient is unique, and the days of one treatment pathway for every patient are long gone. These conversations will lead the way toward real shared decision-making, and will likely be relevant for many of the disease we screen for today.” n

Disclosure: Dr. Julian reported no potential conflicts of interest. Dr. Hwang has served as a consultant or advisor for Genomic Health and has received research funding from Merck.

Inside this Issue of

The ASCO Post More Breast Cancer News Ado-Trastuzumab Emtansine in Metastatic Breast Cancer see page 30 Young Breast Cancer Survivors Understudied and Underserved see page 95 Qigong Practice and Qualityof-Life Benefits in Women with Breast Cancer see page 98 Effects of Menarche and Menopause on Breast Cancer Risk see page 103 Visit The ASCO Post online at ASCOPost.com

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PAGE 34

Expert’s Corner Thoracic Oncology

Genomic Analysis of Squamous Cell Lung Cancer Tumors May Lead to More Targeted Therapies A Conversation with Matthew L. Meyerson, MD, PhD By Jo Cavallo and Harvard Medical School, Boston, about the study results and what they could mean for more effective lung cancer therapies.

Significant Findings

Matthew L. Meyerson, MD, PhD

ast fall, a consortium of more than 300 researchers from The Cancer Genome Atlas (TCGA) Research Network published the results of their large-scale genetic analysis of squamous cell lung cancer in the journal Nature.1 The study, the first of its kind, compared the tumor cells from 178 untreated patients with squamous cell lung cancer to their healthy cells. The investigators found that over 60% of the tumors had genomic alterations in “targetable” signal transduction genes, and 90% showed mutations in TP53, a gene that regulates the cell cycle and functions as a tumor suppressor to prevent cancer from developing. They also identified previously unreported loss-of-function mutations of the HLA-A gene in the tumors. HLA (human leukocyte antigen) helps the immune system distinguish the body’s own proteins from proteins made by foreign invaders. The findings from the study suggest that treatment strategies utilizing customized immunotherapies could be an effective tool in treating squamous cell lung carcinoma, which kills about 50,000 people a year and is second in frequency to adenocarcinoma of the lung. While adenocarcinoma of the lung is the most common type of lung cancer found in nonsmokers, over 90% of squamous cell lung carcinomas are found in smokers and former smokers. The ASCO Post talked with the study’s lead author, Matthew L. Meyerson, MD, PhD, Director of the Center for Cancer Genome Discovery at the Dana-Farber Cancer Institute, Professor of Pathology at Harvard Medical School, and Senior Associate Member of the Broad Institute of MIT

Please talk about some of the major findings from The Cancer Genome Atlas Research Network study of squamous cell lung carcinoma. One of the significant findings of this study was that there are a large number of potentially actionable genomic alterations in squamous cell lung cancer, many of which had not been previously described. They include mutations in the PI3 kinase pathway, particularly in the catalytic gene PIK3CA and in the PTEN tumorsuppressor gene. Also, we found amplification of receptor tyrosine kinases, including

We also found mutations in the kinase domain of EGFR in 2 out of the 178 cases tested. While it’s a very small number, traditionally people always test lung adenocarcinoma for EGFR mutations, and if 1% of patients with squamous cell lung cancer might be treatable with already approved EGFR inhibitors, it seems valuable to test those patients for EGFR mutations as well.

effort to eventually expand accrual to include patients with squamous cell lung carcinoma. In addition, we are going to start seeing clinical trials stratified not only by disease type, but for alterations in specific genes as well. So you might have a specific trial for patients with a BRAF gene mutation or an FGFR3 gene mutation that might span different cancer types.

Clinical Trials and Genomic Profiling

Are lung cancer tumors now routinely genomically tested to determine the most effective therapy for each patient? At the Dana-Farber Cancer Institute, all patients with lung cancer are being tested for a number of major actionable gene alterations. And I think this is also true at the institutions in the Lung Cancer Mutation Consortium. I don’t know if it is happening at community oncology practices, but I think all patients with non–small cell lung cancer should be tested for mutations and other genomic alterations, especially patients who are nonsmokers, because they are the most likely to have actionable alterations in their genomes.

If cancer is now considered a genetic disease rather than a disease of a specific organ, how will it change the way drugs are tested in clinical trials, and how will you get enough patients to enroll in those trials? In order to get patients enrolled in appropriate clinical trials, every patient

All patients with non–small cell lung cancer should be tested for mutations and other genomic alterations, especially patients who are nonsmokers, because they are the most likely to have actionable alterations in their genomes. —Matthew L. Meyerson, MD, PhD

EGFR, ERBB2, and FGFR1, and overexpression of the AKT3 gene. These are all classic signal transduction alterations, and over 60% of the cases of squamous cell carcinomas in the study harbored one of these targetable alterations.

Existing Treatments Are there drugs currently available that can target some of these pathways? Yes. We’ve seen a real profusion of targeted therapies directed against mutant EGFR, ALK translocations, ROS1 translocations, and RET translocations in adenocarcinoma of the lung. Several of those drugs are already approved, and more are in clinical trials. There was not previously the notion that the signal transduction inhibitors would be an effective treatment for squamous cell lung carcinoma, but now we know that a large number of alterations can be considered for clinical trials.

should be tested in a comprehensive way for the potentially actionable genomic alteration in their tumors. We know that there are about 200,000 new cases of lung cancer each year, and between 25% and 30% of them are squamous cell lung cancer. That means there are 50,000 to 60,000 new cases of squamous cell lung cancer every year. Imagine that there is a mutation present in 2% of those patients. That would mean there are 1,000 to 1,200 new patients every year who can be tested in clinical trials with a targeted therapy, providing you do the genomic profiling to identify those patients. The Lung Cancer Mutation Consortium, which comprises 16 cancer institutions nationwide, is designed to accrue patients with non–small cell lung cancers and match their tumor type with trials testing targeted therapies. The initial trials are focusing on lung adenocarcinoma, but there is an

Looking Ahead How might your findings benefit patients with lung cancer in the future? In 2004, our group at Dana-Farber, as well as other groups, discovered EGFR mutations in lung cancer, and I think that started the paradigm of testing patients for gene mutations and using targeted therapies against those mutations. We have seen patients benefit enormously from EGFR inhibitors and more recently from ALK inhibitors. These findings have really changed our view of lung cancer, and we have gone from seeing advanced disease as an almost intractable disease to a situation where there is hope for every patient with lung cancer. But there still is no cure? Yes, that’s true. But in addition to what we have already discussed, there is another area that is beginning to show promise in lung cancer treatment, especially for squamous cell lung cancer, and it is with drugs that affect immune system regulation, such as anti-PD1 or

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PAGE 35

Expert’s Corner

anti-PDL1 antibodies. In our study, we found loss-of-function mutation in the HLA-A gene, which encodes major histocompatibility complex class 1. These mutations downregulate the immune response, so it suggests that the squamous cell lung cancers are somehow using downregulation of the immune response as a mechanism of tumor progression. This is interesting because the squamous cell lung cancers are responding to drugs like anti-PD1 antibodies. That suggests the squamous cell lung cancers may be trying to avoid an im-

mune response because the immune response keeps the cancer in check. It is consistent with the observation that antibodies such as anti-PD1 or anti-PDL1 appear to be effective in the treatment of squamous cell lung cancer. The other interesting feature of squamous cell lung cancers is that they have a very high mutation rate. That means that they have a lot of mutations in many, many different proteins, and these proteins could create neoantigens or neoepitopes that could be recognized by the immune system. So the loss-of-function mutation in HLA-

A provides more evidence that patients with squamous cell lung cancer may have underlying immune control of their cancers, and there may be some benefit achieved with immune system therapy. A related point is this: Now that we have the concept of genomic stratification to help identify patients who will benefit from targeted therapy, we may also use genomic analysis to help identify patients who will benefit from immunomodulatory therapy. Another important suggestion of this study is that our findings are not limited to

squamous cell lung cancer, but can be applied to all types of lung cancer. I’m confident that in the future, therapies will become more targeted and effective and that it will be possible to cure all lung cancers. n

Disclosure: Dr. Meyerson is an inventor of the patent on using the EGFR gene for cancer diagnosis and is the founder of Foundation Medicine, a cancer diagnostics company.

Reference 1. The Cancer Genome Atlas Research Network: Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519-525, 2012.

Study Shows Lung Cancer CT Screening Could Save 12,000 Lives Annually

The Risk of Death From Smoking Now Nearly Identical for Men and Women

By Jo Cavallo

creening all current and former smokers or had quit in the last 15 heavy smokers could prevent over years, the researchers estimated that 12,000 lung cancer deaths a year, ac8.6 million Americans met the NLST cording to a new study published in criteria for lung cancer screening in Cancer.1 The study, funded by the 2010—up from 7 million identified American Cancer Society, arrived at in the NLST. that number based on data from the If the low-dose CT screening proNational Lung gram adopted in the Screening Trial NLST was univerThe researchers (NLST),2 which sally implemented found that heavy among the screenestimated that smokers—those ing-eligible popula8.6 million Americans with at least a 30 tion, concluded the pack-year history met the NLST criteria for researchers, a total of smoking—who of 12,250 lung canlung cancer screening in received low-dose cer deaths, 8,990 in computed to2010—up from 7 million men and 3,260 in mography (CT) women, would be identified in the NLST. screening had a averted each year. n 20% lower chance References of dying from lung cancer than those 1. Ma J, Ward EM, Smith R, et al: who received chest x-rays. Annual number of lung cancer deaths Using data from the 2010 Nationpotentially avertable by screening in the al Health Interview Survey and the United States. Cancer 119(7): 13812010 U.S. Census, and applying the 1385, 2013. NLST criteria for 2. National Lung Screening Trial Repatients aged 55-74 search Team, Aberle DR, Adams AM, et years with at least a al: Reduced lung-cancer mortality with 30 pack-year history low-dose computed tomographic screenof smoking who ing. N Engl J Med 365: 395-409, 2011. were either current

By Jo Cavallo

esearchers from multiple organizacal for men and womtions, including the American Canen smokers. cer Society (ACS), studied the smoking And while the risk trends among men and women over the of death from lung last 50 years and found that women’s cancer appears to have smoking habits in that time have signifistabilized among men cantly increased their risk of dying from since the 1980s, it continues to rise among lung cancer and female smokers. The chronic obstructive study also found that While the risk of pulmonary disease women have a more (COPD) when difficult time quitdeath from lung compared to the ting then men and, cancer appears to smoking histories of as a result, for both earlier generations current and former have stabilized among of female smokers. female smokers the men since the 1980s, it The study, pubnumber of years lished in the New continues to rise among of smoking has inEngland Journal of creased. The study female smokers. Medicine,1 included also showed that the smoking histoquitting smoking at ries of more than 2.2 million adults ages any age dramatically reduces the risk of 55 and older. death from all major smoking-related disAs women began to smoke cigaeases and that quitting outright is much rettes at progressively younger ages and more effective than smoking fewer cigawith the same regularity and as heavily rettes. n as men—smoking prevalence for men Reference peaked in the 1970s and in the 1980s 1. Thun MJ, Carter BD, Feskanich D, et for women—their risk of death became al: 50-year trends in smoking-related morequivalent to men. The relative risks of tality in the United States. N Engl J Med death from lung cancer, COPD, stroke, 368:351-364, 2013. and heart disease are now nearly identi-

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The ASCO Post | APRIL 15, 2013

PAGE 40

American Academy of Dermatology Annual Meeting Dermatologic Oncology

New Data Reported on Melanoma, Cutaneous T-cell Lymphoma, Basal Cell Carcinoma, and Cancer Treatment Side Effects By Caroline Helwick

t the recent American Academy of Dermatology 71st Annual Meeting in Miami Beach, researchers presented interesting findings regard� ing melanoma and other skin cancers. The ASCO Post brings you the follow� ing news briefs on these topics.

Melanoma Incidence Decreases among Adolescents and Children An analysis of Surveillance, Epi� demiology and End Results (SEER) data showed that the incidence of melanoma in children and adoles� cents trended downward over the past decade (2000–2009).1 It is well established that melanoma incidence in adults has been increasing for 40 years, but trends among younger age groups have not been extensively studied. Investigators from Case Western Reserve University, therefore, re� viewed the SEER registries to calculate annual melanoma incidence rates in children and adolescents (age 0–19) from 1973 to 2009 and analyzed inci�

Laura B. Campbell

dence trends in the recent decade from 2000 to 2009. They found that the in� cidence rate was <�0.2 �0.2 0.2 per 100,000 per� sons in 1973, and then followed an in� consistent course to 1997, after which it rose to 0.7 in 2003 but declined to 0.5 by 2009. From 2000 to 2009, sig� nificant decreasing incidence trends were noted. The decreasing incidence trend was most notable for the adolescent age group (age 15–19). The change was significant for male adolescents and for melanomas with good prog� nostic indicators, according to Laura B. Campbell, a medical student at Case Western Reserve University School of Medicine, Cleveland. She said the decline could be the result

of increased adherence to sun pro� tection in recent years as well as de� creased time spent outdoors, with a shift to more time spent at indoor activities such as television� and electronics�based pursuits.

Preemptive Leucovorin May Ameliorate Pralatrexate Toxicity in CTCL Patients with cutaneous T�cell lym� phoma (CTCL) often experience a range of toxicities related to treatment with pralatrexate (Folotyn). In clinical trials and in clinical practice, mucosi� tis and hematologic abnormalities are common dose�limiting toxicities of pralatrexate. Gastrointestinal side ef� fects are also common. Adverse events are not relieved by B12 or folic acid. In a case series presented at the meeting by University of Pittsburgh researchers, CTCL patients who received preemp� tive leucovorin rescue along with prala� trexate were able to tolerate treatment.2 Preemptive leucovorin rescue (50 mg/m2) was given 24 hours after pralatrexate (30 mg/m2 weekly) as a salvage therapy to three patients who either failed to show improvement on prior therapies or experienced in� tolerable toxicity. Clinical responses were observed in all patients without the usual toxicity; no patients devel� oped mucositis. The prophylactic use of leucovorin may alleviate prala� trexate�associated side effects with� out compromising clinical efficacy, reported Sara Story, MD, a cutane� ous oncology clinical fellow at Uni� versity of Pittsburgh Medical Center.

Melanoma Prognosis Improved by Screening Seeing a dermatologist just once can mean the difference between melanoma diagnosed at an early stage, vs a later and more invasive stage, University of Pittsburgh in� vestigators reported.3 The findings support growing evidence that gen� eral screening for melanoma—even once in a lifetime—is cost�effective in adults aged 50 and older. In the study of 405 adults diag� nosed with melanoma, patients with one prior visit to the dermatolo� gist were about 30% more likely to present with noninvasive disease or

Sara Story, MD

melanoma in situ and to have thinner lesions (approximately half the mean Breslow depth), compared with pa� tients lacking a visit to the derma� tologist prior to the diagnosis. Interestingly, the differences seemed to be largely attributable to a higher rate of self�detection of noninva� sive lesions. Among patients who self� detected their cancer, 59% reported a previous dermatology consultation compared with 37% of those who did not (P = .007), said Michelle Cheng, MD, University of Pittsburgh School of Medicine. The findings highlight the critical role played by dermatologists in patient education, she noted.

Tanning Bed Exposure and Melanoma Type Patients with a history of expo� sure to artificial ultraviolet light via tanning beds had a higher risk for melanoma, but their average Breslow thickness at the time of diagnosis— especially for women—was lower than for patients with no history of exposure, a Polish study found.4 Barbara Borkowska, MD, and col� leagues from the Department of Dermatology, CSK MSW, Warsaw, queried 113 patients with cutaneous melanoma about exposure to tan� ning beds throughout their lifetimes. The control group consisted of age� and sex�matched individuals. Tanning bed exposure was highest for patients aged 30 to 39 (94.5%) and 40 to 49 (97.5%), compared to those < 29 (44.4%) and > 50 years of age (15%). The corresponding num� bers in healthy controls were 23.2%, 26.4%, 16.2%, and 38.1%. The average Breslow depth was 0.7 mm in women who declared tanning bed exposure and 1.8 mm in those without exposure, and the scores in men were 1.7 mm and

2.1�mm, mm,, respectively. �odular mela� noma was more than three times as common in patients who reported no exposure to artificial ultraviolet light as in patients claiming expo� sure. There was no correlation be� tween the declared number of expo� sures and the Breslow depth. Exposure to artificial ultraviolet light may be more likely to induce superficial spreading melanoma than nodular melanoma, the investigators suggested.

Neoadjuvant Vismodegib Enhances Cosmesis in Basal Cell Carcinoma Resection of basal cell carcinoma tumors resulted in smaller cosmetic defects when patients received neo� adjuvant vismodegib (Erivedge), in a small series reported by Stanford University investigators.5 The area of the defect was reduced by about 50% in patients who received 3 months of the hedgehog inhibitor vismodegib at 150 mg/d prior to surgical removal. After a median 5.5 months of fol� low�up, no recurrences were seen in any of five patients given the drug prior to surgery for lesions in surgically chal� lenging locations, such as the eyelid, reported Mina Ally, MBBS, a postdoc� toral research fellow at Stanford School of Medicine, Stan� ford, California. The drug is approved for locally advanced and metastatic basal cell carcinoma, but no options exist to reduce surgical morbidity in challenging cases, she said. The interim analysis included five patients with seven lesions treated for a median of 3.4 months. Mean estimated surgical defect decreased from 3 cm2 to 1.6 cm2 after preoperative treatment, a 46% reduction from baseline (P = .008). The downside was cost: For 3 months of treatment, the expenses ex� ceeded $22,000 ($7,500 per month) and some patients needed more than 3 months of the high�priced biologic.

Pruritus in Patients on Targeted Therapy About one in five patients treat� ed with inhibitors of the epidermal

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PAGE 41

American Academy of Dermatology Annual Meeting growth factor receptor or mammalian target of rapamycin (mTOR) develop pruritus, according to literature reviews performed by investigators from Memorial Sloan-Kettering Cancer Center in New York.6,7 The review evaluated 854 patients studied in 45 clinical trials of cetuximab (Erbitux), everolimus (Afinitor), and temsirolimus (Torisel). In the cetuximab meta-analysis (based on six studies), the overall incidence of all-grade pruritus was 18.2%, whereas high-grade pruritus was observed in 2.0% of patients. In the studies of the mTOR inhibitors,

Alyx Rosen

the overall incidence of all-grade pruritus was 14.1% with everolimus and 37.7% with temsirolimus. For these drugs, the investigators were able to calculate a relative risk, vs placebo, which they found to be 1.91 and 5.01, respectively. Prophylaxis, early detection, and proper management of symptoms are important for enhancing quality of life in these patients, said Alyx Rosen, a medical student at Albert Einstein College of Medicine and clinical research fellow at Memorial Sloan-Kettering Cancer Center, New York, who presented the studies. n

Disclosure: Drs. Story, Cheng, and Borkowska, and Ms. Campbell, Ms. Rosen, and Ms. Ally reported no potential conflicts of interest.

References 1. Campbell LB, Bordeux J, Barnholtz-Sloan J, et al: Decreasing trends in melanoma incidence from 2000 to 2009 in children and adolescents. American Academy of Dermatology Annual Meeting. Abstract P6960. Presented March 2, 2013. 2. Story S, Koch E, Geskin L: Does preemptive leucovorin use compromise the efficacy of pralatrexate in CTCL? American Academy of Dermatology Annual Meeting. Abstract P7010. Presented March 3, 2013. 3. Cheng M, Moreau J, Ferris L, et al: The effect of full body skin examinations on the prognosis of melanoma. American Academy of Dermatology Annual

Meeting. Abstract P6226. Presented March 3, 2013. 4. Borkowska B, Kardynal A, Sicinska J, et al: Invasiveness of melanoma in patients exposed to artificial UV light in tanning beds. American Academy of Dermatology Annual Meeting. Abstract P7126. Presented March 3, 2013. 5. Ally M, Aasi S, Oro A, et al: Vismodegib as an adjuvant to surgery for

basal cell carcinomas. American Academy of Dermatology Annual Meeting. Late-breaking abstract. Presented March 2, 2013. 6. Rosen AC, Ensslin C, Wu S, et al: Risk of pruritus in cancer patients treated with cetuximab: a systematic review of the literature and meta-analysis. American Academy of Dermatology Annual Meeting. Abstract P6967. Pre-

sented March 3, 2013. 7. Ensslin C, Rosen A, Wu S, et al: Risk of pruritus in cancer patients treated with inhibitors of the mammalian target of rapamycin, everolimus and temsirolimus: A systematic review of the literature and meta-analysis. American Academy of Dermatology Annual Meeting. Abstract P7000. Presented March 3, 2013.

The ASCO Post | APRIL 15, 2013

PAGE 42

National Comprehensive Cancer Network Annual Conference Adolescent and Young Adult Oncology

New NCCN Guidelines for Patients Available for Adolescents and Young Adults with Cancer

he �ational Comprehensive Can� cer �etwork (�CC�), with sup� port from the �CC� Foundation and the LIVESTRO�G Foundation and through collaboration with Critical Mass: The Young Adult Cancer Alliance (Critical Mass), recently announced the availability of the �CC� Guidelines for Patients: Caring for Adolescents and Young Adults (AYA).

Distinct Biology “The biology of cancer in adoles� cents and young adults differs from that in both younger and older can� cer patients,” said Brandon HayesLattin, MD, Senior Medical Advi�

Unique Challenges According to the LIVESTRO�G Foundation, more than 70,000 young adults, ages 15 through 39, are diag� nosed with cancer each year, and the sur� vival rates for young adults have not in� creased since 1975, unlike the dramatic

Peter F. Coccia, MD

improvement seen in children and older adults. Patients within this age group, of� ten falling between general demograph� ics for pediatric and adult oncology, face a unique set of challenges, such as reen� try into school or the workforce, insur� ance coverage issues, infertility resulting from treatment, neurocognitive effects, and secondary malignancies. “The unique psychosocial and eco� nomic issues of adolescent and young adult patients with cancer have major influences on morbidity and mortal� ity,” said Peter F. Coccia, MD, Ittner Professor and Vice�Chairman of the Department of Pediatrics, University of �ebraska Medical Center, Omaha. Dr. Coccia is a member of the �CC� Board of Directors and Chair of the �CC� Guidelines Panel for Young Adult On� cology. “Experts in AYA oncology from all 21 �CC� member institutions de� veloped both the �CC� Guidelines for AYA Oncology for medical profession� als and the �CC� AYA Guidelines for Patients. It is their hope and expectation that both sets of guidelines will contrib� ute to optimizing care and improving outcomes in AYA patients with cancer.”

Brandon Hayes-Lattin, MD

sor, LIVESTRO�G Foundation. Dr. Hayes�Lattin is Associate Professor, Division of Hematology and Oncol� ogy at Oregon Health & Science Uni� versity (OHSU), Medical Director, AYA Oncology Program at OHSU’s Knight Cancer Institute, and a young adult cancer survivor. “This group also faces unique challenges around im� portant issues such as peer support, diagnosis, treatment, and fertility. The �CC� Guidelines for Patients: Caring for Adolescents and Young Adults pro� vides invaluable information that can help these patients and their loved ones make sense of the diagnosis and work with their health�care team to make the best cancer care decisions possible.” �CC� aims to provide people with cancer and the general public with state� of�the�art cancer treatment information in easy�to�understand language. The �CC� Guidelines for Patients, trans� lations of the �CC� Clinical Practice Guidelines in Oncology, are meant to help people with cancer talk with their physicians about the best treatment op� tions for their disease. These �CC� Guidelines for Patients do not replace the expertise and clinical judgment of the physician.

Empowering Patients “We are pleased to announce the public availability of the adolescent and young adult oncology guide� lines for patients,” said Patricia J. Goldsmith, �CC�’s Executive Vice President and Chief Operating Offi� cer. “The objective of �CC� Guide� lines for Patients is to empower people with cancer to take a more active role

Samuel M. Silver, MD, PhD, Elected Chairman of NCCN Board of Directors

amuel M. Silver, MD, PhD, of the University of Michigan Comprehensive Cancer Center, has been elected Chairman of the �ational Com� prehensive Cancer �etwork (�CC�) Board of Directors. Dr. Silver was previously Vice Chairman of the Board and succeeds Thomas A. D’Amico, MD, of the Duke Cancer Institute. The change in leadership was formalized at the �CC� Board of Directors meeting held in conjunction with the �CC� 18th Annual Conference. Samuel M. Silver, MD, PhD “�CC� thanks Dr. D’Amico for his outstand� ing service as Chairman of the Board of Directors of �CC� during the past 3 years, and we are extremely pleased that Dr. Sam� uel Silver has been elected as our new Chairman of the Board,” said Robert W. Carlson, MD, CEO, �CC�. “We look forward to Dr. Silver’s leadership and to working with him to even further improve the services provided by �CC�.”

Leader in the Field Dr. Silver is the Assistant Dean for Research and Professor of Internal Medicine at the University of Michigan Comprehensive Cancer Center. A recognized leader in the field of oncology, Dr. Silver was elected a Master of the American College of Physicians for 2013, and specializes in hematology. He is holds several leadership roles within �CC�, most notably, Chair of the �CC� Governance Committee and member of the �CC� Executive Com� mittee and the �CC� Guidelines Steering Committee. “I am both humbled and excited to be elected as Chairman of the Board of Directors of the �CC�,” said Dr. Silver. “�CC� represents 21 of the world’s leading cancer centers, and the clinical and research expertise that this encompasses is truly remarkable. This is an exciting time for the �CC�. The Board has just approved an extensive strategic plan, and over the next few years, we are planning many projects, including electronic point of ser� vice deployment of the �CC� Guidelines, the introduction of enhanced oncology pathways, and enlarging our influence in coverage and public policy, among many other changes. I look forward to working with our members, our new CEO, Dr. Robert Carlson, and the wonderful, dedicated �CC� staff.” Dr. D’Amico, of the Duke Cancer Institute, was Chairman of the �CC� Board of Directors since 2010. A committed member of several �CC� com� mittees and �CC� Guidelines Panels, Dr. D’Amico will remain a Member of the Board. Succeeding Dr. Silver as Vice Chairman of the �CC� Board of Directors is Timothy J. Eberlein, MD, of Siteman Cancer Center at Barnes� Jewish Hospital and Washington University School of Medicine. n in their treatment. In making such re� sources available to adolescents, young adults, and their caregivers, �CC� strives to allow these young people to focus on recovery by offering a source of confidence in understanding diag� noses, treatment options, and their subsequent effects. �CC� is apprecia� tive of the support and collaboration from the LIVESTRO�G Foundation and Critical Mass, which made this important guideline possible.”

�CC� offers 11 other �CC� Guidelines for Patients, including those for breast, colon, non–small cell lung, ovarian, pancreatic, and prostate cancers, chronic myelogenous leuke� mia, malignant pleural mesothelioma, melanoma, multiple myeloma, and lung cancer screening. n Editor’s note: Watch future issues of The ASCO Post for an in�depth inter� view with Dr. Peter Coccia about the new patient�friendly guidelines.

NOW APPROVED

The first antibody-drug conjugate (ADC) for HER2-positive (HER2+) metastatic breast cancer

Indication KADCYLA™ (ado-trastuzumab emtansine) injection, for intravenous use, as a single agent, is indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.

Important Safety Information Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY • Do Not Substitute KADCYLA for or with Trastuzumab • Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function • Embryo- Fetal Toxicity: Exposure to KADCYLA can result in embryo- fetal death or birth defects. Advise patients of these risks and the need for effective contraception Please see brief summary of full Prescribing Information on following pages for additional important safety information, including Boxed WARNINGS.

NOW APPROVED Additional Important Safety Information Pulmonary Toxicity • Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in clinical trials with KADCYLA. In EMILIA the overall frequency of pneumonitis was 1.2% • Treatment with KADCYLA should be permanently discontinued in patients diagnosed with ILD or pneumonitis Infusion-Related Reactions, Hypersensitivity Reactions • Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the overall frequency of IRRs in patients treated with KADCYLA was 1.4% • KADCYLA treatment should be interrupted in patients with severe IRR and permanently discontinued in the event of a life-threatening IRR

HER2 Testing • Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA approved tests by laboratories with demonstrated proficiency Extravasation • In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration Nursing Mothers • Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother Pregnancy Registry • Encourage women who may be exposed to KADCYLA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720

• Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate

Adverse Reactions • The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue

Neurotoxicity • In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator group

You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/ medwatch or calling 1-800-FDA-1088.

Thrombocytopenia • In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group

• Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2

In the Phase III EMILIA trial (N=991) versus lapatinib + capecitabine:

Single-agent KADCYLA significantly improved survival1 PRIMARY ENDPOINT: OVERALL SURVIVAL (OS) 100

30.9 months

Proportion surviving (%)

HR=0.682 95% CI: 0.55, 0.85 P=0.0006

70 60 50

25.1 months

40 30 20

KADCYLA (n=495) No. of events: 149 lapatinib + capecitabine (n=496) No. of events: 182

10 0 0

164 133

136 110

111 86

86 63

62 45

38 27

28 17

13 7

5 4

Months No. at risk: 495 KADCYLA lapatinib + 496 capecitabine

485 471

474 453

457 435

439 403

418 368

349 297

293 240

242 204

197 159

Patients received KADCYLA (3.6 mg/kg IV, q3w) or lapatinib (1250 mg po qd, Days 1-21) + capecitabine (1000 mg/m2 po bid, Days 1-14) until disease progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) assessed by independent review committee, OS, and safety.1,2

• KADCYLA increased median OS by 5.8 months vs lapatinib + capecitabine1 • 50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine (9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.55, 0.77; P<0.0001)1 • The most common NCI-CTCAE (version 3) adverse reactions (ARs) Grades ≥3 (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue1

References: 1. KADCYLA Prescribing Information. Genentech, Inc. February 2013. 2. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.

Please see brief summary of full Prescribing Information on following pages for additional important safety information, including Boxed WARNINGS. For more information on KADCYLA, please visit KADCYLA.com

The ASCO Post | APRIL 15, 2013

PAGE 46

National Comprehensive Cancer Network Annual Conference

NCCN Adds Two New Member Institutions

he �ational Comprehensive Can� cer �etwork (�CC�) recently announced the addition of two new �CC� Member Institutions: UC San Diego Moores Cancer Center in La Jolla, California, and the University of Colo�

rado Cancer Center in Aurora, Colorado. “We are extremely pleased that UC San Diego Moores Cancer Center and the University of Colorado Cancer Center have been elected to institu� tional membership in �CC�,” said

Robert W. Carlson, MD, CEO of �CC�. “These two institutions add substantial strength and expertise to the S:6.875” excellence of cancer care, research, and education characteristic of the other 21 world�class member institutions.”

KADCYLA™ (ado-trastuzumab emtansine) Injection for intravenous use Initial U.S. Approval: 2013 This is a brief summary of information about KADCYLA. Before prescribing, please see full Prescribing Information. Do Not Substitute KADCYLA for or with Trastuzumab WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women and no reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, treatment with trastuzumab, the antibody component of KADCYLA, during pregnancy in the postmarketing setting has resulted in oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its mechanism of action. If KADCYLA is used during pregnancy, or if the patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of KADCYLA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin. (2.2, 5.1) • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function. (2.2, 5.2) • Embryo-Fetal Toxicity: Exposure to KADCYLA can result 5.4 Pulmonary Toxicity in embryo-fetal death or birth defects. Advise patients Cases of interstitial lung disease (ILD), including pneumonitis, of these risks and the need for effective contraception. some leading to acute respiratory distress syndrome or fatal (5.3, 8.1, 8.6) outcome have been reported in clinical trials with KADCYLA. Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) 1 INDICATIONS AND USAGE has been reported, with one case of grade 3 pneumonitis. Signs KADCYLA™, as a single agent, is indicated for the treatment and symptoms include dyspnea, cough, fatigue, and pulmonary of patients with HER2-positive, metastatic breast cancer who infiltrates. These events may or may not occur as sequelae of previously received trastuzumab and a taxane, separately or in infusion reactions. In the randomized trial (Study 1), the overall combination. Patients should have either: frequency of pneumonitis was 1.2% [see Adverse Reactions (6.1)]. • Received prior therapy for metastatic disease, or • Developed disease recurrence during or within six months of Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. completing adjuvant therapy. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Adverse Reactions (6.1)]. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1 [see Clinical Studies (14.1)]. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2)]. Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 x ULN or bilirubin > 1.5 x ULN prior to the initiation of treatment. In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients). Two of these three cases of NRH were observed in the randomized trial (Study 1) [see Adverse Reactions (6.1)]. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension but with normal transaminases and no manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued. 5.2 Left Ventricular Dysfunction Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution’s normal limits. Treatment with KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Dosage and Administration (2.2)]. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1 [see Clinical Studies (14.1)].

UC San Diego Moores Cancer Center Established in 1977, the UC San Di� ego Moores Cancer Center is one of just 41 �ational Cancer Institute (�CI)– designated comprehensive cancer cen�

and 13.5% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology (13.2)]. 5.8 HER2 Testing Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)]. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 5.9 Extravasation In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

Patients with dyspnea at rest due to complications of advanced 6 ADVERSE REACTIONS malignancy and co-morbidities may be at increased risk of The following adverse reactions are discussed in greater detail in other sections of the label: pulmonary toxicity. • Hepatotoxicity [See Warnings and Precautions (5.1)] 5.5 Infusion-Related Reactions, Hypersensitivity Reactions • Left Ventricular Dysfunction [See Warnings and Precautions (5.2)] Treatment with KADCYLA has not been studied in patients who • Embryo-Fetal Toxicity [See Warnings and Precautions (5.3)] had trastuzumab permanently discontinued due to infusion-related • Pulmonary Toxicity [See Warnings and Precautions (5.4)] reactions (IRR) and/or hypersensitivity; treatment with KADCYLA is • Infusion-Related Reactions, Hypersensitivity Reactions [See not recommended for these patients. Warnings and Precautions (5.5)] Infusion-related reactions, characterized by one or more of • Thrombocytopenia [See Warnings and Precautions (5.6)] the following symptoms − flushing, chills, pyrexia, dyspnea, • Neurotoxicity [See Warnings and Precautions (5.7)] hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of KADCYLA. In the randomized 6.1 Clinical Trials Experience trial (Study 1), the overall frequency of IRRs in patients treated with Because clinical trials are conducted under widely varying KADCYLA was 1.4% [see Adverse Reactions (6.1)]. In most patients, conditions, adverse reaction rates observed in the clinical trials of these reactions resolved over the course of several hours to a day a drug cannot be directly compared to rates in the clinical trials of after the infusion was terminated. KADCYLA treatment should be another drug and may not reflect the rates observed in practice.

In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, One case of a serious, allergic/anaphylactic-like reaction has been musculoskeletal pain, thrombocytopenia, headache, increased observed in clinical trials of single-agent KADCYLA. Medications to transaminases, and constipation. treat such reactions, as well as emergency equipment, should be The ADRs described in Table 6 were identified in patients with HER2positive metastatic breast cancer treated in a randomized trial available for immediate use. (Study 1) [see Clinical Studies (14.1)]. Patients were randomized 5.6 Thrombocytopenia to receive KADCYLA or lapatinib plus capecitabine. The median Thrombocytopenia, or decreased platelet count, was reported in duration of study treatment was 7.6 months for patients in the clinical trials of KADCYLA (103 of 884 treated patients with ≥ Grade KADCYLA-treated group and 5.5 months and 5.3 months for patients 3; 283 of 884 treated patients with any Grade). The majority of these treated with lapatinib and capecitabine, respectively. Two hundred patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the and eleven (43.1%) patients experienced ≥ Grade 3 adverse events nadir occurring by day 8 and generally improving to Grade 0 or in the KADCYLA-treated group compared with 289 (59.2%) patients 1 (≥ 75,000 /mm3) by the next scheduled dose. In clinical trials of in the lapatinib plus capecitabine-treated group. Dose adjustments KADCYLA, the incidence and severity of thrombocytopenia were for KADCYLA were permitted [see Dosage and Administration higher in Asian patients. Independent of race, the incidence of (2.2)]. Thirty-two patients (6.5%) discontinued KADCYLA due to an severe hemorrhagic events in patients treated with KADCYLA was adverse event, compared with 41 patients (8.4%) who discontinued low. lapatinib, and 51 patients (10.5%) who discontinued capecitabine In the randomized trial (Study 1), the overall frequency of due to an adverse event. The most common adverse events leading thrombocytopenia was 31.2% in the KADCYLA-treated group and to KADCYLA withdrawal were thrombocytopenia and increased 3.3% in the lapatinib plus capecitabine-treated group [see Adverse transaminases. Eighty patients (16.3%) treated with KADCYLA had Reactions (6.1)]. The incidence of ≥ Grade 3 thrombocytopenia was adverse events leading to dose reductions. The most frequent 14.5% in the KADCYLA-treated group and 0.4% in the lapatinib plus adverse events leading to dose reduction of KADCYLA (in ≥ 1% of capecitabine-treated group. In Asian patients, the incidence of patients) included thrombocytopenia, increased transaminases, ≥ Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated and peripheral neuropathy. Adverse events that led to dose delays occurred in 116 (23.7%) of KADCYLA treated patients. The most group and 1.3% in the lapatinib plus capecitabine-treated group. Monitor platelet counts prior to initiation of KADCYLA and prior frequent adverse events leading to a dose delay of KADCYLA (in to each KADCYLA dose [see Dosage and Administration (2.2)]. ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, KADCYLA has not been studied in patients with platelet counts fatigue, increased transaminases and pyrexia. interrupted in patients with severe IRR. KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR [see Dosage and Administration (2.2)]. Patients should be observed closely for IRR reactions, especially during the first infusion.

<100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm3) [see Dosage and Administration (2.2)]. Patients with thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant treatment should be closely monitored during treatment with KADCYLA.

5.7 Neurotoxicity Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any 5.3 Embryo-Fetal Toxicity Grade). In the randomized trial (Study 1), the overall frequency of KADCYLA can cause fetal harm when administered to a pregnant peripheral neuropathy was 21.2% in the KADCYLA-treated group

Table 6 reports the ADRs that occurred in patients in the KADCYLAtreated group (n=490) of the randomized trial (Study 1). Selected laboratory abnormalities are shown in Table 7. The most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.

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National Comprehensive Cancer Network Annual Conference ters in the United States, and the only one in the San Diego region. “We are thrilled to join �CC�,” said Scott M. Lippman, MD, Director, UC San Diego Moores Cancer Center. “�CC� and UC San Diego share a mission to save lives through bringing the most effective therapeutic and prevention strategies to cancer patients. We look forward to

Table 6 Summary of Adverse Drug Reactions Occurring in Patients on the KADCYLA Treatment Arm in the Randomized Trial (Study 1)

Adverse Drug Reactions (MedDRA) System Organ Class

KADCYLA (3.6 mg/kg) n=490 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2) n=488 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Blood and Lymphatic System Disorders Neutropenia

6.7

2.0

9.0

4.3

Anemia

14.3

4.1

10.5

2.5

Thrombocytopenia

31.2

14.5

3.3

0.4

1.8

0.2

3.3

0.4

3.3

2.5

Cardiac Disorders Left ventricular dysfunction Eye Disorders Lacrimation increased Dry eye

3.9

3.1

Vision blurred

4.5

0.8

Conjunctivitis

3.9

2.3

0 0.4

Gastrointestinal Disorders Dyspepsia

9.2

11.5

Stomatitis

14.1

0.2

32.6

2.5

Dry Mouth

16.7

4.9

0.2

Abdominal pain

18.6

0.8

17.6

1.6

Vomiting

19.2

0.8

29.9

4.5

Diarrhea

24.1

1.6

79.7

20.7

Constipation

26.5

0.4

11.1

Nausea

39.8

0.8

45.1

2.5 0.2

General Disorders and Administration 8.2

3.1

Pyrexia

18.6

0.2

8.4

0.4

Asthenia

17.8

0.4

17.6

1.6

Fatigue

36.3

2.5

28.3

3.5

Nodular regenerative hyperplasia*

0.4

Portal hypertension*

0.4

0.2

0.8

0.2

9.4

0.6

3.9

Blood alkaline phosphatase increased

4.7

0.4

3.7

0.4

Increased transaminases

28.8

8.0

14.3

2.5

2.7

9.4

4.7 0

Hepatobiliary Disorders

Immune System Disorders Drug hypersensitivity

2.2

Injury, Poisoning, and Procedural Infusion-related reaction

1.4

Infections and Infestations Urinary tract infection Investigations

Metabolism and Nutrition Disorders Hypokalemia

10.2

Musculoskeletal and Connective Tissue Disorders Myalgia

14.1

0.6

3.7

Arthralgia

19.2

0.6

8.4

Musculoskeletal pain

36.1

1.8

30.5

1.4

Nervous System Disorders Dysgeusia

8.0

4.1

0.2

Dizziness

10.2

0.4

10.7

0.2

Peripheral neuropathy

21.2

2.2

13.5

0.2

Headache

28.2

0.8

14.5

0.8

12.0

0.4

8.6

0.2

Psychiatric Disorders Insomnia

Respiratory, Thoracic, and Mediastinal Disorders Pneumonitis

1.2

Dyspnea

12.0

0.8

8.0

0.4

Cough

18.2

0.2

13.1

0.2

Epistaxis

22.5

0.2

8.4

Skin and Subcutaneous Tissue Disorders Pruritus

5.5

0.2

9.2

Rash

11.6

27.5

1.8

5.1

1.2

2.3

0.4

Vascular Disorders Hypertension

* Nodular Regenerative Hyperplasia and Portal Hypertension occurred in the same patient. ND = Not determined

Table 7 Selected Laboratory Abnormalities Lapatinib (1250 mg) + Capecitabine (2000 mg/m2)

KADCYLA (3.6 mg/kg)

Parameter

All Grade %

Grade 3 %

Grade 4 %

All Grade %

Grade 3 %

Grade 4 %

Increased bilirubin

Increased AST

Increased ALT

component of KADCYLA, disrupts microtubule function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant monkeys at doses up to 25 mg/kg (about 7 times the clinical dose), trastuzumab crossed the placental barrier during the early and late phases of gestation. The resulting concentrations of trastuzumab in fetal blood and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse findings.

8.3 Nursing Mothers It is not known whether KADCYLA, specifically, is excreted in Decreased human milk, but IgG is known to be excreted in human milk. In 83 14 3 21 <1 <1 platelet count lactating monkeys, trastuzumab was excreted in small amounts Decreased (about 0.3% of maternal serum concentrations) in breast milk after 60 4 1 64 3 <1 hemoglobin post-partum doses of 25 mg/kg (about 7 times the clinical dose of Decreased KADCYLA). Because many drugs are excreted in human milk and 39 3 <1 38 6 2 neutrophils because of the potential for serious adverse reactions in nursing Decreased 33 3 0 31 6 <1 infants from KADCYLA, a decision should be made whether to potassium discontinue nursing or discontinue KADCYLA, taking into account the importance of the drug to the mother [see Warnings and 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune Precautions (5.3)]. response to KADCYLA. 8.4 Pediatric Use A total of 836 patients from six clinical studies were tested at Safety and effectiveness of KADCYLA have not been established in multiple time points for anti-therapeutic antibody (ATA) responses pediatric patients. to KADCYLA. Following KADCYLA dosing, 5.3% (44/836) of patients 8.5 Geriatric Use tested positive for anti-KADCYLA antibodies at one or more post- Of 495 patients who were randomized to KADCYLA in the randomized dose time points. The presence of KADCYLA in patient serum at trial (Study 1) [see Clinical Studies (14.1)], 65 patients (13%) were ≥ 65 the time of ATA sampling may interfere with the ability of this assay years of age and 11 patients (2%) were ≥ 75 years of age. In patients to detect anti-KADCYLA antibodies. As a result, data may not ≥ 65 years old (n=138 across both treatment arms) the hazard ratios accurately reflect the true incidence of anti-KADCYLA antibody for progression-free survival (PFS) and Overall Survival (OS) were development. In addition, neutralizing activity of anti-KADCYLA 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. antibodies has not been assessed. Population pharmacokinetic analysis indicates that age does not Immunogenicity data are highly dependent on the sensitivity and have a clinically meaningful effect on the pharmacokinetics of specificity of the test methods used. Additionally, the observed ado-trastuzumab emtansine [see Clinical Pharmacology (12.3)]. incidence of a positive result in a test method may be influenced 8.6 Females of Reproductive Potential by several factors, including sample handling, timing of sample KADCYLA can cause embryo-fetal harm when administered during collection, drug interference, concomitant medication and the pregnancy. Counsel patients regarding pregnancy prevention and underlying disease. Therefore, comparison of the incidence of planning. Advise females of reproductive potential to use effective antibodies to KADCYLA with the incidence of antibodies to other contraception while receiving KADCYLA and for 6 months following products may be misleading. Clinical significance of anti-KADCYLA the last dose of KADCYLA. antibodies is not yet known. If KADCYLA is administered during pregnancy or if the patient 7 DRUG INTERACTIONS becomes pregnant while receiving KADCYLA, immediately report No formal drug-drug interaction studies with KADCYLA have exposure to the Genentech Adverse Event Line at 1-888-835-2555. been conducted. In vitro studies indicate that DM1, the cytotoxic Encourage women who may be exposed during pregnancy to enroll component of KADCYLA, is metabolized mainly by CYP3A4 and to in the MotHER Pregnancy Registry by contacting 1-800-690-6720 a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 [see Patient Counseling Information (17)]. inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 8.7 Renal Impairment telithromycin, and voriconazole) with KADCYLA should be avoided No dedicated renal impairment trial for KADCYLA has been due to the potential for an increase in DM1 exposure and toxicity. conducted. Based on the population pharmacokinetics, as well Consider an alternate medication with no or minimal potential to as analysis of Grade 3 or greater adverse drug reactions and dose inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is modifications, dose adjustments of KADCYLA are not needed in unavoidable, consider delaying KADCYLA treatment until the strong patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) CYP3A4 inhibitors have cleared from the circulation (approximately or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose 3 elimination half-lives of the inhibitors) when possible. If a strong adjustment can be recommended for patients with severe renal CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot impairment (CLcr less than 30 mL/min) because of the limited data be delayed, patients should be closely monitored for adverse available [see Clinical Pharmacology (12.3)]. reactions. 8.8 Hepatic Impairment In vitro studies in human liver microsomes indicates that DM1 is 8 USE IN SPECIFIC POPULATIONS metabolized by CYP3A4/5. The influence of hepatic impairment on 8.1 Pregnancy the pharmacokinetics of ado-trastuzumab emtansine conjugate has Pregnancy Category D [see Warnings and Precautions (5.3)] not been determined. Risk Summary 10 OVERDOSAGE KADCYLA can cause fetal harm when administered to a pregnant There is no known antidote for overdose of KADCYLA. In clinical woman. There are no adequate and well-controlled studies of trials, overdose of KADCYLA has been reported at approximately KADCYLA in pregnant women. No reproductive and developmental two times the recommended dose which resulted in Grade 2 toxicology studies have been conducted with ado-trastuzumab thrombocytopenia (resolved 4 days later) and one death. In the fatal emtansine. Nevertheless, two components of KADCYLA case, the patient incorrectly received KADCYLA at 6 mg/kg and died (trastuzumab and DM1) are known or suspected to cause fetal harm approximately 3 weeks following the overdose; a cause of death and or death when administered to a pregnant woman. If KADCYLA is a causal relationship to KADCYLA were not established. administered during pregnancy, or if a patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus. Patients should be advised to use effective contraception during treatment with KADCYLA and for 6 months following the last dose of KADCYLA. If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

—Robert W. Carlson, MD

membership by �CC�,” said Dan Theodorescu, MD, PhD, Director, CU Cancer Center. “�CC� has been a national leader in advancing the qual� ity and practice of cancer medicine. We look forward to contributing our expertise and ideas while supporting �CC�’s national and international ini� tiatives in patient care and research.” n

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Human Data In the post-marketing setting, treatment with trastuzumab during pregnancy has resulted in cases of oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped. In one case, trastuzumab therapy resumed after the amniotic fluid index improved, and oligohydramnios recurred.

These two institutions add substantial strength and expertise to the excellence of cancer care, research, and education characteristic of the other 21 world-class member institutions.

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The University of Colorado Cancer Center is Colorado’s only �CI�desig�

ente Colorado, and �ational Jewish Health). University of Colorado Hospital (UCH) is the primary adult teaching hospital and where the majority of CU Cancer Center clinical care is delivered and research is conducted. “We are honored and humbled by being elected to institutional

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University of Colorado S:6.875” Cancer Center

nated comprehensive cancer center. The center is a consortium of three state universities, including the Uni� versity of Colorado (CU) in Boulder and University of Colorado in Den� ver, and six institutions (University of Colorado Health, Children’s Hospi� tal Colorado, Denver Health, Denver VA Medical Center, Kaiser Perman�

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working with fellow premier �CC� in� stitutions to impact the outcomes of can� cer care and to influence the direction of the cancer field.”

KADCYLA™ (ado-trastuzumab emtansine)

Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way Animal Data South San Francisco, CA There were no reproductive and developmental toxicology studies 94080-4990 conducted with ado-trastuzumab emtansine. DM1, the cytotoxic U.S. License No: 1048

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Journal Spotlight Gastrointestinal Oncology

SIGGAR Trials Compare CT Colonography vs Barium Enema and Colonoscopy in Evaluation for Colon Cancer By Matthew Stenger

he companion UK Special Inter� est Group in Gastrointestinal and Abdominal Radiology (SIGGAR) tri� als compared computed tomographic (CT) colonography with barium en� ema and colonoscopy in patients with symptoms suggestive of colon cancer. As recently reported by the SIGGAR investigators in Lancet,1,2 the find� ings of the two tri� als indicate that CT colonography is more sensitive than barium enema and suggest that the test provides a similarly sensitive and less invasive alternative to colonoscopy, albeit with a much higher rate of referral for additional colonic investigation. Optimal use of CT colonography will require devel� opment of protocols for best practice and guidelines on patient referral.

CT Colonography vs Barium Enema Trial In the comparison with barium en� ema,1 3,804 patients aged 55 years or older were randomly assigned to CT colonography (n = 1,277) or barium enema (n = 2,527). Patients were well balanced for sex (62% and 61% fe� male), age (median 69 years; 55–64, 65–74, and 75–84 years for 33%, 39%, and 26% and for 33%, 39%, and 25%), and symptoms. Symptoms included change in bowel habits in 76% of both groups (including “looser, more frequent” in 42% and 40%), rectal bleeding in 30% of both groups, abdominal pain in 32% of both groups, anemia in 12% and 13%, and weight loss in 14% and 13%. The primary outcome measure was detection of colorectal cancer or large (≥�� 10 mm) polyps. Patients un� derwent flexible sigmoidoscopy prior to the randomized procedure at some study hospitals.

Detection Rates The detection rate of colorectal cancer or large polyps was significantly higher in the CT colonography group (7.3% vs 5.6%, relative risk [RR] = 1.31, P = .0390), with the difference largely reflecting greater detection of large polyps (3.6% vs 2.2%, P = .0098); there was no significant difference in

detection of cancer (3.7% vs 3.4%, P = .66). Analysis of detection rates including only those patients who actually un� derwent their randomized procedure (n = 2,300 in barium enema group and n = 1,206 in CT colonography group) and excluding those in whom cancer or large polyps had been detected by prior flexible sigmoidoscopy (0.5% of CT colonography group and 0.6% of barium enema group) showed that the detection rate was still significantly higher in the CT colonography group (7.0% vs 5.2%, P = .023). The rate of additional colonic inves� tigation was significantly higher after CT colonography (23.5% vs 18.3%, P = .0003), including higher rates for investigation of suspected cancer/large polyps (11.0% vs 7.5%, P = .0005) and for suspected smaller polyps (7.2% vs 2.3%, P�< <�.0001). �.0001). .0001). Among patients hav� ing additional investigation, cancer or a large polyp was found in similar proportions in the two groups (29% and 28%). Fewer CT colonography patients underwent additional colonic

Extracolonic malignancy was found in 13 of these patients, and extracolonic diagnoses that explained at least one of the patients’ presenting symptoms were made in 31. Four patients in the barium enema group (cardiac arrest, abdominal pain, rectal bleeding, and collapse) and one in the CT colonography group (free gas in the abdomen during the proce� dure) had unplanned hospital admis� sions that were considered possibly procedure�related within 30 days after the procedure.

CT Colonography More Sensitive, Preferred The investigators concluded: Re� sults of our study show that [CT colonography] is more sensitive than [barium enema] for detection of colorectal cancer or large polyps, and we have previously reported that [CT colonography] is preferred by patients. The higher sensitivity of [CT colonography] for small polyps and its ability to detect extracolonic lesions offer equivocal benefits, since

Computed Tomographic Colonography ■ CT colonography was more sensitive than barium enema in detecting colorectal cancer or large polyps.

■ CT colonography was as sensitive as colonoscopy in detecting colorectal cancer or large polyps, but patients undergoing CT colonography were more than three times as likely to be referred for additional colonic investigation.

investigation due to inadequate exami� nation or clinical uncertainty (5.2% vs 8.5%, P = .0005). During 3�year follow up, colorectal cancer was diagnosed in 3 patients in the CT colonography group and 12 patients in the barium enema group who were not diagnosed on initial CT colonography or barium enema. Miss rates were thus 7% (3 of the total of 45 cancers detected) in the CT colonog� raphy group and 14% (12 of 85 cancers detected) in the barium enema group, with the difference not being statisti� cally significant. Extracolonic findings led to addi� tional investigation in 87 (7.5%) of the CT colonography patients who were not diagnosed with colorectal cancer.

these incur additional costs and pa� tients might be referred for investiga� tion of findings that are clinically un� important. However, this risk can be managed if more widespread use of [CT colonography] is accompanied by protocols for best practice, includ� ing guidelines on patient referral for both radiologists and referring clini� cians. Training and quality assurance for radiologists are also needed if the capabilities of [CT colonography] are to be fully realized. With these provisos, our results suggest that [CT colonography] should now replace [barium enema] as the preferred radiological test for patients with symptoms suggestive of colorectal cancer.1

CT Colonography vs Colonoscopy Trial In the second trial,2 1,580 patients aged 55 years or older were randomly assigned to receive CT colonography (n = 533) or colonoscopy (n = 1,047). The primary outcome measure was the proportion of patients with additional colonic investigations. Patients were well balanced for sex (55% and 55% female), age (median 68 years; 55–64, 65–74, and 75–84 years for 41%, 35%, and 21% and for 37%, 36%, and 24%), and symptoms. Symptoms included change in bowel habits in 72% and 74% (including “looser, more frequent” in 40% and 39%), rectal bleeding in 45% and 41%, abdominal pain in 23% and 22%, ane� mia in 11% and 13%, and weight loss in 15% of both groups.

Additional Investigation Patients in the CT colonography group were more than three times as likely to have additional colonic inves� tigations (30.0% vs 8.2%, RR = 3.65, P < .0001). �early half of the referrals in the CT colonography group were for small polyps or clinical uncertain� ty. Overall, additional investigations were performed for suspected can� cer/large polyps in 15.6% of the CT colonography group and 1.1% of the colonoscopy group, smaller suspected polyps in 9.2% and 0.1%, and clinical uncertainty in 5.3% and 7.0%. Cancer or large polyps were found in 34% of CT colonography patients and 17% of colonoscopy patients referred for addi� tional colonic investigation. Referral rates differed significantly by sex (P = .0002): men were more than six times as likely to have addi� tional colonic examination after CT colonography compared with colonos� copy, with women being twice as likely to have additional investigation. There was no difference in referral rates ac� cording to age. There was also no difference in rates of detection of colorectal can� cer or large polyps between the CT colonography group and colonosco� py group (10.7% vs 11.4%, RR = 0.94, P = .69). Analysis of detection rates including only patients who actually underwent their randomized proce� continued on page 50

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

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

1.0 TREANDA (n=153)

0.9

Chlorambucil (n=148)

18 Months

0.8

median PFS

0.7 0.6 0.5 0.4

6 Months

0.3

median PFS

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

0.1 0 0

Months

*TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). HR=hazard ratio. CI=confidence interval.

TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatment-naïve patients with Binet stage B or C (Rai stages I–IV) CLL who required treatment (N=301). Patients were scheduled to receive either TREANDA 100 mg/m2 intravenously on Days 1 and 2 (n=153) or chlorambucil 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles. The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia.

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. • TREANDA is administered with a convenient dosing schedule – The recommended CLL dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day treatment cycle, up to 6 cycles Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA Please see accompanying brief summary of full Prescribing Information.

The ASCO Post | APril 15, 2013

Page 50

Journal Spotlight

CT Colonography continued from page 48

dure (n = 967 in colonoscopy group and n = 503 in CT colonography group) and excluding those in whom cancer or large polyps had been detected by prior flexible sigmoidoscopy (0.4% of CT colonography group) showed similar results (10.7% vs

12.0%, P = .47). During 3-year followup, 1 additional cancer was found in the CT colonography group, yielding a miss rate of 3.4% (1 of the total of 29 cancers detected). No cancers were missed in the colonoscopy group (total of 55 detected). With regard to other colorectal finings, significantly more patients in

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

the CT colonography group were diagnosed with diverticulosis (54% vs 35%, P < .0001), whereas significantly more in the colonoscopy group were diagnosed with colitis (1% vs 3%, P = .0022) or anal pathology (2% vs 7%, P = .0002). Extracolonic findings led to additional investigation in 48 (10.1%) of the CT colonography pa-

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber singleuse vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates. TRE-2511e (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

November 2012

tients who were not diagnosed with colorectal cancer. Extracolonic malignancy was found in 9 of these patients and extracolonic diagnoses that explained at least one of the patients’ presenting symptoms were made in 17. Three patients in the colonoscopy group (abdominal pain, rectal bleeding, and diarrhea and vomiting) had unplanned hospital admissions that were considered possibly procedurerelated within 30 days after the procedure. A patient in the CT colonography group who underwent colonoscopy 22 days after CT colonography for removal of lesions was admitted immediately after colonoscopy for suspected perforation and discharged the following day. These investigators concluded: [I]n our pragmatic trial of symptomatic patients, [CT colonography] was associated with a high referral rate for additional tests. These referrals have the potential to increase anxiety and overall cost, and—in patients referred for colonoscopy—mitigate the advantage of avoiding an endoscopic examination. For most patients, however, [CT colonography] offers a similarly sensitive, less invasive alternative to colonoscopy. With wider implementation, there will be a need for protocols to improve specificity, along with attention to referral criteria and an emphasis on radiologist training and assessment. With these in place, our results suggest that [CT colonography] should be considered as an alternative first-line investigation for patients with symptoms suggestive of colorectal cancer.2 n Disclosure: The studies were funded by National Institute for Health Research (NIHR) Health Technology Assessment Program, NIHR Biomedical Research Centres, Cancer Research UK, Engineering and Physical Sciences Research Council Multidisciplinary Assessment of Technology Centre for Healthcare, and NIHR Collaborations for Leadership in Applied Health Research and Care.

References 1. Halligan S, Wooldrage K, Dadswell E, et al: Computed tomographic colonography versus barium enema for diagnosis of colorectal cancer or large polyps in symptomatic patients (SIGGAR): A multicentre randomized trial. Lancet. February 13, 2013 (early release online). 2. Atkin W, Dadswell E, Wooldrage K, et al: Computed tomographic colonography versus colonoscopy for investigation of patients with symptoms suggestive of colorectal cancer (SIGGAR): A multicentre randomized trial. Lancet February 13, 2013 (early release online). see perspective on page 51

ASCOPost.com | APRIL 15, 2013

PAGE 51

Journal Spotlight Perspective

CT Colonography Reconsidered By David H. Kim, MD

he parallel SIGGAR trials recently published in Lancet add to the grow� ing body of literature regarding the utility of computed tomographic (CT) colo� nography in the detection of colorectal polyps and cancers. These papers rein� force the results seen in other large multi� center trials1�3 and echo the positive clini� cal experience with CT colonography over the past 10 years.

Comparing Modalities These trials raise a number of impor� tant points. First, the performance of CT colonography is equivalent to optical colonoscopy and far superior to barium enema. At the 10�mm threshold, there was no significant difference between CT colonography and colonoscopy in rates of polyps detected within each study cohort (5.1% and 5.8% for CT colonog� raphy and colonoscopy, respectively; P = .53). In contrast, barium enema had a substantially poorer rate. The CT colonography results be� come more impressive when the techni� cal factors are taken into account. The trials recognized that CT colonography represented an evolving technology that would advance over the recruitment of the trial.4 Thus, while some institutions utilized state�of�the�art CT colonography technique, others used older or less rigor� ous parameters that would be considered far from optimal according to today’s standards. Besides these technical factors, the use of multiple readers with varying levels of expertise from over 20 teaching and general hospitals points to the robust nature of this imaging modality and the ability to transfer such performance to the community. Second, extracolonic findings are an important added benefit from CT colo� nography. Additional diagnoses outside of the colorectum are possible due to the cross�sectional nature of this imaging technique (CT colonography is essen� tially a low�dose CT without intravenous contrast). Although often cited as a possible negative consequence to the use of CT colonography, the feared high rate of additional imaging for clinically insig� nificant findings typically has not been Dr. Kim is Associate Professor of Radiology, Section of Abdominal Imaging, and Vice Chair of Education, University of Wisconsin School of Medicine and Public Health, Madison.

seen.5,6 The SIGGAR trials also showed low rates, ranging between 7.5% and 10.1% for the two studies. For this mi� nor additional cost, a large benefit was derived. Combining both studies, 22 extraco� lonic cancers and 34 aortic aneurysms (3�� cm or greater in diameter) were de� tected. This constituted 3.1% of the com� bined CT colonography populations (n�= �= =�1,810). �1,810). 1,810). In comparison, CT colonog� raphy detected colorectal cancers in 4.3%

one more narrowly defines this measure (“additional colonic investigations”) as the rate of inadequate or nondiagnostic exams requiring additional evaluation, CT colonography actually outperforms colonoscopy, with 5.3% of CT colonog� raphy exams being inadequate and 11.3% of colonoscopies being incomplete. Comparisons aside, the high referral rate from CT colonography to colonos� copy in this trial does pose concern if tru� ly reflective of CT colonography use. It is

Hopefully, the SIGGAR results will provide the impetus to move this much needed technology into the community and into wider use. —David H. Kim, MD

in this combined group. Thus, the num� ber of important extracolonic diagnoses approaches the number of colorectal can� cers despite being an incidental byprod� uct of a primarily colorectal examination. Although it can be difficult to know how much improvement in survival is achieved with earlier detection of an ex� tracolonic cancer as opposed to later, symptomatic detection, it is easy to see the large benefit of detecting an unsus� pected aneurysm and treating when appropriate as opposed to discovery at symptomatic rupture. This extracolonic benefit would obviously not be possible at colonoscopy screening.

Other Colonic Investigations On the other hand, the trials report a high rate of “additional colonic investi� gations” for CT colonography, ranging from 23.5% to 30%. Indeed, this result is highlighted, since this metric is a primary outcome measure of the CT colonogra� phy vs colonoscopy trial. This is a rather nonsensical comparison, since any polyp detected on CT colonography requires “additional investigation” or removal at colonoscopy, whereas any colonoscopy� detected polyp can be removed without an additional procedure. Logically, there would be a large difference, although I suspect that it is an easy way to ensure that the trial will achieve a statistically signifi� cant difference for one of its stated aims. If

discrepant with other large clinical series, in which the real�world rates have been much lower, at 8% to 10%.7,8 However, the disparate findings can be easily explained by the lack of a lower referral threshold at CT colonography in the SIGGAR trial. Most practices using CT colonography adhere to C�RADS (CT colonography reporting and data systems) guidelines and ignore polyps 5 mm or less in size.9 When a threshold is applied, referral rates are typically in the 10% range. The �ational CT Colonography trial (ACRI� 6664; � = 2,531) reported that a 12% referral rate would result if a 6�mm threshold were used.1 In effect, the use of a 6�mm threshold places diminutive polyps (which are typically innocuous) in a 5�year follow up window. Long�term outcomes data of screened CT colonog� raphy patients with negative exams have shown that this is a safe and appropriate practice.10 The SIGGAR authors them� selves point out that many of the referrals to colonoscopy “might be avoidable ... if referral is set at 8 mm.”

Closing Thoughts As a final point, a previously published analysis from the SIGGAR trial reported that CT colonography is more accept� able to patients than colonoscopy.11 In practice, we have seen that the addition of CT colonography leads to improved screening participation.12 Hopefully, the

SIGGAR results will provide the impetus to move this much needed technology into the community and into wider use. Given the current dismal state of colorec� tal cancer screening, in which nearly half of the eligible population is not adherent, it would appear that CT colonography should be added to the armamentarium of options to help eradicate this devastat� ing but preventable cancer. n Disclosure: Dr. Kim is a consultant for Viatronix, cofounder of VirtuoCTC, and on the medical advisory board for Digitalartforms.

References 1. Johnson CD, et al: Accuracy of CT colonography for detection of large adeno� mas and cancers. � Engl J Med 359:1207� 1217, 2008. 2. Regge D, et al: Diagnostic accuracy of computed tomographic colonography for the detection of advanced neoplasia in indi� viduals at increased risk of colorectal cancer. JAMA 301:2453�2461, 2009. 3. Pickhardt PJ, et al: Computed tomo� graphic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. � Engl J Med 349:2191�2200, 2003. 4. Halligan S, et al: Design of a multicen� tre randomized trial to evaluate CT colonog� raphy versus colonoscopy or barium enema for diagnosis of colonic cancer in older symp� tomatic patients. Trials 8:32, 2007. 5. Pickhardt PJ, et al: Unsuspected extra� colonic findings at screening CT colonogra� phy. Radiology 249:151�159, 2008. 6. Zalis ME, et al: Diagnostic accuracy of laxative�free computed tomographic colo� nography for detection of adenomatous pol� yps in asymptomatic adults. Ann Intern Med 156:692�671, 2012. 7. Kim DH, et al: CT colonography versus colonoscopy for the detection of ad� vanced neoplasia. � Engl J Med 357:1403� 1412, 2007. 8. An S, et al: Screening CT colonogra� phy in an asymptomatic average�risk Asian population. Am J Roentgenol 191:W100� W106, 2008. 9. Zalis ME, et al: CT colonography re� porting and data system. Radiology 236:3�9, 2005. 10. Kim DH, et al: Five year colorec� tal cancer outcomes in a large negative CT colonography screening cohort. Eur Radiol 22:1488�1494, 2012. 11. von Wagner C, Ghanouni A, Halligan S, et al: Patient acceptability and psychologic consequences of CT colonography com� pared with those of colonoscopy. Radiology 263:723�731, 2012. 12. Benson M, Pier J, Kraft S, et al: Op� tical colonoscopy and virtual colonoscopy numbers after initiation of a CT colonog� raphy program. J Gastrointest Liver Dis 21:391�395, 2012.

In pancreatic cancer, can we look deeper to find answers?

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The ASCO Post | APRIL 15, 2013

PAGE 54

Genitourinary Cancers Symposium Genitourinary Oncology

Similar Outcomes for 18 vs 36 Months of Androgen Blockade in High-risk Prostate Cancer Treated with Radiation By Alice Goodman

ighteen months of hormone ther� apy appears to be as safe and ef� fective as 36 months when combined with radiation for patients with high� risk prostate cancer.1 Patients who re� ceived the shorter course of hormone therapy plus radia� tion had survival rates similar to those who received 36 months of hormones with radiation in a prospective, multicenter, random� ized phase III trial reported at the 2013 Genitourinary Cancers Symposium in Orlando, Florida.

prostate cancer (T3�4, prostate�specif� ic antigen [PSA] > 20 ng/mL or Glea� son score > 7) to radiotherapy to the pelvic area and prostate bed plus 18 months of androgen ablation therapy vs 36 months of androgen ablation therapy (bicalutamide at 50 mg/d orally for 1 month plus goserelin [Zo� ladex] in a 10.8�mg subcutaneous im� plant every 3 months). Demographic and disease charac� teristics of the study population were comparable for the two arms. Median age was 71 years, median PSA level was 16 ng/mL, and median Gleason score was 8. Most patients (59.8%) had Glea�

Shorter-term hormone therapy could have a big impact on the lives of men with prostate cancer, reducing the quantity and intensity of its unpleasant side effects as well as treatment costs. —Abdenour Nabid, MD

“The side effects of hormone therapy are considerable and make most patients’ lives miserable. These include the ‘castration syndrome’— hot flashes, loss of libido, and erectile dysfunction,” stated presenting author Abdenour Nabid, MD, Associate Pro� fessor, Centre Hospitalier de Univer� sitaire de Sherbrooke in Sherbrooke, Canada.

son score over 7; 39.8% had Gleason 8, and 20% had Gleason 9 and 10,” Dr. �a� bid emphasized. At a median follow�up of 77 months, mortality was similar in the two arms of the study: 22.9% in the shorter�duration hormone therapy arm vs 23.8% in the longer�duration arm. Of 147 deaths, 116 patients died of causes other than prostate cancer.

Potential Impact

Survival Rates

“Shorter�term hormone therapy could have a big impact on the lives of men with prostate cancer, reducing the quantity and intensity of its unpleasant side effects as well as treatment costs. We hope these results will convince doctors that they can stop hormone therapy after 1.5 years instead of 2 to 3 years,” Dr. �abid told listeners. Optimal duration of hormone ther� apy in this setting is controversial. To determine whether a shorter course would lead to outcomes comparable to those with the standard of 36 months, investigators from 10 different centers in Quebec randomly assigned 630 pa� tients with node�negative, high�risk

At 5 years, overall survival rates were 92.1% vs 86.8% for the two arms, respectively, and 10�year sur� vival rates were 63.6% vs 63.2%. Dis� ease�specific survival rates at 5 years

EXPERT POINT OF VIEW

“

Thirty�six months of hormone therapy is the standard of care for the treatment of high�risk prostate cancer treated with radiotherapy,” said for� mal discussant Anthony V. D’Amico, MD, PhD, Professor in the Department of Radiation Oncolo� gy at Harvard Medical School and Chief of Genito� urinary Radiation Oncology at Dana�Farber Can� cer Institute and Brigham and Women’s Hospital, Boston. In order to establish whether 18 months vs 36 Anthony V. D’Amico, MD, PhD months of therapy is truly comparable, a noninferi� ority trial is needed with a defined upper boundary of the confidence interval for the hazard ratio, Dr. D’Amico continued. “�oninferiority does not mean equivalence. We need to determine what is acceptable to establish noninferi� ority,” he said. “The present trial was designed as a superiority trial, but should have been designed as a noninferiority trial. The confidence interval is wide (0.83–1.59), and with data presented at this time, the upper boundary could represent a 59% increase in death,” he told listeners.

Longer Follow-up Needed Using an exponential model based on current death rates, it would take 8.5 years to determine whether 18 months is superior. “What we can say using rigorous criteria is 36 months is not superior to 18 months, but 18 months may still be inferior,” he reasoned. “Over longer�term follow�up, this study will ascertain if 18 months can be substituted for 36 months, if we use the same benchmark. Right now, for high� risk patients treated with 70�Gy radiotherapy, 36 months of hormone therapy may be too long, 6 months is too little, and 18 months may be just right. But longer follow�up is needed to make that statement,” he concluded. n Disclosure: Dr. D’Amico reported no potential conflicts of interest.

were 97.6% vs 96.4%, and 10�year disease�specific survival rates were 87.2% in both arms. Age was the only significant factor that predicted overall survival; older patients died more rapidly (P�<�.001) Dr. �abid commented that an earlier study from the European Organisation for Research and Treatment of Cancer (EORTC)2 found that 6 months of hor�

Androgen Blockade in High-risk Prostate Cancer ■ An 18-month course of androgen blockade achieved similar overall and disease-specific survival compared with 36 months when given with radiation to men with high-risk prostate cancer.

■ A shorter course of hormone therapy could improve quality of life and reduce treatment costs in this setting.

■ Longer follow-up is needed to establish with certainty whether 18 months can replace the standard 36 months of androgen ablation in conjunction with radiation for men with high-risk prostate cancer.

mone therapy resulted in inferior sur� vival compared with 36 months. “The present study suggests that 18 months may be a threshold beyond which there is no further gain. Eighteen months does the job,” he stated. Quality�of�life data from the study will be analyzed soon, Dr. �abid said. n Disclosure: Dr. �abid reported no potential conflicts of interest.

References 1. �abid A, Carrier �, Martin A�G, et al: High�risk prostate cancer treated with pelvic radiotherapy and 36 versus 18 months of androgen blockage: Results of a phase III randomized study. 2013 Geni� tourinary Cancers Symposium. Abstract 3. Presented February 14, 2013. 2. Bolla M, de Reijke TM, Van Tien� hoven G, et al: Duration of androgen sup� pression in the treatment of prostate can� cer. � Engl J Med 360:2516�2527, 2009.

ASCOPost.com | APRIL 15, 2013

PAGE 55

News

American Association for Cancer Research Inaugurates the First Class of Fellows of the AACR Academy

he American Association for Can� cer Research (AACR) inaugurated the first class of Fellows of the AACR Academy at the association’s annual meeting held this month in Washing� ton, DC. The AACR Academy has been created to recognize and honor distin� guished scientists whose major scientific contributions have propelled significant innovation and progress against can� cer. These Fellows have been selected through a rigorous peer review process that evaluates individuals on the basis of their stellar scientific achievements in cancer research. The inaugural class of Fellows was inducted into the AACR Academy on April 5, 2013, at the �ational Museum of Women in the Arts in Washington, DC.

Inaugural Fellows of the AACR Academy Karen H. Antman, MD, Boston University School of Medicine David Baltimore, PhD, California Institute of Technology Françoise Barré-Sinoussi, PhD, In� stitut Pasteur Paul Berg, PhD, Stanford University School of Medicine Joseph R. Bertino, MD, The Can� cer Institute of �ew Jersey; University of Medicine and Dentistry, Robert Wood Johnson Medical School; The Stem Cell Institute of �.J. J. Michael Bishop, MD, G. W. Hooper Research Foundation; Univer� sity of California, San Francisco Mina J. Bissell, PhD, Lawrence Berkeley �ational Laboratory Elizabeth H. Blackburn, PhD, Uni� versity of California, San Francisco Sydney Brenner, MB, BCh, DPhil, Founder, Acidophil, LLC; Salk Institute for Biological Studies Angela H. Brodie, PhD, University of Maryland School of Medicine Mario R. Capecchi, PhD, Universi� ty of Utah School of Medicine; Howard Hughes Medical Institute Webster K. Cavenee, PhD, Ludwig Institute for Cancer Research; Univer� sity of California, San Diego Martin Chalfie, PhD, Columbia University Zhu Chen, MD, PhD, 12th Stand� ing Committee of the �ational People’s Congress; 15th Chinese Peasants and

Workers Democratic Party, Central Committee Aaron J. Ciechanover, MD, DSc, Technion�Israel Institute of Technology Bayard D. Clarkson, MD, Memorial Sloan�Kettering Cancer Center Donald S. Coffey, PhD, Johns Hop� kins University School of Medicine Stanley N. Cohen, MD, Stanford University Suzanne Cory, PhD, University of Melbourne Carlo M. Croce, MD, The Ohio State University School of Medicine Tom Curran, PhD, The Children’s Hospital of Philadelphia Research Insti� tute; Perelman School of Medicine; Uni� versity of Pennsylvania Brian J. Druker, MD, Knight Cancer Institute, Oregon Health and Science University; Howard Hughes Medical Institute Raymond N. DuBois, MD,PhD, The Biodesign Institute; Arizona State University Sir Martin J. Evans, PhD, Cardiff University Emmanuel Farber, MD,PhD, Uni� versity of Toronto Napoleone Ferrara, MD, Moores Cancer Center, University of California, San Diego Isaiah J. Fidler, D.V.M., PhD, The University of Texas MD Anderson Can� cer Center Bernard Fisher, MD, University of Pittsburgh Joseph F. Fraumeni Jr., MD, �a� tional Cancer Institute Emil Frei III, MD, Dana�Farber Can� cer Institute, Harvard Medical School Elaine V. Fuchs, PhD, Rockefeller University; Howard Hughes Medical Institute Judy E. Garber, MD, MPH, Dana� Farber Cancer Institute; Harvard Medi� cal School Walter Gilbert, PhD, Harvard Uni� versity Alfred G. Gilman, MD,PhD, Uni� versity of Texas Southwestern Medical Center Carol W. Greider, PhD, Johns Hop� kins University School of Medicine Roger C. L. Guillemin, MD,PhD, Salk Institute for Biological Studies Sir John B. Gurdon, D.Phil, Well� come Trust/Cancer Research U.K. Gur�

don Institute William N. Hait, MD,PhD, Global Head at Janssen Research and Develop� ment, LLC Leland H. Hartwell, PhD, Arizona State University; Fred Hutchinson Can� cer Research Center Avram Hershko, MD, PhD, Tech� nion�Israel Institute of Technology; �ew York University School of Medicine James F. Holland, MD, Mount Sinai Medical Center Jimmie C. Holland, MD, Memorial Sloan�Kettering Cancer Center Waun Ki Hong, MD, The University of Texas MD Anderson Cancer Center Leroy E. Hood, MD, PhD, Univer� sity of Washington Molecular and Cel� lular Biology Program; Keck Graduate Institute of Applied Life Sciences H. Robert Horvitz, PhD, Massa� chusetts Institute of Technology; MIT Koch Institute for Integrative Cancer Research; MIT McGovern Institute for Brain Research; Howard Hughes Medi� cal Institute Susan Band Horwitz, PhD, Albert Einstein Cancer Center; Albert Einstein College of Medicine Sir R. Timothy Hunt, PhD, Clare Hall Laboratories, Cancer Research U.K. Tony Hunter, PhD, Salk Institute Cancer Center; The Salk Institute for Biological Studies Tyler Jacks, PhD, David H. Koch In� stitute for Integrative Cancer Research; Massachusetts Institute of Technology; Howard Hughes Medical Institute Peter A. Jones, PhD, DSc, Universi� ty of Southern California (USC) �orris Comprehensive Cancer Center V. Craig Jordan, PhD, DSc, Lom� bardi Comprehensive Cancer Center, Georgetown University Yuet Wai Kan, MD, University of California, San Francisco Mary-Claire King, PhD, University of Washington Eva Klein, MD, PhD, Karolinska In� stitutet George Klein, MD, PhD, Karolin� ska Institutet Alfred G. Knudson Jr., MD, PhD, Fox Chase Cancer Center Brian K. Kobilka, MD, Stanford University School of Medicine Margaret L. Kripke, PhD, The Uni� versity of Texas MD Anderson Cancer

Center Philip Leder, MD, Harvard Medical School Robert J. Lefkowitz, MD, Howard Hughes Medical Institute; Duke Univer� sity Medical Center Arnold J. Levine, PhD, Simons Center for Systems Biology, Institute for Advanced Study; Cancer Institute of �ew Jersey Lawrence A. Loeb, MD, PhD, Jo� seph Goldstein Memorial Cancer Re� search Laboratory, University of Wash� ington School of Medicine Tak W. Mak, PhD, Ontario Cancer Institute, Princess Margaret Cancer Cen� tre; University of Toronto Lynn M. Matrisian, PhD, Pancreatic Cancer Action �etwork Frank McCormick, PhD, Helen Diller Family Comprehensive Cancer Center; University of California, San Francisco John Mendelsohn, MD, Sheik Ka� lifa Bin Zayed Al �ahyan Institute for Personalized Cancer Therapy; MD An� derson Cancer Center Donald Metcalf, MD, Professor Emeritus, University of Melbourne; Carden Fellow in Cancer Research, Di� vision of Cancer and Hematology, the Walter and Eliza Hall Institute of Medi� cal Research Enrico Mihich, MD, Dana�Farber Cancer Institute Beatrice Mintz, PhD, Fox Chase Cancer Center Luc Montagnier, MD, World Foun� dation for AIDS Research and Preven� tion; Centre �ational de la Recherché Scientifique; Professor Emeritus, Pasteur Institute Harold L. Moses, MD, Vanderbilt� Ingram Comprehensive Cancer Center Sir Paul M. Nurse, PhD, Francis Crick Institute Olufunmilayo I. Olopade, MD, University of Chicago Pritzker School of Medicine Arthur B. Pardee, PhD, Harvard Medical School Martine J. Piccart, MD, PhD, Uni� versité Libre de Bruxelles; Jules Bordet Institute Sir Bruce A. J. Ponder, MB,BChir, PhD, Cancer Research U.K. Cambridge Research Institute; University of Cam� bridge; Cambridge University Hospitals continued on page 63

What if

engineering the antiBody could iMPRoVE adcc?

Immune Effector Cell

Therapeutic Antibody

Target Cell

*Based on preclinical models.

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

Visit Genentech BioOncology BOOTH 10005 at the 2013 ASCO Annual Meeting to learn more

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

Sugar Residue

Sugar Removal

Increased Binding

SugarS MaY aY coMproMiSe iMMuNe a

gLYcoeNgiNeeriNg MaY a iNcreaSe aY

gLYcoeNgiNeeriNg couLD LeaD

eFFecTor–aNTiBoDY BiNDiNg

BiNDiNg aFFiNiTY

To iMproVeD aDcc

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

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

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

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

For more information, visit ResearchBcell.com

The ASCO Post | APRIL 15, 2013

PAGE 58

Expert’s Corner Hematology

Gene Transfer Therapy Is Producing Prolonged Remissions in Patients with Advanced Leukemia A Conversation with David L. Porter, MD By Jo Cavallo

David L. Porter, MD

n August 2011, researchers from the University of Pennsylvania pub� lished their breakthrough findings of a pilot study showing sustained remis� sions of up to 1 year in a small num� ber of patients with advanced chronic lymphocytic leukemia (CLL) who had been treated with genetically en� gineered versions of their own T cells. The study results, published in both The New England Journal of Medicine1 and Science Translational Medicine,2 were the first to show prolonged re� sponses using gene transfer therapy to create “serial killer” T cells aimed at cancerous tumors. The treatment, which is now known as CTL019, involves isolat� ing patients’ T cells and genetically modifying them using a lentiviral vec� tor expressing an antibody�like pro� tein called chimeric antigen receptor (CAR), pioneered by the University of Pennsylvania researchers. CAR is expressed on the surface of the T cells and binds to CD19, a protein ex� pressed on lymphoma and leukemia cells and also on normal B cells. The reengineered T cells are then infused back into patients to kill cells express� ing CD19. There were 12 patients in the pi� lot study, including 10 with advanced CLL and two children with acute lymphoblastic leukemia (ALL). Last December, David L. Porter, MD, Director of Blood and Marrow Trans� plantation and Professor of Medicine at the Abramson Cancer Center of the University of Pennsylvania, and principal investigator of the study, presented updated study results at the 2012 Annual Meeting of the Ameri� can Society of Hematology. Dr. Por�

ter’s presentation showed longer�term outcomes in 10 patients treated with CTL019, including 9 CLL patients with relapsed/refractory disease who had received a median of five previous therapies and a 7�year�old girl with relapsed/refractory ALL. Only three patients in the study had no response at all to the therapy. The ASCO Post talked with Dr. Por� ter about the long�term outcomes of patients treated with CTL019, how gene transfer therapy may be appli� cable in other cancers, and the next phase in the therapy’s development.

Current Status and Next Steps What is the current disease status of the patients treated with CTL019? Three of the CLL patients and both of the ALL patients had a complete re�

eloma and in solid tumors? Yes it is. We think that one of the critical aspects of our study is that the lentiviral vector can be used to geneti� cally modify cells directed at other tar� gets. It doesn’t have to be just CD19. The problem with some of these other cancers, of course, is identifying very specific tumor targets. In CLL and ALL, CD19 is an ideal tumor target because it only appears on the can� cer cells and healthy B cells. In other tumors it is much more difficult to identify such restricted tumor�specific markers. But clinical trials are under� way or being planned for solid tumors, including pancreatic and ovarian can� cers and mesothelioma. Trials in breast cancer have already been conducted. If you have an effective vector and the appropriate target, this technique can

These are patients who had not had a complete remission after several prior, very potent therapies. After CTL019 therapy, they have no detectable CLL. —David L. Porter, MD

sponse to the therapy initially. Of the three adults with CLL who had a com� plete response, all are still in remission between 8 months and 2½ years later. Of the two patients with ALL, one remains in remission longer than 8 months and one has had a recurrence of her disease. What is your next step in this research? Our next step is to treat larger numbers of patients and get a better understanding of who this therapy works for, when it works, and to bet� ter understand the side effects, includ� ing their cause and how to manage them. We also want to understand is� sues relating to dosing and timing of T�cell administration. In addition, we are starting to treat other CD19�pos� itive malignancies, including different types of non�Hodgkin lymphoma and ALL in adults.

Other Applications Is gene transfer therapy applicable in other blood cancers such as multiple my-

absolutely be applied to other cancers. Our group at the University of Pennsylvania has done trials with ge� netically modified T cells to target a couple of different antigens in mul� tiple myeloma. CD19 is probably not going to be the ideal target for most cases, but there might be other targets that one can try to target. Does CTL019 have the potential to replace bone marrow transplantation in the treatment of lymphoma and leukemia? Certainly for CLL and maybe for ALL and some non�Hodgkin lympho� mas, the only known curative therapy is an allogeneic bone marrow trans� plant. But transplants are associated with mortality rates that in the best of circumstances approach 20%. Ob� viously, if we had the ability to eradi� cate patients’ cancers in a safer and more effective way, the goal would be to treat them without bone marrow transplant. We don’t know if we have done that at this point. The study follow�up is

relatively short, and we have treated very small numbers of patients. That said, we have had patients who have had complete eradication of their tu� mor without a bone marrow trans� plant, when there was little else avail� able to them. So we hope that this treatment has the potential to replace transplant, at least for these diseases.

Risks and Their Management What are the risks involved in gene transfer therapy? The side effects we see with CTL019 largely involve cytokine re� lease syndrome, in which patients exhibit profound cytokine symptoms such as very high fevers, rigors, nau� sea, and diarrhea, and in more extreme cases, capillary leak, hypoxia, and hy� potension. We found that patients with cytokine release syndrome also have high levels of interleukin (IL)�6 and that by administering an anti– IL�6 receptor antibody called tocili� zumab (Actemra), these reactions can be stopped almost instantaneously. Some patients develop a tumor ly� sis syndrome, which on some level is a rather remarkable side effect. These cells are so potent that they can in� duce a delayed tumor lysis syndrome as they expand. We know that the anticytokine therapy has been effective when needed, but we don’t know the op� timal timing of its administration or whether administering it will inhibit the antitumor reaction. We are trying to learn more about this strategy as we treat more patients. The other side effect of the therapy is that it destroys healthy B cells along with the cancerous cells. This is po� tentially an ongoing problem. Patients develop B�cell aplasia and hypogam� maglobulinemia, and potentially be� come more prone to certain kinds of infections. We manage this problem by giving patients intravenous immunoglobulin infusions. We believe that CTL019 es� sentially provides a prolonged vaccine effect, and that as long as the reengi� neered T cells are there, patients won’t be able to develop normal B cells. They won’t develop a recurrence of CLL either, which is a good thing, but

ASCOPost.com | APRIL 15, 2013

PAGE 59

Expert’s Corner

they won’t be able to develop normal B cells, so it is a potential long�term complication of the therapy that so far we have been able to manage.

Differences in Response

in tumor properties that may account for differences in response, or whether there are differences in the biologic properties of the cell products that are infused into these patients.

The treatment does not work for everyone. Do you know why? �o, we don’t. We are trying to fig� ure out whether there is any difference

Are the patients who experienced complete remissions cured of their cancer? There is no way of knowing.

Homoharringtonine/ Omacetaxine

DA). The 3�year event�free survival rates were higher with the addition of homoharringtonine: HAA 35% vs DA 23%, P = .002; HAD 33% vs DA 23%, P = .08. Overall survival and relapse� free survival were significantly better for HAA vs DA in patients with favor� able or intermediate cytogenetic cat� egories (P = .014 for survival; P = .02 for relapse�free survival).5 In the Chinese studies, the homo� harringtonine doses ranged from 2 to 8�� mg given as short intravenous infu� sion or intramuscularly. Cardiovascu� lar complications (severe hypotension, arrhythmias) were significant. The studies in the United States (in the 1980s) used short intravenous infusions, which were dose�limited by severe cardiovascular complications.1 Later studies in leukemia used continu� ous infusion schedules over 24 hours at dose ranges of 5 to 9 mg/m2 daily for 7 to 9 days, reporting complete response rates of 15% to 20%, but still serious

continued from page 1

holds a record for the longest time of development of an anticancer agent until FDA approval—almost 40 years.

Past and Present Research Over several decades, the Chinese investigators have identified homohar� ringtonine as an active anticancer agent in acute myeloid leukemia (AML), my� elodysplastic syndrome (MDS), acute promyelocytic leukemia (APL), poly� cythemia vera, and as intrathecal ther� apy for central nervous system (C�S) leukemia.1,2 In AML, homoharringto� nine resulted in complete response rates of 25% as single�agent therapy. In combination with standard chemo� therapy in front�line AML therapy, the complete response rates were 70% to 90%, and the cure rates 30% to 40 %.1,4 A recent randomized study showed that the addition of homoharringto�

Lowering the price of omacetaxine and allowing for patient self-administration will improve access and compliance, broaden the use of omacetaxine, and reduce the cost of care. —Hagop Kantarjian, MD, Susan O’Brien, MD, and Jorge Cortes, MD

nine to standard AML chemotherapy improved complete response and cure rates significantly. A total of 620 pa� tients younger than 60 years old were randomized to DA (cytarabine at 100 mg/m2 daily × 7 and daunorubicin at 40 to 45 mg/m2 daily × 3), vs HAD (cytarabine, daunorubicin, and homo� harringtonine at 2 mg/m2 IV daily × 7), vs HAA (cytarabine, aclarubicin [an improved anthracycline not marketed in the United States] at 40 mg/m2 daily × 3, and homoharringtonine).5 The complete response rates after one course of therapy were significant� ly higher with the addition of homo� harringtonine (66% vs 54%, P = .005 for HAA vs DA; P = .03 for HAD vs

cardiovascular complications in 30% of patients.6 Lower doses and longer exposure schedules of homoharringto� nine at 2.5 to 3 mg/m2 daily × 14 elimi� nated the cardiovascular complications and were further developed in CML.7 Through the 1980s and 1990s, ho� moharringtonine was investigated as a single agent, and in combination with low�dose cytarabine, with interferon� alpha, and with both, in late and early chronic�phase CML.1,8�13 These stud� ies, summarized in several previous reviews, confirmed the anti�CML ef� ficacy of homoharringtonine.

Semisynthetic Formulation The development of homohar�

These are patients who had not had a complete remission after several prior, very potent therapies. After CTL019 therapy, they have no de� tectable CLL. But it’s always hard to use a word like “cure” without longer follow�up. n

Disclosure: Dr. Porter is listed as an inventor on a patent for this technology, entitling him to future royalties.

Hagop Kantarjian, MD

References 1. Porter DL, Levine BL, Kalos M, et al: Chimeric antigen receptor�modified T cells in chronic lymphoid leukemia. � Engl J Med 365:725�733, 2011. 2. Kalos M, Levine BL, Porter DL, et al: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leuke� mia. Sci Transl Med 3(95):95ra73, 2011.

Susan O’Brien, MD

ringtonine was hampered by several factors: difficult production and un� reliable source supply, toxicity profile of the original dose schedules, large quantities of bulk of cephalotaxus trees required (rare, from China), the success of tyrosine kinase inhibitors in CML, and the uncertainty of the role of homoharringtonine in the context of tyrosine kinase inhibitors. In 1998, Jean�Pierre Robin et al reported on the first semisynthetic formulation of homoharringtonine.14 Pilot studies confirmed the efficacy of the semisynthetic homoharringtonine, known later as omacetaxine.15,16 In 2004, ChemGenex provided a stable source of omacetaxine for future studies. This led to the development, con� duct, and completion of the FDA piv� otal trials of omacetaxine in CML after failure of several tyrosine kinase in� hibitors and in the setting of CML and T315I mutations.17 In a phase II study of subcutaneous omacetaxine at 1.25 mg/m2 twice daily for 14 days during induction and for 7 days during main� tenance, 62 patients in chronic phase with T315I mutation were treated. A complete hematologic response was achieved in 77%, with a median re� sponse duration of 9.1 months. Twen� ty�three percent of patients achieved a major cytogenetic response, which was complete in 16%. The estimated 3�year survival rate was 60%.17 In the context of the phase�II �II II stud� ies conducted, an updated analysis involved 122 patients (81 in chronic� phase CML, 41 in accelerated�phase CML) treated regardless of muta� tion status, who had previously been

Jorge Cortes, MD

treated with two or more tyrosine kinase inhibitors (including imatinib [Gleevec]). Among the 81 patients in chronic phase, 16 (20%) achieved a major cytogenetic response (complete in 10%, partial in 10%). The median duration of major cytogenetic response was 18 months. Four patients (5%) had a minor cyto� genetic response. The median overall survival was 34 months. Among the 41 patients in accelerated phase, 11 (27%) had a major hematologic response for a median duration of 9 months. Six patients (14%) had a cytogenetic re� sponse. The median overall survival was 16 months.18 The first submission to the FDA re� sulted in a negative Oncologic Drugs Advisory Committee (ODAC) vote for omacetaxine approval in CML and T315I mutation, because of the lack of a standardized molecular test for T315I. The subsequent FDA submis� sion for omacetaxine in the setting of CML after failure of two or more ty� rosine kinase inhibitors resulted in the FDA approval in October 2012.

Future Research The FDA approval of omacetaxine in CML for the narrow indication of CML in chronic or accelerated phases post failure of two or more tyrosine ki� nase inhibitors is the beginning of the real research into different potential uses of omacetaxine in leukemia. This is analogous to the ongoing research continued on page 63

To prevent SREs in patients with BREAST CANCER and bone metastases

vs zoledronic acid

Better prevent SREs1 MEDIAN TIME TO FIRST SRE IN BREAST CANCER1*

27 26.4 At

Months (study end)

median time not yet reached

Months

XGEVA® 120 mg Q4W (n = 1,026)

XGEVA® acts precisely to bind RANK Ligand, a key mediator of bone resorption, and inhibit osteoclast formation, function, and survival1

zoledronic acid 4 mg Q4W (n = 1,020)

HR = 0 0.82; 82; P = 0 0.010, 010 0 superiority

• XGEVA® reduced the risk of first SRE by 16% vs zoledronic acid in patients with other solid tumors or multiple myeloma (P < 0.001, noninferiority; P = 0.060, NS for superiority)1* XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma Convenient 120 mg subcutaneous injection administered once every 4 weeks1 Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia1 Approximately 70% of patients are expected to have $0 out-of-pocket cost for XGEVA®2† *Data from the international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046) and in patients with bone metastases from other solid tumors (excluding breast and prostate cancer) or multiple myeloma (N = 1,776). The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.1 † Estimated amount of Medicare beneficiaries with supplemental coverage and commercially insured patients with no OOP cost; based on XGEVA® payor mix and coverage of XGEVA® and other similar products. Does not include costs related to office visit, physician, staff, or administrative charges associated with administering XGEVA®.

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

IMPORTANT SAFETY INFORMATION Hypersensitivity • XGEVA is contraindicated in patients with clinically signiﬁcant hypersensitivity to any component of the product. ®

Hypocalcemia • XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct preexisting hypocalcemia prior to XGEVA® treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. • Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ) • Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®.

• Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture • Atypical femoral fracture has been reported with XGEVA®. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents. A number of reports note that patients were also receiving treatment with glucocorticoids at the time of fracture. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Interruption of XGEVA® therapy should be considered, pending a risk/ beneﬁt assessment, on an individual basis.

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

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

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

REFERENCES: 1. XGEVA® (denosumab) prescribing information, Amgen. 2. Data on ﬁle, Amgen.

S:9.5”

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: Hypersensitivity. Xgeva is contraindicated in patients with clinically signiﬁcant hypersensitivity to any component of the product (see Adverse Reactions). WARNINGS AND PRECAUTIONS: Hypocalcemia. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva (see Adverse Reactions). These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis. PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth and decreased neonatal growth (see Use in Specific Populations). There are no adequate and well controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. 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.

are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and beneﬁts in continuing or discontinuing treatment with Xgeva. Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other ﬁndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone a Table 1. Per-patient Incidence of Selected Adverse Reactions of Any Severity growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth (Trials 1, 2, and 3) malalignment; and decreased neonatal growth. At birth out to one month of age, infants Xgeva Zoledronic Acid had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and Body System n = 2841 n = 2836 strength returned to normal; there were no adverse effects on tooth eruption, though % % dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; GASTROINTESTINAL and minimal to moderate mineralization in multiple tissues was seen in one recovery Nausea 31 32 animal. There was no evidence of maternal harm prior to labor; adverse maternal Diarrhea 20 19 effects occurred infrequently during labor. Maternal mammary gland development was GENERAL normal. There was no fetal NOAEL (no observable adverse effect level) established for Fatigue/ Asthenia 45 46 this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis INVESTIGATIONS and led to postnatal impairment of dentition and bone growth. Pregnant RANKL 18 9 Hypocalcemiab knockout mice showed altered maturation of the maternal mammary gland, leading Hypophosphatemiab 32 20 to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in NEUROLOGICAL full Prescribing Information). Headache 13 14 Nursing Mothers. It is not known whether Xgeva is excreted into human milk.

Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, a decision should be made whether to discontinue nursing or discontinue the drug, 2, and 3, and meeting one of the following criteria: taking into account the importance of the drug to the mother. Maternal exposure • At least 1% greater incidence in Xgeva-treated patients, or to Xgeva during pregnancy may impair mammary gland development and lactation • Between-group difference (either direction) of less than 1% and more than based on animal studies in pregnant mice lacking the RANK/RANKL signaling 5% greater incidence in patients treated with zoledronic acid compared to pathway that have shown altered maturation of the maternal mammary gland, placebo (US Prescribing Information for zoledronic acid) leading to impaired lactation postpartum. However, in cynomolgus monkeys treated b with denosumab throughout pregnancy, maternal mammary gland development Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; (0.71 – 0.9 mmol/L) for phosphorus] however, development and lactation have not been fully evaluated (see Nonclinical Severe Mineral/Electrolyte Abnormalities Toxicology [13.2] in Full Prescribing Information). • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment of patients treated with zoledronic acid. Of patients who experienced severe with Xgeva may impair bone growth in children with open growth plates and hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes (see Warnings and Precautions and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) Use in Specific Populations). at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than eruption. Adolescent primates treated with denosumab at doses 5 and 25 times 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of (10 and 50 mg/kg dose) higher than the recommended human dose of patients treated with zoledronic acid. 120 mg administered once every 4 weeks, based on body weight (mg/kg), had Osteonecrosis of the Jaw abnormal growth plates, considered to be consistent with the pharmacological In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab patients in the Xgeva group and 1.3% of patients in the zoledronic acid group (see exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Warnings and Precautions). When events occurring during an extended treatment decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and phase of approximately 4 months in each trial are included, the incidence of mesenteric lymph nodes. Some bone abnormalities recovered once exposure was confirmed ONJ was 2.2% in patients who received Xgeva. The median time to ONJ ceased following birth; however, axillary and inguinal lymph nodes remained absent was 14 months (range: 4 – 25). 6 months post-birth (see Use in Pregnancy). Postmarketing Experience. Because postmarketing reactions are reported Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) voluntarily from a population of uncertain size, it is not always possible to reliably were 65 years of age or older. No overall differences in safety or efficacy were estimate their frequency or establish a causal relationship to drug exposure. observed between these patients and younger patients. The following adverse reactions have been identified during post approval use of Xgeva: Renal Impairment. In a trial of 55 patients without cancer and with varying • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. degrees of renal function who received a single dose of 60 mg denosumab, Immunogenicity. As with all therapeutic proteins, there is potential for patients with a creatinine clearance of less than 30 mL/min or receiving dialysis immunogenicity. Using an electrochemiluminescent bridging immunoassay, less were at greater risk of severe hypocalcemia with denosumab compared to than 1% (7/2758) of patients with osseous metastases treated with denosumab patients with normal renal function. The risk of hypocalcemia at the recommended doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to dosing schedule of 120 mg every 4 weeks has not been evaluated in patients 3 years tested positive for binding antibodies. No patient with positive binding with a creatinine clearance of less than 30 mL/min or receiving dialysis (see antibodies tested positive for neutralizing antibodies as assessed using a Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] chemiluminescent cell-based in vitro biological assay. There was no evidence of in full Prescribing Information). altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly OVERDOSAGE: There is no experience with overdosage of Xgeva. dependent on the sensitivity and specificity of the assay. Additionally, the observed HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. incidence of a positive antibody (including neutralizing antibody) test result may be Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. influenced by several factors, including assay methodology, sample handling, timing Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to of sample collection, concomitant medications, and underlying disease. For these temperatures above 25°C/77°F or direct light and must be used within 14 days. reasons, comparison of antibodies to denosumab with the incidence of antibodies Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous to other products may be misleading. DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted shaking of Xgeva.

RESPIRATORY Dyspnea Cough

21 15

18 15

PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) • Persistent pain or slow healing of the mouth or jaw after dental surgery (see Warnings and Precautions) • Pregnancy or nursing (see Warnings and Precautions and Use in Specific Populations) Advise patients of the need for: • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva on ﬁndings in animals. In utero denosumab exposure in cynomolgus monkeys Advise patients that denosumab is also marketed as Prolia®. Patients should resulted in increased fetal loss, stillbirths, and postnatal mortality, along inform their healthcare provider if they are taking Prolia. with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva Amgen Manufacturing Limited, a subsidiary of Amgen Inc. in pregnant women. Women should be advised not to become pregnant when One Amgen Center Drive taking Xgeva. If this drug is used during pregnancy, or if the patient becomes Thousand Oaks, California 91320-1799 pregnant while taking this drug, the patient should be apprised of the potential ©2010-2013 Amgen Inc. All rights reserved. hazard to the fetus. Women who become pregnant during Xgeva treatment Printed in USA. 68257-R2-V2

with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There ADVERSE REACTIONS: The following adverse reactions are discussed below and was no evidence that various anticancer treatments affected denosumab systemic elsewhere in the labeling: exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 • Hypocalcemia (see Warnings and Precautions) months were not altered by concomitant chemotherapy and/or hormone therapy. The • Osteonecrosis of the Jaw (see Warnings and Precautions) median reduction in uNTx/Cr from baseline to month 3 was similar between patients The most common adverse reactions in patients receiving Xgeva (per-patient receiving concomitant chemotherapy and/or hormone therapy (see Clinical incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, Pharmacology [12.2] in full Prescribing Information). and nausea (see Table 1). The most common serious adverse reaction in patients USE IN SPECIFIC POPULATIONS: receiving Xgeva was dyspnea. The most common adverse reactions resulting in Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: discontinuation of Xgeva were osteonecrosis and hypocalcemia. Xgeva can cause fetal harm when administered to a pregnant woman based 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 other clinical trials and may not reﬂect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were

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Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-ﬁve percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-ﬁve percent of patients who received Xgeva received concomitant chemotherapy.

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Perspective

Homoharringtonine/ Omacetaxine continued from page 59

with high�dose cytarabine on different schedules in AML and lymphoma, and with high�dose daunorubicin in AML, 30 to 40 years after their FDA approval. The high level of activity of omac� etaxine in CML and its efficacy against dormant CML clones makes it an ideal agent to eradicate residual CML disease and for CML molecular cure. Future studies should investigate the addition of omacetaxine to tyrosine kinase inhibitors in patients with CML in complete cytogenetic response with persistent molecular disease. In AML, omacetaxine could be in� vestigated as low�intensity therapy in combination with low�dose cytarabine or hypomethylating agents for treat� ment of older patients with AML not fit for intensive chemotherapy, or in whom intensive chemotherapy is not ben� eficial. Combinations of omacetaxine with standard chemotherapy in younger patients with AML should be further explored. Omacetaxine could also be in� vestigated in all patients with AML fol� lowing completion of standard therapy, as consolidation�maintenance therapy to eradicate minimal residual disease. In MDS, omacetaxine should be evaluated in patients who fail therapy with hypomethylating agents and in whom the expected median survival is about 6 months. It may be useful in combination therapy with hypomethyl� ating agents in front�line MDS therapy. Additional uses of omacetaxine

Fellows of the AACR Academy continued from page 55

Sir Richard J. Roberts, PhD, �ew England Biolabs, Inc. Irwin A. Rose, PhD, University of California, Irvine Janet D. Rowley, MD, University of Chicago Frederick Sanger, PhD, University of Cambridge Alan C. Sartorelli, PhD, Yale Uni� versity School of Medicine Andrew V. Schally, PhD, University of Miami Phillip A. Sharp, PhD, David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology Charles J. Sherr, MD,PhD, St. Jude Children’s Research Hospital; Howard Hughes Medical Institute

may be in the settings of APL, myelo� proliferative conditions such as poly� cythemia vera, and as intrathecal ther� apy for resistant C�S leukemia.

Additional Issues Two elephants in the room need to be addressed: (1) the high cost of the drug (about $24,000 for induc� tion and $12,000 for a maintenance course), and (2) the FDA mandate that the drug cannot be self�administered (even though all prior research studies with subcutaneous omacetaxine were self�administered without any safety concerns). Lowering the price of omac� etaxine and allowing for patient self� administration will improve access and compliance, broaden the use of omac� etaxine, and reduce the cost of care. �ow, the future looks quite bright for the little drug that could. n

Disclosure: Dr. Kantarjian has received research grants from ChemGenex. Dr. O’Brien has consulted for Teva. Dr. Cortes has received research grants from ChemGenex and is a consultant for Teva.

References 1. Kantarjian HM, Talpaz M, Santini V, et al: Homoharringtonine. History, cur� rent research, and future directions. Can� cer 92:1591�1605, 2001. 2. Grem JL, Cheson BD, King SA, et al: Cephalotaxine esters: Anti�leukemic ad� vance or therapeutic failure? J �atl Cancer Inst 80:1095�1103, 1988. 3. Quintas�Cardama A, Kantarjian H, Cortes J: Homoharringtonine, omacetax� ine mepesuccinate, and chronic myeloid leukemia circa 2009. Cancer 115:5382� 5392, 2009.

Osamu Shimomura, PhD, Boston University School of Medicine Dennis J. Slamon, MD,PhD, Rev� lon/UCLA Women’s Cancer Research Program, Jonsson Comprehensive Cancer Center; David Geffen School of Medicine, University of California, Los Angeles Oliver Smithies, D.Phil, University of �orth Carolina School of Medicine at Chapel Hill Michael B. Sporn, MD, Geisel School of Medicine at Dartmouth Louise C. Strong, MD, The Uni� versity of Texas MD Anderson Cancer Center Takashi Sugimura, MD, Toho Uni� versity; �ational Cancer Center Sir John E. Sulston, PhD, Univer� sity of Manchester Jack W. Szostak, PhD, Howard

4. Liu J, Mi Y, Fu M, et al: Intensive in� duction chemotherapy with regimen con� taining intermediate dose cytarabine in the treatment of de novo acute leukemia. Am J Hematol 84:422�427, 2009. 5. Jin J, Wang J, Chen F, et al: Homo� harringtonine�based induction regimens for patients with de novo acute myeloid leukemia: A multicenter randomized con� trolled phase 3 trial. Blood 120(ASH An� nual Meeting):Abstract 45, 2012. 6. Warrell RP Jr, Coonley CJ, Gee TS: Homoharringtonine: An effective new drug for remission induction in refractory nonlymphoblastic leukemia. J Clin Oncol 3:617�621, 1985. 7. Kantarjian HM, Keating MJ, Wal� ters RS, et al: Phase II study of low�dose continuous infusion homoharringtonine in refractory acute myelogenous leukemia. Cancer 63:813�817, 1989. 8. O’Brien S, Kantarjian H, Keating M, et al: Homoharringtonine therapy induces responses in patients with chronic my� elogenous leukemia in late chronic phase. Blood 86:3322�3326, 1995. 9. O’Brien S, Kantarjian H, Koller C, et al: Sequential homoharringtonine and interferon�alpha in the treatment of early chronic phase chronic myelogenous leuke� mia. Blood 93:4149�4153, 1999. 10. Kantarjian HM, Talpaz M, Smith TL, et al: Homoharringtonine and low� dose cytarabine in the management of late chronic�phase chronic myelogenous leu� kemia. J Clin Oncol. 18:3513�3521, 2000. 11. Stone RM, Donohue KA, Stock W, et al: Cancer and Leukemia Group B, A phase II study of continuous infusion Ho� moharringtonine and cytarabine in newly diagnosed patients with chronic myeloid leukemia: CALGB study 19804. Cancer Chemother Pharmacol 63:859�864, 2009.

Hughes Medical Institute; Harvard Uni� versity; Massachusetts General Hospital Roger Y. Tsien, PhD, University of California, San Diego; Howard Hughes Medical Institute Arthur C. Upton, MD, University of Medicine and Dentistry, Robert Wood Johnson Medical School George F. Vande Woude, PhD, Van Andel Research Institute Bert Vogelstein, MD, Sidney Kim� mel Comprehensive Cancer Center, Johns Hopkins University School of Medicine; Howard Hughes Medical In� stitute Peter K. Vogt, PhD, The Scripps Research Institute Daniel D. Von Hoff, MD, Trans� lational Genomics Research Insti� tute; Mayo Clinic; Scottsdale Health Care; University of Arizona College of

12. O’Brien S, Talpaz M, Cortes J, et al: Simultaneous homoharringtonine and in� terferon�alpha in the treatment of patients with chronic�phase chronic myelogenous leukemia. Cancer 94:2024�2032, 2002. 13. O’Brien S, Giles F, Talpaz M, et al: Results of triple therapy with interferon�al� pha, cytarabine, and Homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Phila� delphia chromosome�positive chronic my� elogenous leukemia in early chronic phase. Cancer 98:888�893, 2003. 14. Robin J, Dhal R, Dujardin G, et al: The first semi�synthesis of enantiopure homoharringtonine via anhydrohomohar� ringtonine from a preformed chiral acyl moiety. Tetrahedron Lett 40:2931�2934, 1999. 15. Marin D, Kaeda JS, Andreasson C, et al: Phase I/II trial of adding semisyn� thetic homoharringtonine in chronic my� eloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib. Cancer 103:1850�01855, 2005. 16. Quintas�Cardama A, Kantarjian H, Garcia�Manero G, et al: Phase I/II study of subcutaneous homoharringtonine in pa� tients with chronic myeloid leukemia who have failed prior therapy. Cancer 109:248� 255, 2007. 17. Cortes J, Lipton JH, Rea D, et al: Phase 2 study of subcutaneous omacetax� ine mepesuccinate after TKI failure in pa� tients with chronic�phase CML with T315I mutation. Blood 120:2573�2580, 2012. 18. Cortes J, �icollini F, Wetzler M, et al: Subcutaneous omacetaxine in chronic or accelerated chronic myeloid leukemia resistant to two or more tyrosine�kinase inhibitors including imatinib. Blood 118(ASH Annual Meeting):Abstract 2761, 2011.

Pharmacy Geoffrey M. Wahl, PhD, Salk Institute for Biological Studies James D. Watson, PhD, Cold Spring Harbor Laboratory Lee W. Wattenberg, MD, Ma� sonic Cancer Center, University of Minnesota Robert A. Weinberg, PhD, Mas� sachusetts Institute of Technology; Ludwig/MIT Center for Molecular Oncology John H. Weisburger, PhD, �ew York Medical College Jane Cooke Wright, MD, De� ceased (1919 – 2013) Shinya Yamanaka, MD, PhD, Kyoto University; University of California, San Francisco Harald zur Hausen, MD, German Cancer Research Center

The ASCO Post | APRIL 15, 2013

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Direct from ASCO

ASCO-SEP®, 3rd Edition, Features Digital Formats and Complementary Study Tools

SCO has released the latest edi� tion of ASCO-SEP®, a compre� hensive resource designed to help medical providers assess and im� prove their level of knowledge in the various areas of oncology, enabling them to provide care that will op� timize the quality of life for people with cancer. ASCO-SEP, 3rd Edition, authored by a team of experts in the various subject areas, features all new self�assessment questions that correspond with each of the 22 updated chapters, offered in both print and eBook versions; an Online Question Bank; and the new ASCO Flashcards app.

Useful Resource According to the editor, Charles L. Loprinzi, MD, Regis Profes� sor of Breast Cancer Research at the Mayo Clinic, “ASCO-SEP is a useful resource for a broad range of health�care professionals.” Of course, it serves as an ideal study guide for fellows preparing for board examinations and medical providers preparing for mainte� nance of certification exams. But is also a helpful general education tool for physician assistants, nurse practitioners, oncology nurses, re� searchers, and other professionals who work in oncology settings. Moreover, physicians can turn to the publication to research options for individual patients under their care. ASCO-SEP includes more than 700 pages that cover key oncology topics, including all major cancer types, cancer prevention and epide� miology, molecular biology, thera� peutic modalities, clinical trials and biostatistics, symptom manage� ment, palliative and end�of�life care, and geriatric care. Accompanying case studies, graphs, charts, tables, and images help make these top� ics easier to digest quickly. And the more than 170 new self�evaluation questions, with answer rationales

ASCO-SEP is a useful resource for a broad range of health-care professionals. —Charles L. Loprinzi, MD

and references, help users assess their comprehension.

Multiplatform Support Recognizing that busy health� care providers today rely heavily on digital notepads, electronic read� ers, and smartphones, ASCO has made this publication available as an eBook that is compatible with iPhone, iPad, iPod, Kindle, and �ook devices. The eBook is provid� ed along with the print edition at no additional cost. Individuals looking for addi� tional learning opportunities can access the Online Question Bank and ASCO Flashcards app. The 100 predominately case�based questions in the Online Question Bank differ from those included in the print and eBook, and they similarly include answer rationales and references for suggested read� ing. Users can track their scores, re� take missed questions, and submit scores for continuing medical edu� cation credit. Meanwhile, ASCO Flashcards is an app with 200 flashcards that high� light the key points covered in each chapter of the book, presented in an easy�to�digest format. It allows users to self test their knowledge and sort the flashcards based on topic areas of strength and weakness to guide further study. The app is compatible with iOS (iPhone or iPad) and An� droid devices. A Web�based version is also available for individuals us� ing a different platform. The Online

Question Bank and ASCO Flash� cards app may be purchased sepa� rately or in a discounted bundle with the ASCO-SEP book.

Valuable Study Tool Wells Messersmith, MD, Direc� tor of the Gastrointestinal Medical Oncology Program and Co�head of the Division of Medical Oncology at University of Colorado School of Medicine, relied on ASCO-SEP to help him prepare for his recent maintenance of certification exam. “My overall studying really changed once I started using the SEP pro� gram,” he says.

tee and a member of the American Board of Internal Medicine’s Medi� cal Oncology Board, “The� ASCOSEP� program organizes all that information for you, with a defined number of chapters covering what the experts think are the main topics. Subjects are boiled down into various targeted modules with helpful tables and figures, as well as practice questions. For a busy person studying for the exam, that’s really what you need.”

Expert Opinions Dr. Messersmith added that he appreciated knowing that the con� tent in ASCO-SEP is written by ex� perts in the field, many of whom have been members of American Board of Internal Medicine ques� tion committees. “Even in my own area of specialization, it was inter� esting to read these expert opin� ions,” he said. The timing of his maintenance of certification exam—shortly before the release of ASCO-SEP, 3rd Edition—was unfortunate,

My overall studying really changed once I started using the SEP program. —Wells Messersmith, MD

Having previously tried using a variety of study materials, such as national guidelines and online resources, he found that it was in� efficient to comb through docu� ments from various sources that often contained irrelevant informa� tion. According to Dr. Messersmith, who is also a member of ASCO’s Lifelong Learning Subcommit�

Dr. Messersmith said, noting that he would have benefited from the electronic offerings and additional study tools. For more information on ASCOSEP, 3rd Edition, please visit univer� sity.asco.org/SEP. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | APRIL 15, 2013

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Direct from ASCO

Philanthropy Spotlight

ASCO Leadership Development Program Participants ‘Give Back’ by Supporting the Conquer Cancer Foundation

n the fast�paced world of oncol� ogy, where the science of patient care is constantly evolving, it is critical for practitioners—and, by extension, their Society—to con� sistently be one step ahead. For ASCO and the Conquer Cancer Foundation, that means maintain� ing a strong focus not only on the leading edge of the oncology profession, but also on cultivating the next generation of oncology leaders. It was with this principle in mind that ASCO launched its Leadership Development Program (LDP) in 2009. This program was designed to provide formal leadership train� ing for mid�career oncologists inter� ested in improving their skills and serving in increasingly challenging roles within ASCO or in other or� ganizations. Through the program, participants gain extensive exposure to the roles and mission of ASCO, its leadership, and the Society’s power� ful place in developing the future of cancer care.

Hands-on Approach A key part of the LDP curricu� lum involves breaking the partici� pants into small groups and pro� viding a hands�on opportunity to grapple with a unique need or chal� lenge within ASCO. The partici� pants are tasked with identifying the scope of the project, develop� ing a plan to undertake topics of

interest, and making formal recom� mendations to the ASCO Board of Directors. This year, the Conquer Cancer Foundation was chosen as an LDP area of interest. Over the past few months a team of four LDP par� ticipants—Tanios Bekaii-Saab,

Tanios Bekaii-Saab, MD

MD, of The Ohio State University; Sanjay Goel, MD, MS, of Monte� fiore/Albert Einstein College of Medicine; Michael Thompson, MD, PhD, of ProHealth Care Re� gional Cancer Center; and Anne Tsao, MD, of The University of Texas MD Anderson Cancer Cen� ter—and their mentor Jamie Von Roenn, MD, of the Lurie Compre� hensive Cancer Center of �orth�

Sanjay Goel, MD, MS

Michael Thompson, MD, PhD

As Dr. Goel puts it, “It was only once I began the LDP in earnest that I truly appreciated the broad� er role that the Foundation plays within ASCO. The most surprising fact was that the Foundation sup� ports many of the endeavors that ASCO is involved in, including the ASCO Annual Meeting and the multidisciplinary symposia, like GI and GU.”

As ASCO members, we benefit tremendously from the strength and reach of an organization that speaks and advocates on our behalf and on behalf of millions of cancer patients. —Tanios Bekaii-Saab, MD

western University, have worked with ASCO and Foundation staff to, among other things, develop a strategic answer to one of the Foundation’s most pointed ques� tions: Why exactly should ASCO Members support the Conquer Cancer Foundation?

Advocacy through Information Dr. Tsao received both a Con� quer Cancer Foundation of ASCO Young Investigator Award (YIA) and Career Development Award (CDA). “These grants jump�started my academic career and enabled me to create a successful multidis� ciplinary program at my institution in a rare tumor type. I wouldn’t have been able to do that� without the Foundation’s support,” she says. But even with this insider per� spective, the group was still surprised to learn of the scope of the Founda� tion’s support of ASCO’s mission.

Besides supporting ASCO’s educational program, the Founda� tion also fuels the Society’s inter� national programs and its patient information resources, including the patient information website Cancer.�et, and will play a key role in building support for ASCO’s revolutionary new CancerLinQ rapid learning system. Unfortu� nately, one of the challenges the LDP group is facing is a lack of awareness. “I don’t think the gen� eral ASCO membership is aware of the history and scope of the Foun� dation or the importance of future projects to the oncology commu� nity,” say Dr. Thompson.

Leading by Giving Back The Leadership Development Group will present a formal recom� mendation to the ASCO Board of Directors at its May meeting, but in the meantime each of the partici� pants has chosen to directly support

Anne Tsao, MD

ASCO’s mission and advance cancer research and education in a much more personal way: They have all chosen to become Conquer Cancer Foundation donors. For Dr. Goel, “The decision to support the Foundation was easy. To simply give back. I have been lucky enough to receive a fairly prestigious award from the Foundation, which changed my outlook…and more� over, provided a real morale boost to my career.” Dr. Tsao agrees. As she puts it: “I am very committed to give back to the Foundation and make sure that others have the same opportunity that I did.” “ASCO has been at the center of my professional career develop� ment,” says Dr. Thompson. “I am grateful and want to give back to my organization and help new oncolo� gists develop in research and clinical care.” Dr. Bekaii�Saab takes a slightly wider view: “As ASCO members, we benefit tremendously from the strength and reach of an organization that speaks and advocates on our behalf and on behalf of millions of cancer patients. In addition to volun� teering through various committees, giving to the Foundation ensures that our organization’s mission con� tinues to lead the way in cancer care, research and education.” The 2013 Leadership Develop� ment Program participants invite you to join them in supporting the Conquer Cancer Foundation and the mission of ASCO. To make a gift to� day, visit www.conquercancerfoun� dation.org/donate. n © 2013. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | APRIL 15, 2013

PAGE 66

Direct from ASCO

ASCO’s State Oncology Societies Booth Provides a Place for Relationship Building and Sharing Best Practices

ant to learn how to best lobby your local state legislators on the issues that affect your practice in your state? Or finally meet the execu-

tive director of your state’s oncology society? Look for the State Oncology Societies Booth at ASCO’s Annual

Meeting this year. The booth will be located in the Oncology Professionals Hall, to the left of the entrance. The State Oncology Societies Booth

is an important way that ASCO helps unite state societies with each other and with their members every year at the Annual Meeting.

Lori Aubrey

Both booth space and conference registration are free to state affiliate representatives, who can promote their society to nonmembers visiting the Oncology Professionals Hall. The booth also offers state society leaders the opportunity to meet with current and potential corporate sponsors for their organizations.

Connecting Personally and Professionally Leaders from different state societies also network with each other at the State Oncology Societies Booth. “The booth is a great place to connect with other society leaders, providing a meeting space for society members to check in and connect with their state or regional affiliate, and [engage] with other society leaders,” says Lori Aubrey, Executive Director of Northern New England Clinical Oncology Society. “The booth’s inviting, comfortable layout provides for intimate meeting space among the enormity of the hall.”

Valuable Exchange of Best Practices All state and regional societies are invited to send a representative to the booth, who will interact with providers as they come by. Mary Malloy, Executive Director of the Michigan Society of Hematology & Oncology (MSHO), observes, “It’s very beneficial to be able to network with my peers, both formally during the ASCO-developed continued on page 68

ASCOPost.com | APRIL 15, 2013

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Direct from ASCO

Conquer Cancer Foundation Arms Patients with Knowledge through patientACCESS

eceiving a cancer diagnosis can be a frightening and over� whelming experience, and the first thing many people do upon receiv� ing the news is seek out information, hoping to be em� powered through knowledge. At the Conquer Cancer Foundation, we are working to en� sure that vital in� formation—focusing on everything from breakthrough research to treat� ment options and survivorship—is available and easily accessible when�

ever and wherever patients need it. We are pleased to announce that, in partnership with the Ameri� can Society of Clinical Oncology (ASCO), we are making it possible for patients being treated for cancer and their caregivers to gain free access to medical research published in AS� CO’s Journal of Clinical Oncology and Journal of Oncology Practice. This new initiative is called patientACCESS.

Empowering Patients Through our support of this pro� gram, the Foundation is helping put the latest cancer research discoveries from around the world immediately at the fingertips of patients searching for the most up�to�date information, empowering them to make better in� formed health�care decisions. Well� informed patients are truly their own

best advocates and invaluable part� ners for physicians. This is one reason why we also help fund ASCO’s pa� tient information program, including Cancer.�et, where patients can find oncologist�approved information on more than 120 cancer types and learn more about patientACCESS and how to get the latest research findings at no cost. It is estimated that, in 2012, there were more than 1.5 million new can� cer cases in the United States alone,1 and virtually everyone in the world, in some way and at some point, will eventually be touched by cancer. To�

gether, we can make a difference. To� gether, we can make sure that people continue to have access to the best cancer information. Please join us— make a gift today to help empower patients now and in the future. Visit www.conquercancerfoundation.org/ donate. n Reference 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society, 2012. © 2013. American Society of Clinical Oncology. All rights reserved.

The Foundation’s support of the patientACCESS initiative is made possible through our Mis� sion Endowment fund.

ASCO Develops New Physician Payment Reform Webpage and Four-part Educational Series

o help keep its members and the cancer community apprised and educated on the issue of pay� ment reform, ASCO has developed a payment reform webpage and is� sued an ASCO in Action educational series. This four�part series is de� signed to help ASCO members bet� ter understand the complex issue of physician payment reform:� Part�1 pro� vides an overview of the issue; Part 2 discusses the Sus� tainable Growth Rate formula; Part 3 provides details on the current buy and bill system of reimbursing for oncology drugs; and Part 4 discusses payment reform options being con� sidered as alternatives to the current fee�for�service system. To read the series, go to ASCO’s physician pay� ment reform page at www.asco.org/ paymentreform.

Guideline on Central Venous Catheter Care ASCO recently issued a guide� line on central venous catheter care for people living with cancer.

The guideline, which published in the Journal of Clinical Oncology on March 4, addresses catheter type, insertion site, and placement, as well as the prevention and manage� ment of both catheter�related infec� tion and thrombosis. To view the full guideline, please go to: www. asco.org/guidelines/cvc.

Affordable Care Act ‘Sunshine’ Rule The Centers for Medicare and Medicaid Services recently an� nounced a final rule implementing Section 6002 of the Affordable Care Act (the “�ational Physician Pay� ment Transparency Program: Open Payments”). The final rule, common� ly called the “Sunshine” rule, will make information publicly available about payments or other transfers of value from applicable manufacturers to physicians and teaching hospitals (“covered recipients”), and about physician (or immediate family members of a physician) ownership or investment interests in applicable manufacturers and group purchasing organizations (GPOs). Under this rule, applicable manu�

facturers must report annually to the U.S. Department of Health and Hu� man Services Secretary all payments or transfers of value (including gifts, consulting fees, research activities, speaking fees, meals, and travel) from applicable manufacturers to covered recipients. Applicable manufacturers and GPOs must also report owner�

ship and investment interests held by physicians (or their immediate fam� ily members) in such entities. For additional details, please see the final rule at https://www.federalregister. gov/public�inspection. n © 2013. American Society of Clinical Oncology. All rights reserved

Managing Side Effects: Urinary Incontinence

ancer.�et recently added an ar� ticle on urinary incontinence to help patients learn how to cope with this side effect. In the article, patients can learn about the causes of urinary incontinence and how it is diagnosed, as well as read about the treatment op� tions and how it can be managed. To

The ASCO Post | APRIL 15, 2013

PAGE 68

Direct from ASCO

State Oncology Societies continued from page 66

Springboard for Program Development

information sessions, and informally discussing our experiences and best practices—different strategies for member retention, for example.” Often, such information exchang� es result in notable gains. “Two years ago at the booth, Mary Malloy had on display an ex� ample of her group membership recognition award,” says Ms. Aubrey. “The following year, we incorporated practice awards into a group mem� bership structure. The result of the new group membership and recog� nition program? More than 120 new members!”

Change and growth at the state societies can come via exchanges between executives and providers visiting the booth. Ms. Malloy re� calls that an MSHO member shared an idea regarding professional de� velopment for training fellows. She recruited him as course director on the spot, and the MSHO instituted a career development forum for their Hem/Onc fellows the follow� ing spring. Ms. Molloy adds that, by popular demand, the program will be expanded this year, and it all started with the meeting at the State Oncology Societies Booth

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

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

What’s Hot in

JCO

JCO.org

Mary Malloy

that connected a society member’s great idea with MSHO program de� velopment. Another year, a Wisconsin physi� cian dropped by the booth. Those at the booth helped him get involved in revitalizing his state society from

Volume 7, Issue 3

May 2011

Journal of oncology Practice The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

the ground up. A similar scenario occurred with the West Virginia so� ciety. One more success story from the State Oncology Societies Booth: After hearing feedback from state affiliate members last year, ASCO’s Government Relations Committee developed model legislation on oral chemotherapy parity for members to take back to their states and use to lobby their state legislatures. To learn more about the 2013 ASCO Annual Meeting, visit http:// chicago2013.asco.org/ n © 2013. American Society of Clinical Oncology. All rights reserved.

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

What’s Hot in

JOP

JCO.org

Randomized Phase III Trial of ABVD Versus Stanford V With or Without Radiation Therapy in Locally Extensive and AdvancedStage Hodgkin Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperative Oncology Group (E2496) by Leo I. Gordon, et al

Screening Intervention to Identify Eligible Patients and Improve Accrual to Phase II-IV Oncology Clinical Trials by Leo Chen, et al

Systematic Review of Acupuncture in Cancer Care: A Synthesis of the Evidence by M. Kay Garcia, et al

Efficiency of Colorectal Cancer Care Among Veterans: Analysis of Treatment Wait Times at Veterans Affairs Medical Centers by Ryan P. Merkow, et al

Randomized Phase III Trial of Induction Chemotherapy With Docetaxel, Cisplatin, and Fluorouracil Followed by Surgery Versus Up-Front Surgery in Locally Advanced Resectable Oral Squamous Cell Carcinoma by Lai-ping Zhong, et al

Ethics in Oncology: An Annotated Bibliography of Important Literature by Laura L. Tenner, et al

Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma by Antoni Ribas, et al

Measuring Clinical Trial–Associated Workload in a Community Clinical Oncology Program by Marjorie J. Good, et al

Breast Cancer Follow-Up and Management After Primary Treatment: American Society of Clinical Oncology Clinical Practice Guideline Update by James L. Khatcheressian, et al

Use of Continuous Infusion Pumps During Radiation Treatment by Kate Bak, et al

When hemoglobin fallsâ&#x20AC;Ś

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

Catch hemoglobin levels before they fall too far Reduce RBC transfusions and achieve a gradual and steady Hb rise with Aranesp

®1-4

• In untreated patients whose Hb fell below 10 g/dL, 1 in 3 required an RBC transfusion within 6 weeks*5 • Aranesp® significantly reduced the need for RBC transfusions by 48% compared to placebo†2,3 • Aranesp® can be synchronized with the majority of chemotherapy regimens, including Q3W6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa CIA trials. Patients had baseline Hb ≥ 10 g/dL and decline to Hb < 10 g/dL at least once during the study-treatment period. Kaplan-Meier (K-M) estimates were calculated for the incidence of patients with transfusions by Weeks 0, 3, 6, and 9 after Hb < 10 g/dL was reached. Seventy-two percent of patients had lung cancer.5 †Data from a randomized, double-blind, placebo-controlled trial of 314 anemic (Hb ≤ 11 g/dL) patients with lung cancer receiving platinum-containing chemotherapy. Patients received once-weekly treatment with either Aranesp® (2.25 mcg/kg) or placebo, administered by subcutaneous injection, for up to 12 weeks. Per the pivotal trial protocol, doses were withheld if Hb exceeded 14 g/dL for women or 15 g/dL for men.3

INDICATION and LIMITATIONS OF USE Aranesp® (darbepoetin alfa) is for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Aranesp® is not for use: • In patients receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy • In patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure • As a substitute for RBC transfusions in patients requiring immediate correction of anemia Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being.

References: 1. Vansteenkiste J, Hedenus M, Gascon P, et al. BMC Cancer. 2009;9:311. doi:10.1186/1471-2407-9-311. 2. Aranesp® (darbepoetin alfa) Prescribing Information, Amgen. 3. Vansteenkiste J, Pirker R, Massuti B, et al. J Natl Cancer Inst. 2002;94:1211-1220. 4. Canon JL, Vansteenkiste J, Bodoky G, et al. J Natl Cancer Inst. 2006;98:273-284. 5. Pirker R, Collins H, Legg J, et al. J Clin Oncol. 2011;29(suppl). Abstract e19637. 6. Data on file, Amgen; [Tandem Anti-cancer and Tumor Audit].

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799

RBC = red blood cell

Hb = hemoglobin

Q3W = once every three weeks

Important Safety Information including Boxed WARNINGS for Aranesp® (darbepoetin alfa) WARNING: ESAs Increase the Risk of Death, Myocardial Infarction, Stroke, Venous Thromboembolism, Thrombosis of Vascular Access and Tumor Progression or Recurrence Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL • No trial has identified a hemoglobin target level, Aranesp® dose, or dosing strategy that does not increase these risks • Use the lowest Aranesp® dose sufficient to reduce the need for red blood cell (RBC) transfusions Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions • Use ESAs only for anemia from myelosuppressive chemotherapy, and discontinue upon completion of a chemotherapy course

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

BRIEF SUMMARY: Consult package insert for complete prescribing information. Aranesp┬о (darbepoetin alfa) Injection, for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: t *O DPOUSPMMFE USJBMT QBUJFOUT FYQFSJFODFE HSFBUFS SJTLT GPS EFBUI TFSJPVT BEWFSTF DBSEJPWBTDVMBS SFBDUJPOT BOE TUSPLF XIFO BENJOJTUFSFE FSZUISPQPJFTJT TUJNVMBUJOH BHFOUT &4"T UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- t /P USJBM IBT JEFOUJmFE B IFNPHMPCJO UBSHFU MFWFM "SBOFTQ EPTF PS EPTJOH TUSBUFHZ UIBU EPFT OPU JODSFBTF UIFTF SJTLT t 6TF UIF MPXFTU "SBOFTQ EPTF TVGmDJFOU UP SFEVDF UIF OFFE GPS SFE CMPPE cell (RBC) transfusions. Cancer: t &4"T TIPSUFOFE PWFSBMM TVSWJWBM BOE PS JODSFBTFE UIF SJTL PG UVNPS QSPHSFTTJPO PS SFDVSSFODF JO DMJOJDBM TUVEJFT PG QBUJFOUT XJUI CSFBTU OPO TNBMM DFMM MVOH IFBE BOE OFDL MZNQIPJE BOE DFSWJDBM DBODFST t #FDBVTF PG UIFTF SJTLT QSFTDSJCFST BOE IPTQJUBMT NVTU FOSPMM JO BOE DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS 5P FOSPMM JO UIF &4" "113*4& 0ODPMPHZ 1SPHSBN WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF t 5P EFDSFBTF UIFTF SJTLT BT XFMM BT UIF SJTL PG TFSJPVT DBSEJPWBTDVMBS BOE UISPNCPFNCPMJD SFBDUJPOT VTF UIF MPXFTU EPTF OFFEFE UP BWPJE RBC transfusions. t 6TF &4"T POMZ GPS BOFNJB GSPN NZFMPTVQQSFTTJWF DIFNPUIFSBQZ t &4"T BSF OPU JOEJDBUFE GPS QBUJFOUT SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF BOUJDJQBUFE PVUDPNF JT DVSF t %JTDPOUJOVF GPMMPXJOH UIF DPNQMFUJPO PG B DIFNPUIFSBQZ DPVSTF

INDICATION AND USAGE "OFNJB %VF UP $IFNPUIFSBQZ JO 1BUJFOUT 8JUI $BODFS Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp is not indicated for use: t *O QBUJFOUT XJUI DBODFS SFDFJWJOH IPSNPOBM BHFOUT CJPMPHJD QSPEVDUT or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. t *O QBUJFOUT XJUI DBODFS SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF anticipated outcome is cure. t "T B TVCTUJUVUF GPS 3#$ USBOTGVTJPOT JO QBUJFOUT XIP SFRVJSF JNNFEJBUF correction of anemia.

CONTRAINDICATIONS

Aranesp is contraindicated in patients with: t 6ODPOUSPMMFE IZQFSUFOTJPO t 1VSF SFE DFMM BQMBTJB 13$" UIBU CFHJOT BGUFS USFBUNFOU XJUI "SBOFTQ PS PUIFS erythropoietin protein drugs. t 4FSJPVT BMMFSHJD SFBDUJPOT UP "SBOFTQ

WARNINGS AND PRECAUTIONS *ODSFBTFE .PSUBMJUZ .ZPDBSEJBM *OGBSDUJPO 4USPLF BOE 5ISPNCPFNCPMJTN *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI $,% DPNQBSJOH IJHIFS IFNPHMPCJO UBSHFUT H E- UP MPXFS UBSHFUT H E- "SBOFTQ BOE PUIFS &4"T increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. 6TJOH "SBOFTQ UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- JODSFBTFT UIF SJTL of serious adverse cardiovascular reactions and has not been shown to provide BEEJUJPOBM CFOFmU 6TF DBVUJPO JO QBUJFOUT XJUI DPFYJTUFOU DBSEJPWBTDVMBS EJTFBTF BOE TUSPLF 1BUJFOUT XJUI $,% BOE BO JOTVGmDJFOU IFNPHMPCJO SFTQPOTF UP &4" UIFSBQZ may be at even greater risk for cardiovascular reactions and mortality than other QBUJFOUT " SBUF PG IFNPHMPCJO SJTF PG HSFBUFS UIBO H E- PWFS XFFLT NBZ DPOUSJCVUF to these risks. * O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI DBODFS "SBOFTQ BOE PUIFS &4"T increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. *O DPOUSPMMFE DMJOJDBM USJBMT &4"T JODSFBTFE UIF SJTL PG EFBUI JO QBUJFOUT VOEFSHPJOH DPSPOBSZ BSUFSZ CZQBTT HSBGU TVSHFSZ $"#( BOE UIF SJTL PG EFFQ WFOPVT UISPNCPTJT %75 JO QBUJFOUT VOEFSHPJOH PSUIPQFEJD QSPDFEVSFT 1BUJFOUT XJUI $BODFS An increased incidence of thromboembolic reactions, some serious and lifeUISFBUFOJOH PDDVSSFE JO QBUJFOUT XJUI DBODFS USFBUFE XJUI &4"T *O B SBOEPNJ[FE QMBDFCP DPOUSPMMFE TUVEZ TFF 4UVEZ JO 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO PG XPNFO XJUI NFUBTUBUJD CSFBTU DBODFS SFDFJWJOH DIFNPUIFSBQZ patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered UP QSFWFOU BOFNJB NBJOUBJO IFNPHMPCJO MFWFMT CFUXFFO BOE H E- PS IFNBUPDSJU CFUXFFO BOE 5IJT TUVEZ XBT UFSNJOBUFE QSFNBUVSFMZ XIFO JOUFSJN SFTVMUT EFNPOTUSBUFE B IJHIFS NPSUBMJUZ BU NPOUIT WT BOE B IJHIFS SBUF PG GBUBM UISPNCPUJD SFBDUJPOT WT JO UIF mSTU NPOUIT PG UIF TUVEZ BNPOH QBUJFOUT USFBUFE XJUI FQPFUJO BMGB #BTFE PO ,BQMBO .FJFS FTUJNBUFT BU UIF UJNF PG TUVEZ UFSNJOBUJPO UIF NPOUI TVSWJWBM XBT MPXFS JO UIF FQPFUJO BMGB HSPVQ UIBO JO UIF QMBDFCP HSPVQ WT )3 $* Q 1SFTDSJCJOH BOE %JTUSJCVUJPO 1SPHSBN GPS "SBOFTQ JO 1BUJFOUT 8JUI $BODFS *O PSEFS UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS BOE BOFNJB due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN SFRVJSFNFOUT 5P FOSPMM WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF "EEJUJPOBMMZ QSJPS UP each new course of Aranesp in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Aranesp.

*ODSFBTFE .PSUBMJUZ BOE PS *ODSFBTFE 3JTL PG 5VNPS 1SPHSFTTJPO PS 3FDVSSFODF JO 1BUJFOUT 8JUI $BODFS &4"T SFTVMUFE JO EFDSFBTFE MPDPSFHJPOBM DPOUSPM QSPHSFTTJPO GSFF TVSWJWBM BOE PS PWFSBMM TVSWJWBM 4FF 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO 5IFTF mOEJOHT XFSF observed in studies of patients with advanced head and neck cancer receiving SBEJBUJPO UIFSBQZ 4UVEJFT BOE JO QBUJFOUT SFDFJWJOH DIFNPUIFSBQZ GPS NFUBTUBUJD CSFBTU DBODFS 4UVEZ PS MZNQIPJE NBMJHOBODZ 4UVEZ BOE JO QBUJFOUT XJUI OPO small cell lung cancer or various malignancies who were not receiving chemotherapy PS SBEJPUIFSBQZ 4UVEJFT BOE Hypertension "SBOFTQ JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI VODPOUSPMMFE IZQFSUFOTJPO *O "SBOFTQ DMJOJDBM TUVEJFT BQQSPYJNBUFMZ PG QBUJFOUT XJUI $,% SFRVJSFE JOJUJBUJPO PS intensiямБcation of antihypertensive therapy during the early phase of treatment. )ZQFSUFOTJWF FODFQIBMPQBUIZ BOE TFJ[VSFT IBWF CFFO SFQPSUFE JO QBUJFOUT XJUI $,% receiving Aranesp. Appropriately control hypertension prior to initiation of and during treatment with "SBOFTQ 3FEVDF PS XJUIIPME "SBOFTQ JG CMPPE QSFTTVSF CFDPNFT EJGmDVMU UP DPOUSPM Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Seizures "SBOFTQ JODSFBTFT UIF SJTL PG TFJ[VSFT JO QBUJFOUT XJUI $,% %VSJOH UIF mSTU TFWFSBM months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for OFX POTFU TFJ[VSFT QSFNPOJUPSZ TZNQUPNT PS DIBOHF JO TFJ[VSF GSFRVFODZ Lack or Loss of Hemoglobin Response to Aranesp For lack or loss of hemoglobin response to Aranesp, initiate a search for causative GBDUPST F H JSPO EFmDJFODZ JOGFDUJPO JOnBNNBUJPO CMFFEJOH *G UZQJDBM DBVTFT PG MBDL PS MPTT PG IFNPHMPCJO SFTQPOTF BSF FYDMVEFE FWBMVBUF GPS 13$" *O UIF BCTFODF PG 13$" GPMMPX EPTJOH SFDPNNFOEBUJPOT GPS NBOBHFNFOU PG QBUJFOUT XJUI BO insufямБcient hemoglobin response to Aranesp therapy. Pure Red Cell Aplasia $BTFT PG 13$" BOE PG TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT UIBU BSJTF GPMMPXJOH UIF EFWFMPQNFOU PG OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO IBWF CFFO reported in patients treated with Aranesp. This has been reported predominantly in QBUJFOUT XJUI $,% SFDFJWJOH &4"T CZ TVCDVUBOFPVT BENJOJTUSBUJPO 13$" IBT BMTP CFFO SFQPSUFE JO QBUJFOUT SFDFJWJOH &4"T GPS BOFNJB SFMBUFE UP IFQBUJUJT $ USFBUNFOU BO JOEJDBUJPO GPS XIJDI "SBOFTQ JT OPU BQQSPWFE *G TFWFSF BOFNJB BOE MPX SFUJDVMPDZUF DPVOU EFWFMPQ EVSJOH USFBUNFOU XJUI "SBOFTQ XJUIIPME "SBOFTQ BOE FWBMVBUF QBUJFOUT GPS OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO $POUBDU "NHFO ".(&/ UP QFSGPSN BTTBZT GPS CJOEJOH BOE OFVUSBMJ[JOH BOUJCPEJFT 1FSNBOFOUMZ EJTDPOUJOVF "SBOFTQ JO QBUJFOUT XIP EFWFMPQ 13$" GPMMPXJOH USFBUNFOU XJUI "SBOFTQ PS PUIFS FSZUISPQPJFUJO QSPUFJO ESVHT %P OPU TXJUDI QBUJFOUT UP PUIFS &4"T Serious Allergic Reactions 4FSJPVT BMMFSHJD SFBDUJPOT JODMVEJOH BOBQIZMBDUJD SFBDUJPOT BOHJPFEFNB CSPODIPTQBTN TLJO SBTI BOE VSUJDBSJB NBZ PDDVS XJUI "SBOFTQ *NNFEJBUFMZ BOE permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs. Dialysis Management 1BUJFOUT NBZ SFRVJSF BEKVTUNFOUT JO UIFJS EJBMZTJT QSFTDSJQUJPOT BGUFS JOJUJBUJPO PG "SBOFTQ 1BUJFOUT SFDFJWJOH "SBOFTQ NBZ SFRVJSF JODSFBTFE BOUJDPBHVMBUJPO XJUI IFQBSJO UP QSFWFOU DMPUUJOH PG UIF FYUSBDPSQPSFBM DJSDVJU EVSJOH IFNPEJBMZTJT Laboratory Monitoring &WBMVBUF USBOTGFSSJO TBUVSBUJPO BOE TFSVN GFSSJUJO QSJPS UP BOE EVSJOH "SBOFTQ treatment. Administer supplemental iron therapy when serum ferritin is less than NDH - PS XIFO TFSVN USBOTGFSSJO TBUVSBUJPO JT MFTT UIBO 5IF NBKPSJUZ PG QBUJFOUT XJUI $,% XJMM SFRVJSF TVQQMFNFOUBM JSPO EVSJOH UIF DPVSTF PG &4" UIFSBQZ 'PMMPXJOH JOJUJBUJPO PG UIFSBQZ BOE BGUFS FBDI EPTF BEKVTUNFOU NPOJUPS IFNPHMPCJO XFFLMZ VOUJM UIF IFNPHMPCJO JT TUBCMF BOE TVGmDJFOU UP NJOJNJ[F UIF OFFE GPS 3#$ transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

ADVERSE REACTIONS $MJOJDBM 5SJBM &YQFSJFODF #FDBVTF DMJOJDBM USJBMT BSF DPOEVDUFE VOEFS XJEFMZ WBSZJOH DPOEJUJPOT BEWFSTF reaction rates observed in the clinical trials of a drug cannot be directly compared UP SBUFT JO UIF DMJOJDBM USJBMT PG PUIFS ESVHT BOE NBZ OPU SFnFDU UIF SBUFT PCTFSWFE in practice. $BODFS 1BUJFOUT 3FDFJWJOH $IFNPUIFSBQZ "EWFSTF SFBDUJPOT XFSF CBTFE PO EBUB GSPN B SBOEPNJ[FE EPVCMF CMJOE QMBDFCP DPOUSPMMFE TUVEZ PG "SBOFTQ JO QBUJFOUT "SBOFTQ QMBDFCP XJUI FYUFOTJWF TUBHF TNBMM DFMM MVOH DBODFS 4$-$ SFDFJWJOH QMBUJOVN CBTFE DIFNPUIFSBQZ "MM QBUJFOUT XFSF XIJUF XFSF NBMF BOE UIF NFEJBO BHF XBT ZFBST SBOHF UP ZFBST PG UIF TUVEZ QPQVMBUJPO XFSF GSPN /PSUI "NFSJDB 8FTUFSO &VSPQF BOE "VTUSBMJB 1BUJFOUT SFDFJWFE "SBOFTQ BU B EPTF PG NDH PS QMBDFCP XFFLMZ GPS XFFLT UIFO FWFSZ XFFLT GPS B UPUBM PG XFFLT BOE UIF NFEJBO EVSBUJPO PG FYQPTVSF XBT XFFLT SBOHF UP XFFLT "EWFSTF SFBDUJPOT XFSF BMTP CBTFE PO EBUB GSPN SBOEPNJ[FE EPVCMF CMJOE QMBDFCP DPOUSPMMFE TUVEJFT JODMVEJOH UIF 4$-$ TUVEZ EFTDSJCFE BCPWF UIBU FOSPMMFE QBUJFOUT "SBOFTQ QMBDFCP XJUI OPO NZFMPJE NBMJHOBODJFT .PTU QBUJFOUT XFSF XIJUF NBMF BOE UIF NFEJBO BHF XBT ZFBST SBOHF UP ZFBST PG UIF TUVEZ QPQVMBUJPO XFSF GSPN /PSUI "NFSJDB 8FTUFSO &VSPQF BOE "VTUSBMJB %PTJOH BOE TDIFEVMFT WBSJFE CZ TUVEZ GSPN PODF XFFLMZ UP PODF FWFSZ XFFLT BOE UIF NFEJBO EVSBUJPO PG FYQPTVSF XBT XFFLT SBOHF UP XFFLT 5ISPNCPWBTDVMBS "EWFSTF 3FBDUJPOT JO 1BUJFOUT 3FDFJWJOH $IFNPUIFSBQZ SCLC Study Adverse Reaction 5ISPNCPFNCPMJD "EWFSTF 3FBDUJPOT O

Arterial .ZPDBSEJBM JOGBSDUJPO 7FOPVT 1VMNPOBSZ FNCPMJTN $FSFCSPWBTDVMBS EJTPSEFST

"MM 1MBDFCP controlled Studies

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

DRUG INTERACTIONS

/P GPSNBM ESVH JOUFSBDUJPO TUVEJFT IBWF CFFO DPOEVDUFE XJUI "SBOFTQ

USE IN SPECIFIC POPULATIONS Pregnancy 1SFHOBODZ $BUFHPSZ $ There are no adequate and well-controlled studies of Aranesp use in pregnant women. *O BOJNBM SFQSPEVDUJPO BOE EFWFMPQNFOUBM UPYJDJUZ TUVEJFT "SBOFTQ JODSFBTFE FBSMZ QPTU JNQMBOUBUJPO MPTT 6TF "SBOFTQ EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFmU KVTUJmFT UIF QPUFOUJBM SJTL UP UIF GFUVT 8IFO "SBOFTQ XBT BENJOJTUFSFE JOUSBWFOPVTMZ to healthy pregnant rats and rabbits, there was no evidence of embryofetal UPYJDJUZ PS PUIFS BEWFSTF PVUDPNFT BU UIF JOUSBWFOPVT EPTFT UFTUFE VQ UP NDH LH EBZ 5IJT BOJNBM EPTF MFWFM PG NDH LH EBZ JT BQQSPYJNBUFMZ GPME IJHIFS UIBO UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF EFQFOEJOH PO UIF QBUJFOU T USFBUNFOU JOEJDBUJPO 4MJHIUMZ SFEVDFE GFUBM XFJHIUT XFSF PCTFSWFE XIFO IFBMUIZ SBU BOE SBCCJU NPUIFST SFDFJWFE EPTFT PG NDH LH PS NPSF 5IJT EPTF PG NDH LH JT OFBS UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF 8IJMF OP BEWFSTF FGGFDUT on uterine implantation occurred in animals, there was an increase in early postJNQMBOUBUJPO MPTT JO BOJNBM GFSUJMJUZ TUVEJFT *U JT OPU DMFBS XIFUIFS UIF JODSFBTFE QPTU JNQMBOUBUJPO MPTT SFnFDUT B ESVH FGGFDU PO UIF VUFSJOF FOWJSPONFOU PS PO UIF DPODFQUVT /P TJHOJmDBOU QMBDFOUBM USBOTGFS PG "SBOFTQ XBT EFUFDUFE *O B QFSJ QPTUOBUBM EFWFMPQNFOU TUVEZ QSFHOBOU GFNBMF SBUT SFDFJWFE "SBOFTQ intravenously every other day from implantation throughout pregnancy and MBDUBUJPO 5IF MPXFTU EPTF UFTUFE NDH LH EJE OPU DBVTF GFUBM UPYJDJUZ UIJT EPTF JT BQQSPYJNBUFMZ FRVJWBMFOU UP UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF "U NBUFSOBM EPTFT PG NDH LH BOE IJHIFS QVQT IBE EFDSFBTFE GFUBM CPEZ XFJHIUT which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation. 8PNFO XIP CFDPNF QSFHOBOU EVSJOH "SBOFTQ USFBUNFOU BSF FODPVSBHFE UP FOSPMM JO "NHFO T 1SFHOBODZ 4VSWFJMMBODF 1SPHSBN 1BUJFOUT PS UIFJS QIZTJDJBOT TIPVME DBMM ".(&/ UP FOSPMM /VSTJOH .PUIFST *U JT OPU LOPXO XIFUIFS "SBOFTQ JT FYDSFUFE JO IVNBO NJML #FDBVTF NBOZ ESVHT BSF FYDSFUFE JO IVNBO NJML DBVUJPO TIPVME CF FYFSDJTFE XIFO "SBOFTQ JT BENJOJTUFSFE to a nursing woman. Pediatric Use The safety and efямБcacy of Aranesp in pediatric cancer patients have not been established. Geriatric Use 0G UIF QBUJFOUT XJUI $,% JO DMJOJDBM TUVEJFT PG "SBOFTQ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS 0G UIF QBUJFOUT JO DMJOJDBM TUVEJFT SFDFJWJOH "SBOFTQ BOE DPODPNJUBOU DBODFS DIFNPUIFSBQZ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS /P EJGGFSFODFT JO TBGFUZ PS FGmDBDZ XFSF PCTFSWFE between older and younger patients.

OVERDOSAGE

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

Aranesp Placebo Aranesp Placebo O O O O

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

Aranesp┬о EBSCFQPFUJO BMGB

Manufactured by: "NHFO .BOVGBDUVSJOH -JNJUFE B TVCTJEJBSZ PG "NHFO *OD 0OF "NHFO $FOUFS %SJWF 5IPVTBOE 0BLT $" This product, the process of its manufacture, or its use, may be covered by one or NPSF 6 4 1BUFOUT JODMVEJOH 6 4 1BUFOU /P ┬к "NHFO *OD "MM SJHIUT SFTFSWFE 3 7

ASCOPost.com | APRIL 15, 2013

PAGE 73

In Memoriam

C. Everett Koop, MD, Surgeon General Under Ronald Reagan, Dies at 96 By Ronald Piana

C. Everett Koop, MD

T:14”

B:14.25”

S:13”

ppointed by the President and called “America’s Doctor,” the Surgeon General’s chief task is to protect and advance the health of the nation. Most of our Surgeon Generals have tiptoed around hot-button public health issues that might bruise political sensibilities and their own careers. C. Everett Koop, MD—known to many as “Koop”—was a Surgeon General who, irrespective of politics, fought the good fight for the health of all Americans, and in the process became a household name. He died on February 25, 2013, at 96.

1946, Dr. Koop became the Surgeonin-Chief at the Children’s Hospital of Philadelphia, where he established the country’s first neonatal surgical intensive care unit in 1956. His practice-changing innovations in pediatric surgery improved and saved the lives of countless children. In 1971, Dr. Koop became Professor of Pediatrics at the University of Pennsylvania School of Medicine, Philadelphia. It was in Philadelphia where he performed surgery in uncharted medical territory; he invented techniques that he used to separate conjoined twins who otherwise might have died. He also developed anesthetic practices for small bodies and metabolisms. In 1957, Dr. Koop performed the then near impossible separation of two female babies conjoined at the pelvis, which garnered him interna-

that critical medical knowledge wasn’t being actively shared. “Each day of those early years in pediatric surgery I felt I was on the cutting edge,” he wrote. “Some of the procedures that landed on the operating table at Children’s had not even been named. I was troubled by fears that someone might have performed a certain procedure successfully but hadn’t bother to write it up.” A man of action, Dr. Koop addressed those fears by becoming the first Editor-in-Chief of the Journal of Pediatric Surgery when it was founded in 1996.

Tenure as Surgeon General In 1976, Dr. Koop, an unabashed conservative, expressed his concerns about abortion, euthanasia, and infanticide in a book titled, The Right to Live, The Right to Die. In 1981, Dr. Koop was

Throughout his term, turbulent as it was, he shouldered quarrelsome health issues that might have been shunned by a less bold doctor, bringing them to the arena of public discourse.

Early Career Born in Brooklyn, New York, in 1916, he was the only child of German immigrants whose family ethos was rooted in hard work and dedication. Dr. Koop excelled throughout school, earning his MD from Cornell Medical College in 1941. A colorful figure, the eccentrically bearded, straight-backed doctor looked like he could man the helm of a tall ship. But it was with our most delicate patients that Dr. Koop began leaving his mark on medicine. In

tional recognition. A doctor’s doctor, he was unfazed by the gathering public attention that would help shape his illustrious career. Years later, in 1974, Dr. Koop once again performed an astounding surgical feat. He successfully separated twins conjoined at the spine. They shared a liver, colon, and parts of the intestines; their entire trunks were merged. Dr. Koop published prodigiously in the literature, expressing concern

appointed Deputy Assistant Secretary for Health by the newly inaugurated President Ronald Reagan. Liberal politicians and women’s groups drew a line in the sand as it became clear that Dr. Koop would be President Reagan’s nominee for Surgeon General. Amidst protests, President Reagan appointed Dr. Koop as the U.S. Surgeon General; the Senate confirmed his nomination by a vote of 60 to 24. He was sworn into office on January 21, 1982.

 In Memoriam

C. Everett Koop, MD October 14, 1916 - February 25, 2013 

Dr. Koop served as Surgeon General from 1982 to 1989, a 7-year term marked by contentious public health issues that Dr. Koop dealt with in his inimitable style—most notably, his stance on abortion and the emerging AIDS pandemic. He opposed abortion, but he was a free-thinker, and when he refused to be pressured into preparing a report stating that abortion was psychologically harmful to women, it brought a heated reaction from some in the Reagan administration. Conservatives also took exception to his call to have frank discussions about sexual practices and his advocacy for expanding the use of condoms to combat the spread of AIDS. Throughout his term, turbulent as it was, he shouldered quarrelsome health issues that might have been shunned by a less bold doctor, bringing them to the arena of public discourse.

Later Years Dr. Koop’s long life was not without personal tragedy. His son David was killed in a rock-climbing fall during his junior year at Dartmouth College. Years later, he and his wife Elizabeth discussed their terrible loss in a book titled, Sometimes Mountains Move. Dr. Koop said the book was a humble attempt to help others who had lost a child. Hearing of Dr. Koop’s death, American Medical Association President Jerry Lazarus noted, “Because of what he did, and the way he did it, he had a dramatic impact on public health.” Koop, America’s Doctor, will be sadly missed. n

The ASCO Post | APRIL 15, 2013

PAGE 74

Announcements Palliative Care

New Partnership Will Harness Technology to Foster Improved Palliative Care in Oncology

SCO and the American Academy of Hospice and Palliative Care Medicine (AAHPM) have announced a joint initiative to support delivery of highquality palliative care in medical oncology. The initiative, funded by the Agency for Health Care Research & Quality, aims to address the complex care needs of patients with advanced cancer, including relief or prevention of symptoms. The 3-year project will create a vir-

Sandra M. Swain, MD, FACP

tual learning collaborative (VLC)—a Web-based technology platform—to efficiently and broadly disseminate evidence-based palliative care approaches in oncology. The VLC will include coordinated, customized learning modules, social networking capabilities, and a toolbox of evidence-based resources to help translate the latest research into practice.

Innovative Program “We recognize that palliative care is an essential component of care for patients with cancer. This partnership will help get the latest palliative care evidence

medicine physician, and Principal Investigator on the VLC grant.

Pilot Project

Timothy E. Quill, MD, FACP, FAAHPM

directly into the hands of oncologists so that palliative care can be provided as early as possible,” said ASCO President Sandra M. Swain, MD, FACP. “Never before has a national study tested a technology platform, like the VLC, to spread practice-changing palliative care research and connect oncologists to share best practices and promote improvement.” The partnership between ASCO and AAHPM to forward broad implementation of palliative care for patients who need it is also practice-changing. Current AAHPM President, Timothy E. Quill, MD, FACP, FAAHPM, and PresidentElect Amy P. Abernethy, MD, FACP, FAAHPM, coauthored a recent piece in The New England Journal of Medicine on the importance of coordinated generalist-plus-specialist palliative care.1 “The oncologist or treating specialist could manage many palliative care problems, initiating a specialist palliative care consultation for more complex situations. The VLC moves this goal from concept to practical reality,” said Dr. Abernethy, an oncologist and palliative

Twenty oncology practices from around the country will be recruited to participate in a structured practice improvement pilot project, enabled by the VLC. Pilot practices will report data on palliative care quality using ASCO’s Quality Oncology Practice Initiative (QOPI®). They will share best practices and resources through the VLC, and benefit from expert and peer guidance as they implement local improvements.

Amy P. Abernethy, MD, FACP, FAAHPM

Qualitative and quantitative evaluation will assess oncology practitioners’ perceptions of the VLC, assess the impact of the VLC on performance related to primary palliative care, and inform additional refinements to the platform and the toolbox of content and resources. Ultimately, project leaders aim to provide a proven palliative care toolbox to all ASCO members for use in their practices, and to leverage the VLC platform to address

other targets for practice improvement. Despite a growing consensus about the benefits of routine palliative care in oncology, results from QOPI demonstrate the need for improved symptom management, greater attention to psychosocial issues, discussions about goals of care, and appropriate referral to hospice—all core skills of palliative care. “The VLC project builds on ASCO’s long-standing leadership in fostering the delivery of palliative care in the oncology setting,” said Dr. Abernethy. “As palliative care is increasingly woven into the fabric of health care across specialties, it will be critical to see that it is well integrated within the cancer care delivery system.” Palliative care emphasizes medically appropriate goal setting, open communication with patients and families, and meticulous symptom assessment and control. Palliative care interventions have been shown to improve patients’ life quality, symptoms, and satisfaction, as well as reduce caregiver stress. Research has confirmed the benefits of palliative care for patients with advanced cancer. Studies have shown that patients who received early palliative care had a better quality of life, less depression, and in some cases lived longer than those who had routine care. n Reference 1. Quill TE, Abernethy AP: Generalist plus specialist palliative care—creating a more sustainable model. N Engl J Med. March 6, 2013 (early release online).

Indiana University Researchers Earn $3.2 Million Grant to Develop, Improve Therapies for Pancreatic Cancer

wo Indiana University researchers have been awarded a multiyear, $3.2 million grant to develop and improve therapies for pancreatic cancer, the fourth leading cause of cancer death in the United States. Mark R. Kelley, PhD, Betty and Earl Herr Professor of Pediatric Oncology Research, and Melissa L. Fishel, PhD, Assistant Research Professor of Pediatrics, both at the IU School of Medicine, were awarded a 5-year grant (CA167291) from the National Cancer Institute of the National Institutes of Health. The two Indiana University Melvin and Bren Simon

Cancer Center researchers will focus on investigating the signaling pathways and molecular mechanisms that contribute to pancreatic tumor progression and resistance to therapy.

Role of Tumor Microenvironment In their laboratory research, Drs. Kelley and Fishel plan to block redox factor 1 (Ref-1), a protein crucial to regulating pancreatic tumor growth and metastasis, using a promising inhibitor that Dr. Kelley and colleagues have developed. “We hope to better understand how

Melissa L. Fishel, PhD and Mark R. Kelley, PhD

this protein signals and functions in the tumor microenvironment as well as in the tumor cells. We’re hoping that if we can inhibit the function of Ref-1, we can blunt

the tumor’s ability to live,” Dr. Fishel said. Researchers have been learning that a tumor’s microenvironment plays a significant role in the life and death of a tumor. “We’re realizing that it’s not just the tumor that has to be treated,” Dr. Kelley added. “You have to treat the tumor and the surrounding support structure, its microenvironment. Because pancreatic cancer is hard to treat, we think Ref-1 is a viable target both in the tumor and the microenvironment.” This latest pancreatic cancer project builds on Dr. Kelley’s ongoing research continued on page 76

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

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

AND...

• 37% reduction in risk of death vs placebo (P < 0.0001; HR = 0.63 [95% CI, 0.53-0.75])1 • XTANDI can be taken with or without food1 • Patients were allowed, but not required, to take glucocorticoids1 —

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

• Oral, once-daily dosing1 • The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1 • Seven patients (0.9%) out of 800 treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1

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

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot ﬂush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% grade 3-4) and in 6% of patients on placebo (no grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients and 2% of patients on placebo. One percent of XTANDI patients compared to 0.3% of patients on placebo died from infections or sepsis. Falls or injuries

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include enzalutamide (XTANDI) with a category 1 recommendation for use following docetaxel in patients with mCRPC.2

related to falls occurred in 4.6% of XTANDI patients vs 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas. Grade 1 or 2 hallucinations occurred in 1.6% of XTANDI patients and 0.3% of patients on placebo, with the majority on opioid-containing medications at the time of the event. Drug Interactions: Effect of Other Drugs on XTANDI Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Coadministration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If coadministration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Effect of XTANDI on Other Drugs XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is coadministered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for brief summary of Full Prescribing Information.

L Learn earn m more ore a att X XtandiHCP.com tandiHCP.com References: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.1.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed December 20, 2012. To view the most recent and complete version of the guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. © 2013 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 013A-076-7020-1 2/13 XTANDI, Astellas, and the ﬂying star logo are trademarks of Astellas Pharma Inc.

The ASCO Post | APRIL 15, 2013

PAGE 76

Announcements

into using inhibitors to prevent cancer cells from repairing the damage caused by anticancer therapies.

Changing the Standard of Care Drs. Kelley and Fishel will collaborate with other IU Simon Cancer Center researchers, including internationally recognized cancer researcher Murray Korc,

MD, the Myles Brand Professor of Cancer Research at the IU School of Medicine and Director of the Indiana UniversityPurdue University Indianapolis Pancreatic Cancer Signature Center. The research team also includes Theresa Guise, MD, Jerry and Peggy Throgmartin Professor of Oncology, and Mircea Ivan, MD, PhD, Assistant Professor of

Medicine, both at the IU School of Medicine. Dr. Guise is an expert on tumor microenvironment and metastatic disease, while Dr. Ivan is an expert in hypoxia, a condition in which there is a decrease in the oxygen supply. Pancreatic tumors are hypoxic, which makes them more aggressive and difficult to treat. â&#x20AC;&#x153;Our hope and goal is to change the

standard of care because itâ&#x20AC;&#x2122;s not working,â&#x20AC;? Dr. Fishel said.Â â&#x20AC;&#x153;Our hope is to bring a new therapyâ&#x20AC;&#x201D;or a new one that would be used in conjunction with a current therapyâ&#x20AC;&#x201D;to make inroads against this disease. Even if a new therapy doesnâ&#x20AC;&#x2122;t kill the tumor, if it can penetrate the microenvironment to help other drugs get to the tumor, that would be beneficial.â&#x20AC;? n

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

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information. ------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel. --------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@. -------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. --------------------------------- ADVERSE REACTIONS ------------------------------Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4. 7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders Asthenic Conditionsa 9.0 44.4 9.3 Peripheral Edema 1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 24.3 4.0 Arthralgia 17.3 1.8 Musculoskeletal Pain 1.3 0.3 Muscular Weakness 9.8 6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

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

Gastrointestinal Disorders Diarrhea 21.8 1.1 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 0.0 Dizzinessb Spinal Cord 7.4 6.6 3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0 0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0 0.3 Upper Respiratory Tract Infectiond Lower Respiratory 2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0 Anxiety 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 1.0 Pollakiuria 4.8 0.0 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

ASCOPost.com | APRIL 15, 2013

PAGE 77

Announcements

Dual Awards Pay Tribute to Gender Equity Trailblazers

he University of Texas MD Anderson Cancer Center in Houston recently recognized two leading advocates for women in medicine and research. Karen Antman, MD, Provost of

the Boston University Medical Campus and Dean of its School of Medicine since 2005, was the recipient of the 2013 Margaret L. Kripke Legend Award for Promotion of Women in Cancer Medicine and Cancer Re-

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

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @. -------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

search. At the MD Anderson award ceremony in March, she delivered a lecture titled, â&#x20AC;&#x153;Kripke, a Role Model for Todayâ&#x20AC;&#x2122;s Leaders in Cancer Research and an Update on the Progress of Women.â&#x20AC;?

Live: 7"w Ă&#x2014; 10"h

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8& PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\ XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Maria Alma Rodriguez, MD, Vice President of Medical Affairs and Professor of Lymphoma/Myeloma at MD Anderson, received the institutionâ&#x20AC;&#x2122;s inaugural Presidentâ&#x20AC;&#x2122;s Leadership Award for Advancing Women Faculty. Her presentation was titled â&#x20AC;&#x153;Advancement of Women Faculty Matters.â&#x20AC;? â&#x20AC;&#x153;Iâ&#x20AC;&#x2122;m delighted that we honor and recognize two people who advocate above and beyond the expected for the career advancement of women faculty,â&#x20AC;? said MD Anderson President Ronald DePinho, MD. â&#x20AC;&#x153;Recipients of both awards were chosen based on demonstrating, through their words and actions, a deep personal and professional commitment to this value.â&#x20AC;?

Role Model and Change Agent Dr. Antman, an internationally recognized expert on breast cancer, mesotheliomas, and sarcomas, advocates for leadership diversity and leverages her academic position to support faculty development programs and research on women in academic medicine. An inspiration and mentor to many women, she recognizes her opportunity to be a role model, change agent, and voice for others. â&#x20AC;&#x153;The Kripke award is a tremendous honor,â&#x20AC;? Dr. Antman said.Â â&#x20AC;&#x153;Margaret Kripke is a pioneer who opened doors for me and many other women in medicine and science. As President of the American Association for Cancer Research, she gave me the first opportunity to be an AACR program chair, and Iâ&#x20AC;&#x2122;ve always regarded her as a role model.â&#x20AC;?

Inspiring and Encouraging Women Faculty

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

ONCOLOGY

A noted scientist and oncologist, Dr. Rodriguez developed and oversees MD Andersonâ&#x20AC;&#x2122;s Survivorship Program, Quality Officer Program, and Psychosocial Council. She also developed the hospitalâ&#x20AC;&#x2122;s Nocturnalist Program. Her clinical expertise is in the treatment of lymphoid malignancies, with a focus on aggressive B-cell lymphomas and salvage chemotherapy. â&#x20AC;&#x153;Iâ&#x20AC;&#x2122;m deeply honored to receive this award,â&#x20AC;? Dr. Rodriguez said.Â â&#x20AC;&#x153;Not only is this the first time this recognition has been given to someone within our institution, but it is also a very meaningful symbol of our commitment to leadership development for women.â&#x20AC;? n

The ASCO Post | APRIL 15, 2013

PAGE 78

Perspective

The Future of Clinical Guidelines in Oncology By William T. McGivney, PhD

William T. McGivney, PhD

linical guidelines, like those of ASCO and the National Comprehensive Cancer Network (NCCN), clearly have represented the standard of care and, to a large extent, the basis for coverage policy, especially in the area of medical oncology. However, guidelines increasingly seem to be in the shadow of an “algorithmic pathway eclipse”—that is, the increasing import of clinical pathways as a tool in decision-making and policy-setting— casting uncertainty with respect to the continuation and extent of guideline influence. Guidelines have been criticized for providing a multitude of clinical options with insufficient attention paid to the comparative effectiveness or cost of the options that are provided. In response, the cancer care delivery system has witnessed the development and provision of clinical pathways that seek to prioritize and circumscribe available options through comparative evaluation. To their credit, developers of guidelines have taken notice and have initiated steps to specify preferred options.

Targeting Payers Payers responded positively when altruistic clinicians and commerDr. McGivney is Principal, McGivney Global Advisors.

Visit

cial entities began to develop clinical pathways or guideline derivatives that sought to be more selective regarding available options for specific patient subpopulations based on comparative effectiveness and cost considerations. A number of commercial pathway products became available, with some targeting a customer market of payers. These products offered the narrowing of options based on scientific evidence and cost as evaluated by the pathway developers. Payers favor the availability of such pathway products, as such pathways can be asserted to represent the thinking of oncologists about appropriate options. The development of pathway products has not been limited to commercial enterprises. Community practices (large and small) and large academic and nonacademic hospital centers or

iKnowMed product from US Oncology has had its decision-assist tools successfully integrated into an electronic health record for some time. Other pathway companies are following suit and negotiating with oncology-specific electronic health record companies and larger enterprises to integrate pathways electronically into electronic health record systems.

‘Crosswalked’ Systems The next necessary step is to compare the elements and results of, or “crosswalk,” the electronic decisionassist tools between providers and payers. This is needed so that both sides are using the same clinical logic and evidence in the same system, to determine the appropriateness of treatment options for specific patient subpopulations. The availability of such a “cross-

Whatever the underlying decision processes and methods, information and data on the effectiveness, safety, and cost of treatment will need to be delivered in valid, concise, electronic packages to address the decision-making needs of all involved cancer care constituencies. — William T. McGivney, PhD

networks have developed pathways that proffer the opportunity to deliver treatment of equivalent or improved effectiveness and safety but at a lower cost, or at least in a manner that might diminish the rate of rising costs of cancer care. For larger academic centers, the need to become more efficient and competitive from a cost perspective is a partial driver for pathway development. Pathway and pathway-like products are being formatted as electronic decision-assist tools marketed by companies such as D3 Solutions, Elekta, Eviti, and McKesson. The McKesson

walked” system would diminish the contention between payer and oncologist, would lessen the wasted efforts of counterproductive haggling on both sides, and would get patients and clinicians answers in a more assured and timely manner. While pathways represent a partial algorithmic dimming of guidelines, the looming bundled or episodebased payment methods may even more broadly eclipse the more general guidelines. Under such scenarios, actual and detailed measurement of resource consumption and resultant

clinical outcomes may diminish the practice need for a guideline product. Provider-side proponents of bundled payments for oncology are increasing in number. Leaders, both in the community and in academic settings, have indicated that they will pursue such financial arrangements with payers. In this scenario, the financial terms of an agreement may establish the more dominant guideline for practice.

Ultimate Roles of Guidelines The ultimate roles of guidelines may fall to educating overburdened clinicians and to remaining the basis for overall coverage policies. Both roles are important. Community oncologists who treat six, eight, or more tumor types are being challenged by the rapid advance of scientific knowledge. Payers are being challenged similarly. The availability of recognized, authoritative, freely available, and timely guidelines provides a sound and common basis for the education and decision-making of providers and payers. The integration of guidelines and pathways in electronic systems will be critical to maintain and enhance improvement of cancer care. The cancer care delivery system manages millions of patients and hundreds of millions of decisions every year. As our scientific and clinical knowledge base expands, treatment decisions may become more complex or biomarker-driven. The cancer care delivery system likely will try episode-based or bundled payment methods. Whatever the underlying decision processes and methods, information and data on the effectiveness, safety, and cost of treatment will need to be delivered in valid, concise, electronic packages to address the decision-making needs of all involved cancer care constituencies. n

Disclosure: Dr. McGivney is a consultant for pharma/biotech companies.

website at ASCOPost.com

ASCOPost.com | APRIL 15, 2013

PAGE 79

Patient’s Corner

It Takes a Village to Survive Ovarian Cancer

My family, my faith, and my partnership with my medical team give me hope for the future. By Dee Sparacio, as told to Jo Cavallo

y odyssey with ovarian cancer started in May 2005, when I saw my gynecologist for an annual exam and mentioned an odd twinge I had been experiencing on my left side. A subsequent pelvic ultrasound followed by an MRI showed that my ovaries were enlarged, and my doctor warned me that the problem could be serious. She made an appointment for me with a gynecologic oncologist. Because I was 49, the oncologist recommended a hysterectomy and removal of my ovaries.

fight this cancer together. I was offered a phase I clinical trial that included intravenous selenium, plus carboplatin and paclitaxel. My husband and I are both scientists, and we did our homework on the treat-

time, I had lesions on my spleen and liver. Following surgery to remove my spleen and resection my liver, I was again prescribed the combination chemotherapy regimen of carboplatin and paclitaxel, and I’m once again in remission.

Cancer takes away control over your life. Being in partnership with my medical team gave me back some of that control. —Dee Sparacio

Reassuring Words When I woke up in the recovery room after the surgery, the oncologist said, “Sorry, Dee, you have stage IIIB ovarian cancer, but I will do everything in my power to make you well.” Although the fact that I had metastatic ovarian cancer was frightening, hearing my doctor—and later the rest of my medical team—assure me that everything possible would be done to make me well again, made me feel like we were a team and we were going to

A Team Effort ment regimen being recommended. We thought it offered me the best chance for a successful outcome, although I had real concerns about whether I would complete the nine cycles of therapy. But by April 2006, I was disease-free and able to resume my teaching career, until the cancer recurred 4 years ago. This

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

When you see a code that you would like to scan, start your code-reading application.

The code will scan automatically.

Position your device in front of the code so that it fills about half your screen.

Watching presentations of the latest clinical trials on potential new therapies and studies being done on survivorship issues, including coping with long-term treatment side effects, and actually being able to talk with the scientists afterward, gave me a greater appreciation of their efforts and hope for the future. I spread that feeling of hope through my blog and in lectures I give to other ovarian cancer survivors. I know that the chances I could have another recurrence are high, but knowing that the disease is getting more research attention is comforting to me.

If the scan is successful, you will be rerouted to the targeted link.

Finding Hope through Research Although my treatment and subsequent side effects—severe neuropathy in my toes and “chemobrain”—have made it difficult for me to resume my teaching career, my experience with cancer has given me a new vocation: cancer advocate. I launched a blog to help other women with ovarian cancer and, last June, I attended ASCO’s Annual Meeting in Chicago, made possible with a grant I received from the Society’s Conquer Cancer Foundation, to learn about current research in the disease. I know the key to surviving this uncommon and often fatal cancer is earlier detection and more effective treatments, and the only way that will be possible is through research.

I’m lucky. I have a wonderful family and support system, as well as a strong faith, all of which have helped me get through the past 7 years and help me face the future. Having a supportive medical team, including my oncologists, who I could communicate with and who made me feel like we were all in this fight together, gave me confidence I would survive. They presented information and treatment plans in a way I could understand, and there was always someone available to answer my questions, so I never felt alone. Cancer takes away control over your life. Being in partnership with my medical team gave me back some of that control. n Dee Sparacio lives in Hightstown, New Jersey.

Patient Advocate Scholarship Program

he Conquer Cancer Foundation’s Patient Advocate Scholarship Program enables advocates to attend ASCO meetings so they may further educate themselves on important advances in their areas of interest. The scholarship program is one of many programs ASCO and the Conquer Cancer Foundation provide for advocates, helping them to be even more effective in understanding and communicating research and information on cancer. Patient advocates often apply the knowledge and education they gained from attending ASCO meetings when they participate in various advocacy related roles and activities. Advocates play an extremely important role as they work to make a difference in the lives of people affected by cancer. For more information, visit www.cancer.net/advocacy-and-policy. ASCO Staff Contact: Jeannine Salamone, Communications and Patient Information Dept. 571-483-1358 Jeannine.salamone@asco.org n

THORACIC ONCOLOGY UPDATE:

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

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

At Least 10 Known Molecular Biomarkers in NSCLC3

with similar clinical stage and tumor histology can have dramatically different

50% of NSCLC cases are linked to one of

clinical outcomes.4

KRAS

at least 10 currently known biomarkers

Indeed, biomarkers may give clinicians

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

Unknown EGFR

as well as the treatment sensitivity/

ALK

resistance of the tumor to specific agents.4,5

TP53

Moreover, as genomic and mutational PIK3CA

IDH1

CTTNB1

HER2 NRAS

BRAF

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

Now that more than half of NSCLC cases

ultimate goal of this approach to

can be linked to one or more of these

treatment is to identify every driver

biomarkers, it is possible to subdivide

mutation for non-small cell lung cancer,

the histological subtypes of NSCLC

and design a corresponding treatment

— adenocarcinoma, squamous cell

for each of these oncogenes.1,2,4

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

In partnership with:

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

investigational agents in clinical trials.2,3

Sponsored by:

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

According to recent studies, more than

may test positive for mutations or other

These molecular subsets show the

Curbside Consult New Diagnostic Paradigm: Histology + Molecular Profile

For patients whose tumors test positive

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

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

Recently it has been proposed that

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

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

But in the future, molecular profiling

a growing consensus that molecular

will help an increasing proportion

profiling — testing the tumor at biopsy

of patients with NSCLC because the

for all appropriate biomarkers — should

additional information it reveals about

be part of the clinician’s standard

their tumor has the potential to guide

approach to pathologic evaluation.1,2

clinical management.2,7

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

Molecular Profiling Is Key in NSCLC

Clinical Practice Guidelines in Oncology

The discovery of biomarkers has

(NCCN Guidelines®) for all non-squamous

demonstrated the molecular complexity

non-small cell lung cancer (NSCLC)

of NSCLC, and it highlights the need

histologies, which state :

to move toward molecularly based

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

of “ Determination the specific molecular

from these developments. As additional mutations are discovered

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

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

”

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

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

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

The NCCN® recommends EGFR and ALK

Oncology at UC Davis Comprehensive

testing for all advanced non-squamous

Cancer Center, “Our goal is to learn the

NSCLC, in order to guide treatment

‘molecular fingerprint’ of each person’s

decisions. Multiplex molecular profiling

lung cancer, and to personalize their

assays may make the prospective

therapy based on this information. The

discoveries that could make this possible

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

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

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

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

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

are being made at a rapid pace.”

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

Printed in USA/November 2012

CRI433117-04

The ASCO Post | APRIL 15, 2013

PAGE 82

Health-care Policy Clinical Trials

Implementing a National Cancer Clinical Trials System for the 21st Century IOM meets again to follow up on 2011 goals. By Margot J. Fromer

n March 2011, the National Cancer Policy Forum of the Institute of Medicine (IOM), in conjunction with ASCO, held a workshop to discuss a collaborative approach to making the National Cancer Institute (NCI)funded clinical trials system more viable and productive. That workshop included discussions about the roles of NCI and the cooperative groups; how payers are and could be involved; interactions among industry, the Food and Drug Administration (FDA), and the publicly funded clinical trials system; and the roles of investigators and patient advocates. At the end of the 2-day workshop, the IOM established four goals. 1. Improve speed and efficiency of the design, launch, and conduct of clinical trials. 2. Incorporate innovative science and trial design into cancer clinical trials. 3. Improve prioritization, selection, support, and completion of cancer clinical trials. 4. Incentivize the participation of patients and physicians in clinical trials.

radiotherapy and imaging services, strategic planning and prioritization, adult and pediatric central institutional review boards, a data management system, and centralized round-the-clock patient registration. “In addition, we have significantly cut the time from study development to trial activation,” he said. “Between 2006 and 2008, the median time to activation for phase III trials was 830 days. Now, as a result of new targets, our median time to activation is 395 days.” He added that, to increase speed and efficiency, NCI has agreed with FDA to rapidly review approved phase III trials at the concept stage,

Efforts to Meet the Goals

has coordinated processes for development and review of trials under FDA Special Protocol Assessment, and works with FDA to coordinate early review of biomarkers. Goal 2—Regarding the goal of innovative science and trial design, Dr. Doroshow said that NCI is revising some grants to include collection of tissue samples from patients in cooperative group trials and other NCI-supported investigations, and is developing procedures for requesting biospecimens banked from NCI trials. Shared information technology (IT) infrastructure will enhance specimen inventories. “We also have initiated the Biomarker, Imaging, and Quality of Life Studies Funding Program to ensure that critical correlative studies are incorporated into phase III and large phase II trials. NCI is working with the Investigational Drug Steering Committee to design phase II trials, create new designs and endpoints, and focus on safety, efficiency, and selected patient populations. Goal 3—“The Clinical Trials and

Two years later, in February 2013, IOM and ASCO held a follow-up workshop on the same topic. It fell to James M. Doroshow, MD, NCI Deputy Director for Clinical and Translational Research, to address the goals. Goal 1—He described the new NCI National Clinical Trials Network

James M. Doroshow, MD

(NCTN), which consists of up to four adult groups and one pediatric group, designed to meet the first goal regarding speed and efficiency. Its peer review process focuses on research strategy, collaboration, and operational efficiency. To that end, trials are designed with integral molecular screening and translational science. NCTN contains

Translational Research Advisory Committee will evaluate NCI’s clinical trials programs, strategic vision, and the overall effectiveness of studies conducted by NCTN. In addition, we revamped the prioritization process for phase III and large phase II trials,” said Dr. Doroshow. NCI also is modernizing its IT infrastructure with a clinical management system, enhancing trial participant diversity, working with patient advocates in concept development and accrual planning, and increasing reimbursement for patients, as well as funding for critical biomarker, imaging, and quality-of-life studies. Goal 4—To motivate participation

Revamping the Clinical Trials System ■ Based on goals established at a March 2011 workshop, the National Cancer

Policy Forum of the Institute of Medicine recently held a follow-up meeting to assess progress in making the NCI-funded clinical trials system more efficient and productive.

■ Participants concluded that consolidation of the system’s coooperative

groups has been beneficial, and while it continues to be a work in progress, accrual and funding challenges remain.

in trials, Dr. Doroshow said that NCI continues to work with the National Institutes of Health and other federal agencies to define and shape national policy on participation and reimbursement, as well as educate patients and payers about the benefits of trials. It is working with the FDA to incorporate genomic tests and companion diagnostics into trials.

Bringing Clinical Trials to the Community Worta McCaskill-Stevens, MD, Chief, NCI Community Oncology and Prevention Trials Research Group, noted how sophisticated and complex cancer management is. “We need molecular-based delivery systems to apply all the new advances, and the laboratories best suited to evaluate them are in the community. To complicate things, oncology care is changing in other ways as well—for instance, in the number of practices merging with one another and the increased hospital acquisition of private practices.” In part because much of the cancer endeavor takes place in the community, the National Community Oncology

Worta McCaskill-Stevens, MD

Research Program (NCORP) was established to develop a single community-based program that integrates the Community Clinical Oncology Program, the Minority-Based Community Clinical Oncology Program, and the Community Cancer Centers Program. “NCORP builds on the strength of all, and expands research opportunities,” said Dr. McCaskill-Stevens. Clinical trials will continue to be a significant NCORP function, along with additional research priorities and opportunities in health services and behavioral, dissemination, and outcomes research. Dr. McCaskill-Stevens outlined the salient components: ■ Linkage of community-based organizations with a variety of research capacities to NCTN ■ Support of various types of oncology practices, as well as public-private partnerships ■ Integration of cancer care disparities, care delivery research (investigation of how social factors, financing, organizational structures, health technology, and individual behavior affect outcomes), minority accrual, and clinical trials ■ Cancer control, prevention, treatment, and post-treatment surveillance trials, especially in minority and underserved populations ■ Special emphasis on over- and underdiagnosis, post-treatment surveillance, precancerous lesions, and mechanisms of treatment and cancer-related symptoms

Restructuring the Cooperative Groups One of the major criticisms arising from the 2011 workshop was the unwieldy nature of the Clinical Trials Cooperative Group Program. It comprised 10 groups, involving more than 3,100 institutions, and 14,000 investigators who enrolled more than 25,000

ASCOPost.com | APRIL 15, 2013

PAGE 83

Health-care Policy

Robert L. Comis, MD

patients in trials each year. The Cooperative Group Program has been instrumental in establishing standards for patient care and clinical research. Nevertheless, it faced challenges that threatened its productivity: stagnant and declining funding, inefficient processes, extensive and complex government oversight, and lack of resources to pursue cutting-edge research. The workshop participants focused on three areas in which the program was particularly problematic: logistics and potential consequences of consolidation, opportunities for encouraging collaboration among groups and other institutions, and mechanisms for shifting the role of NCI from oversight to support. It strongly urged consolidation. Robert L. Comis, MD, Group Co-Chair, ECOG-ACRIN Cancer Research Group, told this year’s workshop, “If we wanted to end up with a successful reconfiguration with strong scientific programs, the groups needed to emerge from the process with an enhanced ability to perform innovative, science-driven clinical trials.” He added that flexibility was key to maximizing the potential of the restruc-

tured system. “The federal guidelines for grant review have allowed us to make our own decisions about the formation of our structures, and as I look across the system, I do see the groups preserving and enhancing areas of scientific and functional expertise.” The groups now include: ■ Alliance for Clinical Trials in Oncology, consisting of Cancer and Leukemia Group B (CALGB), North Central Cancer Treatment

■ Southwest Oncology Group (SWOG) These five have 426 patients in phase I trials, 4,440 in phase II, 14,486 in phase III, and 110 in pilot studies, for a total of 19,462 patients in cooperative group trials.

Notable Successes Dr. Comis described recent examples of ways in which consolidation and modernization have been successful:

We have significantly cut the time from study development to trial activation. Between 2006 and 2008, the median time to activation for phase III trials was 830 days. Now, as a result of new targets, our median time to activation is 395 days. —James M. Doroshow, MD

Group (NCCTG), and American College of Surgeons Oncology Group (ACOSOG) ■ Children’s Oncology Group (COG) ■ ECOG-ACRIN Cancer Research Group, from the merger of the Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN) ■ NRG Oncology, consisting of the National Surgical Adjuvant Breast and Bowel Project (NSABP), Radiation Therapy Oncology Group (RTOG), and Gynecologic Oncology Group (GOG)

■ Excellent cross-group and cancer center interactions toward the development of proposals for Integrated Translational Science Centers, which will maximize interactions throughout the NCTN. This will provide opportunities to strengthen the interdependence among the groups and the many cancer center and SPORE investigators. As a result, these investigators can contribute their scientific insights to group studies and leverage the data generated from group trials and the associated, wellannotated specimens to generate further discoveries.

■ In non–small cell lung cancer, the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) will be coordinated by the Alliance and ECOG-ACRIN, targeting patients with early-stage disease who harbor EGFR mutations. ALK and EGFR mutations will be assayed in Clinical Laboratory Improvement Amendments (CLIA)-approved labs prior to patient randomization, with approximately 8,000 patients screened for both mutations so that approximately 800 patients can be randomly assigned to the study arms. Deep-sequencing studies on formalin-fixed paraffin-embedded fixed tumor tissue will be sequenced by the NCI Center for Cancer Genomics—its first major interaction with the NCTN and one of the largest initiatives ever to be performed in lung cancer. Screened patients as well as randomly assigned patients will be followed for their clinical outcome. Consolidation has been beneficial, said Dr. Comis. It continues to be a work in progress and has led to better understanding of our strengths, weaknesses, and opportunities. “There are still challenges, though. Accrual is decreasing, and infrastructure support is not what we’d like it to be. Money is always a problem, especially now, at a time of financial constriction for everyone involved,” he said. n

Disclosure: Drs. Doroshow, McCaskillStevens, and Comis reported no potential conflicts of interest.

Highlights of ACCC Annual Meeting Include Discussion of Trends Shaping the Future of Health Care By Margot J. Fromer

he 39th Annual National Meeting of the Association of Community Cancer Centers (ACCC) was held in Washington, DC, in March. With a focus on business, economics, and policy, the program included the inauguration of a new ACCC President (see page 102), a keynote speech on the future of health care, and panels on the impact of a divided Congress on health care and the challenges involved in defining quality care.

Forecasting the Future of Health Care What is likely to get in the way of providing quality cancer care, and what

can smooth out the bumps in the road to cost-effectiveness? These were two major questions that Jeffrey C. Bauer, PhD, addressed in his keynote speech. Dr. Bauer is an independent health futurist and medical economist—and, as he declared at the outset, a strong critic of the Affordable Care Act. “Political reforms are not an effective way to fix how health care is provided,” he commented. “Health care will change more in this decade than it has in the past 50 years, but for that change to be positive, it is critical that we analyze information about alternative actions,” he said. He described trends that will

shape the future: ■ A revolution in medical science is shifting providers’ core function from acute care to chronic disease management. The one-size-fits-all clinical paradigm is being replaced by personal predictive medicine, and diseases long seen as single entities are now recognized as different conditions with a range of biologic interactions. Care will be more costeffective as therapies are matched to individual patients. ■ New information and communication technologies are transforming business models and production processes. Robust IT networks will

be the necessary foundation of good medical practice, and integrated record systems will be essential for cost-effective cancer care. ■ The end of growth in health-care spending is restructuring providerpatient relationships. Governments and employers are reaching the limits of their ability and willingness to spend more on health care, and the market will shift from fee-forservice reimbursement (quantity) to value-based payment (quality). Demand will change significantly as patients are expected to pay an increasing share of the costs. continued on page 85

This is the biologic medicine That the patient counts on That the nurse trusts That the pharmacist has confidence in That the doctor relies on Because it was manufactured knowing the patient’s treatment depends on it. Building confidence in the quality and supply of biologic medicines starts with a deeper understanding of how these medicines are made. After all, there’s so much at stake.

That’s why manufacturing matters. Learn more at

buildingbiologics.com

ASCOPost.com | APRIL 15, 2013

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Health-care Policy

ACCC Annual Meeting

all survival is not the only appropriate measure of quality. Patients want and need other elements of care, but we’re still not sure what they are. In other words, we need to know what really bothers people about having cancer.

continued from page 83

■ Problems with government-driven reform are compelling providers to develop successful futures on their own, in spite of state or federal mandates. The rushed legislative process produced a flawed Affordable Care Act that is unlikely to be improved by amendments. Legal challenges will serve only to create an uncertain environment for conforming to the law. Dr. Bauer forecasted that by 2015, 30% of health-care delivery systems will not be doing business as they are today (or not doing business at all), 45% will still be in business (but precariously), and 25% will be in business and thriving as a result of making needed changes. He suggested a number of ways to provide quality cancer care: Develop integrated and personalized care packages; use information and communication systems to manage services; offer services as inexpensively as possible; build long-term, multi-stakeholder partnerships with other providers, payers, purchasers, and patients; and reinvent cancer care independently of government health reform.

What a Divided Congress Means for Health Care Over the past several years, Congress has been gridlocked over almost everything, and amid the squabbles and outright fights, community oncology has been largely ignored. Matthew

Reimbursement Models and Outcomes Research Matthew Farber

Cara Tenenbaum, Esq

Farber, ACCC Director of Provider Economics and Public Policy, and panelists explored the likelihood of compromise occurring any time soon. He opened the discussion by noting that the many short-term fixes in recent years will not work, especially because Congressional attention is focused on sequestration—and will be for the foreseeable future. Sydney K. Abbott, JD, ACCC Manager of Provider Economics and Public Policy, said that regardless of Congressional attention elsewhere, the association must keep up its educational and lobbying efforts. “Almost everyone is unhappy with Congress. People are angry and know that change is necessary, but they don’t see where it needs to be made. So it is our job to let lawmakers know what has to be done for patients with cancer.” Cara Tenenbaum, Esq, Vice President for Policy and External Affairs, Ovarian Cancer National Alliance, advocates for appropriations and regulations. “All senators and representatives have a lot on their plates. They want to help cancer patients but they look to us

Achievement Award

immie C. Holland, MD, Wayne E. Chapman Chair in Psychiatric Oncology, Memorial Sloan-Kettering Cancer Center, received ACCC’s Annual Achievement Award for excellence in advocacy, dedication, and commitment to the care and treatment of patients with cancer. In her acceptance speech, Dr. Holland noted that too many people shy away from labels that use words beginning with “psych,” so she chose ‘distress’ instead. She developed a distress scale that Jimmie C. Holland, MD functions in much the same way as the widely used and well understood pain scale. The distress scale acknowledges and measures the psychosocial aspects of cancer that in many ways affect patients and their families more deeply than the disease itself. “It occurred to me many years ago that supportive care was lagging way behind curative treatment, and we needed to make improvements in the ways in which we involved the patient’s whole family in treatment decisions,” she said. “We also had to improve the way we dealt with the meaning of life, including end-of-life issues. In short, we needed a new science, complete with clinical trials, that gives credence to patient-reported symptoms and feelings.” n

Clifford Goodman, PhD

as advocates for advice on how to do so,” she said. “It’s up to ACCC members,” said Ms. Abbott. “Congress is a reactionary organization and will address the issues its members see as important. Therefore, it’s up to us to tell them what we want.”

Quality Cancer Care Should quality cancer care be defined by providers? By payers? By patients? In oncology, where not all treatments are intended to be curative, is an industry-wide definition of quality care possible—or even appropriate? The panelists couldn’t answer the question, but moderator Clifford Goodman, PhD, Senior Vice President, The Lewin Group, pushed hard to stimulate a discussion. He began by noting, “There is a broadening realization that defining high-quality cancer care depends on many perspectives, and the definition will vary across them. Survival is no longer the sole element in determining quality of care.” Randall A. Oyer, MD, Cancer Program Director, Lancaster (Pennsylvania) General Hospital, said that for care to be valuable, expenditures must be allocated and used wisely. “Consumers have expectations that may not be possible to meet,” he said, adding, “We also have to take into consideration the change in management from acuity to chronicity.” Linda House, RN, Executive Vice President of External Affairs, Cancer Support Community, noted that cancer is most prevalent in people over age 65, who are among the most empowered. “A lot of them believe they know what cancer treatment involves, but they don’t know what it means—and neither do we. So before we can assess whether people are receiving good care, we must first identify what it is.” John Fox, MD, Senior Medical Director, Priority Health, noted that patients are concerned with much more than 5-year survival, and in fact, over-

Payers are affecting treatment decisions by using various reimbursement models that incorporate quality (such as reducing hospital admissions) in decision-making. The pathways approach is one such model. The panelists acknowledged that use of pathways as a way to make decisions about treatment is increasing, but there was no agreement about whether this is a good thing. Do pathways improve quality or act as a barrier to good care? What parameters should affect their use, and should they be used at all? Are they indeed a good quality indicator? And if so, should the goal be total compliance with recommended pathways? Dr. Goodman noted that outcomes research is likely to strengthen the role

Linda House, RN

John Fox, MD

of patients in decision-making. “Most people are interested in dimensions beyond survival, such as side effects and quality of life.” The panelists agreed with Dr. Jimmie Holland that levels of distress should be assessed and screening tools developed (see sidebar). They also agreed that when patients play a role in decision-making, they are more likely to be satisfied with the treatment they receive, and thus view their care as good. However, said Ms. House, health literacy needs improvement so patients can benefit more, objectively and psychologically, from whatever decisions they make. Dr. Goodman asked a final question, the most difficult one: How will we know when we’re delivering highquality care? At Dr. Goodman’s prodding, the panel arrived at a tentative collective response: Quality care happens when patients receive the treatment they want. n

The ASCO Post | APRIL 15, 2013

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Health-care Policy Cancer Research

AACR Briefs Congressional Staffers on Importance of Continued Funding for Research By Margot J. Fromer

As we all now know, the start of the sequestration prescribed by the Budget Control Act of 2011 was delayed until March 1, 2013, by the American Taxpayer Relief Act of 2012. With Congress unable to strike a deal, the mandatory reductions in Federal spending were triggered on March 1. Those reductions will actually be spread out over the next decade, but about $85 billion is due to be cut this year, with a major impact on cancer research. The following report details what that impact might entail in the coming months, as addressed by AACR and NCI speakers before the March 1 deadline.

nosed with the disease this year, and approximately 570,000 will die of it.

‘Engine of Discovery’ Cancer mortality overall has decreased somewhat, but there are still several types of cancer about which almost nothing can be done, said Douglas Lowy, MD, NCI Deputy Director. He said that the National Cancer Institute (NCI) is an “engine of discovery” in both basic and clinical cancer research. He used as an example the definitive spiral CT scan trial that showed a 20% decrease in mortality for certain types of lung cancer. “It involved 50,000 people and cost

n a sunny day in February, more than 100 Congressional staffers heard foul weather predictions for the future of cancer research if Congress were to go ahead with its proposed sequestration cuts. Jon Retzlaff, MPA, MBA, Managing Director of Science Policy and Government Affairs, American Association for CanKenneth C. Anderson, MD

$250 million, but it was worthwhile. This is the kind of work that NCI can do more easily when it has increasing budgets.”

Translational Research

Jon Retzlaff, MPA, MBA

cer Research (AACR), opened the briefing by noting that support for cancer research is eroding, with a current $1.5 billion National Institutes of Health (NIH) budget cut tacked on to an overall 20% decrease during the past decade. “If sequestration goes through, it could mean a potential drop of 1,000 research awards, and total employment supported by NIH awards would fall by more than 20,000. And all this comes at a time when the number of opportunities in cancer research has never been greater.” He went on to say that although there are now 13.7 million cancer survivors in the United States, about 1.6 million Americans will be diag-

Kenneth C. Anderson, MD, Kraft Family Professor of Medicine, Harvard Medical School and Dana-Farber Cancer Institute, does B-cell malignancy research, especially focusing on multiple myeloma. He has developed in vitro and in vivo models to identify novel targets and validate therapies targeting the myeloma cell and its bone marrow milieu. Importantly, he has translated preclinical studies to the bedside, establishing a treatment paradigm using new therapies that target tumor cells, tumor-host bone marrow interactions, and the bone marrow microenvironment to overcome drug resistance and improve patient outcomes. He helped to lead clinical trials of proteasome inhibitor bortezomib (Velcade) and the immunomodulatory drug lenalidomide (Revlimid). FDA has approved both for treatment of myeloma.

“We need to better understand the microenvironment in which multiple myeloma grows in the bone marrow in order to develop better therapies,” said Dr. Anderson. “So far, we have markedly increased response rates and doubled or tripled patient survival. Indeed, for some patients, myeloma is a chronic disease, and we want to be able to achieve that goal for all of them. Only by supporting research will this be possible, and both patients and their families are counting on us.” However, said Dr. Lowy, with flat budgets, new projects can be started only if existing projects are reduced or phased out. Despite sequestration going into effect, the NCI is still seriously considering major endeavors such as the RAS project. Mutations in the RAS gene occur in about 30% of all patients with cancer, and the push now is to develop targeted treatments based on understanding the oncogenic mechanisms by which RAS contributes to cancer. M. Robert Carr, a former Democratic Representative from Michigan and currently Adjunct Professor of Political Management at George Washington University—and Dr. Anderson’s patient—described his experience with multiple myeloma and his gratitude for bortezomib, which has put him into complete remission. He noted how lucky he was to have

M. Robert Carr

been the recipient of federally funded research—and to have been in a position to have immediate access to bortezomib.

The Cancer Genome Atlas Anna D. Barker, PhD, is currently Professor and Co-Director of Complex Systems Research at Arizona State University and former NCI Deputy Director and Deputy Director for

Anna D. Barker, PhD

Strategic Scientific Initiatives. In her former role, she was instrumental in developing and implementing The Cancer Genome Atlas program—now in its eighth year—will map genome changes in 25 different cancers. So far, it has completed comprehensive sequencing, characterization, and analysis of the changes in glioblastoma multiforme, ovarian cancer, colon cancer, and breast cancer, and has collected the necessary samples for most of the other cancers. The ultimate goal for The Cancer Genome Atlas is integration of genomic information and patient data to provide an unprecedented multidimensional database that will inform the development of a new generation of targeted diagnostics and drugs. “Cancer is heterogeneous and represents a large number of different diseases—which makes it very difficult to predict the response of individual patients. We do know that know that the cost of treating cancer is staggering, and the number of cases of cancer is expected to rise significantly (estimates approach 30%) in the next decade. These increases, combined with the costs of other chronic diseases, represent a looming health-care and economic crisis.” She added that the data compiled as a result of completion of the Human Genome Project in 2003, allowed the NIH to undertake TCGA. As with the Human Genome Project, the level of complexity and cost of TCGA could only be accomplished through support from the federal government. Undoubtedly, TCGA will contribute in both known and unknown ways to our future efforts to understand and control cancer. Therefore, said Dr. Barker, it is imperative that Congress continue to fund critical projects such as TCGA and sustain our nation’s support for cancer and biomedical research. n

Because Endocrine Monotherapy Can Only Take You So Far

In postmenopausal women with advanced HR+, HER2-negative breast cancer after failure of treatment with letrozole or anastrozole

Change the Treatment Paradigm With AFINITOR Plus Exemestane AFINITOR plus exemestane more than doubles median progression-free survival (PFS) over exemestane monotherapy1

Median PFS in BOLERO-2 (Investigator Radiological Review)1 100

HR=0.45 [95% CI, 0.38-0.54] Log-rank P value: <0.0001

7.8 months Placebo plus exemestane: 3.2 months

AFINITOR plus exemestane:

PFS Probability (%)

Median PFS: 3.2 months

55%

Median PFS: 7.8 months

reduction in risk of progression or death2

20 AFINITOR plus exemestane (n/N=310/485) Placebo plus exemestane (n/N=200/239)

0 0

Time (months)

• Median PFS was 7.8 months with AFINITOR® (everolimus) Tablets plus exemestane [95% CI, 6.9-8.5] vs 3.2 months with placebo plus exemestane

[95% CI, 2.8-4.1] (P<0.0001)1

PFS curves for the 2 treatment arms began to diverge at 6 weeks (the first tumor assessment)1,2 An independent central review confirmed a significant PFS improvement with AFINITOR plus exemestane treatment vs placebo plus exemestane1,2 • Median PFS was 11.0 months with AFINITOR plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6]

(HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

BOLERO-2=Breast Cancer Trials of Oral Everolimus; HR=hazard ratio.

T:14”

B:14.25”

S:13”

AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. Important Safety Information.

• AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients • There have been reports of noninfectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR, some with

fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared with patients <65 years of age

• Oral ulceration is the most frequently occurring adverse event and occurred in 44% to 86% of AFINITOR-treated patients across the clinical trial

experience. Most of these events were grade 1/2. Grade 3/4 stomatitis was reported in 4% to 9% of patients

• Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have

also been reported; monitoring of laboratory tests is recommended

• The use of live vaccines and close contact with those who have received live vaccines should be avoided • AFINITOR can cause fetal harm when administered to a pregnant woman

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

References: 1. AFINITOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2012. 2. Data on file. Study CRAD001Y2301. Novartis Pharmaceuticals Corp; 2012.

• Careful monitoring and appropriate dose adjustments for adverse

Important Safety Information. AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, patients should be managed with dose interruption until symptoms improve • The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 • AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR • The development of pneumonitis has been reported even at a reduced dose Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred • Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR • Treatment of preexisting invasive fungal infections should be completed prior to starting treatment • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients • In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed Renal Failure: • Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR Geriatric Patients: • In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared to 2% in patients <65 years of age • Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

reactions are recommended Laboratory Tests and Monitoring: • Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported • Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter • When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) • Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments Hepatic Impairment: • Exposure of everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended Vaccinations: • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%) • The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%) Laboratory Abnormalities: • The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%) • The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%)

Please see Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

10/12

AFB-1043056

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009

T:14”

B:14.25”

S:13”

Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations]. Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 e Median duration of treatment 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration

Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo c

Key observed laboratory abnormalities are presented in Table 3. Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory Parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Agents That May Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information]. Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

T:14”

B:14.25”

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A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Pediatric use of AFINITOR Tablets is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in diseaserelated symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown. Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least one serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups. Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information].The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information]. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (ChildPugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Distributed by: Novartis Pharma Stein AG Novartis Pharmaceuticals Corporation Stein, Switzerland East Hanover, New Jersey 07936 © Novartis T2012-153 August 2012

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NCI Guide Helps Providers Get Adolescent and Young Adult Patients Involved in End-of-life Care By Keegan Bales

nabling adolescent and young adult (AYA) patients to become involved in advance care planning can help parents and health-care agents make informed decisions, alleviate distress, and possibly improve the patients’ quality of life, according to researchers at the National Cancer Institute’s Pediatric Oncology Branch, who reported their findings at the 10th Annual Conference of the American Psychosocial Oncology Society (APOS), held recently in Huntington Beach, California.1-3 These investigators have created a document for adolescents and young adults diagnosed with a terminal illness. The goal of the document, titled Voicing My Choices: A Planning Guide for Adolescents & Young Adults, is to address the unique emotional, social, and spiritual needs of young people with life-threatening illnesses (see The ASCO Post, January 15, 2013, page 70).

Opening up Discussions The group found that AYAs want to discuss end-of-life issues with those they trust, but few resources exist to help them cope. Documenting their thoughts and wishes gives these youth an opportunity to be involved in their care, give meaning to their life, and leave a legacy for their family and friends. NCI is now working on helping hospitals around the country implement Voicing My Choices with seriously ill adolescents and young adults as part of the care provided. “Dealing with end-of-life care is difficult for both the caregivers and the adolescent or young adult as they often avoid conversations in order to protect each other,” said NCI postdoctoral fellow Sima Zadeh. Ms. Zadeh and coauthors Lori Wiener, PhD, Director of the Psychosocial Support and Research Program and Staff Scientist in the Pediatric Oncology Branch, Center for Cancer Research at NCI, and Maryland Pao, MD, Assistant Professor at Johns Hopkins Medicine and Clinical Training Director at the National Institute of Mental Health, presented their work in a poster at the APOS meeting. “It is the responsibility of the healthcare team to open these discussions and allow the AYA and caregivers a safe place to have these important conversations,” Ms. Zadeh said.

Study Details Phase 11 of the research included focus groups and one-on-one interviews with 20 patients diagnosed with cancer or HIV. Participants reviewed Five Wishes, an existing advance care planning guide for adults, and asked whether concepts included were helpful to individuals their age living with serious health problems, appropriate for their peers, and stressful to contemplate. The results showed that AYAs found items related to how they would like to be remembered and treated very helpful and those pertaining to specific medical decisions somewhat less important. When asked which content was missing, the participants requested space to write letters, express how they would like to be remembered on their birthday and holidays, and plan the details of their memorial service. Phase 2 of the study contained 52 participants, ranging in age from 16 to

APOS Best Program Award

his poster by Ms. Zadeh and colleagues was one of two tied for the Best Program award, presented by the APOS Scientific Program Committee at the Annual Meeting. The two award-winning posters were: ■ Helping Providers to Help Adolescents and Young Adults be Involved in End-of-life Care: The Conversation No One Wants to Have. Sima Zadeh,1 Lori Wiener,1 and Maryland Pao2 ■ Psychosocial Distress Screening in a Community Cancer Center: A Descriptive Study of Distress Over the Course of Treatment. Christine DeVore,3,4 Jana Bolduan Lomax,3 Mark Aoyagi,4 Marybeth Lehto4 National Cancer Institute; 2National Institute of Mental Health; 3Exempla Health System; 4University of Denver.

Recommendations for Providers There are several important factors for health-care providers to consider when utilizing Voicing My Choices. Both the patient and the family should have an adequate understanding of the child’s

It is the responsibility of the healthcare team to open these discussions and allow the AYA and caregivers a safe place to have these important conversations. — Sima Zadeh

28 years. These participants were asked to compare a newly created document to Five Wishes. Respondents liked both closed- and open-ended questions. They also appreciated colorful pages that were easy to read and understand. The adolescents and young adults interviewed found discussion of medical treatment the most taxing topic and their spiritual wishes the least difficult. No significant differences were found among patients of varying diagnoses, genders, races, or ages. “Allowing them to take part in their end-of-life care—by sharing their preferences for the types of treatments they do or do not want and a means to document how they want to be remembered—allows them to regain a sense of self,” Ms. Zadeh said. “This process can also deepen the safety and trust felt in their relationships with both their caregivers and providers.”

diagnosis and prognosis. Many parents are resistant to having the discussion and/or involving the AYA patient in the decision-making because they are reluctant to anticipate a dismal outcome and fear that doing so will communicate a loss of hope to their child. Health-care providers are sometimes uncertain of how and when to introduce the issue. They often feel uncomfortable, unprepared, and unskilled in having end-oflife discussions, as their primary objective is to provide curative treatment. The researchers suggest that providers develop a standardized approach that includes consistently addressing patients and their families, particularly when cure is not possible. A trusted provider should introduce advanced care planning when patients and caregivers are in a relatively stable state of mind, not during a crisis. These discussions should take place early

on, soon after diagnosis. It should be made clear that discussion of end-of-life wishes is to respect the patients treatment wishes throughout the treatment trajectory and does not indicate that anyone has given up hope. NCI recommends that each topic within Voicing My Choices be presented as a separate “module,” beginning with the sections addressing comfort and support. Patients should be reminded that the document can be revised if the situation changes. Especially when making decisions about life support treatments, the adolescent or young adult should work alongside a provider because, even with the glossary, many of the concepts can be difficult to understand. Moving forward, the team plans to do further research on the utility and feasibility of Voicing My Choices. They hope that the document can be a useful tool to guide treatment and respect AYA wishes. n

Disclosure: Funding for this study was provided by the Intramural Program of the NCI/NIH.

References 1. Zadeh S, Wiener L, Pao M: Helping providers to help adolescents and young adults be involved in end-of-life care: The conversation no one wants to have. Abstract P2-4. 2013 American Psychosocial Oncology Society Annual Conference, Presented February 16, 2013. 2. Wiener L, Zadeh S, Battles H, et al: Allowing adolescents and young adults to plan their end-of-life care. Pediatrics 130:897-905, 2012. 3. Wiener L, Zadeh S, Wexler L, et al: When silence is not golden: Engaging adolescents and young adults in discussions around end-of-life care choices. Pediatr Blood Cancer 60:715-718, 2013.

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City of Hope Investigators Find Young Breast Cancer Survivors Understudied and Underserved By Keegan Bales

esearchers at City of Hope National Medical Center in Duarte, California, have been studying the effects of breast cancer on young women, particularly ethnic minorities and lower socioeconomic populations. They have found that young women are increasingly being diagnosed with breast cancer, yet remain understudied and underserved. Specifically, more exploration needs to be done into how health-care providers can improve follow-up care among minority survivors. The team hopes that examining age-specific factors and the particular medical and psychosocial vulnerabilities of this group will result in improved care.

In interacting with young survivors, we observed the presence of heightened fear and uncertainty, yet tremendous energy, creativity, and talents. —Kimlin Ashing-Giwa, PhD

Monica Rosales, PhD, at the 10th Annual Conference of the American Psychosocial Oncology Society (APOS), held recently in Huntington Beach, California.1

Study Design

Monica Rosales, PhD

“The study findings suggest that examining ethnic and linguistic factors among younger survivors is necessary to better address their specific needs, including appropriate and timely high-quality care for ethnic minority young breast cancer survivors,” said

African American, English-language-preferred Latina, and Spanishlanguage-preferred Latina breast cancer survivors under 50 years old participated in the study. All were within 1 to 6 years of their breast cancer diagnosis, which ranged from stage 0 to III. They were recruited from the California Cancer Registry and hospital registries. “In interacting with young survivors, we observed the presence of heightened fear and uncertainty, yet tremendous energy, creativity, and talents,” said Kimlin Ashing-Giwa, PhD. “These women are very motivated to work with clinicians and researchers to advance the science and practice for

improved outcomes and well-being.” The researchers examined satisfaction of young breast cancer survivors with their care, specifically examining where their treatment took place. Those who had a regular medical home they went to when feeling sick and for preventive and follow-up care were contented with their treatment. Those who received care at a doctor’s office, rather than an urgent care facility, reported greater patient satisfaction. Spanish-speaking Latinos were less likely to report having a medical home. This is likely because they struggle to find affordable health-care coverage and resources available in their native language.

vor population increases, investigating the experience of ethnic and linguistic minorities among young breast cancer survivors, to better understand their follow-up care and satisfaction with their care, can contribute to efforts to improve survivorship outcomes.” Moving forward, the researchers want to examine the most urgent follow-up care needs of young breast cancer survivors’ and improve survivorship by designing intervention studies to meet those needs and promote adherence to follow-up care guidelines. They also want to create a treatment and survivorship care plan that is tailored to this underserved population. “Unfortunately, breast cancer among premenopausal women seems to be on the increase, especially among ethnic minority women,” Dr. AshingGiwa said. “When breast cancer occurs in young women, the medical, physical, psychosocial, and overall impacts can be more severe. Greater research and clinical attention must be given to this at-risk population.” n Disclosure: Drs. Rosales and Ashing-Giwa reported no potential conflicts of interest.

First Study of Its Kind “Ours is the first study to report on demographic and medical characteristics and satisfaction with care among African American and Latina young breast cancer survivors,” Dr. Rosales said. “As the ethnic minority breast cancer survi-

Reference 1. Rosales M, Ashing-Giwa K: Young breast cancer survivors’ quality of care. Abstract P2-15. 2013 American Psychosocial Oncology Society Annual Conference, Presented February 16, 2013.

Tobacco Cessation Treatment Needed in Routine Cancer Care By Keegan Bales

esearchers at Memorial SloanKettering Cancer Center reported that a new behavioral tapering intervention combined with cessation counseling and pharmacotherapy did not affect short- and long-term abstinence rates compared to cessation counseling and pharmacotherapy alone among smokers newly diagnosed with cancer.1 The group’s poster tied for best overall at the 10th Annual Conference of the American Psychosocial Oncology Society (APOS). Jamie S. Ostroff, PhD, lead author of the study, said that despite the numerous risks, a recent populationbased study2 showed that 16% of adult

cancer survivors continue to smoke; a higher proportion is observed among survivors of tobacco-related cancers. Persistent smoking has been linked to treatment complications, cancer recurrence, second primary malignancies, poorer quality of life, and death. The current study examined whether patients prescribed a scheduled reduced smoking regimen prior to hospitalization for surgical treatment in addition to counseling and nicotine replacement therapy would be more likely to quit smoking than those who received only counseling and nicotine replacement therapy. The study showed that patients who

Dr. Ostroff said this research “underscores the importance of integrating evidence-based tobacco cessation treatment into routine cancer care.” n

Jamie S. Ostroff, PhD

were older and diagnosed with lung cancer were more likely to quit smoking. Overall, however, there was no difference between the two groups. Of the participants, 32% in both groups abstained from smoking after 6 months.

References 1. Ostroff J, Burkhalter J, Cinciripini P, et al: Randomized trial of a presurgical, scheduled reduced smoking intervention for patients newly diagnosed with cancer. 2013 American Psychosocial Oncology Society Annual Conference. Abstract P150. Presented February 15, 2013. 2. Underwood JM, Tai E, White A, et al: Persistent smoking and other tobacco use after a tobacco-related cancer diagnosis. J Cancer Surviv 6:333-344, 2012.

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Pilot Study Seeks to Offer Social Support to Patients with Mesothelioma By Keegan Bales

esearchers at Memorial Sloan-Kettering Cancer Center (MSKCC) reported that group therapy sessions may help patients cope with mesothelioma. Their two-part pilot study, which began recruitment in May 2011, is examining the emotional burden of the

Virtual Discussion Group Part 2 of the study is a virtual discussion group conducted primarily over the phone, although there is an Internet component. It includes six 1-hour sessions

facilitated by a social worker. The topics covered are determined by the patients on the call and range from family support to treatment options to disease education. According to the researchers, one

challenge has been the inability of patients to navigate the computer technology. However, the Internet has allowed patients to participate who might oth- Trim: erwise not be able to do so because of

Jimmie Holland, MD

cancer and offers discussion groups as a source of support for patients. Jimmie Holland, MD, senior author of the study said the project’s goal is to identify patients’ needs and quality of life and determine the feasibility and promise of a virtual support group for patients with mesothelioma. The researchers reported their preliminary findings in a poster presented at the American Psychosocial Oncology Society (APOS) Annual Conference, held recently in Huntington Beach, California.1

Patient Questionnaire Little research has addressed the unique psychological issues of mesothelioma patients and their caregivers. Thus, part 1 of the ongoing study is a questionnaire about their physical, emotional, and social well-being. Patients often complete the survey while in clinic. It takes 45 minutes to finish, and can be taken home to minimize the burden. At the time of the APOS meeting, 61 people had participated. The recruitment goal is 90. Overall, 69% of participants are male and 84% are white. The respondents range in age from 35 to 83 years old. Data from part 1 1 of the study indicate that patients with mesothelioma have high social and family well-being but poor physical health. Most patients were not highly depressed based on self-reporting. The most common coping method was emotional support followed by acceptance. The least used was behavioral disengagement and substance abuse.

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

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APOS Annual Conference

their location or deteriorating health. Part 2 found that patient well-being did not change significantly after group therapy. However, 87% of participants reported being satisfied or extremely satisfied with the experience, and 87% agreed that they obtained useful or :15.5” somewhat useful information from the session. Most participants said they

Caraline Craig

would recommend the group to other cancer patients. Moving forward, the team at MSKCC hopes to “complete recruitment and use information collected from the study to find ways to lessen physical and emotional stress on patients with mesothelioma,” said research assistant Caraline Craig. n

Disclosure: Dr. Holland and Ms. Craig reported no potential conflicts of interest.

Reference 1. Craig C, Blackler L, Starr T, et al: The psychosocial impact of mesothelioma: A pilot study examining patient needs and the promise of a virtual discussion group. 2013 American Psychosocial Oncology Society Annual Conference. Abstract P2-55. Presented February 16, 2013.

ORAL, ONCE-DAILY THERAPY1

TRANSFORM THE TREATMENT OF ADVANCED BCC Erivedge— a unique treatment option • Systemic therapy that targets dysregulated Hedgehog pathway signaling, a known driver of BCC1,2 • One 150-mg capsule a day until disease progression or unacceptable toxicity1 • Erivedge reduced lesions in patients with advanced BCC1,3 Objective response rates (ORR) by IRF from ERIVANCE1,3* laBCC (n=63)

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

ORR (95% CI)

Median response duration (months) (95% CI)

*Patients received at least 1 dose of Erivedge with independent pathologist-conﬁrmed diagnosis of BCC. Response in laBCC: absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on sampling biopsy. Response in mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. IRF=Independent Review Facility. laBCC=locally advanced BCC. mBCC=metastatic BCC. CI=conﬁdence interval. NE=not estimable.

Adverse Reactions

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

See what you can offer your patients with advanced BCC at www.Erivedge.com References: 1. Erivedge® (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. 2. Epstein EH. Nat Rev Cancer. 2008; 8:743-754. 3. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012;366:2171-2179.

Trim:10.75”

Complete response

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

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

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Journal Spotlight Integrative Oncology

Qigong Practice Associated with Quality-of-life Benefits in Women Undergoing Radiation Therapy for Breast Cancer By Matthew Stenger

igong (“qi” or “chi” = energy flow, “gong” = skill or achievement) is an integrated mind-body exercise and meditative practice that in-

volves rhythmic breathing coordinated with repetition of fluid movements and calm focus on the body. A study reported in Cancer by Zhen Chen, MD, T:7”

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont) All aBCC Patients (N = 138) Grade 3 Grade 4 All Grades 3 (%) (%) (%) 1

MedDRA Preferred Term

Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].

All aBCC1 Patients (N = 138) MedDRA Preferred Term

Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

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

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

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). t "EWJTF QBUJFOUT UIBU &3*7&%(& FYQPTVSF EVSJOH QSFHOBODZ DBO cause embryo-fetal death or severe birth defects. t *OTUSVDU GFNBMF QBUJFOUT PG SFQSPEVDUJWF QPUFOUJBM UP VTF B IJHIMZ effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t *OTUSVDU BMM NBMF QBUJFOUT FWFO UIPTF XJUI QSJPS WBTFDUPNZ UP VTF condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. t *OTUSVDU QBUJFOUT UP JNNFEJBUFMZ DPOUBDU UIFJS IFBMUIDBSF QSPWJEFS if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. t *OTUSVDU QBUJFOUT UP JNNFEJBUFMZ SFQPSU BOZ QSFHOBODZ FYQPTVSF UP ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. t *OGPSN GFNBMF QBUJFOUT PG UIF QPUFOUJBM GPS TFSJPVT BEWFSTF reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. t "EWJTF QBUJFOUT OPU UP EPOBUF CMPPE PS CMPPE QSPEVDUT XIJMF UBLJOH ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t "EWJTF QBUJFOUT UP TXBMMPX &3*7&%(& DBQTVMFT XIPMF BOE OPU UP crush or open the capsules.

ERIVEDGE ® [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0001559500 HED0000832301

the University of Pennsylvania, Philadelphia; and Dresden University of Technology, Germany, showed that regular qigong practice was associated with reduced depressive symptoms in Chinese women undergoing radiation therapy for breast cancer.1 Quality-of-life benefits were particularly marked among women with higher depressive symptoms at the start of radiotherapy.

Study Details In the study, 96 women with breast cancer stage 0 (ductal carcinoma in situ, for example) to III scheduled to receive 5 to 6 weeks of radiotherapy were randomly assigned to qigong practice (n = 49) or a wait list control group (n = 47). The qigong group was to receive five 40-minute sessions per week during radiotherapy. Symptoms of depression, fatigue, sleep disturbance, and overall quality of life were assessed by the Center for Epidemiologic Studies Depression Scale, Brief Fatigue Inventory, Pittsburgh Sleep Quality Index, and Functional Assessment of Cancer–General instruments, respectively. Cortisol rhythm was assessed using saliva samples. Outcomes were measured in the middle of radiotherapy, at the end of radiotherapy, and at 1 month (the primary outcome measure time point) and 3 months after completion of radiotherapy.

T:10”

1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients

and colleagues from Fudan University Shanghai Cancer Center, China; The University of Texas MD Anderson Cancer Center, Houston; Hospital of

Qigong Sessions All qigong sessions were taught by the same instructor and consisted of preparation, main, and ending exercises. Preparation exercise included relaxation through gentle breathing and meditation, synchronizing the breath with slow, shallow squatting movements, and synchronizing the breath with gentle arm movements in front of the abdomen. The main exercise consisted of participants walking in a circle, synchronizing their breathing, arm movements, and steps while focusing on the movement of their body with the goal of calming the mind, relaxing the body, and revitalizing their “life force” (qi); this activity was done first slowly and then quickly. The ending exercise consisted of breathing ex-

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Journal Spotlight

ercises, arm movements in front of the abdomen, and self-massage in a standing position. There were no significant differences between the qigong and control groups at baseline with regard to age (mean, 45 and 45 years), marital status (46% and 40% married), level of education (at least some college for 55% and 50%), income, stage of disease (0 in 4% and 7%, I in 17% and

group (P = .05), indicating significant group differences in changes in depression over time. At 1 month after completion of radiotherapy, the qigong group had a lower adjusted mean score (10.01 vs 12.14), with the difference approaching significance (P = .09); the two groups had similar mean scores at 3 months after radiotherapy. There were no significant differences between groups with regard to fatigue, sleep dis-

The results of the study indicate that qigong may lead to reductions in depressive symptoms over time and may be especially useful for women who report high symptoms of depression at baseline. 31%, II in 35% and 36%, and III in 35% and 15%), time since surgery (16.5 and 15 weeks), or number of radiotherapy fractions (25 in 78% and 78%). A difference in surgery type approached significance (mastectomy and lumpectomy in 37% and 63% vs 56.5% and 43.5%, P = .07). There were no significant differences between groups at baseline with regard to depressive symptoms, fatigue, sleep disturbance, overall quality of life, or cortisol slope. Adherence to the qigong program was high, with 30% of women in the group attending 100% of sessions, 65% attending at least 80%, and 78% attending at least 50%; only 13% attended less than 20% of sessions. Among all patients, there was a significant reduction in depression scores over time (P = .001); this effect was significantly moderated by treatment

turbance, overall quality of life, or cortisol slope or awakening response.

Women with Higher Baseline Depression Scores Significant group by time by baseline depression score interactions were observed for depressive symptoms score, fatigue score, and overall quality-of-life score. Thus, the investigators analyzed outcomes according to whether patients had high or low (mean ± 1 standard deviation) baseline depressive symptom scores. For each of these measures, there were no differences between groups when analysis was limited to patients with low baseline depression scores. Among those with high baseline scores, women in the qigong group had marginally significantly lower depression scores during radiotherapy (least mean square 16.4 vs 23.6, P =

Qigong in Women with Breast Cancer ■ Regular qigong practice was associated with reduced depressive

symptoms in Chinese women undergoing radiation therapy for breast cancer.

■ Although no significant differences in depression scores between the total qigong and control groups were observed, depression scores decreased significantly over time for all patients; this effect was moderated by treatment group, indicating significant group differences in changes over time.

■ Among women with higher depressive symptom scores at baseline,

qigong was associated with significantly better depressive symptoms, fatigue, and overall quality-of-life outcomes at 1 month after radiotherapy.

EXPERT POINT OF VIEW By Lorenzo Cohen, PhD

t is clear from our study, and other studies examining mind-body interventions in patients with cancer, that it is important for patients to consider participating in some kind of program to manage their stress and improve their quality of life. This is particularly true for patients who are vulnerable to adjustment problems, such as those experiencing depressive symptoms. There are many different mind-body programs that can be useful during cancer care, with qigong Lorenzo Cohen, PhD being one of them. Patients will often ask which mind-body program is the best for reducing stress and improving quality of life. The answer is, “the one you will do every day and make a part of your life.” n Disclosure: Dr. Cohen was the principal investigator in the qigong study.

Dr. Cohen is Professor in the Departments of General Oncology and Behavioral Science, and Director of the Integrative Medicine Program, The University of Texas MD Anderson Cancer Center, Houston.

.06) and significantly lower scores at 1 month (15.5 vs 29.1, P < .001) and 3 months (12.7 vs 26.5, P < .05) after completion of radiotherapy than the women in the control group. Similarly, among women with high baseline depression scores, those in the qigong group had significantly better fatigue scores at 1 month after radiotherapy (2.93 vs 4.19, P < .05) and significantly better overall quality-of-life scores at 1 month after radiotherapy (82.4 vs 66.3, P < .01), as well as a clinically significant difference in quality-of-life scores (defined as a difference of ≥ 7 points) at 3 months after radiotherapy (85.5 vs 78.1). Baseline depressive symptoms did not significantly moderate group by time interactions for sleep disturbance or cortisol slope or awakening response. As noted by the investigators, the absence of differences between groups in cortisol rhythm suggests that the improvement in depressive symptoms is not explained by improved cortisol regulation. The finding that qigong was most effective in patients with greater baseline levels of depression is consistent with results of a large meta-analysis indicating that psychosocial interventions in patients with cancer are most effective in those with higher preintervention levels of distress or depression.2

The investigators concluded that the results of the study “indicate that qigong may lead to reductions in depressive symptoms over time and may be especially useful for women who report high symptoms of depression at baseline. Studies involving a blinded design with an active control group, selecting for high levels of baseline depressive symptoms, and longer-term follow up will be necessary to examine the generalizability of our findings and to deepen our understanding of this promising therapeutic approach.” The investigators currently are conducting a threearm trial of qigong including an active control group. n

Disclosure: The study was supported by a National Cancer Institute grant. At the time of publication, Bob Thornton, MD, was with Merck & Co, but he was on the MD Anderson staff when the research was conducted. The authors reported no potential conflicts of interest.

References 1. Chen Z, Meng Z, Milbury K, et al: Qigong improves quality of life in women undergoing radiotherapy for breast cancer. Cancer. January 25, 2013 (early release online). 2. Schneider S, Moyer A, Knapp-Oliver S, et al: Pre-intervention distress moderates the efficacy of psychosocial treatment for cancer patients: A meta-analysis. J Behav Med 33:1-14, 2010.

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Journal Spotlight Hematology

Addition of Liposomal Daunorubicin Improves Early Outcome in Patients with Pediatric Relapsed AML By Matthew Stenger

ptimal reinduction therapy for patients with relapsed pediatric acute myeloid leukemia (AML) remains undefined. Liposomal daunorubicin (DaunoXome), which offers the potential for reduced cardiotoxicity compared with traditional daunorubicin, is effective in this setting. Gertjan J.L. Kaspers, MD, PhD, and colleagues in the International BerlinFrankfurt-Münster Study Group recently reported what may be the first randomized trial and the largest trial conducted to date in pediatric relapsed AML.1 In this investigator-initiated international phase III trial, published in the Journal of Clinical Oncology, the addition of liposomal daunorubicin to FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor [filgrastim (Neupogen)]) improved early bone marrow status in patients with relapsed pediatric AML. Overall survival was similar with the two treatments, although subgroup analysis suggested a potential advantage with the liposomal daunorubicin-containing regimen in patients with better prognostic characteristics.

Study Details The trial was performed by 13 groups in 20 countries, with patient enrollment occurring from November 2001 through April 2009. A total of 394 patients aged less than 21 years with relapsed or primary refractory AML were randomly assigned to liposomal daunorubicin plus FLAG or FLAG alone followed by FLAG, given in 28-day cycles. Granulocyte colony-stimulating factor was given at 200 µg/m2 on days 0 to 5 and immediately followed by fludarabine 30 mg/m2 on days 1 to 5; liposomal daunorubicin was given at 60 mg/m2 after fludarabine on days 1, 3, and 5, and cytarabine 2,000 mg/m2

was started 4 hours after fludarabine on days 1 to 5. Patients with complete response after two courses went on to intensive or low intensive consolidation therapy prior to stem cell transplantation. The primary endpoint of the trial was 28-day bone marrow status, assessed shortly before the second course of chemotherapy. Patients in the liposomal daunorubicin and control groups were well balanced for sex (57% and 60% male), age (median 9 and 10 years), proportion of patients with less than 20% blasts (16% and 20%), nonfavorable cytogenetics (79% and 81%), and disease status (early relapse, late relapse, and primary refractory disease in 48%, 44%, and 8%, respectively, and 46%, 48%, and 6%, respectively). Overall, 20% of patients had core-binding factor AML. Patient groups were balanced for types of consolidation, stem cell transplantation, and allogeneic stem cell transplantation, and for time to transplant from complete response (median 105 and 107 days).

Response Rates The rate of good response (≤ 20% blasts) at 28 days was significantly higher in the liposomal daunorubicin group (80% vs 70%, odds ratio [OR] = 0.60, P = .04). Among patients with less than 20% blasts at baseline, 10% of those in the liposomal daunorubicin group vs 26% of those in the FLAG group had more than 20% blasts at day 28 (P = .088). Response rates were 70% vs 54% (P = .04) in patients with early relapsed AML, 90% vs 84% in those with late relapsed disease, 100% vs 94% in those with corebinding factor AML, and 76% vs 64% (P = .048) in those with unfavorable cytogenetics. Complete response rates were 69% in daunorubicin patients and 59% in control patients (P = .07), including

Liposomal Daunorubicin plus FLAG in Pediatric Relapsed AML ■ A large randomized international trial of pediatric relapsed AML found

a 4-year probability of overall survival of 38% among the 394 children randomly assigned to liposomal daunorubicin plus FLAG or FLAG alone.

■ Liposomal daunorubicin treatment was associated with better early bone marrow response and complete response rate among all patients and improved survival in the subgroup of patients with core-binding factor AML.

Further Reflections on a Successful Trial By Stacey Berg, MD

he authors are to be congratulated for successfully conducting a randomized study of FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor [Neupogen]) vs FLAG plus liposomal daunorubicin (DaunoXome) in relapsed pediatric acute myeloid leukemia (AML). The difficulty in conducting such a study must not be underestimated; nearly 400 patients from 20 countries were enrolled over a period of more than 7 years. Stacey Berg, MD Neither the 4-year overall survival rate nor the complete remission rate differed between the two treatments, although early response was better in the FLAG/liposomal daunorubicin arm. Interestingly, however, for patients with favorable cytogenetics, treatment with FLAG/liposomal daunorubicin resulted in an overall survival rate of 82%, vs 58% with FLAG (P = .04). The authors comment that this difference may be the result of patients with a more favorable prognosis benefiting from more-intensive therapy in general.

Critical Lessons There are two critical lessons from this study. First, we must strive to continue to improve the outcome of front-line treatment of pediatric AML, because the prognosis after relapse remains unsatisfactory. Second, we can and must conduct rigorous studies of new therapies in AML and other diseases, even when such studies are difficult and time-consuming. For both arms of this study, overall survival was better than would likely have been predicted based on historical controls. Without randomization, the improvement might have been erroneously attributed to the addition of liposomal daunorubicin to FLAG. Thus, although the clinical benefit of liposomal daunorubicin appears to be modest at best in this setting, the study overall should be considered a success because of the important information it provides. n Disclosure: Dr. Berg reported no potential conflicts of interest.

Dr. Berg is Professor of Pediatrics at Baylor College of Medicine and Director of Clinical Research at Texas Children’s Cancer Center, Houston.

rates of 97% vs 91% in patients with core-binding factor AML and 62% vs 55% in patients with other cytogenetics. The estimated cumulative incidence of relapse at 4 years was higher in the liposomal daunorubicin group (29% vs 19%, P = .02). Probability of survival at 4 years did not differ between the two groups (40% vs 36%, P = .54). A post hoc subgroup analysis showed that among patients with core-binding factor AML, probability of survival at 4 years was higher in the daunorubicin group (82% vs 58%, P = .04), with estimated cumulative incidence of relapse at 4 years being nonsignificantly lower (17% vs 22%, P = .59).

Treatment group was not a significant prognostic factor for overall survival on univariate or multivariate analysis. On regression analysis for overall survival including treatment group, time to relapse, and cytogenetic risk, there was a significant interaction of favorable cytogenetic risk and liposomal daunorubicin treatment indicating a survival benefit of liposomal daunorubicin in the patient subgroup with favorable cytogenetics (hazard ratio [HR] = 0.3, 95% confidence interval [CI] = 0.1-0.9, P = .034).

Similar Toxicity Grade 3 or 4 toxicity was similar in continued on page 102

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Journal Spotlight

Liposomal Daunorubicin in Pediatric AML continued from page 100

the two treatment groups apart from skin toxicity, which occurred in 4% of liposomal daunorubicin patients and 1% of control patients (P = .04). Among grade 3 or 4 toxicities, thrombocytopenia, neutropenia, and anemia occurred in 94%, 97%, and 85% of the liposomal daunorubicin/FLAG group, respectively, and 98%, 98%, and 89% of the FLAG group, respectively; infections occurred in 40% vs 31%, nausea in 21% vs 20%, and fever in 18% vs 17%. Grade 3 or 4 acute cardiotoxicity occurred in five patients in the liposomal daunorubicin group (2.7%; one with grade 4) vs one patient in the control group (0.6%). Cardiotoxicity always coincided with

fever and infections, and none of the episodes was fatal. Long-term cardiotoxicity data are not yet available.

Conclusions With regard to the overall findings of the trial, the authors stated: “We report the first (to our knowledge) randomized study in pediatric relapsed AML. In this multinational setting, we achieved the best outcome for these children reported thus far, with a 4-year [probability of overall survival] of 38% in [the entire] group of 394 children…. International collaboration is feasible in the treatment of pediatric relapsed AML and should be pursued….” With regard to the findings on the addition of liposomal daunorubicin, they noted that the nature of the trial

prohibited close monitoring of all details of treatment and outcome, limiting the analysis of such factors as types of consolidation, quality of response according to minimal residual disease monitoring, and differences in first-line treatment. Nevertheless, they stated: [T]he main study end point is robust and can be used in future studies in relapsed AML, even though more detailed immunophenotyping of blasts to discriminate them from regenerating normal blasts and information on [minimal disease monitoring] will be useful in addition. One may argue that the clinical benefit of [liposomal daunorubicin] is unknown at best, because [overall survival] did not improve significantly. However, it should be taken into account that therapy after induc-

tion was heterogeneous and may have been intensified in patients with poor early treatment response.

A better early treatment response and an improved complete response rate are clinically positive findings, they noted, as is the significantly higher probability of overall survival with liposomal daunorubicin plus FLAG for core-binding factor AML. n

Disclosures: Drs. Kaspers and Reinhardt have received compensation from Galen for consultant or advisory roles.

Reference 1. Kaspers GJL, Zimmermann M, Reinhardt D, et al: Improved outcome in pediatric relapsed acute myeloid leukemia: Results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol 31:599-607, 2013.

New ACCC Officers and Trustees

esults of the election of new officers and trustees (2013–2014) for the Association of Community Cancer Centers (ACCC) were announced recently at the ACCC Annual National Meeting.

First Nonphysician ACCC President Elected Virginia Vaitones, MSW, became ACCC President at the 39th Annual National Meeting held in Washington, DC, in March. She is an oncology social worker—the first such professional to head ACCC— at PenBay Medical Center in Rockport, Maine. Ms. Vaitones has been an active member of ACCC since 2002, working on the Program Guidelines and Governmental Affairs Committees. She helped develop ACCC’s patient navigation materials and recently served on advisory boards for the Financial Information and Learning Network and Improving Quality Care in Small-Population Cancers: Multiple Myeloma Project. “I am a strong believer in the interdisciplinary team that is needed in today’s cancer care programs to help our patients and their caregivers navigate the complexities of care,”

said Ms. Vaitones. “I can think of no other organization that better understands and supports those ideas and programs.” The ASCO Post asked Ms. Vaitones if she thought that inauguration of a social worker—of any nonphysician, for that matter—will change

Pen Bay Medical Center, Cancer Care Center, Rockport, Maine ■ President-Elect: Becky L. Dekay, MBA Louisiana State University Health Sciences Center Feist-Weiller Cancer Center, Shreveport, Louisiana

I am a strong believer in the interdisciplinary team that is needed in today’s cancer care programs to help our patients and their caregivers navigate the complexities of care. —Virginia Vaitones, MSW

the way ACCC functions. She said that it will surely have an effect. “I’m hopeful that other disciplines within cancer care will become involved in the organization; we can’t afford to work in silos any longer.” She added, “ACCC, as the only interdisciplinary organization for cancer programs, is uniquely positioned to be a voice for the entire oncology team.” ACCC’s officers and new Board of Trustees members for 2013–2014 are: ■ President: Virginia T. Vaitones, MSW, OSW-C

■ Secretary: Steven L. D’Amato, BSPharm, BCOP Maine Center for Cancer Medicine Scarborough, Maine ■ Treasurer: Jennie R. Crews, MD PeaceHealth St. Joseph Medical Center Bellingham, Washington ■ Immediate-Past President: George Kovach, MD Iowa Cancer Specialists, PC Joining the Board of Trustees are: ■ Randall A. Oyer, MD Lancaster General Hospital Lancaster, Pennsylvania

■ Nicole Bradshaw, MS, MBA St. Luke’s Mountain States Tumor Institute Nampa, Idaho ■ Colleen Gill, MS, RD, CSO University of Colorado Hospital, University of Colorado Cancer Center Aurora, Colorado Re-elected to the Board were: ■ Brenda Nevidjon, MSN, RN, FAAN Duke Comprehensive Cancer Center Durham, North Carolina ■ Kim Woofter, RN, OCN Michiana Hematology-Oncology, PC South Bend, Indiana Rotating off the Board after serving two consecutive terms are: ■ Frances Becker, LCSW, OSW-C Stamford Hospital, Bennett Cancer Center Stamford, Connecticut ■ Heidi Floden, PharmD GW Medical Faculty Associates Washington, DC ■ Thomas L. Whittaker, MD, FACP IU Health Central Indiana Cancer Centers Indianapolis, Indiana n

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Journal Spotlight Breast Cancer

Effects of Menarche and Menopause on Breast Cancer Risk: Meta-analysis Findings By Matthew Stenger

enarche and menopause mark the onset and offset of ovarian and endocrine activity associated with reproduction, and early menarche and late menopause are known to increase risk of breast cancer. In a recent Lancet Oncology article, the Collaborative Group on Hormonal Factors in Breast Cancer reported findings of a metaanalysis that assessed the strength of these risk associations and determined whether the associations differ by characteristics of affected women or tumor subtypes.1 The meta-analysis included individual data from 117 epidemiologic studies involving 118,964 women with invasive breast cancer and 306,091 women without such disease, of whom none had used menopausal hormone therapy. The studies were performed in 35 countries, mostly in Europe or North America. The median year of birth of women with breast cancer was 1939, and the median age at cancer diagnosis was 54 years.

with no family history). Heterogeneity across groups was not significant for any other factor examined (ie, year of birth, ethnic origin, parity, age at

first birth, height, body mass index as young adult, oral contraceptive use, menopausal status, and age at menopause in postmenopausal women).

Information on tumor characteristics was available from 85 studies. The association with age at menarche continued on page 104

INHIBIT ANDROGEN PRODUCTION

Menarche Among controls, mean age at menarche was 13.1 years, with 65% reporting menarche at 12 to 14 years and 16% having menarche at 11 years or younger. Breast cancer risk increased by 5% for each year younger at menarche (relative risk [RR] = 1.050 [P < .0001] for each year) when results were stratified by study, age, year of birth, parity and age at first birth, height, current body mass index, smoking, and alcohol consumption. Additional adjustment by ethnic origin, hormonal contraceptive use, and family history of breast cancer altered the excess relative risk estimate by less than 1%. On subgroup analyses, the relative risk for each year younger at menarche was reduced by current body mass index ≥ 25 kg/m2, although the effect was significant only for postmenopausal women (RR = 1.031, P = .006 for heterogeneity with lower body mass index); by greater attained age in postmenopausal women (1.039 for age ≥ 65 and 1.044 for age 55–64, P = .04 for heterogeneity among age groups); and by family history of breast cancer (1.001, P = .01 for heterogeneity

BLOCK THE ANDROGEN RECEPTOR

Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN ®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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Journal Spotlight

Breast Cancer Risk continued from page 103

was significantly stronger for lobular tumors vs ductal tumors (RR = 1.073 vs 1.035 for each year younger at menarche, P = .0001 for heterogeneity). There was no significant difference in relative risk according to estrogen receptor status.

postmenopausal women. The relative risk for breast cancer decreased significantly more rapidly after menopause (P < .0001) in lean vs overweight or obese women, likely reflecting at least in part differences in estradiol concentrations between the two groups. The proportion of breast tumors that were estrogen receptor–positive and of

Women Aged 45 to 54 Years Among postmenopausal controls, mean age at natural menopause was 49.3 years, with menopause occurring in 15% before age 45 and 75% between 45 and 54 years. There was little association between age at menarche and age at menopause. Late menopause was weakly associated with year of birth, childbearing history, body mass index, and alcohol consumption, with the strongest association being a negative association with smoking. The short-term effect of reduced ovarian hormone reduction on breast cancer risk was assessed by restricting analysis to 31,000 cases and 70,000 controls aged 45 to 54 years. Among these women, risk was 43% greater among premenopausal women than among postmenopausal women of identical age (RR = 1.43, P < .0001), indicating a rapid decline in risk soon after menopause; risk in perimenopausal women was intermediate between these two groups. Subgroup analyses showed little heterogeneity, except for an attenuation of risk in premenopausal women by adiposity. Premenopausal women with body mass index ≥ 25 kg/m2 had lower risk than leaner women, whereas the reverse was found for

Postmenopausal Women In analysis restricted to postmenopausal women, relative risk for breast cancer increased by 2.9% for each year older at menopause (RR = 1.029, .0001 for each year older at menoP < .0001 pause) with stratification for study, year of birth, age, parity and age at first birth, height, current body mass

Menarche/Menopause and Breast Cancer Risk ■ Breast cancer risk was increased by 5% for each year younger at menarche

and by 2.9% for each year older at menopause; risk increased by a significantly greater factor for each year younger at menarche vs each year older at menopause, suggesting that effects of menarche and menopause on risk may not be simply related to an increased number of total reproductive years.

■ Among women aged 45 to 54 years, risk of breast cancer was increased by 43% in premenopausal women compared with postmenopausal women of an identical age.

■ Increased current adiposity reduced risk associated with earlier menarche in postmenopausal women, reduced risk in premenopausal women aged 45 to 54, and reduced the relative risk per year older at menopause in postmenopausal women. In women aged 45 to 54 years, reduced adiposity was associated with more rapid decline in risk following menopause.

■ Relative risk for each year younger at menarche and each year older at

menopause was increased for lobular vs ductal tumors; relative risk for each year older at menopause was increased for estrogen receptor– positive vs estrogen receptor–negative disease.

lobular histology increased with age in both premenopausal and postmenopausal women, with a sudden decrease occurring for both estrogen receptor– positive and lobular tumors around the time of menopause. Heterogeneity between premenopausal women and postmenopausal women aged 45 to 54 years was significant for both estrogen receptor status and tumor histology.

index, smoking, and alcohol consumption. Additional adjustment for ethnic origin, age at menarche, family history of breast cancer, and hormonal contraceptive use altered the excess relative risk estimate by less than 1%. Relative risks did not differ significantly between women with natural menopause and those with bilateral oopherectomy. The relative risk for breast cancer per

year older at menopause was reduced by current body mass index ≥ 25 kg/ .008 for heterogem2 (RR = 1.024, P = .008 neity between higher and lower body mass index) and age < 25 years at first birth (1.023, P = .03 for heterogeneity between younger and older age at first birth); the relative risk was not significantly affected by the other patient characteristics examined. The relative risk was significantly increased for estrogen receptor–positive disease (1.031, P = .01 for heterogeneity with estrogen receptor–negative disease) and for lobular histology (1.036, P = .006 for heterogeneity with ductal histology). Among postmenopausal women, the relative risk for each year younger at menarche (1.045) was significantly greater than the relative risk for each year older at menopause (P = .001 for heterogeneity). As summarized by the authors, “Breast cancer risk increased by a significantly greater factor for every year younger at menarche than for every year older at menopause, indicating that menarche and menopause may not affect breast cancer risk merely by extending women’s total reproductive years. Endogenous ovarian hormones are more relevant for estrogen receptor–positive disease than for estrogen receptor–negative disease and for lobular than for ductal tumors.” n Reference 1. Collaborative Group on Hormonal Factors in Breast Cancer: Menarche, menopause, and breast cancer risk: Individual participant meta-analysis, including 118,964 women with breast cancer from 117 epidemiological studies. Lancet Oncol 13(11):1141-1151, 2012.

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Announcements

Jonathan Friedberg, MD, Named Director of the James P. Wilmot Cancer Center

onathan Friedberg, MD, MMSc, has been appointed Director of the James P. Wilmot Cancer Center at the University of Rochester Medical Center in New York. Dr. Friedberg joined the Medical Center in 2002 and was named Chief of the Division of Hematology/Oncology in the Department of Medicine in 2009. He has served as Acting Director of the Wilmot Cancer Center since July 2012.

Chief Executive Officer of the University of Rochester Medical Center. “He leads with warmth and respect for those around him, while at the same

time driving multiple initiatives forward at a rapid pace. I have no doubt that Wilmot›s broad mission, that is, to deliver the most advanced cancer

care, to expand the reach of our services regionally, and to be a leader in cancer research, will thrive under Jonathan’s leadership.”n

Jonathan Friedberg, MD, MMSc

“Our scientific understanding of cancer – of how it begins in our cells, how it progresses, and how we can stop it – has increased dramatically over the last decade,” said Dr. Friedberg. “Wilmot’s greatest strength is that we have clinicians and researchers working together, studying cancer and applying the latest scientific knowledge to the care of every patient. One of my goals for Wilmot is to create an environment that nurtures those interactions so that we deliver the highest quality of care for our patients.” Dr. Friedberg is a clinical researcher whose work focuses on development of novel therapies for patients with lymphoma. He is a member of the lymphoma committee in the Southwest Oncology Group, and has served as principal investigator on many clinical trials for Hodgkin lymphoma and nonHodgkin’s lymphoma. Dr. Friedberg earned his medical degree from Harvard Medical School. His postgraduate training included an internship and residency at Massachusetts General Hospital. He also completed medical oncology and hematology fellowships at Dana-Farber/Partners Cancer Care. He earned an MMSC degree in clinical investigation from Harvard Medical School. “Jonathan is respected across the institution as an academic and clinical leader of exceptional vision and talent,” said Bradford C. Berk, MD, PhD,

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

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Journal Spotlight Breast Cancer

CDC Reports Racial Disparity in Breast Cancer Mortality By Matthew Stenger

reast cancer deaths have declined over the past 2 decades, with approximately half of the decrease estimated to be due to advances in early detection and treatment. However, not all racial groups have benefited equally from these advances. A recent report from the Centers for Disease Control and Prevention showed that black women have a higher death rate from breast cancer despite having a lower incidence.1 The report summarized findings from the United States Cancer Statistics dataset for 2005 to 2009, including mortality data from the National Vital Statistics System and incidence data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results program. Annual invasive breast cancer incidence and mortality rates for black women and white women were age-adjusted to the 2000 U.S. standard population. Staging data excluded cases identified only by autopsy or death certificate.

Incidence and Disease Stage Among women of all races, an average of 205,246 cases of breast cancer was diagnosed each year from 2005 to

stages, compared with 35% of cases in white women (30% regional, 5% distant). Rates per 100,000 population for black vs white women were 61.0 vs 75.7 for localized disease, 42.3 vs 36.8 for regional disease, and 9.6 vs 6.0 for distant disease.

Relative Mortality Breast cancer mortality was 41% higher in black women, with mortality rates of 31.6 deaths/100,000 population in black women and 22.4/100,000 in white women. The mortality-to-incidence ratio was 0.27 in black women, representing 27 deaths per 100 breast cancer cases, compared with 0.18 in white women, representing 18 deaths per 100 cases. A total of 40 states and the District of Columbia had a sufficient number of breast cancer deaths to be included in a by-state analysis of mortality-to-incidence ratio. The ratios for black women showed greater variability and were generally higher than those for white women; states reported ratios as high as 0.30 to 0.33 for black women, with no states reporting ratios this high for white women. The authors noted that several factors likely contribute to the increased propor-

Breast Cancer in Black vs White Women ■ Black women had a lower incidence of breast cancer, but a higher rate of more-advanced disease than did white women.

■ Breast cancer mortality was 41% higher in black women than in white women.

Fig. 1: Invasive female breast cancer incidence and mortality rates, by race—United States, 2005– 2009. Source: CDC’s National Program of Cancer Registries, the National Cancer Institute’s Surveillance, Epidemiology, and End Results program, and National Vital Statistics System mortality data.1

subtypes with a poorer prognosis, particularly triple-negative cancers. Other studies indicate that black women do not receive the same quality of treatment for breast cancer, and it has been estimated that up to approximately 20% of the mortality difference between black women and white women could be eliminated if both populations received the same treatments. It has also been reported that a smaller percentage of black women begin treatment within 30 days of diagnosis compared with white women.

Steps to Eliminate Disparities 2009, with an annual average of 173,970 cases in white women and 21,942 cases in black women. Black women had an incidence rate of 116.9 cases/100,000 cases/100,000 population, compared with 122.1/100,000 for white women (Fig. 1). However, cancer was more advanced at diagnosis in black women; 45% of cases in black women were at regional (37%) or distant (8%)

tion of advanced cancers and higher mortality rate among black women. Some studies indicate lower mammography use and longer intervals between screening mammograms in black women. Black women also have longer times to diagnosis after an abnormal mammogram compared with white women. Black women are more frequently found to have tumor

The authors concluded, “At the individual level, the maximal effectiveness of screening for breast cancer can only be achieved when all women have access to timely follow-up testing after abnormal breast cancer exams and state-of-the-art treatment. More research is needed to determine the best screening and treatment strategies for aggressive breast cancers.

Optimal health-care delivery can be strengthened through performancebased reimbursement, expanded use of information technology, and quality assurance-reporting protocols. More work also is needed to develop, evaluate, and disseminate additional interventions to decrease inequities in follow-up after an abnormal mammogram and receipt of treatment.” They note that the National Cancer Institute has recently funded a multisite program with the goal of supporting research to improve recruitment, screening, diagnosis, and referral to treatment for breast, colon, and cervical cancers. Additional information can be found at http://appliedresearch.cancer.gov/networks/prospr. n Reference 1. Centers for Disease Control and Prevention: Vital signs: Racial disparities in breast cancer severity—United States, 20052009. MMWR 61:922-926, 2012.

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Lab Notes

Ongoing Molecular Research in the Science of Oncology NOVEL MECHANISMS p53 Inactivation in the Tumor Microenvironment Promotes Tumor Progression via Immunosuppressive Lymphoid-like Stromal Network Inactivation of the tumor suppressor p53 through somatic mutations is observed in approximately half of cancers. The finding that p53 mutations sometimes occur in tumor-associated fibroblasts and are correlated with an increased rate of metastases and poor prognosis suggests that p53 dysfunction in the tumor microenvironment promotes tumor establishment and progression. In studying the potential role of p53 inactivation in the tumor microenvironment, Guo and colleagues compared the growth of subcutaneously inoculated B16F1 melanoma in p53-null and wildtype mice. Tumor growth was markedly accelerated in p53-null mice and was correlated with marked increases in CD11b +Gr-1 + myeloid-derived suppressor cells, FoxP3 + regulatory T cells, and loss of effector function compared with wild-type mice. The increased immunotolerance of the tumor microenvironment was associated with marked expansion of a specialized stromal network in the tumor and spleen. These stromal cells expressed markers of fibroblastic reticular cells of lymphoid organs and were readily expanded in culture from p53-null but not wild-type mice. The cells produced high levels of inflammatory cytokines/chemokines and immunosuppressive molecules that enhanced myeloidderived suppressor cell differentiation; further, the cells significantly accelerated tumor progression in wild-type mice when injected along with B16F1. The investigators concluded, “Together, our results show that tumorstroma interaction in hosts with dysfunctional p53 exacerbates immunosuppression by expanding the lymphoid-like stromal network that enhances [myeloid-derived suppressor cell] differentiation and tumor progression.”

Guo G, Marrero L, Rodriguez P, et al: Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoidlike stromal network. Cancer Res 73:16681675, 2013.

TARGETED THERAPY Effects of siRNA Combining TGF-β1 Silencing and RIG-I Activation in Pancreas Cancer

Dysregulation of TGF-β signaling promotes tumor growth, invasion, metastasis, and a potent immunosuppressive network in pancreas cancer. A strategy for disrupting the continued on page 108

Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer. References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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Lab Notes

Ongoing Molecular Research continued from page 107

tumor-promoting pathway is the silencing of TGF-β by use of smallinterfering (si) RNA. Ellermeier and colleagues found that the introduction of a triphosphate group at the 5′ end of siRNA (ppp-siRNA) allowed gene silencing to be combined with immune activation via the cytosolic helicase retinoic acid-inducible gene I (RIG-I), a ubiquitously expressed receptor that recognizes viral RNA. The investigators validated RIG-I as a therapeutic target by showing that its activation in pancreatic carcinoma cells induced interferon regulatory transcription factor-3 phosphorylation, production of type I interferon, production of chemokine CXCL10, and caspase-9–mediated tumor cell apoptosis. They then generated a bifunctional ppp-siRNA that combined RIG-I activation with gene silencing of TGF-β1 (ppp-TGF-β) and assessed its effects in the orthotopic Panc02 mouse model of pancreatic cancer. Injection of ppp-TGF-β resulted in reduced systemic and tumor-associated TGF-β levels, high levels of type I interferon and CXCL10 in serum and tumor tissue, increased systemic immune cell activation, and marked tumor cell apoptosis in vivo. Treatment with pppTGF-β in mice with established tumors significantly prolonged survival compared with ppp-RNA or TGF-β siRNA treatment alone. Recruitment of activated CD8+ T cells to the tumor was observed along with a reduced fre-

quency of CD11b+ Gr-1+ myeloid cells, with therapeutic efficacy being dependent on levels of CD8+ T cells. The investigators concluded, “[C] ombining TGF-β gene silencing with RIG-I signaling confers potent antitumor efficacy against pancreatic cancer by breaking tumor-induced CD8+ T cell suppression.” Ellermeier J, Wei J, Duewell P, et al: Therapeutic efficacy of bifunctional siRNA combining TGF-β1 silencing with RIG-I activation in pancreatic cancer. Cancer Res 73:1709-1720, 2013.

Mixed-lineage Kinase 4 Interacts with Activated RAS Signaling in Colorectal Cancer Colorectal cancer that is microsatellite stable but chromosomally unstable is characterized by poor prognosis and remains largely intractable at the metastatic stage. Mutational analysis has shown that the mixed lineage kinase 4 (MLK4) protein kinase is frequently mutated in microsatellite-stable colorectal cancer, with approximately 50% of the mutations occurring in KRAS- or BRAF-mutant tumors. This kinase has not been characterized, and the potential role of MLK4 somatic mutations in oncogenesis has not been established. Martini and colleagues recently reported that MLK4-mutated alleles in colorectal cancer are constitutively active and increase the transformation and tumorigenic capacity of RAS-mutated cell lines.

Gene expression silencing and targeted knockout of MLK4 impaired the oncogenic activity of KRAS- and BRAF-mutant cancer cells both in vitro and in xenograft models. MLK4 was found to directly phosphorylate MEK1 (MAP2K1), with MEK/ERK (MAPK1) signaling being impaired in the MLK4 knockout cells. The investigators concluded, “These findings suggest that MLK4 inhibitors may be efficacious in KRAS- and BRAF-mutated [colorectal cancers] and may provide a new opportunity for targeting such recalcitrant tumors.” Martini M, Russo M, Lamba S, et al: Mixed lineage kinase MLK4 is activated in colorectal cancers where it synergistically cooperates with activated RAS signaling in driving tumorigenesis. Cancer Res 73:1912-1921, 2013.

BIOMARKERS Three-marker Assay for Early Detection of Renal Cancer Early detection of renal cell carcinoma using biomarkers remains challenging. Kim and colleagues recently evaluated a three-marker assay consisting of nicotinamide N-methyltransferase (NNMT), L-plastin (LCP1), and nonmetastatic cells 1 protein (NM23A). After validation of the three-marker assay in patients with renal cell carcinoma and control subjects, a scoring method based on the cut-point of

each of the three markers was used to evaluate the diagnostic performance of the marker combination. Plasma levels of NNMT, LCP1, and NM23A were highly elevated in patients with renal cell carcinoma (P < .0001). In 289 blind sample tests with 175 control subjects and 114 patients with kidney cancer, the diagnostic accuracies of NNMT alone and the three-marker assay were 0.913 and 0.932, respectively. When 90% specificity was defined, the sensitivities of NNMT and the three-marker assay were 71.9% and 95.7%, respectively. The three-marker assay had a positive predictive value of 87.2% and a negative predictive value of 97%. The investigators concluded, “The composite assay with NNMT, LCP1, and NM23A [is] a promising novel serum marker assay for the early detection of malignant kidney tumors covering subtypes of [renal cell carcinoma] with high diagnostic characteristics. NNMT/LCP1/NM23A triple markers could be a helpful screening assay to detect early [renal cell carcinoma].” n Kim DS, Choi YD, Moon M, et al: Composite three-marker assay for early detection of kidney cancer. Cancer Epidemiol Biomarkers Prev 22:390-398, 2013. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

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2013 Oncology Meetings April International Society for Extracellular Vesicles 2013 Conference April 17-20 • Boston, MA For more information: www.isevmeeting.org IV Latin American Symposium of Gastroenterology Oncology April 17-20 • Vina del Mar, Chile For more information: www.slago.com 3rd ITLT Essen 2013 Interdisciplinary Treatment of Liver Tumors April 18-20 • Essen, Germany For more information: www.itlt.org The Arizona Clinical Oncology Society Spring Membership Conference April 19 • Phoenix, Arizona For more information: www.tacos-oncology.com/ Ultrasound in the New Millennium: The Cancer Patient April 19-20 • Houston, Texas For more information: www.mdanderson.org/conferences 7th Conference on Experimental and Translational Oncology April 20-24 • Portoroz, Slovenia For more information: www.ceto.si Highlights of ASH® in Latin America April 25-26 • Santiago, Chile For more information: www.hematology.org/meetings

May 2013 Annual Paris Melanoma Conference May 2-3 • Paris, France For more information: www.primeoncology.org/ parismelanoma2013 5th IMPAKT Breast Cancer Conference May 2-4 • Brussels, Belgium For more information: www.esmo.org

Precision Medicines in Breast Cancer May 9-10 • London, United Kingdom For more information: www.precisionmedicines.com European Multidisciplinary Conference in Thoracic Oncology May 9-11 • Lugano, Switzerland For more information: www.esmo.org The Psychological Impact of Cancer for Patients, Carers, and Families May 15 • Milton Keynes, United Kingdom For more information: www8.open.ac.uk/health-and-socialcare/main/research/research-events/ psychological-impact-of-cancer Iowa Oncology Society Spring Membership Conference May 17-18 • West Des Moines, Iowa For more information: www.ios-iowa.com

The Bone Marrow Niche, Stem Cells, and Leukemia: Impact of Drugs, Chemicals, and the Environment May 29-31 • New York, New York For more information: www.nyas.org/bonemarrow

3rd International Symposium on Lung-Sparing Therapies for Malignant Pleural Mesothelioma May 18, 2013 • Santa Monica, California For more information: www.cme.ucla.edu/courses/ 5th Symposium on Cancer Metastasis and the Lymphovascular System and the 8th International Sentinel Node Society Congress May 27-29, 2013 • San Francisco, California For more information: www.sn-cancermets.org Targeting Cancer Drug Resistance May 28-30 • Chicago, Illinois For more information: www.cancer-drugresistance.com

Breast Cancer Conference– Triple Negative Breast Cancer June 26-28 • London, United Kingdom For more information: www.breakthroughconference.org.uk

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

MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes.com

July WIN 2013 Symposium: Personalized Cancer Therapy: From Innovation

California Breast Cancer Research Symposium: From Research to Action: Two Decades of Change May 17-18 • Costa Mesa, California For more information: www.cabreastcancer.org/ symposium/ State of the Art Techniques Symposium May 17-19 • San Antonio, Texas For more information: www.astro.org/ stateofthearttechniques

2nd International Breakthrough

to Implementation July 10-12 • Paris, France For more information: www.winsymposium.org 12th International Congress on the

June Molecular and Translational Oncology Workshop June 14-18 • Fort Myers, Florida For more information: www.cancereducationconsortium. org/programs_mtow.html 12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch British Gynaecological Cancer Society Annual Scientific Meeting June 20-21 • Belfast, Ireland For more information: bgcsconference.com 6th International Nasopharyngeal Carcinoma Symposium June 20-22 • Istanbul, Turkey For more information: www.npc2013.org

Future of Breast Cancer July 18-20 • Huntington Beach, California For more information: www.gotoper.com/conferences 14th International Lung Cancer Congress July 25-27 • Huntington Beach, California For more information: www.gotoper.com/conferences Up Close and Personalized: The 2nd International Congress on Personalized Medicine July 25-28 • Paris, France For more information: www.upcp.org Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences

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2013 Oncology Meetings August Best of ASCO® Chicago August 9-10 • Chicago, Illinois For more information: boa.asco.org Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org 11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

September SGI Summit Turkey 2013: Innovations in Obstetrics and Gynecology September 6-8 • Istanbul, Turkey For more information: www.sgiturkey2013.org/ Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org

ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13 Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences

Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu 28th Annual Offering of Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: from Bench to Bedside to Biomarkers September 30-October 3 • Boston, Massachusetts For more information: steelelab.mgh.harvard.edu/ tumorcourse/

18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 10th International Conference of the Society for Integrative Oncology: Translational Science in Integrative Oncology October 20-22, 2013 • Vancouver, British Columbia For more information: www.integrativeonc.org

The 2nd International Multidisciplinary Forum on Palliative Care (IMFPC 2013) October 3-6 • Sofia, Bulgaria For more information: www.imfpc.org

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

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

51st Annual Meeting of the Japan Society of Clinical Oncology October 24-26 • Kyoto, Japan For more information: www2.convention.co.jp/jsco2013/

9th International Symposium on Hodgkin Lymphoma October 12-15, 2013 • Cologne, Germany For more information: www.hodgkinsymposium.org/

15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in

EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de 9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/ International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw

October

International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/About+ASCO/ International+Affairs/International+Cli nical+Trials+Workshops

Multidisciplinary Symposium on Head and Neck Cancer November 2 • Chicago, Illinois For more information: www.gotoper.com/conferences

Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

11th Annual School of Breast Oncology November 7-10 • Atlanta, Georgia For more information: www.gotoper.com/conferences Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro New York Lung Cancer Symposium November 9 • New York, New York For more information: www.gotoper.com/conferences African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information: www.aortic2013.org

December

November

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

Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org

36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org

INDICATION: Iclusig™ (ponatinib) is a kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Introducing Iclusig™ (ponatinib) Unlock efficacy for resistant or intolerant CML and Ph+ ALL patients IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY See full prescribing information for complete boxed warning • Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. • Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity. Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, has occurred in Iclusig-treated patients. Overall, 11% of patients experienced an arterial thrombosis event of any grade, and serious arterial thrombosis occurred in 8% of Iclusigtreated patients. 30 of 34 patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors. Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. Hepatotoxicity: Hepatotoxicity that has resulted in liver failure and death occurred in 3 Iclusig-treated patients with BP-CML or Ph+ ALL. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver

function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated. Congestive Heart Failure: Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure (CHF) or left ventricular dysfunction (LVD), with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of CHF or LVD. Monitor patients for signs or symptoms consistent with CHF and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious CHF. Hypertension: Eight patients treated with Iclusig (2%) experienced treatmentemergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations. Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Hemorrhage: Serious bleeding events occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients.

C H R O N I C P H A S E C M L (C P - C M L )

More than half of CP-CML patients resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy achieved MCyR.

(144/267) 95% CI: 48-60

MCyR

% (118/267)

CCyR 95% CI: 38-50 Most patients who achieved MCyR also achieved CCyR.

Median duration of follow-up was 10 months.1

Response rates in CP-CML patients by number of prior TKIs.1

1 prior TKI

75%

MCyR

(12/16) (95% CI: 48-93)

Iclusig is an oral medication taken once daily with or without food.

2 prior TKIs

MCyR

(63/98) (95% CI: 54-74)

≥3 prior TKIs

45%

MCyR

(69/153) (95% CI: 37-53)

Learn more about Iclusig efficacy in the T315I mutation and in all phases of resistant or intolerant CML and Ph+ ALL at Iclusig.com.

Iclusig was evaluated in a single-arm, open-label, international, multicenter trial. All patients were administered 45 mg of Iclusig once daily. Patients were assigned to one of six cohorts based on disease phase (chronic phase CML [CP-CML]; accelerated phase CML [AP-CML]; or blast phase CML [BP-CML]/Ph+ ALL), resistance or intolerance (R/I) to prior TKI therapy, and the presence of the T315I mutation. The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR).

The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage. Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated. Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended. Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy. Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig. The most common non-hematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia. Please see the brief summary of the Prescribing Information on the following pages, including the Boxed Warning. Note: Unless otherwise indicated, data presented are from Iclusig [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2012. Reference: 1. Data on file.

BRIEF SUMMARY BRIEF SUMMARY Iclusig (ponatinib) Iclusig (ponatinib) Rx only Rx only Please consult full Prescribing Information, including Boxed Warning, Please consult full Prescribing Information, including Boxed Warning, available at Iclusig.com. available at Iclusig.com.

WARNING: ARTERIAL THROMBOSIS and and HEPATOTOXICITY WARNING: ARTERIAL THROMBOSIS HEPATOTOXICITY Arterial Thrombosis: Arterial Thrombosis: • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and and Administration (2.3)(2.3) and and Warnings and and Precautions (5.1)]. events [see Dosage Administration Warnings Precautions (5.1)]. Hepatotoxicity: Hepatotoxicity: • Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor • Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity [see Dosage and Administration (2.3)(2.3) and Warnings and and Iclusig for hepatotoxicity [see Dosage and Administration and Warnings Precautions (5.2)]. Precautions (5.2)]. 1

1 INDICATIONS INDICATIONS ANDAND USAGE USAGE ™ ™ Iclusig Iclusig (ponatinib) (ponatinib) is indicated is indicated for the fortreatment the treatment of adult of adult patients patients with with chronic chronic phase, phase, accelerated accelerated phase, phase, or blast or blast phase phase chronic chronic myeloid myeloid leukemia leukemia (CML) (CML) that that is resistant is resistant or intolerant or intolerant to prior to prior tyrosine tyrosine kinase kinase inhibitor inhibitor therapy therapy or Philadelphia or Philadelphia chromosome chromosome positive positive acuteacute lymphoblastic lymphoblastic leukemia leukemia (Ph+(Ph+ ALL)ALL) that that is resistant is resistant or intolerant or intolerant to prior to prior tyrosine tyrosine kinase kinase inhibitor inhibitor therapy. therapy.

This This indication indication is based is based uponupon response response rate rate [see [see Clinical Clinical Studies Studies (14)].(14)]. ThereThere are no aretrials no trials verifying verifying an improvement an improvement in disease-related in disease-related symptoms symptoms or increased or increased survival survival with with Iclusig. Iclusig. 4

4 CONTRAINDICATIONS CONTRAINDICATIONS NoneNone

5 WARNINGS WARNINGS ANDAND PRECAUTIONS PRECAUTIONS

5.1 5.1 Thrombosis and Thromboembolism Thrombosis and Thromboembolism

required required urgent urgent clinical clinical intervention intervention for hypertension for hypertension associated associated with with confusion, confusion, headache, headache, chestchest pain,pain, or shortness or shortness of breath. of breath. Treatment-emergent Treatment-emergent hypertension hypertension occurred occurred in 67% in 67% of patients of patients (300/449) (300/449) [see [see Adverse Adverse Reactions Reactions (6)]. In (6)]. patients In patients with with baseline baseline systolic systolic BP<140 BP<140 mm mm Hg and Hg baseline and baseline diastolic diastolic BP<90mm BP<90mm Hg, 78% Hg, 78% (220/282) (220/282) experienced experienced treatment-emergent treatment-emergent hypertension; hypertension; 49%49% (139/282) (139/282) developed developed StageStage 1 hypertension 1 hypertension (defined (defined as systolic as systolic BP≥140 BP≥140 mm mm Hg orHgdiastolic or diastolic BP≥90 BP≥90 mm mm Hg) while Hg) while 29%29% developed developed StageStage 2 hypertension 2 hypertension (defined (defined as systolic as systolic BP≥160 BP≥160 mm mm Hg orHgdiastolic or diastolic BP≥100 BP≥100 mm Hg). mm Hg). In 131 In patients 131 patients with with StageStage 1 hypertension 1 hypertension at baseline, at baseline, 61%61% (80/131) (80/131) developed developed StageStage 2 hypertension. 2 hypertension. Monitor Monitor and manage and manage bloodblood pressure pressure elevations. elevations. 5.5 5.5 P ancreatitis P ancreatitis Clinical Clinical pancreatitis pancreatitis occurred occurred in 6%in (28/449) 6% (28/449) of patients of patients (5% (5% gradegrade 3) treated 3) treated with with Iclusig. Iclusig. Pancreatitis Pancreatitis resulted resulted in discontinuation in discontinuation or treatment or treatment interruption interruption in 6%in of 6%patients of patients (25/449). (25/449). Twenty-two Twenty-two of theof28 thecases 28 cases of pancreatitis of pancreatitis resolved resolved within within 2 weeks 2 weeks with with dosedose interruption interruption or or reduction. reduction. The incidence The incidence of treatment-emergent of treatment-emergent lipase lipase elevation elevation was was 41%.41%. Check Check serum serum lipase lipase everyevery 2 weeks 2 weeks for the forfirst the first 2 months 2 months and then and then monthly monthly thereafter thereafter or asor as clinically clinically indicated. indicated. Consider Consider additional additional serum serum lipase lipase monitoring monitoring in patients in patients with with a history a history of of pancreatitis pancreatitis or alcohol or alcohol abuse. abuse. DoseDose interruption interruption or reduction or reduction may may be required. be required. In cases In cases where where lipase lipase elevations elevations are accompanied are accompanied by abdominal by abdominal symptoms, symptoms, interrupt interrupt treatment treatment with with Iclusig Iclusig and evaluate and evaluate patients patients for pancreatitis for pancreatitis [see [see Dosage Dosage and Administration and Administration (2.3)].(2.3)]. Do not Doconsider not consider restarting restarting Iclusig Iclusig until until patients patients havehave complete complete resolution resolution of symptoms of symptoms and lipase and lipase levelslevels are less are less thanthan 1.5 x1.5 ULN. x ULN. 5.6 5.6 Hemorrhage Hemorrhage Serious Serious bleeding bleeding events, events, occurred occurred in 5%in (22/449) 5% (22/449) of patients of patients treated treated with with Iclusig, Iclusig, including including fatalities. fatalities. Hemorrhagic Hemorrhagic events events occurred occurred in 24% in 24% of patients. of patients. The incidence The incidence of serious of serious bleeding bleeding events events was was higher higher in patients in patients with with AP-CML, AP-CML, BP-CML, BP-CML, and Ph+ and Ph+ ALL.ALL. Cerebral Cerebral hemorrhage hemorrhage and gastrointestinal and gastrointestinal hemorrhage hemorrhage werewere the most the most commonly commonly reported reported serious serious bleeding bleeding events. events. MostMost hemorrhagic hemorrhagic events events occurred occurred in patients in patients with with gradegrade 4 thrombocytopenia 4 thrombocytopenia [see [see Warnings Warnings and Precautions and Precautions (5.9)].(5.9)]. Interrupt Interrupt Iclusig Iclusig for serious for serious or severe or severe hemorrhage hemorrhage [see [see Dosage Dosage and and Administration Administration (2.3)].(2.3)]. 5.7 5.7 Fluid Retention Fluid Retention FluidFluid retention retention events events judged judged as serious as serious occurred occurred in 3%in (13/449) 3% (13/449) of patients of patients treated treated with with Iclusig. Iclusig. One One instance instance of brain of brain edema edema was was fatal.fatal. Serious Serious fluid fluid retention retention events events in more in more thanthan 1 patient 1 patient included: included: pericardial pericardial effusion effusion (6/449, (6/449, 1%), 1%), pleural pleural effusion effusion (5/449, (5/449, 1%), 1%), and ascites and ascites (2/449, (2/449, <1%). <1%).

Arterial Arterial Thrombosis Thrombosis

In total, In total, fluid fluid retention retention occurred occurred in 23% in 23% of theofpatients. the patients. The most The most common common fluid fluid retention retention events events werewere peripheral peripheral edema edema (16%), (16%), pleural pleural effusion effusion (7%),(7%), and pericardial and pericardial effusion effusion (3%).(3%).

Cardiovascular, Cardiovascular, cerebrovascular, cerebrovascular, and peripheral and peripheral vascular vascular thrombosis, thrombosis, including including fatalfatal myocardial myocardial infarction infarction and stroke and stroke havehave occurred occurred in Iclusig-treated in Iclusig-treated patients. patients.

Monitor Monitor patients patients for fluid for fluid retention retention and manage and manage patients patients as clinically as clinically indicated. indicated. Interrupt, Interrupt, reduce, reduce, or discontinue or discontinue Iclusig Iclusig as clinically as clinically indicated indicated [see [see Dosage Dosage and Administration and Administration (2.3)].(2.3)].

C ardiac Arrhythmias C ardiac Arrhythmias Serious Serious arterial arterial thrombosis thrombosis occurred occurred in 8%in(34/449) 8% (34/449) of Iclusig-treated of Iclusig-treated patients. patients. Twenty-one Twenty-one patients patients 5.8 5.8 required required a revascularization a revascularization procedure procedure (16 patients (16 patients with with coronary coronary revascularization, revascularization, 4 patients 4 patients Symptomatic Symptomatic bradyarrhythmias bradyarrhythmias that that led toleda requirement to a requirement for pacemaker for pacemaker implantation implantation occurred occurred with with peripheral peripheral arterial arterial revascularization, revascularization, and 1and patient 1 patient with with cerebrovascular cerebrovascular revascularization). revascularization). in 3 (1%) in 3 (1%) Iclusig-treated Iclusig-treated patients. patients. The cardiac The cardiac rhythms rhythms (1 case (1 case each)each) identified identified werewere complete complete Overall, Overall, fifty-one fifty-one patients patients (11%)(11%) experienced experienced an arterial an arterial thrombosis thrombosis eventevent of any of grade. any grade. heartheart block, block, sick sick sinussinus syndrome, syndrome, and atrial and atrial fibrillation fibrillation with with bradycardia bradycardia and pauses. and pauses. Advise Advise patients patients to report to report signssigns and symptoms and symptoms suggestive suggestive of slow of slow heartheart rate rate (fainting, (fainting, dizziness, dizziness, or or Myocardial Myocardial infarction infarction or worsening or worsening coronary coronary artery artery disease disease was was the most the most common common arterial arterial chestchest pain).pain). thrombosis thrombosis eventevent and occurred and occurred in 21inpatients 21 patients (5%)(5%) of Iclusig-treated of Iclusig-treated patients. patients. Eleven Eleven of of thesethese patients patients developed developed congestive congestive heartheart failure failure concurrent concurrent or subsequent or subsequent to thetomyocardial the myocardial Supraventricular Supraventricular tachyarrhythmias tachyarrhythmias occurred occurred in 25in(5%) 25 (5%) Iclusig-treated Iclusig-treated patients. patients. AtrialAtrial fibrillation fibrillation ischemic ischemic event. event. was was the most the most common common supraventricular supraventricular tachyarrhythmia tachyarrhythmia and occurred and occurred in 20inpatients. 20 patients. The other The other supraventricular supraventricular tachyarrhythmias tachyarrhythmias werewere atrialatrial flutter flutter (4 patients), (4 patients), supraventricular supraventricular tachycardia tachycardia Serious Serious cerebrovascular cerebrovascular events events werewere reported reported in 2%in (8/449) 2% (8/449) of Iclusig-treated of Iclusig-treated patients. patients. Two Two (4 patients), (4 patients), and atrial and atrial tachycardia tachycardia (1 patient). (1 patient). For 13 Forpatients, 13 patients, the event the event led toledhospitalization. to hospitalization. patients patients experienced experienced hemorrhagic hemorrhagic conversion conversion of theofinitial the initial ischemic ischemic event. event. FourFour patients patients developed developed Advise Advise patients patients to report to report signssigns and symptoms and symptoms of rapid of rapid heartheart rate rate (palpitations, (palpitations, dizziness). dizziness). stenosis stenosis of large of large arterial arterial vessels vessels of theofbrain the brain (e.g.,(e.g., carotid, carotid, vertebral, vertebral, middle middle cerebral cerebral artery). artery). M yelosuppression M yelosuppression Serious Serious peripheral peripheral arterial arterial events events werewere reported reported in 2%in (7/449) 2% (7/449) of Iclusig-treated of Iclusig-treated patients. patients. ThreeThree 5.9 5.9 patients patients developed developed digital digital or distal or distal extremity extremity necrosis; necrosis; 2 of 2these of these patients patients had diabetes had diabetes mellitus mellitus Severe Severe (grade (grade 3 or 4) 3 or myelosuppression 4) myelosuppression occurred occurred in 48% in 48% (215/449) (215/449) of patients of patients treated treated with with Iclusig. Iclusig. and peripheral and peripheral arterial arterial disease disease and required and required amputations. amputations. The incidence The incidence of these of these events events was was greater greater in patients in patients with with accelerated accelerated phase phase CMLCML (AP-CML), (AP-CML), blastblast phase phase CMLCML (BP-CML) (BP-CML) and Ph+ and Ph+ ALL ALL thanthan in patients in patients with with chronic chronic phase phase CMLCML (CP-CML). (CP-CML). Thirty Thirty of 34ofIclusig-treated 34 Iclusig-treated patients patients who who experienced experienced a serious a serious arterial arterial thrombosis thrombosis eventevent had had Obtain Obtain complete complete blood blood counts counts every every 2 weeks 2 weeks for the for first the first 3 months 3 months and then and then monthly monthly or asor as one or onemore or more cardiovascular cardiovascular risk factors risk factors (e.g.,(e.g., myocardial myocardial infarction, infarction, coronary coronary artery artery disease, disease, clinically clinically indicated, indicated, and adjust and adjust the dose the dose as recommended as recommended [see [see Dosage Dosage and Administration and Administration (2.2)].(2.2)]. angina, angina, stroke, stroke, transient transient ischemic ischemic attack, attack, hypertension, hypertension, diabetes diabetes mellitus, mellitus, hyperlipidemia, hyperlipidemia, and and smoking). smoking). Patients Patients with with cardiovascular cardiovascular risk factors risk factors are atareincreased at increased risk for riskarterial for arterial thrombosis thrombosis 5.10 5.10 Tumor Lysis Syndrome Tumor Lysis Syndrome with with Iclusig. Iclusig. Interrupt Interrupt and consider and consider discontinuation discontinuation of Iclusig of Iclusig in patients in patients who who develop develop arterial arterial Two Two patients patients (<1%) (<1%) treated treated with with Iclusig Iclusig developed developed serious serious tumor tumor lysislysis syndrome. syndrome. BothBoth cases cases thrombotic thrombotic events events [see [see Dosage Dosage and Administration and Administration (2.3)].(2.3)]. occurred occurred in patients in patients with with advanced advanced CML.CML. Hyperuricemia Hyperuricemia occurred occurred in 7%in (30/449) 7% (30/449) of patients, of patients, Venous Venous Thromboembolism Thromboembolism the majority the majority had chronic had chronic phase phase CMLCML (19 patients). (19 patients). Due Due to thetopotential the potential for tumor for tumor lysislysis syndrome syndrome in patients in patients with with advanced advanced disease disease (AP-CML, (AP-CML, BP-CML, BP-CML, or Ph+ or Ph+ ALL),ALL), ensure ensure adequate adequate hydration hydration Venous Venous thromboembolic thromboembolic events events occurred occurred in 3%in of 3%Iclusig-treated of Iclusig-treated patients, patients, including including deepdeep and treat and treat high high uric acid uric acid levelslevels priorprior to initiating to initiating therapy therapy with with Iclusig. Iclusig. venous venous thrombosis thrombosis (9 patients), (9 patients), pulmonary pulmonary embolism embolism (4 patients), (4 patients), and 1and case 1 case eacheach of portal of portal vein vein thrombosis, thrombosis, and retinal and retinal vein vein thrombosis. thrombosis. Consider Consider dosedose modification modification or discontinuation or discontinuation of Iclusig of Iclusig5.11 5.11 Compromised Wound Healing and Gastrointestinal Perforation Compromised Wound Healing and Gastrointestinal Perforation in patients in patients who who develop develop serious serious venous venous thromboembolism thromboembolism [see [see Dosage Dosage and Administration and Administration (2.3)].(2.3)]. No formal No formal studies studies of theofeffect the effect of Iclusig of Iclusig on wound on wound healing healing havehave beenbeen conducted. conducted. Based Based on the on the 5.2 5.2 Hepatotoxicity Hepatotoxicity mechanism mechanism of action of action [see [see Clinical Clinical Pharmacology Pharmacology (12.1)], (12.1)], Iclusig Iclusig couldcould compromise compromise wound wound healing. healing. Serious Serious gastrointestinal gastrointestinal perforation perforation (fistula) (fistula) occurred occurred in one in patient one patient 38 days 38 days post-cholecystectomy. post-cholecystectomy. Hepatotoxicity Hepatotoxicity that that has resulted has resulted in liver in liver failure failure and death and death occurred occurred in Iclusig-treated in Iclusig-treated patients. patients. Fulminant Fulminant hepatic hepatic failure failure leading leading to death to death occurred occurred in aninIclusig-treated an Iclusig-treated patient patient within within one week one week of of Interrupt Interrupt Iclusig Iclusig for atforleast at least 1 week 1 week priorprior to major to major surgery. surgery. The decision The decision whenwhen to resume to resume Iclusig Iclusig starting starting Iclusig. Iclusig. Two Two additional additional fatalfatal cases cases of acute of acute liver liver failure failure also also occurred. occurred. The fatal The fatal cases cases afterafter surgery surgery should should be based be based on clinical on clinical judgment judgment of adequate of adequate wound wound healing. healing. occurred occurred in patients in patients with with BP-CML BP-CML or Ph+ or Ph+ ALL.ALL. Severe Severe hepatotoxicity hepatotoxicity occurred occurred in allindisease all disease cohorts. cohorts. 5.12 5.12 Embryo-Fetal Toxicity Embryo-Fetal Toxicity The incidence The incidence of aspartate of aspartate aminotransferase aminotransferase (AST)(AST) or alanine or alanine aminotransferase aminotransferase (ALT)(ALT) elevation elevation Iclusig Iclusig can cause can cause fetalfetal harmharm whenwhen administered administered to a pregnant to a pregnant woman woman based based on itsonmechanism its mechanism was was 56%56% (all grades) (all grades) and 8% and (grade 8% (grade 3 or 34).orIclusig 4). Iclusig treatment treatment may may resultresult in elevation in elevation in ALT, in ALT, of action of action and findings and findings in animals. in animals. Ponatinib Ponatinib caused caused embryo-fetal embryo-fetal toxicity toxicity in rats in rats at exposures at exposures AST,AST, or both. or both. ALT or ALTAST or AST elevation elevation was was not reversed not reversed by the bydate the date of last of follow-up last follow-up in 5%inof5% patients. of patients. lowerlower thanthan human human exposures exposures at theatrecommended the recommended human human dose.dose. If thisIf drug this drug is used is used during during Monitor Monitor liver liver function function teststests at baseline, at baseline, at least at least monthly monthly or asorclinically as clinically indicated. indicated. Interrupt, Interrupt, pregnancy, pregnancy, or if or theifpatient the patient becomes becomes pregnant pregnant whilewhile taking taking this drug, this drug, the patient the patient should should be be reduce reduce or discontinue or discontinue Iclusig Iclusig as clinically as clinically indicated indicated [see [see Dosage Dosage and Administration and Administration (2.3)].(2.3)]. apprised apprised of theofpotential the potential hazard hazard to thetofetus. the fetus. Advise Advise women women to avoid to avoid pregnancy pregnancy whilewhile taking taking Iclusig Iclusig [see [see Use in Use Specific in Specific Populations Populations (8.1)].(8.1)]. 5.3 5.3 Congestive Heart Failure Congestive Heart Failure Twenty Twenty patients patients treated treated with with Iclusig Iclusig (4%)(4%) experienced experienced serious serious congestive congestive heartheart failure failure or or left ventricular left ventricular dysfunction, dysfunction, with with 4 fatalities. 4 fatalities. Thirty-three Thirty-three patients patients treated treated with with Iclusig Iclusig (7%)(7%) experienced experienced any grade any grade of congestive of congestive heartheart failure failure or left orventricular left ventricular dysfunction. dysfunction. Monitor Monitor patients patients for signs for signs or symptoms or symptoms consistent consistent with with congestive congestive heartheart failure failure and treat and treat as clinically as clinically indicated, indicated, including including interruption interruption of Iclusig. of Iclusig. Consider Consider discontinuation discontinuation of Iclusig of Iclusig in patients in patients who who develop develop serious serious congestive congestive heartheart failure failure [see [see Dosage Dosage and Administration and Administration (2.3)].(2.3)]. 5.4 5.4 Hypertension Hypertension EightEight patients patients treated treated with with Iclusig Iclusig (2%)(2%) experienced experienced treatment-emergent treatment-emergent symptomatic symptomatic hypertension hypertension as a as serious a serious adverse adverse reaction, reaction, including including hypertensive hypertensive crisis. crisis. These These patients patients

6 6 ADVERSE REACTIONS ADVERSE REACTIONS Because Because clinical clinical trialstrials are conducted are conducted underunder widely widely varying varying conditions, conditions, adverse adverse reaction reaction ratesrates observed observed in theinclinical the clinical trialstrials of a drug of a drug cannot cannot be directly be directly compared compared with with ratesrates in theinclinical the clinical trialstrials of another of another drugdrug and may and may not reflect not reflect the rates the rates observed observed in clinical in clinical practice. practice. The following The following adverse adverse reactions reactions are discussed are discussed in greater in greater detaildetail in other in other sections sections of theof the prescribing prescribing information: information: • Thrombosis • Thrombosis and Thromboembolism and Thromboembolism [see [see Warnings Warnings and Precautions and Precautions (5.1)](5.1)] • Hepatotoxicity • Hepatotoxicity [see [see Warnings Warnings and Precautions and Precautions (5.2)(5.2) and Dosage and Dosage and Administration and Administration (2.3)](2.3)] • Congestive • Congestive HeartHeart Failure Failure [see [see Warnings Warnings and Precautions and Precautions (5.3)](5.3)]

• Hypertension [see [see Warnings and Precautions (5.4)](5.4)] • Hypertension Warnings and Precautions Adverse Adverse drug reactions, drug reactions, reported reported using using MedDRA MedDRA and graded and graded using using NCI-CTC-AE NCI-CTC-AE v 4.0 (NCI v 4.0Common (NCI Common Terminology Terminology Criteria Criteria for for Adverse Adverse Events) Events) for assessment for assessment of toxicity. of toxicity. • Pancreatitis [see [see Dosage and Administration (2.3)(2.3) and Warnings and Precautions (5.5)](5.5)] • Pancreatitis Dosage and Administration and Warnings and Precautions • Hemorrhage [see [see Warnings and Precautions (5.6)](5.6)] • Hemorrhage Warnings and Precautions Treatment-emergent, Treatment-emergent, all causality all causality eventsevents • Fluid Retention [see [see Warnings and Precautions (5.7)](5.7)] • Fluid Retention Warnings and Precautions (a) derived (a) derived from blood from blood pressure pressure (BP) measurement (BP) measurement recorded recorded monthly monthly while while on trialon trial • Cardiac Arrhythmias [see [see Warnings and Precautions (5.8)](5.8)] • Cardiac Arrhythmias Warnings and Precautions (b) includes (b) includes cardiac, cardiac, centralcentral nervous nervous system, system, and peripheral and peripheral arterial arterial ischemia ischemia • Myelosuppression [see [see Dosage and Administration (2.2)(2.2) and Warnings and Precautions (5.9)](5.9)] (c) includes • Myelosuppression Dosage and Administration and Warnings and Precautions (c) includes cardiac cardiac failure,failure, cardiac cardiac failurefailure congestive, congestive, cardiogenic cardiogenic shock,shock, cardiopulmonary cardiopulmonary failure,failure, ejection ejection fraction fraction decreased, decreased, pulmonary pulmonary edema, edema, right ventricular right ventricular failurefailure The adverse reactions described in this werewere identified in a single-arm, open-label, The adverse reactions described in section this section identified in a single-arm, open-label, (d) includes (d) includes abdominal abdominal pain, abdominal pain, abdominal pain upper, pain upper, abdominal abdominal pain lower, pain lower, abdominal abdominal discomfort discomfort international, multicenter trial trial in 449 patients with with CMLCML or Ph+ ALL ALL whose disease was was international, multicenter in 449 patients or Ph+ whose disease (e) includes aphthous aphthous stomatitis, stomatitis, lip blister, lip blister, mouthmouth ulceration, ulceration, oral mucosal oral mucosal eruption, eruption, oral pain, oral oropharyngeal pain, oropharyngeal pain, pharyngeal pain, pharyngeal considered to betoresistant or intolerant to prior tyrosine kinase inhibitor (TKI)(TKI) therapy including considered be resistant or intolerant to prior tyrosine kinase inhibitor therapy including(e) includes ulceration, stomatitis, stomatitis, tonguetongue ulceration ulceration thosethose with with the BCR-ABL T315IT315I mutation. All patients received a starting dosedose of 45ofmg the BCR-ABL mutation. All patients received a starting 45Iclusig mg Iclusig ulceration, (f) includes gastricgastric hemorrhage, hemorrhage, gastricgastric ulcer hemorrhage, ulcer hemorrhage, hemorrhagic hemorrhagic gastritis, gastritis, gastrointestinal gastrointestinal hemorrhage, hemorrhage, hematemesis, hematemesis, onceonce daily.daily. At the of analysis, the median duration of treatment with with Iclusig was was 337 337 daysdays(f) includes Attime the time of analysis, the median duration of treatment Iclusig hematochezia, hemorrhoidal hemorrhoidal hemorrhage, hemorrhage, intra-abdominal intra-abdominal hemorrhage, hemorrhage, melena, melena, rectalrectal hemorrhage, hemorrhage, and upper and upper gastrointestinal gastrointestinal in patients with with CP-CML, 362 362 daysdays in patients with with AP-CML, 89 days in patients with with BP-CML, in patients CP-CML, in patients AP-CML, 89 days in patients BP-CML, hematochezia, hemorrhage hemorrhage and 81 in patients with with Ph+ Ph+ ALL.ALL. The median dosedose intensity was was 37 mg, of theof the anddays 81 days in patients The median intensity 37 or mg,83%, or 83%, (g) includes (g) includes burning burning sensation, sensation, hyperesthesia, hyperesthesia, hypoesthesia, hypoesthesia, neuralgia, neuralgia, neuropathy neuropathy peripheral, peripheral, paresthesia, paresthesia, peripheral peripheral expected 45 mg expected 45dose. mg dose. sensorimotor sensorimotor neuropathy, neuropathy, polyneuropathy polyneuropathy

Adverse reactions reported in more thanthan 10%10% of allofpatients treated with with Iclusig in this are are Adverse reactions reported in more all patients treated Iclusig in trial this trial presented in Table 4. Overall, the most common non-hematologic adverse reactions (≥ 20%) presented in Table 4. Overall, the most common non-hematologic adverse reactions (≥ 20%) Table 5: Serious Adverse Reactions (SAR) Table 5: Serious Adverse Reactions (SAR) werewere hypertension, rash,rash, abdominal pain,pain, fatigue, headache, dry skin, constipation, arthralgia, hypertension, abdominal fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. nausea, and pyrexia. Cardiovascular disorders Cardiovascular disorders Arterial Arterial ischemic ischemic eventevent The rates of treatment-emergent adverse events resulting in discontinuation werewere 13%13% in CPThe rates of treatment-emergent adverse events resulting in discontinuation in CPMyocardial Myocardial infarction infarction or worsening or worsening coronary coronary arteryartery disease disease CML,CML, 11% 11% in AP-CML, 15%15% in BP-CML, and 9% Ph+ ALL.ALL. The most common adverse events in AP-CML, in BP-CML, and in9% in Ph+ The most common adverse events Stroke Stroke or TIAor TIA that that led toledtreatment discontinuation werewere thrombocytopenia (4%)(4%) and infections (1%).(1%). to treatment discontinuation thrombocytopenia and infections Peripheral Peripheral arterial arterial disease disease DoseDose modifications (dose(dose delays or dose reduction) due to reactions occurred in 74% of of modifications delays or dose reduction) dueadverse to adverse reactions occurred in 74% the patients. The most common adverse reactions (≥5%) that that led toleddose modifications include the patients. The most common adverse reactions (≥5%) to dose modifications include thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), rashrash (11%), abdominal pain pain thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), (11%), abdominal (11%), pancreatitis (6%),(6%), and ALT, AST,AST, or GGT increased (6%).(6%). (11%), pancreatitis and ALT, or GGT increased Table 4: Adverse Reactions Occurring in >10% of Patients, Any Group Table 4: Adverse Reactions Occurring in >10% of Patients, Any Group CP-CML CP-CML AP-CML AP-CML BP-CML BP-CML Ph+ ALL Ph+ ALL (N=270) (N=270) (N=85) (N=85) (N=62) (N=62) (N=32) (N=32) System Organ Class System Organ Class Any Any CTCAE CTCAE Any Any CTCAE CTCAE Any Any CTCAE CTCAE Any Any CTCAE CTCAE Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade (%) (%)3 / 4 3 / 4(%) (%)3 / 4 3 / 4(%) (%)3 / 4 3 / 4(%) (%)3 / 4 3 / 4 (%) (%) (%) (%) (%) (%) (%) (%) Cardiac or Vascular disorders Cardiac or Vascular disorders Hypertension Hypertension (a) (a) 68 68 39 39 71 71 36 36 65 65 26 26 53 53 31 31 Arterial Arterial ischemia ischemia (b) (b) 13 13 7 7 12 12 6 6 8 8 5 5 3 3 0 0 Cardiac Cardiac Failure Failure (c) (c) 6 6 4 4 6 6 2 2 15 15 11 11 6 6 6 6 Gastrointestinal disorders Gastrointestinal disorders Abdominal Abdominal pain (d) pain (d) 49 49 10 10 40 40 8 8 34 34 6 6 44 44 6 6 Constipation Constipation 37 37 2 2 24 24 2 2 26 26 0 0 47 47 3 3 Nausea Nausea 23 23 1 1 27 27 0 0 32 32 2 2 22 22 0 0 Diarrhea Diarrhea 16 16 1 1 26 26 0 0 18 18 3 3 13 13 3 3 Vomiting Vomiting 13 13 2 2 24 24 0 0 23 23 2 2 22 22 0 0 Oral mucositis Oral mucositis (e) (e) 10 10 1 1 15 15 1 1 23 23 0 0 9 9 3 3 GI hemorrhage GI hemorrhage (f) (f) 2 2 <1 <1 8 8 1 1 11 11 5 5 9 9 6 6 Blood and lymphatic system disorders Blood and lymphatic system disorders Febrile Febrile neutropenia neutropenia 1 1 <1 <1 4 4 4 4 11 11 11 11 25 25 25 25 Infections and infestations Infections and infestations Sepsis Sepsis 1 1 1 1 5 5 5 5 8 8 8 8 22 22 22 22 Pneumonia Pneumonia 3 3 2 2 11 11 9 9 13 13 11 11 9 9 3 3 Urinary Urinary tract tract infection infection 7 7 1 1 12 12 1 1 0 0 0 0 9 9 0 0 UpperUpper respiratory respiratory tract tract infection infection 11 11 1 1 8 8 0 0 11 11 2 2 0 0 0 0 Nasopharyngitis Nasopharyngitis 9 9 0 0 12 12 0 0 3 3 0 0 3 3 0 0 Cellulitis Cellulitis 2 2 1 1 4 4 2 2 11 11 3 3 0 0 0 0 Nervous system disorders Nervous system disorders Headache Headache 39 39 3 3 28 28 0 0 31 31 3 3 25 25 0 0 Peripheral Peripheral neuropathy neuropathy (g) (g) 13 13 2 2 8 8 0 0 8 8 0 0 6 6 0 0 Dizziness Dizziness 11 11 0 0 5 5 0 0 5 5 0 0 3 3 0 0 Respiratory, thoracic, Respiratory, thoracic, and mediastinal disorders and mediastinal disorders Pleural Pleural effusion effusion 3 3 1 1 11 11 2 2 13 13 0 0 19 19 3 3 Cough Cough 12 12 0 0 17 17 0 0 18 18 0 0 6 6 0 0 Dyspnea Dyspnea 11 11 2 2 15 15 2 2 21 21 7 7 6 6 0 0 Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders RashRash and related and related conditions conditions 54 54 5 5 48 48 8 8 39 39 5 5 34 34 6 6 Dry skin Dry skin 39 39 2 2 27 27 1 1 24 24 2 2 25 25 0 0 Musculoskeletal and connective Musculoskeletal and connective tissue disorders tissue disorders Arthralgia Arthralgia 26 26 2 2 31 31 1 1 19 19 0 0 13 13 0 0 Myalgia Myalgia 22 22 1 1 20 20 0 0 16 16 0 0 6 6 0 0 Pain in Pain extremity in extremity 17 17 2 2 17 17 0 0 13 13 0 0 9 9 0 0 BackBack pain pain 15 15 1 1 11 11 2 2 16 16 2 2 13 13 0 0 Muscle Muscle spasms spasms 12 12 0 0 5 5 0 0 5 5 0 0 13 13 0 0 BoneBone pain pain 12 12 <1 <1 12 12 1 1 11 11 3 3 9 9 3 3 General disorders and administration General disorders and administration site conditions site conditions Fatigue Fatigue or asthenia or asthenia 39 39 3 3 36 36 6 6 35 35 5 5 31 31 3 3 Pyrexia Pyrexia 23 23 1 1 31 31 5 5 32 32 3 3 25 25 0 0 Edema, Edema, peripheral peripheral 13 13 <1 <1 19 19 0 0 13 13 0 0 22 22 0 0 Pain Pain 8 8 <1 <1 7 7 0 0 16 16 3 3 6 6 3 3 ChillsChills 7 7 0 0 11 11 0 0 13 13 2 2 9 9 0 0 Metabolism and nutrition disorders Metabolism and nutrition disorders Decreased Decreased appetite appetite 8 8 <1 <1 12 12 1 1 8 8 0 0 31 31 0 0 Investigations Investigations Weight Weight decreased decreased 6 6 <1 <1 7 7 0 0 5 5 0 0 13 13 0 0 Psychiatric disorders Psychiatric disorders Insomnia Insomnia 7 7 0 0 12 12 0 0 8 8 0 0 9 9 0 0

Hemorrhage Hemorrhage CNS hemorrhage CNS hemorrhage Gastrointestinal Gastrointestinal hemorrhage hemorrhage Cardiac Cardiac failurefailure Effusions* Effusions* AtrialAtrial fibrillation fibrillation Venous Venous thromboembolism thromboembolism Hypertension Hypertension Gastrointestinal disorders Gastrointestinal disorders Pancreatitis Pancreatitis Abdominal Abdominal pain pain Blood and lymphatic system disorders Blood and lymphatic system disorders Febrile Febrile neutropenia neutropenia Thrombocytopenia Thrombocytopenia Anemia Anemia Infections Infections Pneumonia Pneumonia Sepsis Sepsis General General Pyrexia Pyrexia

N (%)N (%) 34 (8%) 34 (8%) 21 (5%) 21 (5%) 8 (2%) 8 (2%) 7 (2%) 7 (2%) 22 (4%) 22 (4%) 10 (2%) 10 (2%) 10 (2%) 10 (2%) 20 (4%) 20 (4%) 13 (3%) 13 (3%) 11 (2%) 11 (2%) 10 (2%) 10 (2%) 8 (2%) 8 (2%) 23 (5%) 23 (5%) 17 (4%) 17 (4%) 13 (3%) 13 (3%) 13 (3%) 13 (3%) 12 (2%) 12 (2%) 24 (4%) 24 (4%) 11 (2%) 11 (2%) 14 (3%) 14 (3%)

*includes *includes pericardial pericardial effusion, effusion, pleuralpleural effusion, effusion, and ascites and ascites

Laboratory Abnormalities Laboratory Abnormalities Myelosuppression commonly reported all patient populations. The frequency of grade Myelosuppression was was commonly reported in allinpatient populations. The frequency of grade 3 or 43 or 4 thrombocytopenia, neutropenia, and anemia higher in patients AP-CML, BP-CML, thrombocytopenia, neutropenia, and anemia was was higher in patients with with AP-CML, BP-CML, and Ph+ in patients CP-CML and Ph+ ALL ALL than than in patients with with CP-CML (see (see TableTable 6). 6). Table 6: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities Table 6: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities Laboratory Test Laboratory Test CP-CML CP-CML AP-CML AP-CML BP-CML BP-CML Ph+ ALL Ph+ ALL (N=270) (N=270) (N=85) (N=85) (N=62) (N=62) (N=32) (N=32) (%) (%) (%) (%) (%) (%) (%) (%) Hematology Hematology Thrombocytopenia Thrombocytopenia 36 36 47 47 57 57 47 47 (platelet (platelet countcount decreased) decreased) Neutropenia Neutropenia (ANC(ANC decreased) decreased) 24 24 51 51 55 55 63 63 Leukopenia Leukopenia (WBC(WBC decreased) decreased) 14 14 35 35 53 53 63 63 Anemia Anemia (Hgb (Hgb decreased) decreased) 9 9 26 26 55 55 34 34 Lymphopenia Lymphopenia 10 10 26 26 37 37 22 22 ANC=absolute ANC=absolute neutrophil neutrophil count,count, Hgb=hemoglobin, Hgb=hemoglobin, WBC=white WBC=white blood cell blood count cell count *Reported *Reported using NCI-CTC-AE using NCI-CTC-AE v 4.0 v 4.0

Table 7: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Table 7: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Laboratory Test Safety Population Laboratory Test Safety Population N=449 N=449 Any Grade* Grade 3/4 Any Grade* Grade 3/4 (%) (%) (%) (%) Liver function tests Liver function tests ALT increased 53 53 8 8 ALT increased AST increased 41 41 4 4 AST increased Alkaline phosphatase increased 37 37 2 2 Alkaline phosphatase increased Albumin decreased 28 28 1 1 Albumin decreased Bilirubin increased 19 19 1 1 Bilirubin increased Pancreatic enzymes Pancreatic enzymes Lipase increased 41 41 15 15 Lipase increased Amylase increased 3 3 <1 <1 Amylase increased Chemistry Chemistry Glucose increased 58 58 6 6 Glucose increased Phosphorus decreased 57 57 8 8 Phosphorus decreased Calcium decreased 52 52 1 1 Calcium decreased Sodium decreased 29 29 5 5 Sodium decreased Glucose decreased 24 24 0 0 Glucose decreased Potassium decreased 16 16 2 2 Potassium decreased Potassium increased 15 15 2 2 Potassium increased Sodium increased 10 10 <1 <1 Sodium increased Bicarbonate decreased 11 11 <1 <1 Bicarbonate decreased Creatinine increased 7 7 <1 <1 Creatinine increased Calcium increased 5 5 0 0 Calcium increased Triglycerides increased 3 3 <1 <1 Triglycerides increased ALT=alanine ALT=alanine aminotransferase, aminotransferase, AST=aspartate AST=aspartate aminotransferase. aminotransferase. *Graded *Graded using NCI-CTC-AE using NCI-CTC-AE v 4.0 v 4.0

DRUG INTERACTIONS Based on in vitro studies ponatinib is a substrate of CYP3A4/5 and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)].

7.1

Drugs That Are Strong Inhibitors of CYP3A Enzymes In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 mg once daily [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

7.2

Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of Iclusig with strong CYP3A inducers was not evaluated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)]. Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.3

Drugs That Elevate Gastric pH Coadministration of Iclusig with drugs that elevate the gastric pH was not evaluated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.4

Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 [also known as BCRP] (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

USE IN SPECIFIC POPULATIONS

8.1

regnancy P Pregnancy Category D Risk Summary Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Iclusig in pregnant women. Advise women to avoid becoming pregnant while taking Iclusig. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis. At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

8.3

Nursing Mothers It is unknown whether ponatinib 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 ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother.

8.4

Pediatric Use The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

8.5

Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Patients of age ≥ 65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6

Hepatic Impairment Iclusig has not been studied in patients with hepatic impairment. As hepatic elimination is a major route of excretion for Iclusig, hepatic impairment may result in increased ponatinib exposure. Avoid Iclusig in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure [see Clinical Pharmacology (12.3)]. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

8.7

Renal Impairment Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

OVERDOSAGE Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally self-administered 165 mg on cycle 1 day 2. The patient experienced fatigue and non-cardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion. In the event of an overdose of Iclusig, stop Iclusig, observe the patient and provide appropriate supportive treatment. Manufactured for: ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street Cambridge, MA 02139-4234 For information contact: 1-855-55-ARIAD (855-552-7423) medinfo@ariad.com PB/0213/0103/US

ASCOPost.com | APRIL 15, 2013

PAGE 117

Society of Gynecologic Oncology Gynecologic Oncology

Intraperitoneal Chemotherapy Gives Ovarian Cancer Patients Better Chance of Survival

atients with advanced ovarian cancer who undergo intensive treatment with chemotherapy that bathes the abdomen are significantly more likely to live longer than those who receive standard intravenous (IV) chemotherapy, according to a study that analyzed long-term follow-up from two landmark Gynecologic Oncology Group (GOG) trials comprising 876 patients. Results of the study were presented at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, held in Los Angeles in March.

Study Details Women who receive the treatment in the form of intraperitoneal, or IP, chemotherapy are 17% more likely to survive longer than those who have IV chemotherapy, according to the analysis, which had a median follow-up of more than 10 years. Median survival was more than 5 years (62 months) for patients in the IP group and about 4 years (51 months) for patients in the IV group. The findings also suggest women who complete most or all of the recommended six cycles of IP therapy are likely to live longer than women who

complete four or fewer cycles. After 5 years, 59% of patients who completed five or six cycles of IP therapy were alive, compared to 33% of those who completed three or four cycles and 18% of those who completed one or two cycles. Patients who are unable to

Medical Group in Orange County, California, of Kaiser Permanente and Assistant Professor of Obstetrics and Gynecology at the University of California, Irvine School of Medicine. “But there is also a caution that it should be administered by a physi-

Intraperitoneal Chemotherapy for Ovarian Cancer ■ Women with advanced ovarian cancer who receive intraperitoneal (IP)

chemotherapy are 17% more likely to survive longer than those who have intravenous chemotherapy.

■ Median survival was more than 5 years (62 months) for patients in the IP group and about 4 years (51 months) for patients in the IV group.

■ After 5 years, 59% of patients who completed five or six cycles of IP therapy were alive, compared to 33% of those who completed three or four cycles, and 18% of those who completed one or two cycles.

receive the full six cycles of IP therapy typically transition to IV chemotherapy for the remaining cycles.

‘A Potential Lifesaver’ “Too many women do not receive an explanation about the advantages and disadvantages of IP therapy and that it could be a potential lifesaver,” said Devansu Tewari, MD, Director of Gynecologic Oncology for the Southern California Permanente

cian who has expertise in the treatment and can best manage the risks and side effects.” Every year, more than 22,000 women are diagnosed with ovarian cancer and more than 15,000 die of the disease. In standard IV chemotherapy, the drugs are infused into the bloodstream and throughout the body, whereas IP treatment directs the chemotherapy to the abdomen. This not only places a high concentration of cancer-killing

drugs where they are needed, but the chemotherapy agents are absorbed more slowly, providing more exposure to the medicine. Intraperitoneal is recommended by the National Cancer Institute for women who have had optimal surgery. Because IP therapy is more rigorous, some of the side effects are also more intense, such as numbness in the hands and feet and abdominal pain, and some women are unable to complete the suggested six cycles of therapy. Researchers found younger, healthier patients were more likely to complete more cycles of IP. “There is no question IP therapy should be much more widely offered, and advanced ovarian cancer patients should consult with gynecologic oncologists or medical oncologists with experience in this cancer who have the expertise to determine the best therapy,” said Dr. Tewari. “At the very least, these women should be treated by someone who has experience with IP therapy issues and knowledge of whether she would be a good candidate.” n

Majority of Ovarian Cancer Patients Do Not Receive Recommended Treatment, Study Shows

omen are 30% less likely to die of ovarian cancer if they have guideline-recommended treatment, yet nearly two-thirds of those with the disease do not receive it, often because they are cared for at hospitals that treat a small number of ovarian cancer patients. These are the findings of a study of more than 13,000 patients presented at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, held in Los Angeles in March

Study Definitions Women with ovarian cancer treated by high-volume surgeons and at highvolume hospitals were more likely to receive therapy recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice

Guidelines, according to the study. A high-volume surgeon is one who treats 10 or more ovarian cancer patients a year; a high-volume hospital treats 20

of death among American women. “There may be a number of reasons women do not receive guideline-adherent care, such as that low-volume

Patients need to be their own advocates and ask the provider and hospital how many ovarian cancer patients they treat, how many ovarian cancer surgeries they perform, and their ovarian cancer patients’ rates of survival. —Robert E. Bristow, MD

or more per year. More than 15,000 women die of ovarian cancer each year, making it the fifth leading cause

hospitals may not have access to gynecologic oncologists who specialize in this care,” said Robert E. Bristow,

MD, Director of the Division of Gynecologic Oncology at the University of California, Irvine Medical Center. “Patients need to be their own advocates and ask the provider and hospital how many ovarian cancer patients they treat, how many ovarian cancer surgeries they perform, and their ovarian cancer patients’ rates of survival. If a surgeon only performs two ovarian cancer surgeries a year, you don’t want to be one of those two.”

Key Findings The study was an analysis of treatment of 13,321 ovarian cancer patients reported to the California Cancer Registry from 1999 through 2006. NCCN guideline-adherent care includes a combination of surgery and chemotherapy continued on page 118

The ASCO Post | APRIL 15, 2013

PAGE 118

Society of Gynecologic Oncology Ovarian Cancer continued from page 117

depending on the stage of the cancer. Only 4,952 patients (37%) received care recommended by NCCN guidelines, researchers found. Patients who did not receive guideline-adherent care were 30% more likely to die of ovarian cancer during the 5-year follow-up period.

The study is the first large-scale population-based analysis to validate the NCCN treatment recommendations, showing that they correlate with improved clinical outcomes, said Dr. Bristow. The majority of patients were treated at low-volume hospitals and by low-volume surgeons: 81% of

patients had surgery at low-volume hospitals and 62% of surgeries were performed by low-volume surgeons, although in 22% of cases, no surgeon was identified. High-volume hospitals were significantly more likely to administer guideline-adherent care than low-volume hospitals (50.8% vs 34.1%, P < .001).

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

Even patients treated at high-volume hospitals and by high-volume surgeons received guideline-adherent therapy only about half the time. Appropriate care was delivered at high-volume hospitals 51% of the time and by high-volume surgeons 48% of the time. Dr. Bristow pointed out that in many cases these physicians provided some of the recommended care, such as the appropriate chemotherapy or surgery, but not both. He also noted that not all patients should necessarily receive guideline-recommended care. For example, aggressive guideline-directed care might be more harmful than helpful to an elderly, frail woman. “This shows we have a lot of room to improve,” said Dr. Bristow. “We need to become more sophisticated and to determine what the best performing physicians are doing different from everyone else, establish best practices, and then enforce them to improve outcomes.” n

New Vice President of Indiana Cancer Services

olly Goe, RN, MSN, has been named Vice President of Indiana University Health Cancer Centers, Indianapolis. She has been serving as interim Vice President since October after being named the program’s Executive Director for Clinical Operations last April.

• Specific information for survivors

Available at:

or visit

drlacoutureskincare.com

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

Holly Goe, RN, MSN

Before joining IU Health in April 2012, Ms. Goe worked at the University of Pittsburgh Medical Center in Pittsburgh for 4 years, serving in several leadership positions in clinical research services. Before that, she held positions in nursing and nurse leadership at facilities throughout Indiana. n

ASCOPost.com | APRIL 15, 2013

PAGE 119

Book Review

Radiation, Still Misunderstood after All These Years By Ronald Piana

ver the past few decades, radiation therapies have rapidly advanced, due, in large part, to an increasing technologic armamentarium. Among modern science’s most impressive machines, for example, 220-ton particle accelerators can generate nearlight-speed beams of protons, with sniper-like precision, to their tumor targets. Hence, of the three oncologic disciplines, radiation oncology is perhaps the least understood, especially among patients. People can reduce oncologic surgery to the scalpel and medical oncology to cancer-killing chemicals, but that easy-to-grasp reductionism defies radiation therapy’s exotic particles and rays. After all, radiation both kills and cures. Its awesome energy can reduce a major city to a charred moonscape or direct a curative beam into an intraocular tumor. It is no small task to conflate our knowledge about radiation into a readable book, but that is what Robert Peter Gale, MD, and Eric Lax partnered to do with Radiation: What It Is, What You Need to Know. For the most part, Dr. Gale and Mr. Lax offer readers a good, thoroughly informative read.

Minor Gripes Using the 2011 Fukushima Daiichi nuclear power plant catastrophe in Japan as the most recent reason to fear radiation, the authors’ preface, “A Note to the Reader,” begins with a sort of caveat: “Virtually everything is radioactive, including us; some things are just more radioactive than others.” The preface ends with, “Frightening as the topic of this book might be in some ways, information and education can relieve some, if not most, anxiety about radiation.” Legendary editor Harold Ross once famously declared about his new magazine, The New Yorker, “it is not edited for the old lady in Dubuque.” Similarly, Radiation, with its sometimes-dense reading, is not for readers who don’t have an affinity for science books. So the cautionary preface seems unnecessary and a bit condescending. That’s a small gripe, but in a book that expects its readers to follow quantity compari-

sons of thorium-230 and uranium-234, it’s worth noting. To their credit, the authors give a panoramic view of radiation within a neat package of a few hundred pages. Another pleasant surprise is the eye-pleasing text, set in Times New Roman—unusual for a book. The book’s architecture is another winner, organized in nine chapters with well-thought-out subheads—it suits a cover-to-cover reader or one looking to peruse and skip. On that note, another minor gripe. I’m not sure what percentage of readers pass over a book’s introduction, especially if it runs more than a page or two, but enough do, so authors should heed this caveat: If you’ve written a compelling, 20-page info-jammed introduction (as is the case with Radiation), call it Chapter 1 instead of Introduction. To illustrate the power of radiation, the authors begin their introduction with a throat-grabbing tale that takes place in Brazil in 1985, in which a cus-

through so many technicalities, let’s examine how scientists analyze radiation emitted, energy absorbed, and biological damage from that radiation, so that we can make the one judgment that really matters: What am I exposed to, and is it bad for me?” Radiation is a technically challenging subject, and the authors do a good job “slogging” through the very dense but necessary scientific explanations, after which, their inner storytellers take off, deftly using anecdotes and snippets from radiation’s interesting history. This balancing act between dense science and highly readable storytelling usually gets the necessary yinyang right.

The authors give a well-balanced look at radiation’s dangers and benefits, beginning with an effective explanation of the radiation-induced oncogenic process and some of the book’s most interesting stories, even treating the readers to a couple of radiation murder capers. tody battle over a radiation therapy machine sets off a medical mystery drama that could be a made-for-TV movie. Do not skip the introduction.

Balancing Act Chapter 1, “Assessing the Risks,” delves into the possibilities of developing cancer from radiation. It begins on July 16, 1945, in a desert in New Mexico where the explosion of the Trinity test—the first atomic bomb— “generated a light brighter than any ever seen on Earth.” After an arresting opening, the pages begins to crawl across the desert of radionuclides and microsieverts until the authors declare, “Having slogged

Radiation, Cancer, and Medicine As for chapters of special interest to readers of The ASCO Post, chapter 4, “Radiation and Cancer.” and chapter 6, “Radiation and Medicine,” jump out. In chapter 4, the authors give a well-balanced look at radiation’s dangers and benefits, beginning with an effective explanation of the radiationinduced oncogenic process and some of the book’s most interesting stories, even treating the readers to a couple of radiation murder capers. The treatment of UV exposure and skin cancers is packed with good information, some myth-busting included. Chapter 6 wades into some rough

Title: Radiation: What It Is, What You Need to Know Author: Robert Peter Gale, MD, and Eric Lax Publisher: Knopf Publication date: January 29, 2013 Price: $26.95; Hardcover, 288 pages

waters, tackling the always-controversial area of breast and lung cancer screening. The authors make what some in the oncology community might feel to be facile arguments, such as: “From a radiobiology perspective, screening mammograms are a good example of the benefits (early diagnosis of breast cancer) exceeding the potential risks (exposure to ionizing radiations).” If only it were that simple.

Final Pages The authors have added a smartly put-together Q&A following the last chapter. This is not an easy thing to do, but it has the feel of an ASCO meeting, when audience members amble up to the mikes. That last chapter, “Summing Up,” begins with an unnecessary apology: “To the readers who struggled through these 206 pages of complex, sometimes dense text referencing controversial and unresolved viewpoints, our admiration and gratitude.” There is no reason to apologize for dense text in a science-subject book, especially when parts are well written, entertaining, and informative. However, also in the “Summing Up” chapter is the following statement: “One-half of our annual radiation exposure comes from medical procedures of which one-third or one-half may be unnecessary.” There is no referenced supportive data to back up this rather bold claim. As science writers, the authors should know better. Maybe here an apology is necessary. That said, despite a few potholes, Radiation is worth the ride. n

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

ASCOPost.com | APRIL 15, 2013

PAGE 123

In the News Genitourinary Oncology

Recently Reported Long-term Outcomes Could Motivate More Men with Prostate Cancer to Consider Active Surveillance By Charlotte Bath

ifteen years after being treated with radical prostatectomy or externalbeam radiation for localized prostate cancer, “the prevalence of erectile dysfunction was nearly universal,” among men enrolled in a long-term functional outcomes analysis of the Prostate Cancer Outcomes Study (PCOS). There

David F. Penson, MD, MPH

were no significant relative differences in the odds of urinary incontinence or bowel urgency between men treated with prostatectomy or radiotherapy. “Considering the often long duration of survival after treatment for prostate cancer, these data may be used to counsel men considering treatment for localized disease,” the study investigators concluded. The study was published in The New England Journal of Medicine1 and reported by the medical and consumer press. The newspaper The Tennessean quoted senior author David F. Penson, MD, MPH, as saying that both surgery and radiation “cause a whole heck of a lot of side effects.” In an interview with NBC News, Dr. Penson said, “So many of these men have low-risk disease that probably doesn’t need to be treated.” Dr. Penson is the Director of the Center for Surgical Quality and Outcomes Research, Professor of Urologic Surgery, and Ingram Professor of Cancer Research at Vanderbilt University Medical Center in Nashville. Dr. Penson expanded on these remarks in an interview with The ASCO Post. While men diagnosed with localized prostate cancer generally are aware of the possible side effects of treatment, “I don’t think they appreciate the degree to which it occurs,” Dr. Penson said. “They are told that it is a possibility, but I don’t think they really appreciate just how real the possibility is.” He said that the results of the

study can help men “get the complete picture” about the long-term effects of treatment for localized prostate cancer and decide what is best for them.

Disease-specific Functional Outcomes The PCOS study involved 3,533 men diagnosed with localized prostate cancer in 1994 or 1995. The current analysis was limited to 1,655 men diagnosed between the ages of 55 and 74 and whose primary treatment was either prostatectomy (1,164 men) or external-beam radiation (491 men). In addition to baseline assessments,

the men completed self-administered surveys containing items on clinical outcomes and disease-specific healthrelated quality of life at 2, 5, and 15 years after diagnosis. According to the study report, “Men in the prostatectomy group were significantly more likely than those in the radiotherapy group to report having erections insufficient for intercourse at 2 years” (78.8% vs 60.8%) and 5 years (75.7% vs 71.9%). Preserving sexual function for 2 to 5 more years may be a factor in opting for radiotherapy. “There is no denying the fact that there are men who in their

Expect Questions from Your Patients

ecently reported data from the Prostate Cancer Outcome Study (PCOS) can “serve as a tool for a medical oncologist, a urologic oncologist, or a radiation oncologist to say, ‘Here is what could happen on average at 2, 5, 15 years after treatment with either surgery or radiation,’” according to the study’s senior author David F. Penson, MD, MPH, Director of the Center for Surgical Quality and Outcomes Research, Professor of Urologic Surgery, and Ingram Professor of Cancer Research at Vanderbilt University Medical Center in Nashville. What did happen in the study was that 2 and 5 years after treatment, men treated with radical prostatectomy were more likely to report erectile dysfunction and urinary incontinence, and men treated with external-beam radiation reported significantly higher rates of bowel urgency. By year 15, however, “erectile dysfunction was almost universal” (occurring in 87% of those in the prostatectomy group and 93.9% of those in the radiotherapy group) and there were no significant relative differences in urinary or bowel functional outcomes. “We know that anywhere from 20% to 50% of prostate cancers diagnosed in the PSA era are ‘overdiagnosed.’” Dr. Penson told The ASCO Post. The combination of factors—odds of overdiagnosis and the risks of erectile dysfunction, urinary incontinence, and bowel urgency—results in “many, but not all, patients being open to the idea of active surveillance,” Dr. Penson said.

‘Unprogramming’ Patients Counseling patients about treatment options “requires time and a thoughtful approach,” Dr. Penson continued. “It often requires explaining the situation to the patient’s partner and to their family members.” It can be difficult to “unprogram” patients who believe that a diagnosis of cancer demands treatment, he noted. While patients may not be comfortable with the idea of active surveillance at first, “when you talk to them, often they begin to see the real benefits of closely watching their tumor and understanding that it may be in their best interest not to immediately have surgery or radiation treatment.” Dr. Penson said “the majority of patients that I see have gone to the Internet and have talked to their friends. They want to have a role. Sure, they want the doctor’s opinion, and the doctor’s opinion is probably the most important factor in their decision-making process.” But patients “want to make their own choices about their health care,” he added, “and for health issues that have received extensive media coverage, such as prostate cancer, patients are aware that there are different treatment methods.” n

late 60s may want to maintain that sexual function for 2 or 3 years. Conversely, there may be young men who, for whatever reason, whether it is cancer control or another reason, choose to sacrifice that upfront sexual function,” Dr. Penson stated. “At 15 years, the prevalence of erectile dysfunction was nearly universal, affecting 87.0% of men in the prostatectomy group and 93.9% of those in the radiotherapy group. Nonetheless, only 43.5% of men in the prostatectomy group and 37.7% of those in the radiotherapy group reported being bothered with respect to sexual symptoms. The possible reasons for the second finding include declining sexual interest with age, acceptance of sexual dysfunction over time, or both,” the report continued. Patients who had prostatectomy were more likely to have urinary incontinence than those who had radiotherapy at 2 years (9.6% vs 3.2%) and 5 years (13.4% vs 4.4%). “However, no significant between-group difference in the odds of urinary incontinence was noted at 15 years,” the investigators reported. “Patients undergoing prostatectomy were less likely to have bowel urgency at 2 years (13.6% vs 34%) and 5 years (16.3% vs 31.3%), again with no significant betweengroup difference in the odds of bowel urgency at 15 years,” they added.

Two Major Messages “If you look at the results, you see that initially sexual functioning is much worse after surgery, but by about 5 years, things are evening out, certainly by 15 years. For urinary continence, it is worse for surgery. For bowel dysfunction, it is worse with radiation,” Dr. Penson summarized. “I hope that patients and providers take away two points from this.” The first point is that treatment for localized prostate cancer “is a personalized decision,” Dr. Penson stressed. “What works for one patient may not work best for another. For some patients, 2 years’ loss of sexual functioning isn’t going to be acceptable.” continued on page 124

The ASCO Post | APRIL 15, 2013

PAGE 124

In the News

Prostate Cancer Outcomes continued from page 123

The second point is that patients who have low-risk disease should perhaps “pause and think, ‘Maybe I should try active surveillance, because I may be able to avoid these complications altogether,’” Dr. Penson continued. “I recognize that every man with prostate cancer has to be treated differently because this is a preferencesensitive decision. I look at these data and I say to myself, ‘If I were newly diagnosed with localized prostate cancer and it was a low-risk tumor, given the fact that the risk of having problems with surgery or radiation are high, maybe I should be thinking about active surveillance,’” Dr. Penson said. “Maybe these data will make a few men think a little more carefully about that option.”

Active Surveillance vs Watchful Waiting Active surveillance “is a reasonable option,” Dr. Penson said. “We know from the trials that have come out recently, specifically the Prostate Cancer Intervention Versus Observation Trial (PIVOT),2 that in low-risk patients and older patients, there is no difference in outcomes between surgery and watchful waiting, which is actually somewhat different than active surveillance,” Dr. Penson noted. “At this point, we can accept active surveillance as a standard of care, not the standard of care, in low-risk patients. That difference is a key point,” he stressed. “Watchful waiting is the old version of conservative management,” Dr. Penson explained. “We would watch and only make an intervention if patients were symptomatic or if they suddenly

changed their status. With active surveillance, we are actively following patients, repeating prostate-specific antigen (PSA) measurements, repeating biopsies, and depending on which protocol you accept, there are thresholds for intervention.” Those thresholds could include a change seen on a repeat biopsy or a rapid rise in PSA and would signal a “need to aggressively intervene with surgery or radiation,” he added. Patients need to understand the difference between watchful waiting and active surveillance and know that if they choose not to have treatment with surgery or radiation, they can have active surveillance instead. “That is a key point because patients may interpret watchful waiting as ‘watching and wait-

declines in sexual and urinary function over the duration of the study, and the causes of these declines probably include both advancing age and additional cancer treatments.” Dr. Penson explained that “additional cancer treatments” referred only to additional treatments for prostate cancer. “If a man has a recurrence, regardless of whether he had surgery or radiation, the most common form of treatment is going to be hormonal treatment, which is hellish on sexual function,” he said. The authors acknowledged that “the precise contribution of prostate cancer treatment to age-dependent changes in urinary, sexual, and bowel function remains unknown, given the absence of an untreated, age-matched control cohort.”

If I were newly diagnosed with localized prostate cancer and it was a low-risk tumor, given the fact that the risk of having problems with surgery or radiation are high, maybe I should be thinking about active surveillance. —David F. Penson, MD, MPH

ing for me to drop dead,’ whereas active surveillance is an active follow-up protocol. Active surveillance ensures that if there are any signs that the tumor is not clinically indolent—that it is actually more aggressive—we will make an intervention in a timely manner and hopefully in such a way that it will have the same outcome as if the patient were treated earlier.”

Effects of Normal Aging The report notes that “regardless of treatment, patients had significant

Dr. Penson cited one study, led by another PCOS investigator, Richard M. Hoffman, MD, MPH, Professor in the Department of Internal Medicine at the University of New Mexico Cancer Center in Albuquerque, and published in Cancer,3 that compared changes in health-related quality of life between men diagnosed with localized prostate cancer with a cohort of age-matched controls identified using data files from the New Mexico Motor Vehicles Department and the Centers for Medicare and Medicaid Ser-

vices. Those investigators concluded, “Prostate carcinoma treatment led to significant 5-year declines in urinary and sexual function that far exceeded age-related changes in controls. Bowel function and general [health-related quality of life] were not affected by cancer status.”

Incrementally Better Outcomes Patients enrolled in PCOS in 1994 and 1995 and some physicians have remarked to Dr. Penson that prostate cancer treatment has improved since then. “Urologists will say, ‘Now we are better with the surgery and we have robotics surgery,’ and radiologists will say, ‘Now we have intensity-modulated radiation therapy and our outcomes are better,’ and I acknowledge that,” Dr. Penson said. “I think the outcomes are better. But I don’t think they are exponentially better. I think they are incrementally better and I think that it is almost a cop-out to say, ‘We’re not going to pay any attention to these data because we are so much better now.’” n

Disclosure: Dr. Penson received research grants via his institution from NIH/NCI for the Prostate Cancer Outcomes Study.

References 1. Resnick MJ, Koyama T, Fan KH, et al: Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med 368:436-445, 2013. 2. Wilt TJ, Brawer MK, Jones KM, et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367:203-213, 2012. 3. Hoffman RM, Gilliland FD, Penson DF, et al: Cross-sectional and longitudinal comparisons of health-related quality of life between patients with prostate carcinoma and matched controls. Cancer 101:2011-2019, 2004.

Immunoassay Test May Help Identify Early Kidney Cancer By Jo Cavallo

enal cell carcinoma is the most common form of adult kidney cancer and the third most common urologic malignancy, accounting for about 2% of all malignancies and 2% of cancer-related deaths worldwide. It is also one of the most difficult cancers to detect and treat because it is usually found after it has metastasized to other organs. The results of a new immunoassay that tests for the presence of three serum/plasma biomarkers appears promising for the early detection

of malignant kidney tumors, according to a new study published in the journal Cancer Epidemiology, Biomarkers & Prevention.

Three Potential Biomarkers The immunoassay developed by researchers from Genomine Inc., measured the levels of three potential biomarkers for kidney cancer: nicotinamide N-methyltransferase (NNMT), L-plastin (LCP1), and nonmetastatic cells 1 protein (NM23A) in 189 plas-

ma samples taken from 102 healthy controls and patients with benign tumors and 87 patients with kidney cancer. The test found that plasma levels of NNMT, LCP1, and NM23A were highly elevated in the patients with kidney cancer (P < .0001). The researchers then tested the ability of the immunoassay to distinguish plasma samples taken from the healthy controls and the patients with kidney cancer and found that the assay was highly accurate, correctly identifying 90% of

the samples from the healthy controls and 94.4% of the samples from patients with kidney cancer. To validate the accuracy of the assay, the researchers blind tested an additional 100 plasma samples from 73 healthy controls and 27 patients with kidney cancer and found that 67 of the samples from the healthy controls and all of the samples from the kidney cancer patients were classified correctly. The FDA is currently evaluating the assay for approval. n

ASCOPost.com | JULY 15, 2012

PAGE 125

Announcements

Ramon Parsons, MD, PhD, Named Chair of Oncological Sciences at the Icahn School of Medicine at Mount Sinai

enowned scientist Ramon E. Parsons, MD, PhD, has been named Chair of the Department of Oncological Sciences at the Icahn School of Medicine at Mount Sinai, New York. Dr. Parsons is a researcher

Ramon E. Parsons, MD, PhD

in cancer genetics and will bring an interdisciplinary, holistic approach to Mount Sinai’s research team. His appointment was effective in March. Dr. Parsons’ research goals include identifying the genetic and biochemical changes that lead normal cells to develop into aggressive cancer cells. He discovered the PTEN tumor-suppressor gene, which provided a critical therapeutic target in a variety of carcinomas including breast, brain, prostate, and endometrial cancers. He favors organ-based studies that rely on human tissues, which he feels are essential to understanding the biochemistry of disease.

Previous Position Formerly a Professor of Breast Cancer Research, Medicine, Pathology, and Cell Biology in the Institute for Cancer Genetics and in The Herbert Irving Comprehensive Cancer Center (HICCC) at New YorkPresbyterian Hospital, he also led the HICCC’s Breast Cancer Program. “We are entering a new era in cancer research in which genetics and genomics are playing a central role,” said Dr. Parsons. “Mount Sinai recognizes this and is leading the charge in its commitment to multidisciplinary, translational cancer research. I look forward to leading such an innovative group of researchers and to recruit additional world-class scientists to the Department of Oncological Sciences.” The recruitment of Dr. Parsons follows the appointment of Stuart

Aaronson, MD, Jack and Jane B. Aron Professor and formerly Chair of the Department of Oncological Sciences, as Founding Chair Emeritus of the

department after 20 years of exceptional leadership at Mount Sinai. As a highly funded researcher in the department of Oncological Sciences at

Mount Sinai, Dr. Aaronson will focus more on his active laboratory and continue to seek new discoveries in cancer research. n

The ASCO Post | APRIL 15, 2013

PAGE 126

ASCO State Affiliates Focus on the Louisiana Oncology Society By Jo Cavallo

lic policy issues that affect the quality of our practices and care for our patients. The Society addresses our inherently local and regional issues, and provides an opportunity to be most effective in carrying out that three-part mission.

Oral Chemotherapy Parity Law

Roy S. Weiner, MD

ounded on September 1, 1992, by John M. Rainey, MD, the Louisiana Oncology Society has had numerous legislative successes (see sidebar) since that time, including leading the effort to support Louisiana’s Oral Chemotherapy Parity Law, which was passed in 2012 and is now in effect throughout the state. The Society has also been instrumental in forging relationships among oncologists and oncology fellows across Louisiana and in neighboring states, and in ensuring that patients receive quality care. The ASCO Post talked with Roy S. Weiner, MD, President of the Louisiana Oncology Society and Associate Dean for Clinical Research and Training at Tulane University School of Medicine, New Orleans, about the Society’s history, its mission, and its future goals.

Three-part Mission What is the mission of the Louisiana Oncology Society? The mission of our Society is to promote collegiality among its members, provide continuing medical education opportunities, and serve as an advocacy group for pub-

Your most recent legislative accomplishment is passage of Louisiana’s Oral Chemotherapy Parity Law. How will the law impact care for patients with cancer? This was a big effort, but we had a strong ally in Rep. Greg Cromer, Chairman of the House Committee on Insurance. Rep. Cromer worked with his colleagues to pass the bill, and our members testified before committee legislators about the importance of passage of the bill. We also worked with the Louisiana Board of Pharmacy to support the legislation. The Oral Chemotherapy Parity Law ensures that patients will have access to oral cancer medications without being subjected to undue financial hardship because of high deductibles or copayments for these drugs. Now there is parity between oral and intravenous cancer drugs, so patients will be able to afford— and get—the most appropriate therapy for their cancer.

Current Challenges What current challenges do you face as a state society? Our greatest challenge is to be able to provide cancer care that satisfies our high standards while falling within the resource allocation for compensation. But the services that we can offer patients are constantly threatened. About a month ago, Louisiana Governor Bobby Jindal decided to

curtail state funds for endof-life palliative care, and through a great effort by our Society membership and our patients, we were able to get a reprieve until June 30. There is a legislative session between now and then, and I hope we can be effective in being able to retain that care for our patients. If so, we will be able to add to the tremendous track record of legislative success since the formation of the Louisiana Oncology Society.

Annual Meetings How many meetings with members do you have each year? We have an annual meeting that

is held jointly with oncologists from the state of Mississippi in order to get a critical mass and extend our collegiality to our neighbors. One of the features of our annual meeting is a debate on a topi-

Legislative Accomplishments of the Louisiana Oncology Society ■ In 1995, a genetic privacy law was passed defining genetic information

as personal property and including specific penalties for genetic privacy violations.

■ In 1998, legislation was passed allowing health coverage for early

mammography screening and an annual Pap test. Women do not need a referral for annual mammography.

■ In 1999, Senate Bill 761 was passed, requiring insurance companies to

cover the medical costs of patients with cancer enrolled in phase II through phase IV clinical trials.

■ In 2002, Louisiana signed into law a 12-cent per pack increase in the state

cigarette tax, bringing the total tax amount to 36 cents per pack. Three cents of the tax on each pack of cigarettes is earmarked for the Louisiana Cancer Research Consortium, a joint effort of Tulane University and Louisiana State University in New Orleans. Two cents per pack is earmarked for a cancer center at LSU Shreveport.

■ In 2009, legislation was passed prohibiting insurance companies from

sending bone marrow transplant patients out of state for treatment if an accredited facility exists within the state.

■ In 2012, Louisiana passed the state’s first Oral Chemotherapy Parity

Law, protecting patients with cancer from incurring high out-of-pocket copayments and deductibles for oral cancer drugs, which were previously required under some health insurance plans. Copays are limited to $100 per prescription.

Visit the State Oncology Societies Booth at the ASCO Annual Meeting See page 66 for more information or visit: http://chicago2013.asco.org

ASCOPost.com | APRIL 15, 2013

PAGE 127

ASCO State Affiliates cal issue among medical oncology fellows from the academic training programs in Louisiana and Mississippi. We have three medical schools in Louisiana—Tulane University School of Medicine, LSU School of Medicine in New Orleans, and LSU Medical Center in Shreveport—and one medical school in Mississippi, at the University of Mississippi. The debate allows fellows to get to know each other in friendly competition. We hold another annual meeting

and office managers also participate in those meetings. In addition, we have frequent conference calls to keep members current on issues.

Patient Connection Does having a state society also provide the opportunity for members to stay connected with patients? Yes, it does. As you know, Louisiana has been the victim of severe weather. The Louisiana Oncology Society has established a website where

The guiding principles of the Louisiana Oncology Society are to promote collegiality among its members, encourage continuing medical education, and advocate public health-care policy for cancer survivors.

Fast Facts about the Louisiana Oncology Society ■ John M. Rainey, MD, and a small group of oncologists founded the

Louisiana Oncology Society on September 1, 1992. There are 61 members in the Society.

■ The guiding principles of the Louisiana Oncology Society are to promote

collegiality among its members, encourage continuing medical education, and advocate public health-care policy for cancer survivors.

■ The Society educates members about reimbursement and electronic health record management.

■ The Society provides representation on legislative issues. ■ The Society maintains a website where patients can find local medical

resources in any parish throughout the state and maintains a hurricane message board to provide uninterrupted communication between patients with cancer and their oncologists during natural disasters.

■ Visit www.laoncologysociety.org for additional information. be able to continue their cancer treatment regardless of where they are.

Immediate Goals in New Orleans, which is devoted to clinical practice issues, such as reimbursement concerns and concerns regarding electronic medical records,

patients can find help in locating medical care within the state if they are displaced during storms. It certainly gives us comfort to know our patients will

What goals do you want to address immediately? We plan to offer educational programming and opportunities for

oncologists in a variety of different practice settings, including in private community-based settings as well as in hospital- and academicbased positions. We are trying to expand our programs and services to keep up with the changes in oncologists’ needs. n

Alex’s Lemonade Stand Foundation Introduces Centers of Excellence Program to Further Childhood Cancer Research

lex’s Lemonade Stand Foundation (ALSF), a registered 501(c)(3) charity, is furthering its commitment to finding cures for all children with cancer by introducing the ALSF Centers of Excellence program. The Centers of Excellence program aims to fund the research of leading childhood cancer institutions committed to developing and conducting early-phase clinical trials. The first institutions that will receive the funding of $350,000 per year, renewable annually for up to 5 years for a total of $1.75 million, are Baylor College of Medicine, DanaFarber Cancer Institute, and the University of California San Francisco. The Centers of Excellence program will join an already extensive grants program dedicated to finding better treatments and ultimately cures for all children with cancer. The purpose of the program is threefold: to facilitate the evolution of new therapeutic concepts from the preclinical arena into fully

developed clinical trials; to rapidly and efficiently conduct phase I and phase II trials of highly innovative therapies; and to train individuals in the field of developmental therapeutics and cancer pharmacology.

New Program Will Be ‘Transformational’ Unlike all of the other ALSF grant programs, the Centers for Excellence applicants were chosen by the Foundation and invited to apply for funding. Those chosen will utilize half of the funds to enhance clinical trial infrastructure and half to support the training of scholars in drug development allowing the clinical trial program to grow in the field of pediatric oncology. “Since inception with our daughter’s front yard lemonade stand, Alex’s Lemonade Stand Foundation has always been dedicated to moving childhood cancer research forward,” said Jay Scott, Alex’s father and Co-Executive Director of the Foundation. “Whether it

Not only will the award aid immeasurably in increasing the number and quality of phase I and II studies available [now] for children with refractory cancer, but equally importantly, they will help children in the future by training the next generation of leaders in developmental therapeutics. —Stacey Berg, MD

was through motivating promising young researchers to join the field of oncology or filling the gaps where funding was missing, the Foundation has continued to evolve and will now work toward backing the next generation of leaders in the pediatric cancer field.” “The ALSF Centers of Excellence Award will be transformational,” said Stacey Berg, MD, of Baylor College of Medicine. “Not only will the award aid immeasurably in increasing the number and quality of phase I and II studies available [now] for children with refractory

cancer, but equally importantly, they will help children in the future by training the next generation of leaders in developmental therapeutics.” At each institution where funding is being given, a Principal Investigator will be charged with overseeing the program. In addition to Dr. Berg at Baylor College of Medicine, Carlos Rodriguez-Galindo, MD, will oversee the program at Dana-Farber, while Katherine Matthay, MD, will lead the program at the University of California San Francisco. n

Important Safety Information

Additional Important Safety Information

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

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

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

STRENGTHEN HER DEFENSE

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

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

•

Placebo + Herceptin + docetaxel

PERJETA + Herceptin + docetaxel

100 90

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

80 70

18.5 MONTHS

60 PFS (%)

•

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

6.1-Month Improvement in Median IRF†-Assessed PFS1

12.4 MONTHS

40 30 20 10 0

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

402 406

345 311

267 209

139 93

32 17

10 7

0 0

MONTHS P+H+D Pl+H+D

83 42 Patients at risk

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

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

PER0001010502

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

Printed in USA.

(01/13)

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

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

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

Grades 3-4 %

Frequency rate % All Grades %

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

Grades 3-4 %

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

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

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

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

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

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

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Letters to the Editor Opinion

Another Perspective on Accountable Care Organizations

read with great interest Dr. Richard Boxer’s editorial on accountable care organizations in the January 15 issue of The ASCO Post. Much of what he says is unfortunately true. There are several points that I would like to make, however. First of all, Dr. Boxer states that the “principle that defines the reason for accountable care organizations is … that health care in America … demands creative reform.” Accountable care organizations are hardly a new or creative idea. The insurance industry made similar attempts in the late 1990s and early 2000s to develop a system based on the doctrine of “each according to his ability, to each according to his needs.”

Solutions Doomed to Failure The capitation of 10 years ago generally failed because (1) patients hated it, (2) our internal medicine colleagues were not trained or equipped to understand the subtleties of subspecialty care and thus were not the “gatekeepers” envisioned by the utopian planners, and (3) it did not save money. Secondly, accountable care orga-

nizations and their cousins in the Affordable Care Act are statist solutions, which are neither new nor creative. In fact, they are quite predictably destructive. Statist solutions like Medicare, Medicaid, diagnosis-related groups, electronic medical records, and evidence-based medicine are the reasons we require health-care reform in the first place. Inevitably, all statist solutions eventually fail under their own

n looking at a recent issue of The ASCO Post, I noted that expert opinions from specialists were published alongside a number of clinical reports. Below each opinion was a disclosure statement, often saying that the expert had no conflict of interest to report. While I do not know each of these individuals, I am certain they were chosen for the expertise in their respective areas. Further, they have likely published on the particular subject, including perhaps original research citing the advantages of a different therapy or conclusion from that reported in The ASCO Post.

The ASCO Post What’s Your Opinion?

True Intentions The true intention of the accountable care system is to ration care under the guise of “evidence-based medicine” and “quality care” with the expressed intent of saving money/resources. Un-

Accountable care organizations are even more concerning as they fundamentally alter the relationship between the patient and the doctor. —Jonathan Schwartz, MD

weight and require further statist solutions to correct their shortcomings. Any system of reform that continuously creates the need for more reform can hardly be considered creative. Accountable care organizations are even more concerning as they fundamentally alter the relationship between the patient and the doctor. Previously, the doctor’s role had traditionally been as the advocate for the individual patient. Under accountable

Conflicts of Interest

care organizations, the doctor will no longer be the advocate for the individual, but will be coerced into becoming the advocate for the system.

fortunately, such a cold-hearted, bureaucracy-laden system will inevitably harm many individuals who do not fall into the bell-shaped curve of evidencebased cookbook medicine, especially those with rare and unusual conditions. Is this a system in which we as physicians wish to participate? Clearly, the people who stand to derive the greatest benefit from this will be the central planners in Washington, DC, and in academia, who

stand to gain the power of life-anddeath decisions over the individual patient and the doctor. The final frontier of freedom between the individual patient and physician will have been breached forever. What is truly amazing and at the same time frightening is the silence of our profession and the willing collaboration of so many of our colleagues to support such an immoral system, which will ultimately destroy our profession and irrevocably hurt so many innocent individuals.

Moral Obligation Again, I call on ASCO to develop committees of truly forward-thinking individuals who seek to develop true creative reforms based on knowledge of the choices of the individual through the free market. This understanding is the only hope for developing a just health-care system. It is our moral obligation as physicians to maintain our role as defenders of the individual patient against whatever authoritarian system comes along, no matter what the specious justification for that system. n —Jonathan Schwartz, MD Tucson, Arizona

Disclosure: Appropriate or Not? Experts such as these might possibly serve as advisors to drug companies. For example, if one doctor favors a different cancer treatment regimen than another, expressing a potential for conflict, if in fact one does exist, does not weaken the expert’s opinion but the relationship should be made apparent. n —Laurence Baker, DO Ann Arbor, Michigan Dr. Baker is Chair of the Southwest Oncology Group and Collegiate Professor of Cancer Developmental Therapeutics at the University of Michigan, Ann Arbor.

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

he ASCO Post is an outstanding publication that I always look forward to reading. I also understand there are policies and rules to be followed, particularly regarding conflicts of interest and disclosures from contributors. I am writing in regard to “Cancer Has Made Me A Better Doctor,” by David Posner, MD (The ASCO Post, March 15, 2013, page 1). Dr. Posner shared a deeply per-

sonal and courageous story about his own experiences as a patient with recurrent cancer. Was it necessary to end this moving narrative with the statement “Dr. Posner reported no potential conflicts of interest”? n —M. Steven Piver, MD Buffalo, New York Dr. Piver is Medical Director of the M. Steven Piver, M.D. Center for Women’s Health and Wellness and Senior Gynecologic Oncologist for Sisters of Charity Hospital in Buffalo, New York.

Publisher’s Note: Regarding the letters from Dr. Baker and Dr. Piver, readers have on occasion written to The ASCO Post to question whether a particular disclosure statement was comprehensive. The disclosure statement serves as a means to allow readers to determine in their own opinion whether there is any perceived conflict of interest between an individual cited and material discussed in a particular article. Inclusion of a disclosure statement following every article has become almost second nature in many medical publications, including The ASCO Post. While important in many instances, there are times when a disclosure statement is not appropriate, as Dr. Piver has thoughtfully reminded us. Dr. David Posner shared a selfless and inspiring personal essay; certainly The ASCO Post should have recognized this as one such time and omitted the disclosure statement. Watch for more on this important topic in future issues. n

The ASCO Post | APRIL 15, 2013

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Pioneers in Oncology Barrie R. Cassileth, MS, PhD, Champion of Integrative Oncology, Continues to Nurture Growth of the Field By Ronald Piana

sociated with cancer care, which can last through survivorship. I feel very strongly that cancer care should not be limited to the delivery of oncology therapies; treatment should be balanced by careful and nuanced attention to the patient’s physical and emotional needs.

Barrie R. Cassileth, MS, PhD

ver the past decade, integrative oncology has gained wide acceptance as an evidenced-based way to improve the lives of patients with cancer throughout the continuum of their care. The ASCO Post recently spoke with Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan-Kettering Cancer Center, New York. An early proponent of integrative oncology, Dr. Cassileth founded the Integrative Medicine Service at Memorial Sloan-Kettering as well as the Society for Integrative Oncology, which will hold its 10th International Conference later this year.

Mission and Its Components Please give the readers a snapshot of integrative oncology at your center. Sloan-Kettering’s Integrative Medicine Service was established in 1999. The fundamental mission is to employ a variety of nonpharmacologic therapies to help manage the difficult physical and emotional symptoms as-

How is the integrative service at your center organized? There are a number of categories and programs in integrative oncology that are delivered at Sloan-Kettering. Each program has a manager and several assistants, all of whom are also therapists or practitioners. The main programs are physical fitness programs, acupuncture treatment, massage and touch therapies, mind/body therapies such as meditation and

Growth and Acceptance of Integrative Oncology Has the field seen growth since you first began the program at SloanKettering? Yes, integrative oncology has spread widely over the past decade, to the point that virtually all NCI-desig-

The term ‘integrative’ has been corrupted by fringe elements that suggest ‘alternative’ therapies can be used in addition to, or in lieu of mainstream cancer treatments. This is grossly inappropriate because there are no alternatives to mainstream cancer care. —Barrie R. Cassileth, MS, PhD

self-hypnosis, music therapy that promotes a general sense of well-being, and nutritional counseling. Perhaps the most important component of the collective integrative oncology approach is physical fitness, because it is the only program that has definitely been associated with a survival benefit in cancer. Although the data are not totally in, studies in

The ‘About Herbs’ Website

breast, prostate, and colorectal cancers have indicated that there is an actual survival benefit for patients who engage in appropriate exercise. That finding needs further study in the greater clinical picture, because patients who perform routine fitness activities tend to have other healthful habits such as proper diet, so the benefits we see might be part of a broader healthy lifestyle in that group of patients.

he “About Herbs” site (http://www.mskcc.org/cancer-care/integrativemedicine/about-herbs-botanicals-other-products) provides objective information for oncologists and health-care professionals, including a clinical summary for each agent and details about constituents, adverse effects, interactions, and potential benefits or problems. • Total number of hits to date: 15,790,000 • Total number of visitors to date: 2,191,000 • Average hits per day: 4,326 • Voted among The New York Times’ top nine most important health information sites • Named one of the top five websites in medicine by Scientific American in 2003 n

nated comprehensive cancer centers in the United States, as well as many of the nation’s smaller clinical centers, offer some form of integrative oncology services. The scope of these programs differs from center to center. I believe that Sloan-Kettering has one of, if not the most comprehensive programs in the country, in the sense that we offer all the major services in the field, as well as inpatient and outpatient care, an intensive research program, and a great deal of patient and professional education, so we can be seen as a model for institutions that want to develop or expand their programs. Do you feel that integrative oncology is fully understood in the broader cancer population? Everything we do is evidencebased, but the term “integrative” has been corrupted by fringe elements that suggest “alternative” therapies can be used in addition to, or in lieu of mainstream cancer treatments. This

is not only grossly inappropriate but also frightening, simply because there are no alternatives to mainstream cancer care, which is now producing cure rates of about 66% and growing. Alternative therapies are bogus cures promoted primarily on the Internet by those who seek to mislead and profit from vulnerable people with cancer. Unfortunately, the FDA’s ability to stop false advertising of bogus cancer therapies has its limits. The people behind these charlatan Web-based companies are very creative and quickly resurface under new names. Medical quackery is a $40�billion �billion billion per year industry in the U.S. alone. Teasing out valid information about herbs and botanicals from the millions of Web pages of spurious cancer-related content is very difficult. One of the first things we did at the outset of our program, which is now 14 years old, was to establish our free “About Herbs” website. It has two entry portals—one for patients and the public, the other for oncologists and other medical professionals. The site provides objective information, including a clinical summary for each agent and details about constituents, adverse effects, interactions, and potential benefits or problems. And we just launched a free app that was created by Memorial Sloan-Kettering, which is downloadable to most of the portable technologies.

Current Investigations Are there any ongoing research programs you’d like to share with the readers? We’ve studied a variety of interventions such as acupuncture, massage therapy, and botanicals and herbs. One of the promising areas we’re looking at is acupuncture, a modality that has a huge amount of data supporting its use in relieving pain and nausea. We did a study with our head and neck cancer group looking at acupuncture in xerostomia, a debilitating side effect of radiation oncology, leaving many patients housebound. We found that acupuncture actually enabled salivation, a rare and significant step in this clinical setting. Based on results from early pub-

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Pioneers in Oncology

Closing Thoughts Any last thoughts on your work in the field? I receive e-mail and telephone inquires about integrative oncology from practitioners and patients across

SIO’s 10th International Conference

he Society for Integrative Oncology (SIO) will be holding its 10th International Conference in Vancouver, Canada, from Sunday, October 20, 2013 to Tuesday, October 22, 2013. This year’s SIO theme: “From bedside, to bench, to best practices.” The conference will include keynote speakers, plenary and concurrent sessions, and workshops that will highlight the latest research, methodologic issues, and dialogue in the field of integrative oncology. n

the country and internationally. We are constantly expanding our efforts to serve as a useful, easily accessible asset to cancer patients, survivors, families, and oncology professionals. I would urge oncologists and leaders of cancer centers of all sizes to develop integrative oncology programs and offer the information and services that

are very much needed by our patients and survivors. Contemporary cancer care requires both expert oncologic treatment and attention to the physical and emotional symptoms that often endure well into survivorship. Integrative medicine provides the tools that patients can use to control many such symptoms on their own. n

About Herbs Visit the About Herbs website at www.mskcc.org/aboutherbs

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

A SIGNIFICANT THREAT IN mCRPC

90%

Bone metastases are the leading cause of death in patients with mCRPC.1 In a large cohort study of patients with prostate cancer, mortality at year 1 was nearly 5 times higher in the subgroup of patients who had bone metastases.2 At year 5, survival fell from 56% in patients without bone metastases to just 3% in patients with bone metastases.2 Skeletal-related events (SREs) increase mortality associated with bone metastases in mCRPC.2 Bone metastases often lead to pathologic fractures, spinal cord compression, hypercalcemia, and bone marrow insufficiency—events that can cause intense pain from bone deconstruction and nerve compromise.3 Moreover, SREs are a key driver of mortality in prostate cancer.4 Prostate cancer tumor cells are uniquely suited to proliferate within the bone microenvironment.1 As a result, bone represents the earliest and most common site of prostate cancer metastasis.5 In fact, 84% to 92% of patients with mCRPC show evidence of bone metastases.6,7

OF PATIENTS WITH mCRPC SHOW EVIDENCE OF BONE METASTASES6,7

BONE METASTASES SIGNIFICANTLY DECREASE SURVIVAL2 100

Bone metastases No bone metastases

90 80

Survival probability (%)

lished pilot studies looking at acupuncture in lymphedema, we recently initiated a large randomized trial. The pilot studies showed that acupuncture reduced arm circumference, so this is another exciting area of research. Depending on the results, we may look at acupuncture in leg lymphedema, which sparked this line of investigation. Several years ago, I mentioned acupuncture during a presentation to a group at Sloan-Kettering. Some months later, as I was walking through the center’s lobby, a woman came over to me and said that she was at my lecture. After explaining that she had very bad leg lymphedema following gynecologic surgery (a common side effect), she said that she sought acupuncture as a last resort. To my surprise, she lifted up her dress and said, “look.” Both legs were normal, absolutely no sign of swelling. That incident was the catalyst for our pursuit of acupuncture for lymphedema. It is very important to note that acupuncture is safe in lymphedema, without complications or infections from the needles. Many patients, and even doctors, operate under the assumption that acupuncture might exacerbate the swelling, which has been proved to be an unfounded concern.

56% alive at 5 years

60 50 40 30 20

3% alive at 5 years

10 0

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

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

Bayer and the Bayer Cross are registered trademarks of Bayer HealthCare Inc.

600-10-0001-12b

January 2013.

Printed in USA.

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

Flaxseed Scientific name: Linum usitatissimum Common names: Flax, linseed, lint bells, linum

ietary supplement use by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information. The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on complementary therapies commonly used by patients with cancer. We chose flaxseed for this issue because of its increasing use by breast cancer patients. Integrative Oncology is compiled by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine, and Jyothirmai Gubili, MS, Editor of About Herbs, Memorial Sloan-Kettering Cancer Center. The free About Herbs website and the free About Herbs application are managed by K. Simon Yeung, PharmD, LAc, Memorial Sloan-Kettering Cancer Center.

Overview

Believed to have originated in ancient Egypt, flax is an annual plant cultivated worldwide. One of the world’s oldest crops, it has served many purposes. The fiber from the stem was used to produce cloth and fishnets, while the seeds were consumed as food.

The seeds and oil have also been used in traditional medicine to treat constipation and urinary tract infections, to control menopausal symptoms, and to treat coughs, colds, acne, and burns. Flaxseed is rich in omega-3 fatty acids that are known to protect against a variety of medical problems including heart disease, arthritis, and inflammatory bowel disease. It also contains phytoestrogens called lignans, which exert anticancer effects in vitro. However, human data are limited. Also, because flaxseed contains phytoestrogenic lignans, patients with hormone receptor–positive breast cancer should consult their oncologists before taking flaxseed supplements. Flaxseed is available in the form of whole seeds, oil, capsule, powder, and as linseed cakes in many grocery and health food stores. It is promoted as an anticancer and cardioprotective agent despite lack of conclusive clinical evidence.

The Science

Flaxseed has demonstrated chemoand renoprotective effects in patients with lupus nephritis.1,2 Supplementation with a major lignan derived from flaxseed improved glycemic control in type 2 diabetic patients.3 Data on the cholesterol-lowering effects of flaxseed are mixed.4,5 Preclinical data indicate that flaxseed inhibits the growth and metas-

OF NOTE Flaxseed contains phytoestrogens called lignans, which exert anticancer effects in vitro, but human data are limited. Patients with hormone receptor-positive breast cancer should consult their oncologists before taking flaxseed supplements. tasis of breast6 and prostate cancer cells,7 as well as melanoma.8 It has also improved survival in mice by reducing radiation therapy–induced lung damage.9 In patients with prostate10 and breast cancers,11 flaxseed supplementation reduced tumor biomarkers. It was shown to benefit women with

polycystic ovarian syndrome by reducing androgen levels.12 A moderate reduction of estrogens and androgens, which may afford protection against breast cancer, was also seen in postmenopausal women.13 Current data on the effects of flaxseed in relieving menopausal symptoms are limited and inconsistent.14,15 Additional studies are underway.16

Adverse Effects

Increased bowel movements,17 constipation and flatulence,18 and anaphylaxis19 have been reported following ingestion of flax. A case of flaxseed mimicking polyposis coli, a significant risk factor for colorectal carcinoma, also was reported following flaxseed supplementation.20 n

Disclosure: Drs. Cassileth and Yeung and Ms. Gubili reported no potential conflicts of interest.

References 1. Haggans CJ, Hutchins AM, Olson BA, et al: Effect of flaxseed consumption on urinary estrogen metabolites in postmenopausal women. Nutr Cancer 33:188-195, 1999. 2. Clark WF, Kortas C, Heidenheim AP, et al: Flaxseed in lupus nephritis: A two-year nonplacebo-controlled crossover study. J Am Coll Nutr 20(suppl 8):143-148, 2001. 3. Pan A, Sun J, Chen Y, et al: Effects of a flaxseed-derived lignan supplement in type 2 diabetic patients: A randomized, double-blind, cross-over trial. PLoS ONE. 2(11):e1148, 2007. 4. Lemay A, Dodin S, Kadri N, et al: Flaxseed dietary supplement versus hormone replacement therapy in hypercholesterolemic menopausal women. Obstet Gynecol 100:495-504, 2002. 5. Fukumitsu S, Aida K, Shimizu H, et al: Flaxseed lignan lowers blood cholesterol and decreases liver disease risk factors in moderately hypercholesterolemic men. Nutr Res 30(7):441-446, 2010. 6. Chen J, Stavro PM, Thompson LU: Dietary flaxseed inhibits human breast cancer growth and metastasis and downregulates expression of insulin-like growth factor and epidermal growth factor receptor. Nutr Cancer 43:187-192, 2002. 7. Lin X, Gingrich JR, Bao W, et al: Effect of flaxseed supplementation on prostatic carcinoma in transgenic mice. Urology 60:919-924, 2002. 8. Yan L, Yee JA, Li D, et al: Dietary flaxseed supplementation and experi-

mental metastasis of melanoma cells in mice. Cancer Lett 124:181-186, 1998. 9. Christofidou-Solomidou M, Tyagi S, Tan KS, et al: Dietary flaxseed administered post thoracic radiation treatment improves survival and mitigates radiation-induced pneumonopathy in mice. BMC Cancer 11:269, 2011. 10. Demark-Wahnefried W, Polascik TJ, George SL, et al: Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates in men presurgery. Cancer Epidemiol Biomarkers Prev 17:3577-3587, 2008. 11. Thompson LU, Chen JM, Li T, et al: Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer. Clin Cancer Res 11:3828-3835, 2005. 12. Nowak DA, Snyder DC, Brown AJ, et al: The effect of flaxseed supplementation on hormonal levels associated with polycystic ovarian syndrome: A case study. Curr Top Nutraceutical Res 5:177181, 2007. 13. Sturgeon SR, Heersink JL, Volpe SL, et al: Effect of dietary flaxseed on serum levels of estrogens and androgens in postmenopausal women. Nutr Cancer 60:612-618, 2008. 14. Lemay A, Dodin S, Kadri N, et al: Flaxseed dietary supplement versus hormone replacement therapy in hypercholesterolemic menopausal women. Obstet Gynecol 100:495-504, 2002. 15. Pruthi S, Qin R, Terstreip SA, et al: A phase III, randomized, placebo-controlled, double-blind trial of flaxseed for the treatment of hot flashes: North Central Cancer Treatment Group N08C7. Menopause 19:48-53, 2012. 16. National Institutes of Health: [Open studies for flaxseed in cancer.] Available at www.clinicaltrials.gov/ct2/re sults?term=flax+AND+cancer&recr=Op en. Accessed March 4, 2013. 17. Cunnane SC, Hamadeh MJ, Liede AC, et al: Nutritional attributes of traditional flaxseed in healthy young adults. Am J Clin Nutr 61:62-68, 1995. 18. Demark-Wahnefried W, Price DT, Polascik TJ, et al: Pilot study of dietary fat restriction and flaxseed supplementation in men with prostate cancer before surgery: Exploring the effects on hormonal levels, prostate-specific antigen, and histopathologic features. Urology 58:47-52, 2001. 19. Leon F, Rodriguez M, Cuevas M: Anaphylaxis to Linum. Allergol Immunopathol 31:47-49, 2003. 20. Petty DR, Mannion RA: A case of multiple linseeds mimicking polyposis coli on double contrast barium enema. Clin Radiol 58:87-88, 2003.

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News Survivorship

Number of Cancer Survivors Expected to Increase to 18 Million by 2022

he American Association for Cancer Research recently released its second Annual Report on Cancer Survivorship in the United States. The report shows that as of January 2012, there were approximately 13.7 million cancer survivors in the United States, a number that is expected to rise by 31% to 18 million by 2022.

“However, we clearly need to have better diagnostic tools and better treatments for lung cancer.”

New Challenges Emerge According to Dr. Rowland, the in-

—Julia Rowland, PhD

sus Bureau, both government-funded databases. In addition to providing estimates of future cancer survival trends, the report shows that survival is not uniform across cancer subtypes. Currently, women with breast cancer account for 22% of survivors, while men with prostate cancer make up 20%. People with lung cancer, the second most common cancer in terms of diagnosis, only represent 3% of survivors. “For patients with prostate cancer, we have a nearly 100% 5-year survival rate, and breast cancer has made tremendous strides as well, with 5-year survival rising from 75% in 1975 to almost 89% in 2012,” said Dr. Rowland.

New iN every issue Of

JnCCn

• NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Bladder Cancer NCCN Guidelines® insights: Melanoma In this new section, Panel members shed light on the process behind the creation of the NCCN Guidelines, clarifying why and how these important decisions are made.

• radiation Modalities in Prostate Cancer • symptom Management for Brain Tumors • A Patient with Anaplastic Lymphoma Kinase–Positive Non–small Cell Lung Cancer with Development of Leptomeningeal Carcinomatosis while on Targeted Treatment with Crizotinib • using NCCN Clinical Practice Guidelines in Oncology to Measure the Quality of Colorectal Cancer Care in the veterans Health Administration

Cancer Survivors ■ The current number of cancer survivors is 13.7 million.

■ The increase expected in the

number of survivors by 2022 is primarily due to aging of the population.

■ Survival is not uniform across cancer types.

NEW

Read the April Issue of JNCCN:

NEW

By 2020, we expect that two-thirds of cancer survivors are going to be age 65 or older.

will have had a previous malignancy. “How to ensure that these patients lead not only long lives, but healthy and productive lives, will be a vital challenge to all of us,” said Dr. Rowland. n

InsIght

Aging of Population “The increase in the number of survivors will be due primarily to an aging of the population. By 2020, we expect that two-thirds of cancer survivors are going to be age 65 or older,” said Julia Rowland, PhD, Director of the Office of Cancer Survivorship at the National Cancer Institute. The current report was based on an analysis of the Surveillance, Epidemiology and End Results Program and population projections from the U.S. Cen-

crease in the cancer survivor population will present new challenges for the health care community. Patients diagnosed with cancer will likely have comorbid conditions that need to be managed, and Rowland estimates 16%

DowNloAD the JNCCN App Visit the iTunes store or use your QR code reader to download the JNCCN mobile application.

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In the Literature

Emerging Clinical Data on Cancer Management LARYNGEAL CANCER Two Studies Focus on Treatment Strategies for Preserving the Larynx While Increasing Survival Two recent studies in the Journal of Clinical Oncology focused on treatment strategies to preserve the larynx while increasing survival of patients with cancer of larynx.

RTOG 91-11 Ten-year results from the Radiation Therapy Oncology Group (RTOG) 91-11 trial found that both chemotherapy regimens tested—induction chemotherapy with PF (cisplatin/fluorouracil) followed by radiotherapy and concomitant cisplatin/radiotherapy— were more effective than radiotherapy alone in achieving the composite endpoint of laryngectomy-free survival among patients with stage III or IV glottic or supraglottic squamous cell cancer. The researchers reported that locoregional control and larynx preservation were significantly improved with concomitant cisplatin/radiotherapy compared with both the induction arm and radiotherapy alone. Among the 520 analyzable patients, 172 were assigned to radiotherapy alone and 174 were assigned to each of the two chemotherapy arms. Of the 148 patients who underwent laryngectomy, 32 patients were in the concomitant arm (81.7% larynx preservation), 55 in the induction arm (67.5% larynx preservation), and 61 in the radiotherapy-alone arm (63.8%) “Concomitant cisplatin/[radiotherapy] resulted in a 54% relative reduction in risk of laryngectomy compared with [radiotherapy] alone (hazard ratio [HR] = 0.46; 95% confidence interval [CI] = 0.30–0.71; P < .001) and a 42% reduction compared with the induction arm (HR = 0.58; 95% CI = 0.37–0.89; P=.005),” the investigators noted. “Overall survival did not differ significantly, although there was a possibility of worse outcome with concomitant relative to induction chemotherapy (HR = 1.25; 95% CI = 0.98–1.61; P = .08),” the investigators reported.

A total of 374 patients have died. The radiotherapy group had the highest percentage of deaths attributed to larynx cancer (48.4%) and the concomitant group had the lowest (29.2%). Deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8%) than with induction chemotherapy (20.8%) or radiotherapy alone (16.9%). “No differences in late toxicity or speech or swallowing function were demonstrated, but there was an unexplained increase in deaths unrelated to cancer in patients who received concomitant cisplatin/[radiotherapy]. This may be responsible for the absence of a survival advantage for the concomitant treatment group,” the researchers concluded.

TREMPLIN Trial Conducted by researchers in France and Belgium, the phase II TREMPLIN trial compared induction chemotherapy with TPF (docetaxel, cisplatin, and fluorouracil) followed by either chemoradiotherapy or bioradiotherapy for larynx preservation in previously untreated patients with stage III/ IV larynx/hypopharynx squamous cell carcinoma. The authors concluded that no evidence supported the superiority of one treatment over another or over outcomes reported with induction chemotherapy followed by radiotherapy alone, as in the French Groupe Oncologie Radiothérapie Tête et Cou (GORTEC) 2000-01 trial. Induction chemotherapy consisted of three cycles of docetaxel and cisplatin at 75 mg/m2 each on day 1 and fluorouracil at 750 mg/m2 per day on days 1 through 5. The dropout rate after induction chemotherapy was substantial (24%), so only 116 of the 153 enrolled in the study were included in the randomization. Those with < 50% response underwent salvage surgery, while those with ≥ 50% response were randomly assigned to conventional radiotherapy (70 Gy) with concurrent cisplatin at 100 mg/m2 per day on days 1, 22, and 43 of radiotherapy (arm A, 60 patients) or concurrent cetuximab (Erbitux) at a 400-mg/m2 loading dose and 250 mg/ m2 per week during radiotherapy (arm B, 56 patients). Overall toxicity of both chemoradiotherapy and bioradiotherapy was

substantial following induction chemotherapy. However, treatment compliance was higher in the bioradiotherapy arm, the researchers reported. An intent-to-treat analysis found no significant difference in larynx preservation (defined as the absence of any residual disease that would justify salvage total laryngectomy) at 3 months between arm A (95%) and arm B (93%) or in larynx function preservation (defined as a disease-free larynx in place, without tracheotomy or feeding tube), at 87% in arm A and 82% in arm B. Overall survival at 18 months was 92% in arm A and 89% in arm B. “There were fewer local treatment failures in arm A than in arm B; salvage surgery was feasible in arm B only,” the authors noted. “Endpoints were evaluated on the randomly assigned population only, which represented 76% of the patients included in the trial; thus, they are inflated. They were considered in an exploratory attempt to possibly selecting one arm for a phase III trial. Of course, no formal test can be made from these data,” the authors stated. They added that comparison to published data from other larynx preservation trials would be inappropriate due to selection bias.

Commentary In an editorial accompanying the two studies, Everett E. Vokes, MD, of the University of Chicago Medical Center, noted, “Both trials reaffirmed current standards of concurrent chemoradiotherapy (frequently preferred in the United States) and induction chemotherapy (fre-

quently preferred in Europe). RTOG 91-11 provides us with hard data on [laryngectomy-free survival], larynx preservation, and disease-free survival that give an advantage to a concomitant approach over PF induction. The trial also has soft data on late survival that remain unexplained but are concerning and appear to favor induction. Although induction chemotherapy in the short term results in lower larynx preservation and local control, its favorable long-term outcome suggested by RTOG 91-11 should not be ignored.” Dr. Vokes stated that the conclusion of the TREMPLIN investigators not to move to phase III III sett setting ing “appears appropriate, especially in view of the toxicities associated with the administration of intensified therapy.” He added that the TREMPLIN trial “confirms that practitioners should continue to choose either induction or concomitant therapy but not both, and it failed to identify a role for cetuximab-based therapy in laryngeal cancer. These results are compatible with similar data from recent larger randomized trials that found no benefit from the addition of induction chemotherapy to concomitant chemoradiotherapy or of a sequential TPF carboplatin/radiation approach compared with concomitant cisplatin radiation alone.” In addition to the articles summarized above, the Journal of Clinical Oncology also recently published an Oncology Grand Rounds article titled, “Larynx Preservation for Patients With Locally Advanced Laryngeal Cancer.” Along with a case presentation and suggested management approaches,

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In the Literature

the article includes a review of the relevant literature. Forastiere AA, et al: J Clin Oncol 31:845-852, 2013. Lefebvre JL, et al: J Clin Oncol 31:853-859, 2013. Vokes EE: J Clin Oncol 31:833-835, 2013. Corry J, et al: J Clin Oncol 31:840844, 2013.

complicated modeling procedures” and “may benefit from the inclusion of additional predictors,” the authors noted. In addition, the model based risks on a median follow-up of 9.2 years, “which exceeds the follow-up in the NLST and makes estimates inaccurate when applied to the NLST.” Among the aims of the current study were to

modify and update the PLCO model and make it apply directly to NLST data.

Updated Model PLCOM2012, was developed and validated with data from the 80,375 persons in the PLCO control and intervention groups who had ever smoked.

“In the validation data set, 14,144 of 37,332 persons (37.9%) met NLST criteria. For comparison, 14,144 highest-risk persons were considered positive (eligible for screening) according to PLCOM2012 criteria. We compared the accuracy of PLCOM2012 criteria with NLST criteria to detect lung cancontinued on page 138

LUNG CANCER Modified and Updated Riskprediction Model Is More Efficient in Identifying Persons for Lung Cancer Screening An updated and modified lung-cancer risk-prediction model developed from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial “was more sensitive” for lung cancer detection than criteria from the National Lung Cancer Screening Trial (NLST), according to a study in The New England Journal of Medicine. Compared with NLST standards, criteria for the new model, known as PLCOM2012, “had improved sensitivity (83.0% vs 71.1%, P < .001) and positive predictive value (4.0% vs 3.4%, P = .01), without loss of specificity (62.9% and. 62.7%, respectively; P = .54); 41.3% fewer lung cancers were missed,” the researchers reported. The NLST criteria include an age between 55 and 74 years, a history of smoking of at least 30 pack-years, and less than 15 years since cessation of smoking. “These selection criteria were intended to increase the yield of lung cancers, but they exclude many known risk factors for lung cancer,” the researchers noted. Additional criteria were included in the lung-cancer risk-prediction model the investigators previously developed and validated involving former and current smokers in PLCO control and intervention groups. “Model predictors included age, level of education, body mass index, family history of lung cancer, chronic obstructive pulmonary disease, chest radiography in the previous 3 years, smoking status (current smoker vs former smoker), history of cigarette smoking in pack-years, duration of smoking, and quit time (the number of years since the person quit smoking),” the researchers reported. While the NLST model “has high predictive discrimination,” it “can be cumbersome to apply because it uses

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T:10.25" S:9.5" PAGE 138

The ASCO Post | APRIL 15, 2013

In the Literature

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Emerging Clinical Data continued from page 137

cer,” the researchers explained. “Among 37,332 smokers in the PLCO intervention group, the PLCOM2012 selected 81 more persons for screening who received a diagnosis of lung cancer in follow-up than did the NLST criteria. If one assumes a 15% rate of overdiagnosis, then 69 of these persons can be considered to have ‘true’ life-threatening lung cancer,” the authors reported. “In conclusion, the PLCOM2012 predicted the 6-year risk of lung cancer with high accuracy and was more efficient at identifying persons for lung cancer screening, as compared with the NLST criteria,” the authors stated. “Because the mortality reduction from CT screening effectiveness did not vary according to lung-cancer risk, it appears that use of the PLCOM2012 to select persons for lung-screening programs could potentially be an effective method leading to improved cost-effectiveness of screening with additional deaths from lung cancer prevented.” Tammemägi MC, et al: N Engl J Med 368:728-736, 2013.

MULTIPLE MYELOMA Thalidomide/Prednisone Maintenance after Stem Cell Transplant Improves Progression-free but Not Overall Survival Maintenance therapy with thalidomide (Thalomid) and prednisone after autologous stem cell transplantation in patients with multiple myeloma improved progression-free survival but not overall survival, according to results of a phase III trial reported in Blood. Patients receiving maintenance therapy were more likely to experience adverse events and report worsening health-related quality of life “with respect to cognitive function, dyspnea, constipation, thirst, leg swelling, numbness, dry mouth, and balance problems,” the investigators reported. The randomized, controlled trial compared thalidomide/prednisone as maintenance therapy with observation in 332 patients. Eligible patients were required to have received melphalan at 200 mg/m2 followed by autologous stem cell transplantation. “The study precluded the use of bortezomib (Velcade) or lenalidomide (Revlimid) before [autologous stem cell transplantation] to isolate the impact

of maintenance with thalidomide,” the researchers noted. The trial was conducted and analyzed by the National Cancer Institute of Canada Clinical Trials Group, and patients were accrued from centers in Canada and, in collaboration with the Eastern Cooperative Oncology Group, the United States.

Study Results At a median follow-up of 4.1 years, overall survival was 68% among patients receiving thalidomide/prednisone and 60% in the observation group (HR = 0.77; P = .18). The maintenance therapy was, however, “associated with superior myeloma-specific progression-free survival and progressionfree survival (for both outcomes, the 4-year estimates were 32% vs 14%; HR = 0.56; P < .0001) and more frequent venous thromboembolism (7.3% vs none; P = .0004). Median survival after first disease recurrence was 27.7 months with thalidomide/prednisone and 34.1 months in the observation group,” the investigators reported. “Twelve thromboembolic events were observed in patients receiving thalidomide/prednisone and there were no events in the observation arm (12 of 165 or 7.3% vs 0; P = .0004),” the researchers wrote. Nonhematologic events that occurred more frequently in the patients receiving thalidomide/prednisone included hyperglycemia, edema, hypertension, and fatigue. “Our findings of inferior [healthrelated quality of life] outcomes in patients receiving thalidomide/prednisone call into question the benefits of a strategy to provide this agent as maintenance therapy for all patients and invite evaluations of predictive biomarkers that might better direct this treatment,” the authors concluded. “Future trials should also be conducted to determine whether other agents, such as lenalidomide or bortezomib, may demonstrate survival and/or [health-related quality of life] benefits as maintenance therapy after [autologous stem cell transplantation]. Finally, our results juxtaposing [progression-free survival, healthrelated quality of life, and overall survival] support ongoing debates about which outcomes should drive treatment policies, especially when sequencing of newly available therapies is possible.” n Stewart AK, et al: Blood 121:15171523, 2013.

Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. Avastin in combination with fluoropyrimidine‑irinotecan or fluoropyrimidine‑ oxaliplatin based chemotherapy is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.

T:10.25" S:9.5" AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

(approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

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

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

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

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

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

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

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

20%

26%

39% 10% 15% 2%

47% 35% 26% 9%

26% 1%

32% 6%

19%

40% 32% 25% 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. Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

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

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥65 years (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab

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

S:12.5"

Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). [See Warnings and Precautions (5.8).]

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

T:13" S:12.5"

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

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

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

NOW APPROVED: Avastin continued beyond first progression in MCRC In combination with fluoropyrimidine-based chemotherapy following a first-line Avastin-containing regimen...

Think Avastin

Continuing to deliver proven overall survival The only biologic to prospectively demonstrate significant overall survival (OS) in a Phase III MCRC trial after treatment with a first-line Avastin-containing regimen1 Median OS:

Percentage Surviving

100

11.2 vs 9.8 months

(HR=0.81 [95% CI, 0.69–0.94], P=0.0057)

80 60

Avastin + fluoropyrimidine-based chemotherapy* (n=409) Fluoropyrimidine-based chemotherapy* alone (n=411)

40 20 0

24 OS (Months)

*Chemotherapy combinations included both irinotecan- and oxaliplatin-containing regimens. At first progression, chemotherapy was switched: oxaliplatin→irinotecan or irinotecan→oxaliplatin.1

1.7-month increase in median PFS beyond first progression with Avastin plus fluoropyrimidine-based chemotherapy*: 5.7 vs 4.0 months with fluoropyrimidine-based chemotherapy* alone (HR=0.68 [95% CI, 0.59–0.78], P<0.0001)1 There was no significant difference in response rate1

MCRC=metastatic colorectal cancer; HR=hazard ratio; CI=confidence interval; PFS=progression-free survival.

Indications

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidineoxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%)

AVA0001557000

Printed in USA.

Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

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

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

When continued beyond first progression in MCRC, no new safety signals were observed in Study ML18147 when Avastin was administered in second-line MCRC patients who progressed on an Avastin-containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. Reference: 1. Avastin Prescribing Information. Genentech, Inc. January 2013.

(01/13)