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Omacetaxine for CML

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| Managing Brain Metastases

40

| Day in the Life of an Oncology Fellow

VOLUME 4, ISSUE 1

72

JANUARY 15, 2013

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

San Antonio Breast Cancer Symposium

Adjuvant Tamoxifen for Women with ER-positive Breast Cancer: 10 Years Superior to 5 Years

ASCOPost.com

Are We Winning the War on Cancer?

F

ive years of tamoxifen has long been considered the standard of care as adjuvant therapy for women with estrogen receptor–positive breast cancer. However, extending tamoxifen treatment for 10 years reduced the risk of dying by 29% durRichard Gray, MD ing the second decade after diagnosis compared with standard therapy in the international Adjuvant Tamoxifen–Longer Against Shorter (ATLAS) study. ATLAS results were presented at the 2012 San Antonio Breast Cancer Symposium and published simultaneously in The Lancet.1,2 “Five years of tamoxifen is very effective, and we know there is a carryover effect after stopping, with about a 30% reduction in mortality over the next 5

© SABCS/Todd Buchanan, 2012

By Alice Goodman

years. ATLAS evaluated whether longer-term treatment could improve upon the carryover effect of 5 years of treatment,” said Richard Gray, MD, Clinical Trial Service Unit, University of Oxford, United Kingdom.

Key Results “In the period 10 to 14 years after diagnosis, we found many fewer recurrences: 617 in the group receiving 10 years of tamoxifen vs 711 in patients treated with 5 years of tamoxifen. Breast cancer mortality and overall survival were similarly affected by longer duration of tamoxifen,” he continued. There were 331 See Page 101 breast cancer–related deaths in the 10-year group vs 397 in the 5-year group, and 639 vs 722 deaths from all causes, respectively. continued on page 12

Quality Care Symposium

Does Health-care Quality Translate to Value?

By Franco Cavalli, MD, FRCP

O

n December 23, 1971, President Richard Nixon signed the U.S. National Cancer Act. This date is widely considered to mark the beginning of the so-called “War on Cancer,” although that phrase was introduced only later on. Over recent decades, journalists have from time to time questioned whether we are winning this “war,” while most oncologists have tended to give a much more positive evaluation of the progress being made.1

Unusual Gathering To mark its 30th anniversary, the Eurocontinued on page 105

Prof. Cavalli is Scientific Director of the Oncology Institute of Southern Switzerland, Professor of Oncology at the University of Bern, Switzerland, Chairman of the Scientific Committee of the European School of Oncology, and Past-President of the Union for International Cancer Control.

A Payer’s Perspective on the ‘Episode of Care’ Payment Model By Ronald Piana

O

MORE IN THIS ISSUE

n March 23rd, 2010, President Obama signed into law the Patient Protection and Affordable Care Act, enacting sweeping change in our healthcare system. An underlying theme of the legislation is the realignment of our payment system so that it places value over volume of services. At ASCO’s first Quality Care Symposium, held recently in San Diego, Lee N. Newcomer, MD, MHA, Senior Vice President, UnitedHealthcare, discussed a payment meth-

odology that addresses that priority and that might represent one possible future for oncology practice. Dr. Newcomer began his presentation with a graph showing that unless qualitative cost measures are implemented in health care, by 2018 it will take half of a family’s income to pay for insurance premiums and out-of-pocket expenses. “Naturally, we can’t let that happen, so it’s incumbent on people like those of us here in San Diego to do something about it. To that end, I’m going to talk about a solution we attempted at UnitedHealthThe current system of oncology drug care called the ‘episode payment’ project,” said Dr. revenue dependence was created 40 Newcomer.

years ago. No one thought it would be a problem, but it is, and it’s vital that we address ways to fix it.

— Lee N. Newcomer, MD, MHA

Oncology Meetings Coverage ASH Annual Meeting������������ 3, 7, 17-20 San Antonio Breast Cancer Symposium���������������������������������16 Quality Care Symposium�������������� 22, 27 35th ESMO Congress������������������� 66, 68 FDA Update������������������������������������9, 54-58 Gene Profiling for Unknown Primary�������������������������������������53 Direct from ASCO������������������������������ 59-63 Pioneers in Oncology: Judah Folkman� 79 Dr. Allen S. Lichter on ASCO Initiatives����������������������������������������91

Setting up a New System “Our objective was to find a way in which phycontinued on page 22

Send your comments to editor@ASCOPost.com

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The ASCO Post  |   JANUARY 15, 2013

PAGE 2

News

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

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

Associate Editors Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Douglas W. Blayney, MD Stanford University Medical Center

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

Philip D. Bonomi, MD Rush University Medical Center

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

Richard Boxer, MD University of Miami

George W. Sledge, MD Indiana University

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

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

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

Last-minute ‘Fiscal Cliff’ Deal by Congress Again Averts Medicare Cuts to Physicians

A

last-minute patch to the sustainable growth rate formula included in the “fiscal cliff ” deal averted massive cuts to oncologists who care for and treat Medicare patients. “This endof-year crisis management once again demonstrates the critical need for fundamental reform of the Medicare reimbursement system,” commented ASCO President-Elect Clifford A. Hudis, MD, in a statement after the deal was achieved.

(HHS),” Dr. Hudis continued. “By allowing these as an alternative to quality reporting currently required by the Centers for Medicare and Medicaid Services, Congress has taken a critical first step towards a more robust quality monitoring system in cancer,” he said. “ASCO worked to achieve bipartisan support for this provision, which begins in 2014, and will continue to work in 2013 with the HHS Secretary and the Administration to ensure

This end-of-year crisis management once again demonstrates the critical need for fundamental reform of the Medicare reimbursement system. —Clifford A. Hudis, MD

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

Michael P. Link, MD Stanford University Medical Center

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

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

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

Harborside Press® Publishing Staff

“ASCO is pleased the legislation includes a provision that allows physicians to satisfy federal quality reporting requirements through clinical data registries approved by the U.S. Department of Health and Human Services

ASCO’s Quality Oncology Practice Initiative® (QOPI) can be used to fulfill the quality reporting requirements,” said Dr. Hudis. “Unfortunately, the triple-threat of continued on page 38

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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PAGE 3

ASH Annual Meeting Hematology

Pivotal Trial Shows Robust Activity of Ponatinib in Some Heavily Pretreated Leukemias By Alice Goodman

T

he pivotal phase II Ponatinib Ph+ ALL and CML Evaluation (PACE trial) found that 1  year of treatment with the novel investigational drug ponatinib achieved robust activity in heavily pretreated patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL). Responses occurred early, were generally deep and durable, and were seen regardless of mutation status or disease stage. This is promising news for patients who don’t respond or lose their response to initial treatment with the approved tyrosine kinase inhibitors imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna).

study at the 54th Annual Meeting of the American Society of Hematology in Atlanta.1 Ponatinib was engineered to overcome mutations associated with resistance to tyrosine kinase inhibitor therapy. The drug is the only tyrosine kinase inhibitor currently in use known to be effective against the T315I mutation. PACE enrolled 449 patients: 270 with chronic-phase CML, 85 with accelerated-phase CML, and 94 with blast-phase CML or Philadelphia chromosome–positive ALL. At

Ponatinib is generally well tolerated, and more studies in CML and [Philadelphia chromosome–positive] ALL will be forthcoming

Durable Responses “These results show that ponatinib has outstanding activity regardless of the stage or presence or absence of mutations associated with resistance, and responses are durable. Ponatinib is generally well See Page 101 tolerated, and more studies in CML and [Philadelphia chromosome–positive] ALL will be forthcoming,” stated lead author Jorge E. Cortes, MD, Professor of Medicine, Deputy Chair of the Department of Leukemia, and Chief of the CML and AML Sections at The University of Texas MD Anderson Cancer Center in Houston. He presented the findings of the PACE

sponse, 57% of those in accelerated-phase CML achieved a major hematologic response, and 34% of those in blast-phase CML or with Philadelphia chromosome–positive ALL achieved a major hematologic response. Dr. Cortes focused his presentation on 267 evaluable patients in chronic-phase CML, 84% whom were resistant to other tyrosine kinase inhibitors. Detailed results in advanced-phase patients were presented separately. Among chronic-phase patients,

—Jorge E. Cortes, MD

baseline, between 84% and 95% were resistant to dasatinib or nilotinib; about 92% were treated with two or more prior lines of tyrosine kinase inhibitor therapy, and 53% to 60% received three or more prior tyrosine kinase inhibitors.

Key Findings Regarding primary endpoints, 56% of those in chronic-phase CML achieved a major cytogenetic re-

Ponatinib in CML and Ph+ ALL ■■ In the 449-patient PACE trial, the tyrosine kinase inhibitor ponatinib achieved robust activity in heavily pretreated patients with chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia.

■■ Responses occurred early, were deep and durable, and were seen regardless of mutation status or disease stage.

■■ The drug is the only tyrosine kinase inhibitor known to be effective against the T315I mutation.

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

67% had any cytogenetic response, 56% had a major cytogenetic response, and 46% had a complete cytogenetic response. A major molecular response (BCR-ABL–to–standardized control gene ratio ≤ 0.1) was achieved in 34% of this group. “Molecular responses are deep and durable,” Dr. Cortes said. “At 12 months, 91% of all chronic-phase patients with [major cytogenetic response] maintained their response,” he stated. Responses were maintained regardless of mutational status. A major cytogenetic response was achieved in 49% of patients with no mutations, 57% of those with any non-T315I mutation, and 70% of those with the T315I mutation. Ponatinib was well tolerated, with skin rash, abdominal pain, headache, dry skin, and constipation of any grade occurring in more than one-

Aaron D. Schimmer, MD, FRCPC, PhD

third of patients. Grade 3/4 adverse events were rare. Grade 3 pancreatitis was reported in 6% of patients, and only one patient had to come off study because of pancreatitis.

Looking Ahead Dr. Cortes said that other studies of ponatinib are planned, both as front-line therapy and in patients for whom one previous tyrosine kinase inhibitor has failed. “This study shows that we have a drug that works in patients with mutations that cause resistance. These patients no longer respond to other drugs. This study, as well as others presented at the meeting, show that what we have learned about genetic abnormalities is paying off in terms of therapy,” stated Aaron D. Schimmer, MD, FRCPC, PhD, a medical oncologist at Princess Margaret Cancer Center, University Health Network, Toronto, Canada. n

Disclosure: Dr. Cortes receives research support from Ariad, Pfizer, Chemgenex, Bristol-Myers Squibb, and Novartis; and is a consultant for Ariad, Pfizer, and Teva. Dr. Schimmer reported no potential conflicts of interest.

Reference 1. Cortes J, Kim D-W, Pinella-Ibarz J, et al: 12-month follow-up of the PACE trial. 2012 ASH Annual Meeting. Abstract 163. Presented December 9, 2012. Editor’s Note: Ponatinib (Iclusig) was recently approved by the FDA for treatment of adult patients with CML or AML (see page 9 for more information).

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.


Important Safety Information

Additional Important Safety Information

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

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

• • • • •


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

STRENGTHEN HER DEFENSE

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

Extend progression‑free survival (PFS) with an FDA‑approved HER2 dimerization inhibitor1,2

6.1-Month Improvement in Median IRF†-Assessed PFS1 Placebo + Herceptin + docetaxel 100

• Consistent PFS results were observed across a broad range of patient subgroups • At the time of analysis, there were 191 (47.5%)

90

1

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

80 70

18.5 MONTHS

60 PFS (%)

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

PERJETA + Herceptin + docetaxel

50

12.4 MONTHS

40 30 20 10 0 0

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

5

10

15

20

25

30

35

40

32 17

10 7

0 0

0 0

MONTHS P+H+D Pl+H+D

402 406

345 311

267 209

139 93

83 42 Patients at risk

• In the randomized trial, the overall frequency of hypersensitivity reactions/anaphylaxis was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group • If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate

medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown Most Common Adverse Reactions The most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. For more information, scan the QR code or visit www.PERJETA.com.

• •

© 2012 Genentech USA, Inc.

All rights reserved.

PER0001010501

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

Printed in USA.

(09/12)


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

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

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

Grades 3-4 %

Frequency rate % All Grades %

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

Grades 3-4 %

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

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

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

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

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

PERJETA™ (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990

PERJETA is a trademark of Genentech, Inc. 6/12 PER0000999400 © 2012 Genentech, Inc. 10139000


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PAGE 7

Expert’s Corner Clinical Guidelines

National Comprehensive Cancer Network Appoints New CEO A Conversation with Robert W. Carlson, MD By Ronald Piana

Robert W. Carlson, MD

T

he National Comprehensive Cancer Network (NCCN) recently appointed nationally regarded breast cancer expert Robert W. Carlson, MD, as its new CEO. Previously, Dr. Carlson was Professor of Medicine in the Division of Oncology and Medical Informatics, Stanford University Medical Center; he first joined the Stanford faculty in 1983. The ASCO Post spoke with Dr. Carlson about his new role at NCCN, which commenced on January 2, 2013.

Making the Move What are your thoughts about leaving Stanford? I’ve been at Stanford for 40 of the past 42 years, so I have many significant attachments to this wonderful institution that fosters creativity and discovery in a robust atmosphere of diversity. The hardest part of leaving, of course, is separating from richly productive relationships I’ve developed over the years with colleagues, staff, students, and especially with my patients. What persuaded your decision to accept the CEO position at NCCN? Simply put, the draw to NCCN is very strong. The organization’s ongoing ability and potential to improve the lives of cancer patients globally continues to mature, and I want to be a part of that crucially important process.

Evolution of NCCN How has the NCCN changed in terms of its vision? I wasn’t in the room when NCCN was founded, but I was just outside the door, one of the early participants. When NCCN was first orga-

nized in the mid-1990s, it was really in response to the increasing influence of HMOs and the threat they represented to the ability of academic medical institutions to care for cancer patients. I think NCCN’s founding leadership envisioned the organization’s goal was based largely on its ability to negotiate contracts with payers and, in turn, respond to the threats posed by the increased leverage of HMOs. However, the payers were concerned that academic cancer centers were simply providing too much expensive care. NCCN responded by creating clinical practice guidelines so the payers would have a clear understanding of the value of care they were paying for. Over the years, NCCN guidelines have become the gold standard in the United States, viewed as optimal cancer care. In fact, the guidelines are now used, in part, as defining what payers should cover. So the core product of NCCN has been inverted over the years, changing from one designed to justify treatment delivered, to one that is used to establish what payers should cover, from the community setting to academic institutions.

opportunities to the oncology community—these are well-established, vibrant programs that we plan to continue. But we are a dynamic organization that is constantly seeking ways to improve our ability to serve the oncology community. For instance, in 2012, the NCCN website has had more than 4 million downloads of our guidelines alone. We also have more than 1.5  million unique users of our website’s products. We’re developing tools to facilitate faster and more seamless provider access to the guidelines within the context of electronic medical records (EMRs), which enables their use in real-time patient care. We are also collaborating with several pharmaceutical companies on initiatives to support translational research led by our member institutions. Further, the organization is strengthening its relationships with payers by seeking to improve the quality of information we provide. This will maximize the efficiencies among payers, providers, and patients, and at the same time minimize health-care waste in the system.

Ongoing Initiatives

You mentioned that JNCCN is flourishing, what part does the journal play in the overall picture?

These are fiscally challenging times. Are you confident that NCCN will be able to maintain and grow its large portfolio of services? There’s no question that we are living in challenging times, and it will take creativity and flexibility to accomplish our goals. But I believe we are well positioned to continue providing a wide array of cutting-edge services for the cancer community. Of course, maintaining the fiscal health of an organization of our size, reach, and ambitions requires a dedication to maintaining fiscal health. Please give the readers a snapshot of the NCCN’s ongoing work. We will continue our annual guideline conference in Florida, the Journal of the National Comprehensive Cancer Network ( JNCCN) is flourishing with a rapidly increasing impact factor, and we have our ongoing CME programs that provide educational

Role of JNCCN

a wonderful job of expanding the journal’s editorial reach and content, giving the publication an international presence.

Cost and Value of Care Cost and value of cancer care is under growing scrutiny, as CEO is this something that you feel NCCN will spend more energy on? We absolutely need to emphasize our attention to cost as it relates to value. First off, providing optimal cancer services is usually the most cost-effective and value-driven way to treat patients. Our goal of optimal care for the individual patient is firmly aligned with the value proposition of care. Plus, our member institutions, users of our guidelines and services, payers, and business collaborators are all calling for us to provide valuedriven care. The challenge, of course, is determining a cost-effective, value-based way to deliver care across a wide spectrum of interested parties, starting with payers, patients, and providers, all of whom might have a different take on what constitutes value. Then we need to address different regional and economic issues within that larger picture. These are major challenges, but I believe that NCCN will find innovative ways to address the cost-and-

Our goal of optimal care for the individual patient is firmly aligned with the value proposition of care. Plus, our member institutions, users of our guidelines and services, payers, and business collaborators are all calling for us to provide value-driven care. —Robert W. Carlson, MD

The JNCCN is a terrific educational product that allows us to publish the guidelines for wide dissemination. Importantly, the journal focuses on specific areas in the guidelines where new information or ongoing controversies can be addressed. This gives us the ability to expand the manuscript portions of the guidelines for the interested reader. Moreover, our Editor-in-Chief, Harold Burstein, MD, PhD, has done

value–driven equation. For instance, NCCN has entered into an extensive collaboration with a Washington, DC–based not-for-profit organization called the National Business Group on Health, which represents more than 350 of the nation’s Fortune 500 employers. We’re working with them to build model cancer-benefit templates that will not only be used by the group’s employers, but also by continued on page 8


The ASCO Post  |   JANUARY 15, 2013

PAGE 8

Expert’s Corner

Robert W. Carlson, MD continued from page 7

other companies. Remarkably, the resources that we’ve developed through this collaboration have been downloaded more than 72,000 times. It’s clear that our constituencies are insisting that NCCN must address the issue of cost and value, and we are rising to that call.

growth in the coverage and accessibility for our guidelines by EMR implementation and collaborations. The organization also needs to grow its outreach and presence in the healthcare policy arena. To handle this growth will require establishing priorities and at the same time remaining in close contact with

our members and those in the community setting. It’s important to note that as we move forward into new and exciting challenges, we need to work with other professional organizations so we can all benefit from the creative energy of a collective power base. n

National Comprehensive Cancer Network Visit NCCN at www.NCCN.org

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

Managing Growth Is there any single challenge you see as you prepare to assume the role of CEO? The major challenge for NCCN is undoubtedly how we manage growth, and there are a series of dimensions that define growth. I do expect NCCN to add more member institutions— how many and how rapidly is still an emerging discussion. We should see

Contact

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

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

Advertising

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

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

Simulated image based on locally advanced BCC patient at Week 24. Indication

Erivedge (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. ®

Boxed Warning and Additional Important Safety Information • Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen

• Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant • Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555

Blood Donation

• Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge

Nursing Mothers

• Inform female patients of the potential for serious adverse reactions in nursing infants from Erivedge, taking into account the importance of the drug to the mother

Trim:


ASCOPost.com  |   JANUARY 15, 2013

PAGE 9

FDA Update

FDA Approves Ponatinib to Treat CML and Philadelphia Chromosome–positive ALL

I

n December, the FDA granted accelerated approval to ponatinib (Iclusig) for the treatment of adult pa:15.5” tients with chronic-, accelerated-, 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 (ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. Pona-

tinib is an oral, third-generation, pan– BCR-ABL tyrosine kinase inhibitor that targets CML cells with the T315I mutation. The drug was approved continued on page 10

ORAL, ONCE-DAILY THERAPY1

TRANSFORM THE TREATMENT OF ADVANCED BCC Erivedge— a unique treatment option 1Z38366Y0396063131

• Systemic therapy that targets dysregulated Hedgehog pathway signaling, a known driver of BCC1,2 • One 150-mg capsule a day until disease progression or unacceptable toxicity1 • Erivedge reduced lesions in patients with advanced BCC1,3 Objective response rates (ORR) by IRF from ERIVANCE1,3* laBCC (n=63)

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

ORR (95% CI)

Median response duration (months) (95% CI)

*Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. Response in laBCC: absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on sampling biopsy. Response in mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. IRF=Independent Review Facility. laBCC=locally advanced BCC. mBCC=metastatic BCC. CI=confidence interval. NE=not estimable.

Adverse Reactions

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

© 2012 Genentech USA, Inc. All rights reserved. HED0001559500 Printed in USA.

See what you can offer your patients with advanced BCC at www.Erivedge.com References: 1. Erivedge® (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. 2. Epstein EH. Nat Rev Cancer. 2008; 8:743-754. 3. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012;366:2171-2179.

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%


The ASCO Post  |   JANUARY 15, 2013

PAGE 10

FDA Update

Ponatinib Approved

ment option to patients with CML who are not responding to other drugs, particularly those with the T315I mutation who have had few therapeutic options,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research. “[Ponatinib] is the third drug

continued from page 9

more than 3 months ahead of the its prescription user fee goal date of March 27, 2013, the date the agency was scheduled to complete review of the drug application. “The approval of [ponatinib] is important because it provides a treat-

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 Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

-

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

-

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

PACE Trial The approval was based on the results of the PACE trial, a multicenter,

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*OTUSVDUBMMNBMFQBUJFOUT FWFOUIPTFXJUIQSJPSWBTFDUPNZ UPVTF 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*OTUSVDUQBUJFOUTUPJNNFEJBUFMZSFQPSUBOZQSFHOBODZFYQPTVSFUP 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"EWJTFQBUJFOUTOPUUPEPOBUFCMPPEPSCMPPEQSPEVDUTXIJMFUBLJOH 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.

T:10”

1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138  patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10  months (305  days; range 0.7  to  36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥  10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥  10% of Advanced BCC Patients

2

approved to treat CML and the second drug approved to treat ALL this year, demonstrating FDA’s commitment to approving safe and effective drugs for patients with rare diseases.”

international, single-arm clinical trial of 449 patients with disease that was resistant or intolerant to prior tyrosine kinase inhibitor therapy. The drug’s effectiveness was demonstrated by a reduction in the percentage of cells expressing the Philadelphia chromosome genetic mutation to less than 35%, a major cytogenetic response. Fifty-four percent of all patients and 70% of patients with the T315I mutation achieved major cytogenetic response. The median duration of major cytogenetic response had not yet been reached at the time of analysis. In accelerated- and blast-phase CML and Philadelphia chromosome–positive ALL, ponatinib’s effectiveness was determined by the number of patients who experienced major hematologic response. Results showed: ■■ 52% of patients with acceleratedphase CML experienced major hematologic response for a median duration of 9.5 months; ■■ 31% of patients with blast-phase CML achieved major hematologic response for a median duration of 4.7 months; and ■■ 41% of patients with Philadelphia chromosome–positive ALL achieved major hematologic response for a median duration of 3.2 months. Ponatinib is being approved with a Boxed Warning alerting patients and health care professionals that the drug can cause blood clots and liver toxicity. The most common side effects reported during clinical trials include high blood pressure, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. n

Important VIdeo HIgHlIgHts from

ASH 2012 Dr. James Armitage, Editor-in-chief of The ASCO Post, interviews leading experts: • Dr. Richard Fisher on lymphomas • Dr. Hagop Kantarjian on leukemias • Dr. Sagar Lonial on multiple myeloma Presented by The ASCO Post. Recorded at ASH 2012 in Atlanta, Georgia.

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

Visit ASCOPost.com to view webcast program.


ASCOPost.com  |   JANUARY 15, 2013

PAGE 11

ASH Annual Meeting Hematology

Overall Survival Benefit Achieved with Pomalidomide in Advanced Myeloma By Caroline Helwick

S

upport for the oral immunomodulatory agent pomalidomide for multiple myeloma took a step forward when the phase III MM-003 trial showed a survival advantage in patients with advanced disease, in addition to a doubling in progression-free survival, when pomalidomide was given with low-dose dexamethasone.

Meletios A. Dimopoulos, MD

Interim Analysis The data for the open-label phase III MM-003 trial of 455 patients with relapsed or refractory myeloma were reported at the 54th Annual Meeting of the American Society of Hematology by Meletios A. Dimopoulos, MD, Professor and Chairman of the Department of Clinical Therapeutics at Alexandra Hospital in Athens, Greece.1 The study crossed the prespecified superiority boundary at the interim analysis. Therefore, the Data Safety Monitoring Board recommended that the single-agent dexamethasone arm

be discontinued and patients crossed over to receive the novel combination. “We saw a statistically significant increase in progression-free survival from about 2 months with high-dose dexamethasone to 4 months with this combination, and this difference translated to a significant overall survival advantage as well,” he said. “The benefit of pomalidomide plus low-dose dexamethasone has now been shown in the context of a prospective randomized trial, and it is superior to the current standard of care in patients with relapsed/refractory myeloma,” he maintained. Pomalidomide is considered more potent than the other available immunomodulatory drugs, thalidomide (Thalomid) and lenalidomide (Revlimid). Trials in the first-line setting are now underway, and pomalidomide is under consideration for approval by the FDA.

Overall Survival Benefit Observed After a median follow-up of 18 months, the median progression-free survival was 15.7 weeks with pomalidomide at 4 mg plus low-dose dexamethasone at 20 mg vs 8 weeks with singleagent high-dose dexamethasone (20 mg administered more frequently), which was a 55% reduction in risk (P < .001). While median overall survival was

Pomalidomide in Relapsed/Refractory Multiple Myeloma ■■ The phase III MM-003 trial showed that the combination of pomalidomide at 4 mg plus low-dose dexamethasone doubled progression-free survival time and provided a benefit in overall survival as well.

■■ Overall survival was 34 weeks with high-dose dexamethasone but has not been reached with pomalidomide/low-dose dexamethasone.

EXPERT POINT OF VIEW

S

haji K. Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, commented on the findings. “Patients with myeloma are living longer, but the disease comes back in the majority. We really need new drugs, and I think the main message of this study is that clearly patients do live longer on this combination,” he said. When asked whether pomalidomide might replace lenalidomide in myeloma, he pointed Shaji K. Kumar, MD out that this would not be done in the absence of formal comparisons of the two immunomodulatory agents. “I am not sure that is even necessary,” he added, “because we look at pomalidomide as being able to work in about one-third of patients in whom lenalidomide has stopped working. We are thinking of each of these drugs as building blocks for improving survival in myeloma.” n Disclosure: Dr. Kumar reported no potential conflicts of interest.

34 weeks with high-dose dexamethasone, it has not been reached with pomalidomide/low-dose dexamethasone. This yielded a 47% risk reduction <������������������� ������������������ .001), and Dr. Difor mortality (P  �������������������� mopoulos projected that the average patient would be alive for about 1 year. Good tolerability was observed in patients receiving the combination, with side effects occurring as expected. The greatest difference in tolerability from the single agent was a higher incidence of neutropenia with the combination (42% vs 15%). But the incidence of infection was similar in both arms of the study. At the time of the analysis, 45% of patients on the combination arm and 25% in the single-agent arm remained on study. More of the high-dose dexamethasone arm discontinued the regimen due to disease progression (48% vs 35%). “We believe this study provides the basis for considering this combination

as a new standard of care for hard-totreat patients who have exhausted most standard treatments for their refractory disease,” Dr. Dimopoulos stated. “And we believe See Page 101 pomalidomide may offer even greater benefit if studied among less heavily treated patients.” n

Disclosure: Dr. Dimopoulos has received honoraria from Celgene.

Reference 1. Dimopoulos MA, Lacy MQ, Moreau P, et al: Pomalidomide in combination with low-dose dexamethasone demonstrates a significant progression-free survival and overall survival advantage in relapsed/ refractory multiple myeloma: A phase 3, multicenter, randomized, open-label study. 2012 ASH Annual Meeting. Abstract LBA6. Presented December 11, 2012.

Don’t Miss These Important Reports in this Issue of The ASCO Post ASCO Initiatives for 2013 Discussed with Allen S. Lichter, MD, see pages 27 and 91

Richard J. Boxer, MD, FACS, on Accountable Care Organizations, see page 51

Visit The ASCO Post online at ASCOPost.com

Barrie S. Cassileth, MS, PhD, on Integrative Oncology, see page 93


The ASCO Post  |   JANUARY 15, 2013

PAGE 12

34th Annual San Antonio Breast Cancer Symposium Adjuvant Tamoxifen

Optimal Duration of Tamoxifen Treatment

continued from page 1

Study Details

ATLAS enrolled 6,846 women with estrogen receptor–positive breast cancer from 36 countries between 1996 and 2005. About 50% had node-positive disease, and all women had been taking tamoxifen for 5 years. Women were randomly assigned to continue with 5 more years of tamoxifen or to no more tamoxifen. The majority of women with ERpositive breast cancer were postmenopausal (89% in both groups, those

■■ Ten years of adjuvant tamoxifen extends survival compared with the

standard 5 years of therapy in patients with estrogen receptor–positive breast cancer.

■■ The benefits of longer duration of tamoxifen emerge 10 to 14 years after diagnosis.

■■ Results of ATLAS should be discussed with women with estrogen receptor– positive breast cancer who are candidates for hormonal therapy.

continuing tamoxifen to 10 years and those stopping tamoxifen at 5 years). Approximately 9% and 10%, respectively, were premenopausal at ATLAS

trial entry and 2% in each group were either perimenopausal or menopausal status unknown. The effects of longer tamoxifen

EXPERT POINT OF VIEW metrial cancer is very low in premenopausal women. In my opinion, the results of this trial will impact treatment of premenopausal women,” Dr. Ravdin stated.

Risk vs Benefit Peter Ravdin, MD

P

utting these results in perspective, Peter Ravdin, MD, moderator of a San Antonio Breast Cancer Symposium press conference where ATLAS findings were discussed, said that in the United States, there is currently a different strategy for pre- and postmenopausal women. Tamoxifen is used as primary hormonal therapy in premenopausal women, because aromatase inhibitors are not effective, he continued. “In postmenopausal women, aromatase inhibitors in general are slightly superior to tamoxifen and represent the standard of care,” he said. Dr. Ravdin is Director of the Breast Health Clinic at the Cancer Therapy and Research Center at the University of Texas Health Sciences Center San Antonio, Texas. “The results of ATLAS are most relevant for younger women. When they approach 5 years of therapy, usually we tell them to stop. ATLAS tells us that 10 years are superior to 5 years. I’m going to be comfortable telling them that. The risk of endo-

The question is open about how long to continue hormonal therapy, whether with tamoxifen or aromatase inhibitors. “The biology of the disease is such that some women are fated to have late relapses, and ATLAS suggests we can do better by treating women with hormonal therapy beyond 5 years,” he said. Dr. Ravdin cautioned that it is important to weigh risk vs benefit. “Women at high risk of late relapse, with positive nodes, and/or bigger tumors are strong candidates for continuing therapy. But a patient with a small grade 1 tumor and low risk of early and late relapse may decide she doesn’t want 5 more years of tamoxifen or hormonal therapy. The side effects can be very bothersome, and some women will have difficulty considering therapy beyond 5 years for a small benefit—an additional onethird reduction of a very small risk to begin with,” he stated.

Important Implications These results are relevant for premenopausal women for whom aromatase inhibitors are not an option, and also relevant to a wider range of women who may not want

to take aromatase inhibitors because they find the side effects difficult, said Sandra M. Swain, MD, FACP, 2012–2013 President of ASCO and Medical Director of the Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC. “These results have important implications in the United States, for patients who cannot tolerate aromatase inhibitors, which is many women. This is an underappreciated problem. Women are concerned about quality of life, and you can’t expect women in their 50s and 60s who are already beginning to feel the effects of aging to suffer for a 2% absolute benefit,” she stated.

Sandra M. Swain, MD, FACP

ATLAS also has important global health implications, Dr. Swain continued. “In some countries, money is a big issue, and tamoxifen is an inexpensive drug. Longer treatment saves lives,” she said.

Disclosure: Drs. Ravdin and Swain reported no potential conflicts of interest.

on rates of recurrence or death were larger after 10 years than in the period 5 to 9 years after diagnosis. Over the period 5 to 14 years after diagnosis, the risk of breast cancer death was 12.2% for 10-year users vs 15.0% for 5-year users, for an absolute gain of 2.8% favoring the longer treatment duration. “The greatest benefit for longerterm tamoxifen emerged 10 to 14 years after diagnosis,” he said. In the second decade after diagnosis, those who took tamoxifen for 10 years had a 25% lower recurrence rate and 29% lower breast cancer mortality rate compared with those who had only 5 years of tamoxifen therapy. The trade-off with 10 years vs 5 years of treatment could be more side effects, including an increase in endometrial cancer. But in this study, the cumulative risk of death from endometrial cancer between 5 and 14 years after diagnosis was 0.4% for the continuing tamoxifen users vs 0.2% for those who did not continue. “The reduction in breast cancer deaths with 10 years of tamoxifen far outweighs this small risk of endometrial cancer and other adverse events, particularly in younger women who have a low background risk,” Prof. Gray said. “The absolute mortality gain with 10 years of tamoxifen at 15 years after diagnosis is 12%, or 1 in 8 balanced against 1 in 250 cases of endometrial cancer deaths,” he noted.

Disclosure: Prof. Gray potential conflicts of interest.

reported

■ no

References 1. Davies C, Pan H, Godwin J, et al, for the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group: ATLAS—10 v 5 years of adjuvant tamoxifen in ER+ disease: Effects on outcome in the first and in the second decade after diagnosis. 2012 San Antonio Breast Cancer Symposium. Abstract S1-2. Presented December 5, 2012. 2. Davies C, Pan H, Godwin J, et al, for the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. December 5, 2012 (early release online).


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

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

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


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

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

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

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

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

08Z11121R3

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


ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castrationresistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions]. Adrenocortical insufficiency [see Warnings and Precautions]. Hepatotoxicity [see Warnings and Precautions]. Food effect [see Warnings and Precautions]. Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months. The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA). Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions]. Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities). Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Prednisone (N=791) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % Musculoskeletal and connective tissue disorders 29.5 4.2 Joint swelling/discomfort2 26.2 3.0 Muscle discomfort3 General disorders 26.7 1.9 Edema4 Vascular disorders Hot flush 19.0 0.3 Hypertension 8.5 1.3 Gastrointestinal disorders Diarrhea 17.6 0.6 Dyspepsia 6.1 0 Infections and infestations Urinary tract infection 11.5 2.1 Upper respiratory tract infection 5.4 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 Nocturia 6.2 0 Injury, poisoning and procedural complications 5 5.9 1.4 Fractures Cardiac disorders 6 Arrhythmia 7.2 1.1 Chest pain or chest discomfort 7 3.8 0.5 Cardiac failure8 2.3 1.9 1 2 3

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

4.1 2.3

18.3

0.8

16.8 6.9

0.3 0.3

13.5 3.3

1.3 0

7.1 2.5

0.5 0

7.6

0

5.1 4.1

0.3 0

2.3

0

4.6 2.8 1.0

1.0 0 0.3

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

ZYTIGA® (abiraterone acetate) Tablets 4 5 6

Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms. Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations. In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated. Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%). Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebocontrolled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: ZYTIGA is not indicated in children. Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. Manufactured by: Patheon Inc. Mississauga, Canada

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

© Janssen Biotech, Inc. 2012

Revised: July 2012

08Z12237B


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34th Annual San Antonio Breast Cancer Symposium Breast Cancer

Radiation Therapy for Patients with Invasive Breast Cancer: 3 Weeks Proves as Effective as 5 Weeks By Alice Goodman

T

en-year follow-up of the two-part UK Standardisation of Breast Radiotherapy Trials (START) supported the 5-year findings, demonstrating that a 3-week course of adjuvant radiation therapy is equivalent to a 5-week course of radiation for women with invasive breast cancer. The update was presented at the 2012 San Antonio Breast Cancer Symposium.1 Five-year results of START A, presented in 2008, showed that breast cancer is as sensitive to fraction size as

group) vs 39 Gy or 41.66 Gy delivered in 13 fractions over 5 weeks. “This study allowed interpolation to enable a direct estimate of fraction sensitivity,” Dr. Yarnold explained. START B had a pragmatic design, and enrolling 2,215 patients with the same criteria from 35 centers in the United Kingdom. Patients were randomly assigned to receive the same control arm treatment vs 40 Gy in 15 fractions over 3 weeks. Baseline characteristics in both tri-

Patients [with invasive breast cancer] can be safely treated to a lower dose with fewer fractions than the historical standard. —John Yarnold, MD

late-reacting normal tissues, so there is no advantage to 2-Gy fractions. Fiveyear results of START B showed that patients can be safely and effectively treated at a total lower dose of radiation with fewer fractions than the historical standard of 50 Gy delivered over 5 weeks. “No detrimental effects of hypofractionation were identified in the trial or in any subgroup. These results support the current [National Institute for Health and Clinical Excellence] (NICE) guidelines for 40 Gy in 15 fractions as the UK standard of care for all patients with invasive breast cancer,” stated lead author John Yarnold, MD, on behalf of the START trialists. Dr. Yarnold is Professor of Clinical Oncology at The Institute of Cancer Research in London.

Study Specifics START A enrolled 2,236 women with complete surgical excision of stage I to III invasive breast cancer with one involved lymph node and no known metastasis. Patients were randomly assigned to 50 Gy delivered in 25 fractions over 5 weeks (control

als were comparable in the treatment arms. Mean age was 57 years, 25% had node-positive disease, 33% received adjuvant chemotherapy, and 75% were on adjuvant tamoxifen. Patients enrolled in START B had slightly more favorable prognostic features, Dr. Yarnold said. START A showed no evidence that the control arm was better than the other two arms in terms of adverse events, and there was clear evidence that 39 Gy was associated with fewer side effects, he continued. No significant differences were observed between 50  Gy and 41.6  Gy in tumor control; local recurrence rates were comparable. “39 Gy was slightly more gentle on

the cancer,” Dr. Yarnold commented.

Adverse Events START B showed a clear reduction in adverse events with 40������� ������ Gy delivered in 15 fractions vs 50 Gy in 25 fractions. The risk of adverse events was reduced by 23% using the shorter schedule, with an absolute 8% reduction in adverse events. According to physician assessment, rates of adverse events were lower in the 40-Gy arm, including breast shrinkage, induration, and edema. No difference in recurrence was observed between the two arms. “It is unlikely for the shorter schedule to be more than 1% inferior, and it could be 2.5% better in tumor control,” Dr. Yarnold told listeners.

Further Analysis Subgroup analysis of both START A and START B showed no difference in outcomes by age, primary surgery type, presence or absence of axillary nodes, tumor grade, use of boost radiation, and adjuvant therapy. “We conclude that there is no advantage to the continued use of 2-Gy fractions [as in 50 Gy delivered in 25 fractions]. Patients can be safely treated to a lower dose with fewer fractions than the historical standard,” Dr. Yarnold stated. During the discussion following the presentation, Dr. Yarnold said, “I see no reason why 40 Gy delivered in 15 fractions should not be adopted as the standard in other countries.”

U.S. Perspective “This study proves again that short-course radiation is as good as a longer course. The main advantages

Duration of Adjuvant Radiotherapy for Invasive Breast Cancer ■■ A shorter course of adjuvant radiation therapy—consisting of a total dose of 40 Gy delivered in 15 fractions over 3 weeks—was as effective as the standard 5-week course with 50 Gy delivered in 25 fractions in a large randomized trial.

■■ These findings were confirmed at 10-year follow-up in a large randomized trial conducted in the United Kingdom.

■■ The shorter course is now the standard of care in the UK.

of a short course is that it is more convenient for patients and it costs much less than the previous standard,” stated Alphonse Taghian, MD, PhD, Professor of Radiation Oncology at Harvard Medical School and Chief of the Breast Radiation Oncology Service at Massachusetts General Hospital in Boston. Twenty-five percent of the women who participated in the SMART trial were node-positive, and the UK standard applies to all women who require adjuvant radiation. In general, in the United States, the 3-week course is given to node-negative patients and is being used at some centers. “Some radiation oncologists in the United States are concerned about giving a 3-week course without a radiation boost. At Massachusetts General, we follow the Canadian fractionation schedule, treating the whole breast for 3 weeks and 1  day, and adding a boost over 4  days, to complete treatment in 4 weeks instead of our standard 6 weeks,” Dr. Taghian said. The Radiation Therapy Oncology Group (RTOG) is currently running a clinical trial comparing 6  weeks of standard radiation vs 3 weeks of radiation including a boost. That trial has enrolled higher-risk, node-negative patients with stage 0 to II breast cancer. “If results of this study show that the short course with the boost is as effective as the 5- or 6-week course, that will satisfy radiation oncologists who feel the boost is needed. If the study is positive, the short course will become a standard option for patients who fulfill the eligibility criteria,” he said. n Disclosure: Drs. Yarnold and Taghian reported no potential conflicts of interest.

Reference 1. Haviland JS, Agrawal RK, Aird E, et al: The UK START (Standardisation of Breast Radiotherapy) Trials: 10-year follow-up results. 2012 San Antonio Breast Cancer Symposium. Abstract S41. Presented December 6, 2012.


ASCOPost.com  |   JANUARY 15, 2013

PAGE 17

ASH Annual Meeting Hematology

Oral Proteasome Inhibitor May Be a Game-changer in Myeloma By Caroline Helwick

A

n investigational oral proteasome inhibitor currently known as MLN9708 could make the treatment of multiple myeloma much more convenient and possibly less neurotoxic, according to the results of a phase I/II study of treatment-naive multiple myeloma patients presented at the 54th Annual Meeting of the American Society of Hematology.1

Shaji K. Kumar, MD

MLN9708, given in combination with the immunomodulatory agent lenalidomide (Revlimid), achieved an overall response rate exceeding 90%, with complete responses seen in approximately one-quarter of patients, according to Shaji K. Kumar, MD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota. “There is increasing attention toward developing highly effective regimens that at the same time will be better tolerated, more convenient, and able to be taken for a long time,” Dr. Kumar said. The thought is that combining an oral proteasome inhibitor that carries less risk for peripheral neurotoxicity with an oral immunomodulatory agent might achieve this.

First Oral Proteasome Inhibitor “The goal was to develop a highly effective, safe, and convenient all-oral regimen for the initial treatment of myeloma,” he said. MLN9708 is the first oral proteasome inhibitor to enter clinical trials in myeloma, and it appears to be less neurotoxic than its predecessor, bortezomib (Velcade). When given intravenously twice a week, bortezomib is associated with an overall rate of neuropathy of about 30%, though the new subcutaneous formulation is associated with about half the risk of this side effect. With MLN9708, severe neuropathy is generally seen in fewer

than 5% of patients. With MLN9708, “the peripheral neuropathy signal has been fairly low, compared with what we expect with

bortezomib-based regimens, and the oral delivery of the treatment makes a lot of difference to patients in terms of quality of life.” Dr. Kumar said.

First-line Setting “Given the activity and toxicity profile of MLN9708 we wanted to explore continued on page 18

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

Trials Now Enrolling

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

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

Primary Endpoint: • Progression-free survival (PFS)

Primary Endpoint: • Progression-free survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

Key Secondary Endpoint: • Overall survival (OS) Combination Therapy Phase* Maintenance Phase (6 cycles) (for additional 18 months)

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

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

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + PLD 50 mg/m2 IV Q4W

OS

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

Trebananib IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Trebananib IV QW Monotherapy

ENDPOINTS

Primary

PFS 2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Key Secondary

Placebo IV QW Monotherapy

OS

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

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

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

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

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

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

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

© 2013 Amgen Inc. All rights reserved.


The ASCO Post  |   JANUARY 15, 2013

PAGE 18

ASH Annual Meeting Oral Proteasome Inhibitor continued from page 17

the feasibility and efficacy of combining MLN9708 with lenalidomide and dexamethasone,” Dr. Kumar said. The similar combination of bortezomib plus lenalidomide/dexamethasone is a very effective regimen, he noted. The first phase of the study established the recommended phase II dose of the drug (4.0 mg weekly) in 15 patients. Another 50 patients were recruited to evaluate the efficacy of MLN9708 at 4.0 mg weekly (days 1, 8, and 15) in combination with lenalidomide (25 mg/d on days 1–21) and dexamethasone (40 See Page 101 mg/d on days 1, 8, 15, and 22) with the treatment continued for a maximum of 12 cycles. MLN9708 was then continued as maintenance therapy until disease progression. In the 20 patients who wished to undergo an autologous stem cell transplant, stem cells were successfully collected. Overall, 52 patients were evaluable for response after a median of six cycles of treatment; 58% of them achieved at least a very good partial response, including 23% with a complete response, and 32% achieved a partial response. The depth of response deepened with increasing exposure to treatment. After eight cycles, the complete

response rate was 32%. In the three patients who completed all 12 cycles, 100% of patients achieved at least a very good partial response. “We are fairly confident that with increased duration, we will see further improvement in the response numbers,” he said, adding that many patients responded after only one cycle of the regimen.

Additional Data Dr. Kumar further reported that 100% of patients had a reduction in Mprotein levels, and almost all patients with a complete response were negative for minimal residual disease. Though follow-up time is short, an estimated 93% of patients remain free of disease progression at 1 year, he added. “The number of patients at risk beyond 1 year is very low, and the data need to mature,” he cautioned. Twenty-one patients (32%) reported neuropathy, which was grade  1 in the majority (20%), grade 2 in 9%, and grade 3 in 3%. “Note that grade 3 and higher peripheral neuropathy was very low,” he said. About 40% of patients reported minor rash, fatigue, nausea, vomiting, and diarrhea, which were managed with dose reductions and supportive care. Grade 4 events were observed in just four patients. MLN9708 has entered a phase  III trial in multiple myeloma, and two

MLN9708 in Multiple Myeloma ■■ MLN9708 is an investigational oral proteasome inhibitor that has low neurotoxicity.

■■ In treatment-naive multiple myeloma patients, MLN9708 in combination

with lenalidomide produced responses in over 90% of patients; after eight cycles, one-third of patients achieved a complete response.

■■ Grade 3 peripheral neuropathy was observed in only 3% of patients.

EXPERT POINT OF VIEW

A

ntonio Palumbo, MD, Chief of the Myeloma Unit at the University of Torino in Italy, told The ASCO Post that the results with MLN9708 “look quite interesting,” and the drug could change the treatment of the disease. “This combination, with lenalidomide, accelerates response, and the ability to have an oral proteasome inhibitor is a real improvement,” he said. “The expectation is to have equal efficacy with an Antonio Palumbo, MD oral agent, and that would be a ‘plus’ for this disease in the future.” He added that he is more impressed with having an oral compound than by the possibility that neuropathy seems less with MLN9708 than with bortezomib. “There is less neuropathy, true, but I believe the major advance is related to the oral delivery. Today, with weekly infusion of bortezomib, neuropathy is less of a problem than it used to be.” n Disclosure: Dr. Palumbo reported no potential conflicts of interest.

additional trials are planned in newly diagnosed and in relapsed/refractory patients.

Effective in Amyloidosis The oral proteasome inhibitor MLN9708 also showed strong activity in the first-line treatment of patients with relapsed or refractory systemic light-chain amyloidosis, investigators reported at the ASH meeting.2 To date, this phase I study has enrolled 22 patients, 17 at the maximum tolerated dose of 4.0  mg and 5 at 5.5�������������������������������   ������������������������������ mg. A total of 15 patients received at least one cycle and were evaluable for response. Of these, 2 patients achieved a complete response, 5 achieved at least a very good partial response, and 1 demonstrated a partial response to the drug. Hematologic response durations of up to 14.7 months were observed, and there were three cardiac organ responses among nine evaluable patients, reported Giampaolo Merlini, MD, Director of the Center for Research and Treatment

of Systemic Amyloidosis, and of the Biotechnology Research Laboratories, Scientific Institute Policlinico San Matteo, and Professor of Clinical Biochemistry, University of Pavia, Italy. The phase III TOURMALINE-ALI is ongoing in newly diagnosed amyloidosis patients. n Disclosure: Dr. Kumar reported no potential conflicts of interest.

References 1. Kumar SK, Berdeja JG, Niesvizky R, et al: A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma. 2012 ASH Annual Meeting. Abstract 332. Presented December 10, 2012. 2. Merlini G, Sanchorawala V, Zonder JA, et al: MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis: Results of a phase I study. 2012 ASH Annual Meeting. Abstract 731. Presented December 10, 2012.

Umbilical Cord Blood Transplant: Two Units are No Better Than One in Children with Hematologic Malignancies By Alice Goodman

U

se of two partially HLA-matched units of umbilical cord blood were not superior to a single unit if it contained an adequate number of hematopoietic stem cells, according to a randomized study by the Blood and Marrow Clinical Trials Network. Results were reported at the 54th Annual Meeting of the American Society

of Hematology (ASH) in Atlanta.1 Single units of umbilical cord blood are used in children, but adults undergoing hematopoietic stem cell transplantation often require more units. “We hypothesized that infusing two units of umbilical cord blood would improve outcomes [in children],” explained lead author John E. Wagner,

MD, Director of the Pediatric Blood and Marrow Transplant Program at the University of Minnesota in Minneapolis.

Unexpected Findings “Our findings, while unexpected, affirm that the standard transplant approach using a single unit of umbilical

cord blood is optimal so long as the unit offers a sufficient number of cells. Still, the study also showed that a double–umbilical cord blood transplant, while not better than See Page 101 an adequate singlecontinued on page 19


ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ignite a meaningful response

WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1,500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug Please see Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on following pages.


For metastatic breast cancer patients failing combination chemotherapy or relapsing within 6 months of adjuvant therapy; prior therapy should have included an anthracycline unless clinically contraindicated.

Rely on evidence

from a phase III trial vs an established regimen Inclusion criteria1

ABRAXANE® 260 mg/m2 IV

• Females at least 18 years of age • Measurable metastatic breast cancer • ECOG performance status 0 to 2 • No prior taxane therapy for metastatic disease

30-minute infusion q3w (n=233) No standard premedication RANDOMIZATION

N=460

Paclitaxel injection 175 mg/m2 IV

ECOG=Eastern Cooperative Oncology Group.

3-hour infusion q3w (n=227) Standard steroid premedication required

The ABRAXANE approved indication is the same as that of paclitaxel injection for metastatic breast cancer2 • The primary efficacy end point assessed was reconciled target lesion response rate (recTLRR) — recTLRR was based on independent radiologic assessment of tumor responses — recTLRR was reconciled with investigator-reported responses and includes only responses achieved in the first 6 cycles of therapy • Secondary efficacy end points included overall response rate, time to disease progression, and overall survival, among other measures1

Important Safety Information DOSAGE AND ADMINISTRATION • Dose adjustment is recommended for patients with moderate and severe hepatic impairment and patients who experience severe neutropenia or severe sensory neuropathy during treatment with ABRAXANE • Withhold ABRAXANE if AST >10 x ULN or bilirubin >5 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicities • Monitor patients closely


Illuminate

a superior tumor response (recTLRR) recTLRR (PRIMARY END POINT) VS PACLITAXEL INJECTION FOR ALL RANDOMIZED PATIENTS IN THE PHASE III TRIAL IN METASTATIC BREAST CANCER

ABRAXANE®

21.5% (50/233) 95% CI: 16.19%-26.73%

n=233

Paclitaxel injection

11.1%

n=227

(25/227) 95% CI: 6.94%-15.09% P=0.003*

0

10

20

30

40

50

60

70

80

90

100

recTLRR (%) * From Cochran-Mantel-Haenszel test stratified by first-line vs > first-line therapy.

• ABRAXANE demonstrated superior recTLRR (primary end point) of 21.5% vs 11.1% for paclitaxel injection in all randomized patients (P=0.003) • recTLRR was the prospectively defined, protocol-specific end point, based on independent radiologic assessment of tumor responses reconciled with investigator responses (which also included clinical information) for the first 6 cycles of therapy. The recTLRR was lower than the investigator-reported response rates, which are based on all cycles of therapy • There was no statistically significant difference in overall survival between the 2 study arms To learn more about ABRAXANE, contact your local Celgene sales representative or go to www.abraxane.com.

WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dosedependent and a dose-limiting toxicity of ABRAXANE • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 for metastatic breast cancer (MBC) and Days 1, 8, and 15 for non-small cell lung cancer (NSCLC) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3

Nervous System • Sensory neuropathy is dose- and schedule-dependent Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • The starting dose should be reduced for patients with moderate or severe hepatic impairment

Please see Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on following pages.


For metastatic breast cancer patients failing combination chemotherapy or relapsing within 6 months of adjuvant therapy; prior therapy should have included an anthracycline unless clinically contraindicated.

Visible results

in a challenging patient population recTLRR (PRIMARY END POINT) VS PACLITAXEL INJECTION FOR PATIENTS WHO FAILED COMBINATION CHEMOTHERAPY OR RELAPSED WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY

ABRAXANE®

15.5% (20/129) 95% CI: 9.26%-21.75%

n=129

Paclitaxel injection n=143

0

8.4% (12/143) 95% CI: 3.85%-12.94% 10

20

30

40

50

60

70

80

90

100

recTLRR (%) • ABRAXANE demonstrated recTLRR of 15.5% vs 8.4% for paclitaxel injection in patients who failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy • recTLRR was the prospectively defined, protocol-specific end point, based on independent radiologic assessment of tumor responses reconciled with investigator responses (which also included clinical information) for the first 6 cycles of therapy. The recTLRR was lower than the investigator-reported response rates, which are based on all cycles of therapy • Prior therapy included an anthracycline unless clinically contraindicated

Patients treated with ABRAXANE received a median of 6 cycles of therapy (range: 1-18)1

WARNINGS AND PRECAUTIONS Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman Use in Men • Men should be advised not to father a child while receiving ABRAXANE

ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with singleagent use of ABRAXANE in the MBC study were alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), abnormal ECG (all patients 60%; patients with normal baseline 35%), fatigue/asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), AST elevation (any 39%), alkaline phosphatase elevation (any 36%), anemia (all cases 33%; severe 1%), nausea (any 30%; severe 3%), diarrhea (any 27%; severe <1%) and infections (24%)

References: 1. Data on file. Celgene Corporation. 2. Taxol [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company. Rev April 2011.


ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Important Safety Information WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1,500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 for metastatic breast cancer (MBC) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with MBC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to >100,000 cells/mm3 Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 for MBC followed by a dose reduction for all subsequent courses of ABRAXANE Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • The starting dose should be reduced for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • 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 • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE

ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with single-agent use of ABRAXANE in the MBC study were alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), abnormal ECG (all patients 60%; patients with normal baseline 35%), fatigue/asthenia (any 47%; severe 8%), myalgia/ arthralgia (any 44%; severe 8%), AST elevation (any 39%), alkaline phosphatase elevation (any 36%), anemia (all cases 33%; severe 1%), nausea (any 30%; severe 3%), diarrhea (any 27%; severe <1%) and infections (24%) • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note included vomiting (any 18%; severe 4%), renal dysfunction (any 11%; severe 1%), fluid retention (any 10%; severe 0%); mucositis (any 7%; severe <1%), hepatic dysfunction (elevations in bilirubin 7%), hypersensitivity reactions (any 4%; severe 0%), thrombocytopenia (any 2%; severe <1%), and injection site reactions (<1%). In all ABRAXANE treated patients (n=366) ocular/ visual disturbances were reported (any 13%; severe 1%). Dehydration and pyrexia were also reported • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Post-marketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or to human albumin has not been studied • There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel 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, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who receiv ed ABRAXANE for MBC Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • Dose adjustment is recommended for patients with moderate and severe hepatic impairment and patients who experience severe neutropenia or severe sensory neuropathy during treatment with ABRAXANE • Withhold ABRAXANE if AST >10 x ULN or bilirubin >5 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicities • Monitor patients closely

Please see Brief Summary for ABRAXANE, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on following pages. ABRAXANE® is a registered trademark of Celgene Corporation. ©2012 Celgene Corporation 12/12 US-ABR120055a(1)


ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a brief summary; refer to full prescribing information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. 1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC = 6 mg•min/mL on Day 1 only of each 21-day cycle, beginning immediately after the completion of ABRAXANE administration. 2.3 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated. Monitor patients closely [see Warnings and Precautions (5.4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin Levels ABRAXANE Dosea Levels MBC NSCLC Mild < 10 x ULN > ULN to ≤ 1.25 x ULN 260 mg/m2 100 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN 200 mg/m2 75 mg/m2 Severe < 10 x ULN 2.01 to 5 x ULN 130 mg/m2 b 50 mg/m2 c > 10 x ULN OR > 5 x ULN not eligible not eligible MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Increase dose to 75 mg/m2 in subsequent courses, as tolerated.

2.4 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. • In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2. • Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL) Neutropenic Fever (ANC less than 500/mm3 First 75 4.5 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC Second 50 3 less than 1500/mm3 OR ANC less than 500/mm3 Third Discontinue Treatment for more than 7 days First 75 4.5 Platelet count less than 50,000/mm3 Second Discontinue Treatment First 75 4.5 Severe sensory Neuropathy – Second 50 3 Grade 3 or 4 Third Discontinue Treatment 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC) and 47% of patients with non-small cell lung cancer (NSCLC). Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at


least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.4)]. 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.4)]. 5.3 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5.4 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.5 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.6 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. 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. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.7 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)] The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE were neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thrombocytopenia (30%), and anemia (16%). 6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 3 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 (continued)


Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial.

Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose- and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group). Table 4 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients. Table 4: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) plus carboplatin plus carboplatin Grades Grade Grades Grade 1-4 (%) 3-4 (%) 1-4 (%) 3-4 (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 5 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.


Table 5: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups Paclitaxel Injection ABRAXANE (200 mg/m2 (100 mg/m2 weekly) every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) MedDRA Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 System Organ v 12.1 Toxicity Toxicity Toxicity Toxicity Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General Edema 10 0 4 <1 disorders and peripheral administration site conditions Respiratory Epistaxis 7 0 2 0 thoracic and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective Myalgia 10 <1 19 2 tissue disorders a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. 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. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history. Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.4 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. There are no clinically important pharmacokinetic drug-drug interactions between carboplatin and ABRAXANE [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.6)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. 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. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). 8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made 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 ABRAXANE in pediatric patients have not been evaluated.


8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment. 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information). • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.7)]. • Patients must be informed of the risk of low blood cell counts and instructed to contact their physician immediately for fever or evidence of infection. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties, or signs of an allergic reaction. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE. • Patients must be informed that hypersensitivity reactions may occur, which could be severe and sometimes fatal. Manufactured for: Celgene Corporation Summit, NJ 07901 ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2012 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006; 7,820,788; 7,923,536; 8,034,375; 8,268,348; and RE41,884. ABRPI.004/PPI.004 10/12


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ASH Annual Meeting Excellent Preliminary Results for Ibrutinib in Chronic Lymphocytic Leukemia By Alice Goodman

A

lthough still in preliminary testing with no phase III data, ibrutinib is poised to become an important new agent for patients with chronic lympho-

relapsed/refractory patients.1,2 Moreover, the drug appears to be extremely safe thus far, with little or no myelosuppression as a single agent over about 3 years of experience in clinical trials.

Highly Effective, Well Tolerated Drug CLL expert John Byrd, MD, lead author of the larger of the phase��������� II������ studies reported at the ASH meeting, stated,

“Rarely does a drug come along that helps patients this much. This drug is highly effective and very well tolerated. We are looking forward to Pharmacyclics bringing this drug forward. The quicker we get this drug across the finish line, the better.” Dr. Byrd is D. Warren Brown Chair of Leukemia Research and Director of the Division of Hematology at Ohio State University Comprehensive Cancer Center in Columbus.

Ibrutinib in Chronic Lymphocytic Leukemia John Byrd, MD

cytic leukemia (CLL). Two phase�������� II����� trials reported at the 54th Annual Meeting of the American Society of Hematology (ASH) found that ibrutinib achieved excellent response rates and progression-free survival in previously untreated elderly patients, patients with relapsed/refractory disease, and high-risk

■■ The novel Bruton’s tyrosine kinase inhibitor ibrutinib achieves excellent

response rates and progression-free survival as a single agent and in combination with rituximab in preliminary studies of patients with chronic lymphocytic leukemia.

■■ Encouraging outcomes were seen in elderly treatment-naive patients,

relapsed/refractory patients, and high-risk relapsed/refractory patients.

■■ The adverse event profile of ibrutinib suggests that this drug is very well tolerated, with little or no myelosuppression and transient grade 1/2 adverse events.

Umbilical Cord Blood

Key Data

continued from page 18

No difference between the two treatment arms was observed in the overall rate of engraftment, Dr. Wagner continued. Both arms did better than the historical experience in children with leukemia. The rate of neutrophil recovery at day 42 was 89% with single-unit umbilical cord blood and 86% with double-unit umbilical cord blood. The incidence of grade II–IV acute graft-vs-host disease was almost identical in both arms: 56% vs 57% (with most grade II), respectively. The rate of chronic graft-vs-host disease was 28% vs 31%. “The risk of relapse was surprisingly low after umbilical cord blood transplant, with no real difference between the two arms,” he said. At 1 year, the relapse rate was 12% in the single [umbilical cord blood] arm vs 14% in the double [umbilical cord blood] arm. Typically, the relapse rate is 30% to 35% in pediatric patients. Dr. Wagner noted that the relapse rate could increase with longer follow-up, although this is not likely to change much since

unit transplant, is a useful and effective strategy in those instances where an adequate single unit is not available, such as in adults,” he said. Furthermore, having verified the safety of this approach, the double umbilical cord blood model may also be a useful tool for testing new strategies focused on improving engraftment and immune recovery, he added.

John E. Wagner, MD

The study randomly assigned 224 pediatric patients with acute leukemias to single– vs double–umbilical cord blood transplant. Importantly, all received a modified conditioning regimen containing fludarabine, which likely had a beneficial effect for all patients in this study. Both the single–umbilical cord blood and double–umbilical cord blood groups had a similar number of donor/patient mismatches.

most patients are beyond 2 years posttransplant. No significant difference in diseasefree survival was seen between the two arms: 68% vs 64%. Dr. Wagner said that the results in this trial were superior to past studies and likely attributed to the modified conditioning regimen used in the trial. The cost of transplant is an important issue, he noted. One cord unit costs on average $40,000, and two units are therefore twice as much. “Use of two units is justifiable but only in the circumstance when one unit does not contain the number of cells needed,” Dr. Wagner said, adding, “We have to continually look for ways to improve safety and reduce the cost of transplant.”

Pediatric vs Adult Patients “This study showed there is no benefit of adding a second unit when effective conditioning is used in children,” commented Vanderson Rocha, MD, Professor at Oxford University, United

Umbilical Cord Blood for Stem Cell Transplants in Children ■■ Two units of umbilical cord blood were not superior to one unit—in terms of engraftment rates, relapse, and survival—in children with hematologic malignancies who underwent transplantation.

■■ One unit remains the standard of care for children.

Ibrutinib is an investigational inhibitor of Bruton’s tyrosine kinase, a key mediator of B-cell survival See Page 101 mechanisms. In preclinical studies, ibrutinib blocked these mechanisms, driving cells into apoptosis. The novel agent is being studied alone or in combination with other drugs for the treatment of several B-cell malignancies, including CLL and small lymphocytic leukemia (SLL), a similar disease with slightly different manifestations.

Multicenter Trial The phase Ib/II, multicenter trial reported by Dr. Byrd enrolled three groups of 116 patients with CLL or SLL: elderly treatment-naive patients, relapsed/refractory patients, and highrisk relapsed/refractory patients.1 At the ASH Annual Meeting, he presentcontinued on page 20

Vanderson Rocha, MD

Kingdom, and moderator of an ASH press conference where these findings were discussed. “For some years, double [umbilical cord blood] transplant was assumed to produce better outcomes for adults. With reduced-intensity conditioning, we have better outcomes and lower relapse rates for adults in first remission. There is still a role for double [umbilical cord blood] transplants in adults, for whom one unit is not sufficient.”  Disclosure: Drs. Wagner and Rocha reported no potential conflicts of interest.

Reference 1. Wagner J, Eapen M, Carter S, et al: No survival advantage after double umbilical cord blood (UCB) compared to single UCB transplant in children with hematologic malignancy: Results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501) randomized trial. 2012 ASH Annual Meeting. Abstract 359. Presented December 10, 2012.


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ASH Annual Meeting Hematology

Ibrutinib in CLL continued from page 19

ed results for elderly treatment-naive patients (n =  31) and pooled results for relapsed/refractory and high-risk relapsed/refractory patients (n = 85). At 26 months, single-agent ibrutinib produced an estimated progressionfree survival rate of 96% in elderly treatment-naive patients and estimated progression-free survival rate of 75% in relapsed refractory high-risk CLL/SLL patients. Overall response rates were 68% in the treatment-naive patients at a median follow-up of 20.3 months and 71% in the relapsed/refractory and high-risk relapsed refractory group at a median follow-up of 15.7 months. At 26 months, estimated overall survival rates were 96% and 83%, respectively. Treatment-naive elderly patients and relapsed/refractory patients received oral ibrutinib at 420  mg/d or 840  mg/d; the high-risk relapsed/

refractory group received 420 mg/d. Patients with relapsed/refractory disease had been treated with at least two prior therapies; those in the high-risk group experienced a relapse within 2 years of chemoimmunotherapy. Ibrutinib was very well tolerated. Most adverse events were grade 1 or 2. The most common treatment-related adverse events were diarrhea, fatigue, nausea, and rash. Myelosuppression was rare.

Single-center Trial A second phase II, single-center study was based on 40 patients with high-risk CLL treated with the combination of ibrutinib plus rituximab (Rituxan), a standard agent in this setting.2 Overall response rate was 83% in these high-risk pretreated patients. Of 40 patients, 38 have no evidence of disease progression and are continuing therapy. This group of patients is known to

EXPERT POINT OF VIEW

M

artin Dreyling, MD, Professor at the University of Munich in Germany, said the most important lymphoma studies presented at the 2012 ASH Annual Meeting focused on ibrutinib, the first-in-class Bruton’s tyrosine kinase inhibitor. “Basic science has gone mainstream. We will see a revolution during the next 5 years in the treatment of lymphoma [and other cancers] based on understanding of both genetic alterations and epigenetics,” he commented. Martin Dreyling, MD “The Bruton’s tyrosine kinase inhibitor ibrutinib is the molecule of the year,” he continued. “This drug is a major advance—one of the three major advances that I have seen over 25 years of treating hematologic cancers. The first was rituximab [Rituxan], the second was imatinib [Gleevec], and now we have ibrutinib.” Phase II studies of ibrutinib presented at the ASH meeting focused on chronic lymphocytic leukemia (abstracts 187 and 189), mantle cell lymphoma (abstract 904), and diffuse large B-cell lymphoma (abstract 686). “These studies show impressive and unprecedented response rates with excellent tolerability,” Dr. Dreyling said. “We are all anxious to see the results of phase III trials and to have this drug available to treat our patients.” Lymphoma session moderator Joshua Brody, MD, of Mount Sinai School of Medicine, New York, was equally impressed. “Ibrutinib is great in a few tumors—mantle cell and chronic lymphocytic leukemia—and it is very encouraging in others,” he said. “We are seeing fantastic data.” He added “While we still can’t cure relapsed/refractory mantle cell lymphoma, the good news is that we now have a lot of treatment choices, and some are quite good. The overall survival rate today is certainly not as dismal as Joshua Brody, MD the historical 3- to 5-year rate that is often quoted.” n Disclosure: Dr. Dreyling is on the scientific advisory board of Celgene, Janssen, Pfizer, and Roche; has received speakers honoraria from Celgene, Janseen, Mundipharma, Pfizer, and Roche; and receives support of academic studies (to the institution) from Celgene, Janssen, Mundipharma, Pfizer, and Roche. Dr. Brody reported no potential conflicts of interest.

EXPERT POINT OF VIEW

“P

atients are very excited about this new, well tolerated drug for chronic lymphocytic leukemia (CLL). Ibrutinib is available orally and is not chemotherapy. It produces excellent responses. This is particularly important for elderly [ie, age 65 and older] patients who are not always fit enough to withstand the chemotherapy regimens we use to treat younger patients. The drug is also particularly promising for high-risk patients such as those with abnormalities of TP53,” stated Claire Dearden, Claire Dearden, MD MD, moderator of a press conference at ASH. Dr. Dearden is Consultant Haematologist and Head of the Chronic Lymphocytic Leukaemia Unit at The Royal Marsden and The Institute of Cancer Research, and Medical Director of the South West London Cancer Network.

‘Welcome Advance’ If phase III studies validate the phase��������������������������������������� II������������������������������������ findings, ibrutinib will be considered a welcome advance, she continued. “At last, we could have our hands on an easy-to-take drug that may be very safe and effective in these patient groups for whom we haven’t previously had a good treatment. It would be a chemotherapy-free regimen as effective as chemotherapy,” she stated. “This is hugely exciting for us as clinicians and also for patients who are taking this drug. They feel better very quickly without many of the side effects of chemotherapy, other than diarrhea,” she stated. n Disclosure: Dr. Dearden reported no potential conflicts of interest.

have worse outcomes than low- and intermediate-risk patient, explained lead author Jan Burger MD, Associate Professor at The University of Texas MD Anderson Cancer Center in Houston. “This study shows profound activity for this combination in high-risk patients with CLL. The overall response rate is favorable compared with

Jan Burger MD

standard treatment, and the toxicity compares favorably to other treatment options,” stated Dr. Burger. Patients were treated with ibrutinib at 420 mg/d combined with rituximab. High-risk criteria for entry included one of the following characteristics: deletion of 17p; TP53 mutation, deletion of 11q, or short (< 3 years) remission after first-line chemoimmunotherapy. No disease progression was observed in 95% of the entire group and

in 90% of those with 17p deletions ibrutinib achieved rapid reduction in the size of lymph nodes and spleen; 84% experienced > 50% decrease in lymph node size. As in the trial by Dr. Byrd and colleagues, treatment was well tolerated, with transient and infrequent grade  3/4 toxicities that included febrile neutropenia, anemia, mucositis, and pneumonia. n

Disclosure: Dr. Byrd reported no potential conflicts of interest. Dr. Burger has received research funding from Pharmacyclics, Gilead, Genzyme, and Noxxon.

References 1. Byrd JC, Furman RR, Coutre S, et al: The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve and relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) patients including patients with high-risk disease: New and updated results of 116 patients in a phase Ib/II study. 2012 ASH Annual Meeting. Abstract 189. Presented December 9, 2012. 2. Burger JA, Keating M, Wierda WG, et al: The Btk inhibitor ibrutinib (PCI32765) in combination with rituximab is well tolerated and displays profound activity in high-risk chronic lymphocytic leukemia (CLL) patients. 2012 ASH Annual Meeting. Abstract 187. Presented December 9, 2012.


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2012 Quality Care Symposium Health-care Quality and Value continued from page 1

sicians are rewarded for identifying and implementing best practices in an environment where evidence-based care was consistently used,” said Dr. Newcomer. He added that the balancing act would be to end the oncologist’s dependence on drug selection for practice survival while retaining present income levels. “The current system of oncology drug revenue dependence was created 40 years ago. No one thought it would be a problem, but it is, and it’s vital that we address ways to fix it,” he commented. “To reach that goal, we needed a performance measurement system with data. So, we asked physicians who entered the program to give us a single sheet of clinical information, including histology, stage, relevant genetics, and current status, which meant, for instance, that they needed to differentiate between an adjuvant patient and one who is relapsed with metastatic disease,” said Dr. Newcomer. He explained that the single-page format, combined with claims data, provided a comprehensive view of care by which they could create a fairly crude but effective longitudinal health record. “This allowed us to put patients in the right buckets and follow everything that happed to them in their cancer care experience. This information was collected in claims data, so we could harvest the outcomes and feed that back to the physicians,” said Dr. Newcomer.

The Program The first step in the program was to create episode categories. “We looked at patients with breast, lung, or colon

cancer and divided them into 24 different clinical scenarios. We had general agreement on the treatment strategies, but a lot of disagreement on the specifics,” said Dr. Newcomer. “Next, we found five large volunteer practice groups, all with strong clinical and business leaders. We asked the groups to pick the medical regimen they thought was best for each of the 24 clinical scenarios, with the understanding that once the group comes to consensus, every UnitedHealthcare patient in the episode program would be treated with the selected regimen unless they had a medical contraindi-

said Dr. Newcomer.

Incentivize Value, Not Margin “We took all of the margin that the groups used to make on selected drugs and called it a ‘patient care fee,’ which was paid in total—a bundled payment—on the first visit. So we gave the doctors a substantial upfront check. Going forward, as the drug regimens changed, we paid the practice for the cost of the drug, but the patient care fee didn’t change unless we saw an improvement in the outcomes data, or the total cost of treating these patients was lowered, in which case

I came out of this program feeling very optimistic, because I believe we’ve learned that improvement can be measured and costs can be reduced without sacrificing value. —Lee N. Newcomer, MD, MHA

cation,” commented Dr. Newcomer. He pointed out that the most important aspect of the program was for each of the five groups to be consistent with their treatment selections for the 24 clinical categories. “When you do things the same way, there is less complexity and error rates fall, which leads to scientific methods that systematically improve care. We could now track how well the therapies worked for these patients and compare the results among the five groups. The group leaders had to agree to meet annually to discuss and compare outcomes. The goal was to get consensus on what constituted a best practice,”

we shared a third of that savings with the group,” said Dr. Newcomer. They looked at total cost of care, survival, time to progression for the first regimen in metastatic disease, and hospital admissions for uncontrolled pain. After the data were collected, bar graphs were created to illustrate the results of each of the 24 clinical episodes, and the various measures were analyzed against the national group average to determine patterns of care. As an example, Dr. Newcomer looked at the average total cost per episode in the breast adjuvant setting. “Each of the five groups committed to treatment with TC [docetaxel/ cyclophosphamide], and the first

thing that struck us was the tremendous variation in drug costs. Digging deeper, we found that only half of the patients actually received TC; the other half received a more costly regimen. So, here are medical groups committed to consistency, but they couldn’t get half their patients on the regimens they selected. The lesson is that at an operational level, this kind of behavior change is very hard to accomplish, but our project showed that it’s worth the effort,” stressed Dr. Newcomer.

We Have to Do Something “We have a sense of urgency because we have to figure out how to reduce our escalating costs and still deliver value. And our hope was that this program would begin putting in place quality measurements and the incentives to follow them,” said Dr. Newcomer. He noted that although the episode payment program exposed some of the hurdles that will need to be overcome, quality measurement in oncology is possible and minimal clinical data are required to begin a program. “Payer-provider collaboration is a win/win situation because we both learn from the discussions about value. There are a lot of bumps in the road ahead, especially if practices are dealing with smaller payers who don’t have the resources and data capture ability of UnitedHealthcare. However, I came out of this program feeling very optimistic, because I believe we’ve learned that improvement can be measured and costs can be reduced without sacrificing value,” concluded Dr. Newcomer. n

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

Measuring and Improving Quality in Oncology Practices By Ronald Piana

T

he seed for ASCO’s Quality Oncology Practice Initiative (QOPI®) was planted a decade ago by Joseph Simone, MD, when he contemplated the feasibility of studying a volunteer group of oncologists to measure the quality of care they provide and share those results with their colleagues. Dr. Simone’s original vision has since grown far beyond its original scope. At ASCO’s first Quality Care Symposium in San Diego, Michael N. Neuss, MD, Chair of ASCO’s QOPI steering committee,

discussed the program’s first 5 years of data. Dr. Neuss is Chief Medical Officer and Professor of Clinical Medicine at Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

Biannual Analysis “Our project was geared to identify which factors in the QOPI project correlated with improvement—whether related to practice or measures—and to see if, in fact, practices improved over time,” said Dr. Neuss, mentioning that the QOPI self-reporting program

is analyzed twice a year. “There have been approximately 50 quality measures that were stable during the first 5 years of QOPI, and we used those measures for this analysis, which included 308 practices and approximately 2,000 physicians, representing about 15% of the nation’s medical oncology workforce,” explained Dr. Neuss. The overall quality scores were constructed based on questions from different domains, such as breast cancer, end-of-life care, colon and rectal

cancers, non–small cell lung cancer, non-Hodgkin lymphoma, and symptom toxicity management. “If we look at multivariate analysis in those factors associated with improvement, the highest correlations were seen for a new clinical practice, such as the introduction of a treatment drug or a genetic test associated with a drug. And when we looked at the interaction at the new practice over time, it showed the largest corollary of improvement within any variable within our measure continued on page 26


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

40

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

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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.

24

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

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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

24

OS (months) Updated analysis of ZELBORAF

§

Updated analysis of dacarbazine

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

© 2012 Genentech USA, Inc. All rights reserved. BRF0000653202 Printed in USA.

zelboraf.com


The ASCO Post  |   JANUARY 15, 2013

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2012 Quality Care Symposium Measuring Quality continued from page 22

set,” said Dr. Neuss. According to the group’s findings, measures seemed to fall into three distinct areas: those that showed great improvement over time, those that showed no improvement because they were already too high to

improve, and those that showed no improvement despite a large opportunity to improve. “Although we saw a wide variation in baseline achievement among the practices that obscures any statistical significance to these measures [outside of the study model], I think that the underlying reality is a nice trend in improvement,”

said Dr. Neuss. Dr. Neuss next looked at whether adjuvant therapy in breast, colon, and non–small cell lung cancer was appropriately recommended to patients in the large data sets. “The level of achievement was very high, indicating that practices are doing very well in this setting. In fact, for these three diseases, the Michael N. Neuss, MD

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

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.

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

8

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7

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*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.

baseline achievement is more than 90%,” commented Dr. Neuss.

More Work to Be Done “The news is not as encouraging for measures such as the appropriate documentation of smoking cessation status, the risk of infertility, and fertility preservation in patients for whom these evidence-based measures would be applicable. As we know, measuring smoking is a ‘meaningful use’ criterion, and practices do very well in documenting tobacco use. However, we see that only 20% to 30% of the time, practices make an attempt to get their patients to quit smoking,” said Dr. Neuss. He added that there is a similar pattern of poor compliance in discussing fertility preservation options with patients with cancer who are of childbearing age. Dr. Neuss continued, “Because of the very varied initial attainment levels, we constructed a model to look at the overall achievement when normalized for baseline accomplishment. We saw that adjusted mean quality scores improved from 71% to 85%, which is significant. Also, when we looked at how the introduction of new measures did over time, we saw a very dramatic improvement,” noted Dr. Neuss. Indeed, the improvement over time was highly statistically significant (P < .0001). continued on page 27

How Do We Know We’re Giving the Right Care? According to Michael N. Neuss, MD, speaking at the 2012 Quality Care Symposium, clinicians need to:

■■ Give the right treatment for the patient at the right time

■■ Agree on the right care ■■ Value the patient’s input ■■ Recognize that patients are unique

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

■■ Measure and try to improve BRF0000422001 Initial U.S. Approval: August 2011 © 2012 Genentech, Inc


ASCOPost.com  |   JANUARY 15, 2013

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2012 Quality Care Symposium ASCO’s Approach to Health Information Technology and the Rapid-learning System By Ronald Piana

LinQ’s core is the ability to measure quality in the oncology practice, measure outcomes, report in real time, and provide new methods of data exploration and hypothesis generation. “The real-time collection of quality and outcomes will allow the system to learn and improve the care of cancer patients by driving higher value and better outcomes,” said Dr. Lichter.

Rapid-learning System Allen S. Lichter, MD

T

he slow, but inevitable evolution of electronic oncology healthcare systems has already, at least conceptually, moved to the next generation of machines that not only store and process data, but also have the ability to provide real-time clinical decision support. At ASCO’s first Quality Care Symposium in San Diego, ASCO CEO Allen S. Lichter, MD, unveiled the Society’s ambitious addition to the evolution of the rapid-learning system.

Paving the Way Forward “It’s my pleasure to launch the maiden voyage of ASCO’s contribution to the rapid-learning system, CancerLinQ. The idea of a rapid-learning system has been floating around for a long time. The Institute of Medicine [IOM] has dedicated an unprecedented amount of its attention to this idea, which culminated in a monumental report on the earning health-care system. The report gave rationale, data, and specific recommendations on how to move forward. ASCO has embraced the vision outlined by the IOM and others, and that’s the origin of CancerLinQ, the next evolution of our quality programs,” said Dr. Lichter. Dr. Lichter explained that Cancer-

Measuring Quality continued from page 26

Dr. Neuss used some of the experimental circumstances that led to what became known as the Hawthorne effect—in which industry workers making the same product were aggregated in communal rooms and showed increased performance—as an example of interventions that increase benefits. (The more general premise of the Haw-

“Although very complex, the core of the rapid-learning system is a circle that is really a classic feedforwardfeedback cycle of quality improvement. It begins at the point of care where the data are collected by computer, transformed, and aggregated; then the data are analyzed and services are provided in compliance with important measures,” said Dr. Lichter. The system, explained Dr. Lichter, has a second cycle attached to it. “Once the data are analyzed, it can go through peer review and feedback, generate

will never fill in the grid solely through clinical trial data. However, with the second cycle of the rapid-learning system—where the correlation and trend analysis occurs—we can improve the effectiveness of our guidelines,” said Dr. Lichter.

The Prototype After laying the foundation by engaging leaders in the oncology community, hammering out a business plan, and doing the legal and technology analysis, ASCO’s work on the prototype system began. Dr. Lichter said that the group set out to construct the prototype with five goals: 1. Provide “lessons learned about the technological and logistical challenges of a full-scale implementation of CancerLinQ 2. Demonstrate value-added tools, such as the ability to measure a clinician’s performance on a subset of the Quality Oncology Practice Initiative (QOPI®) in real time

While there is much work to be done, we have shown that the core functions of a health learning system are within our grasp, setting the stage for fundamental and unprecedented transformation. — Allen S. Lichter, MD

new hypotheses, and do correlation and trend analysis. That second process begins to make our guidelines and guidance better,” said Dr. Lichter. “Right now, as in most medical specialties, the majority of things we do are based on consensus or good solid hunches, not on level 1 clinical trial evidence. In fact, there are so many decision points in oncology that we

3. Create new ways of exploring clinical data and hypothesis generation 4. Demonstrate our capability to develop rapid, real-time clinical support based on clinical guidelines and integrate them into an electronic health record system 5. Demonstrate the ability to capture and aggregate complete longitudinal patient records from any source

thorne effect is that behavior during the course of a study may be the result of social situations and the subjects’ awareness that they are being observed.) “I would submit to you that the workers got better because they were made into a team instead of individuals. And the lesson here is that when practitioners and their patients work as a team, they improve quality care together,” said Dr. Neuss.

Lessons Learned So Far Dr. Neuss stressed that medical oncology practices have improved in some but not all measures of care, and though improvement is rapid for many measures, those with the greatest improvement are the ones measuring the adoption of new information or treatments. “On many of the adjuvant treatments, it appears that QOPI partici-

and make use of the data. “After taking the key points from the original feedforward-feedback cycle, we built a rather crude oncology [electronic health record system] from an open-source [electronic health record] so we could interact with the system and develop batch filing and processing of data. In other words, we developed automatic processing so we were able to understand the data that were being sent to us from various aggregates of medical records,” commented Dr. Lichter.

Analytic Component Using an elegant visual platform called Galileo Cosmos™, Dr. Lichter demonstrated a drag-and-drop feature that allows the user to enter all pertinent clinical information about a particular patient and screen See Page 101 the information against a particular regimen. The program graphically illustrates the various outcomes in a multiplicity of clinical scenarios. Dr. Lichter toggled back and forth, visually comparing and contrasting the outcomes of different agents. “With this kind of data capture, we can begin to show and analyze outcomes and answer interesting and complex clinical questions in real time,” said Dr. Lichter. After showing multiple slides that explored the interactive capabilities of the prototype electronic medical record— from practice guidelines to adverse events—Dr. Lichter noted that many of the key nodal points in a learning health-care system are currently feasible. continued on page 28

pants are already doing well. However, measuring is not enough. We have to improve our care by using collaborative models. To that end, networks have spontaneously sprung up within the QOPI practices…. [P]ayers have been very supportive of these important quality initiatives—QOPI is truly a collaborative effort with downstream benefits for our patients,” concluded Dr. Neuss. n


The ASCO Post  |   JANUARY 15, 2013

PAGE 28

2012 Quality Care Symposium Developing Cancer Care Pathways for the New Environment By Ronald Piana

A

s community practices and the insurance industry seek cost-effective ways to adapt to the Patient Protection and Affordable Care Act, the evolving concept of cancer care pathways is emerging as a strategy that may help control oncology costs and add value to care. At ASCO’s recent Quality Care Symposium in San Diego, Peter G. Ellis, MD, Director of Medical Oncology Network for the University of Pittsburgh Medical Center (UPMC) Cancer Center, discussed his institution’s experience with cancer care pathways. Dr. Ellis explained that UPMC Cancer Center is a distinct product line of UPMC, which is a not-for-profit health system that provides health services and insurance coverage in Western Pennsylvania. “After developing a cancer care delivery system across a large network of academic and community sites, we wondered what kind of quality we have. So we sent out surveys of five case studies to all of our providers, asking them how they would handle each clinical issue, and we got back 25 different answers,” said Dr. Ellis. He added, “we sought to assess the quality of our delivery system and develop cancer care pathways to drive standardized care, lower costs, and increase trial accrual. It was a forward-thinking idea for 2004, almost a decade ago.”

Why Pathways Now? Pathways made sense then, Dr. Ellis noted, but “why do we need them now?” he asked. He continued, “We still need the benefits of standardized care, but now we also have to prepare for health-care reform that will usher in the new era of medical homes and accountable care organizations. We also need to have the ability for reporting our outcomes to our value-conscious consumers and to facilitate practicehospital comanagement relationships. Moreover, pathways may also be used to aggregate large networks of physicians under clinically integrated sys-

Rapid-learning System continued from page 27

Work in Progress

Stressing that CancerLinQ is still very much a work in progress, Dr. Lichter said, “We have learned about the technological and logisti-

tems and make sure that they have the latest clinical information at point of service,” said Dr. Ellis.

University of Pittsburgh Medical Center Definition of Cancer Pathways ■■ Continually updated, evidence-based treatment algorithms for specific

The Pathway Process “To begin our pathways development process, we set up disease-specific committees, in which we asked for volunteer co-chairs to lead each committee. On each committee, one chair was an academician and one was community based—the chairs were selected for their expertise in the treatment of that specific disease,” commented Dr. Ellis. The initial goal of the committees was to define the states and stages of disease for which a treatment is needed, and to define common comorbidities that would commonly occur and be likely to demand alternative therapies. “The overriding goal was to de-

cancer presentations and common patient comorbidities that drive practices to best care

■■ Developed and maintained by the oncologists who treat the patients ■■ Delivered at point of care, patient-specific, interactive decision-support tool ■■ Resulting in standardization with measurable proof of performance and conservation of health-care resources

tees meet quarterly via webinar. We first review any conflict of interest disclosures that may influence decisions. Then we review new evidence and debate that evidence until consensus is established for possible changes to the pathway,” he said. Dr. Ellis stressed that there are sig-

We are in a changing practice environment, and effective pathway programs drive standardization across multiple sites for numerous physicians, increasing adherence to increasingly complex evidence-based medicine. —Peter G. Ellis, MD

way to get practices on board with pathways is to be honest and emphasize their proven value in reducing medical errors, improving patient outcomes, driving practice efficiencies, and measuring success,” said Dr. Ellis. He added that it’s important to mention the emergence of accountable care organizations and medical homes as key drivers of patient referrals. “And of course, make sure they know it’s okay to go ‘off pathway,’” said Dr. Ellis. “Finally,” he emphasized, “you need to make this tool easy to use! You cannot expect doctors to adopt a system that is burdensome on their already overtaxed practice. Imbed the pathways in a convenient point-of-care decision support tool that helps physicians select treatments. Hopefully, practices will be able to integrate the pathways into their current flow, either as a stand-alone tool or with their electronic medical records,” said Dr. Ellis. “Challenges aside, we are in a changing practice environment, and effective pathway programs drive standardization across multiple sites for numerous physicians, increasing adherence to increasingly complex evidence-based medicine. Properly implemented, pathways improve practice efficiency and conserve health-care resources, which is a vital component for today’s oncology practices,” concluded Dr. Ellis. n

fine therapies for 80% of our patients. We are not going to have pathways that apply to all the patients who walk in our doors. There is art to what we do, and although not all patients will fit into the pathways, we feel that the 80% who do will benefit from reductions in unwarranted variation in care that we see,” said Dr. Ellis. The committees collect and review all relevant published clinical literature and determine a single best recommendation for each state, stage, and presentation of disease including common comorbidities, based on a threetier process of efficacy, toxicity, and cost. “These are living documents that need to be maintained, so the commit-

nificant challenges to developing and initiating clinical pathways. “It seems like a pretty straightforward process, but it isn’t. For instance, there is a lack of head-to-head data for many of the regimens, and assigning worth to very expensive new drugs that have marginally improved outcomes becomes a difficult task. Also, the need to drive standardization via consensus where there are no clear data can be a challenge create an obstacle to the pathways,” said Dr. Ellis. According to Dr. Ellis, the benefits of clinical pathways outweigh the challenges of implementation. “The best

Disclosure: Dr. Ellis is Chief Medical Officer for Via Oncology and owns stock in D3 Oncology Solutions.

cal challenges involved in a full-scale CancerLinQ implementation. And we have demonstrated value-added tools, such as the ability to measure a clinician’s performance on a subset of QOPI measures in real time,” he noted.

“We have also shown our ability to develop rapid clinical decision support based on guidelines, and integrate them into a demonstration [electronic health record] system. And while there is much work to be done, we have shown that the

core functions of a health learning system are within our grasp, setting the stage for fundamental and unprecedented transformation,” said Dr. Lichter. n

Getting Doctors on Board

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


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

©2012 Amgen Inc. All rights reserved. Not for Reproduction. G69514-R1-V2 68701-R1-V2

RBC = red blood cell

Hb = hemoglobin

Q3W = once every three weeks


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

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


BRIEF SUMMARY: Consult package insert for complete prescribing information. Aranesp┬о (darbepoetin alfa) Injection, for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: t *ODPOUSPMMFEUSJBMT QBUJFOUTFYQFSJFODFEHSFBUFSSJTLTGPSEFBUI TFSJPVT BEWFSTF DBSEJPWBTDVMBS SFBDUJPOT  BOE TUSPLF XIFO BENJOJTUFSFE FSZUISPQPJFTJTTUJNVMBUJOHBHFOUT &4"T UPUBSHFUBIFNPHMPCJOMFWFM PGHSFBUFSUIBOHE- t /P USJBM IBT JEFOUJmFE B IFNPHMPCJO UBSHFU MFWFM  "SBOFTQ EPTF  PS EPTJOHTUSBUFHZUIBUEPFTOPUJODSFBTFUIFTFSJTLT t 6TFUIFMPXFTU"SBOFTQEPTFTVGmDJFOUUPSFEVDFUIFOFFEGPSSFECMPPE cell (RBC) transfusions. Cancer: t &4"T TIPSUFOFE PWFSBMM TVSWJWBM BOEPS JODSFBTFE UIF SJTL PG UVNPS QSPHSFTTJPO PS SFDVSSFODF JO DMJOJDBM TUVEJFT PG QBUJFOUT XJUI CSFBTU  OPOTNBMMDFMMMVOH IFBEBOEOFDL MZNQIPJE BOEDFSWJDBMDBODFST t #FDBVTF PG UIFTF SJTLT  QSFTDSJCFST BOE IPTQJUBMT NVTU FOSPMM JO BOE DPNQMZXJUIUIF&4""113*4&0ODPMPHZ1SPHSBNUPQSFTDSJCFBOEPS EJTQFOTF"SBOFTQUPQBUJFOUTXJUIDBODFS5PFOSPMMJOUIF&4""113*4& 0ODPMPHZ1SPHSBN WJTJUXXXFTBBQQSJTFDPNPSDBMMGPS GVSUIFSBTTJTUBODF t 5PEFDSFBTFUIFTFSJTLT BTXFMMBTUIFSJTLPGTFSJPVTDBSEJPWBTDVMBS BOE UISPNCPFNCPMJD SFBDUJPOT  VTF UIF MPXFTU EPTF OFFEFE UP BWPJE RBC transfusions. t 6TF&4"TPOMZGPSBOFNJBGSPNNZFMPTVQQSFTTJWFDIFNPUIFSBQZ t &4"T BSF OPU JOEJDBUFE GPS QBUJFOUT SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZXIFOUIFBOUJDJQBUFEPVUDPNFJTDVSF t %JTDPOUJOVFGPMMPXJOHUIFDPNQMFUJPOPGBDIFNPUIFSBQZDPVSTF

INDICATION AND USAGE "OFNJB%VFUP$IFNPUIFSBQZJO1BUJFOUT8JUI$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 *OQBUJFOUTXJUIDBODFSSFDFJWJOHIPSNPOBMBHFOUT CJPMPHJDQSPEVDUT  or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. t *OQBUJFOUTXJUIDBODFSSFDFJWJOHNZFMPTVQQSFTTJWFDIFNPUIFSBQZXIFOUIF 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 6ODPOUSPMMFEIZQFSUFOTJPO t 1VSFSFEDFMMBQMBTJB 13$" UIBUCFHJOTBGUFSUSFBUNFOUXJUI"SBOFTQPSPUIFS erythropoietin protein drugs. t 4FSJPVTBMMFSHJDSFBDUJPOTUP"SBOFTQ

WARNINGS AND PRECAUTIONS *ODSFBTFE.PSUBMJUZ .ZPDBSEJBM*OGBSDUJPO 4USPLF BOE5ISPNCPFNCPMJTN *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI $,% DPNQBSJOH IJHIFS IFNPHMPCJO UBSHFUT HE-  UPMPXFSUBSHFUT  HE-  "SBOFTQBOE PUIFS&4"T increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. 6TJOH"SBOFTQUPUBSHFUBIFNPHMPCJOMFWFMPGHSFBUFSUIBOHE-JODSFBTFTUIFSJTL of serious adverse cardiovascular reactions and has not been shown to provide BEEJUJPOBMCFOFmU6TFDBVUJPOJOQBUJFOUTXJUIDPFYJTUFOUDBSEJPWBTDVMBSEJTFBTFBOE TUSPLF1BUJFOUTXJUI$,%BOEBOJOTVGmDJFOUIFNPHMPCJOSFTQPOTFUP&4"UIFSBQZ may be at even greater risk for cardiovascular reactions and mortality than other QBUJFOUT"SBUFPGIFNPHMPCJOSJTFPGHSFBUFSUIBOHE-PWFSXFFLTNBZDPOUSJCVUF 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. *ODPOUSPMMFEDMJOJDBMUSJBMT &4"TJODSFBTFEUIFSJTLPGEFBUIJOQBUJFOUTVOEFSHPJOH DPSPOBSZBSUFSZCZQBTTHSBGUTVSHFSZ $"#( BOEUIFSJTLPGEFFQWFOPVTUISPNCPTJT %75 JOQBUJFOUTVOEFSHPJOHPSUIPQFEJDQSPDFEVSFT 1BUJFOUTXJUI$BODFS An increased incidence of thromboembolic reactions, some serious and lifeUISFBUFOJOH PDDVSSFEJOQBUJFOUTXJUIDBODFSUSFBUFEXJUI&4"T *O B SBOEPNJ[FE  QMBDFCPDPOUSPMMFE TUVEZ TFF 4UVEZ  JO 5BCMF  JO 1SFTDSJCJOH *OGPSNBUJPO PGXPNFOXJUINFUBTUBUJDCSFBTUDBODFSSFDFJWJOHDIFNPUIFSBQZ  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 UPQSFWFOUBOFNJB NBJOUBJOIFNPHMPCJOMFWFMTCFUXFFOBOEHE-PSIFNBUPDSJU CFUXFFOBOE 5IJTTUVEZXBTUFSNJOBUFEQSFNBUVSFMZXIFOJOUFSJNSFTVMUT EFNPOTUSBUFEBIJHIFSNPSUBMJUZBUNPOUIT WT BOEBIJHIFSSBUFPG GBUBMUISPNCPUJDSFBDUJPOT WT JOUIFmSTUNPOUITPGUIFTUVEZBNPOH QBUJFOUTUSFBUFEXJUIFQPFUJOBMGB#BTFEPO,BQMBO.FJFSFTUJNBUFT BUUIFUJNFPG TUVEZUFSNJOBUJPO UIFNPOUITVSWJWBMXBTMPXFSJOUIFFQPFUJOBMGBHSPVQUIBOJO UIFQMBDFCPHSPVQ WT)3 $* Q  1SFTDSJCJOHBOE%JTUSJCVUJPO1SPHSBNGPS"SBOFTQJO1BUJFOUT8JUI$BODFS *OPSEFSUPQSFTDSJCFBOEPSEJTQFOTF"SBOFTQUPQBUJFOUTXJUIDBODFSBOEBOFNJB due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and DPNQMZXJUIUIF&4""113*4&0ODPMPHZ1SPHSBNSFRVJSFNFOUT5PFOSPMM WJTJUXXX FTBBQQSJTFDPNPSDBMMGPSGVSUIFSBTTJTUBODF"EEJUJPOBMMZ QSJPSUP 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.PSUBMJUZBOEPS*ODSFBTFE3JTLPG5VNPS1SPHSFTTJPOPS3FDVSSFODF JO1BUJFOUT8JUI$BODFS &4"T SFTVMUFE JO EFDSFBTFE MPDPSFHJPOBM DPOUSPMQSPHSFTTJPOGSFF 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 SBEJBUJPOUIFSBQZ 4UVEJFTBOE JOQBUJFOUTSFDFJWJOHDIFNPUIFSBQZGPSNFUBTUBUJD CSFBTUDBODFS 4UVEZ PSMZNQIPJENBMJHOBODZ 4UVEZ BOEJOQBUJFOUTXJUIOPO small cell lung cancer or various malignancies who were not receiving chemotherapy PSSBEJPUIFSBQZ 4UVEJFTBOE  Hypertension "SBOFTQ JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI VODPOUSPMMFE IZQFSUFOTJPO *O "SBOFTQ DMJOJDBM TUVEJFT  BQQSPYJNBUFMZ  PG QBUJFOUT XJUI $,% SFRVJSFE JOJUJBUJPO PS intensiямБcation of antihypertensive therapy during the early phase of treatment. )ZQFSUFOTJWFFODFQIBMPQBUIZBOETFJ[VSFTIBWFCFFOSFQPSUFEJOQBUJFOUTXJUI$,% receiving Aranesp. Appropriately control hypertension prior to initiation of and during treatment with "SBOFTQ3FEVDFPSXJUIIPME"SBOFTQJGCMPPEQSFTTVSFCFDPNFTEJGmDVMUUPDPOUSPM Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Seizures "SBOFTQJODSFBTFTUIFSJTLPGTFJ[VSFTJOQBUJFOUTXJUI$,%%VSJOHUIFmSTUTFWFSBM months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for OFXPOTFUTFJ[VSFT QSFNPOJUPSZTZNQUPNT PSDIBOHFJOTFJ[VSFGSFRVFODZ Lack or Loss of Hemoglobin Response to Aranesp For lack or loss of hemoglobin response to Aranesp, initiate a search for causative GBDUPST FH JSPOEFmDJFODZ JOGFDUJPO JOnBNNBUJPO CMFFEJOH *GUZQJDBMDBVTFTPG MBDLPSMPTTPGIFNPHMPCJOSFTQPOTFBSFFYDMVEFE FWBMVBUFGPS13$"*OUIFBCTFODF PG 13$"  GPMMPX EPTJOH SFDPNNFOEBUJPOT GPS NBOBHFNFOU PG QBUJFOUT XJUI BO insufямБcient hemoglobin response to Aranesp therapy. Pure Red Cell Aplasia $BTFTPG13$"BOEPGTFWFSFBOFNJB XJUIPSXJUIPVUPUIFSDZUPQFOJBTUIBUBSJTF GPMMPXJOH UIF EFWFMPQNFOU PG OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO IBWF CFFO reported in patients treated with Aranesp. This has been reported predominantly in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erious Allergic Reactions 4FSJPVT BMMFSHJD SFBDUJPOT  JODMVEJOH BOBQIZMBDUJD SFBDUJPOT  BOHJPFEFNB  CSPODIPTQBTN TLJOSBTI BOEVSUJDBSJBNBZPDDVSXJUI"SBOFTQ*NNFEJBUFMZBOE 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 IFQBSJOUPQSFWFOUDMPUUJOHPGUIFFYUSBDPSQPSFBMDJSDVJUEVSJOHIFNPEJBMZTJT 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-PSXIFOTFSVNUSBOTGFSSJOTBUVSBUJPOJTMFTTUIBO5IFNBKPSJUZPG QBUJFOUTXJUI$,%XJMMSFRVJSFTVQQMFNFOUBMJSPOEVSJOHUIFDPVSTFPG&4"UIFSBQZ 'PMMPXJOHJOJUJBUJPOPGUIFSBQZBOEBGUFSFBDIEPTFBEKVTUNFOU NPOJUPSIFNPHMPCJO XFFLMZVOUJMUIFIFNPHMPCJOJTTUBCMFBOETVGmDJFOUUPNJOJNJ[FUIFOFFEGPS3#$ transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

ADVERSE REACTIONS $MJOJDBM5SJBM&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 UPSBUFTJOUIFDMJOJDBMUSJBMTPGPUIFSESVHTBOENBZOPUSFnFDUUIFSBUFTPCTFSWFE in practice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tudy Adverse Reaction 5ISPNCPFNCPMJD"EWFSTF3FBDUJPOT  O 

Arterial .ZPDBSEJBMJOGBSDUJPO 7FOPVT 1VMNPOBSZFNCPMJTN $FSFCSPWBTDVMBSEJTPSEFST

"MM1MBDFCP 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"NPOHBMMQMBDFCPDPOUSPMMFETUVEJFT BCEPNJOBMQBJO WT BOE FEFNB WT XFSFSFQPSUFENPSFGSFRVFOUMZJOQBUJFOUTSFDFJWJOH"SBOFTQ DPNQBSFE UP UIF QMBDFCP HSPVQ *O UIF 4$-$ TUVEZ UIF JODJEFODF PG BCEPNJOBM QBJO WT BOEFEFNB WT JOUIF"SBOFTQUSFBUFEQBUJFOUT 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 GSFRVFODZPSFTUBCMJTIBDBVTBMSFMBUJPOTIJQUPESVHFYQPTVSF The following adverse reactions have been identiямБed during postmarketing use of Aranesp: t 4FJ[VSFT t 13$" t 4FSJPVTBMMFSHJDSFBDUJPOT Immunogenicity "TXJUIBMMUIFSBQFVUJDQSPUFJOT UIFSFJTBQPUFOUJBMGPSJNNVOPHFOJDJUZ/FVUSBMJ[JOH antibodies to darbepoetin alfa that cross-react with endogenous erythropoietin and PUIFS&4"TDBOSFTVMUJO13$"PSTFWFSFBOFNJB XJUIPSXJUIPVUPUIFSDZUPQFOJBT  *O DMJOJDBM TUVEJFT  UIF QFSDFOUBHF PG QBUJFOUT XJUI BOUJCPEJFT UP "SBOFTQ XBT FYBNJOFEVTJOHUIF#JBDPSF┬оBTTBZ4FSBGSPNQBUJFOUTXJUI$,%BOE cancer patients were tested. At baseline, prior to Aranesp treatment, binding BOUJCPEJFT XFSF EFUFDUFE JO  QBUJFOUT   XJUI $,% BOE  DBODFS QBUJFOUT   %VSJOH "SBOFTQ UIFSBQZ SBOHF  UP  XFFLT  B GPMMPXVQ TBNQMF XBT UBLFO0OFBEEJUJPOBMQBUJFOUXJUI$,%BOEBEEJUJPOBMDBODFSQBUJFOUTEFWFMPQFE BOUJCPEJFTDBQBCMFPGCJOEJOH"SBOFTQ/POFPGUIFQBUJFOUTIBEBOUJCPEJFTDBQBCMF PGOFVUSBMJ[JOHUIFBDUJWJUZPG"SBOFTQPSFOEPHFOPVTFSZUISPQPJFUJOBUCBTFMJOFPSBU FOEPGTUVEZ/PDMJOJDBMTFRVFMBFDPOTJTUFOUXJUI13$"XFSFBTTPDJBUFEXJUIUIF presence of these antibodies. The incidence of antibody formation is highly dependent on the sensitivity and TQFDJmDJUZPGUIFBTTBZ"EEJUJPOBMMZ UIFPCTFSWFEJODJEFODFPGBOUJCPEZ 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

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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 QPTUJNQMBOUBUJPO MPTT 6TF "SBOFTQ EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFmU KVTUJmFTUIFQPUFOUJBMSJTLUPUIFGFUVT8IFO"SBOFTQXBTBENJOJTUFSFEJOUSBWFOPVTMZ to healthy pregnant rats and rabbits, there was no evidence of embryofetal UPYJDJUZ PS PUIFS BEWFSTF PVUDPNFT BU UIF JOUSBWFOPVT EPTFT UFTUFE  VQ UP  NDHLHEBZ 5IJT BOJNBM EPTF MFWFM PG  NDHLHEBZ JT BQQSPYJNBUFMZ GPME IJHIFS UIBO UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF  EFQFOEJOH PO UIF QBUJFOUTUSFBUNFOUJOEJDBUJPO4MJHIUMZSFEVDFEGFUBMXFJHIUTXFSFPCTFSWFEXIFO IFBMUIZSBUBOESBCCJUNPUIFSTSFDFJWFEEPTFTPGNDHLHPSNPSF5IJTEPTFPG NDHLHJTOFBSUIFDMJOJDBMSFDPNNFOEFETUBSUJOHEPTF8IJMFOPBEWFSTFFGGFDUT 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 QPTUJNQMBOUBUJPOMPTTSFnFDUTBESVHFGGFDUPOUIFVUFSJOFFOWJSPONFOUPSPOUIF DPODFQUVT/PTJHOJmDBOUQMBDFOUBMUSBOTGFSPG"SBOFTQXBTEFUFDUFE *O B QFSJQPTUOBUBM EFWFMPQNFOU TUVEZ  QSFHOBOU GFNBMF SBUT SFDFJWFE "SBOFTQ intravenously every other day from implantation throughout pregnancy and MBDUBUJPO 5IF MPXFTU EPTF UFTUFE   NDHLH  EJE OPU DBVTF GFUBM UPYJDJUZ UIJT EPTF JT BQQSPYJNBUFMZ FRVJWBMFOU UP UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF "U NBUFSOBMEPTFTPGNDHLHBOEIJHIFS QVQTIBEEFDSFBTFEGFUBMCPEZXFJHIUT  which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation. 8PNFOXIPCFDPNFQSFHOBOUEVSJOH"SBOFTQUSFBUNFOUBSFFODPVSBHFEUPFOSPMM JO"NHFOT1SFHOBODZ4VSWFJMMBODF1SPHSBN1BUJFOUTPSUIFJSQIZTJDJBOTTIPVME DBMM ".(&/ UPFOSPMM /VSTJOH.PUIFST *UJTOPULOPXOXIFUIFS"SBOFTQJTFYDSFUFEJOIVNBONJML#FDBVTFNBOZESVHTBSF FYDSFUFEJOIVNBONJML DBVUJPOTIPVMECFFYFSDJTFEXIFO"SBOFTQJTBENJOJTUFSFE to a nursing woman. Pediatric Use The safety and efямБcacy of Aranesp in pediatric cancer patients have not been established. Geriatric Use 0GUIFQBUJFOUTXJUI$,%JODMJOJDBMTUVEJFTPG"SBOFTQ XFSFBHFBOE PWFS XIJMFXFSFBHFBOEPWFS0GUIFQBUJFOUTJODMJOJDBMTUVEJFTSFDFJWJOH "SBOFTQBOEDPODPNJUBOUDBODFSDIFNPUIFSBQZ XFSFBHFBOEPWFS 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 TIPVMECFNBOBHFEXJUIEJTDPOUJOVBUJPOPSSFEVDUJPOPG"SBOFTQEPTBHFBOEPSXJUI QIMFCPUPNZ BTDMJOJDBMMZJOEJDBUFE$BTFTPGTFWFSFIZQFSUFOTJPOIBWFCFFOPCTFSWFE GPMMPXJOHPWFSEPTFXJUI&4"T

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Aranesp┬о EBSCFQPFUJOBMGB

Manufactured by: "NHFO.BOVGBDUVSJOH-JNJUFE BTVCTJEJBSZPG"NHFO*OD 0OF"NHFO$FOUFS%SJWF 5IPVTBOE0BLT $" This product, the process of its manufacture, or its use, may be covered by one or NPSF641BUFOUT JODMVEJOH641BUFOU/P   ┬к"NHFO*OD"MMSJHIUTSFTFSWFE 37


ASCOPost.com  |   JANUARY 15, 2013

PAGE 33

JCO Spotlight Supportive Care

Tumor Grade Is Associated with Risk for Venous Thromboembolism By Matthew Stenger

R

ecent data suggest that risk for venous thromboembolism is associated with biologic aggressiveness of cancer. Findings in the Vienna Cancer and Thrombosis Study, recently reported by Ahlbrecht and colleagues in Journal of Clinical Oncology, indicate that patients with higher-grade tumors are at significantly increased risk of venous thromboembolism.1 Further, tumor grade was found to be associated with changes in levels of Ddimer, leukocytes, and hemoglobin— biomarkers that have also been linked with venous thromboembolism risk.

Study Details

T:14”

B:14.25”

S:13”

In the study, 747 patients with newly diagnosed solid tumors or progression of disease after remission were followed for a median of 526 days for occurrence of symptomatic and objectively confirmed venous thromboembolism. Patients were not routinely screened for the disease. Accidentally detected thrombotic events were counted as venous thromboembolism events if they were considered clinically significant by the study adjudication committee. Patients had a median age of 63 years, and 54% were male. Sites of cancer included lung in 20.3%, breast in 19.1%, colorectal in 17.4%, prostate in 17.4%, pancreas in 8.8%, stomach in 6.7%, kidney in 4.6%, and “other” in 5.8%. For tumor grade, a three-level grading system (grades 1 to 3) was used for breast and prostate cancer, and a four-level system was used for other cancers. Overall, 62.7% of patients had low-grade tumors (7.0% grade 1 and 55.7% grade 2) and 37.3% had high-grade tumors (35.7% grade 3 and 1.6% grade 4). Disease was localized in 49.0% and consisted of distant metastasis in 50.5%. Histology consisted of adenocarcinoma in 83.5% of patients and nonadenocarcinoma in 16.1%, primarily squamous cell carcinoma of various sites, renal clear cell carcinoma, and small cell lung cancer. During the study peri-

od, 46.9% of patients received surgery, 66.1% received chemotherapy, and 44.8% received radiotherapy. During up to 2 years of follow-up, 282 patients (37.8%) died without clear evidence of venous thromboembolism. Objectively confirmed venous thromboembolism occurred in 52 patients (7.0%), including asymptomatic disease in 11. The cumulative probability of venous thromboembolism in the entire population was 5.5% after 6 months and 6.2% after 1 year.

cinoma vs nonadenocarcinoma) and tumor sites (high-risk vs low-risk); sites considered to pose high risk for venous thromboembolism were the pancreas, gastrointestinal system, lung, and kidney, and low-risk sites were the breast, prostate, and “other” sites. On this analysis, high-grade tumors were associated with a significant twofold increased risk of venous thromboembolism (HR = 2.0, 95% CI = 1.1–3.5, P = .015). A similar outcome was found in a

Tumor grade is a routine parameter available for almost all solid tumor types and thus represents an easy tool for risk assessment of cancer-associated venous thromboembolism. Of all venous thromboembolism events, most were either isolated deep-vein thrombosis of the lower extremity (36.5%) or isolated pulmonary embolism (36.5%). By cancer site, 26.9% of events occurred in patients with pancreas cancer, 23.1% in those with colorectal cancer, 17.3% in those with stomach cancer, 15.4% in those with lung cancer, and 5.8% each in those with prostate, breast, and other cancer sites.

High-grade Tumors Predict Increased Risk Overall, 51.9% of venous thromboembolism events occurred in patients with low-grade tumors (5.8% in those with grade 1 and 46.2% in those with grade 2) and 48.1% occurred in those with high-grade tumors (46.2% in those with grade 3 and 1.9% in those with grade 4). On univariate analysis, patients with high-grade tumors had a significant 80% increase in risk for venous thromboembolism (hazard ratio [HR] = 1.8, 95% confidence interval [CI] = 1.0–3.1, P = .04). A multivariate model adjusted for distant metastasis, sex, age, and interaction between histology (adenocar-

Cancer-associated Venous Thromboembolism ■■ On multivariate analysis, high tumor grade was associated with an

approximately twofold increased risk of venous thromboembolism.

■■ High tumor grade was associated with higher D-dimer levels and leukocyte counts, and lower hemoglobin levels.

second multivariate model including distant metastasis, interaction between histology and tumor sites, and treatment (surgery, chemotherapy, and radiotherapy), with high-grade tumors being associated with a 90% increased risk of venous thromboembolism (HR = 1.9, 95% CI = 1.1–3.3, P = .023). On KaplanMeier analysis, the cumulative probability of venous thromboembolism after 6 months was 8.2% in patients with highgrade tumors vs 4.0% in those with lowgrade tumors (P = .037).

Tumor Grade and Biomarkers High-grade tumors were associated with differences in some of the biomarkers previously reported to be predictive of venous thromboembolism. Patients with high-grade tumors had significantly higher median D-dimer levels (0.78 vs 0.64 µg/ mL, P =  .008) and leukocyte counts <���������������  �������������� .001) and sig(7.5 vs 6.8 × 109/L, P ���������������� nificantly lower median hemoglobin levels (12.9 vs 13.2 g/dL, P  =  .008). There were no differences between patients with high-grade tumors and those with low-grade tumors with regard to other biomarkers, including prothrombin fragment 1 + 2, sPselectin, clotting factor VIII activity, and platelet count. A third multivariate model included the independent variables from the first two models (ie, tumor grade, histology, and tumor sites) and the biomarkers D-dimer, hemoglobin, platelet count, and leukocyte count—all routinely

available clinical or laboratory variables. On this model, the adjusted hazard ratio for venous thromboembolism for high-grade tumors was 1.9 (95% CI = 1.1–3.3, P = .023). Also independently associated with venous thromboembolism were high-risk tumor sites (HR = <������������  ����������� .001), ade4.3, 95% CI = 2.1–9.0, P ������������� nocarcinoma histology (HR = 2.7, 95% CI  = 1.1–6.9, P  =  .038), and D-dimer level greater than 1.32  µg/mL (75% percentile of the population; HR = 2.2, 95% CI = 1.3–3.9, P = .005). The findings in this study suggest that tumor differentiation may play an important role in the development of cancer-related venous thromboembolism. As stated by the investigators, “Tumor grade is a routine parameter available for almost all solid tumor types and thus represents an easy tool for risk assessment of cancer-associated [venous thromboembolism]. Because thromboprophylaxis … is still a major challenge, it may be useful to incorporate the tumor grade in risk assessment models…. This could enable improved assessment of the [venous thromboembolism] risk in the heterogeneous population of patients with cancer.” n See Page 101

Reference 1. Ahlbrecht J, Dickmann B, Ay C, et al: Tumor grade is associated with venous thromboembolism in patients with cancer: Results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 30:38703875, 2012.

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The ASCO Post  |   JANUARY 15, 2013

PAGE 34

JCO Spotlight Supportive Care

Fixed-dose Apixaban Reduces Risk of Recurrent Venous Thromboembolism By Alice Goodman

V

enous thromboembolism is a frequent problem in cancer patients, and approximately 20% of all patients who develop the disease have a recurrence. Extending treatment with two fixed doses of the investigational agent apixaban, a factor Xa inhibitor without laboratory monitoring, may provide a simple, effective, and safe strategy for long-term management of venous thromboembolism, according to a study presented at the 54th Annual Meeting of the American Society of Hematology in Atlanta.1

Acceptable Safety “Both doses of anticoagulant reduced the risk of recurrent venous thromboembolism by about 80%. The rates of major bleeding were low and comparable to those in the placebo group,” said lead author Giancarlo Agnelli, MD, Professor of Internal Medicine and Director of the Department of Internal and Cardiovascular Medicine and Stroke Unit at Perugia University Hospital in Perugia, Italy. “This regimen has the potential to eliminate many of the challenges we face when treating patients with warfarin, including drug and food interactions, and the need for ongoing monitoring, which can simplify ongoing management of this condition.”

Dr. Agnelli and coauthors calculated that the number of patients needed to treat to prevent 1 episode of recurrent or nonfatal venous thromboembolism is 14, which is low and acceptable, he said. On the other hand, the number of patients needed to treat to cause 1 episode of major or clinically relevant nonmajor bleeding is 200. The randomized, double-blind, placebo-controlled AMPLIFY-EXT study compared two doses of apixaban—2.5 mg and 5 mg—given as secondary prophylaxis vs placebo in patients with deep-vein thrombosis/venous thromboembolism who had completed 6 to 12  months of anticoagulant therapy. Patients were treated with apixaban for 12  months. Safety data were evaluated 30 days after treatment initiation.

Key Results The primary endpoint of symptomatic recurrent venous thromboembolism or all-cause death occurred in 3.8% of patients on the 2.5-mg dose and 4.2% on the 5 mg-dose vs 11.6% on placebo. Recurrent venous thromboembolism or thrombosis-related death was reported in 1.7% of patients on the 2.5mg dose, 1.7% on the 5-mg dose, and 8.8% of the placebo group. Recurrent thrombosis, thrombosis-related death, myocardial infarction, stroke, or cardio-

Extended Treatment of Venous Thromboembolism ■■ An investigational oral factor Xa inhibitor, apixaban, reduced the risk of

fatal and nonfatal venous thromboembolism by 80% in patients who have had 6 to 12 months of previous anticoagulant therapy.

■■ No monitoring is necessary with this agent, and treatment is minimally dependent on renal clearance.

■■ Apixaban is being reviewed by FDA.

EXPERT POINT OF VIEW

P

ress conference moderator Agnes Y. Lee, MD, Medical Director of the Thrombosis Program and Associate Professor of Medicine at the University of British Columbia and Vancouver Coastal Health in Canada, said that apixaban is the third in a new line of anticoagulants for long-term prevention of thrombotic events. “This is an important trial showing that apixaban is highly effective and safe for long-term treatment of venous thromboembolism. By contrast with dabigaAgnes Y. Lee, MD tran [Pradaxa] and rivaroxaban [Xarelto], the other two Xa inhibitors, apixaban therapy is minimally dependent (< 20%) on renal clearance. This gives us another therapeutic option and it is suitable for patients with moderate renal impairment,” Dr. Lee continued. “More options are better so we can personalize therapy for our patients. This study shows how we can improve patient outcomes by conducting rigorous randomized trials,” she said. Nevertheless, it’s important to point out that the study included only 42 patients with cancer, Dr. Lee told The ASCO Post. “The results might not apply to patients with cancer, who have a higher risk of treatment failure with anticoagulants than patients without cancer. Also, there are chemotherapeutic agents that do interact with this drug’s clearance mechanisms, raising a concern that therapeutic drug levels might not be achieved if patients are receiving certain chemotherapeutic drugs.” n Disclosure: Dr. Lee reported no potential conflicts of interest.

vascular-related deaths were reported in 2.1% of the 2.5-mg group, 2.3% of the 5-mg group, and 10% of placebo patients. “Both doses of apixaban reduced the risk of recurrent [venous thromboembolism and venous thromboembolism–related] death by 80%,” Dr. Agnelli stated. The rates of major bleeding associated with both doses of apixaban were similar to placebo: 0.2% with 2.5 mg, 0.1% with 5 mg, and 0.5% with placebo. These data will be part of the submission package to the FDA, but have not yet been submitted, he noted.

The optimal duration of treatment with apixaban is not yet established. In this study, 1 year of treatment achieved risk reduction in venous thromboembolism without increased risk of major bleeding. n

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

Reference 1. Agnelli GC, Buller HR, Cohen A, et al: Two doses of apixaban for the extended treatment of venous thromboembolism. 2012 ASH Annual Meeting. Abstract LBA-1. Presented December 11, 2012.

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ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

now indicated in combination with carboplatin for the first-line treatment of advanced Non–Small Cell lung Cancer

Scan with your mobile device to learn more at www.abraxane.com

Please see Important Safety Information for ABRAXANE, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on adjacent pages, and Brief Summary on following pages.


ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Important Safety Information WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1,500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 for metastatic breast cancer (MBC) and Days 1, 8, and 15 for non-small cell lung cancer (NSCLC) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1,500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • The starting dose should be reduced for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood

Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • 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 • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with single-agent use of ABRAXANE in the MBC study were alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), abnormal ECG (all patients 60%; patients with normal baseline 35%), fatigue/ asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), AST elevation (any 39%), alkaline phosphatase elevation (any 36%), anemia (all cases 33%; severe 1%), nausea (any 30%; severe 3%), diarrhea (any 27%; severe <1%) and infections (24%) • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note included vomiting (any 18%; severe 4%), renal dysfunction (any 11%; severe 1%), fluid retention (any 10%; severe 0%); mucositis (any 7%; severe <1%), hepatic dysfunction (elevations in bilirubin 7%), hypersensitivity reactions (any 4%; severe 0%), thrombocytopenia (any 2%; severe <1%), and injection site reactions (<1%). In all ABRAXANE treated patients (n=366) ocular/visual disturbances were reported (any 13%; severe 1%). Dehydration and pyrexia were also reported • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Non-Small Cell Lung (NSCLC) Cancer Study • Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin in NSCLC were anemia (28%); neutropenia (47%); thrombocytopenia (18%), and peripheral neuropathy (3%) • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin for NSCLC were anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC were anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE were neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

Please see Brief Summary for ABRAXANE, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on following pages.

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group) Post-marketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or to human albumin has not been studied • There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel 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, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • Dose adjustment is recommended for patients with moderate and severe hepatic impairment and patients who experience severe neutropenia or severe sensory neuropathy during treatment with ABRAXANE • Withhold ABRAXANE if AST >10 x ULN or bilirubin >5 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicities • Monitor patients closely

ABRAXANE® is a registered trademark of Celgene Corporation. ©2012 Celgene Corporation 11/12 US-ABR120070


ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a brief summary; refer to full prescribing information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. 1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC = 6 mg•min/mL on Day 1 only of each 21-day cycle, beginning immediately after the completion of ABRAXANE administration. 2.3 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated. Monitor patients closely [see Warnings and Precautions (5.4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin Levels ABRAXANE Dosea Levels MBC NSCLC Mild < 10 x ULN > ULN to ≤ 1.25 x ULN 260 mg/m2 100 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN 200 mg/m2 75 mg/m2 Severe < 10 x ULN 2.01 to 5 x ULN 130 mg/m2 b 50 mg/m2 c > 10 x ULN OR > 5 x ULN not eligible not eligible MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Increase dose to 75 mg/m2 in subsequent courses, as tolerated. 2.4 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to

Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. • In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2. • Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose 2 (mg/m ) (AUC mg•min/mL) Neutropenic Fever (ANC less than 500/mm3 First 75 4.5 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC Second 50 3 less than 1500/mm3 OR Third Discontinue Treatment ANC less than 500/mm3 for more than 7 days First 75 4.5 Platelet count less than 50,000/mm3 Second Discontinue Treatment First 75 4.5 Severe sensory Neuropathy – Second 50 3 Grade 3 or 4 Third Discontinue Treatment 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC) and 47% of patients with non-small cell lung cancer (NSCLC). Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.4)]. 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.4)]. 5.3 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience


a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5.4 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.5 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.6 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. 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. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.7 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (â&#x2030;Ľ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (â&#x2030;Ľ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)] The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE were neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thrombocytopenia (30%), and anemia (16%). 6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 3 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer. Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 (continued)

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Febrile Neutropenia 2 1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose


of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial. Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose- and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma,

43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group). Table 4 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients. Table 4: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) plus carboplatin plus carboplatin Grades Grade Grades Grade 1-4 (%) 3-4 (%) 1-4 (%) 3-4 (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 5 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin. Table 5: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups Paclitaxel Injection ABRAXANE (200 mg/m2 2 (100 mg/m weekly) every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) MedDRA Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 System Organ v 12.1 Toxicity Toxicity Toxicity Toxicity Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General Edema 10 0 4 <1 disorders and peripheral administration site conditions 7 0 2 0 Respiratory Epistaxis thoracic and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective 10 <1 19 2 tissue disorders Myalgia a Peripheral

neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. 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. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.


Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord par esis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.4 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. There are no clinically important pharmacokinetic drug-drug interactions between carboplatin and ABRAXANE [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.6)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. 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. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made 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 ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.3), Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment. 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information). • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.7)]. • Patients must be informed of the risk of low blood cell counts and instructed to contact their physician immediately for fever or evidence of infection. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties, or signs of an allergic reaction. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE. • Patients must be informed that hypersensitivity reactions may occur, which could be severe and sometimes fatal. Manufactured for: Celgene Corporation Summit, NJ 07901 ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2012 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006; 7,820,788; 7,923,536; 8,034,375; 8,268,348; and RE41,884. ABRPI.004/PPI.004 10/12


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PAGE 35

In the Clinic Hematology

Omacetaxine for Chronic or Accelerated Phase CML Patients with Resistance/Intolerance to Tyrosine Kinase Inhibitors By Matthew Stenger

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

Indication On October 26, 2012, the FDA granted accelerated approval to omacetaxine mepesuccinate (Synribo) for the treatment of adult patients with chronic phase or accelerated phase chronic myeloid leukemia (CML) with resistance or intolerance to two or more tyrosine kinase inhibitors.1,2 The decision was based on response rates. As yet, there are no trials verifying an improvement in disease-related symptoms or increased survival with omacetaxine.

OF NOTE Omacetaxine’s approval was based on response rates; no trials have yet demonstrated an improvement in disease-related symptoms or increased survival. Approval was based on findings in a combined cohort of adult patients with CML from two trials.1–3 All patients had received two or more approved tyrosine kinse inhibitors and had evidence of resistance or intolerance to dasatinib (Sprycel) or nilotinib (Tasigna). Patients with New York Heart Association class III or IV heart disease, active ischemia, or other uncontrolled cardiac conditions were excluded from the studies. Patients received subcutaneous omacetaxine at 1.25 mg/m2 twice daily for 14 consecutive days every 28

days (induction cycle). Responding patients received the same dose for 7 consecutive days every 28 days (maintenance cycle). Patients could receive maintenance treatment for up to 24 months. Among 76 patients with chronic phase CML, median age was 59 years, 62% were male, 30% were aged ≥ 65 years, and 80% were Caucasian; in 47%, treatment with imatinib (Gleevec), dasatinib, and nilotinib had failed, and most had received prior non–tyrosine kinase inhibitor treatments, most commonly hydroxyurea (54%), interferon (30%), and cytarabine (29%). A major cytogenetic response occurred in 14 patients (18.4%, 95%���������������   �������������� confidence interval [CI] = 10.5%–29.0%). Among patients with major cytogenetic response, mean time to onset was 3.5 months and median response duration was 12.5 months. Among 35 patients with accelerated phase CML, median age was 63 years, 57% were male, 46% were aged ≥  65 years, and 68% were Caucasian (23% African American); 63% had failed treatment with imatinib, dasatinib, and nilotinib and most had received prior non–tyrosine kinase inhibitor treatments, most commonly hydroxyurea (43%), interferon (31%), and cytarabine (29%). Major hematologic response occurred in 5 patients (14.3%, 95%  CI  = 4.5%–30.3%); none of the patients had a major cytogenetic response. Among patients with major hematologic response, mean time to onset was 2.3 months and median duration of response was 4.7 months.

How It Works The mechanism of action of omacetaxine mepesuccinate has not been fully elucidated, but it includes inhibition of protein synthesis and activity that is independent of direct Bcr-Abl

Omacetaxine in Chronic Myeloid Leukemia ■■ Omacetaxine mepesuccinate (Synribo) was approved to treat adults with chronic or accelerated phase chronic myeloid leukemia who are resistant or intolerant to two or more tyrosine kinase inhibitors.

■■ The induction dose is 1.25 mg/m2 via subcutaneous injection twice daily

for 14 consecutive days of a 28-day cycle, repeated every 28 days until hematologic response; the maintenance dose is 1.25 mg/m2 twice daily for 7 consecutive days of a 28-day cycle.

binding. It binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaeabacteria. The agent was found to have activity in CML patients in the pre–tyrosine kinase inhibitor era. In vitro, omacetaxine reduces levels of the Bcr-Abl oncoprotein and Mcl-1, an antiapoptotic Bcl-2 family member, and its activity is not affected by presence of Bcr-Abl mutations. It has exhibited activity in mouse models of wild-type and T315I mutant Bcr-Abl CML and in CML patients with the T315I mutation.

Study Endpoints Major cytogenetic response: 0%–35% Philadelphia chromosome–positive metaphases in the bone marrow with at least 20 metaphases Major hematologic response: Either a complete hematologic response (normal peripheral complete blood count
and differential and the absence of blasts in the blood) or no evidence of leukemia in the setting of peripheral blood counts that have not normalized

How It Is Given Omacetaxine is given at an induction dose of 1.25 mg/m2 via subcutaneous injection twice daily for 14 consecutive days of a 28-day cycle; cycles should be repeated every 28 days until patients achieve a hematologic response. The recommended maintenance dose is 1.25 mg/m2 via subcutaneous injection twice daily for 7 consecutive days of a 28-day cycle. Treatment should continue for as long as clinical benefit is observed. Treatment cycles may be delayed or the number of days of dosing during the cycle reduced for hematologic toxicities (eg, neutropenia, thrombocytopenia). Complete blood counts should be performed weekly during induction and initial maintenance cycles. After initial maintenance cycles, complete blood counts should be monitored every 2 weeks or as clinically indicated. In patients experiencing grade  4 neutropenia or grade 3 thrombocytopenia, the next cycle should be delayed until

OF NOTE Omacetaxine carries warnings/ precautions for myelosuppression, bleeding, hyperglycemia, and embryo-fetal toxicity. the absolute neutrophil count is ≥ 1.0 9 /L and platelet count is ≥  50 × × 10 9 10 /L, and the number of dosing days in the next cycle should be reduced by 2 (ie, to 12 or 5 days).

Safety Profile Safety data are from 163 patients receiving omacetaxine in clinical trials. Among 108 patients with chronic phase CML, 87% had grade 3 or 4 adverse events, including thrombocytopenia (67%), neutropenia (45%), anemia (36%), bone marrow failure (16%), and febrile neutropenia (10%); the most common grade 3 or 4 nonheSee Page 101 matologic adverse events were infections/infestations (11%; bacterial, fungal, viral, nonspecified) and fatigue (5%). Serious adverse events occurred in 51% of patients with chronic phase CML, with the most common being bone marrow failure (10%), thrombocytopenia (10%), infection (8%), and febrile neutropenia (6%). Discontinuation due to adverse events occurred in 18% of patients, with the most common reasons being pancytopenia, thrombocytopenia, and increased ALT (2% each). Death occurred in five patients (5%), due to cerebral hemorrhage in two, multiorgan failure in one, disease progression in one, and unknown cause in one. Among 55 patients with accelerated phase CML, 84% had grade 3 or 4 adverse events, including thrombocycontinued on page 36

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 (http://www.fda.gov/ medwatch/report.htm).


The ASCO Post  |   JANUARY 15, 2013

PAGE 36

In the Clinic Hematology

Faster Rituximab Infusion for Previously Untreated Follicular Non-Hodgkin and Diffuse Large B-cell Lymphomas By Matthew Stenger

O

n October 19, 2012, FDA approved a 90-minute infusion for rituximab (Rituxan) starting at cycle 2 for patients with previously untreated follicular non-Hodgkin or diffuse large B-cell lymphoma who do not experience a grade  3 or 4 infusion-related reaction during cycle 1.1 Patients with clinically significant cardiovascular disease and those with high circulating lymphocyte counts (≥  5,000/µL) before cycle  2 should not receive the faster infusion. The non-Hodgkin lymphoma indications affected by the approval are previously untreated follicular, CD20-positive, B-cell non-Hodgkin lymphoma in combination with first-line chemotherapy and previously untreated diffuse large B-cell lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or other anthracycline-based chemotherapy regimens. The recommended dose of rituximab in non-Hodgkin lymphoma is 375  mg/ m2 via IV infusion given on day 1 of each cycle of chemotherapy for up to eight doses in both follicular non-Hodgkin and diffuse large B-cell lymphoma patients. For the initial dose in cycle 1, rituximab infusion is initiated at a rate of 50 mg/h; in the absence of infusion toxicity, the rate is increased by 50 mg/h increments every 30 minutes to a maximum of 400 mg/h.

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 (http://www.fda.gov/ medwatch/report.htm).

Omacetaxine in CML continued from page 35

topenia (49%), anemia (36%), neutropenia (18%), and febrile neutropenia (16%); the most common grade 3 or 4 nonhematologic adverse events were infections/infestations (20%), fatigue (9%), and diarrhea (7%). Serious adverse events occurred in 60% of these patients, including febrile neutropenia (18%), infection (11%), thrombocytopenia (9%), anemia (7%), diarrhea (6%), and convulsions (6%). Discontinuation due to adverse

New Infusion Recommendations Under the new approval, a 90-minute infusion can be administered in cycle 2 with a glucocorticoid-containing regimen in patients who do not experience a grade������������������������������������  ����������������������������������� 3 or 4 infusion-related adverse reaction in cycle 1. The 90-minute infusion is started at a rate of 20% of the total dose given in the first 30 minutes, with the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through cycle 6 or 8).

First-line Rapid-infusion Rituximab in Lymphoma ■■ FDA has approved a 90-minute infusion for rituximab (Rituxan) starting

at cycle 2 for patients with previously untreated follicular non-Hodgkin or diffuse large B-cell lymphoma who do not experience a grade 3/4 infusionrelated reaction during cycle 1.

■■ The recommended dose of rituximab in non-Hodgkin lymphoma is 375 mg/m2 via IV infusion given on day 1 of each cycle of chemotherapy for up to 8 doses in both follicular non-Hodgkin and diffuse large B-cell lymphoma patients.

they did not experience a grade 3 or 4 infusion-related adverse event in cycle��������������������������������  ������������������������������� 1 and had a circulating lymphocyte count < 5,000/µL before cycle 2. All patients were premedicated with acetaminophen and an antihistamine and received the glucocorticoid component of their chemotherapy prior to rituximab infusion. Patients who tolerated the 90-minute infusion in cycle 2 continued to receive subsequent rituximab infusions at this rate for the remainder of the treatment regimen (through cycle 6 or 8).

phoma patients (who received CHOP). No grade 4 or 5 infusion-related reactions were reported in cycle 2. These results are comparable to those reported for cycle 2 in rituximab trials using the standard infusion regimen.

Approval of the faster infusion rate is based on findings in an open-label, single-arm, multicenter phase III trial (RATE trial) in which 363 patients with previously untreated follicular non-Hodgkin lymphoma (n  =  113) or diffuse large B-cell lymphoma (n = 250) received rituximab 375 mg/ m2 plus CVP (cyclophosphamide, vincristine, prednisone) in follicular non-Hodgkin lymphoma patients and CHOP in diffuse large B-cell lymphoma patients.2 Patients with clinically significant cardiovascular disease were excluded from the study. Patients were eligible for a 90-minute rituximab infusion in cycle 2 if

Infusion-related Reactions

For cycles 2 through 8, the incidence of grade  3 or 4 infusion-related reactions was 2.8% (95% CI = 1.3%–5.0%). No acute fatal infusion-related reactions were observed. n

events occurred in 33% of patients, with the most common causes being leukocytosis (6%) and thrombocytopenia (4%). Death occurred in five patients (9%), due to cerebral hemorrhage in two and disease progression in three. Omacetaxine carries warnings/precautions for myelosuppression (including fatal thrombocytopenia, neutropenia, and anemia), bleeding (including fatal cerebral hemorrhage and severe gastrointestinal hemorrhage), hyperglycemia, and embryo-fetal toxicity. There

are no identified drug interactions with omacetaxine and no recommendations for dose modifications according to renal or hepatic function or with concomitant administration of CYP450 inducers or inhibitors (omacetaxine is not a substrate of CYP450 enzymes). There are no specific contraindications to omacetaxine use. n

OF NOTE The faster infusion is contraindicated in cases of clinically significant cardiovascular disease and high circulating lymphocyte counts before cycle 2.

RATE Trial Details

The main outcome measure of the trial was the development of grade 3 or 4 infusion-related reactions on the day of or the day after the 90-minute infusion in cycle 2. The incidence of grade 3 infusion-related reactions in cycle 2 was 1.1% (95% confidence interval [CI] = 0.3%–2.8%) among See Page 101 all patients, including an incidence of 3.5% (95%  CI  = 1.0%–8.8%) in follicular non-Hodgkin lymphoma patients (who received CVP) and 0.0% (95%  CI  = 0.0%–1.5%) in diffuse large B-cell lym-

References 1. U.S. Food and Drug Administration: Omacetaxine mepesuccinate. Available at http://www.fda.gov/Drugs/Information-

OF NOTE If the rapid infusion is tolerated in cycle 2, the same rate can be used through the remaining treatment cycles.

References 1. US Food and Drug Administration: Rituximab infusion. Available at http:// www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm324890.htm. Accessed November 9, 2012. 2. RITUXAN® (rituximab) injection for intravenous use prescribing information, Biogen Idec Inc and Genentech, Inc, October 2012. Available at http://www. accessdata.fda.gov/drugsatfda_docs/ label/2012/103705s5367s5388lbl.pdf. Accessed November 9, 2012.

OnDrugs/ApprovedDrugs/ucm325990. htm. Accessed November 12, 2012. 2. SYNRIBO™ (omacetaxine mepesuccinate) for injection, for subcutaneous use, prescribing information, Teva Pharmaceuticals USA, Inc, October 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203585lbl.pdf. Accessed November 12, 2012. 3. Cortes J, Lipton JH, Rea D, et al: Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 120:2573-2580, 2012.


NOW APPROVED for the treatment of patients with metastatic

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

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

AND... • 37% reduction in risk of death vs placebo

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

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

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

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

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

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

Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial

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

were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information.

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


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

PAGE 38

News

Fiscal Cliff Deal continued from page 2

sequestration cuts to cancer research, physician reimbursement, and drug review oversightâ&#x20AC;&#x201D;jeopardizing oncologistsâ&#x20AC;&#x2122; ability to care for their patientsâ&#x20AC;&#x201D;is only temporarily averted, with the new 113th Congress having just 2 months to

resolve the mandatory spending cuts. ASCO will continue to advocate for the protection of critical funding to the National Cancer Institute, Medicare, and the Food and Drug Administration,â&#x20AC;? he added. Dr. Hudis concluded, â&#x20AC;&#x153;ASCO is pleased cancer patients and their doc-

tors have a momentary reprieve from political brinksmanship, but the new year will continue to bring major policy challenges. ASCO stands ready to work with Congress, the Administration, and the medical community to ensure that the nearly 1.6Â million individuals who will receive a cancer diagnosis this year

have access to high-quality, high-value care and services.â&#x20AC;?

AMA Statement â&#x20AC;&#x153;Congress averted a drastic cut of 26.5% from hitting physicians who care for Medicare patients on January 1,â&#x20AC;? stated American Medi-

(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 >VHH8VHLQ6SHFLÂżF3RSXODWLRQV@. -------------------------- 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 WRUDWHVLQWKHFOLQLFDOWULDOVRIDQRWKHUGUXJDQGPD\QRWUHĂ&#x20AC;HFWWKHUDWHVREVHUYHG 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. 7KHPRVWFRPPRQDGYHUVHGUXJUHDFWLRQV Â&#x2022; UHSRUWHGLQSDWLHQWVUHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHDDUWKUDOJLDKRWĂ&#x20AC;XVKSHULSKHUDOHGHPDPXVFXORVNHOHWDOSDLQKHDGDFKH 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 UHDFWLRQVZHUHUHSRUWHGDPRQJRI;7$1',WUHDWHGSDWLHQWVDQGRI 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]HGFOLQLFDOWULDOWKDWRFFXUUHGDWDÂ&#x2022;DEVROXWHLQFUHDVHLQIUHTXHQF\LQ the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders  9.0 44.4 9.3 Asthenic Conditionsa Peripheral Edema  1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4  24.3 4.0 Arthralgia   17.3 1.8 Musculoskeletal Pain  1.3  0.3 Muscular Weakness 9.8  6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

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

Gastrointestinal Disorders Diarrhea 21.8 1.1  0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9  0.0     Dizzinessb Spinal Cord 7.4 6.6  3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0  0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0  0.3 Upper Respiratory Tract Infectiond Lower Respiratory  2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0  Anxiety  0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8  1.0 Pollakiuria 4.8 0.0  0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin  0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Laboratory Abnormalities ,QWKHUDQGRPL]HGFOLQLFDOWULDO*UDGHQHXWURSHQLDRFFXUUHGLQRI 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 DUPVRISDWLHQWVRQ;7$1',DQGRQSODFHERH[SHULHQFHG*UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQGRISDWLHQWVRQSODFHER *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, WDFWLOHRUXQGHÂżQHG


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

PAGE 39

News

cal Association President Jeremy A. Lazarus, MD. â&#x20AC;&#x153;This patch temporarily alleviates the problem, but Congressâ&#x20AC;&#x2122; work is not complete; it has simply delayed this massive, unsustainable cut for 1Â year. Over the next months, it must act to eliminate this ongoing problem once and for all,â&#x20AC;? he said.

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 &RDGPLQLVWUDWLRQRIDVWURQJ&<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'RVDJHDQG$GPLQLVWUDWLRQ  DQG&OLQLFDO3KDUPDFRORJ\  @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQYLYR. 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&OLQLFDO3KDUPDFRORJ\@ 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&OLQLFDO3KDUPDFRORJ\  @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQYLYR. 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., ERVHQWDQHIDYLUHQ]HWUDYLULQHPRGDÂżQLOQDIFLOOLQ DQG6W-RKQÂśV:RUWPD\DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH&OLQLFDO3KDUPDFRORJ\@. 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&OLQLFDO3KDUPDFRORJ\@. -------------------------- 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 ZHUHDQGRYHUZKLOHSHUFHQWZHUHDQGRYHU1RRYHUDOOGLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV2WKHUUHSRUWHGFOLQLFDOH[SHULHQFHKDVQRWLGHQWLÂżHGGLIIHUHQFHVLQ 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 YROXQWHHUVQRVLJQLÂżFDQWGLIIHUHQFHLQHQ]DOXWDPLGHFOHDUDQFHZDVREVHUYHG LQSDWLHQWVZLWKSUHH[LVWLQJPLOGWRPRGHUDWHUHQDOLPSDLUPHQW P/PLQÂ&#x201D; FUHDWLQLQHFOHDUDQFH>&U&/@Â&#x201D;P/PLQ FRPSDUHGWRSDWLHQWVDQGYROXQWHHUV ZLWKEDVHOLQHQRUPDOUHQDOIXQFWLRQ &U&/Â&#x2022;P/PLQ 1RLQLWLDOGRVDJH 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&OLQLFDO3KDUPDFRORJ\@. 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\@

Jeremy A. Lazarus, MD

â&#x20AC;&#x153;This last-minute action on the part of Congress is a clear example of how the Medicare program is increasingly unreliable for physicians and patients,â&#x20AC;? Dr. Lazarus added. â&#x20AC;&#x153;This instability stalls progress in moving Medicare toward new health-care delivery models that can improve value for patients through

Live: 7"w Ă&#x2014; 10"h

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYHPHDVXUHVWDNLQJLQWRFRQVLGHUDWLRQWKHKDOIOLIHRIGD\V,QDGRVH 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 LQYLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQYLYR mouse micronucleus assay. %DVHGRQQRQFOLQLFDOÂżQGLQJVLQUHSHDWGRVHWR[LFRORJ\VWXGLHVZKLFKZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RIWKHSURVWDWHDQGVHPLQDOYHVLFOHVZDVREVHUYHGDWÂ&#x2022;PJNJGD\ 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 DWÂ&#x2022;PJNJGD\ WLPHVWKHKXPDQH[SRVXUHEDVHGRQ$8&  PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFWSDWLHQWVWRWDNHWKHLUGRVHDWWKHVDPHWLPHHDFKGD\ RQFHGDLO\  XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUPSDWLHQWVUHFHLYLQJD*Q5+DQDORJWKDWWKH\QHHGWRPDLQWDLQWKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUPSDWLHQWVWKDW;7$1',KDVEHHQDVVRFLDWHGZLWKDQLQFUHDVHG 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; ,QIRUPSDWLHQWVWKDW;7$1',PD\FDXVHGL]]LQHVVPHQWDOLPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUPSDWLHQWVWKDWWKH\VKRXOGQRWLQWHUUXSWPRGLI\WKHGRVHRUVWRS ;7$1',ZLWKRXWÂżUVWFRQVXOWLQJWKHLUSK\VLFLDQ,QIRUPSDWLHQWVWKDW 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; $SSULVHSDWLHQWVRIWKHFRPPRQVLGHHIIHFWVDVVRFLDWHGZLWK;7$1', DVWKHQLDIDWLJXHEDFNSDLQGLDUUKHDDUWKUDOJLDKRWĂ&#x20AC;XVKSHULSKHUDO 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; ,QIRUPSDWLHQWVWKDW;7$1',PD\EHKDUPIXOWRDGHYHORSLQJIHWXV 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.

better care coordination. Physicians want to work with Congress to move past this ongoing crisis and toward a Medicare program that ensures access to care and the best health outcomes for patients and a stable, rewarding practice environment for physicians.â&#x20AC;?

ASH Statement A statement issued by the American Society of Hematology (ASH) on the deal noted that the Society was pleased about immediate protection for biomedical research and physician reimbursement, but urged Congress to protect programs from further cuts and the â&#x20AC;&#x153;next cliff.â&#x20AC;? â&#x20AC;&#x153;While the legislation passed protects the country from going over a fiscal cliff for the time being, the Society is keenly aware that NIH and other nondefense discretionary programs are not safeguarded from future cuts, and there is not a permanent solution for the flawed physician payment formula,â&#x20AC;? the statement read. â&#x20AC;&#x153;Given this uncertain outlook, ASH will continue to urge lawmakers to provide balanced deficit reduction that does not further cut discretionary programs like NIH. The Society will educate Congress about the value of biomedical research so that all members of the new 113th Congress understand that this is not the time to defund science and that discoveries made possible by investments in NIH generate incredible returns in the form of lives and jobs and importantly help secure Americaâ&#x20AC;&#x2122;s position as a global economic force.â&#x20AC;? n

The ASCO Post Follow us on

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,QF6DQ)UDQFLVFR&$ Issued: August 2012 $(1=%56 Rx Only Š 2012 Astellas Pharma US, Inc. XTANDIŽ is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

@ASCOPost


The ASCO Post  |   JANUARY 15, 2013

PAGE 40

Pearls in Neuro-oncology

Management of Brain Metastases By Ganesh Shankar, MD, PhD, and Daniel P. Cahill, MD, PhD

A

n increasing portion of patients with cancer are manifesting brain metastases, with a prevalence of up to 40% and an incidence of approximately 170,000 new cases per year in the United States. The goal for management of brain metastasis is to achieve control of symptoms and recurrence, both at existing sites of metastasis (local control) and through the prevention of new lesions (distal or regional control). This control can then contribute, in combination with systemic treatments, to improved neurologic function, performance staDr. Shankar is Senior Resident, Department of Neurosurgery, Massachusetts General Hospital. Dr. Cahill is Assistant Professor in Neurosurgery, Harvard Medical School, and Attending Neurosurgeon, Massachusetts General Hospital, Boston.

tus, and potentially overall survival. The evidence-based treatment of brain metastasis in any individual patient will often incorporate surgical resection, stereotactic radiosurgery, and whole-brain radiation therapy over the course of the illness.1 Most importantly, treatments directed at brain metastases must be coordinated with treatments for systemic disease. Here, we frame the key considerations for appropriately guiding therapeutic decisions for patients with brain metastases.

Patient Characteristics Decision-making about brain metastases requires knowledge of expected overall survival in a patient with metastatic cancer. Will this patient live long enough that control of metastatic disease in the brain will

contribute to an improvement in overall outcome? In historical studies, improved survival in patients with brain metastases was associated with age ≤ 65 years, Karnofsky performance status (KPS) ≥  70, controlled systemic disease, and isolated brain relapse. A recently proGanesh Shankar, MD, PhD Daniel P. Cahill, MD, PhD posed Diagnosis-Specific metastases. These lesions are are often Graded Prognostic Assessment from the subcentimeter in size and are amenable Radiation Therapy Oncology Group has to treatment by whole-brain irradiation further accounted for the histology of or stereotactic radiosurgery (or both), the primary malignancy, which can more on an outpatient basis. Traditionally raaccurately predict the range of a single dioresistant histologies such as melanopatient’s expected survival (Fig. 1).2 ma, renal cell carcinoma, and sarcoma Tumor Characteristics are associated with poor rates of local Use of screening MRI in patients control when only whole-brain irradiawith cancer has yielded increased detion is administered. tection of small, asymptomatic brain Surgical resection is usually indicated in the local control of larger (> 3 cm in diameter) lesions causing mass effect, those resulting in significant surrounding edema, obstructive hydrocephalus, and especially for those in the posterior fossa. Clinical equipoise remains on the management of asymptomatic lesions between 1 cm and 3 cm, for which local control can be achieved by either surgery or stereotactic radiosurgery.

Surgical Resection

Fig. 1. Graded prognostic assessment (GPA) worksheet to estimate survival from brain metastases (BM) by diagnosis. Subtype: Basal: triple negative; LumA: ER/PR positive, HER2 negative; LumB: triple positive; HER2: ER/PR negative, HER2 positive. ECM = extracranial metastases; ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; KPS = Karnofsky performance score; LumA = luminal A; LumB = luminal B; PR = progesterone receptor. © 2012 American Society of Clinical Oncology. Reprinted, with permission, from Sperduto PW, et al.2

Two randomized controlled trials demonstrate survival benefit with surgical resection and whole-brain radiotherapy as compared with whole-brain radiotherapy alone for the management of a single brain metastasis in patients with good performance status. Level 2 evidence suggests that lesions larger than 3����������������������������������  ��������������������������������� cm or those resulting in mass effect may have improved outcomes with surgical resection rather than stereotactic radiosurgery. Taken together with the randomized controlled trial data for stereotactic radiosurgery of a single lesion (see below), there is strong evidence for a survival benefit from an initial strategy of focally directed therapy (surgery or stereotactic radiosurgery) for patients with a single brain metastasis and good performance status. Available data are insufficient to guide management for patients with lower performance status (KPS < 70). This subgroup may have decreased overall survival secondary to systemic continued on page 48


Because Endocrine Monotherapy Can Only Take You So Far


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

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

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

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

7.8 months Placebo plus exemestane: 3.2 months

AFINITOR plus exemestane:

PFS Probability (%)

80

60

Median PFS: 3.2 months

55%

Median PFS: 7.8 months

reduction in risk of progression or death2

40

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

0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

Time (months)

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

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

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

(HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

BOLERO-2=Breast Cancer Trials of Oral Everolimus; HR=hazard ratio.


T:14”

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AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. Important Safety Information.

• AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients • There have been reports of noninfectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR, some with

fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared with patients <65 years of age

• Oral ulceration is the most frequently occurring adverse event and occurred in 44% to 86% of AFINITOR-treated patients across the clinical trial

experience. Most of these events were grade 1/2. Grade 3/4 stomatitis was reported in 4% to 9% of patients

• Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have

also been reported; monitoring of laboratory tests is recommended

• The use of live vaccines and close contact with those who have received live vaccines should be avoided • AFINITOR can cause fetal harm when administered to a pregnant woman

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

References: 1. AFINITOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2012. 2. Data on file. Study CRAD001Y2301. Novartis Pharmaceuticals Corp; 2012.


• Careful monitoring and appropriate dose adjustments for adverse

Important Safety Information. AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, patients should be managed with dose interruption until symptoms improve • The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 • AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR • The development of pneumonitis has been reported even at a reduced dose Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred • Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR • Treatment of preexisting invasive fungal infections should be completed prior to starting treatment • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients • In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed Renal Failure: • Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR Geriatric Patients: • In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared to 2% in patients <65 years of age • Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2012 Novartis

reactions are recommended Laboratory Tests and Monitoring: • Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported • Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter • When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) • Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments Hepatic Impairment: • Exposure of everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended Vaccinations: • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%) • The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%) Laboratory Abnormalities: • The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%) • The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%)

Please see Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

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AFB-1043056


AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009

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Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations]. Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.


The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 e Median duration of treatment 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration

Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo c

Key observed laboratory abnormalities are presented in Table 3. Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory Parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Agents That May Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information]. Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.


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A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Pediatric use of AFINITOR Tablets is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in diseaserelated symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown. Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least one serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups. Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information].The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information]. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (ChildPugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Distributed by: Novartis Pharma Stein AG Novartis Pharmaceuticals Corporation Stein, Switzerland East Hanover, New Jersey 07936 © Novartis T2012-153 August 2012


The ASCO Post  |   JANUARY 15, 2013

PAGE 48

Pearls in Neuro-oncology

Management of Brain Metastases

Adjuvant Whole-brain Radiation Therapy

continued from page 40

No study has yet been reported with enough power to observe a difference in survival for patients receiving stereotactic radiosurgery alone compared to those undergoing stereotactic radiosurgery and whole-brain radiotherapy. However, there has been a significant difference

progression, and thus local control of asymptomatic brain lesions may not improve their overall outcome.

Stereotactic Radiosurgery While resection is recommended for single brain metastases larger than 3 cm in locations amenable to surgery, stereotactic radiosurgery appears to offer an equivalent option for the management of a smaller single lesion in terms of local control and survival (Fig. 2).3 Level 1 evidence supports the use of stereotactic radiosurgery for single brain metastases (in addition to whole-brain radiotherapy) in patients with KPS ≥ 70 to obtain improved survival. Indeed, with regard to lesions <����������������������������  ��������������������������� 3��������������������������  ������������������������� cm, level����������������  ��������������� 2 evidence suggests equivalence of surgical resection and stereotactic radiosurgery when used together with whole-brain radiotherapy in terms of recurrence and survival rates. Stereotactic radiosurgery combined with whole-brain radiotherapy may be superior to whole-brain irradiation alone to preserve function in patients with two to four metastatic lesions. Which patients with multiple metastases may benefit from stereotactic radiosurgery is currently an area of active study; factors such as tumor histology or potential response to systemic targeted therapeutics may play an important role.

reserved as salvage therapy at the time of brain recurrence. Ongoing randomized controlled trials will clarify whether withholding of upfront whole-brain radiotherapy affects intracranial recurrence, survival, and neurocognitive function, with the hope that evidence-based criteria can be developed to guide the sequenced application of these treatments.

The goal of brain metastasis management is to achieve local and regional control as a means of preserving performance status and neurologic function and potentially improving overall survival. —Ganesh Shankar, MD, PhD, and Daniel R. Cahill, MD, PhD

noted in local and distant recurrence in patients for whom whole-brain radiotherapy is withheld. The timing of wholebrain irradiation has therefore been controversial. Patients with asymptomatic brain metastases and extensive systemic disease are able to initiate chemotherapy sooner if the intracranial disease is initially treated with stereotactic radiosurgery, and whole-brain radiotherapy is withheld until distal failure in the brain. Given the lack of clear survival benefit and the well known detrimental effects on cognitive function with adjuvant wholebrain radiation therapy,4 an alternative treatment paradigm is close postoperative (or post–stereotactic radiosurgery) surveillance, with whole-brain radiotherapy

Recommendations The goal of brain metastasis management is to achieve local and regional control as a means of preserving performance status and neurologic function and potentially improving overall survival. Patients with a single brain metastasis (up to 30% of patients on initial presentation) have a proven survival benefit from focally directed therapy (stereotactic radiosurgery or surgery). Surgical resection and stereotactic radiosurgery appear to have therapeutic equivalence for asymptomatic supratentorial lesions less than 3 cm. These modalities are particularly important for the local control of traditionally radioresistant histologies such

Pearls in Neuro-oncology is guest edited by Tracy Batchelor, MD, Director, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, and Professor of Neurology, Harvard Medical School, Boston. The series is intended to provide the practicing oncologist with guidance in managing neuro-oncology issues that may present in their patients with cancer. as melanoma, renal cell carcinoma, and sarcoma. While whole-brain radiotherapy clearly affects intracranial recurrence rates when applied after resection or stereotactic radiosurgery, the effect on overall survival has been less easily demonstrable. Taken together with the potential detrimental effects of whole-brain radiotherapy on neurocognitive function, this has led to clinical trials to identify patient subgroups in which whole-brain irradiation may be reserved as salvage therapy. n Disclosure: Drs. Shankar and Cahill reported no potential conflicts of interest.

Fig. 2: (a–d) Screening MRI scan of a 46-year-old man with a past medical history of non–small cell lung cancer, demonstrating two lesions in the brain— one in the left frontoparietal region measuring 1.5 × 2.2 cm × 2 cm and one in the right parietal lobe measuring 1.6 × 1.7 cm × 1.8 cm (2a). Stereotactic radiosurgery was administered and followed by whole-brain radiation therapy. These enhancing lesions were less noticeable at 1 month (2b) and 5 months (2c) post–stereotactic radiosurgery. Nine months later, the previously treated metastatic sites in the parietal areas seem to be stable (2d). No new lesions are appreciated. He ultimately died from progressive systemic disease 16 months after the cerebral metastases were treated. (2e–2h) A 59-year-old, right-handed woman with renal cell carcinoma presented with hemorrhagic metastasis in the left motor cortex 17 months following initial diagnosis. This lesion was in the motor cortex adjacent to the intrinsic hand motor area (2e). She underwent stereotactic radiosurgery with a decrease in enhancement at 2 months and 8 months post-treatment. She had neither recurrence nor new metastatic brain lesions on surveillance imaging for at least 15 months following stereotactic radiosurgery (2h).

References 1. Robinson PD, Kalkanis SN, Linskey ME, et al: Methodology used to develop the AANS/CNS management of brain metastases evidence-based clinical practice parameter guidelines. J Neurooncol 96:11-16, 2010. 2. Sperduto PW, Kased N, Roberge D, et al: Summary report on the graded prognostic assessment. J Clin Oncol 30:419-425, 2012. 3. Andrews DW, Scott CB, Sperduto PW, et al: Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363(9422):1665-72, 2004. 4. Chang EL, Wefel JS, Hess KR, et al: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol 10:1037-1044, 2009.


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PAGE 49

Announcements

Peter P. Yu, MD, Elected ASCO President, 2014–2015, Others Named to ASCO Board

P

eter P. Yu, MD, has been elected President of ASCO for a 1-year term beginning in June 2014. He will take office as President-Elect during the ASCO Annual Meeting in Chicago in June 2013. Additionally, three new members were elected to the ASCO Board of Directors, and three new members were elected to the ASCO Nominating Committee. “I am both honored and privileged by the opportunity to lead ASCO,” said Dr. Yu. “I have been fortunate to serve

Peter P. Yu, MD

the Society for many years in a volunteer capacity, and in doing so, have developed a depth and breadth of knowledge and experience on issues that are important for the advancement of cancer science and care. As President of the Society, I look forward to working collaboratively with the membership, staff, and Board of Directors to further advance the ASCO mission and vision.”

Career Highlights Dr. Yu is currently the Director of Cancer Research at Palo Alto Medical Foundation. He received his medical degree from Brown University, and performed his internship and residency in Internal Medicine at St. Luke’sRoosevelt Hospital and a fellowship in Neoplastic Diseases at Mount Sinai Hospital. Dr. Yu was also a Research Fellow and Associate at Memorial Sloan-Kettering Cancer Center. Dr. Yu is well known for his knowledge and understanding of how health information technology can advance the prevention, diagnosis, and treatment of cancer care. Since joining ASCO in 1986, Dr. Yu has served on the Quality of Care, Cancer Research, and Clinical Practice Committees, the Health Information Technology Workgroup (current Chair), Integrated Media and Technology Committee, and Board of Directors, among others. He was also

previously the ASCO State Affiliate Society President of the Association of Northern California Oncologists and is currently an active blogger on ASCOconnection.org.

Newly Elected ASCO Board Members ASCO’s Board of Directors comprises oncology leaders who are elected to positions reflecting various spe-

cialties within the oncology field. The following physicians will begin 3-year terms as members of ASCO’s Board of Directors starting in June 2013: continued on page 50


The ASCO Post  |   JANUARY 15, 2013

PAGE 50

Announcements

ASCO Elections continued from page 49

Therese M. Mulvey, MD, FASCO, has been elected to one of the Community Oncologist seats. Dr. Mulvey is the Physician-in-Chief at Southcoast Centers for Cancer Care, part of Southcoast Health System, with centers in Fairhaven and Fall River, Massachusetts. An active member

since 2001, she currently serves on ASCO’s Quality of Care Committee, Clinical Practice Committee, and the Cost of Cancer Care Task Force. Dr. Mulvey has been a Fellow of ASCO since 2010. Neal J. Meropol, MD, has been elected to the Medical Oncologist seat. Dr. Meropol is a Professor of Medicine and Chief of the Division of Hematology and

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% INDICATIONS AND USAGE Hispanic, 2% Black, and < 1% Asian, Native American or other. Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated malignancies receiving myelosuppressive anticancer drugs patients. associated with a clinically significant incidence of febrile Table 1. Adverse Reactions With ≥ 5% Higher Incidence neutropenia. Neulasta is not indicated for the mobilization of peripheral blood in Neulasta Patients Compared to Placebo in Study 3 progenitor cells for hematopoietic stem cell transplantation. System Organ Class Placebo Neulasta 6 mg CONTRAINDICATIONS Preferred Term (N = 461) SC on Day 2 Do not administer Neulasta to patients with a history of serious (N = 467) allergic reactions to pegfilgrastim or filgrastim. Musculoskeletal and connective tissue disorders WARNINGS AND PRECAUTIONS Bone pain 26% 31% Splenic Rupture Pain in extremity 4% 9% Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen Leukocytosis or splenic rupture in patients who report left upper abdominal In clinical studies, leukocytosis (WBC counts > 100 x 109/L) or shoulder pain after receiving Neulasta. was observed in less than 1% of 932 patients with nonmyeloid Acute Respiratory Distress Syndrome malignancies receiving Neulasta. No complications attributable Acute respiratory distress syndrome (ARDS) can occur in patients to leukocytosis were reported in clinical studies. receiving Neulasta. Evaluate patients who develop fever and Immunogenicity lung infiltrates or respiratory distress after receiving Neulasta, for As with all therapeutic proteins, there is a potential for ARDS. Discontinue Neulasta in patients with ARDS. immunogenicity. Binding antibodies to pegfilgrastim were Serious Allergic Reactions detected using a BIAcore assay. The approximate limit of Serious allergic reactions, including anaphylaxis, can occur in detection for this assay is 500 ng/mL. Pre-existing binding patients receiving Neulasta. The majority of reported events antibodies were detected in approximately 6% (51/849) occurred upon initial exposure. Allergic reactions, including of patients with metastatic breast cancer. Four of 521 anaphylaxis, can recur within days after the discontinuation of pegfilgrastim-treated subjects who were negative at baseline initial anti-allergic treatment. Permanently discontinue Neulasta developed binding antibodies to pegfilgrastim following in patients with serious allergic reactions. Do not administer treatment. None of these 4 patients had evidence of Neulasta to patients with a history of serious allergic reactions neutralizing antibodies detected using a cell-based bioassay. to pegfilgrastim or filgrastim. The detection of antibody formation is highly dependent on Use in Patients With Sickle Cell Disorders the sensitivity and specificity of the assay, and the observed Severe sickle cell crises can occur in patients with sickle cell incidence of antibody positivity in an assay may be influenced disorders receiving Neulasta. Severe and sometimes fatal sickle by several factors, including assay methodology, sample cell crises can occur in patients with sickle cell disorders handling, timing of sample collection, concomitant medications, receiving filgrastim, the parent compound of pegfilgrastim. and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence Potential for Tumor Growth Stimulatory Effects on of antibodies to other products may be misleading. Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor Postmarketing Experience through which pegfilgrastim and filgrastim act has been found The following adverse reactions have been identified during on tumor cell lines. The possibility that pegfilgrastim acts post approval use of Neulasta. Because these reactions are as a growth factor for any tumor type, including myeloid reported voluntarily from a population of uncertain size, it is not malignancies and myelodysplasia, diseases for which always possible to reliably estimate their frequency or establish pegfilgrastim is not approved, cannot be excluded. a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more ADVERSE REACTIONS of the following factors: (1) seriousness of the reaction, (2) The following serious adverse reactions are discussed in reported frequency of the reaction, or (3) strength of causal greater detail in other sections of the Brief Summary: relationship to Neulasta. • Splenic Rupture [See Warnings and Precautions] Gastro-intestinal disorders: Splenic rupture [see Warnings • Acute Respiratory Distress Syndrome [See Warnings and Precautions] and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions] • Use in Patients with Sickle Cell Disorders [See Warnings Hypersensitivity reactions: Allergic reactions/hypersensitivity, and Precautions] including anaphylaxis, skin rash, and urticaria, generalized • Potential for Tumor Growth Stimulatory Effects on Malignant erythema and flushing [see Warnings and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity. Skin and subcutaneous tissue disorders: Sweet’s syndrome, Clinical Trials Experience Cutaneous vasculitis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials DRUG INTERACTIONS of a drug cannot be directly compared with rates in the clinical No formal drug interaction studies between Neulasta and other trials of another drug and may not reflect the rates observed in drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may clinical practice. Neulasta clinical trials safety data are based upon 932 patients result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The USE IN SPECIFIC POPULATIONS ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy Category C tumors (n = 53) and lymphoma (n = 56) received Neulasta There are no adequate and well-controlled studies in pregnant after nonmyeloablative cytotoxic chemotherapy. Most patients women. Pegfilgrastim was embryotoxic and increased received a single 100 mcg/kg (n = 259) or a single 6 mg pregnancy loss in pregnant rabbits that received cumulative (n = 546) dose per chemotherapy cycle over 4 cycles. doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies with metastatic or non-metastatic breast cancer receiving the potential risk to the fetus. docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use

Oncology at University Hospitals Case Medical Center & Case Western Reserve University, Associate Director for Clinical Research at Case Comprehensive Cancer Center, Associate Director for Clinical Programs at University Hospitals Seidman Cancer Center, and the Dr. Lester E. Coleman, Jr. Endowed Chair in Cancer Research and Therapeutics. An ASCO

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2012 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

65481-R1-V1

member since 1993, he serves on the Cost of Care Task Force and Cancer Communications Committee, and Co-Chairs the ASCO/AACR Methods in Clinical Cancer Research workshop. Paulo Marcelo Gehm Hoff, MD, PhD, FACP, has been elected to one of the Undesignated Specialty seats. Dr. Hoff is the Professor of Oncology and General Director of the ICESP-Instituto do Câncer do Estado de São Paulo, at the University of São Paulo, as well as General Director of the Oncology Center at the Hospital Sírio Libanês, Brazil. He is a voluntary faculty member at the University of Miami. An ASCO member since 1996, he currently serves on the Gastrointestinal Cancers Symposium Planning Committee.

Newly Elected Members of ASCO Nominating Committee Three newly elected ASCO Nominating Committee members will serve 3-year terms beginning in June 2013: Roscoe F. Morton, MD, FACP, has been elected to the Community Oncologist seat on the Nominating Committee. Dr. Morton is a partner at Medical Oncology and Hematology Associates of Iowa. He is also a Clinical Assistant Professor at the University of Iowa College of Medicine-Des Moines. Dr. Morton currently serves ASCO in numerous capacities including as Chair of the State Affiliate Working Group and a member of both the Clinical Practice Committee and the Special Awards Selection Committee. Lee M. Ellis, MD, has been elected to one of the Undesignated Specialty seats on the Nominating Committee. Dr. Ellis is a Professor of Surgery and Cancer Biology at The University of Texas MD Anderson Cancer Center and is also the William C. Liedtke, Jr. Chair in Cancer Research. Dr. Ellis currently serves ASCO in numerous capacities including as Chair of the Cancer Research Committee and Track Leader, Tumor Biology of the Education Committee. Kim Allyson Margolin, MD, has been elected to one of the Undesignated Specialty seats on the Nominating Committee. She will serve as the Chair of the Nominating Committee in 2015–2016. Dr. Margolin is an Associate Director for the HematologyOncology Fellowship and a Professor in the Division of Oncology at the University of Washington and Director of the University of Washington/Seattle Cancer Care Alliance clinical research program in melanoma and kidney cancer. Dr. Margolin has served on the ASCO Cancer Education Committee and Best of ASCO® Planning Committee. n


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PAGE 51

Health-care Policy

Accountable Care Organizations: The New Normal? By Richard J. Boxer, MD, FACS

Richard J. Boxer, MD, FACS

T

he accountable care organization was introduced into our lexicon during a public meeting of the Medicare Payment Advisory Commission in 2006, and the term became ubiquitous when it was specified in the Patient Protection and Affordable Care Act of 2010. After the November 6 election, accountable care organizations became a fact of life. The principle that defines the reason for accountable care organizations is the near-uniform belief that health care in America is fractionated, too expensive, and demands creative reform.

Basic Principles Through accountable care organizations, the Affordable Care Act envisions the transformation of current volume-based, potentially perverse incentives to overtest and overtreat, to value-based incentives for delivery of high-quality, lower-cost health care. These organizations are designed to coordinate care through a robust system of patient-centered primary care health professionals. However, medical and surgical specialists rapidly have Dr. Boxer is Clinical Professor at the University of Wisconsin, Madison, and the Medical College of Wisconsin (Milwaukee), and former Professor of Clinical Urology at the University of Miami.

become an integral part of these organizations. Oncology, which accounts for 10% of health-care expenses, certainly will be impacted. Although the Affordable Care Act described accountable care organizations as a means of coordinating care for Medicare beneficiaries, private insurers are embracing the concept. So, what exactly are accountable care organizations? Ideally, they are integrated systems of physicians and other health providers that increase

ing quality metrics. However, the projected budget for Medicare in that same period of time is $6.2 trillion. Thus, the extraordinary effort to create accountable care organizations will save approximately 0.08% of the Medicare budget. This is known by the Congressional Budget Office as “budget dust.” In addition, the estimate of legal and consulting fees to create the existing and near-future accountable care organizations is $1  billion. Already, 20% of the savings is consumed, and the process has just begun.

It is up to oncologists to honestly and transparently work for the benefit of the patient with cancer, but simultaneously understand that the status quo is over, and quality-based care that promotes improved outcomes will be the new normal. —Richard J. Boxer, MD, FACS

practices at a rapid pace. In 2000, 20% of primary care doctors and 5% of specialists were employed by hospital systems. In 2012, 40% of primary doctors and 22% of specialists are employed. And this will continue until the vast majority will be controlled. It is highly unlikely that this extraordinary aggregation of physicians and the creation of accountable care organizations is a coincidence. Physicians have always been an uncontrollable and independent lot. That, like fragmentation of care and fee-for-service, will soon be a historical vignette. Oncologists have a lot at stake. Throughout the nation, many practices are being purchased by integrated health systems. This may result in more oncologists integrating their practices into large single-specialty groups to preserve their independence and create outcomes and value-based oncology centers of excellence.

Accountability Question coordinated care and improve patient outcomes. They can be independent physician organizations, integrated delivery systems (hospitals and their participating physicians), multispecialty group practices, physician-hospital organizations (nonemployee medical staff), or virtual physician organizations (commonly in rural areas). Theoretically, the money saved by a successful accountable care organization will be shared in certain undetermined percentages by the insurer (including Medicare) and the organization itself (including the doctors). The Congressional Budget Office has predicted that accountable care organizations will save Medicare $5����� ���� billion over the first 8 years, by eliminating unnecessary or redundant procedures, sharing clinical information, and meet-

In further evidence of the money involved, it is estimated to cost $10 million to $30 million to create a fully functional accountable care organization. Who has that kind of money? The answer is commonly, but not uniquely, integrated health systems— ie, the hospitals.

Added Rationale H.L. Mencken famously said, “When somebody says it’s not about the money, it’s about the money.” Nevertheless, it seems clear that in the immediate future, there is little money to be saved or shared. Thus, the best reason to create and support the accountable care organization concept is for improved patient outcomes. But is there another reason? Hospital systems have been buying

The question on all physicians’ minds is: To whom are the accountable care organizations accountable? Physicians staunchly fight for the accountability to be to the patient, not the bottom line. Yet, one of the reasons for the Affordable Care Act is the crisis produced by the very system that physicians were central in creating. There is no turning back. The federal health-care legislation may be slightly modified, but it is the future of health-care delivery. It is up to oncologists to honestly and transparently work for the benefit of the patient with cancer, but simultaneously understand that the status quo is over, and qualitybased care that promotes improved outcomes will be the new normal. n

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

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The dual role that integrins play on both tumor and endothelial cells may contribute to the aggressive nature of glioblastoma PRESENTING

THE

ROLE

OF

I N T E G R I N S

in Glioblastoma

• Gliomas account for approxiately 80% of all malignant brain and central nervous system tumors in adults.1 Glioblastoma is the most aggressive form of gliomas.2 • Integrins are a family of at least 24 distinct cell surface heterodimer receptors. As cell surface receptors, integrins regulate cellular behavior by way of signal transmission between extracellular and intracellular spaces through interactions with extracellular ligands.3, 4, 5 • Integrins are overexpressed on tumor cells and vasculature but not widely expressed on normal tissues and blood vessels.3, 5 • The overexpression and activity of integrins are important for proliferation, migration, invasion, and survival of glioblastoma cells.3 Integrins also support tumor growth and progression by promoting tumor-associated angiogenesis.6 References 1. Central Brain Tumor Registry of the United States. http://www.cbtrus.org/2011-NPCR-SEER/ WEB-0407-Report-3-3-2011.pdf. Accessed October 6, 2011. 2. Louis DN, et al. Acta Neuropathol. 2007;114:97-109. 3. Desgrosellier JS, et al. Nat Rev Cancer. 2010;10:9-22. 4. Hynes RO. Cell. 2002;110:673-87. 5. Lu X, et al. Perspect Medicin Chem. 2008;2:57-73. 6. Tabatabai G, et al. Target Oncol. 2010;5:175-81.

To view an informative animation on the role of integrins in GBM, please visit our website at www.emdserono.integrins.com

111020-160332

EMD Serono, Inc. is a subsidiary of Merck KGaA, Darmstadt, Germany


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JCO Spotlight Molecular Tumor Profiling

Gene Profiling Directs Site-specific Therapy for Carcinoma of Unknown Primary Site By Matthew Stenger

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atients with carcinoma of unknown primary site usually receive empiric therapy (eg, with taxane/platinum or gemcitabine/ platinum regimens), resulting in a median overall survival of approximately 9������������������������ ����������������������� months. As reported recently in Journal of Clinical Oncology, Hainsworth and colleagues have shown that molecular tumor profiling with a 92-gene assay can predict tissue of origin in most patients, and that assay-directed site-specific treatment is associated with overall survival that compares favorably with that seen with empiric therapy.1

Study Details The study prospectively enrolled 289 patients with carcinoma of unknown primary. Patients had to have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, no prior systemic chemotherapy, measurable or evaluable disease, and adequate organ function. Patients were excluded if they had a single resectable metastasis. Of the 289 patients, 252 (87%) had successful molecular profiling assays, with tumor samples or quantities of viable RNA in samples being inadequate for the remainder. Among the 252 patients with successful assays, median age was 64 years (range, 26–89 years), 54% were female, and 69% See Page 101 had two or more metastatic sites. Histology consisted of adenocarcinoma in 51%, poorly differentiated adenocarcinoma in 24%, poorly differentiated carcinoma in 18%, squamous carcinoma in 5%, poorly differentiated neuroendocrine carcinoma in 1%, and poorly differentiated neoplasm in 1%.

Four Tissues Account for 55% of Predicted Sites The assay predicted a tissue of origin in 247 (98%) of the 252 patients. Twenty-six different tissues of origin were identified. These included the biliary tract in 21%, urothelium in 12%, and colorectum and non-small cell lung in 11% each, with these sites accounting for 55% of all predicted

sites. Other predicted tissues of origin included: pancreas and breast in 5% each; ovary, gastroesophageal, and kidney in 4% each; and liver in 3%. Of the assay predictions, 119 (48%) were made with 80% or greater probability. Of the 252 patients with successful assays, 223 (88%) remained on study and received treatment. Of the 29 patients not remaining on study, 16 no longer met eligibility criteria (declining performance status in 15, brain metastases in 1) and 13 discontinued the study as a result of patient decision (refusal of recommended treatment) or physician preference (usually doubt regarding assay findings). Of these 223 patients, 194 (87%) received assay-directed therapy; of the 29 patients not receiving assay-directed therapy, 23 received treatment pre-

Gene Profiling to Determine Tissue of Cancer Origin ■■ The molecular profiling assay predicted a tissue of origin in 98% of patients with sufficient biopsy samples, with the prediction having at least 80% probability in 48% of these cases.

■■ The biliary tract, urothelium, colorectum, and non–small cell lung accounted for 55% of predicted tissues of origin.

■■ Overall, median overall survival was 12.5 months in patients receiving

assay-directed site-specific therapy, including overall survival of 13.4 months in those with treatment-responsive tumor types and 7.6 months in those with less-responsive tumor types.

overall survival was 13.4 months in 115 patients with tumor types considered to be treatment-responsive (ie, colorectal, breast, ovary, kidney, prostate, bladder, non–small cell lung, germ cell, poorly differentiated neuroendocrine, and small cell lung cancers) and 7.6 months (P = .04) in 79 patients with less-responsive tumor types (ie, biliary tract, pancreas,

We feel that the body of evidence is sufficient to support the use of molecular tumor profiling in the standard management of patients with [carcinoma of unknown primary]. ferred by their physician, 5 received protocol-directed therapy for unclassifiable tumors, and 1 had rapid deterioration of condition during palliative radiotherapy. Site-specific therapies consisted of the following: taxane/bevacizumab (Avastin) for breast; FOLFOX (leucovorin, fluorouracil [5-FU], and oxaliplatin) or FOLFIRI (leucovorin, 5-FU, and irinotecan), or variants, plus bevacizumab for colorectal; platinumbased doublet plus bevacizumab for non–small cell lung; paclitaxel/carboplatin plus bevacizumab for ovary; gemcitabine/erlotinib (Tarceva) for pancreas; sunitinib (Sutent) or bevacizumab with or without interferon for renal; and standard guideline-based first-line treatment for other diagnoses.

Survival Findings Among the 194 patients receiving assay-directed site-specific therapy, median overall survival was 12.5 months (95% confidence interval [CI] = 9.1–15.4 months). Median

gastroesophageal, liver, sarcoma, cervix, carcinoid, endometrium, mesothelioma, melanoma, skin, thyroid, head and neck, and adrenal cancers). Analysis by prediction probability and tumor responsiveness showed median overall survival of 15.4 months for the treatment responsive/≥��������������������� �������������������� 80% probability subgroup (n = 42), 13.4 months for the treatment responsive/<�����������  ���������� 80% probability subgroup (n = 57), 8.2 months for the less-responsive/≥80% probability subgroup (n  =  37), and 7.0 months for the less responsive/<  80% probability subgroup (n = 58), with P = .03 for the trend. For the most common predicted tumor types, median overall survival was not reached at more than 24 months for breast cancer (n  =  10), while for others was reached at 29.6 months for ovary (n  =  10), 15.9 months for non–small cell lung (n��������������������������������   ������������������������������� =������������������������������   ����������������������������� 23), 12.5 months for colorectal (n  =  26), 11.7 months for renal (n = 9), 8.4 months for urothelium

(n =  27), 8.2 months for pancreas (n = 12), and 6.8 months for biliary tract cancers (n = 45).

Need for More Evidence? The investigators posed the question of how much additional evidence would be necessary for molecular profiling to be accepted as a standard component of diagnosis for patients with carcinoma of unknown primary. A randomized phase III trial would provide definitive evidence, but such a trial would have inherent difficulties and would require large numbers of patients in order to generate conclusions regarding outcomes for the numerous potential tissues of origin. Moreover, interpretation of such a study would be complicated by the fact that first-line empiric therapy is identical or similar to standard sitespecific therapy for some of the moreresponsive tumor types and that patients who might be expected to benefit from site-specific vs empiric therapy would constitute a minority of the study population. In addition, many patients and physicians may be reluctant to accept randomized assignment to treatment in such a setting. As stated by the investigators, “At this time, we feel that the body of evidence is sufficient to support the use of molecular tumor profiling in the standard management of patients with [carcinoma of unknown primary]. Patients who will benefit most … are those predicted to have treatment-responsive tumor types. With an increasing number of effective molecularly targeted therapies available, an assay prediction may also lead to the identification of additional therapeutic continued on page 54


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FDA Update

New Drug Application Submitted for Radium-223 for the Treatment of Castration-resistant Prostate Cancer with Bone Metastases

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ayer HealthCare announced that the company has submitted a New Drug Application to the FDA seeking approval for radium Ra 223 dichloride (radium-223), an investigational compound for the treatment of patients with castration-resistant prostate cancer with bone metastases.

resistant prostate cancer with bone metastases. The trial enrolled 921 patients in more than 100 centers in 19 countries. The study treatment consisted of up to six intravenous administrations of

radium-223 or placebo each separated by an interval of 4 weeks. The primary endpoint of the study was overall survival. Secondary endpoints included time to occurrence of

Important Safety Information

“If approved, radium-223 has the potential to play a key role in the treatment of men with [castration-resistant prostate cancer] that has metastasized to the bone,” said Pamela A. Cyrus, MD, Vice President and Head of U.S. Medical Affairs, Bayer HealthCare Pharmaceuticals.

ALSYMPCA Trial The submission was based on data from the ALSYMPCA trial, a phase III, randomized, double-blind, placebo-controlled international study of radium-223 with best supportive care vs placebo with best supportive care in symptomatic patients with castration-

Gene Profiling for Cancer of Unknown Origin continued from page 53

options. For example, an assay prediction of non–small cell lung cancer could lead to the identification of unsuspected EGFR or ALK mutations. A sizable percentage of patients with [carcinoma of unknown primary] will not currently benefit from assay-directed therapy, because effective therapy for these tumor types does not currently exist. However, confidence in the assay predictions will allow these patients to receive effective therapy as the standard therapy for these tumor types improves.”

Reference 1. Hainsworth JD, Rubin MS, Spigel DR, et al: Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: A prospective trial of the Sarah Cannon Research Institute. J Clin Oncol. October 1, 2012 (early release online).

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

skeletal-related events, time to total alkaline phosphatase and prostate-specific antigen progression, total alkaline phosphatase response and normalization, safety, and quality of life. n

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

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

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

ISTODAX® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation 10/11 IST11038


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FDA Update

Elekta Receives FDA 510(k) Clearance for Clarity 4D Monitoring

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lekta has received 510(k) clearance from the FDA for its Clarity 4D Monitoring software, enabling U.S. medical centers to implement a new way of reducing the uncertainty caused by prostate motion during radi-

ation treatment. Physicians will be able to monitor the motion of the prostate and surrounding tissues and organs in real-time and with submillimeter accuracy during the delivery of therapeutic radiation beams.

The ability to continuously visualize the prostate’s precise location constantly during treatment is especially important for clinicians pursuing advanced prostate protocols, such as reduced margin hypofractionated

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

RECHARGE THE POSSIBILITIES

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

therapy or advanced stereotactic ablative body radiotherapy.

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FDA Update

Clarity 4D Monitoring continued from page 55

Clarity a possible ‘game-changer’ is that it’s simple, inexpensive, and will enable real time continuous monitoring of the prostate - increasingly critical as we consider techniques such as hypofractionation, which entails treating patients in shorter therapy courses, but

with longer individual treatments,” says James Wallace, MD, radiation oncologist at Fletcher Allen Health Care in Burlington, Vermont. “We know that the prostate moves during these prolonged treatments and we are going to have to account for it in some way. The capability to observe the prostate from the beginning of the fraction to the end

will be incredibly powerful.” “[The image quality is] remarkably clear compared to other ultrasound technology and in our experience comparable to MRI in terms of our ability to identify structures in the lower pelvis,” he noted. The capability to image anatomy during treatment could provide other

Only

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

advantages as well, according to Di Yan, DSc, Chief Physicist at William Beaumont Hospital in Royal Oak, Michigan. “We have been interested in developing methods for adaptive therapy for a while now,” he says. “The missing link has been the anatomical information from a continuous imaging

with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate. 5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

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

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FDA Update

source. Clarity 4D Monitoring with an Autoscan probe has great potential to provide that missing link.”

Continuous Target Visualization 4D monitoring of the prostate with Clarity during treatment offers continuous tracking of the target and imaging

of the surrounding anatomy, including the bladder, rectum and penile bulb, the latter thought to be responsible for erectile function. Clearly visualizing these structures during treatment could enable clinicians to create plans with tighter margins around intended targets, thereby minimizing radiation exposure to healthy tissue.

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

Clarity 4D Monitoring uses Autoscan acquisition technology, which robotically acquires live transperineal ultrasound images of soft tissue anatomy from the linear accelerator control area. It is a comfortable, noninvasive imaging procedure that does not involve any extra radiation dose and does not require the use of implanted markers. n

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

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Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication.


The ASCO Post  |   JANUARY 15, 2013

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FDA Update

FDA Expands Abiraterone’s Use for Late-stage Prostate Cancer

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n December, the FDA approved an expanded indication for abiraterone acetate (Zytiga) in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

Trial Design The approval was based on a trial randomly assigning patients with metastatic castration-resistant prostate cancer who had not received cytotoxic chemotherapy to either abiraterone acetate plus pred-

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

nisone (n = 546) or placebo plus prednisone (n = 542). Entry was restricted to patients with metastases to the bone, soft tissue, or lymph nodes. Patients with moderate to severe cancer pain or opiate use for cancer pain were excluded.  All pa-

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

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

Cosmos Communications 718.482.1800

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tients had a prior orchiectomy or continued to receive a gonadotropin-releasing hormone analog. The coprimary endpoints were radiographic progression-free survival and

overall survival. Treatment with abiraterone acetate improved radiographic progression-free survival.   The median radiographic progression-free survival was 8.3 months in the placebo arm and had not yet been reached for those receiving abiraterone acetate (HR = 0.43 [95% CI = 0.35–0.52], P < .0001]. At the prespecified third interim analysis, median overall survival was 35.3 and 30.1 months in the abiraterone acetate and placebo arms, respectively (HR = 0.79 [95% CI = 0.66–0.96]).  These results did not cross the O’Brien-Fleming boundary for statistical significance.  The primary endpoints were supported by statistically significant improvements in time to opiate use and time to cytotoxic chemotherapy.

Safety Data Safety data were evaluated in 1,333 patients with metastatic castration-resistant prostate cancer who received abiraterone acetate plus prednisone and in 934 patients who received placebo plus prednisone in this and the other pivotal trial. The most common (≥10%) adverse reactions included fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion.   The most common laboratory abnormalities (> 20%) included anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. The recommended dose and schedule for abiraterone acetate is 1,000 mg administered orally once daily in combination with prednisone 5 mg administered orally twice daily.   Abiraterone acetate must be taken on an empty stomach.  No food should be consumed for at least 2 hours before and for at least 1 hour after abiraterone acetate.  Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. n


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PAGE 59

Direct from ASCO

ASCO Top Five List Highlighted in IOM Workshop

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s part of the Institute of Medicine’s (IOM) National Cancer Policy Forum workshop on delivering affordable cancer care in the 21st century, ASCO’s Top Five list was highlighted as an example of a way to improve quality of care for patients while reducing unnecessary costs. Lowell Schnipper, MD, Chair of ASCO’s Cost of Cancer Care Task

Lowell Schnipper, MD

Force, spoke about the Top Five list and its impact on improving value and quality of cancer care. “Physicians inherently want to do the right thing. Part of that means not performing medical tests or treatments that have little or no clinical benefit,” Dr. Schnipper said. “Guidance like that provided by ASCO’s Top Five list also helps physicians in the exam rooms when discussing treatment options with patients.” Additionally, Dr. Schnipper highlighted the work of a Cost of Cancer Care Task Force policy statement that encourages physicians to address financial concerns and burdens with their patients. “We set out with one initial principle in mind: The cost of cancer care should be a part of routine interaction

Save the Date 2013 Gastrointestinal Cancers Symposium January 24–26, 2013 Moscone West Building

with patients, giving the growing burden many of them are facing,” he said.

Evaluating the Impact Dr. Schnipper also emphasized the need to measure and evaluate the impact of ASCO’s Top Five list. To that end, ASCO is currently planning on incorporating the Top Five list items into its measures set as part of the Quality Oncology Practice Initiative® to demonstrate physician behavior and uptake of the Top Five list recommendations. Ezekiel Emanuel, MD, of the University of Pennsylvania School of Medicine, praised ASCO’s efforts on the Top Five list and called on the Society to continue adding to its list. The IOM workshop included a series of panel discussions on policy issues related to the value, cost con-

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SCO has secured $3 million in new funding and key data sharing arrangements to support the development of CancerLinQ™, a ground-breaking information technology initiative that aims to achieve

2013 Genitourinary Cancers Symposium Rosen Shingle Creek Orlando, Florida

2013 ASCO Annual Meeting May 31–June 4, 2013 McCormick Place Chicago, Illinois

© 2013. American Society of Clinical Oncology. All rights reserved.

ASCO Secures Major Funding and Data License Agreements for CancerLinQ™

San Francisco, California

February 14–16, 2013

tainment, and reimbursement of cancer care as well as the economic incentives for inSee Page 101 novation and technology diffusion in cancer care. A full workshop summary is expected to be published in 2013. On the heels of the IOM workshop, Consumer Reports recently featured ASCO’s Top Five List in an article designed to help patients and consumers understand the lists recommendations and what it means for patients being treated for cancer. View the article online by scanning the QR code above. n

higher quality, higher value cancer care with better outcomes for patients. ASCO’s Conquer Cancer Foundation has received generous commitments from Susan G. Komen for the Cure, Helsinn Group, and Genentech. The Komen gift will support the completion and evaluation of a breast cancer-specific prototype of the CancerLinQ system, while the other two gifts will enable ASCO to begin developing the full system based on lessons learned from the prototype. The new commitments

are in addition to roughly $1 million in donor funding already received, as well as ASCO’s own significant investment in the initiative. ASCO has also completed agreements with Maine Center for Cancer Medicine, Marin Specialty Care and Marin General Hospital, Space Coast Cancer Center and Tennessee Oncology, as well as IntrinsiQ, LLC, to provide anonymous case data on approximately 100,000 patients for inclusion in the CancerLinQ prototype—far more than the target of 30,000 that ASCO had set for this initial stage of development. This comprehensive set of de-identified clinical information on individuals with breast cancer has enabled ASCO to quickly begin assessing the prototype with a robust, real-world dataset. CancerLinQ™ is supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology. For more information, please visit: www.asco.org/cancerlinq n © 2013. American Society of Clinical Oncology. All rights reserved.


The ASCO Post  |   JANUARY 15, 2013

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Direct from ASCO

New ASCO Statement Outlines Agenda to Advance Cancer Survivorship Care

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n response to the needs of a growing population of cancer survivors, ASCO has released a position statement, recently published online in the Journal of Clinical Oncology. Developed through the work of the ASCO Cancer Survivorship Committee, the statement outlines a comprehensive agenda for achieving high-quality cancer survivorship care. Improvements in early detection of first malignancies and the development of effective therapies have contributed to a dramatic increase in cancer survivors, who are at increased risk for long-term morbidity and premature mortality. These individuals’ cancer-related follow-up care needs extend beyond surveillance for cancer recurrence. As a result, the ASCO statement outlines a comprehensive approach to survivorship care that incorporates general health promotion, primary and secondary cancer prevention, and symptom management of common long-term and late effects.

Melissa Hudson, MD

According to Melissa Hudson, MD, Immediate Past-Chair of the Survivorship Committee and Director of the Cancer Survivorship Division at St. Jude Children’s Research Hospital, “ASCO’s goal is to develop tools and facilitate the development of infrastructure that will help its members determine how survivorship care can be optimally integrated within their current practice standards.”

Developing Clinical Guidance A major area gap in survivorship care today is the availability of clinical guidelines on the longterm clinical management of survi-

Smita Bhatia, MD

vors of adult-onset cancer. Limited research in adult-onset cancer late effects requires extrapolation from other populations to identify effective screening and treatment methods, said Smita Bhatia, MD, ASCO Cancer Survivorship Committee Member and Associate Director of Population Sciences at City of Hope Comprehensive Cancer Center. She added that the resulting consensusbased recommendations will be developed using a modified Delphi approach. “It’s a bit more challenging to [develop guidance] within the context of the heterogeneity of adult-onset malignancies,” compared with the pediatric cancer patient population, said Dr. Hudson. “We should be drawing upon the expertise of leaders in the survivorship field to develop clinical consensus-based guidance to serve the needs of the current patients,” which, said Dr. Hudson, will also help identify important areas for research. To address this need, ASCO has begun work on developing guidelines on the management of late- and long-term effects, through collaboration between the Cancer Survivorship and Clinical Practice Guidelines committees. The focus of these guidelines will be on common symptoms or clinical issues that reach across a diversity of cancer types. The first three guidelines— slated for completion this spring— will address fatigue, neuropathy, and depression.

Expanding Research Initiatives To strengthen the foundation for such clinical guidelines, ASCO is also working to in-

crease “the quality of evidence, the abundance of evidence, [and] the robustness of evidence in survivorship care,” according to Gregory Reaman, MD, member of ASCO’s Survivorship Committee and Associate Director in the FDA’s Office of Hematology and Oncology Products. He noted that, as a first step toward identifying knowledge gaps, ASCO recently undertook a survey to develop an inventory of existing research initiatives and activities. Combined with a literature review and an assessment of survivorship research activities at cancer centers designated by the National Cancer Institute (NCI), the survey data will facilitate the prioritization of future research efforts.

Gregory Reaman, MD

Noting that economic constraints are an obstacle to the development of such studies, Dr. Reaman says that ASCO plans to advocate for the prioritization of existing resources for survivorship research initiatives. Most notably, in its statement ASCO encourages the NCI to incorporate survivorship-related data elements into the current redesign and reorganization of its clinical trial infrastructure, which will have “profound implications” for advancing survivorship research, according to Dr. Reaman. Given the resource limitations, another goal articulated in the statement is to leverage innovative clinical research methods, such as the collection of self-reported data from study participants or the use of a uniform treatment summary, completed at the end of protocol therapy. Such approaches could limit the burden of “adding yet another layer on already

Volume 30, Issue 33

November 20, 2012

Journal of CliniCal onCology Official Journal of the American Society of Clinical Oncology

Oncology Grand Rounds: Emerging Treatment Options for Advanced-Stage Mycosis Fungoides. R.E. Drews Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. L.N. Shulman et al Open-Label, Multicenter, Randomized Phase III Trial of Adjuvant Chemoradiation Plus Interferon Alfa-2b Versus Fluorouracil and Folinic Acid for Patients With Resected Pancreatic Adenocarcinoma. J. Schmidt et al. Editorial: C.H. Crane et al Prospective International Multicenter Phase II Trial of Intravenous Pegylated Liposomal Doxorubicin Monochemotherapy in Patients With Stage IIB, IVA, or IVB Advanced Mycosis Fungoides: Final Results From EORTC 21012. R. Dummer et al HIV Status Does Not Influence Outcome in Patients With Classical Hodgkin Lymphoma Treated With Chemotherapy Using Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine in the Highly Active Antiretroviral Therapy Era. S. Montoto et al. Editorial: L.D. Kaplan Understanding the Pathway: Janus Reveals Another Face: The Biologic Rationale for Targeting Janus Kinase 2 in Lymphoma. A. Mullally et al

www.jco.org

stressed investigators and an already stressed infrastructure,” Dr. Reaman said.

Improving Care Coordination Meanwhile, recognizing that optimal survivorship care will require a multidisciplinary care infrastructure, ASCO is also evaluating models of survivorship care and methods to optimize the transition of patients between oncology and primary care providers (PCPs). “With the burgeoning number of cancer survivors and the burgeoning number of visits needed for acute therapy…we don’t have the space for oncologists to be following [all of] these patients for life,” said Kevin Oeffinger, MD, ASCO Cancer Sur-

Kevin Oeffinger, MD

vivorship Committee Chair-elect and Director of the Adult Long-term Follow-up Program at Memorial Sloan-Kettering Cancer Center. ASCO’s statement advocates for a risk-stratified approach that maximizes limited resources “for patients [who] have truly unique or high-risk features and need the expertise and the care that can be delivered by a can-


ASCOPost.com  |   JANUARY 15, 2013

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Direct from ASCO

cer center or by an oncology practice.” A patient with a low risk of cancer recurrence and a low risk of late effects who is psychosocially stable likely will receive adequate follow-up care from a PCP, through coordination with the patient’s oncologist. Even the highrisk patient needs to be followed by a PCP for non-cancer and non-cancer therapy needs, he added. ASCO strongly supports the position that effective communication between the oncologist and the PCP is essential to ensure that the cancer survivor receives appropriate long-term follow-up care in the primary care setting based on the patient’s risk profile. This requires the oncologist to provide information—in the form of a treatment summary and care plan—that “demystifies the cancer experience.” He added that such information should be presented in an easy-to-read format that outlines the three to five key clinical issues to monitor in the patient. ASCO’s websites offers both oncologists and patients access to treatment summary and survivor-

Mary McCabe, RN, MA

ship care plan templates to help provide a roadmap for managing care following active treatment.

Advocating for Policy Change In an effort to encourage systemwide change during these fiscally uncertain times, ASCO advocates for leveraging existing legislation to support initiatives to improve cancer survivorship care quality, while ensuring that all patient have access to adequate and affordable coverage. This includes continued support of legislation aimed at comprehensive care coordination, such as provisions of the Affordable Care Act like accountable care organizations and medical homes; working within the framework of

essential health benefits to define and advocate for services essential to cancer survivors; pushing for inclusion of survivorship in the development of national and state cancer control plans; and increasing policymaker awareness of cancer survivorship issues.

Mary McCabe, RN, MA, Director of Memorial Sloan-Kettering’s Cancer Survivorship Program and ASCO Cancer Survivorship Committee Chair, said, “Our goal in developing this survivorship agenda is to provide guidance that will assist the oncology community’s efforts to

ensure that all cancer survivors receive coordinated care that includes the full range of services necessary to assure the highest quality of life possible.” n © 2013. American Society of Clinical Oncology. All Rights Reserved.


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Direct from ASCO

Call for Abstracts: 2013 ASCO Annual Meeting Submission Deadline: February 5, 11:59 PM (EST)

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roundbreaking research in cancer care is the cornerstone of ASCO’s Annual Meeting, and the deadline for submitting abstracts to be considered for presentation or publication at this year’s Meeting is fast approaching. The submission deadline is February 5 at 11:59 PM (EST). LateBreaking Abstracts for phase III trials for which no preliminary data are available at the time of the abstract submission deadline, but for which a preplanned analysis of the primary endpoint is scheduled before April 1, may be submitted. “The ASCO Annual Meeting is a highly visible, international platform to present the most exciting advances in clinical cancer research,” said Douglas Yee, MD, Chair of the Annual Meeting’s Scientific Program Committee, and Director of the Masonic Cancer Center at the University of Minnesota. “Beyond the opportunity to present high-impact work, it also serves as a venue to seek feedback, advice, and develop collaborations.”

Building Bridges The Annual Meeting takes place May 31 to June 4 in Chicago. This year’s theme, Building Bridges to Conquer Cancer, emphasizes a growing need in oncology to build a bridge between scientific discoveries and new therapeutics and novel treatments for optimal patient outcomes. Abstracts from all disciplines of oncology research and practice, from translational research to multidisciplinary care, may be submitted. Submissions of superior quality

Abstract Awards

Douglas Yee, MD

will be selected by the ASCO Scientific Program Committee for presentation at the 2013 Meeting and for publication in the 2013 ASCO Annual Meeting Proceedings, a supplement to the Journal of Clinical Oncology. All abstract submissions must be sponsored by an ASCO member.

Volume 29, Issue 15

Notification in March and Beyond In late March, each first author will receive a letter of notification via email regarding abstract selection. First authors of Late-Breaking Abstracts will receive a letter of notification in mid-April. Abstracts that have been chosen for inclusion in the meeting will be released on ASCO.org on May 15, 2013, at 6:00 PM (EDT).

A Record Year Last year, a record of more than 5,000 abstracts were submitted, representing the latest in clinical and translational science in the areas of cancer prevention, diagnosis, and treatment. More than 2,700 abstracts were presented or published, helping to set the standard for cancer care in the United States and around the world.

Give Your Patients the Latest GI Research News

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uring the upcoming Gastrointestinal Cancers Symposium, to be held on January 24–26, direct your patients to www.cancer.net/ gisymposium, where they can get research highlights from the 2013 Symposium. Also, your patients can download or listen to podcasts with ASCO experts explaining what this

These awards are offered through the Conquer Cancer Foundation of ASCO Grants and Awards Program. Award recipients will receive monetary support to attend the Annual Meeting, complimentary Meeting registration, access to the ASCO housing block, and the use of ASCO’s travel agency. For submission guidelines and to submit an abstract, visit asco.org/cfa. For more on the Annual Meeting, visit chicago2013.asco.org. n

In conjunction with submitting an Annual Meeting abstract, oncology fellows and junior faculty may be eligible for several types of awards: a limited number of merit awards, the James B. Nachman ASCO Junior Faculty Award in Pediatric Oncology, and Oncology Trainee Travel Awards. In addition, oncologists from countries with limited resources are encouraged to submit an abstract in conjunction with the application process for the International Development and Education Award (IDEA).

May 20, 2011

© 2013. American Society of Clinical Oncology. All rights reserved.

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

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

What’s Hot in

JCO

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

JCO.org Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101 By Lawrence N. Shulman, et al

Comparative Effectiveness Research in Oncology: An Overview By Gary H. Lyman, et al

Should Response to Preoperative Chemotherapy Affect Radiotherapy Recommendations After Mastectomy for Stage II Breast Cancer? By Jennifer R. Bellon, et al

Open-Label, Multicenter, Randomized Phase III Trial of Adjuvant Chemoradiation Plus Interferon Alfa-2b Versus Fluorouracil and Folinic Acid for Patients With Resected Pancreatic Adenocarcinoma By Jan Schmidt, et al

research means for patients at www. cancer.net/podcasts. n © 2013. American Society of Clinical Oncology. All rights reserved.

Predictors of Locoregional Recurrence After Neoadjuvant Chemotherapy: Results From Combined Analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27 By Eleftherios P. Mamounas, et al


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Direct from ASCO

Community Research Forum Addresses Conundrums Common to Community Practices that Conduct Research Quality assessment and staff workload the focus at inaugural meeting

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t is every research site’s biggest concern. The National Cancer Institute (NCI), the FDA, or drug company sponsors could arrive at any time to comb through a site’s documents related to a specific trial. It’s called an audit, and it’s common. And yet, not all sites that conduct research have proactive quality assurance initiatives in place to keep them audit-ready. Many, it turns out, are just not sure how to develop and launch an internal quality assessment program. Or they feel they don’t have the time or resources.

ment of a variety of research programs.

Quality Assurance Manual

The meeting agenda included a representative from the NCI who told attendees what the agency scrutinizes when auditing a clinical research site, including how variations are scored and what those scores mean. “That really helped define the need for maintaining a quality program in your clinical research program,” said Thomas A. Marsland, MD, MPH, a medical oncologist practicing at the Cancer Specialists of North Florida, who leads the ASCO workgroup developing a manual to help community research sites develop a quality assurance program. The workgroup plans to complete the manual by next year’s meeting. Attendees at this year’s meeting discussed the possibility of a research comMarge Good, RN, BSN, MPH ponent being added to Thomas A. Marsland, MD, MPH ASCO’s Quality Oncology Enter ASCO’s Community Research Practice Initiative (QOPI®) program, a quality measurement and improvement Forum, a new initiative born out of ASprogram for practices. CO’s Board of Directors’ Clinical Trial Strategic Plan of 2010. The Forum’s misWorkload Assessment Tool sion is to tackle key challenges faced by Being Developed community sites involved in research. A second key focus of the Forum For its first meeting, Forum leaders in the coming year is completing the placed a heavy emphasis on developing development of an online workload a program that would equip all types of assessment tool. Once complete, this community sites for the quality assess-

instrument will allow community practices to ascertain the clinical workload associated with individual trials. Developing a “formula” for workload is currently a challenging problem, as clinical trials can range from relatively simple and quick to extremely complicated and time-consuming for staff. Judging workload simply by the number of patients recruited—a typical method—is a highly flawed approach, said Marge Good, RN, BSN, MPH, a nurse consultant in the NCI Division of Cancer Prevention and the leader of the ASCO workgroup developing the workload assessment tool. “Practices have staff that often come to the manager and say, ‘We’re so busy, we’re dying.’ But there’s really no metric for practice managers to compare what their staff is doing with what other practices’ staffs are doing, and say, ‘Yes you are,’ or ‘No, you’re not,’” said Ms. Good. At the meeting, attendees discussed workload issues and considered a number of workload assessment tools. They concluded that the tool developed by Ms. Good in her many years as Administrative Director of Wichita Community Clinical Oncology Program was the most practical and meaningful. Ms. Good explained that the tool is a simple, easy-to-use system that she utilized to collect 10 years of data on trial acuity. From these data, practice leaders were better able to observe how staff members were using their time and to

subsequently balance workloads and hire appropriate staff for the research protocols they were maintaining. The workload assessment group plans to launch a pilot of the tool with many community practices in spring 2013 and present the tool at next year’s Forum meeting.

New Projects to be Launched at Next Year’s Meeting The overall goal of the Forum is to produce helpful tools that will keep research quality high and assist community sites engaged in research. In the coming year the Community Research Forum Planning Committee will discuss additional project concepts that address crosscutting challenges to conducting research in the community setting. The Forum will initiate projects to address these challenges at the 2013 meeting. After all, said Dr. Marsland, with health-care reform upon us—not to mention multiple market-driven changes in research—ASCO wants to be at the forefront of the drive for quality. “It’s important that ASCO define quality and become the voice for quality that is heard loud and clear,” he said. “This role is valid for research and ties in well with ASCO’s many activities and initiatives to promote quality across the whole spectrum of cancer care.” n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCO Report Encourages Further Discussion to Improve REMS Development, Communication

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he oncology community—including providers, patients, and industry—and the FDA should continue to work together to improve the agency’s Risk Evaluation and Mitigation Strategies (REMS) program, according to the report of the ASCO REMS Working Group published online by the Journal of Oncology Practice. “Our report notes that oncology REMS programs should supplement, not duplicate, the education, experience and clinical tools that provid-

ers already have for managing safety concerns,” said James N. Frame, MD, FACP, Chair of ASCO’s REMS Working Group. “The FDA has proposed some meaningful steps to improve the REMS programs. ASCO is eager and well-positioned to work with the agency and drug manufacturers to build on the opportunity to improve care for our patients.” The report summarizes an ASCO-hosted workshop in 2011. It also highlights ongoing oncology community activities and several

FDA actions to accomplish the goals of promoting safe use of oncology products and addressing the challenges of REMS programs. On July 27, 2011, oncologists, hematologists, oncology nurses, pharmacists, patient advocates, the pharmaceutical industry, and FDA officials came together to address oncology community stakeholder concerns and to discuss possible alternative approaches for the management of certain oncology and hematology drugs with REMS reporting requirements. Providers and

the FDA share a common goal of ensuring that cancer patients receive safe and effective care, but experience with the REMS programs has demonstrated that some aspects of the programs do not enhance and sometimes detract from patient care. The ASCO REMS Working Group report is available at http:// jop.ascopubs.org/content/early/2012/10/30/JOP.2012.000620. n © 2013. American Society of Clinical Oncology. All rights reserved.


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Expert’s Corner Genitourinary Oncology

Online Prostate Cancer Information Is Written at Reading Levels above Many Americans’ Literacy Skills A Conversation with Gopal Gupta, MD By Jo Cavallo

level, far beyond the literacy skills of many patients. The ASCO Post recently talked with Dr. Gupta about the results of his study and what oncologists can do to help direct their patients with cancer to more accessible health material, both on the Internet and in print.

Study Methods

Gopal Gupta, MD

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lthough 61% of Americans are going online to access health information,1 many of them may not understand what they find there, including information about prostate cancer treatment options. According to a new study published in The Journal of Urology,2 as many as 90 million Americans have literacy skills below a high school reading level. However, an examination by the study authors of 62 websites catering to prostate cancer and its treatment options found that only 3 were written below a 9th-grade reading level. The result, said study senior author Gopal Gupta, MD, Instructor in Urology and Surgery, Loyola University Medical Center in Maywood, Illinois, is that patients with prostate cancer who have education levels below the 9th grade may be more likely to misunderstand the information they read about their cancer, jeopardizing access to their best treatment options and limiting their ability to participate in the shared decisionmaking process. While the National Institutes of Health (NIH) recommends that physicians and health-care organizations use patient education material written at a 4th through 6th grade reading level, online health information, even at many common consumer medical sites such as WebMD, is often written well above those levels. In fact, Dr. Gupta and his colleagues found that even the American Urological Association Foundation’s website uses prostate cancer treatment information written above the 12th grade reading

How did you find the websites you examined in your study? First, we identified the three most common keywords from over 500 terms related to prostate cancer treatment options. They were “robotic prostatectomy,” “prostate cancer,” and “prostate cancer treatment.” Then we sorted through 270 websites from the top three search engines, excluding any that were non-English and not primarily text (such as YouTube videos). We also removed any sites that appeared as

different options. That led us to look for some way we could supplement these meetings using written materials that patients and their spouses could find online. They could print out these materials to read at their leisure. It was shocking to us that 95% of the websites we analyzed were written above the NIH recommended fourth to sixth grade reading level.

Study Implications What are some of the ramifications of patients with prostate cancer not understanding the information they find online? There are many ramifications. The number 1 goal of providing health information is to better inform patients about their disease and treatment options. One question is what if the different treatment options presented online have different

Oncologists need to be aware of the readability level of the [patient education material they provide] and how much the patient will likely be able to understand from the information. —Gopal Gupta, MD

banner advertisements. The remaining 62 websites were then categorized by source, such as government, academic practice, nonacademic practice, commercial, nonprofit, news, and health. To assess the readability of the sites, we used the Flesch-Kincaid grade level and the Flesch reading ease level. To our dismay, we found that only 3 of the 62 websites were written below a high school reading level.

Many Treatment Options Why did you decide to undertake this study? Prostate cancer is the most common cancer among men in the United States, and there are many treatment options. Our study stemmed from the realization that presenting so many options to patients often left them befuddled about what to do and left practitioners exhausted because they have to explain all the

levels of readability. Furthermore, what if there is a bias inherent in the writing? For example, if all options are equivalent in predicted outcome but the information is presented in numerical order, this may bias a patient’s ability to make an informed decision. Let’s say that in an online discussion of the four treatment options for prostate cancer—active surveillance, robotic prostatectomy, radiation beam therapy, and radiation seed therapy—the material about active surveillance is written at a higher level of understanding then the section on surgery. That could influence the choice of patients reading the information. In addition, the concept of active surveillance can be difficult to explain (and hard for the patient to understand). The idea of having cancer and not actively doing something about it

is a tricky concept for many patients. They have to be willing to participate in ongoing surveillance and trust their physicians as well as the basic principle of having what appears to be a lowgrade cancer that we will continue to watch so we can avoid the downside of committing to immediate therapy. But that’s a tough conversation.

Impact on Practice Have your study findings changed the way you approach discussions with your patients with prostate cancer? As physicians, our job is to do the right thing for our patients and support them in their decision-making process. I don’t want to confuse patients without even knowing it. I’m very careful about the supplemental reading material I hand out or the online resources I recommend to patients for further reading about their prostate cancer diagnosis. I generally use the National Comprehensive Cancer Network (NCCN) Guidelines for Patients (nccn.com), but even that information is written at a 7th to 8th grade reading level, so it is probably above the comprehension of some patients. I’ve also instituted a multidisciplinary approach in my practice, whereby specific experts in radiotherapy, chemotherapy, and surgery present the different treatment options to the patient. So patients with newly diagnosed prostate cancer will meet separately with the surgeon, the radiation oncologist, and me. That way the patient can immediately contrast options, meet with the providers to ask questions, and make a better-informed decision. Our study also found that patients with low-health literacy may not understand even commonly used words such as “erection” and “impotence.” In those cases, you need to use simpler terminology, or define terms as you use them.

Closing Thoughts What can oncologists do to help improve patient education? One of the reasons we conducted continued on page 66


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35th ESMO Congress Breast Cancer

Lumpectomy Rates Inconsistent with Response Rates in Early Breast Cancer By Caroline Helwick

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chieving a pathologic complete response to neoadjuvant chemotherapy does not always reduce the aggressiveness of breast cancer surgery, according to an analysis of the NeoALLTO trial presented at the 2012 European Society for Medical Oncology (ESMO) Congress in Vienna.1

Carmen Criscitiello, MD

Carmen Criscitiello, MD, of the European Institute of Oncology in Milan, Italy, and colleagues determined which factors influenced the type of surgery (mastectomy or lumpectomy) offered to the 429 patients with HER2-positive breast cancer who underwent breast surgery after receiving neoadjuvant therapy within the NeoALTTO trial. “Apparently, the final decision on the type of surgery was mainly based on characteristics observed before therapy,” Dr. Criscitiello noted. “Surgeons and medical oncologists should focus, however, on the characteristics observed after treatment, with discussions occurring in a multidisciplinary way before final decisions are made.”

Surgery after Neoadjuvant Treatment in Breast Cancer ■■ In the NeoALLTO trial of patients with HER2-positive early breast cancer,

achievement of pathologic complete response did not fully correlate with breast-conserving surgery.

■■ Type of surgery planned at diagnosis heavily influenced the surgery performed after neoadjuvant chemotherapy.

■■ Clinicians should not entirely rely on pretreatment characteristics when

choosing between mastectomy and breast-conserving surgery, but they should carefully focus on the response achieved to systemic therapy.

Findings from NeoALLTO NeoALLTO investigators previously reported that the combination of paclitaxel, lapatinib (Tyekrb), and trastuzumab (Herceptin) significantly increased the pathologic complete response rate compared to paclitaxel

EXPERT POINT OF VIEW

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nvited discussant Ian Smith, MD, of The Royal Marsden Hospital and Institute of Cancer Research in London, commented at the ESMO meeting that while all three arms of NeoALLTO, especially the arm with dual HER2 blockade, achieved good pathologic complete response rates, “the breast-conserving surgery rate is perhaps disappointingly low, so we are getting better [pathologic complete response rates] but no additional gains regarding the surgery.” He said the finding that estrogen receptor (ER) negativity was used as a reason to avoid lumpectomy is “particularly disappointing, since ER-negative HER2-positive tumors have the best chance for a [pathologic complete response]—60% or greater.” Dr. Smith noted that in the GeparQuattro study, which involved 445 HER2-positive women treated with trastuzumab and chemother-

Gopal Gupta, MD continued from page 64

this study is because there are four basic treatment options for certain lowrisk prostate cancers. But unlike other cancers, where there are standard proven treatments and algorithms, in prostate cancer the options aren’t as clear-cut. They require a lot of decision-making on the patient’s part.

apy, the pathologic complete response rate was 32% and the breastconservation rate was 63%.1 The reason for the higher rate of conservative surgery, he suggested, “could be that the trials’ surgeons were experienced in, and committed to, the neoadjuvant approach.” Nevertheless, he added, of 154 patients who had mastectomy, 21% had achieved a pathologic complete response; so even in this study the results were not optimal. Part of the problem, he added, is that “the surgeon doesn’t know it’s a [pathologic complete response] until after the surgery.” An understanding of the short-term changes in molecular markers may help better predict who really needs mastectomy, he said. Finally, Dr. Smith concluded, to achieve one of the goals in breast cancer care—to treat effectively while limiting morbidity—“we must train

It is important for oncologists to examine what is in the patient education material they give out in their clinics and practices and on the websites they recommend. Oncologists need to be aware of the readability level of the material and how much the patient will likely be able to understand from the information. Hopefully, the material won’t confuse the patient and it will be

Ian Smith, MD

our surgeons that most patients with HER2-positsive breast cancer do not need mastectomy after neoadjuvant anti-HER2 therapy with chemotherapy.” n

Disclosure: Dr. Smith receives occasional honoraria from Roche for lecturing and chairing meetings.

Reference 1. Untch M, Rezai M, Loibl S, et al: Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: Results from the GeparQuattro study. J Clin Oncol 28:2024-2031, 2010.

helpful and unbiased. We need to do a better job at advocating for appropriate literature for patients so they can not only make better-informed treatment decisions, but can also better understand what is happening to them as they go through recovery. n

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

combined with either drug alone.2 Several international expert panels have recommended that the rate of breast-conserving surgery should increase in patients who respond well to neoadjuvant treatment, as was seen in this trial, Dr. Criscitiello said. But while the pathologic complete response rate was 51.3% with the dual HER2 blockade, breastconserving surgery was performed on only 41.4% of women. Regardless of which treatment the women received, breast-conserving surgery rates hovered around 40%, Dr. Criscitiello reported. “The experimental treatment with paclitaxel plus lapatinib and trastuzumab within the NeoALTTO trial nearly doubled the rate of pathologic complete response compared to treatment with paclitaxel combined with either drug alone,” she said. “However, this successful result did not translate into a higher rate of breast-conserving surgery.”

Factors Influencing Type of Surgery Several factors were found to be related to choice of surgery after systemic therapy, most notably the surgical plan at diagnosis. If breast-conserving surgery was planned in advance, 74% underwent it. On the other hand, 30% of patients initially considered inoperable or requiring mastectomy had References 1. Fox S: The social life of health information, 2011. Available at pewinternet. org/reports/2011/social-life-of-healthinfo/summary-of-findings. Accessed December 3, 2012. 2. Ellimoottil C, Polcari A, Kadlec A, et al: Readability of websites containing information about prostate cancer treatment options. J Urol 188:2171-2176, 2012.


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35th ESMO Congress breast-conserving surgery. Larger tumor size at diagnosis also influenced the type of planned surgery. “Indeed, we saw that tumor characteristics prior to neoadjuvant therapy play a main role in deciding the type of surgery, irrespective of the response to given therapies,” Dr. Criscitiello said. “One of the goals of the neoadjuvant therapy concerns increasing the rate of breast conservation, but this goal is clearly not achieved if the type of surgery is chosen according to baseline characteristics.” Geographic region influenced the choice of treatment at baseline, with breast-conserving surgery significantly less common in developing countries compared to developed countries: 32.1% vs 53.2% (P = .006). This probably represents the lack of radiotherapy in poorer countries. Mastectomy is likely the appropriate choice under these circumstances, several breast cancer specialists suggested at the meeting. Several baseline factors influenced the choice of surgery, with conservative surgery significantly

less likely in the case of tumors that were larger than 5 cm, demonstrated multicentricity or multifocality, or were estrogen receptor–negative. “This study highlights a negative attitude that may deny a large fraction of women the chance of preserving their breasts, with no clinical reasons that justify this decision,” Dr.

Criscitiello concluded. n

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

References 1. Criscitiello C, Azim HA, AgborTarh D, et al: The discrepancy between high pathological complete response rate and low breast conserving surgery

following neoadjuvant therapy: Analysis from the NeoALLTO trial (BIG 1-06). 2012 ESMO Congress. Abstract 2470. Presented September 30, 2012. 2. Baselga J, Bradbury I, Eidtmann H, et al: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): A randomised, openlabel, multicentre, phase 3 trial. Lancet 379:633-640, 2012.

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*Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN ®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 08Z12191


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35th ESMO Congress Breast Cancer

French Investigators Prospectively Test Genomically Driven Treatment in Metastatic Breast Cancer By Caroline Helwick

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hole-genome DNA analysis prospectively identified alterations in metastatic tumors that could be individually targeted with molecular agents, in a study presented at the 2012 European Society for Medical Oncology (ESMO) Congress by Fabrice André, MD, of Institut Gustave-Roussy, Villejuif, France.1

until they develop progressive disease. To date, only 26 patients have shown disease progression and have been matched with treatment that has included 13 different targeted regimens (single agents or combinations)—often PI3K and Akt inhibitors. Evidence of activity has been noted in eight patients (response or stable disease ≥ 4 months). At a press briefing, co-investigator Monica Arnedos, MD, also of Institut Gustave-Roussy, explained, “Most patients still have no need for treatment, as their disease is controlled, but we expect within 3 years to have treated 80 or more patients.”

Fabrice André, MD

First Study of Its Kind The SAFIR-01 trial is the first large-scale—in fact, countrywide— study to prospectively test the entire genome from a biopsy of a metastatic lesion, then match the alteration with a targeted agent. Currently, most genetic testing looks for specific genetic alterations in a limited number of genes, and thus, many treatment opportunities may be lost, said Dr. André. The study used whole-genome (comparative genomic hybridization) arrays to look at genetic copy numbers (gains and losses), and identified “hot spot” mutations, specifically PIK3CA and Akt mutations, which are common in breast cancer. The investigators were able to perform whole-genome analysis on 251 of 393 patients, of whom 172 (69%) were found to have genetic alterations. While the majority of these involved “druggable” genes that can be targeted by an anticancer drug, about 20% were rare and sometimes unexpected alterations. The common occurrence of these low-frequency alterations “highlights the need for whole-genome approaches,” Dr. André said. In the study, patients with metastatic disease undergo biopsy, but their disease is stable at the time of genetic testing. Therefore, they do not receive mutation-guided therapy

Whole-genome Arrays in Breast Cancer ■■ Whole-genome DNA analysis can prospectively identify alterations in

metastatic breast cancer tumors that can be individually targeted with molecular agents.

■■ Genetic alterations were found in over two-thirds of patients in the French SAFIR-01 trial, and many were rare and unexpected.

■■ Targeted treatment was associated with an early signal of activity. ■■ The technique can also be applied in the neoadjuvant setting, but in a study presented at ESMO it did not lead to higher rates of pathologic complete response.

ter University in Canada suggested there may be another risk associated with genomic-driven treatment. “It is likely that the genetic and molecular abnormalities are very complex, and the assumption that we can implement a targeted approach because we can identify these abnormalities may put patients at risk of passing up standard treatments,” he said. “In some ways, it feels like we are on a rollercoaster that is a little out of control.”

“This is the first prospective trial showing that whole-genome expression array is feasible in the context of daily practice within 15 days,” he said. “Gene-expression arrays could be a solution in the future, an all-in-one assay for personalized medicine.”

Neoadjuvant Setting Monica Arnedos, MD

Listener Concerns Upon the conclusion of Dr. Andre’s presentation, questions from the audience indicated that many oncologists are not yet comfortable with exploring genetic alterations in metastatic lesions. Dr. André noted that 18 patients in the study “could not go to biopsy,” and among “several” adverse events were liver hematomas and pneumothorax. “I prefer to have the final analysis before reporting on these,” he said. “It is becoming common to recommend biopsy at the time of relapse, but I do think we should be comfortable with the adverse event rate. I would like to see a large epidemiologic study of adverse events associated with these biopsies.” Peter Ellis, MBBS, PhD, of McMas-

Peter Ellis, MBBS, PhD

In a separate study led by Dr. André, the investigators reported outcomes using whole-genome expression arrays in the neoadjuvant setting, the aim being to match the neoadjuvant chemotherapy to the genetic profile of the tumor.2 Results of the phase III trial, REMAGUS04, showed no increase

Jean-Yves Pierga, MD

in pathologic complete responses after genetically driven treatment, compared with standard treatment. However, patients with a positive probe were more likely to have disappearance of tumor. Moreover, the study proved that whole-genome expression array testing can be accomplished in the clinical setting; 61% of patients were successfully tested and started on targeted treatment, reported Jean-Yves Pierga, MD, of the Institut Curie, Paris.

Christoph Zielinski, MD

Could Affect Drug Approval ESMO press briefing moderator Christoph Zielinski, MD, of the Medical University of Vienna, Austria, commented that the findings from SAFIR-01 trial suggest the field of oncology will “probably move sooner rather than later from an anatomically oriented drug approval process to one oriented toward signaling pathways.” He noted, “Surprising compounds have emerged that we would never expect to work in certain situations, but due to unsuspected genetic alterations, they do. I think this may change the [drug] registration process.” Meanwhile, he believes whole-genome testing should be restricted to the research setting, and not applied in the clinic. “We still have to prove this is the optimum approach, though … this is an enormously important step forward.” n

Disclosure: Drs. André, Arnedos, Ellis, Pierga, and Zielinski reported no potential conflicts of interest.

References available on ASCOPost.com.


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Announcements

Richard I. Fisher, MD, to Join Fox Chase Cancer Center and Temple University School of Medicine

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n March 1, 2013, leading cancer center administrator and nationally recognized hematology/ oncology expert Richard I. Fisher, MD, will assume leadership roles at Fox Chase Cancer Center, a member

efforts to prevail over cancer,” said Michael V. Seiden, MD, PhD, President and CEO of Fox Chase Cancer Center. “I am thrilled to be joining the

leadership team at Fox Chase and Temple,” said Dr. Fisher. “As one of the original NCI-designated Cancer Centers, Fox Chase has a tremendous history of contributions to the fight

against cancer. Now it will become a model for incorporation of a previously independent cancer center into Temple’s modern, comprehensive health system.” n

Richard I. Fisher, MD

of the Temple University Health System, and Temple University School of Medicine, Philadelphia. Currently, Dr. Fisher is Vice President for Strategic and Program Development at the University of Rochester Medical Center, where he is also the Samuel E. Durand Professor of Medicine. For the past 11 years, Dr. Fisher has served as Director of the James P. Wilmot Cancer Center at the University of Rochester School of Medicine and Dentistry and Director of Cancer Services for the Strong Health System in Rochester, New York.

New Responsibilities At Fox Chase Cancer Center, Dr. Fisher will become Executive Vice President, reporting directly to the President and CEO. He will also be Physician-in-Chief, responsible for overseeing and leading the seven clinical department chairs at the Center. Additionally, Dr. Fisher will be one of two Deputy Directors of Fox Chase’s Cancer Center Support Grant, which supports the Center’s status as 1 of 41 National Cancer Institute–designated Comprehensive Cancer Centers in the nation. At Temple University School of Medicine, Fisher will be Senior Associate Dean for Cancer Programs, reporting to the Dean of the School of Medicine. “All of us at Fox Chase Cancer Center welcome Richard Fisher to our leadership team and look forward to the additional momentum his extraordinary capabilities as a cancer center administrator, clinician, and researcher will bring to our

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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Focus on Young Adults

Teens and Young Adults with Cancer Want a Voice in End-of-life Care Having an advance-care planning guide helps patients maintain control and preserve hope, study finds. By Jo Cavallo

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top the list of concerns of adolescents and young adults with a life-threatening cancer are these two considerations: being able to choose the kind of medical treatment they want (or do not want) and expressing their wishes to family and friends about how they want to be remembered, according to a new study published in the journal Pediatrics.1

Advanced Care Planning The focus of the study was to assess and compare the usefulness of two previously developed advancecare planning guides, My Thoughts, My Wishes, My Voice—a guide prepared specifically for adolescents and young adults—and Five Wishes—an advance-care planning guide for adults. The study researchers asked 52 adolescents and young adults, aged 16 to 28, living with metastatic or recurrent cancer (including leukemia, brain tumors, and sarcomas) or HIV/AIDS, to evaluate pages from both guides and suggest any changes they would like to have in content, design, format, or style. The result is the publication of a new guide, Voicing My Choices™: A Planning Guide for Adolescents & Young Adults, which incorporates topics the study participants said were most important to them, including having input in their medical

I

care and treatment decisions, such as the types of life support treatment they want; how they want to be cared for and supported during their illness; who they want making medical care decisions if they can no longer make them; and how they want to be remembered after death.

Finding Meaning “Although it’s not clear that their understanding of death is the same as an adult’s would be in terms of consequences, when adolescents or young adults think about end-of-life, they do think about existential issues and their medical care, and they absolutely think about altruistic ways of living,” said Lori Wiener, PhD,

Branch, Center for Cancer Research at the National Cancer Institute; and lead author of the study. “The majority of study participants wanted to include information in the document that expressed their wish to either donate their cells or their bodies to science so that other people could benefit from their disease,” she continued. “Perhaps these patients, who have already been dealing with life-limiting illnesses, are even more open to giving back to others. It is a way of finding meaning in their life and in their experience.”

Maintaining Control and Independence “Oftentimes, [adolescents and

“Oftentimes, [adolescents and young adults] feel they can’t have conversations about what they want or don’t want in their medical care and under what circumstances because their parents may feel that they are giving up hope. —Lori Wiener, PhD

Director of the Psychosocial Support and Research Program; Staff Scientist in the Pediatric Oncology

Young Survival Coalition Launches Post-treatment Navigator

n December, the Young Survival Coalition released What’s Next? A Young Woman’s Post-treatment Navigator, a survivorship guide to help young breast cancer survivors improve their quality of life after treatment ends. The Young Survival Coalition developed the guide after a 2010 survey it conducted found that 86% of its post-treatment population did not have a survivorship care plan in place following treatment. What’s Next contains information on what breast cancer survivors can expect after treatment ends, including long-term treatment side effects and fertility risks; sexuality and intimacy issues; how to make healthy lifestyle changes; electronic tools to manage medical expenses; and where to find help with financial assistance, as well as other survivorship resources. What’s Next also provides information on the importance of establishing a written follow-up care plan with the help of their oncologist and contains worksheets survivors can use to create a summary of their diagnosis and treatment. Copies of the Post-treatment Navigator are available at youngsurvival.org. n

young adults] feel they can’t have conversations about what they want or don’t want in their medical care and under what circumstances because their parents may feel that they are giving up hope. Parents may not want to have these conversations because they are afraid that if they start talking about ending treatment or end-of-life issues, their child will feel that the parent is giving up hope. The risk is that the child dies in emotional isolation at a time when both the child and the parent need to feel a sense of closeness and comfort each other,” said Dr. Wiener. Having a document in which adolescents and young adults with cancer can express their fears of death, worries over being forgotten, and desires to take part in their medical care decisions, provides an important communication tool for adolescents and young adults, their parents, and their medical team, hoping to en-

sure that these patients will not die emotionally alone, said Dr. Wiener. Future research will help determine whether this tool increases congruence between patients and families or their physician or improves patient outcomes. Allowing adolescents and young adults to participate in their end-oflife decisions also gives them back the sense of control and independence they were robbed of when they became ill. “People in this age group are at a critical developmental stage, where they are negotiating greater independence and autonomy, formulating their self-identity, and trying to define what their role is going to be in life. Living with a lifethreatening illness challenges every one of those developmental goals. Instead of working toward increasing their independence, they find themselves dependent on their parents, their medical team, and medicine,” said Dr. Wiener.

Getting the Conversation Started All medical discussions with seriously ill adolescents/young adults and their parents should begin before there is a medical emergency, and possibly even at the time of diagnosis, said Dr. Wiener. “It’s important to establish early on an open relationship with the patient and the family that is built on honesty. At the time of diagnosis, the oncologist might ask the patient a series of questions such as, What do you understand about your disease? How much information do you want us to share with you? Is it okay if I speak privately See Page 101 with your parents? Are there certain things you would like to speak to me about in private? Do you prefer that we provide you with written material or that we talk everything through?” said Dr. Wiener. “What we need to do is teach everybody on the medical team strategies to have conversations with patients and family members that do


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Focus on Young Adults

not foster a sense of hopelessness,” said Joanne Wolfe, MD, MPH, Division Chief of Pediatric Palliative Care in the Department of Psychosocial Oncology and Palliative Care at Dana-Farber Cancer Institute and Director of Palliative Care at Children’s Hospital Boston. “Starting the conversation with general, openended, and nonthreatening questions provides an opportunity to deepen the conversation later. Having a tool like Voicing My Choices is

ASCO’s Cancer Treatment Summaries for Survivors

A

SCO has developed treatment summaries and survivorship care plans for specific cancers, as well as cancer adjuvant treatment plans and summaries, and guidelines for follow-up care to help survivors maintain information about their cancer and a record of their medical history to use as

they transition to primary care providers. Forms for specific cancer treatment summaries and survivorship care plans See Page 101 can be accessed online at cancer.net/ survivorship/asco-cancer-treatment-summaries. n

Starting the conversation with general, open-ended, and nonthreatening questions provides an opportunity to deepen the conversation later. —Joanne Wolfe, MD, MPH

an important contribution to facilitating these conversations.” For a copy of Voicing My Choices: A Planning Guide for Adolescents & Young Adults, visit the Web page ­agingwithdignity.org/vmc. n Disclosure: Drs. Wiener and Wolfe reported no potential conflicts of interest. Reference 1. 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.

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication.

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.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 08Z12236


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A Day in the Life Never a Dull Moment: A Day in the Life of an Oncology Fellow By Bishoy Faltas, MD, as told to Ronald Piana Oncology fellows represent the future of cancer care, bringing the best and brightest young doctors into a rigorous training environment that molds their future career paths. Due to an impending workforce shortage in cancer care, the public health-care demands placed on today’s oncology fellows will be greater than ever. To give our readers insight into the life of an oncology fellow, The ASCO Post spoke with Bishoy Faltas, MD, who began his hematology/ oncology fellowship this past July at Weill Cornell Medical College in New York.

I

was born and reared in Egypt; I received my medical degree from the University of Asyut, located about 250 miles south of Cairo. After graduation, I pursued training in the United States because I was determined to become the best physician I could be. The high quality of medical training in the United States offered me that opportunity. I was also attracted to the idea of living in a “meritocracy” where advancement is based solely on the quality of one’s work. So I decided to come to the United States in 2006 and started my internal medicine residency in Rochester, New York. I was already leaning toward medical oncology during medical school, after losing my father to laryngeal cancer. During my residency, I found that I truly experienced fulfillment from taking care of patients with cancer, and this drew me more toward oncology.

Finding My Way: Guidance by Mentors During my residency, I was very fortunate to have wonderful mentors. Not only were they excellent role models, but they also helped me realize that oncology was my true calling. In particular, Dr. Paul L. Bernstein, my residency program director has left an indelible mark on my career. He taught me that the good physician is the one who is present at the bedside until the end. I remember for instance one time when he took me along with him to the funeral of one of our patients who had just passed away, to console the patient’s family. His high regard for continuous

scholarship truly inspired me. During my residency, we worked together to develop a rotation for medical residents to spend 2 weeks learning about the molecular basis of different diseases including cancer, while getting hands-on training in basic molecular techniques like polymerase chain reaction (PCR). It was an innovative course that helped me appreciate the biologic complexity of human disease, and it was a lot of fun! Dr. Bernstein encouraged me to follow my passion in oncology. So when the time came, I applied for oncology fellowships, interviewed at multiple places, and finally matched at Weill Cornell Medical College. One of the reasons I chose this program is the very strong mentorship

Last weekend, as I finished rounding on the solid tumor service, I received an emergency call to the ICU for a patient with acute leukemia, admitted with a white cell count of 200,000/mm3. He had severe metabolic acidosis and was intubated. We put in a nasogastric tube and administered hydroxyurea. We started leukapheresis to reduce the blast count. Unfortunately, despite our best efforts, the patient succumbed to the disease and by the end of the day had passed away. Days like this can be difficult, especially when you lose a patient. Learning how to cope with this is an essential part of becoming an oncologist. Oncology is an ever-changing field; one of the biggest challenges of the first year is to master that huge

Now is a great time to go into oncology. I would encourage medical students and residents to seriously consider a career in oncology. —Bishoy Faltas, MD

to engage in research in pursuit of new and exciting ways to diagnose and treat cancer.

Choosing Oncology Now is a great time to go into oncology, There is growing concern about an impending workforce shortage in oncology. Cancer is poised to overtake cardiovascular death as the nation’s top killer. We need more oncologists, and I would encourage medical students and residents to consider a career in oncology. No doubt, an oncology career can be emotionally challenging. You deal with desperately sick patients, but helping these very vulnerable patients is very fulfilling. We are on the verge of seeing the fruits of the explosion of knowledge about the molecular basis of cancer. It is thrilling to be part of a forwardlooking medical field that is rapidly advancing its knowledge base and its ability to cure and palliate the world’s most dreaded disease. I can see it happening before my eyes, and I’m just at the beginning of my career! The prospect of being even a small part of this is very exciting.

Winding Down culture that starts at the highest levels of the department and trickles down to the level of fellows, residents, and medical students.

Exciting Times Fellowship is a very exciting time for me. I’m just 6 months into my 3-year combined hematology-oncology fellowship. The first year of fellowship is composed entirely of clinical rotations, purposely structured in a way that will allow for protected time for research later on. From the second year through the first half of the third year, the focus is on laboratory research, and the last 6 months of the fellowship is composed of electives. In the first year, my weekday schedule and duties are based largely on each specific clinical rotation, varying from day to day. The breadth and richness of the pathology I see is tremendous. On-call duties are infrequent, but the nature of problems one would encounter on the “front lines” is unpredictable.

body of knowledge while staying abreast of the new literature. Finding time to read could be challenging, but the numerous didactic occasions give us a “critical mass” of knowledge necessary to take care of patients.

Looking Ahead After completing my first year, I am very excited about the prospect of conducting laboratory research for the following 18 months. It is an opportunity to really get a deeper understanding of the biology of cancer. As I see patients everyday in the clinic, I see how cancer affects their lives. However, working with cancer cells up close and personal in the lab is quite different, bringing a new dimension to my understanding of cancer— a chance to “know thy enemy.” I am very grateful that my program offers the opportunity of “protected time” to pursue laboratory work. Although my career path is not set in stone, I’m fairly certain that I want to be an academic oncologist. I want

It takes passion and commitment to pursue a career in oncology. As rewarding as taking care of cancer is, our profession is very demanding, and one needs to use downtime to decompress and to refocus on one’s goals. For me, spending time with my family is the best way to unwind. Whenever I can, I try to spend time with my 3-year-old son George, and my wife Mary, who is studying to get into dental school. Although she is a full-time student in a very demanding program, she is always there to support me as I move into new and more challenging phases of my career. Burnout is a real phenomenon in oncology, so I’m fortunate to have a supportive family. When time permits, I take advantage of the numerous cultural attractions New York City has to offer. I have just started golf lessons, although I’m not sure how far that will go. Golf courses are hard to come by, but there is always a driving range nearby. n Disclosure: Dr. Faltas reported no potential conflicts of interest.


ASCOPost.com  |   JANUARY 15, 2013

PAGE 73

News

President Obama Signs High-mortality Cancer Bill into Law ust hours before the end of the 112th Congress, constitutional deadline for approval of a bill passed by that Congress, President Barack Obama signed into law the first legislation requiring comprehensive plans of research action for high-mortality cancers, with lung and pancreatic cancers given priority status for expedited attention.

Landmark Legislation This landmark legislation, included in the National Defense Authorization Act of 2013, requires the National Cancer Institute (NCI) to develop scientific frameworks for addressing cancers with survival rates of less than 50%, with first priority attention to lung and pancreatic cancers. The framework must be sent to Congress within 18 months. “Thank you Mr. President and thank you Congress for giving all of us in the lung cancer community and all those at risk for lung cancer the best possible present for the start of a new year,” said Lung Cancer Alliance President and CEO Laurie FentonAmbrose, whose national organization launched the legislative effort on lung cancer 6 years ago. “This is a new era for lung cancer. We are now out of the shadows,” Ms. Fenton-Ambrose said. “Our mission is to cut lung cancer mortality in half by the end of the decade,” she continued, “and we have added another tool in our arsenal to help make this goal a reality. This legislation, coupled with the validation of CT screening as a bigger potential life saver than any other cancer screening method, and with the Veterans Administration and the Department of Defense starting to screen high-risk veterans and military, could make this goal possible.”

islation was introduced to authorize a comprehensive plan of action. The primary sponsors included Senator Dianne Feinstein (D-CA), then Sen-

members Donna Christensen (DVI), Lois Capps (D-CA), Ed Whitfield (R-KY), and Frank LoBiondo (R-NJ). n

InsIght

JnCCn

NEW

Read the January Issue of JNCCN: • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Small Cell Lung Cancer NCCN Guidelines® Insights: Multiple Myeloma 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.

• Impact of the 7th Edition AJCC Staging Classification on the NCCN Clinical Practice Guidelines in Oncology for Gastric and Esophageal Cancers • Optimizing Fertility Preservation Practices for Adolescent and Young Adult Cancer Patients • Advances in Breast Surgery, 2002–2012

Legislative Saga Lung Cancer Alliance’s legislative saga started in 2006 during the 109th Congress with the passage of a Senate resolution calling lung cancer an urgent public health priority. The original sponsors were then Senators Hillary Rodham Clinton, Chuck Hagel, and Mike DeWine. In the 110th Congress, bipartisan resolutions were passed unanimously by both Houses and in the 111th Congress bipartisan, bicameral leg-

ator and now Kansas Governor Sam Brownback, Senator Johnny Isakson (R-GA), Senator John Kerry (DMA), and House of Representatives

NEw IN EvErY ISSuE OF

NEW

J

register for your free subscription at JNCCN.org

DowNLoaD the JNCCN app Visit the iTunes store or use your QR code reader to download the JNCCN mobile application.


The ASCO Post  |   JANUARY 15, 2013

PAGE 74

News Issues in Oncology

NCI Director Assesses Barriers to Faster Progress in Cancer Research By Ronald Piana

A

t a National Press Club media event in Washington, DC, on September 25, 2012, National Cancer Institute (NCI) Director Harold E. Varmus, MD, addressed a group of 75 reporters and officials. His discussion focused on impediments—biologic, economic, institutional, and cultural—to faster cancer research. In Dr. Varmus’s intro� duction, he noted that over the past

ever, our budget has remained flat for the past 5 years, and when inflation is factored in, NCI’s purchasing power has decreased by about 20% over the past 9 years,” Dr. Varmus explained. He continued, “Because of the dis� crepancy between the promise of sci� ence and adequate funding, the biomed� ical ecosystem is under unusual stress, putting the United States at risk of losing our global scientific leadership role.”

Three Categories of Good News

Harold E. Varmus, MD

40 years, NCI has spent about $90����� ���� bil� lion on research, yet cancer stubbornly remains a leading cause of death in the United States.

Vital Role of Government “The NCI has been in existence since 1937, so we’re celebrating the Institute’s 75th anniversary. It is the first of the socalled “categorical” institutes and cen� ters, which means that it is devoted to a specific disease or type of medical con� dition,” Dr. Varmus began, adding that there are now 27 institutes and centers. Dr. Varmus stressed that the NCI ex� emplifies the vital role government plays in bettering society, despite “some of the antigovernment rants from certain quar� ters.” He enumerated the institute’s mul� tiple contributions, commenting that along with the obvious scientific itiner� ary, the institute adds vibrancy to local and state economies. “The NCI’s yearly budget is just a hair more than $5 billion, which is spent mainly on grants that support thousands of individual scientists, scientific teams, centers, and training programs. How�

Visit

Dr. Varmus broke the NCI into its constituent parts, briefly explaining the goals of each sector. He then asked the rhetorical question: “How are we doing on the goal with which NCI was initially founded—conquering cancer?” In an� swer, he explicated the dizzying array of biologic complexities of cancer that

eloid leukemia. Moderate success has been achieved with targeted therapies in certain forms of lung cancer and my� eloma. Moreover, novel research in im� munotherapies shows promise in har� nessing our body’s immune system to fight cancer,” Dr. Varmus said. He also mentioned advances in surgical and ra� diotherapy techniques, along with im� provements over the past 2 decades in symptom management. He then discussed the third category of “good news”—advances in the basic understanding of the underlying proper� ties of the disease. “We now know unam� biguously that cancer is a disease of our genomes in which the genetic informa� tion is either changed or damaged. And we have new diagnostic categories that are defined by these genetic changes, which give rise to what we now refer to as precision medicine,” Dr. Varmus said.

We are at an unprecedented time in our ability to turn our understanding of cancer into major clinical advances. Yet, it is a sobering time because medical research is hindered by financial shortfalls. —Harold E. Varmus, MD

have confounded faster progress. Then he transitioned into the more realistic goal of controlling and managing cancer, which set the stage for what he called “three major categories of good news.” “First, we’ve seen a slow but steady decline in cancer mortality rates, roughly 1% to 2% per year over 2 decades, which is the best single measure of how we are doing in the battle against cancer. Sec� ond, this progress is not attributable to a single factor, but rather to a combined set of advances in early detection and preventive methods,” Dr. Varmus said. “In addition, we’ve improved sur� vival with a growing array of targeted therapies, the most dramatic of which is imatinib (Gleevec) for chronic my�

Scientific Dilemmas and Fiscal Constraints Despite the advances, Dr. Varmus said the decrease in age-adjusted mortal� ity in many cancers is unacceptably slow. “Moreover,” he continued, “several early detection methods have been overrated, most notably for prostate cancer. And although many cancers are behavior driven, we’ve had insufficient success in tobacco and weight control programs.” Dr. Varmus used a single gene to highlight the scientific dilemma. “We have had significant scientific leads that simply haven’t materialized—like the KRAS mutation, which accounts for about 30% of all cancers—yet we still haven’t developed targeted therapies to

address that clinical challenge.” After restating the obvious problem of deciphering the complex, heteroge� neous biology of cancer, Dr. Varmus affirmed that inadequate financing leads the list of impediments to cancer research. “Because of fiscal constraints, we currently only fund 14% of our grant applicants. Secondary fallout from this stringency is the chilling effect it has on young researchers, many of whom might shy away from the NCI because they feel the atmosphere is self-limiting,” Dr. Varmus said. “[Underfunding] generates an aver� sion-to-risk attitude by grant applicants and review panels, and consequently, they support safe science instead of rev� olutionary science,” he said.

Further Impediments “Researchers in the cancer commu� nity are also faced with an unprecedent� ed wave of data, and we currently don’t know how to create clinical correlations from the different sets of data; solving that informatics problem is another huge challenge,” he noted. Dr. Varmus also addressed a cultural impediment: “I have been a strong pro� ponent of making scientific materials and literature open and accessible so investigators can freely exchange their reagents and findings. Open science is one way to partially counteract the sti� fling effect of fiscal stringency, so it’s an important goal,” he stressed. “We are at an unprecedented time in our ability to turn our understanding of cancer into major clinical advances. Yet, it is a sobering time because medical re� search is hindered by financial shortfalls. Naturally, any cuts to our already tight budget would have devastating conse� quences to the NCI, an institute that contributes greatly to the public welfare. I remain an optimist, but we have to tem� per our goals,” Dr. Varmus concluded. n Disclosure: Dr. Varmus reported no potential conflicts of interest.

website at ASCOPost.com


In the treatment of myelofibrosis What does

REGULATING JAK mean for your patients?


Jakafi® (JAK-ah-fye)—First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*Intermediate or high-risk MF.

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

Jakafi is a registered trademark of Incyte Corporation. © 2012, Incyte Corporation. All rights reserved. RUX-1160A 07/12

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster)


Jakafi demonstrated superior reductions in spleen volume and improvements in symptom scores at Week 241,2,a,b Percent Change in Total Symptom Score (TSS) in Individual Patients From Baseline to Week 24 or Last Observation1,a,b

Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation1,a

150

40 20 0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

100 50 0 -50

IMPROVEMENT WORSENING

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

80

-100

50% Improvement Upper 50th Percentile

Placebo (n = 153)

Upper 50th Percentile

Jakafi (n = 145)

In these charts, each bar represents an individual patient’s response.

Placebo (n = 145)

Worsening of TSS is truncated at 150%.

At Week 24, significantly more patients receiving Jakafi vs placebo had — A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a — A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive patients and JAK2 V617F-negative patients, relative to placebo2

Visit www.jakafi.com/regulate

for more information on Jakafi and MF, plus valuable educational resources.

and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

a

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0).1,2

b Symptom

scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1,2

References: 1. Jakafi Prescribing Information. Incyte Corporation. June 2012. 2. Verstovsek S, Mesa RA, Gotlib J, et al. N Engl J Med. 2012;366:799-807.

Please see Brief Summary of Full Prescribing Information on the following page.

JAK targeted to make a difference


Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a registered trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011-2012 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: June 2012 RUX-1040a


ASCOPost.com  |   JANUARY 15, 2013

PAGE 79

Pioneers in Oncology Physician-Scientist Judah Folkman, MD, Faced Years of Skepticism Before His Theory of Angiogenesis Was Proven

Credit: Children’s Hospital

By Jo Cavallo

Judah Folkman, MD

T

hat Moses Judah Folkman would buck tradition, breaking his family’s long line of rabbinical succession and pursuing a career in science and medicine instead, was evident from the time he was a young child. Born in Cleveland on February 24, 1933, the first child of Rabbi Jerome and Bessie Folkman, young Judah eschewed more conventional children’s books in favor of biographies of Isaac Newton, Madame Marie Curie, and Louis Pasteur.

Early Life At age 7, Judah began accompanying his father on his Saturday hospital visits, where Rabbi Folkman comforted ailing members of his congregation and offered prayers. Meant to prepare Judah for his eventual rabbinic ordination, the visits convinced Judah that he wanted to offer patients more than spiritual solace alone. He wanted to help make them physically well. According to Dr. Folkman’s War: Angiogenesis and the Struggle to Defeat Cancer, by Robert Cooke,1 when Judah told his father of his intention to become a doctor instead of a rabbi, his father replied, “In that case, you can be a rabbi-like doctor.” By the time Judah was in high school, he was conducting experiments on small animals in his basement. For his entry in the Ohio Academy of Sciences competition, he devised a perfusion system powered by a small electric motor and a bicycle pump to keep the heart of a rat beating after being surgically removed. (Dr. Folkman would later jury-rig other devices, including a renal dialysis system

for a patient with acute renal failure, saving the patient’s life.) The experiment garnered Judah a prize in the competition and also put him on the path to Harvard Medical School at age 19, and a stint in the surgical laboratory of Dr. Robert Gross, then Surgeon-in-Chief at Children’s Hospital in Boston. There, he invented the first implantable heart pacemaker. After graduating magna cum laude from Harvard in 1957, Dr. Folkman became a surgical resident at Massachusetts General Hospital. In 1960 he married Paula Prial and soon they had two daughters, Marjorie and Laura. A third child, Kenneth, died in infancy from cystic fibrosis.

Birth of a New Field Soon after beginning his year as Senior Assistant Resident at Massachusetts General Hospital, Dr. Folkman was drafted into the navy and sent to do research at the National Naval Medical Center in Bethesda, Maryland. While

Hospital and continued his research efforts on tumor angiogenesis, although his hypothesis that malignant tumors must have a mechanism to induce the formation of blood vessels was met with growing skepticism—and even ridicule—from researchers steeped in methods that directly kill cancer cells. This skepticism affected his ability to obtain grants from the National Institutes of Health, his chances of being published in medical journals, and his capacity to attract young scientists to work in his lab. “I always viewed Dr. Folkman as an uplifting, inspiring, and genuinely enthusiastic person, but his first grants were rejected as being too visionary, and he fought an uphill battle to prove that a surgeon could transform science. He had to overcome the tunnel vision of that time,” said Steven Brem, MD, Co-Director, Penn Brain Tumor Center; Chief, Neurosurgical Oncology, Department of Neurosurgery at the Hospital of the University of Pennsyl-

Even as a student, I really had those moments of feeling that this man [Judah Folkman] was going to transform medicine. —Steven Brem, MD, former student of Dr. Folkman

conducting laboratory experiments on rabbits and mice implanted with cancer cells, Dr. Folkman noticed their tumors stopped growing when they were removed from the animals’ bodies but started growing again when the cells where implanted in another animal. The discovery led to his theory that tumors needed new blood vessels to provide them with the necessary oxygen and nutrients to keep them proliferating in a process known as “tumor angiogenesis.” During his time in Bethesda, Dr. Folkman also invented an implantable device for timed drug release (later developed as a means of administering the contraceptive levonorgestrel [Norplant]) and donated the patent to the World Population Council. In 1962, Dr. Folkman returned to Mass General to complete his surgical training and later became Chief Resident. Five years later, Dr. Folkman was named Surgeon-in-Chief of Children’s

vania; and a student of Dr. Folkman’s at Harvard Medical School. Dr. Folkman’s belief in angiogenesis as a cancer-cell proliferator was finally vindicated in the late 1980s when a scientist from the biotechnology company Genentech discovered vascular endothelial growth factor (VEGF), a protein that stimulates the formation of new blood vessels. In 2004, Genentech’s drug bevacizumab (Avastin), developed to block VEGF, was approved by the FDA for use in combination with standard chemotherapy drugs in the treatment of metastatic colon cancer, and later, for non–small cell lung cancer and renal cell carcinoma. Bevacizumab was also subsequently approved as a single agent in the treatment of glioblastoma as well as in macular degeneration.

Fulfilling a Father’s Wish A 1998 front-page article in The New York Times heralding Dr. Folk-

man’s laboratory work,2 including the discovery of endostatin and angiostatin as potential cancer fighters, ushered in an era of new hope about an end to cancer. The piece quoted Dr. James Watson, a Nobel laureate for the discovery of the structure of DNA, saying, “Judah is going to cure cancer in 2 years.” But Dr. Folkman refuted that claim in an issue of Scientific American later that year.3 “I don’t think angiogenesis inhibitors will be the cure for cancer,” he said. “But I do think that they will make cancer more survivable and controllable, especially in conjunction with radiation, chemotherapy, and other treatments.” Today, there are a dozen antiangiogenic drugs approved in oncology, including thalidomide (Thalomid), lenalidomide (Revlimid), sunitinib (Sutent), temsirolimus (Torisel), and everolimus (Afinitor), with more on the way. On January 14, 2008, Judah Folkman died of an apparent heart attack while waiting to change planes at a Denver airport on his way to a medical conference in Vancouver, British Columbia. “Dr. Folkman was like no other,” said Dr. Brem. “He was very inspiring and always full of enthusiasm. He could look 30 years or more into the future. His work preceded all of the translational research we have today in cancer and ophthalmology as well as other vascular diseases. He understood the importance of experiments, of logical thinking. Even as a student, I really had those moments of feeling that this man [ Judah Folkman] was going to transform medicine.” Dr. Folkman’s contributions to cancer research, and his career as a relentless scientist, caring physician, and gifted teacher, show beyond doubt that he lived up to his father’s admonition to become “a rabbi-like doctor.” n References 1. Cooke R: Dr. Folkman’s War: Angiogenesis and the Struggle to Defeat Cancer. New York, Random House, 2001. 2. Kolata G: Hope in the lab—a special report: A cautious awe greets drugs that eradicate tumors in mice. The New York Times. May 3, 1998. 3. Ezzell C: Starving tumors of their lifeblood. Scientific American. October 1998.


The ASCO Post  |   JANUARY 15, 2013

PAGE 80

Announcements

New Appointments at Cancer Centers Nationwide

Three Cancer Centers, the Levine Cancer Institute, Fred Hutchinson Cancer Research Center, and Cedars-Sinai, recently announced new appointments.

T

wo new physicians have joined a growing team of cancer experts at Carolinas HealthCare System’s Levine Cancer Institute in Charlotte, North Carolina. Joshua S. Hill, MD, surgical on� cologist, joins Levine Cancer Insti� tute after completing a fellowship in surgical oncology at The University of Texas MD Anderson Cancer Cen� ter’s Department of Surgical Oncol� ogy in Houston. Dr. Hill received his medical degree from The Ohio State University in Columbus and com�

urologic oncology at the University of California Medical Center. Dr. Riggs has extensive clinical trials experience in various areas of

urologic oncology, and he has lec� tured at regional and international meetings on bladder, kidney and testicular cancer, as well as robot-

assisted urologic surgery. He is par� ticularly interested in ways to reduce postoperative complications and im� prove patient experience.

Announcing: J-code

J9042

CD30-directed therapy

effective 1/1/13

CT SCANS Joshua S. Hill, MD

pleted a residency in general surgery at the University of Massachusetts in Worcester. Dr. Hill’s clinical interests focus on gastrointestinal, pancreatic, and liver cancers. He will collaborate with Institute researchers on devel� oping best practices for surgical and nonsurgical treatment of these can� cers. Steve B. Riggs, MD, joins the Institute from Virginia, where he served as Assistant Professor and Associate Program Director of the Department of Urology at Eastern Virginia School of Medicine. Dr. Riggs received his medical degree from Medical University of South Carolina in Charleston. Following a

confirmed responses in relapsed patients

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Steve B. Riggs, MD

surgery internship at Vanderbilt Uni� versity Medical Center in Nashville, he completed a urology residency at University of Mississippi Medical Center in Jackson and a fellowship in

2011 August 19 Acq Tm: 14:05:52

855.4SEAGEN (855.473.2436) SeaGenSecure.com

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; 2012. US/BVP/2011/0104j


ASCOPost.com  |   JANUARY 15, 2013

PAGE 81

Announcements

New Director of Public Health Sciences Division Selected at Fred Hutchinson Cancer Research Center After a national search, Garnet Anderson, PhD, a biostatistician and lead researcher in the Women’s Health Initiative, has been select� ed to become the new Senior Vice

Garnet Anderson, PhD

President and Director of the Pub� lic Health Sciences Division at Fred Hutchinson Cancer Research Cen� ter. She assumed the role January 1, 2013, when Ross Prentice, PhD, the former division director, stepped down after 25 years. Dr. Anderson, principal investiga� tor of the Women’s Health Initiative

After multiple failures,

single-agent response Indicated for the treatment of: • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

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

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

1

32%

40%

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

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

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

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

1

57%

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

29%

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

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

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

Important Safety Information BOXED WARNING

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

Contraindication:

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

Warnings and Precautions:

• Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly. • Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted. • Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. • Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.

• P rogressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS® (brentuximab vedotin)–treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. • Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. • U se in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

Adverse Reactions:

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

Drug Interactions:

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

Clinical Coordinating Center, which is based at Fred Hutchinson, has been on the Public Health Sciences faculty since 1989 and is a member of the division’s Cancer Prevention Research and Biostatistics/Biomath� ematics programs. She has been cen� tral figure in the Women’s Health continued on page 82


The ASCO Post  |   JANUARY 15, 2013

PAGE 82

Announcements

New Appointments continued from page 81

Initiative at Fred Hutchinson since the launch of the study in the early 1990s. She has played a major role in clinical trial design and in overseeing implementation of data management and quality-control activities for this immense and complex undertaking.

She became co-principal investiga� tor of the Women’s Health Initiative Clinical Coordinating Center, with Dr. Prentice, in 2008 and the sole principal investigator in 2011. She is also Associate Director for Cancer Control and Prevention of the Southwest Oncology Group Statistical Center and an Affiliate

Lawrence R. Menendez, MD

Daniel C. Allison, MD, FACS, MBA

Earl Warren Brien, MD

Professor in the Department of Bio� statistics at the University of Wash� ington.

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

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

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

Warnings and precautions Peripheral neuropathy

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

Infusion reactions

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

Neutropenia

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

Tumor lysis syndrome

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

Progressive multifocal leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

ADCETRIS® (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

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

Effect of other drugs on ADCETRIS

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

Effect of ADCETRIS on other drugs

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

Use in specific populations Pregnancy

Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers

It is not known whether brentuximab vedotin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use

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

Renal impairment

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

Hepatic impairment

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

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

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

Dosage and administration

Use in pregnancy

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

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

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

General dosing information

Bone Cancer Surgeons Join Cedars-Sinai Orthopaedic Center Two new Southern California or� thopedic oncologists recently joined Cedars-Sinai Orthopaedic Center in Los Angeles. Lawrence R. Menendez, MD, and Daniel C. Allison, MD, FACS, MBA, have partnered with Earl Warren Brien, MD, Director of Musculoskeletal Tumor Service at the Cedars-Sinai Orthopaedic Cen� ter. The surgeons specialize in meta� static bone disease, sarcoma cancers of the bone and soft tissue, invasive skin cancers and melanomas, and complex tumor-like conditions.  Dr. Menendez and Dr. Allison previously held leadership positions in orthopedic oncology at the Uni� versity of Southern California.  Dr. Menendez served as Chief of the Metastatic Bone Clinic, the Mul� tidisciplinary Sarcoma Center and the Center for Orthopaedic Oncol� ogy.   His research focuses largely on musculoskeletal tumors.   Before joining Cedars-Sinai, Dr. Allison was Assistant Chief of the University of Southern California Center for Orthopaedic Oncology at the University of Southern Califor� nia Norris Cancer Hospital.  He has expertise in musculoskeletal oncolo� gy, joint reconstruction, and anterior hip replacement. n

Dose modification

Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

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

Have You Relocated? Send news of your new title and affilation to The ASCO Post for publication in a future issue. Contact editor@ASCOPost.com


ASCOPost.com  |   JANUARY 15, 2013

PAGE 83

Psychosocial Oncology XXXX

The Rise of the Vintage Readers Book Club By Jimmie C. Holland, MD, Mindy Greenstein, PhD, and Christian J. Nelson, PhD

Jimmie C. Holland, MD

Mindy Greenstein, PhD

F

or the past few years, we have been running an Aging and Can� cer Group at Memorial Sloan-Ketter� ing Cancer Center, to help the fastest growing group of cancer survivors— ie, the elderly—cope with the double whammy of aging and cancer. In some ways, these are opposite problems: Cancer crystallizes the fear of dying, whereas aging often crystallizes the fear of growing older and more infirm as the years go by. One challenge both issues have in common, though, is the sense of isolation they can engender.

Search for Solutions We have tried different approaches to these issues, based on various psy� chological models, particularly the work of Erik and Joan Erikson on de� velopment throughout the life cycle. We convened two “expert panels” of elders to help us pilot our ideas. Not surprisingly, when talk of theories and models of development came up, eyes routinely glazed over. And so we learned to keep theory out of it and stick to everyday life experiences. Then an amazing thing happened, based not on theory, research, or any kind of science, but, instead, on

Christian J. Nelson, PhD

the love between a grandmother and granddaughter. My ( JH) grand� daughter and I decided to start a grandmother/granddaughter book club, to read and discuss the Harvard Classics during her gap year before college. We so enjoyed the exchange of ideas across the generations. But when college finally started and my

keeping in mind the age of our readers, we selected texts from antiquity to the modern era, starting with writings by Ben Franklin and Cicero’s essay, “On Old Age.” If those choices sound dry to you, they were anything but. Whereas the regular group meetings averaged two to four members, the book club meet� ings sometimes had close to a dozen attendees. We could barely squeeze into the same room. Discussions were the most animated since the inception of the group. Clearly, the book club touched something very visceral for its members, who ranged in age from their mid-60s to mid-90s.

Reasons for Success What was it about the Vintage

Whereas the regular group meetings averaged two to four members, the book club meetings sometimes had close to a dozen attendees.… Discussions were the most animated since the inception of the group. Clearly, the book club touched something very visceral for its members, who ranged in age from their mid-60s to mid-90s. young partner became too busy, she suggested I start a new book club for elders interested in tackling the great books of western civilization. Which is exactly what I did. The new group, which we integrated into the Aging and Cancer Group, was called the Vintage Readers Book Club. We devoted one meeting a month to discussing passages from the classics;

Readers Book Club that was so inspir� ing to its members? And why was it so much more popular than the Aging and Cancer Group from which it had sprung? We have some theories. One pos� sibility is a cohort effect. People of a certain age aren’t comfortable with talk� ing about themselves in a therapeutic situation—there’s a stigma to anything

associated with psychiatry. But they can talk about books. Ironically, in talking about books, the conversations regu� larly come back to ourselves—what we think of what the author wrote and how it relates to our own experiences, includ� ing but not limited to our experience of aging and/or dealing with cancer. Which brings us to another pos� sible reason. One of the ways we cope with aging and cancer is simply to live our lives the best we can, and set goals on which to focus. Having a concrete external goal—to discuss Ben Frank� lin’s ideas of what makes us happy, for example—sounds a lot more fun than just generally discussing our problems, even if both discussions end up leading us to the same place! Cicero’s essay on old age was illumi� nating in another way, too. His descrip� tion of ageism thousands of years ago could have popped out of today’s New York Times. And what better way to feel connected to the world than to feel con� nected across boundaries of time and culture. n For further information about the Vintage Readers Book Club, e-mail Dr. Holland at hollandj@mskcc.org. Disclosure: Drs. Holland, Greenstein, and Nelson reported no potential conflicts of interest.

Dr. Holland is Wayne E. Chapman Chair in Psychiatric Oncology and Attending Psychiatrist, Dr. Greenstein is a former chief clinical fellow in the Department of Psychiatry, and Dr. Nelson is a clinical psychologist at Memorial Sloan-Kettering Cancer Center, New York.

Jimmie Holland, MD, Guest Editor Providing care beyond medi� cal treatment, the multidisci� plinary field of psychosocial oncology addresses the psycho� logical, social, and emotional health of the patient with can� cer. On an occasional basis, The ASCO Post will explore the realm of psychosocial oncology with a column guest edited by Jimmie Holland, MD, Wayne E. Chap� man Chair in Psychiatric Oncol� ogy at Memorial Sloan-Kettering Cancer Center, New York. Members of the Vintage Readers Book Club enjoy the Harvard Classics.


The ASCO Post  |   JANUARY 15, 2013

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Patient’s Corner Breast Cancer

I’m Not the Same Person I Was before Cancer

Cancer has changed me in every way: physically, emotionally, and financially. By Tracey Aiello, as told to Jo Cavallo

I

t’s not clear to me—and my doc� tors can’t say with any certainty— whether taking birth control pills for many years had anything to do with my getting breast cancer 3 years ago, at age 44. But the cancer growing in my left breast was diagnosed as stage I, estrogen receptor–positive. Although I never felt a lump in that breast, when I noticed that the nipple had inverted I knew something was terribly wrong. After the diagnosis, my oncologist recommended that I have a complete mastectomy, but the thought of los� ing my whole breast was too scary for me to contemplate, and I asked for a lumpectomy instead. After two lumpectomies failed to provide clear tissue margins, my only recourse was to go ahead with the mastectomy. Before I had the surgery, I under� went 3  months of combination che� motherapy—I can’t remember the drug regimen—plus 6  weeks of daily radiation therapy to reduce the size of the tumor. Unfortunately, the treat� ment not only failed to accomplish its goal, it left me so sick and anxious, I was sure it would kill me long before the cancer.

Burden of Cancer When I was first diagnosed, I thought this cannot be happening to me, I don’t have time to have cancer. I

just wanted to hurry up with the treat� ment and get back to work and to my life. Although my health-care team did a great job of preparing me for the

well-being overwhelmed me to the point of complete collapse, and I had to be hospitalized for depression. I’m still on antidepressants, but the

Although my health-care team did a great job of preparing me for the physical ramifications of treatment, they didn’t explain the devastating financial and mental health repercussions I might suffer. —Tracey Aiello

physical ramifications of treatment, they didn’t explain the devastating financial and mental health repercus� sions I might suffer in the aftermath of the disease. Because I couldn’t work during my treatments—my blood counts were so low I had to have two blood trans� fusions, and I was very weak and nau� seous—I lost my health insurance. I had to use my life savings to pay medi� cal bills and cover day-to-day living expenses. Although my prognosis once treatment was completed was good, the fear of a cancer recurrence cou� pled with anxiety over my financial

fear of a recurrence is with me all the time, although it has lessened over the years. Getting a cancer diagnosis and a treatment plan was just the first step on the road to my recovery. The piece I was missing in the beginning was how to cope with the mental an� guish I would suffer. I understand that when people hear they have can� cer, their first thought is, “Am I going to die?” and all the effort is placed on saving the person’s life. But patients need to have the whole picture of what could possibly happen to them right from the start. It’s not enough to have only half the story.

Rebuilding a Life after Cancer I wish my oncology team had given me educational material about breast cancer that included informa� tion on both the physical and mental aspects of what I could expect and where to find help. It wasn’t until after my surgery and recovery that I realized the depths of my sadness over the loss of my breast and how it is impacting my life even now. I’m a single mom, anwd the reality of my altered body has made dating very difficult. It’s not just my social life that’s been stalled. I’m so worried and nervous about a cancer recurrence and what it would mean to me finan� cially, I have a difficult time concen� trating on my work as a phlebotomy technician. I find myself obsessively checking and double-checking my lab work and questioning my abil� ity to perform even the most routine tasks—something I never did before my cancer diagnosis. Being in a breast cancer support group is helping me cope, and I am getting counseling, which is restoring my sense of optimism for the future. It’s difficult, but I am trying to be more positive, put my cancer behind me, and move on. n Tracey Aiello lives in Cranston, Rhode Island.

Six Presidential Appointees Named to National Cancer Advisory Board

P

resident Barack Obama recently announced his intent to nominate the following individuals to the Na� tional Cancer Advisory Board: David Christiani, MD; Judy E. Garber, MD; Liz Jaffee, MD; Beth Karlan, MD; Mack Roach III, MD; and Charles Sawyers, MD. David Christiani, MS, MD, MPH,

David Christiani, MS, MD, MPH

is the Elkan Blout Professor of Environ� mental Genetics at the Harvard School of Public Health. In addition, Dr. Chris� tiani is a physician at the Pulmonary and Critical Care Unit of Massachusetts Gen� eral Hospital and Professor of Medicine at Harvard Medical School.  He is a recipient of the 2007 Robert S. Kehoe Award for Scientific Achievement from the Ameri� can College of Occupational and Environmental Medicine and the 2004 Harriet Hardy Award from the New England College of Occupational and Environmental Medicine.  Dr. Christiani received his MD degree from Tufts University and his MS and MPH degrees from Harvard University. Judy E. Garber, MD, Judy E. Garber, MD, MPH

MPH, is the Director of the Center for Cancer Genetics and Prevention at the Dana-Farber Cancer Institute. She is Professor of Medicine at Harvard Medical School and serves as Associate Physician at the Brigham and Women’s Hospital.  She is the immediate past President of the American Association for Cancer Research and serves on its Board of Directors.  In addition, she is a member of the Scientific Advisory Board of the Breast Cancer Research Foundation and a Fellow of the Ameri� can Society of Clinical Oncology.  From 2007 to 2012, Dr. Garber served on the Board of Scientific Counselors of the National Cancer Institute.  She received her MD and MPH degrees from Yale University School of Medicine. Elizabeth M. Jaffee, MD, is Co-

Elizabeth M. Jaffee, MD

Director of the Gastrointestinal Cancers Program in the Sidney Kimmel Compre� hensive Cancer Center at Johns Hopkins University. She has been a member of the Johns Hopkins faculty since 1992.  Dr. Jaffee has been Associate Director for Translational Research and the Co-Di� rector of the Skip Viragh Pancreatic Can� cer Center since 2010. She is the Deputy


ASCOPost.com  |   JANUARY 15, 2013

PAGE 85

Announcements

the Department of Radiation Oncology at UCSF. His previous positions at UC� SF’s Department of Radiation Oncology include Associate Professor in Residence from 1994 to 2000 and Assistant Profes� sor in Residence from 1990 to 1994.  He served on the National Cancer Institute Board of Scientific Advisors and current� ly serves on the National Comprehen�

sive Cancer Network’s Guidelines Com� mittee for Prostate Cancer. In 2008, he joined the Board of Directors for the California Division of the American Cancer Society.  Dr. Roach is a Fellow of the American College of Radiology.  He is a recipient of the American Cancer Society Career Development Award, the UCSF Health Net Wellness Award, and

the First Community Service Award. Dr. Roach received his MD degree from Stanford University. Charles Sawyers, MD, is the Chair of the Human Oncology and Pathogen� esis Program at Memorial Sloan Kettering Cancer Center.  In addition, he serves as Professor of Medicine at Weill-Cornell continued on page 90

Beth Y. Karlan, MD

Director of the Institute for Clinical and Translational Research at Johns Hop� kins and serves on the National Cancer Institute’s Experimental Therapeutics Program Panel on Investigational Drugs Committee. She served as a member of the National Cancer Institute’s Rapid Ac� cess to Investigational Drugs Committee from 2006 to 2011, the National Cancer Institute’s Board of Scientific Counsel� ors from 2005 to 2010, and the National Institutes of Health Experimental Im� munology Study Section from 1996 to 2000.  Dr. Jaffee received her MD degree from New York Medical College. Beth Y. Karlan, MD, is the Board of Governors’ Endowed Chair in Gy� necologic Oncology at Cedars-Sinai Medical Center.  She is Associate Direc� tor of Women’s Cancer Programs at the Samuel Oschin Comprehensive Cancer Institute and Editor-in-Chief of Gynecologic Oncology.  In addition, she serves as Professor of Obstetrics and Gynecology at the David Geffen School of Medicine at the University of California at Los An� geles and as Director of the Division of Gynecologic Oncology at Cedars-Sinai Medical Center.  Dr. Karlan is a member of the Board of Directors of the Con� quer Cancer Foundation.  She served as President of the Society of Gynecologic Oncologists in 2005 and Chair of the Department of Defense Ovarian Cancer Research Program Integration Panel in 2002.  Dr. Karlan received her MD de�

FOR A DIFFERENT PERSPECTIVE IN RENAL CELL CARCINOMA, DISCOVER…

ANOTHER SIDE OF RCC

In the United States, RCC is the 9th most common malignancy and accounts for 2% to 3% of all adult cancers.1,2 Incidence rates continue to rise; however, the reason for this increase is unknown. 2 The American Cancer Society estimates that there will be 64,770 new cases of RCC and 13,570 RCCrelated deaths in 2012. 3

Studies have demonstrated the importance of sustained drug levels; however, these levels can be compromised when toxicities lead to dose modifications, interruptions, or discontinuations. 5,8,9 In the Phase 3 trials of targeted agents, 30% to 40% of patients required dose modifications, and in the community setting this percentage may be higher.7 Treatment modifications require significant monitoring by healthcare professionals, and may potentially compromise treatment exposure and patients’ daily living. 5,8

Is good enough, enough? Today’s RCC patients are often active, with busy lifestyles and families. With a median age at diagnosis of only 64, quality of daily living on therapy is critical. 3 While the introduction of targeted therapy has improved the management of advanced disease and the outlook for patients, new challenges and existing unmet needs may compromise not only patients’ everyday life, but overall outcomes.4,5

Furthermore, patients themselves may choose not to adhere to their dosing regimen due to discomfort or dissatisfaction with the toxicity of therapy. 8 Other factors that may affect adherence include misinterpretation of physician instructions, polypharmacy syndrome and lifestyle distractions (e.g., demands of work and family, lack of support).10

Therapy for advanced RCC has evolved…

There may be opportunities to improve patient care

Each therapeutic class of agents is associated with distinct adverse events. Despite recent advances in treatment, side effects remain an important issue in patient management.6

Proactive monitoring, early detection, and prompt management of side effects are important for optimal patient management. Additionally, open communication between patients and healthcare professionals can be crucial to try to avoid premature treatment discontinuations or adverse impacts on patients’ everyday lives. 5,8

Research has shown that a substantial proportion of patients—both in clinical trials and everyday clinical practice—may not receive the full dose of their therapy due to adverse event management.7,8

Go behind the scenes to learn more at www.AnotherSideOfRCC.com. Mack Roach III, MD

gree from Harvard Medical School. Mack Roach III, MD, currently serves as a Professor of Radiation Oncol� ogy and Urology at the University of Cal� ifornia at San Francisco (UCSF). In ad� dition, Dr. Roach serves as the Chair of

AVEO and Astellas are uncompromising in their commitment to RCC References: 1. Centers for Disease Control and Prevention. http://apps.nccd. cdc.gov/uscs/toptencancers.aspx. Accessed January 27, 2012. 2. National Comprehensive Cancer Network. http://www.nccn.org. Published October 18, 2011. Accessed January 27, 2012. 3. American Cancer Society. Atlanta: ACS; 2012. 4. Cowey CL, Hutson TE. Clin Adv Hematol Oncol. 2010;8(5):357-364. 5. Hudes GR, Carducci MA, Choueiri TK, et al. J Natl Compr Canc Netw. 2011;9(suppl 1):S-1-S-30. 6. Appleby L, Morrissey S, Bellmunt J, Rosenberg J. Hematol Oncol Clin North Am. 2011;25(4):893-915. 7. Rini BI. J Clin Oncol. 2009;27(19):3225-3234. 8. Ravaud A. Ann Oncol. 2009;20(suppl 1):i7-i12. 9. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Cancer Chemother Pharmacol. 2010;66(2):357-371. doi:10.1007/s00280-009-1170-y. 10. Moore S. Cancer Nurs. 2007;30:112-122.

An Uncompromising Commitment to RCC

AVEO ONCOLOGY is a trademark of AVEO Pharmaceuticals, Inc. Astellas and the Flying Star logo are trademarks of Astellas Pharma Inc. ©2012 AVEO Pharmaceuticals, Inc. and Astellas Pharma US, Inc.

012I-073-6291

09/12

Printed in USA


The ASCO Post  |   JANUARY 15, 2013

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2013 Oncology Meetings January 2013 Breast-Gynecological International Cancer Congress

3rd Annual San Antonio Breast Cancer Symposium Review January 26 • Omaha, Nebraska For more information: www.nebraskaoncology.org

January 17-18 • Cairo, Egypt For more information: www.bgicc.eg.net/ Highlights of ASH® San Diego, CA and Toronto, Canada January 18-19 • San Diego, CA and Toronto, Ontario, Canada For more information: www.hematology.org/meetings Case-based Clinical Hematology and Oncology 2013: The 10th Annual Review January 18-20 • Scottsdale, Arizona For more information: www.mayo.edu/cme 11th Oncology Update: Advances and Controversies January 18-21 • Steamboat Springs, Colorado For more information: www.mdanderson.org/conferences 2013 Gastrointestinal Cancers Symposium January 24-26 • San Francisco, California For more information: www.gicasymposium.org

The 15th International Symposium on Anti-Angiogenic Therapy: Recent Advances and Future Directions in Basic and Clinical Cancer Research January 31-February 2 • San Diego, California For more information: www.mdanderson.org/conferences

February 2013 Highlights of ASH® Miami, FL and San Francisco, CA February 1-2 • Miami, Florida, and San Francisco, California For more information: www.hematology.org/meetings Interventional Pulmonology in Cancer Patients: An Intensive Hands-on Course February 7-9 • Houston, Texas For more information: www.mdanderson.org/conferences Advances in Orbital Oncology and Oculofacial Plastic Surgery February 8-9 • Houston, Texas For more information: www.mdanderson.org/conferences Integrative Medicine Program’s 1st Annual Integrative Oncology Healthcare Professional Training Conference February 8-9 • Houston, Texas For more information: www.mdanderson.org/conferences

T-cell Lymphoma Forum January 24-26 • San Francisco, California For more information: www.tcellforum.com Highlights of ASH® Dallas, TX and New York, NY January 25-26 • Dallas, Texas, and New York, New York For more information: www.hematology.org/meetings

Methods in Cancer Research Workshop February 9-13 • Al Ahsa, Saudi Arabia For more information: mcrw.kacst.edu.sa ASCO-MECC Palliative Care Workshop February 10-13 • Muscat, Oman For more information: www.asco.org/palliativecare

Genomics in Medicine: Individualized Care for Improved Outcomes February 11-12 • San Francisco, California For more information: www.triconference.com/genomicspersonalized-medicine Second Annual Targeting Cancer Stem Cells: Promising New Therapeutics for Oncology February 11-12 • San Francisco, California For more information: www.triconference.com/targetingcancer-stem-cells/ Quantitative Real-time PCR: Applications for Molecular Diagnostics February 11-12 • San Francisco, California For more information: www.triconference.com/ Quantitative-Pcr/ Molecular Med Tri-Con 2013 February 11-15 • San Francisco, California For more information: www.triconference.com American Psychosocial Oncology Society 10th Annual Conference February 14-16 • Huntington Beach, California For more information: www.apos-society.org 2013 Genitourinary Cancers Symposium February 14-16 • Orlando, Florida For more information: www.gucasymposium.org North Carolina Oncology Association & South Carolina Oncology Society Joint Membership Conference February 14-16 • Greenville, South Carolina For more information: www.ncoa-northcarolina.com Scripps Cancer Center’s 33rd Annual Clinical Hematology and Oncology Conference February 16-19 • San Diego, California For more information: www.scripps.org/events/clinicalhematology-and-oncologyfebruary-16-2013

2013 Multidisciplinary Head and Neck Cancer Update February 22-23 • Weston, Florida For more information: www.clevelandclinicmeded.com 2nd Novel Cancer Therapeutics Summit February 25-26 • Las Vegas, Nevada For more information: www.gtcbio.com

March 2013 International Congress on Targeted Anticancer Therapies March 4-6 • Paris, France For more information: www.tatcongress.org/tat13-home. html 24th Annual Cancer Progress Conference March 5-6 • New York, New York For more information: www.cancerprogressbyDH.com Inaugural Prostate Cancer Research and Translation Symposium March 6-7 • Winston-Salem, North Carolina For more information: northwestahec.wfubmc.edu NCCN 18th Annual Conference: Advancing the Standard of Cancer Care March 14-17 • Hollywood, Florida For more information: www.nccn.org Highlights of ASH® in Asia March 23-24 • Shanghai, China For more information: www. hematology.org/meetings 23rd Annual National Interdisciplinary Breast Cancer Conference March 23-27 • Las Vegas, Nevada For more information: www.breastcare.org/

April 2013 66th Urological Society of Australia and New Zealand Annual Scientific Meeting April 13-16 • Melbourne, Australia For more information: www.usanz2013.com/


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PAGE 87

2013 Oncology Meetings 3rd ITLT Essen 2013 Interdisciplinary Treatment of Liver Tumors April 18-20 • Essen, Germany For more information: www.itlt.org 7th Conference on Experimental and Translational Oncology April 20-24 • Portoroz, Slovenia For more information: www.ceto.si

Interventional Oncology Sans Frontières May 29-June 1 • Cernobbio, Italy For more information: www.iosfc2013.org 2013 ASCO Annual Meeting May 31-June 4 • Chicago, Illinois For more information: www.asco.org

September 2013

May 2013

June 2013

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

12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch 6th International Nasopharyngeal Carcinoma Symposium June 20-22 • Istanbul, Turkey For more information: www.npc2013.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

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/

Highlights of ASH® in Latin America April 25-26 • Santiago, Chile For more information: www.hematology.org/meetings

European Multidisciplinary Conference in Thoracic Oncology May 9-11 • Lugano, Switzerland For more information: www.esmo.org

ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna

MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes.com

July 2013 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

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

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

International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/ About+ASCO/International+Affairs/ International+Clinical+Trials+Works hops 4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in 18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 Society for Hematopathology/ European Association for Haematopathology 2013 Workshop October 24-26 • Houston, Texas For more information: www.mdanderson.org/conferences 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

November 2013 EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de

October 2013

December 2013

Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences

55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.org


The median age of patients in the VISTAâ&#x20AC; trial was 71 years (range: 48-91).


Survival never gets old VELCADE® (bortezomib) delivered >13-month overall survival advantage in combination with MP* vs MP alone for previously untreated multiple myeloma (median 56.4 vs 43.1 months [HR=0.695; 95% CI, 0.57-0.85; p<0.05]; 60.1-month median follow-up†)

Approved for subcutaneous and IV administration‡ VELCADE® (bortezomib) Indication and Important Safety Information INDICATION

VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS

VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS

Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼

Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment. ▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers. ▼

ADVERSE REACTIONS

Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. Please see Brief Summary for VELCADE on next page. *Melphalan+prednisone.

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma (MM). The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p =0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed. ‡ The reconstituted concentration for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL). †

Living Proof


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Announcements

Appointees to National Cancer Advisory Board continued from page 85

Medical College and as an Investigator at the Howard Hughes Medical Institute. Dr. Sawyers has served as the Professor of Cell and Developmental Biology at WeillCornell Medical College since 2011.  He was the Associate Chief of the Division

Charles Sawyers, MD

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted. Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known. Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

of Hematology-Oncology at the Univer� sity of California at Los Angeles School of Medicine from 1996 to 2006. Dr. Sawyers received the Stanley J. Korsmeyer Award from the American Society for Clinical Investigation in 2011 and the Lasker-De� Bakey Clinical Medical Research Award in 2009.   He received MD degree from Johns Hopkins School of Medicine. n

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each). In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

Contact

The ASCO Post

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

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

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Important VIdeo HIgHlIgHts from

ASH 2012 Dr. James Armitage, Editor-in-chief of The ASCO Post, interviews leading experts: • Dr. Richard Fisher on lymphomas • Dr. Hagop Kantarjian on leukemias • Dr. Sagar Lonial on multiple myeloma Presented by The ASCO Post. Recorded at ASH 2012 in Atlanta, Georgia.

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

V-12-0273

12/12

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ASCOPost.com  |   JANUARY 15, 2013

PAGE 91

Expert’s Corner Issues in Oncology

ASCO CEO Discusses the Society’s Initiatives A Conversation with Allen S. Lichter, MD By Ronald Piana the oncology community. It’s chal� lenging, but the future is bright

Maturation of QOPI®

Allen S. Lichter, MD

C

reated in 1964,a the American Society of Clinical Oncology (ASCO) has become the world’s pre� eminent professional cancer organi� zation, with more than 30,000 mem� bers in the United States and abroad, unified by its founders’ “common concern for the patient with cancer.” The ASCO Post recently spoke with ASCO CEO Allen S. Lichter, MD, about what lies ahead as the Society approaches its 50th anniversary in 2014.

Aggressive Agenda Is ASCO well positioned to maintain its aggressive agenda in these challenging economic times? The short answer is yes. Our membership is still growing, and our meetings continue to be successful and well attended. Moreover, our list of journals and publications operate at a very high level. So our combined revenue streams help support the in� frastructure of ASCO and its many robust programs. Having said that, because many of the programs I mentioned are mature, the rate of growth begins to slow, as does any product or service that is long-lived. We are a great or� ganization made up of terrific vol� unteers and executive leaders who have more ideas than the resources to carry them out. Consequently, we spend a lot of time managing our pre� cious resources and exploring inter� esting new ways to bring revenue into ASCO, so that we can initiate more innovative programs and services for ASCO was founded in 1964 by a small group of physcians who aimed to create a society dedicated to issues unique to clinical oncology. a

Please give the readers an update on the Quality Oncology Practice Initiative (QOPI®). QOPI is nearing its 12th opera� tional year, and has been open to the full membership for 6-plus years now. The certification program for outpa� tient oncology practices has been operating for about 2 years; approxi� mately 150 practices have been certi� fied so far, with more coming down the pike. So the general maturation of QOPI has thus far been successful, and we have numerous ambitious plans on the drawing board for the program’s future. For instance, one of QOPI’s drawbacks is that it is a manual chart abstraction, which makes the entry process laborious. We are embarking on an exciting new

improve our clinical care. This is an ongoing project that will go through much iteration, but the end result will be worth the effort.

Electronic Medical Records Is the ASCO Health Information Technology Work Group leading this project? Yes. All of what I’ve just discussed about QOPI’s electronic future is predicated on the widespread dis� semination and interoperability of electronic medical records. ASCO has a vested interest in the health information technology field, and so far we’ve seen a positive response from those practices that have ad� opted electronic medical records. However, there are still many issues that need to be addressed—one, of course, is standardization. We have dozens and dozens of vendors, each with their own system and propri� etary methodology, which creates

It is incumbent on ASCO to make sure that we remain totally engaged, not only in furthering our commitment to advancing cancer research and quality cancer care, but also in efforts to support high-quality care that’s affordable to our patients, as we continue to address the rising costs of care. — Allen S. Lichter, MD

ruption. Also, many physicians com� plain that the use of electronic medi� cal records actually slows the delivery of care and takes attention away from the patient. Our Health Informa� tion Technology Work Group will address all of these issues. It is im� portant to note that although we’re experiencing the inevitable growing pains that accompany new technolo� gies, the wrinkles will eventually be smoothed, and the benefits will far outweigh the inconveniences.

Relationship with NCCN Is there an ongoing working relationship between ASCO and the National Comprehensive Cancer Network (NCCN)? First off, NCCN recently brought on a physician CEO, Robert W. Carlson, MD, a long-time and valued ASCO member (see page 8 for inter� view with Dr. Carlson). NCCN is in the process of finishing a new strate� gic plan, and ASCO officers have met with their leadership to discuss pos� sible collaborative efforts. We are both on the same side of advancing quality cancer care; NCCN adds a terrific contribution to that shared effort with, among other things, their broad and comprehen� sive practice guidelines. So we look forward to working with NCCN on a number of issues that are still in the planning stage.

Executive Leadership project that will evolve QOPI into a fully electronic program that would facilitate a seamless health informa� tion technology process. This would really cut down on labor, one of the main barriers to participation. We have a pilot program set for next year that will migrate QOPI from a manual paper program to an electronic-based system. The ul� timate step is to turn QOPI into a learning health-care model in which we are not only collecting data on process measurements—what the program currently does—but ob� taining information about what happens when certain clinical pro� cedures are done. We can then be� gin to correlate the processes with the outcomes, which will ultimately

confusion because it limits the abil� ity of physicians who are caring for the same patient to share and com� pare data. Using our breast cancer treatment summary as a model, ASCO is work� ing hard with oncologists and ven� dors on a data standardization initia� tive to see if we can define the fields in breast cancer that need to be pop� ulated. That type of electronic treat� ment summary could then be shared among physicians, and we could use the success of the breast project as a stepping-stone and broaden it out to other disease states. When we survey our members, the lack of interoperability is on top of the complaint list, followed closely by excessive costs and practice inter�

Tell us about ASCO’s recent appointment of Richard L. Schilsky, MD, as its new Chief Medical Officer. The ASCO board was very wise in bringing on another physician to an executive leadership role. Seventeen years ago, ASCO recruited its first physician executive, John R. Durant, MD, who recently passed away. Serving as Executive Vice President, Dr. Durant helped centralize the widening array of the Society’s agenda under one administrative roof, a major restructuring achievement. Since then, we have become a much bigger and more complex or� ganization, with deeper reach and interaction into multiple sectors of the health-care and policy system. So continued on page 92


The ASCO Post  |   JANUARY 15, 2013

PAGE 92

Expert’s Corner

Allen S. Lichter, MD continued from page 91

the addition of Dr. Schilsky—a past ASCO President who has leadership experience running cancer centers and clinical trial groups—makes sense in that it enhances our ability to manage a controlled expansion of activities and services. Naturally, I

am very excited to have Dr. Schilsky on board.

Closing Thoughts Any last thought’s on ASCO’s future that you would like to share with the readers? The world of medicine is a challeng� ing, rapidly evolving environment. It

is incumbent on ASCO to make sure that we remain totally engaged, not only in furthering our commitment to advancing cancer research and quality cancer care, but also in efforts to sup� port high-quality care that’s affordable to our patients, as we continue to ad� dress the rising costs of care. The board met in March and creat�

MAY 31-JUNE 4, 2013 | MCCORMICK PLACE | CHICAGO, ILLINOIS

ed a vision for oncology 20 to 25 years down the road. We are in the process of rolling out that vision so that we as a community can have serious dia� logue about the future and make sure we’re steering the ship in the right di� rection. n Disclosure: Dr. Lichter reported no potential conflicts of interest.

Watch future issues of

The ASCO Post for comprehensive coverage of these important meetings:

CALL FOR ABSTRACTS SUBMISSION DEADLINE:

February 5, 2013, at 11:59 PM (EST) Submit an abstract to be considered for presentation or publication at the 2013 ASCO Annual Meeting. The ASCO Annual Meeting attracts over 5,000 abstract submissions representing the latest in clinical and translational science in the areas of cancer prevention, diagnosis, and treatment.

■■ 2012 Quality Care

Symposium November 30–December 1, 2012 San Diego, California

■■ San Antonio Breast

Cancer Symposium December 4–8, 2012 San Antonio, Texas

■■ American Society of

Hematology Annual Meeting December 8–11, 2012 Atlanta, Georgia

■■ 2013 Gastrointestinal

For more information, visit

asco.org/cfa

Cancers Symposium January 24–26, 2013 San Francisco, California.

■■ 2013 Genitourinary

Cancers Symposium February 14–16, 2013 Orlando, Florida

■■ American Psychosocial Oncology Society Annual Conference February 14 - 16, 2013 Huntington Beach, California

Visit The ASCO Post online at ASCOPost.com


ASCOPost.com  |   JANUARY 15, 2013

PAGE 93

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

Green Tea Scientific Name: Camellia sinensis Common Names: Chinese tea, green tea extract, green tea polyphenols, epigallo� catechin gallate (EGCG)

T

he use of dietary supplements by cancer patients has risen significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding re� liable sources of information about dietary supplements can be daunt� ing. Patients typically rely on fam� ily, friends, and the Internet, often receiving misleading information. The ASCO Post’s Integrative On� cology series is intended to facilitate the availability of evidence-based information on alternative and complementary therapies com� monly used by patients with cancer. We selected green tea for this issue because of its continued worldwide popularity as an antioxidant power� house, sought by many to prevent and treat cardiovascular disease and cancer. —Barrie R. Cassileth, PhD Integrative Oncology is compiled by Barrie R. Cassileth, MS, PhD, and Jyothirmai Gubili, MS, Memorial SloanKettering Cancer Center. The About Herbs website is managed by K. Simon Yeung, PharmD, Lac, Memorial Sloan-Kettering Cancer Center.

Overview

Green tea, a beverage consumed worldwide for its purported health bene�

fits, is derived from the leaves of the plant Camellia sinensis. Cultivated originally in East Asia, the plant is now grown in the Middle East and in some parts of Africa. The leaves used to prepare green tea are unfermented. Instead, they are steamed or heated immediately follow� ing harvest. This process preserves the integrity of polyphenols, compounds that act as antioxidants and contribute to the beneficial effects of green tea, by minimizing their oxidation. Green tea has a long history of use in traditional medicine as a stimulant, diuretic, for wound healing, to promote digestion, and to improve heart health. More recently, green tea and its extracts have been utilized to prevent and treat hyperlipidemia, hypertension, athero� sclerosis, and cancer. Green tea is avail� able as a dietary supplement in the form of capsules, extracts, and ointments for external application. However, despite wide consump� tion of green tea for cancer prevention, current data in support of that use are inconclusive. Green tea products also can interact with several prescription drugs, including anticancer agents. Pa� tients should consult their physicians before taking green tea in any form.

I

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integra� tive Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial SloanKettering Cancer Center, New York. The Integrative Medicine Service at Memo� rial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, Barrie R. Cassileth, MS, PhD minerals, and other dietary supplements, and un� proved anticancer treatments. Each of the 260 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. due to cardiovascular disease in both men and women.5 Topical application of green tea ex� tracts has beneficial effects against exter� nal genital and perianal warts.6 Sinecat� echin, a green tea extract used to treat genital warts, is an FDA-approved drug.

See Page 101

Adverse Effects

Hepatitis12-14; pruritic swelling and darkening of lower lip15; as well as thrombotic thrombocytopenic pur� pura have been reported following consumption of green tea.16 Animal studies indicate that when consumed during fasting, green tea ex� tract may increase the risk of toxicity.17

The Science

Green tea has been studied exten� sively over the past few decades. Clinical trials indicate that regular consumption of green tea may reduce the risk of hypertension1 and positively affect mood.2 It also enhances glucose tolerance in healthy individuals,3 but does not im� prove insulin sensitivity or glycemic con� trol in those with type II diabetes.4 Green tea may reduce mortality

find its benefits in preventing stomach cancer.11 Future randomized clinical trials may help re� solve the ambiguity surrounding the an� ticancer potential of green tea.

Herb-Drug Interactions Many preclinical, case-control, and prospective cohort studies indicate that green tea has chemopreventive properties.7-10 However, a meta analy� sis of epidemiologic studies failed to

Anticoagulants / antiplatelets: Consumption of large amounts of green tea (0.5–1.0 gallon/d) may pro� vide enough vitamin K to antagonize the effects of anticoagulants and anti� platelet agents. This effect has not yet

Learn More About

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

www.mskcc.org/aboutherbs

continued on page 94


The ASCO Post  |   JANUARY 15, 2013

PAGE 94

Integrative Oncology Green Tea continued from page 93

been reported in humans.18 Bortezomib: EGCG and other polyphenols in green tea can inhibit the therapeutic effects of bortezo� mib (Velcade) and other boronic acid based proteasome inhibitors.19 Tamoxifen: EGCG was shown to increase the oral bioavailability of tamoxifen.20

OF NOTE Green tea is popular among pa� tients with cancer. Oncologists should be aware of its question� able anticancer effects and of its potential to interact with many prescription drugs, including che� motherapeutic agents. Verapamil: The bioavailability of verapamil increased significantly in the presence of EGCG, thought to be due to P-glycoprotein inhibition by EGCG.21 Irinotecan: A study found EGCG to inhibit transport of irinotecan and its metabolite SN-38 into biliary elimi� nation, resulting in their prolonged half-life, which can increase toxicity.22 UGT (uridine 5’-diphospho-glucuronosyltransferase) substrates: Green tea modulates UGT enzymes in vitro and can increase the side effects of drugs metabolized by them.23 Cytochrome P450 3A4 substrates: Green tea extract inhibits CY� P3A4 and can affect the intracellular

concentration of drugs metabolized by this enzyme.24 Acetaminophen: Green tea in� creased acetaminophen-induced hepatotoxicity in mice when adminis� tered following acetaminophen.25 n Disclosure: Drs. Cassileth and Yeung and Ms. Gubili reported no potential conflicts of interest.

References 1. Yang YC, Lu FH, Wu JS, et al: The protective effect of habitual tea consump� tion on hypertension. Arch Intern Med 164:1534-1540, 2004. 2. Brown AL, Lane J, Coverly J, et al: Effects of dietary supplementation with the green tea polyphenol epigallocatechin3-gallate on insulin resistance and associat� ed metabolic risk factors: Randomized con� trolled trial. Br J Nutr 101:886-894, 2009. 3. Venables MC, Hulston CJ, Cox HR, et al: Green tea extract ingestion, fat oxida� tion, and glucose tolerance in healthy hu� mans. Am J Clin Nutr 87:778-784, 2008. 4. Mackenzie T, Leary L, Brooks WB: The effect of an extract of green and black tea on glucose control in adults with type 2 diabetes mellitus. Metabolism 56:13401344, 2007. 5. Kuriyama S, Shimazu T, Ohmori K, et al: Green tea consumption and mortal� ity due to cardiovascular disease, cancer, and all causes in Japan: The Ohsaki study. JAMA 296:1255-1265, 2006. 6. Stockfleth E, Beti H, Orasan R, et al: Topical polyphenon E in the treatment of external genital and perianal warts. Br J Dermatol 158:1329-1338, 2008. 7. Pisters KM, Newman RA, Coldman B, et al: Phase I trial of oral green tea extract

in adult patients with solid tumors. J Clin Oncol 19:1830-1838, 2001. 8. Sun CL, Yuan JM, Lee MJ, et al: Uri� nary tea polyphenols in relation to gastric and esophageal cancers. Carcinogenesis 23:1497-1503, 2002. 9. Tsao AS, Liu D, Martin J, et al: Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions. Cancer Prev Res (Phila) 2:931-941, 2009. 10. Shanafelt TD, Call TG, Zent CS, et al: Phase 2 trial of daily, oral polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia. Can� cer. July 3, 2012 (early release online). 11. Myung SK, Bae WK, Oh SM, et al: Green tea consumption and risk of stomach cancer: A meta-analysis of epidemiologic studies. Int J Cancer 124:670-677, 2009. 12. Mazzanti G, Menniti-Ippolito F, Moro PA, et al: Hepatotoxicity from green tea: A review of the literature and two un� published cases. Eur J Clin Pharmacol 65:331-341, 2009. 13. Vanstraelen S, Rahier J, Geubel AP: Jaundice as a misadventure of a green tea (Camellia sinensis) lover: A case report. Acta Gastroenterol Belg 71:409-412, 2008. 14. Verhelst X, Burvenich P, Van Sas� senbroeck D, et al: Acute hepatitis after treatment for hair loss with oral green tea extracts (Camellia sinensis). Acta Gastro� enterol Belg 72:262-264, 2009. 15. Lee JI, Cho BK, Ock SM, et al: Pig� mented contact cheilitis: From green tea? Contact Dermatitis 62:60-61, 2010. 16. Liatsos GD, Moulakakis A, Ketiko� glou I, et al: Possible green tea-induced thrombotic thrombocytopenic purpura.

Am J Health Syst Pharm 67:531-534, 2010. 17. Wu KM: Green tea extract induced lethal toxicity in fasted but not in nonfasted dogs. Int J Toxicol 30:19-20, 2010. 18. Taylor JR, Wilt VM: Probable an� tagonism of warfarin by green tea. Ann Pharmacother 33:426-428, 1999. 19. Goldin EB, Lam P, Kardosh A, et al: Green tea polyphenols block the an� ticancer effects of bortezomib and other boronic acid based proteasome inhibitors. Blood 113:5927-5937, 2009. 20. Shin SC, Choi JS: Effects of epigal� locatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats. Anticancer Drugs 20:584-588, 2009. 21. Chung JH, Choi DH, Choi JS: Ef� fects of oral epigallocatechin gallate on the oral pharmacokinetics of verapamil in rats. Biopharm Drug Dispos 30:90-93, 2009. 22. Lin LC, Wang MN, Tsai TH: Fooddrug interaction of (-)-epigallocatechin3-gallate on the pharmacokinetics of iri� notecan and the metabolite SN-38. Chem Biol Interact 174:177-182, 2008. 23. Mohamed ME, Frye RF: Effects of herbal supplements on drug glucuronida� tion. Review of clinical, animal, and in vitro studies. Planta Med 77:311-321, 2011. 24. Wanwimolruk S, Wong K, Wan� wimolruk P: Variable inhibitory effect of different brands of commercial herbal supplements on human cytochrome P-450 CYP3A4. Drug Metabol Drug Interact 24:17-35, 2009. 25. Salminen WF, Yang X, Shi Q, et al: Green tea extract can potentiate acetamin� ophen-induced hepatotoxicity in mice. Food Chem Toxicol 50:1439-1446, 2012.

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


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

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

IMPORTANT SAFETY INFORMATION Hypocalcemia

Osteonecrosis of the Jaw (ONJ)

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

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

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

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

©2012 Amgen Inc. All rights reserved. 7/12 64000-R6-V1 G69095-R1-V1

www.XGEVA.com


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

PERCENTAGE OF PATIENTS WITHOUT SRE

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

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: 19.4 months

40 30

17%

Median time: 27.7 months

20 10

RISK REDUCTION

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

0 0

3

6

9

12

15

18

21

24

27

30

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

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

SUBCUTANEOUS INJECTION

NO DOSE ADJUSTMENTS

PRECISE ACTION

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

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

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

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

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

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

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


T:9.5â&#x20AC;?

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should immunogenicity. Using an electrochemiluminescent bridging immunoassay, less receive care by a dentist or an oral surgeon. In these patients, extensive dental than 1% (7/2758) of patients with osseous metastases treated with denosumab surgery to treat ONJ may exacerbate the condition. doses ranging from 30 â&#x20AC;&#x201C; 180 mg every 4 weeks or every 12 weeks for up to PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant 3 years tested positive for binding antibodies. No patient with positive binding woman. Based on ďŹ ndings in animals, Xgeva is expected to result in adverse antibodies tested positive for neutralizing antibodies as assessed using a reproductive effects. In utero denosumab exposure in cynomolgus monkeys chemiluminescent cell-based in vitro biological assay. There was no evidence resulted in increased fetal loss, stillbirths, and postnatal mortality, along with of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical response associated evidence of absent peripheral lymph nodes, abnormal bone growth and with binding antibody development. The incidence of antibody formation is decreased neonatal growth (see Use in SpeciďŹ c Populations). There are no highly dependent on the sensitivity and speciďŹ city of the assay. Additionally, adequate and well controlled studies with Xgeva in pregnant women. Women the observed incidence of a positive antibody (including neutralizing antibody) should be advised not to become pregnant when taking Xgeva. If this drug is test result may be inďŹ&#x201A;uenced by several factors, including assay methodology, used during pregnancy, or if the patient becomes pregnant while taking this drug, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab the patient should be apprised of the potential hazard to the fetus. with the incidence of antibodies to other products may be misleading. ADVERSE REACTIONS: The following adverse reactions are discussed below DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted and elsewhere in the labeling: with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva t)ZQPDBMDFNJB TFF8BSOJOHTBOE1SFDBVUJPOT

was administered in combination with standard anticancer treatment. Serum t0TUFPOFDSPTJTPGUIF+BX TFF8BSOJOHTBOE1SFDBVUJPOT) denosumab concentrations at 1 and 3 months and reductions in the bone turnover The most common adverse reactions in patients receiving Xgeva (per-patient marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, were similar in patients with and without prior intravenous bisphosphonate therapy. and nausea (see Table 1). The most common serious adverse reaction in patients There was no evidence that various anticancer treatments affected denosumab receiving Xgeva was dyspnea. The most common adverse reactions resulting in systemic exposure and pharmacodynamic effect. Serum denosumab concentrations discontinuation of Xgeva were osteonecrosis and hypocalcemia. at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone Clinical Trials Experience. Because clinical trials are conducted under widely therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar varying conditions, adverse reaction rates observed in the clinical trials of a drug between patients receiving concomitant chemotherapy and/or hormone cannot be directly compared to rates in other clinical trials and may not reďŹ&#x201A;ect the therapy (see Clinical Pharmacology [12.2] in full Prescribing Information). rates observed in practice. The safety of Xgeva was evaluated in three randomized, USE IN SPECIFIC POPULATIONS: double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Information) in which a total of 2841 patients with bone metastasis from prostate Xgeva can cause fetal harm when administered to a pregnant woman based cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple on ďŹ ndings in animals. In utero denosumab exposure in cynomolgus monkeys myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were resulted in increased fetal loss, stillbirths, and postnatal mortality, along with randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid evidence of absent lymph nodes, abnormal bone growth and decreased every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium neonatal growth. There are no adequate and well-controlled studies with Xgeva (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance in pregnant women. Women should be advised not to become pregnant when 30 mL/min or greater. Patients who had received IV bisphosphonates were taking Xgeva. If this drug is used during pregnancy, or if the patient becomes excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an pregnant while taking this drug, the patient should be apprised of the potential active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, hazard to the fetus. Women who become pregnant during Xgeva treatment are or any planned invasive dental procedure. During the study, serum chemistries encouraged to enroll in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or including calcium and phosphorus were monitored every 4 weeks. Calcium and their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 â&#x20AC;&#x201C; 41) and median duration on-study was 13 months (range: 0.1 â&#x20AC;&#x201C; 41). Of patients who received 9HFWB XFSFGFNBMF&JHIUZmWFQFSDFOUXFSF8IJUF )JTQBOJD-BUJOP  Asian, and 3% Black. The median age was 63 years (range: 18 â&#x20AC;&#x201C; 93). SeventyďŹ ve percent of patients who received Xgeva received concomitant chemotherapy.

DOUS2X0319_T_4Pg Tabloid_Update_Aug_12_BS_r8.indd 1

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and beneďŹ ts in continuing or discontinuing treatment with Xgeva.

Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information). OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: t4ZNQUPNTPGIZQPDBMDFNJB JODMVEJOHQBSFTUIFTJBTPSNVTDMFTUJGGOFTT  twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) t4ZNQUPNTPG0/+ JODMVEJOHQBJO OVNCOFTT TXFMMJOHPGPSESBJOBHFGSPNUIF jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) t1FSTJTUFOUQBJOPSTMPXIFBMJOHPGUIFNPVUIPSKBXBGUFSEFOUBMTVSHFSZ (see Warnings and Precautions) t1SFHOBODZPSOVSTJOH(see Warnings and Precautions and Use in SpeciďŹ c Populations) Advise patients of the need for: t1SPQFSPSBMIZHJFOFBOESPVUJOFEFOUBMDBSF t*OGPSNJOHUIFJSEFOUJTUUIBUUIFZBSFSFDFJWJOH9HFWB t"WPJEJOHJOWBTJWFEFOUBMQSPDFEVSFTEVSJOHUSFBUNFOUXJUI9HFWB Advise patients that denosumab is also marketed as ProliaÂŽ. Patients should inform their healthcare provider if they are taking Prolia. Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 Š2012 Amgen Inc. All rights reserved. Printed in USA.

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T:13â&#x20AC;?

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Animal Data: The effects of denosumab on prenatal development have been studied Severity (Trials 1, 2, and 3) in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?). Xgeva Zoledronic Acid In cynomolgus monkeys dosed subcutaneously with denosumab throughout Body System n = 2841 n = 2836 pregnancy at a pharmacologically active dose, there was increased fetal loss during % % gestation, stillbirths, and postnatal mortality. Other ďŹ ndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal GASTROINTESTINAL bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and Nausea 31 32 tooth malalignment; and decreased neonatal growth. At birth out to one month of Diarrhea 20 19 age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects GENERAL on bone quality and strength returned to normal; there were no adverse effects Fatigue/ Asthenia 45 46 on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes INVESTIGATIONS were present, though small; and minimal to moderate mineralization in multiple )ZQPDBMDFNJBb 18 9 tissues was seen in one recovery animal. There was no evidence of maternal 32 20 )ZQPQIPTQIBUFNJBb harm prior to labor; adverse maternal effects occurred infrequently during labor. NEUROLOGICAL Maternal mammary gland development was normal. There was no fetal NOAEL (no )FBEBDIF 13 14 observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of RESPIRATORY denosumab) also caused fetal lymph node agenesis and led to postnatal impairment Dyspnea 21 18 of dentition and bone growth. Pregnant RANKL knockout mice showed altered Cough 15 15 maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information). a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials Nursing Mothers. It is not known whether Xgeva is excreted into human milk. 1, 2, and 3, and meeting one of the following criteria: Measurable concentrations of denosumab were present in the maternal milk t"UMFBTUHSFBUFSJODJEFODFJO9HFWBUSFBUFEQBUJFOUT PS of cynomolgus monkeys up to 1 month after the last dose of denosumab t#FUXFFOHSPVQEJGGFSFODF FJUIFSEJSFDUJPO PGMFTTUIBOBOENPSFUIBO (â&#x2030;¤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and 5% greater incidence in patients treated with zoledronic acid compared to because of the potential for serious adverse reactions in nursing infants from placebo (US Prescribing Information for zoledronic acid) Xgeva, a decision should be made whether to discontinue nursing or discontinue b Laboratory-derived and below the central laboratory lower limit of normal the drug, taking into account the importance of the drug to the mother. Maternal [8.3 â&#x20AC;&#x201C; 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL (0.71 â&#x20AC;&#x201C; 0.9 mmol/L) for phosphorus] signaling pathway that have shown altered maturation of the maternal mammary Severe Mineral/Electrolyte Abnormalities HMBOE  MFBEJOH UP JNQBJSFE MBDUBUJPO QPTUQBSUVN )PXFWFS  JO DZOPNPMHVT t4FWFSFIZQPDBMDFNJB DPSSFDUFETFSVNDBMDJVNMFTTUIBONHE-PSMFTT monkeys treated with denosumab throughout pregnancy, maternal mammary than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% gland development was normal, with no impaired lactation. Mammary gland of patients treated with zoledronic acid. Of patients who experienced severe histopathology at 6 months of age was normal in female offspring exposed to hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia denosumab in utero; however, development and lactation have not been fully and 16% experienced 3 or more episodes (see Warnings and Precautions and evaluated (see Nonclinical Toxicology [13.2] in Full Prescribing Information). Use in SpeciďŹ c Populations). Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and t4FWFSFIZQPQIPTQIBUFNJB TFSVNQIPTQIPSVTMFTTUIBONHE-PSMFTTUIBO effectiveness of Xgeva in pediatric patients have not been established. Treatment 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of with Xgeva may impair bone growth in children with open growth plates and patients treated with zoledronic acid. may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target Osteonecrosis of the Jaw of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in at doses â&#x2030;¤ 10 mg/kg was associated with inhibition of bone growth and tooth 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic eruption. Adolescent primates treated with denosumab at doses 5 and 25 times acid group (see Warnings and Precautions). When events occurring during an (10 and 50 mg/kg dose) higher than the recommended human dose of extended treatment phase of approximately 4 months in each trial are included, 120 mg administered once every 4 weeks, based on body weight (mg/kg), had the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Postmarketing Experience. Because postmarketing reactions are reported decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and voluntarily from a population of uncertain size, it is not always possible to reliably mesenteric lymph nodes. Some bone abnormalities recovered once exposure estimate their frequency or establish a causal relationship to drug exposure. was ceased following birth; however, axillary and inguinal lymph nodes remained The following adverse reactions have been identiďŹ ed during post approval absent 6 months post-birth (see Use in Pregnancy). use of Xgeva: Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) t)ZQPDBMDFNJB Severe symptomatic hypocalcemia, including fatal cases. were 65 years of age or older. No overall differences in safety or efďŹ cacy were Immunogenicity. As with all therapeutic proteins, there is potential for observed between these patients and younger patients.


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In the News Nutrition

Patients Treated for Colon Cancer Can Reduce Risk of Recurrence with Balanced Diet and Lower Carbohydrate Intake By Charlotte Bath

In the News focuses on media re� ports that your patients may have questions about at their next visit. This continuing column will pro� vide summaries of articles in the popular press that may prompt such questions, as well as com� ments from colleagues in the field.

P

atients who have received stan� dard treatment for colon cancer can take positive actions to reduce their risk of recurrence by following a balanced diet with fewer starchy foods that raise total gly� cemic load, accord� ing to Jeffrey A. Meyerhardt, MD, See Page 101 MPH, Associate Professor of Medicine at Dana-Far� ber Cancer Institute in Boston. Dr. Meyerhardt is lead author of a pro� spective, observational study exam�

Jeffrey A. Meyerhardt, MD, MPH

ining the influence of glycemic load, glycemic index, fructose, and carbo� hydrate intake among patients with stage III colon cancer. The study was embedded in a clinical trial (Cancer and Leukemia Group B [CALGB] 89803) compar� ing chemotherapy regimens for pa� tients who underwent complete sur� gical resection of the primary tumor, and had regional lymph node me� tastases but no evidence of distant metastases. Results of the dietary study were published in the Journal of the National Cancer Institute1 and reported in The New York Times2 and by other media outlets.

Earlier Investigation “This is our second study that has looked at diet in this cohort,” Dr. Meyerhardt told The ASCO Post.

“The first study3 was related to the Western pattern diet characterized by higher intake of red meats, pro� cessed meats, sugary desserts, re� fined grains.” Also involving patients with stage III colon cancer, that study found that those in the highest quin� tile of consumption of the Western pattern diet had a threefold increase in cancer recurrence and death com� pared to those in the lowest quintile. The second study was undertaken to “further understand which com� ponent of a Western pattern diet is associated with poorer outcomes and define the impact of dietary glycemic measures on colon cancer survival,” according to the study re� port. Results showed that higher di� etary glycemic load—a measure of the body’s plasma glucose response to foods—and total carbohydrate intake had a statistically significant association with an increased risk of recurrence and mortality. “It’s not that you have to totally avoid carbohydrates or totally avoid red meat,” Dr. Meyerhardt said, “but a healthy balanced diet is probably reasonable.” Dr. Meyerhardt noted that all patients in the study received what would be considered standard care for stage  III colon cancer. “They all received surgery, and they all had ad� juvant chemotherapy.” He stressed that while following a healthy bal� anced diet is reasonable, “it is not a substitute” for treatment.

Physiologic Response to Carbohydrates “Both total carbohydrates and glycemic load—measures that re� flect your body’s response to foods high in those components—lead to higher insulin levels. And we know that insulin and insulin-like growth factors are drivers of colon cancer cell growth,” Dr. Meyerhardt said. “The physiological response to carbohydrates can be quantified by the glycemic index, a qualitative as� sessment of foods calculated as a per� centage of the body’s plasma glucose response to specific foods compared with the response induced by the same amount of carbohydrate from continued on page 101

Expect Questions from Patients

A

study finding that a diet high in total carbohydrates can increase the risk of cancer recurrence and mortality doesn’t mean that patients need to totally avoid carbohydrates, any more than previous findings about increased risk from a Western pattern diet means patients can’t eat any red meat. What the findings do mean, according to lead author Jeffrey Meyerhardt, MD, MPH, Associate Professor of Medicine at Dana-Farber Cancer Institute in Boston, is that “a healthy balanced diet is probably reasonable” for patients to reduce their risk of recurrence and improve their opportunities for survival. That diet should involve foods with a lower glycemic load, a measure of how much eating a specified serving size of a particular food raises blood glu� cose levels. For example, patients can be advised to choose fresh fruits like apples, oranges, and cantaloupes, which have much lower glycemic loads than do dried fruits like dates or raisins. Substituting whole grains for refined grains and choosing brown rather than white rice can also lower the glycemic load.

Complex Issues Dr. Meyerhardt said that when the study was first published in the Journal of the National Cancer Institute and then reported by the media, he was concerned that it might be misinterpreted as meaning that carbohydrates, and particularly sugar, were to be strictly avoided. “It is a little more complex than simply saying sugar makes cancer grow. It is the body’s response to a more starchy type of diet and the impact on glycemic load. It is not that you have to totally avoid sugar, or totally avoid carbohydrates; it has more to do with maintaining lower levels.” The patients participating in the study had stage������������������������� ������������������������ III colon cancer and re� gional lymph node metastases but no evidence of distant metastases, and all had complete resection and adjuvant chemotherapy. While following a healthy balanced diet is reasonable, “it is not a substitute” for treatment,” Dr. Meyerhardt stressed. “Another consideration for colon cancer survivors is that even if they don’t experience a cancer recurrence, they may have a risk for other diseases down the line, including heart disease and diabetes. These dietary measures have also been shown to be preventive against heart disease, diabetes, and other potential comorbidities,” Dr. Meyerhardt noted.

Prediagnosis Diet “Given that patients who consume high glycemic loads or carbohydrates after cancer diagnosis may have consumed a similar diet before diagnosis, we cannot exclude the possibility that individuals with these dietary expo� sures acquire tumors that are biologically more aggressive,” Dr. Meyerhardt and his colleagues stated in the published study. “When you ask patients questions about their diet and lifestyle and other host factors after diagnosis, you could also ask them what they did beforehand, but you would obviously have issues with recall bias. So we chose not to do that.” It is possible, he said, that patients reporting very high carbohydrate diets in the study also had a history of very high car� bohydrate diets before diagnosis, and that may have affected their risk of developing colorectal cancer and of having more aggressive cancer with a higher risk of recurrence. That distinction is relevant, Dr. Meyerhardt noted, because if risk of recurrence is related to the diet patients followed before first developing colorectal cancer, “it is not an actionable item.” Patients can’t retroactively change their diet before diagnosis. “So you hope that you can find recom� mendations for patients to improve their outcome once they already have the diagnosis,” he added. n


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PAGE 101

In the News

Colon Cancer Recurrence Risk continued from page 99

a standard carbohydrate source, usu� ally white bread or pure glucose,” the study report explained. In the study, 1,011 patients com� pleted food questionnaires during and after participating in the adju� vant chemotherapy trial. The ques� tionnaires included 131 food items, vitamins, mineral supplements, and open-ended questions for other sup� plements and foods not listed. The investigators calculated glycemic in� dex values and used them to calcu� late the mean dietary glycemic load “by multiplying the carbohydrate content for each food by its glycemic index value, multiplying that prod� uct by the servings of that food per day, and summing values for all food items reported.” Median follow-up after completion of the first ques� tionnaire was 7.3 years.

Overweight Patients “The primary endpoint of this analysis was disease-free survival. Higher dietary glycemic load was as� sociated with statistically significant worse disease-free, recurrence-free, and overall survival,” the investiga� tors reported. “Moreover, the delete� rious association of dietary glycemic load and total carbohydrate intake on survival was principally observed in patients who were overweight or obese.” Associations between glycemic load and survival differed accord� ing to body mass index. “Compared with patients with the lowest gly� cemic load quintile, those in the highest quintile experienced an ad� justed hazard ratio for disease-free survival of 1.79,” the authors report�

ed. But those with a body mass index ≥ 25  kg/m2 had an adjusted hazard ratio of 2.26. “We looked at a subgroup analy� sis of people who had a [body mass index] of 25 or less, which is consid�

Other Disease Stages Although the current study in� volved only stage III patients with regional lymph node metastases, Dr. Meyerhardt said, “we have looked at energy balance factors—for example,

Although our observational study does not provide conclusive evidence for causality, these findings support the potential role of energy balance factors in colon cancer progression and may offer opportunities to further improve patient survival. —The CALGB 89803 investigators

ered either underweight or normal weight, or people whose [body mass index] was greater than 25, which is overweight and obese, and the as� sociation seemed to be strongest in those who were overweight and obese, which again is biologically plausible,” Dr. Meyerhardt said. Increasing evidence suggests that an energy imbalance between the calories consumed and expended impacts outcomes in colon cancer survival. “People who are physically inactive after diagnosis seem to have a higher risk of recurrence from their colon cancer,” according to pub� lished reports, Dr. Meyerhardt said. These reports consistently show “the importance of energy balance in co� lon cancer survivors and maintaining a healthy energy balance,” he added. The CALGB 89803 investigators concluded, “Although our observation� al study does not provide conclusive evidence for causality, these findings support the potential role of energy balance factors in colon cancer progres� sion and may offer opportunities to fur� ther improve patient survival.”

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.

physical activity—in earlier stages of disease, either stage I or stage II, and we see a similar effect. We haven’t been able to study diet as much in stage I or stage II patients, but at least biologically, it would make sense. Patients with early disease develop a recurrence when they have micro� metastases that are not detected at the time of diagnosis. Assuming that these energy balance factors lead to a biologic response, perhaps insulin or insulin-like growth factors that drive the micrometastases to grow, that would provide the rationale for a similar response in early-stage dis� ease,” he said. “Whether these factors impact people with metastatic disease is a different question, because those are people who already have visible disease, and you are trying to slow the progression,” he continued. “We actually have a very large study for metastatic disease, also embedded in one of the cooperative groups ­trials.” That trial, CALGB/Southwestern Oncology Group (SWOG) 80405,

is a phase� ������������������������ III ������������������������ study comparing che� motherapy regimens for patients with untreated metastatic adeno� carcinoma of the colon or rectum. Patients complete a single question� naire early on, when their ability to maintain physical activity and follow a balanced diet is less likely to be im� pacted by disease progression.

Looking Ahead “We have already collected over 1,400 questionnaires from patients on that trial and will be able to look at those questions on diet and other lifestyle factors,” Dr. Meyerhardt said. The study has completed ac� crual but has not yet reached the primary endpoint of overall sur� vival. Results are expected later in 2013. Questionnaires have also been embedded into another adjuvant chemotherapy trial, CALGB 80702, comparing duration of chemother� apy and celecoxib (Celebrex) vs placebo. “In that trial, we expanded some questions related to energy balance and added questions about other comorbidities,” Dr. Meyer� hardt said.” n

Disclosure: Dr. Meyerhardt reported no po� tential conflicts of interest.

References 1. Meyerhardt JA, Sato K, Niedz� wiecki D, et al: Dietary glycemic load and cancer recurrence and survival in pa� tients with stage III colon cancer: Find� ings from CALGB 89803. J Natl Cancer Inst 104:1702-1711, 2012. 2. O’Connor A: Can foods affect co� lon cancer survival? New York Times. November 9, 2012. 3. Meyerhardt JA, Niedzwiecki D, Hollis D, et al: Association of dietary patterns with cancer recurrence and sur� vival in patients with stage III colon can� cer. JAMA 298:754-764, 2007.

1

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

2

The code will scan automatically.

3

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

4

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


The ASCO Post  |   JANUARY 15, 2013

PAGE 102

In the Literature

Emerging Clinical Data on Cancer Management OVARIAN CANCER Screening and Risk-reduction without Testing Positive for BRCA Mutation Many women who do not test posi�

tive for a BRCA mutation undergo additional ovarian cancer screenings and risk-reducing procedures, despite limited data to determine the effec� tiveness of these interventions among an average-risk population. Results of

an analysis of data from 1,077 women who were surveyed at a median of 3.7 years after BRCA screening, were pub� lished online first by the Archives of Internal Medicine. The women were asked about their subsequent risk-reducing

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and screening interventions, including risk-reducing salpingo-oophorectomy, screening transvaginal ultrasonogra� phy, and screening serum cancer anti� gen 125 (CA-125). BRCA test results were categorized as positive (shown to carry known deleterious BRCA mutation) in 201 (18.7%) of these women, true-nega� tive (negative test result for a known deleterious family BRCA mutation) in 103 women (9.6%), and uninforma� tive negative (negative BRCA results without a known family mutation) or variant of undetermined significance (found to have a change in DNA that has unknown effects on BRCA protein function) in 773 women (71.8%). Women who tested positive as BRCA mutation carriers “were the most likely to receive aggressive in� terventions, with a 69.8% use of [riskreducing salpingo-oophorectomy] and a 28-fold higher odds of receiving [that procedure] compared with women with uninformative BRCA results,” the researchers reported. But many who were not identified as BRCA carriers also received aggressive interventions. “More than 70% of BRCA-tested women in this study—and in the United States—receive uninforma� tive results. In this understudied but important population, a substantial proportion underwent [salpingo-oo� phorectomy] (12.3%) and reported receiving ovarian cancer screening (30.2%) at least once in the preceding 3 years. Long-term ovarian cancer risk in women with uninformative BRCA results has not been carefully defined,” the researchers noted. “For most wom� en with uninformative BRCA results, salpingo-oophorectomy and ovarian cancer screening may not be appropri� ate, barring strong family histories of ovarian cancer.”

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Overall, 19.1% of eligible women underwent risk-reducing salpingooophorectomy and 39.6% percent used screening procedures. Women who received a positive BRCA test re� sult had increased odds of undergoing salpingo-oophorectomy, transvaginal ultrasound, and serum CA-125, while a true-negative BRCA result was asso� ciated with reduced odds of undergo� ing the three procedures. When the researchers compared screening rates in the preceding 3 years on the basis of


ASCOPost.com  |   JANUARY 15, 2013

PAGE 103

In the Literature BRCA results, they found that approxi� mately 69.6% of BRCA carriers, 30.2% percent of women with uninformative BRCA results, and 9.6% percent of women with true-negative BRCA re� sults reported having undergone ovar� ian cancer screening. The study “shows that genetic test� ing, even if negative, does not always allay deep-seated fears of cancer,” noted an accompanying commentary. “The challenge of the field is to identify persons needing additional or different treatment without scaring those who do not into additional interventions.” Mannis GN, et al: Arch Intern Med, December 17, 2012 (early release online). Grann V, Ashley-Thompson, M: Arch Intern Med. December 17, 2012 (early release online).

BREAST CANCER Analysis Suggests Screening Mammography Results in Substantial Overdiagnosis with Small Effect on Mortality An analysis of Surveillance, Epi� demiology, and End Results (SEER) data from 1976 through 2008 “sug� gests that whatever the mortality ben� efit, breast-cancer screening involved a substantial harm of excess detection of additional early-stage cancers that was not matched by a reduction in latestage cancers,” according to a report in The New England Journal of Medicine. “This imbalance indicates a consider� able amount of overdiagnosis involv� ing more than 1 million women in the past 3 decades—and, according to our best-guess estimate, more than 70,000 women in 2008 (accounting for 31% of all breast cancers diagnosed in women 40 years of age or older),” the authors wrote. The introduction of mammography has been associated with a large in� crease in early- stage breast cancer de� tected each year, from 112 to 234 can� cers per 100,000 women—an absolute increase of 122 cancers per 100,000 in the United States. There has also been a decrease in the cases of late-stage breast cancer—from 102 to 94 cases per 100,000. “With the assumption of a constant underlying disease burden, only 8 of the 122 additional early-stage cancers diagnosed were expected to progress to advanced disease. After excluding the transient excess incidence associat� ed with hormone-replacement therapy and adjusting for trends in the inci� dence of breast cancer among women

younger than 40 years of age, we esti� mated that breast cancer was overdi� agnosed (ie, tumors were detected on screening that would never have led to clinical symptoms) in 1.3 million U.S. women in the past 30 years,” the ana� lysts explained.

Serious Questions “Our study raises serious questions about the value of screening mam� mography,” the authors concluded. “It clarifies that the benefit of mortal� ity reduction is probably smaller, and the harm of overdiagnosis probably larger, than has been previously rec� ognized. And although no one can say with certainty which women have cancers that are overdiagnosed, there is certainty about what happens to them: They undergo surgery, radiation therapy, hormonal therapy for 5 years or more, chemotherapy, or (usually) a combination of these treatments for abnormalities that otherwise would not have caused illness. Proponents of screening should provide women with data from a randomized screening trial that reflects improvements in current therapy and includes strategies to miti� gate overdiagnosis in the intervention group. Women should recognize that our study does not answer the ques� tion ‘Should I be screened for breast cancer?’ However, they can rest as� sured that the question has more than one right answer.”

Bleyer A, Welch HG: N Engl J Med 367:1998-2005, 2012.

LUNG CANCER Volume-doubling Time May Help Distinguish Aggressive Cancer from Slow-growing Tumors Changes in the size of lung tumors over time, as measured by volumedoubling times on low-dose computed tomography, can be used to distin� guish aggressive lung cancer from slow-growing or indolent tumors and reduce overdiagnosis that could result in overtreatment and unnecessary morbidity. Results from a retrospec� tive estimation of volume-doubling times in a prospective low-dose com� puted tomography screening cohort also found that lung-cancer specific mortality was low among patients with slow-growing and indolent tumors. The study was published in the Annals of Internal Medicine. The nonrandomized single-center Continuous Observation of Smoking

Subjects (COSMOS) study recruited asymptomatic current or former heavy smokers (≥ 20  pack-years) aged 50 years and up who agreed to 5 consecu� tive years of low-dose computed to� mography. Of the 5,203 enrolled par� ticipants, 4,122 presented for all five annual scans. Of the 175 cases of primary lung cancer diagnosed, 55 were diagnosed at baseline (1.1% of the screened pop� ulation) and 120 were incident cancers detected during subsequent screen� ing rounds. Among those 120 cases, “the main focus of the study,” accord� ing to the authors, 19 (15.8%) were new (no nodule on previous scan) and fast-growing, with a median [volumedoubling time] of 52 days, and 101 (84.2%) had progressed from the year before, including 70 (58.3%) that were fast-growing and 31 (25.8%) that were slow-growing or indolent.

Major Results The median volume-doubling time was 223 for fast-growing and 545 days for slow-growing or indolent cancer. “The median [volume-doubling times] for adenocarcinomas (303 days) was significantly longer than that for squa� mous cell carcinomas (77 days) and cases of small cell cancer (70 days),” the researchers reported. “The main finding of our study is that [volume-doubling time] seems to be a plausible indicator of cancer ag� gressively in cases of incident cancer,” the authors wrote. Prognosis was high� ly favorable for cancers with a volumedoubling time of 200 or more days. “Another important finding of our study was that early diagnosis and early treatment, even of fast-growing cancer resulted in good long-term survival for our patients, most of whom had stage I disease at diagnosis, However, good

long-term survival must be balanced against the risk of invasive procedures for benign disease,” the authors added. In this study, 29 of the screened pa� tients who had surgical biopsy had be� nign disease. “Having identified potentially over� diagnosed lung cancer as slow-growing or indolent lesions, the problem of managing them remains,” the research� ers continued. In this study, all nod� ules suspicious for cancer were treated with surgical resection. The authors acknowledged, however, that “stan� dard resection (lobectomy with lymph node dissection) may be overtreat� ment for slow-growing or indolent lesions, most of which are minimally invasive adenocarcinomas,” and “a less-aggressive approach may be more appropriate.” The authors concluded that the vol� ume-doubling time analysis of cancers diagnosed after the initial screening “suggests that at least approximately 75% of detected cases were aggressive, downsizing the problem of overdiag� nosis. Among the 25% of slow-grow� ing or indolent cases, many are likely to have been overdiagnosed. To limit overtreatment in such cases, minimally invasive limited resection and nonsur� gical treatments should be investigated prospectively.” Veronesi G, et al: Ann Intern Med 157:776-784, 2012.

CHRONIC LYMPHOCYTIC LEUKEMIA Chlorambucil, but Not Fludarabine, Confers Significant Benefit in Older Patients with CLL Among patients aged 70 years and older with chronic lymphocytic

© Mike Twohy / The New Yorker Collection / www.cartoonbank.com

continued on page 104


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In the Literature Emerging Clinical Data continued from page 103

leukemia (CLL), “front-line therapy with fludarabine does not improve outcomes” compared to chlorambucil (Leukeran), according to an analysis of patients enrolled in successive frontline Cancer and Leukemia Group B (CALGB) studies 9011, 9712, 19901, and 10101. The findings also “suggest

rituximab [Rituxan] is beneficial re� gardless of age,” investigators reported in the Journal of Clinical Oncology. A total of 663 patients were evaluat� ed for response, progression-free sur� vival, and overall survival by age group. The regimens used in the CALGB tri� als included chlorambucil (Leukeran), fludarabine, fludarabine plus ritux� imab, fludarabine with consolidation

alemtuzumab (Campath), and fluda� rabine/rituximab with consolidation alemtuzumab. “When looking at [progressionfree survival] within each of the age groups (<� �������� �������� 70 vs ≥� ������������������� 70 ������������������� years), signifi� cant differences were seen among the treatment regimens (P  <  .001),” the researchers reported. The risk of pro� gression decreased 40% for patients

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

< 70 years treated with fludarabine compared to chlorambucil, but did not decrease among patients ≥  70 years. “In contrast, the addition of rituximab to fludarabine decreased the risk of progression by 44% relative to fludara� bine alone (hazard ratio [HR] = 0.56; 95% confidence interval [CI] = 0.43– .001) and did not have a dif� 0.74; P < ����������������������������� ferential effect on [progression-free survival] by age group (P = .55),” the investigators wrote.

Study Implications “Among younger patients, the risk of death when treated with fludarabine decreased by 31% compared with the risk when treated with chlorambucil,” the researchers added. “Although not reaching statistical significance, the risk of death in older patients was es� timated to be 45% higher when treated with fludarabine vs chlorambucil.” Adding rituximab to fludarabine im� proved overall survival among all pa� tients, with the risk of death decreas� ing an estimated 35%. Alemtuzumab consolidation did not provide progres� sion-free or overall survival benefits. These and other results show that “chlorambucil is a reasonable chemo� therapeutic backbone on which to de� sign new combination regimens” for older adults with CLL,” the authors concluded. “With recent data regard� ing the combination of chlorambucil and rituximab in older patients, this combination is certainly a standard therapeutic option for older patients and may be an ideal platform on which to add new targeted agents to improve efficacy. To effectively treat older pa� tients with CLL, new therapies and combinations are needed that are ef� fective yet tolerable even for those patients with comorbid medical con� ditions or limited performance status.” Woyach JA, et al: J Clin Oncol. December 10, 2012 (early release online).

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Four-plus Cups of Coffee Daily Linked to Lower Risk of Death from Oral/Pharyngeal Cancer Consuming four or more cups per day of caffeinated coffee could almost halve the risk of dying from oral/pharyngeal cancer compared to drinking no coffee or drinking it only occasionally, researchers reported in the American Journal of Epidemiology. “A dose-related decline in relative risk was observed with each single cup/day consumed,” the authors stated. “The


ASCOPost.com  |   JANUARY 15, 2013

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Perspective

War on Cancer continued from page 1

pean School of Oncology, founded in 1982 by Umberto Veronesi, MD, con� vened the World Oncology Forum, tasked with evaluating the evidence on whether we are really winning the war on cancer. Eighty experts from five continents and 20 scientific jour� nalists from leading newspapers and magazines gathered in Lugano, Swit� zerland, on October 26–27, 2012, to try to reach a verdict. This was an un� usual gathering, where clinicians and researchers sat alongside specialists in cancer epidemiology, prevention, health policy (and policy implemen� tation and advocacy), while the sci� entific journalists were invited to play devil’s advocate. Intense discussions were kicked off by five keynote lecturers: Paolo Vineis, MD, MPH, FFPH, London; Douglas Hanahan, PhD, Lausanne, Switzerland; Michel Coleman, MD, MSc, MFPHM, London; Sir Rich� ard Peto, MD, FRS, Oxford, UK; and Felicia Knaul, MA, PhD, Bos� ton. The final session, which aimed to secure a consensus statement encapsulating key points from the preceding debates, was charismati� cally moderated by Richard Horton, association was not modified by sex, smoking status, or alcohol use.” Using data from the American Cancer Society Cancer Prevention Study II, the researchers identified 868 deaths due to oral/pharyngeal cancer occurred during 26 years of follow-up among 968,432 men and women who were cancer-free at enrollment. Those who drank four or more cups (237 mL) of caffeinated coffee had “a 49% lower risk of relative to no/occasional coffee intake (relative risk [RR] = 0.51, 95% CI = 0.40, 0.64),” the researchers reported. “The relative risk for decaf� feinated coffee intake was lower among those with daily intake of > 2 cups/day, but the estimate was of marginal statis� tical significance” (RR = 0.61, 95% CI = 0.37—1.01), the investigators add� ed. There was no association found for drinking tea. “Coffee, one of the most commonly consumed beverages worldwide, con� tains a variety of antioxidants, poly� phenols, and other biologically active compounds that may help to protect against development or progression of cancer,” the authors wrote. “The strong inverse association between fatal oral/

BSc, MB, FRCP, FMedSci, Editorin-Chief of The Lancet.

Nuanced Assessment So what was the verdict? First of all it was felt that the phrase “war on can� cer” should be abandoned, since this military terminology precludes a more nuanced assessment of the situation. Important progress has been made in extending survival and improving

rent trends the annual number of new cases is almost doubling over 25 years, and is set to reach 22 million new cases a year by 2030.2 These estimates assume no change in the risk pattern of cancer incidence. A yearly increase of 1% would add roughly another million cases a year.3 While 25 years ago, developing countries accounted for around one half of all new cancers, close to two-thirds of the cancer cases predicted for 2030 will

Notwithstanding many partial successes and the exponential increase in our knowledge of cancer biology—and regardless of the terminology used—the statistics tell a clear story of an escalating crisis that current strategies are failing to adequately address. —Franco Cavalli, MD, FRCP

patients’ quality of life, which the di� chotomy of “victory” or “defeat” fails to reflect. Furthermore, a war can only be won or lost, but cancer is many different diseases, and during the past decades, progress has been spectacular in some cancers (eg, testicular, early breast, pe� diatric), while in many others it has been only marginal or nonexistent. Taking all cancers together, on cur�

occur in low-income countries. This shift in cancer risk is occurring because, in developing countries, tu� mors related to Western lifestyles (eg, breast cancer, lung cancer, colorectal cancer) are accumulating in addition to poverty-linked tumors (eg, cervical cancer). This shift is particularly evi� dent in countries in rapid societal and economic transition, with reductions

pharyngeal cancer and caffeinated cof� fee observed in our study augments the epidemiologic literature on this topic,” they noted.

��������������� .001). In addi� death (HR = 0.695; P <���������������� tion, there is “no emerging safety signal for second primary malignancies fol� lowing VMP,” investigators reported in the Journal of Clinical Oncology. A total of 682 patients at 151 sites in 22 countries were randomly assigned to receive up to nine 6-week cycles of VMP or MP and were then observed every 12 weeks or less. The overall me� dian age was 71 years. “[Overall survival] benefit with VMP was seen across prespecified patient subgroups (age ≥  75 years, stage� ������������������������������ ������������������������������ III myeloma, creatinine clear� ance <  60 mL/min),” the researchers reported. “However, no significant difference was observed in the small subgroup with documented high-risk cytogenetics (n = 46).” Most patients (63% of the VMP group and 73% of the MP group) re� ceived subsequent therapy. The me� dian time to next therapy was longer in the VMP group, 30.7 months vs 20.5 months in the MP group (HR = 0.557, .001). “Among patients who re� P  < ������������������������������ ceived subsequent therapies, survival from start of subsequent therapy was similar following VMP (median, 28.1

Hildebrand JS, et al: Am J Epidemiol. December 9, 2012 (early release on line).

MULTIPLE MYELOMA Persistent Survival Benefit in Patients with Untreated Disease Treated with Bortezomib Added to Melphalan and Prednisone A final analysis of the phase III VIS� TA trial (Velcade as Initial Standard Therapy in Multiple Myeloma: Assess� ment with Melphalan and Prednisone) found a persistent significant benefit in overall survival with VMP (bortezo� mib, melphalan, prednisone) vs MP (melphalan, prednisone) in patients with multiple myeloma who were in� eligible for transplantation. At a me� dian follow-up of 60.1 months (range, 0–74 months), median overall survival was 56.4 months for patients receiv� ing VMP vs 43.1 months for patients receiving MP, a 31% reduced risk of

in infections and infection-related can� cers offset by increasing numbers of cancers associated with reproductive, smoking, dietary, metabolic, and hor� monal factors.4

Mortality Trends The much lower cure rate in low-in� come countries means that, on a global scale, the fatality ratio is set to worsen. Poorer countries account for 85% of deaths from cervical cancer; the cure rate for breast cancer in Gambia and similar countries is below 15%; in the poorest 25 countries, pediatric cancers are fatal in 90% of cases, in contrast to the richest countries, where 90% of children now survive. This explains why at least 13 million cancer deaths are predicted for 2030, compared to about 7 million in 2008. In the developed world, by con� trast, while the annual rate of new cancers is steadily rising, mortality trends have been falling for some time. Better early detection and more effec� tive treatments are contributory fac� tors but play a smaller role than might have been hoped, as Prof. Peto demon� strated. Focusing on men in the 35- to 69-year-old age group, he showed that, in the United Kingdom, it was the continued on page 106

months) or MP (median, 26.8 months; HR = 0.914),” the authors wrote. “Incidence proportions of all malig� nancies and of fatal hematologic malig� nancies and solid tumors were similar between arms,” the researchers report� ed. “Nineteen (6%) of 327 patients in the VMP arm and 13 (4%) of 328 pa� tients in the MP arm reported second primary malignancies. Three patients (1%) in each arm had hematologic malignancies: Two patients in each arm had acute myeloid leukemia (fatal in all four patients), one patient in the MP arm had B-cell non-Hodgkin lym� phoma that was fatal, and one patient in the VMP arm had myelodysplastic syndrome.” The authors concluded that the fi� nal findings of the VISTA phase��������� �������� III tri� al “demonstrate a persistent significant [overall survival] benefit with VMP vs MP. These data are highly robust be� cause of the large patient population and lengthy follow-up and show that VMP resulted in a substantial longterm [overall survival] benefit, with a 13.3-month increase in the median.” n San Miguel JF, et al: J Clin Oncol, December 10, 2012 (early release online).


T:10.25" S:9.5" PAGE 106

The ASCO Post  |   JANUARY 15, 2013

Perspective

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

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

War on Cancer continued from page 105

drop in deaths from smoking-related cancers—from more than 240 per 100,000 in 1965 to only around 80 per 100,000 in 2010—that accounted for almost all the improvement in cancer mortality rates over that period.

Search for a Cure At the World Oncology Forum, there was a strong consensus that searching for ways to cure cancer re� mains a priority. However, current strategies, which rely heavily on pat� ents and short-term shareholders’ val� ue to develop new cancer therapies, are proving unsustainable; the costs of the new generation of drugs is get� ting out of all proportion to the added benefit. Some participants proposed raising the bar for new compounds to get access to the market, to halt the current trend toward performing ever-larger trials, chasing smaller and smaller benefits that might then be statistically, but not clinically, signifi� cant. So notwithstanding many partial successes and the exponential increase in our knowledge of cancer biology— and regardless of the terminology used—the statistics tell a clear story of an escalating crisis that current strate� gies are failing to adequately address.5 Following the 2011 United Nations Summit on Non-Communicable Dis� eases, governments of the world are already committed to cutting by 25% the number of preventable deaths by 2025. This would mean cutting at least 2 million deaths from cancer. To achieve this goal, and in line with the World Cancer Declaration,6 the World Oncology Forum is calling on govern� ments, policymakers, and all those who can help stop these unnecessary

deaths to commit to 10 key strategic points of action.

Future Publications The full World Oncology Forum statement will be published on Febru� ary 4th, World Cancer Day, in the International Herald Tribune under the heading “Stop Cancer Now,” and con� comitantly in Cancer World and to� gether with an editorial in The Lancet. The most important keynote lectures will also be published in The Lancet at a later date. The European School of Oncology may reconvene the World Oncology Forum in Milan in 2 years time, taking advantage of the city’s hosting of the 2015 World Exposi� tion, to evaluate progress in turning the tide against cancer. n Disclosure: Dr. Cavalli reported no potential conflicts of interest.

References 1. De Vita T: A personal note 40 years after the signing of the Cancer Act. Jr Nat Rev Clin Oncol 8:693-694, 2011. 2. Bray F, Jemal A, Grey N, et al: Global cancer transitions according to the Hu� man Development Index (2008-2030): A population-based study. Lancet Oncol 13:790-801, 2012. 3. Cavalli F: Cancer in the develop� ing world: Can we avoid the disaster? Nat Clin Pract Oncol 3:582-583, 2006. 4. Sankaranarayanan R, Swaminathan R, Brenner H, et al: Cancer survival in Africa, Asia and Central America: a popu� lation-based study. Lancet Oncol 11:165173, 2010. 5. Farmer P, Frenk J, Knaul FM, et al: Expansion of cancer care and control in countries of low and middle income: A call to action. Lancet 376:1186-1193, 2010. 6. Cavalli F: The World Cancer Decla� ration: A roadmap for change. Lancet On� col 9:810-811, 2008.

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication.

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. 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).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including

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 4198  patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑88  years (median 60 years), 43.6% male and 83.8% white. The population included 1783  first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9  doses of Avastin, and 337  mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363  patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.


T:10.25" S:9.5" AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60  days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 5, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 7 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

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.

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 signficantly 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

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

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

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

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

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

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

0%

5%

20%

26%

19%

5%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 5 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 7. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving

a

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 4, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] 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 7, 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 (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

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

11/12 AVA0000765903 10127310 Initial U.S. Approval: February 2004 Code Revision Date: November 2012 Avastin® is a registered trademark of Genentech, Inc. © 2012 Genentech, Inc.

S:12.5"

Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 7). [See Warnings and Precautions (5.8).]

a

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 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 5, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

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

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


To confront the threat of angiogenesis in first-line metastatic non-squamous NSCLC…

Think Avastin

Because survival matters most

Percentage Surviving

Avastin plus PC significantly increased median OS by 19% (12.3 vs 10.3 months with PC alone) in Study E45991 100

1-year survival: 51% vs 44%2

80

2-year survival: 23% vs 15%2

60 40

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

20 0

10

20

30

40

50

OS (Months) Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68– 0.94], P=0.013).1 Clinically meaningful 1- and 2-year survival rates were demonstrated with Avastin plus PC (51% and 23%, respectively, vs 44% and 15% with PC alone).2

Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%).2

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

Indication

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.

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%)

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

In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/ pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

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. References: 1. Avastin Prescribing Information. Genentech, Inc. November 2012. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

©2012 Genentech USA, Inc.

All rights reserved.

AVA0000400602

Printed in USA.

(11/12)

www.avastin.com

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