TAP Vol 2 Issue 18 by Harborside Press LLC

HER2-positive breast cancer 3

Electronic health records 49-51

VOLUME 2, ISSUE 18

FDA drug approvals 2011 9, 14, 40

DECEMBER 15, 2011

ASCOPost.com

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

News

FDA Announces Bevacizumab Decision: Agency Will Revoke Breast Cancer Indication Drug not shown to be safe and effective in breast cancer patients, FDA concludes

n November 18, FDA Commissioner Margaret A. Hamburg, MD, said she is revoking the agency’s approval of the breast cancer indication for bevacizumab (Avastin) after concluding that the drug has not been shown to be safe and effective for that use. Bevacizumab will remain on the market as an approved treatment for certain types of colon, lung, kidney, and brain cancers (glioblastoma multiforme).

No Evidence of Benefit “After reviewing the available studies it is clear that women who take [bevacizumab] for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of [bevacizumab] will SEE PAGE 68 provide a benefit, in terms of de-

By Joshua Spendlove, MD, and E. David Crawford, MD

lay in tumor growth, that would justify those risks. Nor is there evidence that use of [bevacizumab] will either help them live longer or improve their quality of life,” Dr. Hamburg said. Bevacizumab’s risks inMargaret A. Hamburg, MD clude severe high blood pressure, bleeding and hemorrhaging, heart attack or heart failure, and the development of perforations in different parts of the body such as the nose, stomach, and intestines. The decision, outlined in Dr Hamburg’s 69-page opinion, involves bevacizumab used in combination with paclitaxel for patients who have not been treated with chemotherapy for metastatic HER2-negative

rostate cancer is the most prevalent nonskin cancer in men. An estimated 16% of men are diagnosed with prostate cancer, yet only 3% of men die from it.1 Unlike other cancers, prostate cancer is associated with a prolonged lead-time, meaning it can take anywhere from 5 to 12 years to become apparent. In addition, there are many forms of prostate cancer that are indolent in nature, being present for years without showing any signs of growth or invasion. In fact, autopsy studies have found that up to 70% of 80-yearold men who died of other causes have prostate cancer.2 Separating men with relatively indolent disease from those with clinically significant disease is the current challenge—a challenge that

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Expert’s Corner

A Conversation with Ezekiel J. Emanuel, MD, PhD How medical ethics and public health-care policy are converging in oncology By Jo Cavallo

Prostate Cancer Screening Reconsidered

Dr. Spendlove is a Resident in Urology at the University of Colorado, Denver. Dr. Crawford is Head of the Section of Urologic Oncology and Professor of Urologic and Radiation Oncology, University of Colorado, Denver.

MORE IN THIS ISSUE

ast September, Ezekiel J. Emanuel, MD, PhD, a leading scholar in bioethics and health-care policy, was named the Diane v.S. Levy and Robert M. Levy University Professor and Vice Provost for Global Initiatives at the University of Pennsylvania

in Philadelphia. His appointment will be shared between the newly created Department of Medical Ethics & Health Policy and the Department of Health Care Management in the Wharton School. A long-time proponent of health-care reform, Dr. Emanuel was a member of the Healthcare Task Force during the Clinton Administration, focusing on the issues of biomediIf you have two equally cal ethics, and later became Chair of the effective treatments and Department of Bioethics at the Clinical Center of the National Institutes of an insurer pays only for the Health, where he trained physicians in the cheaper one, is that rationing ethics of human medical research and incare? And if so, is that a vestigated the ethics of managed care and end-of-life care. In 2009, Dr. Emanuel beproblem? came special advisor for health policy in the White House Office of Management —Ezekiel J. Emanuel, MD, PhD

Oncology Meetings Coverage Pan-Pacific Lymphoma Conference �� 15 2011 European Multidisciplinary Cancer Congress �� 18, 20, 56, 59 American College of Surgeons Annual Congress �� 25 ASCO HIT/EHR Symposium ��49, 50 Direct from ASCO �� 33 Opinion: Medicare Reimbursement �� 71

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A Harborside Press® Publication

The ASCO Post | DECEMBER 15, 2011

PAGE 2

Opinion

Prostate Cancer Screening Reconsidered continued from page 1

Editorial Board James O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center 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 Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology 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 Michael P. Link, MD Stanford University Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center William T. McGivney, PhD National Comprehensive Cancer Network James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina 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 Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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we are still long strides away from overcoming. Screening for prostate cancer aims to detect cancer early enough that treatment can be initiated, to reduce the mortality associated with prostate cancer. However, with screening comes overdiagnosis, and with overdiagnosis comes overtreatment.

No Definitive Values

associated prevalence is 17% for PSA values between 1.1 and 2 ng/mL.3 Early observational studies were aimed at finding out the role of prostate cancer screening. However, many were not well designed and only fueled the debate, with some studies showing no difference in outcome and others showing a modest benefit.4 Two large randomized trials were organized to try and answer the question of screening for prostate cancer.

Screening for prostate cancer reRandomized Trials The Prostate, Lung, Coloreclies on the measurement of serum tal and Ovarprostate-specific ian (PLCO) trial antigen (PSA) to The utility of screening involved over predict the chance and diagnosing prostate 76,000 men from of malignancy. Results are intercancer clearly deteriorates multiple centers across the Unitpreted in a conwith increasing age. ed States. These tinuum of risk.1 There is no definimen, aged 55 to tive value that pre74 years, were dicts with certainty the risk of canrandomly assigned to annual PSA cer. A value of 4 ng/mL is commonly blood tests and digital rectal exams, used as a cutoff for recommending or usual care. After 7 years of followbiopsy; however, extremely low PSA up, more cases of cancer were found levels have been noted with aggresin the screened group than in the sive cancers, and benign conditions control group, as would be expected. such as benign prostatic hyperplaHowever, the results also showed no sia and prostatitis can cause higher benefit and, in fact, possibly some PSA levels. In 2005, Thompson et degree of harm in population screenal determined that there is no “safe” ing for prostate cancer. PSA value, as the prevalence of prosThe other large randomized trial tate cancer associated with a PSA was the European Randomized Study continued on page 74 < 0.5 ng/mL is almost 7%, and the The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2011 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. 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The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

ASCOPost.com | DECEMBER 15, 2011

PAGE 3

Expert’s Corner Breast Cancer

Optimizing HER2-directed Therapy in the Clinic A Conversation with Edith A. Perez, MD By Caroline Helwick asked Dr. Perez to share her approach to HER2-directed therapy.

Testing Considerations Which test do you rely on to determine HER2 status and to select patients for anti-HER2 treatment? My group recently looked for associations between certain tumor characteristics—HER2 protein expression, HER2 gene and chromosome 17 copy number, hormone receptor status—and disease-free survival in the NCCTG N9831 adjuvant trastuzumab (Herceptin) population.1 We confirmed that either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) testing is appropriate for patient selection for trastuzumab. You don’t need both tests

Edith A. Perez, MD

eminal research in the treatment of HER2-positive breast cancer has been led by Edith A. Perez, MD, the Serene M. and Frances C. Durling Professor of Medicine at the Mayo Clinic, Jacksonville, Florida. The ASCO Post

100%

92.4%

80%

86.8%

Event-free

60%

88.0%

85.7%

79.0%

73.7%

40% 20%

AC AC

T+H T

Time from random assignment (years) No. at risk AC T+H AC T

1,952 1,881

1,756 1,652

97.7%

100%

891 702

95.1%

96.1%

80%

Alive

1,300 1,132

495 395

93.0%

92.7%

85.6%

60% 40% 20% 0

AC AC

T+H T

Time from random assignment (years) No. at risk AC T+H AC T

1,991 1,960

1,875 1,816

1,420 1,375

976 886

554 503

Fig. 1: Kaplan-Meier estimates of (A) event-free survival and (B) overall survival in the NCCTG N9831 trial. Disease events include local, regional, or distant recurrence; contralateral breast cancer; second primary cancers; or death as a result of any cause. Overall survival is measured from the time of study enrollment to last contact or death. AC = doxorubicin and cyclophosphamide; H = trastuzumab; T = paclitaxel. Reprinted with permission from Perez EA, et al: J Clin Oncol 29:3366-3373, 2011. Copyright © 2011 by the American Society of Clinical Oncology. All rights reserved. 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

if one is positive. We also found that HER2-positivity, so ER status is reltrastuzumab benefit seems indepenevant. But the degree of gene amplident of HER2/centromere 17 ratio fication, c-myc, polysomy 17, insulin and chromosome 17 copy number. growth factor receptor, and PTEN do There has been confusion regardnot appear to be predictive of a benefit ing the recommendation from ASCO from adjuvant trastuzumab. and the College of American PatholoTreatment Regimens gists against withholding anti-HER2 What do you consider to be the optitreatment in patients with equivocal mal adjuvant anti-HER2 regimen? HER2 test results falling within ranges In deciding upon a chemotherapy that qualified patients for the first adjubackbone, I consider the patient’s overvant HER2-targeted trials (ie, the FDA all condition. My first choice is usually guidelines). Research from our group an anthracycline-based regimen, due can add to this discussion. We will to the totality of the soon be publishing data from multiple data from N9831, The curves continue trials (NCCTG showing the imto diverge, showing the N9831, NSABP portance of using B-31, HERA, Finan IHC > 10% or long-term impact of HER, PACS04). a FISH ratio ≥ 2.0 anti-HER2 therapy, but at I consider a non– (not > 2.2) as the relevant cutoffs the same time we are not a n t h r a c y c l i n e based regimen, ie, for adjuvant anticuring all our patients. TCH (docetaxel/ HER2 therapy.2,3 carboplatin/trastuWhen do you retest patients for HER2 zumab), as a second-best alternative, expression? based on data from BCIRG 006. We know there are patients who are IHC0 or IHC1+ but have some HER2 Do you favor sequential or concurrent gene amplification, and some may use of trastuzumab with chemotherapy, benefit from anti-HER2 treatment. We and how long should trastuzumab be need to determine who they are. Exgiven? panded reflex testing, in which we reN9831 is comparing trastuzumab test patients whose tumors are IHC0, given for 52 weeks following 12 weeks IHC1+, or FISH-negative (using the of paclitaxel (sequential treatment) opposite test), can help do this. to concurrent trastuzumab plus pacliWe performed an analysis of extaxel. We are seeing that the “hazard of panded reflex testing and estimated disease events” (recurrences, contralatthat 3% of retested patients would be eral breast cancer, second primaries, or HER2-positive.4 We also found the death) is much lower, at least numericost-effectiveness ratio of expanded cally, with the concurrent approach. reflex testing in the adjuvant setting to Disease-free survival at 5 years is be below commonly cited thresholds. 84.2% with concurrent treatment and This strategy could reduce the number 79.8% with sequential treatment. Givof inappropriately classified tumors ing trastuzumab concurrently, thereand identify an additional 4,700 pafore, should produce better outcomes. tients per year who might benefit from One year of trastuzumab therapy is adjuvant trastuzumab. still recommended, but shorter and longer durations of treatment are curAre there other tumor markers that rently being studied. should be considered in making decisions It is gratifying to see the longabout anti-HER2 therapy? term benefit of adjuvant trastuzumab We know that estrogen receptor emerging. We recently published our (ER)-positive tumors are associated 4-year follow-up of the joint analysis continued on page 6 with better outcomes in the setting of 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.

In Advanced Renal Cell Carcinoma...

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

Important Safety Information WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Effects: Patients with pre-existing hepatic impairment should use VOTRIENT with caution. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the ﬁrst 18 weeks). Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of

electrolytes within the normal range should be performed. • Hemorrhagic Events: Fatal hemorrhagic events have been reported (all Grades [16%] and Grades 3 to 5 [2%]). VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. • Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack (all Grades [3%] and Grades 3 to 5 [2%]) were observed. Use with caution in patients who are at increased risk for these events. • Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula. • Hypertension: Hypertension, including hypertensive crisis, has been observed. Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed. Hypertension was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite

Move Forward With VOTRIENT In a phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided signiﬁcant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 1,3

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

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

9.2 months (95% CI, 7.4-12.9)

NCCN Guidelines® Category 1 recommendation4 • As a ﬁrst-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology . These Guidelines also include therapies other than VOTRIENT as ﬁrst-line treatment options

WARNING: HEPATOTOXICITY

Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

VOTRIENT: Safety Proﬁle Summary1 • Most common adverse events observed with VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting — Grade 3/4 fatigue occurred in 2% of patients; all grades, 19% of patients — Grade 3/4 asthenia occurred in 3% of patients; all grades, 14% of patients • For any individual adverse reaction in the VOTRIENT arm, the rate of Grade 3/4 adverse events is ≤4%

Most common laboratory abnormalities were ALT and AST increases1 • Grade 3 ALT increases occurred in 10% of patients; grade 4, 2% of patients • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the ﬁrst 18 weeks of treatment with VOTRIENT • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the ﬁrst 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

anti-hypertensive therapy and dose reduction of VOTRIENT. • Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported as an adverse reaction in 26/586 (4%). Monitoring of thyroid function tests is recommended. • Proteinuria: Monitor urine protein. Proteinuria was reported in 44/586 (8%) (Grade 3, 5/586 [<1%] and Grade 4, 1/586 [<1%]). Baseline and periodic urinalysis during treatment is recommended. Discontinue for Grade 4 proteinuria. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Drug Interactions: CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin): Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors. • CYP3A4 Inducers (such as rifampin): Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. • CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

• Adverse Reactions: The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs. 9%), hypertension (40% vs. 10%), hair color changes (depigmentation) (38% vs. 3%), nausea (26% vs. 9%), anorexia (22% vs. 10%), and vomiting (21% vs. 8%). • Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in the VOTRIENT arm versus placebo included increases in ALT (53% vs. 22%), AST (53% vs. 19%), glucose (41% vs. 33%), and total bilirubin (36% vs. 10%); decreases in phosphorus (34% vs. 11%), sodium (31% vs. 24%), magnesium (26% vs. 14%), and glucose (17% vs. 3%); and leukopenia (37% vs. 6%), neutropenia (34% vs. 6%), thrombocytopenia (32% vs. 5%), and lymphocytopenia (31% vs. 24%). • VOTRIENT has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (<1%). Please see Brief Summary of Prescribing Information on adjacent pages. References: 1. VOTRIENT Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061–1068. 3. Data on ﬁle, GlaxoSmithKline. 4. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.1.2012. © National Comprehensive Cancer Network, Inc 2011. All rights reserved. Accessed November 17, 2011. 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.

www.VOTRIENT.com

The ASCO Post | DECEMBER 15, 2011

PAGE 6

Expert’s Corner

Edith A. Perez, MD continued from page 3

of N9831 and B-31 (see sidebar on page 8), which showed 5-year diseasefree survival to be 85.7% for AC→T+H (doxorubicin/cyclophosphamide, followed by paclitaxel plus trastuzumab), vs 73.7% for AC→T, and overall surviv-

al rates of 93% vs 85.6%, respectively (see Fig. 1 on page 3). The curves continue to diverge, showing the longterm impact of anti-HER2 therapy, but at the same time we are not curing all our patients. We still have work to do. What are your recommendations for

managing metastatic disease? I recommend rebiopsying the tumor to assay ER and HER2 status. And I use combinations in most patients, as opposed to single-agent trastuzumab or lapatinib (Tykerb), which are associated with insufficient response rates. These regimens are often taxane-based

BRIEF SUMMARY VOTRIENT (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT™ is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure. [See Clinical Pharmacology (12.3) of full prescribing information.] If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. The dose of VOTRIENT should not exceed 800 mg. Hepatic Impairment: The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day. There are no data in patients with severe hepatic impairment; therefore, use of VOTRIENT is not recommended in these patients. [See Use in Specific Populations (8.6).] Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. [See Drug Interactions (7.1).] Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who can not avoid chronic use of strong CYP3A4 inducers. [See Drug Interactions (7.1).] 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Effects: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed [see Adverse Reactions (6.1)]. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Across all monotherapy studies with VOTRIENT, ALT >3 X upper limit of normal (ULN) was reported in 138/977 (14%) and ALT >8 X ULN was reported in 40/977 (4%) of patients who received VOTRIENT. Concurrent elevations in ALT >3 X ULN and bilirubin >2 X ULN regardless of alkaline phosphatase levels were detected in 13/977 (1%) of patients. Four of the 13 patients had no other explanation for these elevations. Two of 977 (0.2%) patients died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. The safety of VOTRIENT in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT, is unknown. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. [See Dosage and Administration (2.2) and Use in Specific Populations (8.6).]

(such as weekly paclitaxel/carboplatin). Other options are trastuzumab, vinorelbine plus trastuzumab, and aromatase inhibitors plus lapatinib or trastuzumab. For refractory metastatic disease, the essence of management is to continue the anti-HER2 therapy. Good

5.2 QT Prolongation and Torsades de Pointes: In clinical RCC studies of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 11/558 (<2%) of patients. Torsades de pointes occurred in 2/977 (<1%) of patients who received VOTRIENT in the monotherapy studies. In the randomized clinical trial, 3 of the 290 patients receiving VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Hemorrhagic Events: In clinical RCC studies of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) and Grades 3 to 5 (2%)]. Fatal hemorrhage has occurred in 5/586 (0.9%) [see Adverse Reactions (6.1)]. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.4 Arterial Thrombotic Events: In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack [all Grades (3%) and Grades 3 to 5 (2%)] were observed. Fatal events have been observed in 2/586 (0.3%). In the randomized study, these events were observed more frequently with VOTRIENT compared to placebo [see Adverse Reactions (6.1)]. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months and should not be used in those patients. 5.5 Gastrointestinal Perforation and Fistula: In clinical RCC studies of VOTRIENT, gastrointestinal perforation or fistula has been reported in 5 patients (0.9%). Fatal perforation events have occurred in 2/586 (0.3%). Monitor for symptoms of gastrointestinal perforation or fistula. 5.6 Hypertension : In clinical studies, events of hypertension including hypertensive crisis have occurred. Blood pressure should be well-controlled prior to initiating VOTRIENT. Patients should be monitored for hypertension and treated as needed with anti-hypertensive therapy. Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). [See Adverse Reactions (6.1).] In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced [see Dosage and Administration (2.2)]. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. 5.7 Wound Healing: No formal studies on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.8 Hypothyroidism: In clinical RCC studies of VOTRIENT, hypothyroidism reported as an adverse reaction in 26/586 (4%) [see Adverse Reactions (6.1)]. Proactive monitoring of thyroid function tests is recommended. 5.9 Proteinuria: In clinical RCC studies with VOTRIENT, proteinuria has been reported in 44/586 (8%) [Grade 3, 5/586 (<1%) and Grade 4, 1/586 (<1%)] [see Adverse Reactions (6.1)]. Baseline and periodic urinalysis during treatment is recommended. VOTRIENT should be discontinued if the patient develops Grade 4 proteinuria. 5.10 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. [See Use in Specific Populations (8.1).] 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, hemorrhagic events, arterial thrombotic events, gastrointestinal perforation and fistula, and hypertensive crisis [see Warnings and Precautions (5.1-5.5)]. The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy studies which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and

ASCOPost.com | DECEMBER 15, 2011

PAGE 7

Expert’s Corner

There is a strong push to identify specific molecular markers and further define the signaling pathways in HER2 disease. We are also looking for immune correlates and multigene signatures using next-generation sequencing. We are validating assays for P95, extracellular cleaved HER2 that lacks

options include capecitabine (Xeloda) plus trastuzumab or lapatinib, trastuzumab plus lapatinib, vinorelbine plus trastuzumab, and others.

Looking Ahead What does the future hold for HER2directed therapy?

vomiting. The data described below reﬂect the safety proﬁle of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebocontrolled study [see Clinical Studies (14) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received VOTRIENT

Adverse Reactions Diarrhea Hypertension Hair color changes Nausea Anorexia Vomiting Fatigue Asthenia Abdominal pain Headache a

VOTRIENT

Placebo

(N = 290)

(N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 52 3 <1 9 <1 0 40 4 0 10 <1 0 38 <1 0 3 0 0 26 <1 0 9 0 0 22 2 0 10 <1 0 21 2 <1 8 2 0 19 2 0 8 1 1 14 3 0 8 0 0 11 2 0 1 0 0 10 0 0 5 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N = 290)

Parameters Hematologic Leukopenia Neutropenia Thrombocytopenia Lymphocytopenia Chemistry ALT increased AST increased Glucose increased Total bilirubin increased Phosphorus decreased Sodium decreased Magnesium decreased Glucose decreased a

Placebo (N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 37 34 32 31

0 1 <1 4

0 <1 <1 <1

6 6 5 24

0 0 0 1

0 0 <1 0

53 53

10 7

2 <1

22 19

1 <1

0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

the trastuzumab-binding domain and thus may be a source of trastuzumab resistance. For treatment in the adjuvant setting, we are seeing encouraging data for pertuzumab, and in the metastatic setting, the novel T-DM1 drug-antibody conjugate is excit-

Hepatic Toxicity: In a controlled clinical study with VOTRIENT for the treatment of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of signiﬁcant alkaline phosphatase >3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See Dosage and Administration (2.2) of full prescribing information and Warnings and Precautions (5.1).] Hypertension: In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on placebo experienced hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) on placebo. The majority of cases of hypertension were manageable with anti-hypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment with VOTRIENT because of hypertension. VOTRIENT has been associated with hypertensive crisis in patients with various cancer types including RCC. In the overall safety population for RCC (N = 586), one patient had hypertensive crisis on VOTRIENT. [See Warnings and Precautions (5.6).] QT Prolongation and Torsades de Pointes: In a controlled clinical study with VOTRIENT, QT prolongation (≥500 msec) was identiﬁed on routine electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT compared with no patients on placebo. Torsades de pointes was reported in 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings and Precautions (5.2).] Arterial Thrombotic Events: In a controlled clinical study with VOTRIENT, the incidences of arterial thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See Warnings and Precautions (5.4).] Hemorrhagic Events: In a controlled clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See Warnings and Precautions (5.3).] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) patients treated with VOTRIENT. Hypothyroidism: In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range at any post-baseline visit in VOTRIENT compared with the placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. [See Warnings and Precautions (5.8).] Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Proteinuria: In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. [See Warnings and Precautions (5.9).] Lipase Elevations: In a single-arm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients (<1%). Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%). 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations. A dose reduction for VOTRIENT should be considered when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers can not be avoided [see Dosage and Administration (2.2)].

ing. In a phase II trial, T-DM1 was associated with a 41% reduction in disease progression, compared with standard care, and a median diseasefree survival exceeding 14 months.5 It is being studied in the first-line setting in the large (n = 1,092) phase III continued on page 9

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; DECEMBER 15, 2011

PAGE 8

Expertâ&#x20AC;&#x2122;s Corner

Adding Trastuzumab to Adjuvant Chemotherapy By Charlotte Bath

dding trastuzumab (Herceptin) to adjuvant chemotherapy significantly improved disease-free survival of patients with resected stage I to III inva-

sive HER2-positive breast cancer in the phaseÂ III North Central Cancer Treatment Group (NCCTG) N9831 trial. There was also a trend toward a further

7.2 Effects of Pazopanib on CYP Substrates Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. [See Clinical Pharmacology (12.3) of full prescribing information.] 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.10)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of â&#x2030;Ľ3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossiďŹ cation. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses â&#x2030;Ľ3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses â&#x2030;Ľ30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses â&#x2030;Ľ100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses â&#x2030;Ľ3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses â&#x2030;Ľ3 mg/ kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 196 subjects (33%) were aged â&#x2030;Ľ65 years, and 34 subjects (6%) were aged >75 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these subjects and younger subjects. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identiďŹ ed differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully established. In clinical studies for VOTRIENT, patients with total bilirubin â&#x2030;¤1.5 X ULN and AST and ALT â&#x2030;¤2 X ULN were included [see Warnings and Precautions (5.1)]. An interim analysis of data from 12 patients with normal hepatic function and 9 with moderate hepatic impairment showed that the maximum tolerated dose in patients with moderate hepatic impairment was 200 mg per day [see Clinical Pharmacology (12.3) of full prescribing information]. There are no data on patients with severe hepatic impairment [see Dosage and Administration (2.2)]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/ moderate renal impairment (creatinine clearance â&#x2030;Ľ30 mL/min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to signiďŹ cantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/ min) did not inďŹ&#x201A;uence clearance of pazopanib. Therefore, renal impairment is not expected to inďŹ&#x201A;uence pazopanib exposure, and dose adjustment is not necessary.

increase in disease-free survival when trastuzumab was administered concurrently rather than sequentially. â&#x20AC;&#x153;On the basis of a positive risk-benefit

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no speciďŹ c antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not signiďŹ cantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages â&#x2030;Ľ30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses â&#x2030;Ľ10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given â&#x2030;Ľ100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given â&#x2030;Ľ300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses â&#x2030;Ľ3 mg/kg/day, epididymal sperm concentrations at doses â&#x2030;Ľ30 mg/kg/ day, and sperm motility at â&#x2030;Ľ100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaďŹ&#x201A;et that accompanies the product. However, inform patients of the following: t 5IFSBQZ XJUI 7053*&/5 NBZ SFTVMU JO IFQBUPCJMJBSZ MBCPSBUPSZ abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the ďŹ rst 4 months of treatment or as clinically indicated. Inform patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away. t ZFMMPXJOH PG UIF TLJO PS UIF XIJUFT PG UIF FZFT KBVOEJDF t VOVTVBM EBSLFOJOH PG UIF VSJOF t VOVTVBM UJSFEOFTT t SJHIU VQQFS TUPNBDI BSFB QBJO t (BTUSPJOUFTUJOBM BEWFSTF SFBDUJPOT TVDI BT EJBSSIFB OBVTFB BOE WPNJUJOH have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. t 8PNFO PG DIJMECFBSJOH QPUFOUJBM TIPVME CF BEWJTFE PG UIF QPUFOUJBM IB[BSE to the fetus and to avoid becoming pregnant. t 1BUJFOUT TIPVME CF BEWJTFE UP JOGPSN UIFJS IFBMUIDBSF QSPWJEFST PG BMM concomitant medications, vitamins, or dietary and herbal supplements. t 1BUJFOUT TIPVME CF BEWJTFE UIBU EFQJHNFOUBUJPO PG UIF IBJS PS TLJO NBZ occur during treatment with VOTRIENT. t 1BUJFOUT TIPVME CF BEWJTFE UP UBLF 7053*&/5 XJUIPVU GPPE BU MFBTU IPVS before or 2 hours after a meal). VOTRIENT is a trademark of GlaxoSmithKline.

ratio, we recommend that trastuzumab be incorporated into a concurrent regimen with taxane cheSEE PAGE 68 motherapy as an important standard-of-care treatment alternative to a sequential regimen,â&#x20AC;? the investigators stated in the Journal of Clinical Oncology.1 While other phase III clinical trials have assessed either sequential or concurrent incorporation of trastuzumab with chemotherapy, the NCCTG N9831 trial â&#x20AC;&#x153;is the only trial, to the best of our knowledge, prospectively comparing the two different approaches,â&#x20AC;? the researchers explained. â&#x20AC;&#x153;Specifically, it compares the efficacy and safety of chemotherapy alone (arm A), chemotherapy followed by sequential trastuzumab (armÂ B), and chemotherapy with concurrent trastuzumab followed by trastuzumab monotherapy (arm C).â&#x20AC;?

Survival Rates A comparison of arms A and B at a 6-year median follow-up showed â&#x20AC;&#x153;[Disease-free survival] was significantly increased with trastuzumab added sequentially to paclitaxel,â&#x20AC;? the authors reported. The 5-year diseasefree survival rates were 71.8% in arm A, 80.1% in arm B, and 84.4% in arm C. â&#x20AC;&#x153;There was an increase in [disease-free survival] with concurrent trastuzumab and paclitaxel relative to sequential administration, â&#x20AC;Ś but the P value (.02) did not cross the prespecified Oâ&#x20AC;&#x2122;Brien-Fleming boundary (.00116) for the interim analysis,â&#x20AC;? the authors stated. â&#x20AC;&#x153;Comparison of arm B and arm C with a median follow-up of 6 years indicates that although trastuzumab added sequentially to chemotherapy improves [disease-free survival], there is a strong trend toward a better outcome with concurrent trastuzumab,â&#x20AC;? they concluded. Paclitaxel with trastuzumab after doxorubicin and cyclophosphamide â&#x20AC;&#x153;did not appear to have a significantly worse safety profile compared with sequential administration, including cardiac safety.

â&#x2013;

Reference 1. Perez EA, Romond EH, Suman VJ, et al: J Clin Oncol 29:3366-3373, 2011.

ASCOPost.com | DECEMBER 15, 2011

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FDA Update

Edith A. Perez, MD

2. Perez EA, Suman VJ, Davidson NE, et al: Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. October 31, 2011 (early release online). 3. Perez EA, Dueck AC, McCullough A, et al: Do the ASCO/CAP 2007 HER2 Testing Guidelines accurately identify patients who will benefit from adjuvant trastuzumab? Data from the North Central Cancer Treatment Group N9831 Trial. J Natl Cancer Inst. In press 4. Garrison LP, Lalla D, Brammer M, et al: Assessing the potential cost-effectiveness of retesting IHC0, IHC1+ or FISHnegative early-stage breast cancer patients for HER2 status. 2011 ASCO Annual Meeting. Abstract 6133. Presented June 4, 2011. 5. Hurvitz S, Dirix L, Kocksis J, et al: Trastuzumab emtansine (T-DM1) versus trastuzumab plus docetaxel in previously untreated HER2-positive metastatic breast cancer: primary results of a randomized multicenter open-label phase II study. 2011 European Multidisciplinary Cancer Congress. Abstract 5001. Presented September 25, 2011.

continued from page 7

MARIANNE trial in combination with pertuzumab and as a single agent. And the EMILIA trial is comparing T-DM1 to lapatinib/capecitabine in refractory patients. Another fascinating compound is GRN1005, a peptide-drug conjugate that is designed to enable paclitaxel to penetrate the intracerebral compartment via the LRP-1 receptor on the blood-brain barrier. The hope is that this would be an effective treatment of brain metastasis, which is clearly an area of unmet need, especially in HER2-positive patients.

■

Disclosure: Dr. Perez has received research funding from Genentech and GlaxoSmithKline.

References 1. Perez EA, Reinholz MM, Hillman DW, et al: HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial. J Clin Oncol. 2010;28(28):4307-4315.

Coming in Future Issues of The ASCO Post Important Oncology News from:

■■ 53rd Annual Meeting of the American Society of Hematology ■■ 2011 San Antonio Breast Cancer Symposium ■■ 2011 Chemotherapy Foundation Symposium ■■ Society of Integrative Oncology Annual Meeting ■■ Original Columns and Perspectives from Oncology Leaders ■■ Conversations with Experts About Important Issues in Cancer Care ■■ Special Features on Patient Access to Care and Personalized Medicine Treating pNET 22

Biosimilars in cancer treatment 37

VOLUME 2, ISSUE 17

Younger women with breast cancer 56

NOVEMBER 15, 2011

ASCOPost.com

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

2011 European Multidisciplinary Cancer Congress

Aflibercept Improves Overall Survival in Patients with Metastatic Colorectal Cancer By Caroline Helwick

he novel fusion Aflibercept/FOLFIRI in Colorectal Cancer protein aflibercept added to standard chemo■ Aflibercept is a new fusion protein of key domains of the human vascular therapy led to an overall endothelial growth factor (VEGF) receptors 1 and 2. It blocks all VEGF-A survival benefit in a global isoforms, VEGF-B, and placental growth factor. phase III trial of second■ The global phase III VELOUR trial evaluated adding aflibercept to FOLFIRI line metastatic colorectal in the second-line treatment of patients with metastatic colorectal cancer. cancer, reported at the ■ The primary endpoint, overall survival, was improved with aflibercept 2011 European Multidisover FOLFIRI alone; median overall survival was 13.5 and 12.1 months, ciplinary Cancer Congress respectively, and median progression-free survival was 6.9 and 4.7 in Stockholm.1 months. “Adding aflibercept to FOLFIRI [leucovorin, fluorouracil (5-FU), irinotecan] in patients with D’Hebron University Hospital in Barcelona, Spain, metastatic colorectal cancer previously treated with who presented the findings at a Presidential Session. oxaliplatin-based regimens reAflibercept is a new fusion protein of key dosulted in overall survival and promains of the human vascular endothelial growth facgression-free survival benefits that tor (VEGF) receptors 1 and 2. It blocks all VEGF-A are both statistically significant isoforms, as well as VEGF-B and placental growth and clinically meaningful,” said factor, and binds with high affinity. SEE PAGE 60 continued on page 15 Josep Tabernero, MD, of Vall Expert’s Corner

Important Lessons for Oncology from the Front Lines of the AIDS Pandemic

Chemotherapy Drug Shortages: A Preventable Human Disaster By Hagop M. Kantarjian, MD

he issue of chemotherapy drug shortages continues with no end in sight. Many heartfelt human interest stories have been told on television, in newspapers, and even to Congress, but the bottom line is that little, if any, action has been taken.

Uniquely American Problem News of the generic chemotherapy drug crisis hit the airwaves in April, when the shortage of cytarabine, an irreplaceable chemotherapy drug essential to the cure of acute myeloid leukemia (AML), was used to highlight the issue of inadequate supplies of mostly generic drugs. The problem is unique to the United States. Cytarabine-containing chemotherapy regimens cure 40% of patients with AML; without continued on page 63

Hagop M. Kantarjian, MD, is Professor and Chairman, Department of Leukemia, and Associate Vice President for Global Academic Programs, The University of Texas MD Anderson Cancer Center, Houston.

By Ronald Piana

n June 5, 1981, the CDC issued a warning about a rare type of pneumonia discovered among a small group of young gay men in Los Angeles, later determined to be AIDS-related, ushering in the HIV/ AIDS epidemic. Early on, AIDS-related malignancies brought the oncology community into this formidable socio-clinical puzzle. One of the first oncologists on the front lines of the nascent AIDS phenomenon,

internationally regarded AIDS/lymphoma expert, Alexandra Levine, MD, MACP, shared her experiences with The ASCO Post.

Early AIDS Era

What prompted your introduction into HIV/AIDS research and treatment? In 1982, a young man came to my University of Southern California county hospital office with enlarged lymph nodes. I A small piece of thought he had Hodgkin disease, so I arinformation or a major ranged a lymph node biopsy. I remember breakthrough in one scientific looking at the tissue under a microscope with Dr. Robert Lukes, Head of Hematodiscipline can translate logic Pathology at USC. Dr. Lukes had a magnificent eye, seeing things that othvaluable information into ers could not. To my surprise, he said another scientific area. this pathology was something he’d never seen before. —Alexandra Levine, MD, MACP

November Is Lung Cancer Awareness Month

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 European Multidisciplinary Cancer Congress ................15, 24, 41, 49 53rd ASTRO Annual Meeting ............................. 8–11, 14, 30 AACR Basic Cancer Research Meeting ..................................... 39 AACR Conference on Cancer Health Disparities ..................................... 52 Direct from ASCO ....................................... 27

continued on page 20

A Harborside Press® Publication

Visit The ASCO Post online at ASCOPost.com.

2011 in Review: Oncology Drugs/ Indications Newly Approved by FDA

t press time, the FDA had granted approval for the following new agents and indications for cancer treatment in 2011. ■■ Asparaginase Erwinia chrysanthemi (Erwinaze) as a component of a multiagent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in patients who have developed hypersensitivity to E coli–derived asparaginase. November 18, 2011 ■■ Ruxolitinib ( Jakafi) for intermediate and high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis. November 16, 2011 ■■ Cetuximab (Erbitux) in combination with platinum-based therapy plus fluorouracil for the firstline treatment of patients with recurrent locoregional disease and/or metastatic squamous cell carcinoma of the head and neck. November 7, 2011 ■■ Deferiprone (Ferriprox), an oral iron chelator for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. October 14, 2011 ■■ Eculizumab (Soliris) for the treatment of pediatric and adult patients with atypical hemolytic uremic syndrome. September 23, 2011 ■■ Denosumab (Prolia) as a treatment to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer. September 16, 2011 ■■ Crizotinib (Xalkori) for locally advanced or metastatic non– small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. The FDA approved the Vysis ALK Break-Apart FISH Probe Kit concurrently with the crizotinib approval. This companion diagnostic test is designed to detect rearrangements of the anaplastic lymphoma kinase gene in NSCLC. August 26, 2011

■■ Brentuximab vedotin (Adcetris) for: (1) treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates and (2) treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multiagent chemotherapy regimen. August 19, 2011 ■■ Vemurafenib (Zelboraf) for unresectable or metastatic melanoma in patients with the BRAFV600E mutation as detected by an FDAapproved test. August 17, 2011 ■■ Sunitinib (Sutent) for pancreatic neuroendocrine tumors (pNET) in patients with unresectable, locally advanced, or metastatic disease. May 20, 2011 ■■ Everolimus (Afinitor), for progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced, or metastatic disease. May 5, 2011 ■■ Abiraterone acetate (Zytiga) for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel. April 28, 2011 ■■ Vandetanib (Caprelsa), a kinase inhibitor, for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease. April 6, 2011 ■■ Peginterferon alfa-2b (Sylatron), for patients with melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy. March 29, 2011 ■■ Ipilimumab (Yervoy) for the treatment of unresectable or metastatic melanoma. March 25, 2011 ■■ Rituximab (Rituxan) for maintenance therapy for patients with previously untreated follicular, CD-20 positive, B-cell nonHodgkin lymphoma who achieve a response to rituximab in combination with chemotherapy. January 28, 2011

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The ASCO Post | DECEMBER 15, 2011

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Expert’s Corner

Ezekiel J. Emanuel, MD, PhD continued from page 1

and Budget and was one of the chief architects of the Patient Protection and Affordable Care Act signed into law in March 2010. Dr. Emanuel talked with The ASCO Post about the changing role of medical ethics in oncology and how the Affordable Care Act will improve health care for all Americans.

New Role Could you discuss your personal goals and objectives in your new position? Health-care policy encompasses many medical ethical questions, including issues centered on allocating resources and determining what procedures and types of care should be covered. Yet there is very little research being done from the ethics standpoint. We definitely have to analyze those issues more. It’s an area where I think the country is calling out for clarity. For example, if you have two equally effective treatments for a specific disease and an insurer pays only for the cheaper one, is that rationing care? And if so, is that a problem? That is both a health policy issue and a serious medical ethics issue. There are many questions like that where ethics and policy come together. Another example involves care for terminally ill patients and how much we do for them at the end of their lives. I hope that we will be looking at those issues.

Teaching Ethics Could you discuss the training that young physicians and medical students currently receive in medical ethics and how it should or could be improved? There is a requirement for teaching ethics, but the quality and the focus of ethics courses vary, and the manner in which they are taught differs among medical schools. To be honest, the quality of the teachers varies tremendously as well. Some schools have very deep and well developed bioethics programs, but most don’t. So I often see medical ethics being taught by people who really have no training in

Visit

it, which we wouldn’t accept in any other part of the medical school curriculum. That’s one of the problems. At Penn, we are going to try to address that issue by creating a fellowship program so that we train the next generation of bioethicists who can, in turn, be the experts on medical ethics, and teach it to future physicians and nurses.

Ethics and Oncology Please talk about the importance of medical ethics in oncology care. Medical ethics is integral to oncology care. When I ran ethics rounds at the Dana-Farber Cancer Institute, I used to say that every single oncology patient faced at least three ethical dilemmas. Informed consent is one. Do patients really understand what they are signing? There’s typically a

and other providers. It was a great honor to serve President Obama and the nation in this most important of issues.

Optimal Cancer Care If you could make the final decision, what do you believe would be the best system for delivering cancer care to all Americans? First of all, we have to get to a point where we’re delivering care efficiently and we’re delivering the best care at the lowest price. We have a lot of choices in cancer care. In many situations, there are equivalent chemotherapies to treat cancer and we could appropriately choose the lower-priced chemotherapy over the more expensive drugs that really don’t add very much in terms of survival or qualityof-life benefit.

Oncology is the most attractive specialty in medicine because it’s all there: the science, the humanistic aspects of patient care, and the challenging ethical dilemmas. dilemma about allocating resources for treatment because these are very expensive therapies and many of them put a lot of financial pressure on families. And for many patients there’s the dilemma of facing end-of-life care, as there will be for all of us since we’re all going to die someday.

Affordable Care Act Can you share your experience of helping to craft the Patient Protection and Affordable Care Act? One of my roles was to develop ideas and policy alternatives that would help improve quality and reduce costs. We also spent a lot of time working out the details of policy proposals to ensure integrating the uninsured into the health-care system would be efficient and seamless. Two other areas I was particularly involved in were related to creating the health insurance exchanges and reforming the delivery system by changing mechanisms of payment to physicians

In the case of radiation therapy for malignant bone metastases, for example, we know from randomized trials that 1 fraction is as good as 10 fractions. We have to start administering only 1 fraction and not 10, which drives up the cost, not to mention the inconvenience to patients. Those are some of the things the oncology community needs to begin doing. We have to begin the conversation and take a stand about being efficient and when given equivalent options, choosing the less expensive one. There are plenty of things we do that aren’t more beneficial to the patient but that cost more, and we have to stop practicing oncology that way.

Impact of Health-care Reform Do you have any additional comments you would like to offer ASCO members regarding the Affordable Care Act? Here’s the question I always ask people: In 2020, when the pain and

upset of change are past us, will the Affordable Care Act have resulted in a better health-care system or not? And the answer is, undeniably yes. Because of health-care reform, every American is going to have an electronic health record and every American is going to have access to health insurance. We’re going to provide better coordinated care, especially for chronically ill people, and we’re going to have fewer hospital infections and hospital errors. We’re going to have better quality metrics to assess the care we provide, and we’re going to have much more information about the treatments that work and the treatments that don’t work. From every one of those aspects, I think we’re going to have a better health-care system because of health-care reform.

On Being an Oncologist In light of the coming workforce shortage of oncologists, what would you say to encourage young physicians to specialize in oncology? What drew me to oncology was a combination of three things. First, oncology has the most cutting-edge science, so if you’re a science person, it’s the medical specialty to be in. Second, if what really turns you on is getting to know patients and doing the best for them, the field of oncology is the place for that, too. You see patients intensely for months and you’re helping them get through a life-threatening illness. You get to know patients in an intimate way that a primary care provider who sees patients once a year doesn’t. It’s an enormous privilege. And third, if you’re like me, and what interests you are the ethical dilemmas—trying to understand what the right thing to do is in these very complex situations—again, the medical specialty for you is oncology. No matter what your interest is, it seems to me that oncology is the most attractive specialty in medicine because it’s all there: the science, the humanistic aspects of patient care, and the challenging ethical dilemmas.

■

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

website at ASCOPost.com

NOW APPROVED FOR INTERMEDIATE OR HIGH-RISK MYELOFIBROSIS

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION

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 • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • It has been observed that patients with platelet counts <200 X 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 X 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) 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 Please see Brief Summary of Full Prescribing Information on the following page.

RUX-1004C

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The ASCO Post | DECEMBER 15, 2011

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News

Bevacizumab Decision continued from page 1

breast cancer. This indication must now be removed from bevacizumab’s product labeling. Dr. Hamburg’s decision is based on an extensive record,9:16 which includes 7 JK0 BS 12P_Layout 1 11/16/11 AM Page 1 thousands of pages submitted to a

public docket, data from several clinical trials, and the record from a 2-day hearing held in June 2011.

Bevacizumab History Bevacizumab was approved for metastatic breast cancer in February 2008 under the FDA’s accelerated ap-

proval program, which allows a drug to be approved based on data that are not sufficiently complete to permit full approval. The accelerated approval was based on promising results from one study—E2100—that found an improvement in progression-free survival of 5.5 months when combined with pa-

Bevacizumab Update ■■ FDA is revoking its approval of

the breast cancer indication for bevacizumab (Avastin) after concluding that the drug has not been shown to be safe and effective for that use.

■■ Bevacizumab’s risks include 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 trans- 16.8% 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 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 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: November 2011 RUX-1040

severe high blood pressure, bleeding and hemorrhaging, heart attack or heart failure, and the development of perforations in different parts of the body such as the nose, stomach, and intestines.

■■ Bevacizumab will remain on the market as an approved treatment for certain types of colon, lung, kidney, and brain cancers (glioblastoma multiforme).

clitaxel. The subsequent AVADO and RIBBON1 studies have not shown the same extent of progression-free survival benefit when bevacizumab was combined with other agents. FDA’s Center for Drug Evaluation and Research ultimately concluded that the results of these additional studies did not justify continued approval and notified Genentech it was proposing to withdraw approval of the indication. Following the procedures set out in FDA regulations, Genentech requested a hearing on the Center’s withdrawal proposal, with a decision to be made by the Commissioner. That 2-day hearing, which took place June 28–29, 2011, included recommendations from the FDA’s Oncologic Drugs Advisory Committee (ODAC), voting 6–0 in favor of withdrawing approval of bevacizumab’s breast cancer indication. After the hearing, the public docket remained open until August 4, 2011. (In an earlier meeting, ODAC had voted 12–1 in favor of the removal of the breast cancer indication from the bevacizumab label.)

‘Difficult Decision’ “This was a difficult decision. FDA recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use,” Dr. Hamburg said. She added “FDA is committed to working with sponsors to bring promising cancer drugs to market as quickly as possible using tools like accelerated approval. I encourage Ge-

ASCOPost.com | DECEMBER 15, 2011

PAGE 13

News

nentech to consider additional studies to identify if there are select subgroups of women suffering from breast cancer who might benefit from this drug.” Genentech has indicated that a biomarker study of bevacizumab plus paclitaxel will be conducted, but no details have become available.

Emotional Reaction Reaction to the announcement was robust in the lay press. The New York Times (November 19, 2011) reported that the revocation is “an emotional issue that has

pitted the hopes of some desperate patients against the statistics of clinical trials.” Some publications took a strong editorial stance. The Wall Street Journal (November 19, 2011) argued that the FDA’s demand for objective evidence is a subjective standard and criticized the government for interfering with patients’ choices, though Forbes (November 19, 2011) applauded the decision and suggested it was “actually good for the drug industry.” A key issue to patients and their oncologists is coverage. The Centers

for Medicare & Medicaid Services has indicated it has no immediate plans to change coverage policy but will reevaluate coverage options as a result of the FDA’s action. The Wall Street Journal (November 19, 2011) also reported that Aetna and UnitedHealth Group plan to continue covering bevacizumab for breast cancer, in keeping with the National Comprehensive Cancer Network recommendations. However, Blue Shield of California plans to cease coverage, and Cigna is reviewing its policies, according to the newspaper.

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Editor’s note: Soon after FDA announced its decision to revoke the breast cancer indication for bevacizumab, Health Canada announced it will suspend authorization of the drug for use in the treatment of metastatic breast cancer. Based on careful review, Health Canada has concluded that bevacizumab has not been shown to be safe and effective in this use. This decision does not affect Health Canada’s authorization of bevacizumab in Canada for use in the treatment of metastatic colon, rectal, and lung cancers, as well as in the treatment of glioblastoma.

Breast Cancer Experts Voice Opinion and Express ‘Disappointment’ over FDA Decision By Caroline Helwick

abriel N. Hortobagyi, MD, Chair of Medical Breast Oncology at The University of Texas MD Anderson Cancer Center, Houston, said he was “disappointed but not surprised” at the FDA decision to withdraw the bevacizumab (Avastin) indication in breast cancer. “Once the FDA put this in the hands of ODAC, which they carefully handpicked, and the verdict came back 12 to 1, the handwriting was on the wall,” he said. “It would have been hard for the FDA to justify a different decision. I had no great expectations, but I find the process disheartening…. The logic of the entire approval process is flawed.”

Patchwork of Coverage While the Centers for Medicare & Medicaid Services (CMS) has stated that coverage of bevacizumab will continue, Dr. Hortobagyi fears that Congressional cuts to the CMS budget could trigger reconsideration of this stance, due to cost: Nearly $100,000 for a year’s treatment with the drug. “And private insurers are all over the map,” he added. “At least in the short term, we have a patchwork of coverage.” Dr. Hortobagyi is also concerned that the common practice of off-label prescribing in oncology will create additional complexity. “I can imagine a patient going to court when some insurance company decides to withdraw off-label coverage for [bevaci-

zumab] but not for another cancer drug. The future is going to be interesting.”

Larger Issues Kathy D. Miller, MD, Associate Professor and Sheila D. Ward Scholar at Indiana University School of Medicine and principal investigator for the E2100 trial, concurred that the decision is “a disappointment on many levels.” “As lead investigator, I know the care with which E2100 was designed and conducted, and I am passionate about the validity and reliability of the results,” she told The ASCO Post. “But I am actually more disappointed in the larger issues. These include the lack of a biomarker for bevacizumab and the frustration of the current drug approval process. She hoped the bevacizumab debate would culminate in some clarity of these and other far-reaching issues, “but we haven’t seen these larger discussions,” she said. “[Bevacizumab] is not a drug that provides benefit for all patients, but it clearly has benefit for some. Not knowing who these patients are leaves us with having to use [the agent] in a very inefficient, ineffective way,” she said. “And what it takes to get a drug approved— short of an improvement in overall survival—is not clear. It appears to be different from one cancer to another, although the disease is incurable in both cases. The reason for these inconsistencies is not obvious. Some have said that

breast cancer is being held to a higher standard. You could turn this around and say that if this is the standard we need, then why should patients with other cancers settle for less?” The high cost of the drug is a factor, she believes. “If [bevacizumab] were dirt Gabriel N. Hortobagyi, MD Kathy D. Miller, MD cheap we would not be havof E2100, but they cannot be considing this argument. This is an area where ered confirmatory since they were we can learn a lot from our European uncontrolled, had different designs, colleagues. Drugs may be approved or asked different questions. “If the because they meet the regulatory stanchemotherapy backbone is impordards but may not be widely available tant, then we have no confirmatory because individual health systems detrials,” she said. cide the benefits don’t justify the costs. Genentech’s plans to conduct such This is very different from saying there a trial with a VEGF-A biomarker comis not a benefit,” she continued. “In Euponent might fill this void, she said. rope they have separated these issues, Meanwhile access to bevacizumbut in the U.S. we still pretend that cost ab will undoubtedly be a challenge, is not a factor.” she agreed. “Some private insurers Additional Trials stopped providing coverage before Dr. Miller agreed that an additional the decision was made, while others trial evaluating bevacizumab plus pahave announced they will continue clitaxel could help settle the question coverage in spite of it. Access for of the drug’s efficacy in breast cancer. patients who wish to get this drug Preclinical data suggest the chemois now much more dependent upon therapy partner makes a substantial who their insurance carrier is, who difference in outcomes, and the clinitheir oncologist is, and where they cal trials suggested this as well. live. This is not a situation that any of “If this is so, then AVADO and RIBus wants.” Disclosure: Dr. Hortobagyi and Dr. BON1 are not the studies to confirm Miller have reported serving as consultants E2100,” she said. Other phase II studfor Genentech; Dr. Miller has reported ies pairing bevacizumab with paclitaxel receiving research funding from Genentech. have essentially replicated the findings

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How will the FDA decision to revoke bevacizumab’s breast cancer indication affect your practice? The ASCO Post invites readers to share your opinion and perspective on the recent FDA decision to revoke bevacizumab’s breast cancer indication and how this may impact your clinical practice. Write to editor@ASCOPost.com. All contributions will be considered for publication. Watch future issues of The ASCO Post for more on how payers will respond to FDA’s decision.

The ASCO Post | DECEMBER 15, 2011

PAGE 14

FDA Update Hematology

New Drug Approved to Treat Acute Lymphoblastic Leukemia

he FDA has approved asparaginase Erwinia chrysanthemi (Erwinaze) to treat patients with acute lymphoblastic leukemia who have developed hypersensitivity to Escherichia

coli–derived asparaginase (Elspar) and pegaspargase (Oncaspar). Acute lymphoblastic leukemia is the most commonly diagnosed childhood cancer. An estimated 15% to 20% of patients

develop hypersensitivity to products derived from E coli. Asparaginase E chrysanthemi is injected directly into the muscle three times a week and works by depleting the level of asparagine in the blood. Asparagine is essential for cell growth, and its removal from the blood inhibits the growth of cells associated with acute lymphoblastic leukemia. Normal human cells are able to make enough asparagine for their own needs through biosynthesis and will not be affected by treatment with asparaginase E chrysanthemi. “The approval of Erwinaze underscores the FDA’s commitment to the approval of drugs for conditions with limited patient populations with unmet medical needs using novel trial endpoints,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

What role may MUC1 play in NSCLC

Key Clinical Trials The safety and effectiveness of the new agent was evaluated in one clinical trial of 58 patients. Additional safety data were collected from the Erwinaze Master Treatment Protocol (EMTP), an expanded access program that enrolled 843 patients. Patients in both studies were unable to continue receiving pegaspargase or asparaginase derived from E coli due to allergic reactions. In the trial to support efficacy, the endpoint was the measurement of the proportion of patients with sustained asparaginase activity levels that correlate with better leukemia control and survival. All evaluable patients were shown to have maintained the prespecified threshold for asparaginase activity at 48 or 72 hours after dosing. Side effects associated with asparaginase E chrysanthemi treatment include serious hypersensitivity (including anaphylaxis), pancreatitis, abnormal transaminase and bilirubin levels, blood clotting, hemorrhage, nausea, vomiting, and hyperglycemia. Asparaginase E chrysanthemi has been designated as an orphan drug, which identifies the disease as affecting fewer than 200,000 people in the United States. The drug is manufactured by EUSA Pharma Inc, Langhorne, Pennsylvania.

It’s well-known that mucins protect healthy cells, but did you know that aberrant overexpression of mucin 1 (MUC1) by tumor cells may play a role in tumor cell survival?1-3 At EMD Serono, we’re investigating the signiﬁcance of MUC1 and its impact on your patients with NSCLC.

110715-130123

Visit www.emdserono.com to learn more about EMD Serono Oncology. 1. Ahmad R, Raina D, Joshi MD, et al. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69(17):7013-7021. 2. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42): 5667-5677. 3. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816.

EMD Serono Oncology | Combination is key™

EMD Serono, Inc. is an afﬁliate of Merck KGaA, Darmstadt, Germany

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Pan-Pacific Lymphoma Conference Hematology

How Should We Treat Nodular Lymphocyte-predominant Hodgkin Lymphoma? By Matthew Stenger

t the 2011 Pan-Pacific Lymphoma Conference in Kauai, Hawaii, Andreas Engert, MD, Chairman of the German Hodgkin Lymphoma Study Group (GHSG) and Professor of Medicine at the University Hospital of Cologne, Germany, discussed the treatment of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), a variant with a slightly better prognosis than classical Hodgkin lymphoma.

Andreas Engert, MD

Lymphocyte-predominant Hodgkin lymphoma (LPHL) accounts for approximately 5% of all Hodgkin lymphoma cases in Western countries. Histologically, LPHL presents with a nodular pattern (NLPHL) in more than 99% of cases, with the remainder presenting with a diffuse pattern. NLPHL is characterized by atypical lympho-

cytic and histiocytic or “popcorn” cells embedded in a nodular background consisting of small B lymphocytes and other reactive cells (Fig. 1). Lymphocytic and histiocytic cells usually express the B-cell marker CD20 and lack expression of CD15 and CD30, which are the characteristic markers of classical Hodgkin lymphoma. Compared with classical Hodgkin lymphoma, NLPHL is associated with less aggressive tumor growth and lymphadenopathy, which often precede the diagnosis by many years, and a somewhat better prognosis. Patients with early favorable NLPHL (ie, without risk factors) have an excellent prognosis compared with those in early stages with risk factors (early unfavorable) or advanced stages. Current treatment of NLPHL using standard Hodgkin lymphoma protocols may lead to complete remission in 95% of patients. Patients with early unfavorable and advanced stages are usually included in treatment protocols for classical Hodgkin lymphoma. Treatment of early NLPHL is less defined and includes radiotherapy, combined-modality treatment, and, more recently, the anti-CD20 monoclonal antibody rituximab (Rituxan).

Treatment Outcomes in NLPHL vs Classical Disease In a retrospective analysis of the GHSG database including 394 patients with NLPHL and 7,904 with classical Hodgkin lymphoma, complete remission after first-line treatment was achieved in 91.6%, 85.7%, and 76.8% of NLPHL patients in early favorable stages, early unfavorable stages, and advanced stages, respectively, compared with 85.9%, 83.3%, and 77.8%, respectively, of patients with classical Hodgkin lymphoma.1 At a median of 50 months, freedom from treatment failure was observed in 88% of NLPHL patients and 82% of those with classical Hodgkin lymphoma (P = .0093), with overall survival of 96% and 92%, respectively (P = .0166). Among NLPHL patients, freedom from treatment failure rates were 93%, 87%, and 77% in early favorable, early unfavorable, and advanced stages, respectively.

‘Watch-and-Wait’ in Pediatric Patients Watch-and-wait strategies have been used in select pediatric patients with NLPHL to avoid adverse effects of treatment. A French study reported several years ago that included pri-

ASH Honors Janet Rowley, MD, and Brian Druker, MD

he American Society of Hematology (ASH) recognized Janet Rowley, MD, of the University of Chicago Medical Center, and Brian Druker, MD, of Oregon Health & Science University with the 2011 Ernest Beutler Lecture and Prize for their significant advances in the diagnosis and treatment of chronic myeloid leukemia (CML), at the 2011 ASH Annual Meeting, December 10-13, 2011, in San Diego.

Two-part Lectureship The Ernest Beutler Lecture and Prize, named for the late Ernest Beutler, MD, a Past President of ASH and physician-scientist for more than 50 years, is a two-part lectureship that recognizes major translational advances related to a single topic. This award honors two individuals, one who has enabled advances in basic science and

Treating Nodular Lymphocyte-predominant Hodgkin Lymphoma Dr. Engert’s recommendations include:

■■ Stage IA disease: involved-field radiotherapy at 30 Gy

■■ Early favorable disease: two

cycles of ABVD plus involvedfield radiotherapy at 20 Gy

■■ Early unfavorable disease: four cycles of ABVD plus involvedfield radiotherapy at 30 Gy

■■ Advanced-stage disease: six

cycles of BEACOPPesc or six to eight cycles of ABVD

■■ Relapsed disease: two cycles

of DHAP plus BEAM and antiCD20 antibodies

marily children with stage I disease showed that whereas event-free survival was improved with conventional Hodgkin lymphoma treatment vs observation after lymphadenectomy, there was no difference in overall survival between the two approaches continued on page 16

Awards

success stories in translational research, demonstrating how a precise understanding of the molecular cause of the disease led to the development of a very effective targeted cancer treatment,” said ASH President J. Evan Sadler, MD, PhD, of the Washington University School of Medicine in St. Louis.

■

Janet Rowley, MD

another for achievements in clinical science or translational research. In 1973, Dr. Rowley discovered that the chromosomal abnormality found in patients with CML (Philadelphia chromosome) resulted from an abnormal exchange of genetic material between two chromosomes. This chromosomal rearrangement was later shown to result in the production of a defective gene and protein called BCR-ABL that promoted the excessive

Brian Druker, MD

ASH Annual Meeting growth of white blood cells in CML. More recently, Dr. Druker revolutionized treatment for patients with CML by developing STI-571 (imatinib or Gleevec), a treatment for CML that inhibits the BCR-ABL protein. Prior to these discoveries, patients diagnosed with CML typically lived only 3 to 5 years. Today, nearly 90% of CML patients are long-term survivors. “The work done by Drs. Rowley and Druker has made CML one of the great

See next month’s issue of The ASCO Post for coverage of the 2011 American Society of Hematology Annual Meeting and Exposition, December 10-13, 2011, San Diego, California

The ASCO Post | DECEMBER 15, 2011

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Pan-Pacific Lymphoma Conference Hodgkin Lymphoma continued from page 15

(100% at 70 months).2 The findings indicate that watch-and-wait is a reasonable strategy after lymphadenectomy in this population.

Radiotherapy/Rituximab for Early Favorable Disease For adult patients with stage IA disease without risk factors, involvedfield radiotherapy alone may be optimal treatment. A GHSG analysis showed that involved-field radiotherapy was as effective as extended-field radiotherapy and combined-modality therapy in an analysis of 131 patients with stage IA NLPHL without risk factors.3 Complete remission was observed in 100% of patients after involved-field radiotherapy, 98% after extended-field radiotherapy, and 95% after combined-modality therapy. Freedom from treatment failure was 96% with involved-field radiotherapy after 19 months of follow up, 89% with extended-field radiotherapy after 72 months, and 93% with combinedmodality therapy after 70 months. Since CD20 is consistently expressed on NLPHL cells, use of the CD20-directed monoclonal antibody rituximab is rational, and promising results have been seen with the agent in relapsed NLPHL. In a recently reported small phase II study of rituximab in previously untreated patients with early stage IA disease, complete remission was achieved in 85.7% of patients; the overall survival rate was 100% at a median follow-up of 43 months, and progression-free survival rates were 96.4%, 85.3%, and 81.4%, at 1, 2, and 3 years, respectively.4 Although these results appear to be inferior to those with radiotherapy or combined-modality approaches in early-stage disease, further investigation of anti-CD20 antibody–based combinations in this setting is warranted.

ABVD for Early Favorable Disease Recent GHSG studies have involved investigation of changes to standard Hodgkin lymphoma regimens. The GHSG HD10 study, which compared four vs two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), each followed by 20 or 30 Gy involved-field radiotherapy in 1,370 patients with newly diagnosed early favorable Hodgkin lymphoma, found that two cycles of ABVD plus

20 Gy was as effective as four cycles plus 30 Gy.5 At 5 years, freedom from treatment failure rates were 93.0% with four cycles and 91.1% with two cycles and overall survival rates were 97.1% and 96.6%, respectively; no differences in freedom from treatment failure or overall survival were observed according to radiotherapy treatment used. Toxicity was worst with the four-cycle/30-Gy regimen.

BEACOPP vs ABVD for Early Unfavorable Disease The HD11 trial showed that moderate dose escalation using the BEACOPPbaseline regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], and prednisone) did not significantly improve outcome in early unfavorable Hodgkin lymphoma and that four cycles of ABVD should be followed by 30 Gy of involved-field

BEACOPP for Advanced Disease The 10-year follow up of the HD9 trial in 1,196 patients with advancedstage Hodgkin lymphoma indicates a stabilized significant improvement with eight cycles of an escalated-dose BEACOPP regimen (BEACOPPesc) (10-year freedom from treatment failure = 82%, overall survival = 86%) compared with eight cycles of BEACOPPbaseline (70%, 80%) and eight cycles of alternating cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/ABVD (64%, 75%)—P < .001 overall, and P < .0001 and P = .005 for freedom from treatment failure and overall survival comparisons, respectively, between the two BEACOPP regimens).7 These findings challenge ABVD as the standard of care for advanced-stage disease. The ongoing HD18 trial is examining use of positron-emission tomography

Fig. 1: Atypical lymphocytic and histiocytic (“popcorn”) cells in nodular lymphocyte-predominant Hodgkin lymphoma. Courtesy of Francisco Vega, MD, PhD.

radiotherapy.6 The trial compared four cycles of BEACOPPbaseline vs a standard regimen of four cycles of ABVD, each with either 20 or 30 Gy of involvedfield radiotherapy, in 1,395 patients. The BEACOPP regimen was more effective than ABVD when followed by 20 Gy radiotherapy (5-year freedom from treatment failure difference of 5.7%), but there was no difference between regimens when followed by 30 Gy (1.6% difference). There was no difference between 20 Gy and 30 Gy following BEACOPP, whereas inferiority of 20 Gy to 30 Gy (–4.7% difference) following ABVD could not be excluded. Toxicity was greatest in the more intensive treatment arms.

(PET) for detection of residual nodes after two cycles of BEACOPPesc in patients with advanced-stage disease. The trial is asking whether rituximab will improve outcome when added to BEACOPP in those with positive findings and whether a shorter course of BEACOPP is as effective as a longer course in those with negative findings. Patients with positive PET findings are receiving six additional cycles of BEACOPP with or without rituximab. Those with negative findings are receiving either two or six additional cycles of BEACOPP.

Treatment Recommendations In summary, current recommendations for treatment of NLPHL include:

involved-field radiotherapy only, at 30 Gy, for stage IA disease; two cycles of ABVD plus involved-field radiotherapy at 20 Gy for early favorable disease; four cycles of ABVD plus involvedfield radiotherapy at 30 Gy for early unfavorable disease; and either six cycles of BEACOPPesc or six to eight cycles of ABVD for advanced stages of disease. For relapsed disease, options include two cycles of DHAP (dexamethasone, cytarabine, and cisplatin) plus BEAM (carmustine [BiCNU], etoposide, cytarabine, and melphalan) and antiCD20 antibodies. In commenting on current treatment approaches to NLPHL, Dr. Engert noted, “We should try to treat NLPHL patients within clinical trials if possible” in the continuing effort to identify optimal treatment regimens.

■

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

References 1. Nogová L, Reineke T, Brillant C, et al: Lymphocyte-predominant and classical Hodgkin’s lymphoma: A comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol 26:434-439, 2008. 2. Pellegrino B, Terrier-Lacombe MJ, Oberlin O, et al: Lymphocyte-predominant Hodgkin’s lymphoma in children: Therapeutic abstention after initial lymph node resection—a study of the French Society of Pediatric Oncology. J Clin Oncol 21:29482952, 2003. 3. Nogová L, Reineke T, Eich HT, et al: Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin’s lymphoma: A retrospective analysis from the German Hodgkin Study Group (GHSG). Ann Oncol 16:1683-1687, 2005. 4. Eichenauer DA, Fuchs M, Pluetschow A, et al: Phase 2 study of rituximab in newly diagnosed stage IA nodular lymphocytepredominant Hodgkin lymphoma: A report from the German Hodgkin Study Group. Blood 118:4363-4365, 2011. 5. Engert A, Plütschow A, Eich HT, et al: Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 363:640-652, 2010. 6. Eich HT, Diehl V, Görgen H, et al: Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: Final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol 28:41994206, 2010. 7. Engert A, Diehl V, Franklin J, et al: Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol 27:45484554, 2009.

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The ASCO Post | DECEMBER 15, 2011

PAGE 18

2011 European Multidisciplinary Cancer Congress Clinical Trials

Important Briefs from the 2011 European Multidisciplinary Cancer Congress In several trials, new agents fail to impress. By Alice Goodman and Caroline Helwick

early 16,000 people from 16 countries attended this year’s European Multidisciplinary Cancer Congress, held recently in Stockholm. The ASCO Post has featured several key reports from the meeting and will offer further coverage in upcoming issues. Additional noteworthy studies presented at the meeting are summarized below.

Vorinostat Falls Short in Mesothelioma As a second-line treatment for advanced mesothelioma, the oral histone deacetylase inhibitor vorinostat (Zolinza) failed to extend survival in the VANTAGE014 phase III trial.1 The study was the largest of its kind in advanced mesothelioma, enrolling 660 patients with disease progression on first-line pemetrexed (Alimta) plus cisplatin or carboplatin.

Lee Krug, MD

Lee Krug, MD, of Memorial SloanKettering Cancer Center, New York, reported that median overall survival was 30.7 weeks with vorinostat and 27.1 weeks with placebo. There was a statistically significant advantage for progression-free survival with vorinostat, but at a median of 6.3 vs 6.1 weeks, respectively (P < .001), this was not clinically meaningful, Dr. Krug said. Rolf Stahel, MD, PhD, of the University Hospital Zurich, applauded the conduct of such a large study, “but despite this effort, the result is clearly negative,” he noted.

OCEANS Subanalysis Shows Benefit in Main Subgroups The addition of bevacizumab (Avastin) to carboplatin/gemcitabine given at first recurrence of platinumsensitive epithelial ovarian cancer, primary peritoneal cancer, or fallo-

pian tube cancer achieved a 52% reduction in disease progression in the OCEANS trial (reported previously). A subgroup analysis reported in Stockholm showed that the treatment effect of bevacizumab was consistent across the majority of clinically relevant subgroups, including patients with partially platinum-sensitive disease, and those with bulky and less bulky disease.2 In the experimental arm of OCEANS, bevacizumab at 15 mg/kg was given concurrently with chemotherapy, followed by bevacizumab maintenance until disease progression or unacceptable toxicity; the control arm received chemotherapy plus placebo and placebo maintenance. The study included 484 women who experienced first recurrence of disease and had received no prior bevacizumab. Consistent with other trials, adverse events associated with bevacizumab, including hypertension, were more common in the experimental arm. Overall survival data are not yet mature. “Bevacizumab plus chemotherapy followed by bevacizumab until disease progression should be considered an option for recurrent ovarian cancer,” said Carol Aghajanian, MD, Memorial Sloan-Kettering Cancer Center, New York. Regarding these results, as well as those of ICON-7 and GOG-218, formal discussant Stanley Kaye, MD, Royal Marsden Hospital and Institute for Cancer Research, London, said,

Stanley Kaye, MD

“These results taken together certainly indicate that bevacizumab should play a role in the treatment of ovarian cancer. In choosing who to treat, one approach is to select those who have the most to gain, including suboptimally debulked first-line patients as well as

patients with recurrent disease. A key message is that in recurrent disease, bevacizumab should be given with chemotherapy and continued until disease progression.”

Quality of Life with Frontline Bevacizumab Not Compromised Two related abstracts analyzing quality of life in the ICON-7 and GOG-218 trials, respectively, showed that incorporating bevacizumab into front-line therapy of ovarian cancer neither worsened nor improved quality of life.3,4 The trials had different definitions of endpoints and used different doses of bevacizumab. Nevertheless, both studies provide “an unprecedented database on quality of life in ovarian cancer that will be valuable for future studies. More mature qualityof-life data are needed. We would have smarter trial designs if we could select patients who benefit from bevacizumab,” stated formal discussant of these trials, Ate Van der Zee, MD, University Medical Center, Groningen, The Netherlands.

BIBF 1120 Does Not Beat Bevacizumab in Colorectal Cancer A phase I/II trial failed to show a superior benefit for the novel triple angiokinase inhibitor BIBF 1120 plus modified (m)FOLFOX6 (leucovorin, fluorouracil [5-FU], oxaliplatin) compared with bevacizumab plus mFOLFOX6 in patients with metastatic colorectal cancer, reported Eric Van Cutsem, MD, of University Hospital Leuven in Belgium.5 Interim analysis of the 126 patients showed 9-month progression-free survival to be 63% with BIBF 1120 and 69% with bevacizumab. Median progression-free survival was 10.6 months in each arm. “In comparison to bevacizumab, there was similar magnitude of efficacy, safety, tolerability, exposure, and dose intensity of mFOLFOX6, but a lower incidence of serious adverse events,” Dr. Van Cutsem reported. Serious adverse events occurred in 34.1% in the BIBF 1120 arm compared to 53.7% in the bevacizumab arm, primarily due

Eric Van Cutsem, MD

to less gastrointestinal toxicity (11.8% vs 29.3%). The study is ongoing, and overall survival and quality-of-life factors are being evaluated.

Panitumumab Shows Limited Effect in Wild-type KRAS Colorectal Cancer In chemoresistant patients with colorectal cancer selected for the wild-type KRAS gene, panitumumab (Vectibix), given with irinotecan as second-line therapy, produced an insignificant impact on overall survival and a modest improvement in progression-free survival, despite marked improvement in response rates.6 These were the results of PICCOLO, a large randomized trial with prospective molecular stratification, which included 696 patients randomized to irinotecan with or without panitumumab, of whom 460 had wild-type KRAS tumors and had received no prior antiEGFR therapy.

Matt Seymour, MD

Further analysis showed that the benefit of panitumumab was confined to patients whose tumors were also wild-type for BRAF, NRAS, PIK3CA, and KRAS codon 146. Matt Seymour, MD, University of Leeds, UK, said, “We found mutations in one of these other genes in 29% of patients with wild-type KRAS tumors, and for these continued on page 20

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The ASCO Post | DECEMBER 15, 2011

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2011 European Multidisciplinary Cancer Congress Important Briefs continued from page 18

patients panitumumab produced borderline significantly worse survival. Conversely, patients with no mutations had increased benefit in terms of response rate, though disappointingly overall survival was not significantly improved.” “These results suggest that around 30% of patients currently being selected for EGFR therapies based on standard KRAS tests may be gaining no benefit or even being harmed,” Dr. Seymour told listeners. “The value of this study is that the authors went further and looked beyond KRAS mutations,” said Dr. Van Cutsem. “This is pushing us to do more in-depth analysis in our trials. The data are not fully conclusive.”

Chemotherapy Infusion for Liver Metastases in Uveal Melanoma Patients with liver metastases from uveal melanoma experienced a survival benefit after treatment with percutaneous hepatic perfusion, in which chemotherapy is directly infused into the liver.7 “This is the first treatment to show a clinical benefit within a randomized trial in patients with liver metastases from ocular melanoma,” said James F. Pingpank, MD, of the University of Pittsburgh School of Medicine, Pennsylvania. The phase III trial randomly assigned 93 patients to percutaneous hepatic perfusion or best alternative

care. Percutaneous hepatic perfusion saturates the liver with high doses of melphalan delivered via hepatic artery infusion every 4 to 5 weeks. Patients receiving percutaneous hepatic perfusion had a median progression-free survival of 6.1 months, compared with 1.6 months with best

Roussy in Paris, commented, “One of the interesting points is that those patients who crossed over from the best alternative care arm of the study had progression-free survival after ‘late’ treatment with percutaneous hepatic perfusion that is about the same as when percutaneous hepatic perfusion was given upfront [6.5 months overall and 9.2 months with disease confined to the liver].” Percutaneous hepatic perfusion was associated with more grade 3/4 hematologic toxicity, but this was transient. The investigators said this approach might also be used in patients with liver metastases from other cancers.

■

James F. Pingpank, MD

alternative care, a 64% reduction in risk (P < .001). For patients with disease predominantly confined to the liver, median hepatic-only progression-free survival reached 8.0 months vs 1.6 months with best alternative care (P < .0001). “These were highly significant results in the experimental arm,” Dr. Pingpank noted. Overall survival at 1 year, however, was not significantly improved: 29% with percutaneous hepatic perfusion and 26% with best alternative care, with median overall survival being 11.4 and 9.9 months, respectively. This was most likely due to high (> 50%) crossover, he said. Alexander Eggermont, MD, of the Institut de Cancérologie Gustave

Disclosure: Dr. Krug received research funding from Merck. Dr. Seymour reported that the PICCOLO study received some financial support from Amgen. Dr. Kaye is a member of a Roche advisory board for which he has received honoraria. Dr. Eggermont has served on advisory boards for Bristol-Myers Squibb, Delcath, GlaxoSmithKline, Merck, and Roche.

References 1. Krug LM, Kindler H, Calvert H, et al: Vorinostat in patients with advanced malignant pleural mesothelioma who have failed prior pemetrexed and either cisplatin or carboplatin therapy: A phase III, randomized, double-blind, placebocontrolled trial. 2011 European Multidisciplinary Cancer Congress. Abstract 3BA. Presented September 26, 2011. 2. Aghajanian C, Blank SV, Goff B, et al: Efficacy in patient subgroups in OCEANS, a randomized, placebo-controlled phase 3 trial of chemotherapy ± bevacizumab in patients with platinum-sensitive recurrent

epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. 2011 European Multidisciplinary Cancer Congress. Abstract 5LBA. Presented September 25, 2011. 3. Stark D, Nankivell M, Hipert F, et al: Quality of life in the ICON7 GIG phase III randomized clinical trial. 2011 European Multidisciplinary Cancer Congress. Abstract 22LBA. Presented September 26, 2011. 4. Monk BJ, Huang H, Burger RA, et al: Quality of life outcomes of a randomized, placebo-controlled trial of bevacizumab in the front-line treatment of ovarian cancer: A Gynecology Oncology Group study. 2011 European Multidisciplinary Cancer Congress. Abstract 23LBA. Presented September 26, 2011. 5. Van Cutsem E, Prenen H, GuillénPonce C, et al: A phase I/II open-label, randomized study of BIBF 1120 plus mFOLFOX6 compared to bevacizumab plus mFOLFOX6 in patients with metastatic colorectal cancer. 2011 European Multidisciplinary Cancer Congress. Abstract 14LBA. Presented September 27, 2011. 6. Seymour MT, Brown SR, Richman S, et al: Panitumumab in combination with irinotecan for chemoresistant advanced colorectal cancer: Results of PICCOLO, a large, randomized trial with prospective molecular marker stratification. 2011 European Multidisciplinary Cancer Congress. Abstract 6007. Presented September 24, 2011. 7. Pingpank JF, Hughes M, Alexander HR, et al: Percutaneous hepatic perfusion versus best alternative care for patients with melanoma liver metastases—efficacy update of the phase III trial. 2011 European Multidisciplinary Cancer Congress. Abstract 9304. Presented September 24, 2011. Targeted Therapy

Benefit of Panitumumab Seen Primarily in Patients with Recurrent or Metastatic Head and Neck Cancer and HPV-negative Tumors By Caroline Helwick

he addition of panitumumab (Vectibix) to chemotherapy improved overall and progression-free survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck, but its benefit was limited to patients whose tumors were negative for the human papillomavirus (HPV).1 The subanalysis of the phase III SPECTRUM trial, reported at the 2011 European Multidisciplinary Cancer Congress in Stockholm, examined whether subsets of patients benefit more than others to the addition of panitumumab plus platinum-based therapy (cisplatin and fluorouracil). Investigators had previously reported that patients who received the epidermal growth fac-

tor receptor (EGFR) inhibitor had a significant improvement in progressionfree survival but not overall survival, vs the chemotherapy-alone arm. The current study is the first report of treatment outcomes related to HPV status with any drug in the first-line

treatment of recurrent or metastatic squamous cell head and neck cancer, according to lead investigator Jan B. Vermorken, MD, PhD, of the Antwerp University Hospital in Belgium. SPECTRUM evaluated panitumumab in 657 patients with recurrent or metastatic disease, of whom 411 (63%) provided evaluable tissue samples for assessing HPV status. Of these, 23% were HPV-positive (ie, staining of ≥ 10% of cells) and 77% were HPV-negative.

Survival Improved Only in HPV-negative Subset Jan B. Vermorken, MD, PhD

The addition of panitumumab resulted in improved overall survival, but only in the HPV-negative subset,

whose median overall survival was 11.8 months vs 8.6 months in the chemotherapy arm: a 27% statistically significant reduction in the risk of death (P = .02). In contrast, in the HPV-positive subset, the addition of panitumumab was associated with a risk reduction of only 4% (HR = 0.96; 95% CI = 0.59– 1.57, P = .88), Dr. Vermorken reported. “The survival was strikingly and significantly different in the HPVnegative patients who received panitumumab, and this was not the case in the HPV-positive patients,” he noted. Progression-free survival was also significantly improved with panitumumab in the HPV-negative subset, continued on page 22

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The ASCO Post | DECEMBER 15, 2011

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2011 European Multidisciplinary Cancer Congress Benefit of Panitumumab continued from page 20

showing a 32% reduction in risk of progression (P = .002) and a median progression-free survival of 6.5 months vs 5.1 months with chemotherapy alone. In the HPV-positive subset, there was no detectable risk reduction by adding panitumumab (HR = 1.04, 95% CI = 0.67–1.63, P = .85) and median progression-free survival was 5.5 and 5.3 months, respectively.

Other Findings The effect of panitumumab in HPV-negative patients was confirmed in the Cox regression analysis, taking into account the other independent variables, including

performance status, prior platinum use, smoking habits, and severe weight loss. The tests for interaction, however, were not significant (P = .332 for overall survival and .097 for progression-free survival), possibly due to small numbers of patients in the HPV-positive subset. In the chemotherapy-only arm (comprising 190 of the 411 evaluable patients), he added, there was a trend for a more favorable outcome in patients with HPV-positive tumors. However, “this should be confirmed in an independent dataset,” he said. Adverse events in the panitumumab arm were in keeping with typical findings for EGFR inhibitors. Serious adverse events leading to

Panitumumab in Recurrent/Metastatic Head and Neck Cancer ■■ In a subanalysis of the phase III SPECTRUM trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck, the addition of panitumumab to cisplatin-based chemotherapy improved overall survival and progression-free survival in patients with HPVnegative, but not HPV-positive, tumors.

■■ In HPV-negative patients, median overall survival for patients receiving panitumumab/chemotherapy was 11.8 months vs 8.6 months with chemotherapy alone (HR = 0.73).

■■ In HPV-negative patients, median progression-free survival was

6.5 months with panitumumab/chemotherapy vs 5.1 months with chemotherapy alone (HR = 0.68).

■■ HPV is becoming established as a prognostic factor in locally advanced disease, but more study is needed in recurrent/metastatic disease.

CONQUERING

EXPERT POINT OF VIEW

iscussing the presentation, Jean Bourhis, MD, PhD, of the Institut Gustave Roussy in Villejuif, France, said that while HPV has become a major prognostic factor in locally advanced head and neck cancer, its prognostic value in recurrent and metastatic disease is less clear. “The role of HPV in recurrent and metastatic disease for predicting response to EGFR monoclonal antibodies is also unknown,” he said. According to Dr. Bourhis, SPECTRUM has several limitations. It is a subgroup and retrospective analysis, only two-thirds of the patients had HPV This is the first status evaluable, the analysis of HPV was primarily done on the primary description of EGFR (not the recurrent) tumor, and the test inhibition activity for interaction was nonsignificant. Nevertheless, this is the first despecifically in HPVscription of EGFR inhibition activity negative disease. specifically in HPV-negative disease, and the data are consistent with previous findings, he said. “There is a potentially important clinical impact of these findings,” he concluded. “But because of some limitations in the study, there is a need for confirmation and for generating additional level 1 evidence in recurrent/metastatic disease.”

■

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

study or drug discontinuation in the intent-to-treat population (n = 650) occurred in 14% of the panitumumab arm and 12% of the chemotherapyonly arm.

■

Disclosure: Dr. Vermorken has participated in advisory boards and received honoraria for giving lections for Amgen, Merck-Serono, Boehringer-Ingelheim, sanofi-avents, and Genmab.

Reference 1. Vermorken J, Stöhlmacher J, Oliner K, et al: Safety and efficacy of panitumumab in HPV positive and HPV negative recurrent/metastatic squamous cell carcinoma of the head and neck: Analysis of the phase 3 SPECTRUM trial. 2011 European Multidisciplinary Cancer Congress. Abstract 25LBA. Presented September 24, 2011.

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SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T HE 5 - Y E A R S UR VIVAL R ATE I S 17 % F O R PATIENTS W ITH M E TA S TATIC S OF T TIS S UE SA RC OMA , YE T SI G N IF ICANT THER APEUTIC A D VA N CE MENTS AR E LAG GING. 1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

Merck Oncology

The ASCO Post | DECEMBER 15, 2011

PAGE 24

Investigational Agents

Gathering Data Point to Potential Advantages of Vismodegib in Basal Cell Carcinoma and Other Advanced Cancers By Matthew Stenger

ismodegib is a small-molecule, orally active hedgehog pathway inhibitor that has shown considerable promise in treating basal cell carcinoma and is currently being evaluated alone and in combination in earlyphase trials in medulloblastoma and a long list of other cancers.1 Owing to its first-in-class specificity for the Hedgehog pathway and relatively low toxicity, this drug has potential advantages compared with conventional chemotherapy in a variety of settings.

Hedgehog Pathway The hedgehog pathway is a primary regulator of many fundamental processes in vertebrate embryonic development, including stem cell maintenance, cell differentiation, tissue polarity, and cell proliferation. In knockout mice lacking components of the pathway, the brain, skeleton, musculature, gastrointestinal tract, and lungs fail to develop correctly. Although the pathway is normally inactive in differentiated cells, recent data indicate a role of hedgehog signaling in regulating adult stem cells involved in tissue maintenance and regeneration. The pathway consists of three ligands (sonic, Indian, and desert) and two interacting transmembrane receptors, known as patched (PTC) and smoothened (SMO). In the absence of hedgehog ligand binding, PTC and SMO form a complex that inhibits cellular proliferation. With ligand binding, SMO is activated by the dissociation of the PTC receptor, initiating G protein– mediated signaling cascades that upregulate the glioma-associated oncogenes GLI1, GLI2, and GLI3. The associated proteins act as transcription factors that alter gene expression in apoptotic and cell-cycle pathways, as well as in the hedgehog signaling pathway. Reactivation of the hedgehog pathway through mutations or aberrant autocrine or

paracrine ligand stimulation can result in uncontrolled cellular proliferation and tumor formation. Constitutive activation of the hedgehog pathway leading to tumorigenesis is found in basal cell carcinomas and medulloblastoma.2 A variety of other cancers, including prostate, stomach, pancreatic, and colon, cancers, glioma, lymphoma, leukemia, and melanoma also exhibit inappropriate activation of this pathway. This pathway has also been shown to regulate proliferation of cancer stem cells and to increase tumor invasiveness. Vismodegib is a ligand-specific inhibitor of the hedgehog pathway. It suppresses hedgehog signaling by binding to and interfering with the SMO transmembrane receptor, thereby preventing positive signaling to the pathway.

Phase I Trial Vismodegib is furthest along in development in the setting of basal cell carcinoma, the vast majority of cases of which appear to involve aberrant hedgehog signaling.3 In a phase I trial,4 68 patients (including 33 with advanced basal cell carcinoma, 8 with pancreatic cancer, 1 with medulloblastoma, and 17 with other types of cancer) received vismodegib at 150, 270, or 540 mg/d. Grade 4 adverse events occurred in 9% of patients (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia), and 28% experienced a grade 3 event, most commonly hyponatremia (10%), abdominal pain (7%), and fatigue (6%). No maximum tolerated dose was reached. The recommended phase II dose was 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose. Tumor responses were observed in 20 patients, including 19 with basal cell carcinoma and 1 with unconfirmed re-

Vismodegib, a First-in-class Investigational Oral Drug ■■ The hedgehog pathway inhibitor vismodegib has shown promising

results in early-phase trials, primarily in patients with basal cell carcinoma.

■■ The drug is also being investigated in numerous other advanced malignancies.

■■ Based on results of a pivotal phase II trial in basal cell carcinoma, a new drug application was recently submitted to the FDA for vismodegib.

sponse in medulloblastoma; 14 patients had stable disease as best response, and 28 had progressive disease. In patients with basal cell carcinoma, evidence of downmodulation of the oncogene GLI1 was observed in noninvolved skin, indicating inhibition of the hedgehog pathway.

Phase II Trial A pivotal phase II study of vismodegib in patients with advanced basal cell carcinoma (ERIVANCE BCC trial) was reported to meet its primary endpoint of overall response rate as assessed by independent review, showing that vismodegib shrank tumors in a predefined percentage of study subjects.5 This international, single-arm, multicenter, twocohort, open-label study included 104 patients with locally advanced disease (n = 71) or metastatic disease (n = 33). Patients with locally advanced disease had lesions that were inappropriate for surgery (defined as inoperable lesions or those requiring surgery that would result in substantial deformity) and unresponsive to or ineligible for radiotherapy. Metastatic disease was defined as disease that had spread to other parts of the body, including the lymph nodes, lung, bones, or internal organs. Study sites were located in the United States, Australia, and Europe. Patients received oral vismodegib at 150 mg/d until disease progression or intolerable toxicity. Responses were achieved in 43% of patients with locally advanced disease and 30% of those with metastatic disease as assessed by independent review, with investigator assessment (a secondary endpoint of the trial) indicating response rates of 60% and 46%, respectively. The clinical benefit rate, including the proportion of patients with stable disease for more than 24 weeks, was 75% on independent review, and the median duration of progression-free survival for both metastatic and locally advanced disease patients was 9.5 months. The most common adverse events in the phase II trial were muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite, and diarrhea. Serious adverse events occurred in 25% of patients and were considered related to vismodegib treatment in 4%. Seven patients (7%) died, with none of the deaths thought to be related to vismodegib treatment;

in all cases, patients had other preexisting diseases or symptoms that were related to their presumed cause of death.

Further Evaluation On the basis of the findings in the phase II study in basal cell carcinoma, Genentech filed a SEE PAGE 68 new drug application for vismodegib in September.6 The drug is being developed by Genentech in collaboration with Curis. Vismodegib alone or in combination is also being evaluated in early-phase studies in numerous malignancies, including metastatic colorectal cancer, small cell lung cancer, advanced stomach cancer, pancreatic cancer, chondrosarcoma, basal cell nevus syndrome, relapsed multiple myeloma, and recurrent glioblastoma multiforme, in addition to medulloblastoma.7 Phase II studies of vismodegib in ovarian cancer were discontinued in 2010 due to the absence of evidence of sufficient improvement in progression-free survival.

■

References 1. De Smaele E, Ferretti E, Gulino A: Vismodegib, a small-molecule inhibitor of the hedgehog pathway for the treatment of advanced cancers. Curr Opin Investig Drugs 11:707-718, 2010. 2. Gupta S, Takebe N, LoRusso P: Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol 2:237-250, 2010. 3. Caro I, Low JA: The role of the hedgehog signaling pathway in the development of basal cell carcinoma and opportunities for treatment. Clin Cancer Res 16:3335-3339, 2010. 4. LoRusso PM, Rudin CM, Reddy JC, et al: Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res 17:2502-2511, 2011. 5. Roche Media Release: Pivotal study showed vismodegib helped shrink tumours or heal lesions in people with rare form of advanced skin cancer. June 20, 2011. Available at http://www.roche.com. 6. Genentech Media Release: Genentech submits new drug application to FDA for vismodegib for rare form of advanced skin cancer. September 12, 2011. Available at http://www.gene.com. 7. Clinical trials of vismodegib. Available at http://clinicaltrials.gov/.

ASCOPost.com | DECEMBER 15, 2011

PAGE 25

97th Annual American College of Surgeons Clinical Congress Neutrophil/Lymphocyte Ratio Can Upstage Patients with Bladder Cancer By Caroline Helwick

sizable proportion of bladder cancer patients who would benefit from neoadjuvant chemotherapy are not receiving it, researchers from the University of Wisconsin School of Medicine and Public Health, Madison, concluded. Their conclusion was based on their assessment of the neutrophil/ lymphocyte ratio as a way to identify patients with non–organAaron Potretzke, MD c o n f i n e d disease, who may benefit from neoadjuvant chemotherapy.1 Aaron Potretzke, MD, a urology resident, and Tracy M. Downs, MD, FACS, Senior Investigator and Director of the Bladder Cancer Program, reported the findings, which earned the “Posters of Exceptional Merit” award at the 97th Annual American College of Surgeons Clinical Congress in San Francisco.

Upstaging and Outcomes “We are limited in our ability to predict the final pathologic stage of bladder tumors. This is evidenced Tracy M. Downs, MD, FACS by the fact that 50% of radical cystectomy cases are upstaged, and, more importantly, 43% are upstaged from previously organ-confined disease to non–organconfined disease, which has a tremen-

dous impact on prognosis and outcomes,” Dr. Potretzke said. In patients with non–organ-confined disease, neoadjuvant chemotherapy has proven overall and cancer-specific

Through its flagship service offering, P4 Pathways, Cardinal Health Specialty Solutions works with hundreds of community oncologists across the nation to establish clinically proven, evidence-based treatment protocols that promote the delivery of high quality, cost-efficient patient care. Since launching the nation’s first cancer care pathways program in 2008, more

Q: A:

When implemented correctly, cancer care pathways can ultimately play an important role in protecting the longterm financial viability and autonomy of community oncologists. They can help physicians play a meaningful role in improving patient outcomes – and costs – through the consistent use of evidence-based best practices. When coupled with the right compliance measurement tools, pathways can also reduce administrative and other burdens to free up physician time for patient care. Cardinal Health Specialty Solutions is also leveraging pathways to develop new paradigms for compensating physicians for the quality of the care they provide.

■■ It is also predictive in gastric, colon, ovarian, pancreatic, and lymphatic cancers.

Why should oncologists care about cancer care pathways?

Oncologists are increasingly being called upon to do more with less. They’re charged with caring for an increasing number of patients and improving the quality of the care they provide those patients. At the same time, they’re facing the continuing erosion of reimbursement. These challenges are creating uncertain times for community oncology, the backbone of our nation’s cancer care delivery system.

■■ The neutrophil/lymphocyte

patients with non– organ-confined bladder cancer, who may benefit from neoadjuvant chemotherapy.

continued on page 32

A discussion with Bruce Feinberg, M.D., Vice President & Chief Medical Officer, Cardinal Health Specialty Solutions

■■ It can be used to identify

capacity to fight off malignancy and metastasis. It is predictive in gastric, colon, ovarian, pancreatic, and lymphatic cancers, Dr. Potretzke explained.

The Role of Clinical Pathways in Supporting Community Oncology

Neutrophil/Lymphocyte Ratio in Bladder Cancer ratio is an indication of the immune system’s capacity to fight off malignancy.

survival benefits for T3 bladder cancer. Therefore, these patients need to be identified prior to cystectomy, he said. The neutrophil/lymphocyte ratio is an indication of the immune system’s

In your view, what factors make pathways programs ‘work’ for physicians?

Most importantly, pathways must improve outcomes. That has to be the number-one priority. Second, physicians need to lead the development of the pathways they’ll be expected to follow. Third, technology and other tools need to make it as efficient as possible for physicians to implement and track pathways compliance. Cardinal Health Specialty Solutions also believes that pathways should be leveraged to remove administrative burdens – like prior authorization.

than 10 percent of U.S. oncologists have become engaged in P4 Pathways programs, which touch more than 20 million insured patients. Here, Dr. Bruce Feinberg shares his viewpoints on how physician-led pathways programs are creating new paradigms for improving patient care.

We advocate for payors to appropriately incentivize physicians to participate. The most successful pathways programs provide fair reimbursement for generic medications, lock in reimbursement rates for branded drugs and allow physicians to share in cost savings that are created through reduced hospitalization and drug spend.

Cardinal Health Specialty Solutions understands that cancer care pathways represent a shift in the mindset of oncologists. They’re helping us leverage pathways to improve the quality and consistency of care. And they’re developing new models that ensure doctors get fairly compensated for delivering that care to patients. Ram Trehan, MD Greater Washington Oncology Assoc., Silver Spring, MD

Can pathways be used to help physicians deal with drug shortages?

We are piloting an innovative new system that alerts regional Pathways Steering Committees – comprised of practicing oncologists – of current and potential shortages, and mobilizes them to review evidence to recommend next-best alternative therapies. This approach helps providers mitigate the impact shortages have on patient care, ensures consistency in approach and saves physicians a great deal of time.

Dr. Feinberg can be reached at bruce.feinberg@cardinalhealth.com.

Should physicians who do not comply with pathways be penalized?

Cardinal Health Specialty Solutions always leads with a clear mandate that physicians have ultimate control of treatment decisions at the point of care. It’s impossible for 100% of patients to be cared for using a limited set of treatment protocols. That’s why our model allows room for individualized medicine and physician discretion. We set compliance goals, but the physician has ultimate control of treatment decisions at the point of care. For example, we generally expect physicians to be pathways compliant 70+% of the time in year one and 80+% in year two. To date, physician compliance in each of our pathways programs has exceeded these goals.

Q: A:

Is your approach to cancer care pathways working?

Yes. For example, physicians who participate in our more mature pathways programs spend an average of 40% less time than non-participating physicians on the management of the same disease, while their patients experience 15% fewer emergency room (ER) visits and hospitalizations. Reduced ER visits, alone, are a great example of how pathways programs can improve healthcare quality and costs. One of our more mature pathways programs reduced its ER-related expenses by $5 million in one year. These are great examples of physicians using pathways to free up their own time to focus on other areas of patient care while they’re removing unnecessary costs from the system.

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Cardinal Health Specialty Solutions

The ASCO Post | DECEMBER 15, 2011

PAGE 26

OncologyWorldwide Lessons from a Northern Neighbor: A Conversation with Joseph M. Connors, MD A practitioner shares his perspective on Canadian cancer care. By Ronald Piana

Joseph M. Connors, MD

olicy analysts searching for a better understanding of healthcare models often compare the cancer delivery systems of Canada and the United States. The ASCO Post recently spoke with Joseph M. Connors, MD, Clinical Professor and Director of the BC Cancer Agency’s Centre for Lymphoid Cancer, Vancouver, British Columbia. Dr. Connors shed light on his personal experiences, moving from the United States to Canada, and the differences between the two countries’ cancer care systems.

Choosing Medicine Why did you decide to become a physician? I grew up in rural New England on Cape Cod. As a child I was impressed by our family practitioner. He was always doing interesting work and interacting with people in a way that I wanted to. Once I reached college, however, my driving interest was in biology, and I wanted to become a marine biologist. It wasn’t until college graduation approached that I decided to apply to medical school; I was fortunate to be accepted to Yale Medical School, and that very rich academic experience cemented my decision to become a physician.

Early Career What compelled you to pursue oncology as a specialty? I paid my medical school tuition

with scholarships and college loans. At the time, the U.S. Public Health Service offered a program in which they would provide funding for my last 2 years of medical school in exchange for a promise to work within the public health service for 2 years after my residency training. I liked the idea of serving in challenged populations and I agreed. I postponed my public health service until after completing my 4-year residency in internal medicine. The public health service gave me a choice of the Southwest or Alaska. I always thought it would be an adventure to live in Alaska, so I found a position at the Alaskan Indian Health Service. I moved to Alaska with my wife and spent a couple of years there. I still hadn’t decided what specialty I wanted to pursue, but oncology was getting higher on the list. During my first year with the Indian Health Service I went down to Stanford to attend a weeklong course in which several of Stanford’s prominent scientists delivered lectures to internists who were interested in basic biology. It became clear that one field that was going to be at the van-

Canadian System How does the Canadian cancer care delivery system operate? The basic idea is that one centralized agency in each Canadian province, such as British Columbia, provides cancer care to the whole population across the entire province. Canadian health care is government financed, largely with tax revenue support, so anybody with a malignancy interacts with a single agency from diagnosis through the full continuum of care. Moreover, there is a central repository for medical records—a pooling of patient resources in one unified agency that aggregates clinical data and provides funds for subsequent clinical trials. This unified system makes it much easier to access valuable information that can be directly applied to patient care.

Relative Benefits and Limitations Americans are engaged in an ongoing debate about the effectiveness of the U.S. health-care system. What are the benefits of the Canadian system? There are clear-cut differences be-

The next 20 years are going to be extraordinarily productive. We’ll gain insights that will lead to curative advances that are going to astound people. guard of biologic investigations was oncology. So while I was at Stanford, I walked over to the oncology office and asked if there were any fellowships available. As it turned out, a fellowship was available following the last year of my service in Alaska. I applied, they accepted me, and I wound up doing a 2-year oncology fellowship at Stanford. Immediately after my fellowship, I took a position at the British Columbia Cancer Agency, where I’ve been treating patients with lymphoproliferative diseases for 30 years.

tween the U.S. and Canadian delivery systems. Instead of dealing with more than 2,200 payers, as is the case with practitioners in the United States, medical care in general—and especially cancer care—is provided to patients in British Columbia by a single-payer entity. Our system dramatically increases efficiency such that we can administer the whole system based on about 2% of healthcare dollars, as opposed to the more than 20% administration costs in the States. Another benefit for me as a clini-

cian is one fundamental principle: Everyone has access to medical care, no matter who you are. Universal access to high-quality care is not related to income, insurance, or employment status. As a clinician, this is attractive because when I see patients, I don’t question whether they can pay for a particular treatment. So it is liberating in the sense that I can simply map out what I feel is the best therapeutic strategy for my patients, knowing that any treatment with evidence-based benefit for managing the particular disease I’m treating will be covered by our universal health-care system. And the downsides? In the States, treatment decisions rest primarily with the treating oncologist, and as long as patients have adequate coverage or can pay out of pocket, any available treatment is on the table. That’s not the case in Canada. We don’t get to give patients treatments unless they have proven benefit, so we have an entire system devoted to examining what evidence justifies which treatments. As an oncologist treating very sick patients, that kind of oversight can be a bit frustrating. For instance, I cannot give a drug without evidence-based proof that the drug has efficacy and works better than the less-costly alternatives in the particular disease I’m treating. So the drawback to a centralized system is that it constrains innovative behavior, is resistant to change, and is slow to introduce new approaches. The system waits for adequate evidence before moving ahead, especially if the drug or other therapy in question is costly. The advantage of the system in the States is that innovation thrives more readily. In Canada, we’ve sacrificed some on the novel development process in order to provide universal coverage for all our people. continued on page 32

WHAT DOES THE DISCOVERY OF A

Distinct gene mEAn FOR pATIEnTS WITH LOCALLY ADVAnCED OR mETASTATIC ALK-positive nSCLC?

XALKORI (crizotinib) is now approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.

XALKORI is the first ALK-directed therapy offering targeted antitumor activity in patients with locally advanced or metastatic ALK-positive NSCLC 1

In early-phase trials of 255 patients taking XALKORI...* EFFICACY PARAMETER ORR (CR+PR)a [% (95% CI)] Number of responders Duration of responseb [median (range) weeks]

STUDY A (N=136)

STUDY B (N=119)

50% (42%, 59%) 68 41.9 (6.1+, 42.1+)

61% (52%, 70%) 71 48.1 (4.1+, 76.6+)

SELECTED SAFETY INFORMATION XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Other causes of pneumonitis should be excluded. XALKORI should be permanently discontinued in patients with treatment-related pneumonitis. Grade 3 or 4 ALT elevation was observed in 7% of patients in Study A and 4% of patients in Study B. Three patients from Study A (2%) and 1 patient from Study B (<1%) required permanent

discontinuation from treatment. Concurrent elevation in ALT and total bilirubin have occurred. Liver function tests including ALT and total bilirubin should be monitored once a month and as clinically indicated, with more frequent repeat testing for grade 2-4 transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. QTc prolongation has been observed. XALKORI should be avoided in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known

The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation ➤ Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia

XALKORI adverse reactions were usually manageable through dose modification ➤ Dosing interruptions occurred in 36% and 45% of patients, and lasted greater than 2 weeks in 13% and 19% of all patients in Studies A and B, respectively ➤ 44% of patients in Study A and 29% of patients in Study B reduced their dose due to adverse events (AEs) ➤ 6% of patients in Study A and 3% of patients in Study B permanently discontinued therapy due to treatment-related AEs

*XALKORI for the treatment of locally advanced or metastatic NSCLC was investigated in 2 multicenter, single-arm studies. Study A was a phase 2 trial in 136 patients; ALK-positive NSCLC was identified using the Vysis ALK Break Apart FISH Probe Kit. Study B was a phase 1 trial in 119 patients; ALK-positive NSCLC was identified using a number of local clinical trial assays. Patients enrolled in these studies had received prior systemic therapy, with the exception of 15 patients in Study B who had no prior systemic therapy for locally advanced or metastatic disease. The primary efficacy end point in both studies measured objective response rate based on RECIST criteria; duration of response was also evaluated. a One patient was not evaluable for response in Study A; 3 patients were not evaluable for response in Study B. b Preliminary estimate using Kaplan-Meier method. +Censored values.

to prolong the QT interval, periodic monitoring with electrocardiograms and electrolytes should be considered. Permanently discontinue XALKORI for grade 4 QTc prolongation. XALKORI should be withheld for grade 3 QTc prolongation until recovery to ≤ grade 1. Permanently discontinue XALKORI if grade 3 QTc prolongation recurs. Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. Please see additional Important Safety Information on the next page and accompanying brief summary of Prescribing Information. For more information, please visit www.xalkorihcp.com.

Take a picture of this icon with your smart phone to learn more about XALKORI

Now thereâ&#x20AC;&#x2122;s a reason to check Pretreatment testing can help guide therapeutic decisions2 Approval of XALKORI is a compelling reason to start testing advanced NSCLC patients for ALK An FDA-approved test should be used to determine which patients have ALK-positive NSCLC

Please see accompanying brief summary of Prescribing Information. For more information, please visit www.xalkorihcp.com. XALKORI is a registered trademark of Pfizer Inc. References: 1. Sasaki T, Rodig SJ, Chirieac LR, JĂ¤nne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46(10):1773-1780. 2. Perez-Soler R. Individualized therapy in non-small cell lung cancer: future versus current clinical practice. Oncogene. 2009;28(Suppl 1):S38-S45.

XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.

IMPORTANT SAFETY INFORMATION Pneumonitis: XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Other causes of pneumonitis should be excluded. XALKORI should be permanently discontinued in patients with treatment-related pneumonitis. Hepatic Laboratory Abnormalities: Grade 3 or 4 ALT elevation was observed in 7% of patients in Study A and 4% of patients in Study B. Three patients from Study A (2%) and 1 patient from Study B (<1%) required permanent discontinuation from treatment. Concurrent elevation in ALT and total bilirubin have occurred. Liver function tests including ALT and total bilirubin should be monitored once a month and as clinically indicated, with more frequent repeat testing for grade 2-4 transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. QT Interval Prolongation: QTc prolongation has been observed. XALKORI should be avoided in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval, periodic monitoring with electrocardiograms and electrolytes should be considered. Permanently discontinue XALKORI for grade 4 QTc prolongation. XALKORI should be withheld for grade 3 QTc prolongation until recovery to ≤ grade 1. Permanently discontinue XALKORI if grade 3 QTc prolongation recurs. ALK Testing: Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. If the patient or their partner becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse Reactions: Among the 397 patients for whom information on deaths and serious adverse reactions are available, deaths within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9), and other (4). Safety of XALKORI was evaluated in 255 patients with locally advanced or metastatic ALK-positive NSCLC in 2 single-arm clinical trials (Studies A and B). The most common adverse reactions (≥25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia. • Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia were reported in 159 (62%) patients in clinical trials. Ophthalmological evaluation should be considered, particularly if patients experience photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could also be signs of a retinal hole or pending retinal detachment. Caution should be exercised when driving or operating machinery by patients who experience vision disorder. • Neuropathy attributed to study drug was reported in 34 (13%) patients. Grade 2 motor neuropathy and grade 3 peripheral neuropathy were reported in 1 patient each. • Bradycardia has been reported in 12 (5%) patients treated with XALKORI. All of these cases were grade 1 or 2 in severity. • Complex renal cysts have been reported in 2 (1%) patients treated with XALKORI. There were no reports of abnormal urinalyses or renal impairment in these cases. Grade 3 or 4 laboratory abnormalities of neutropenia, thrombocytopenia, and lymphopenia were seen in 5.2%, 0.4%, and 11.4% of patients, respectively. Drug Interactions: Caution should be exercised with concomitant use of moderate CYP3A inhibitors. Grapefruit or grapefruit juice may increase plasma concentrations of crizotinib and should be avoided. The concurrent use of strong CYP3A inducers and inhibitors should be avoided. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue XALKORI. Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Treatment with XALKORI should be used with caution in patients with hepatic impairment. Renal Impairment: No starting dose adjustment is needed for patients with mild and moderate renal impairment. No data are available for patients with end-stage renal disease. Caution should be used in patients with severe renal impairment or patients with end-stage renal disease.

CRI00127A/282258

Printed in USA/ October 2011

The ASCO Post | DECEMBER 15, 2011

PAGE 32

Oncology Worldwide

Joseph M. Connors, MD continued from page 26

Naiveté, Realism, and Optimism Any last thoughts on the state of cancer care? Over the past several decades, oncology has been injected with a steady

dose of realism. We first believed that cancer was going to yield fairly quickly to scientific investigation. That was naive, of course. As we’ve learned, cancer is a more fundamentally biologic process than most other diseases that focus on single organs or exogenous entities. It’s a big, yet understandable,

disappointment to me that over the span of my 30-year career, I have not seen effective curative agents for metastatic epithelial cancer. We’ve found ways to manipulate disseminated disease, but not cure it. But putting on my optimistic hat, I’d give my left arm to be at the beginning

of my career instead of closer to its end. The next 20 years are going to be extraordinarily productive. We’ll gain insights that will lead to curative advances that are going to astound people. And I’m glad I’ll be able to see that unfold.

■

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

Neutrophil/Lymphocyte Ratio continued from page 25

The study included 76 patients with clinical stage ≤ T2 disease who underwent radical cystectomy for urothelial cell cancer. Postoperative pathology categorized patients as upstaged, no change in stage, or downstaged.

Upstaging of Patients Pathologists upstaged 42 patients (55.2%), downstaged 17 (22.4%), and kept the same stage in 17 (22.4%). Patients who were upstaged had statistically significantly higher NLR ratios at baseline vs patients whose stage remained unchanged and those who were downstaged: 4.09, 2.78, and 2.36, respectively (P = .001), he reported. More importantly, this difference in neutrophil/lymphocyte ratio was also observed between non–organconfined and organ-confined groups: 4.17 vs 2.60 (P = .002). “Finally, we determined that 22 patients would have been upstaged based on their preoperative neutrophil/lymphocyte ratio,” Dr. Potretzke said. “We would have at least counseled these patients as to the benefits of neoadjuvant chemotherapy, which could have had a real clinical impact.” The investigators will be implementing neutrophil/lymphocyte ratio in their clinic, and will further assess its utility in a clinical trial in which patients with a high ratio will be randomly assigned to neoadjuvant chemotherapy or immediate cystectomy, he said. Barbara L. Bass, MD, of Methodist Hospital in Houston, who moderated the Posters of Exceptional Merit session, said this research “has the potential to become clinically practice-changing.”

■

Disclosure: Drs. Potretzke, Downs, and Bass reported no potential conflicts of interest.

Reference 1. Downs TM, Potretzke AM, Abel J, et al: Neutrophil-lymphocyte ratio is associated with increased risk of pathological upstaging after radical cystectomy for clinical T2 urothelial carcinoma. American College of Surgeons 97th Clinical Congress. Abstract SE105. Presented October 25, 2011.

ASCOPost.com | DECEMBER 15, 2011

PAGE 33

Direct from ASCO

Medical Students Can Now Be ASCO Members, Thanks to an Intern Who Pressed

SCO has just added a membership category for medical students, spurred on by—you guessed it—a medical student. Daniel G. Stover, MD, knew he wanted to go into oncology from very early on. But when he contacted ASCO to join as an intern, having just graduated from Vanderbilt School of Medicine, he was told that no catego-

become ASCO members just made good sense. “We are already beginning to experience a significant manpower shortage in oncology. We should do everything we can as an organization to highlight the excitement and opportunities in the field and to attract the best people to careers in oncology,” he said. “Ideally, this process

“I had a mentor in oncology when I wrote to ASCO, but that’s definitely not the case for everyone; finding mentors isn’t always easy,” Dr. Stover commented. “Nothing fosters excitement about a topic like engaging with other people like you who are interested in the same thing. Now med students will be able to do that through ASCO.” Although a track at ASCO meetings specifically designed for med students doesn’t yet exist, such programs, along with social events targeting med students, could provide additional substance and value to this new category of ASCO membership, Dr. Rothenberg pointed out.

Robust Networking

ry existed for him. Dr. Stover crafted a letter to ASCO asking that the organization create a new membership category for those who haven’t yet progressed to their oncology fellowship program but already have a keen interest in oncology. “I wanted to be able to engage in ASCO, learn about what it is to be a clinical oncologist, and tap into the resources of the largest clinical oncology organization in the world,” said Dr. Stover, now the Hugh Jackson Morgan Chief Resident in Internal Medicine at Vanderbilt University Medical Center.

A Way to Stanch the Oncologist Shortage Helping him with the letter was his mentor Mace L. Rothenberg, MD, now Senior Vice President of Clinical Development and Medical Affairs for Pfizer Oncology, but then Professor of Medicine and Ingram Professor of Cancer Research at Vanderbilt, as well as an ASCO member who had held various leadership positions since 1986. Dr. Rothenberg agreed that allowing med students to

should begin as early as possible, well before people start their fellowships. This is exactly what we need to be doing on an individual level, as well— helping spur interest in a field that so desperately needs good young physicians.” Dr. Stover’s request was approved, and at the 2011 ASCO Annual Meeting it was made official: Medical students can now be ASCO members.

Reaching Them Earlier The upside for ASCO: helping inspire interest in oncology earlier in the education cycle, and potentially helping alleviate the worsening shortage of oncologists. The upside for med students: access to sessions and thousands of oncologists at ASCOsponsored meetings at a greatly discounted rate, and a yearly subscription to the Journal of Clinical Oncology for $50. Dr. Stover says finding mentors should prove to be one of the key benefits for students, as will the opportunity to network with other likeminded individuals at the same stage in their career.

“There are limited opportunities at medical schools for students to interact with oncology specialists in a meaningful way,” Dr. Rothenberg noted. “I am hopeful that this new membership category will enable students to connect with potential mentors and role models. Med students have so many questions for people who have gone through the same

What’s Hot in

JOP

Top 5 most-accessed articles recently published in Journal of Oncology Practice Volume 7, Issue 3

May 2011

Journal of oncology Practice The Authoritative Resource for Oncology Practices

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

www.jop.ascopubs.org

jop.ascopubs.org

decision-making process as they are facing,” he said. “It would be tremendously beneficial for them to have a way to meet and interact with people at various stages of their careers.” Dr. Stover is already taking advantage of networking provided through ASCO meetings, After attending the Gastrointestinal Cancers Symposium in September, he commented that just being able to attend the meetings and blend in with the fellows, researchers, and other doctors is very edifying. “Getting to meet the people doing the research was inspiring, and their willingness to include me—a 29 year old—in their discussions just floored me,” he said. “Their collegiality was really encouraging. Experiences like the one I just had will help push med students who are on the fence about oncology and excite those who already know it’s what they want to go into, spurring them on to become the people making the big decisions about the field at the meetings 10 years from now.”

■

1. Time for Better Integration of Oncology and Palliative Care Amy Abernethy, et al 7(6): 346 2. Perspectives from the Other Side: A Physician and Cancer Survivor Susan C. Stone 7(6): 348 3. The Integration of Palliative Medicine into Routine Oncological Care: What Does the Evidence Show Us? David J. Debono 7(6): 350 4. Building on Individual, State, and Federal Initiatives for Advance Care Planning, an Integral Component of Palliative and End-of-life Cancer Care Andrew S. Epstein, et al 7(6): 355 5. Taking Care: Community, Family, and Dying in Place J. Russell Hoverman 7(6): 359

The ASCO Post | DECEMBER 15, 2011

PAGE 34

Direct from ASCO

ASCO Helps Survivors Transition into Life after Treatment with New Booklet

rogress against cancer has helped save or extend the lives of millions of patients. Thanks to advances in medical research, there are about 12 million cancer survivors today in the United States. For patients transitioning back into everyday life after surgery, chemotherapy, radiation therapy, or other treatments, it can often be a confusing and even troubling time. To help patients adjust to life after active treatment, ASCO has a free, easy-to-use booklet that explains survivorship as a distinct phase in the cancer experience. The booklet is based on content from ASCO’s patient information website, Cancer.Net (www.cancer. net), and is meant to be given to a patient as the completion of treatment draws near.

Continuum of Care “As oncologists, our involvement in patient care doesn’t end along

with active treatment. We must provide the resources and tools to help guide people through the cancer care continuum,” said Melissa Hudson, MD, Chair of ASCO’s Survivorship Committee and Cancer.Net Associate Editor. ASCO’s booklet helps patients understand what to expect as treatment is completed, explains common challenges faced by survivors, and offers suggestions for next steps following treatment. “There are different definitions of survivorship, but among the most common is people living with, through, and beyond cancer,” said Diane Blum, MSW, Editor-inChief of Cancer.Net. “The period following treatment can be full of uncertainties. It is one of the most complex aspects of the cancer experience because it is different for every person,” she said.

Survivorship Care Plan Following

active

treatment,

Melissa Hudson, MD

many patients find it helpful to keep a Cancer Treatment Summary and Survivorship Care Plan as a convenient way to store information about their cancer, its treatment, and follow-up care. For patients, keeping track of their medical history is useful for future doctors who will provide care. The plan should define the responsibilities of care providers whether they are cancerrelated, non–cancer-related, or psychosocial providers. Clear descriptions of who is responsible for the various aspects of care can optimize care coordination, avoid unneces-

sary use of resources, and ensure that care is patient-centered and harmonized. “One of the best ways to ensure survivors have a smooth transition into their ‘new normal’ is to implement a survivorship care plan. These free forms available from ASCO, are helpful in ensuring doctors, nurses, social workers, and other health professionals are aligned in their goals following active cancer treatment,” said Dr. Hudson. The ASCO forms can be found at asco.org/ treatmentsummary or at cancer. net/treatmentsummaries. ASCO’s free Survivorship booklet is available to download at cancer.net/survivorship. Print copies can be ordered by calling ASCO University’s Bookstore at 888-2733508 or visiting cancer.net/estore. Although the booklet is free, shipping and handling charges apply. © 2011. American Society of Clinical Oncology. All Rights Reserved.

ASCO Issues Blueprint for Transforming Cancer Research in the ‘Molecular Era’ ACCELERATING PROGRESS AGAINST CANCER ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research

NOVEMBER 2011

n November 3, ASCO issued a new report that lays out ASCO’s vision for transforming clinical and translational research to deliver more effective and personalized cancer therapies faster. The report, Accelerating Progress Against Cancer: ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research, also articulates recommendations for achieving that vision over the next several years and ASCO’s commitment to enacting the recommendations. ASCO’s report emphasizes that cancer science is undergoing a period of revolutionary change, thanks to a rapidly growing understanding of the molecular biology of cancer and new

technologies that are leading to entirely new ways to develop therapies. However, the report argues that the U.S. cancer clinical research system is not fully equipped to deliver on the promise of these scientific and technologic advances in three key areas: ■■ Drug and diagnostic development ■■ Clinical trials design and implementation ■■ Health information technology (HIT)

Real-world Recommendations ASCO’s Blueprint provides realworld recommendations for each of these areas that ASCO plans to address, in partnership with policymakers and the cancer community. Specific recommendations include: 1. Establish a new approach to therapeutic development, driven by our more thorough understanding of cancer biology and the advent of new technologies. ■■ Identify and prioritize the molecular targets that have the greatest promise to improve survival.

■■ Incentivize collaboration to encourage industry and researchers to pursue high-priority targeted therapies and diagnostics in combination. 2. Design smarter, faster clinical trials to provide evidence for effective treatments targeted to patients most likely to benefit, sooner. Prioritize trials with the greatest potential benefits for patients, or that address clear unmet needs; shift away from trials that promise only marginal improvements in care. Select trial participants primarily based on molecular characteristics, to ensure that only those who are most likely to benefit are included and that patients aren’t excluded from trials because of health conditions that are not relevant. 3. Harness advances in health information technology to seamlessly integrate clinical research and patient care. ■■ Use HIT tools, including electronic health records (EHRs) and “rapid learning” systems, to enable the experiences of all patients to inform our understanding of the effectiveness and safety of treatments and to

help us focus on the most important research questions. ■■ Standardize EHRs by defining functional requirements, harmonizing data fields, and ensuring secure patient and provider access to information at any time. ■■ Develop industry standards for working with, storing, and capturing information from biospecimens (tissue and blood samples), which are essential to identifying and evaluating new ways to target cancer development.

Plans of Action Over the next 3 years, ASCO plans to work with partners throughout the research community to develop more detailed plans of action for each of the three areas covered in this report. To read the Blueprint, please go to www.asco.org/blueprint. For more about the progress already achieved due to cancer research, visit ASCO’s CancerProgress.Net.

■

ASCOPost.com | DECEMBER 15, 2011

PAGE 35

Direct from ASCO

2012 GU Cancers Symposium to Reflect the Field’s Focus on Personalized Cancer Care

he 2012 Genitourinary Cancers Symposium, to be held in San Francisco February 2–4, will feature some exciting advancements in the field that center on personalized cancer care.

Dr. Gomella is the Bernard W. Godwin Professor of Prostate Cancer at the Jefferson Kimmel Cancer Center in Philadelphia, as well as the center’s Chair of the Department of Urology and Associate Director of Clinical Affairs, and Clinical Director of the Jefferson Kimmel Cancer Center Network.

Truly Multidisciplinary

Leonard G. Gomella, MD

“The major cancer discussed at the meeting tends to be prostate cancer, and there hasn’t yet been a lot of specific targeting of pathways involving gene profiles for prostate cancer,” said Leonard G. Gomella, MD, Chair of the symposium Program Committee. “But we’re starting to see more in that area, and that will be on tap at the meeting.”

Several high-interest trials are expected to be reported at the meeting as late-breaking abstracts, said Dr. Gomella. “Traditionally this meeting serves as a point of reporting important preliminary trials in a variety of tumor types,” he said. “We anticipate that this will be the case this year, with many new agents in late stages of study for prostate, bladder, and kidney cancer in particular.” The multidisciplinary meeting is open to all members of the cancer care community interested in the prevention, screening, evaluation, and management of genitourinary cancer, including medical oncolo-

Help Your Patients Understand the Significant Research from 2011

Direct your patients to www.cancer.net/podcasts to learn about the 2011 Clinical Cancer Advances. In a special podcast, patients can hear

about this year’s most important advances in clinical cancer research and what these advances mean for their treatment and care.

■

gists, urologists, radiation oncologists, radiologists, pathologists, epidemiologists, pharmacologists, and translational-oriented laboratory scientists. “While other meetings are dominated by one particular treatment paradigm, the Genitourinary Cancers Symposium is truly multidisciplinary in scope and content,” said Adam S. Kibel, MD, Chair of the symposium’s Steering Committee and Chief of Urologic Surgery at Brigham and Women’s Hospital. “This maximizes the opportunity to better understand how integrated care can best be used to maximize chance of cure in our patients.”

While other meetings are dominated by one particular treatment paradigm, the Genitourinary Cancers Symposium is truly multidisciplinary in scope and content. Oncology Fellows: Avoiding Myopia Dr. Kibel said he’s particularly excited about the opportunity for young oncologists to broaden their horizons in the field and to be present as academic leaders debate new directions for their various disciplines.

Adam S. Kibel, MD

“Junior faculty and fellows quickly become immersed in the dogma of their institution; an opportunity to hear diverging points of view is invaluable,” said Dr. Kibel. “In addition, at the GU Symposium, they have the opportunity to hear leaders in the field debate the issues and strive to reach consensus on where the field should be going next.” Like last year, many of the symposium’s sessions will be interactive, with attendees encouraged to submit questions during certain sessions via text, tweet, or online. In addition, they’ll be able to access select symposia using their handheld devices or computer, 12 hours after the presentation, searchable by title, author, or track. Attendees will also receive an eTote—a USB device that contains proceedings content in digital format—including meeting abstracts, education articles, and links to the symposium’s Daily News. To learn more about the symposium and to register, go to http:// gucasym.org/.

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2012 Gastrointestinal Cancers Symposium Science and Multidisciplinary Management 2012 Gastrointestinal of GI Malignancies

Cancers Symposium

Science and Multidisciplinary Management of GI Malignancies

January 19–21, 2012 San Francisco, California TARG E T I NG

C A NC E R

C A RE

The ASCO Post | DECEMBER 15, 2011

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Direct from ASCO

Clinical Cancer Advances 2011: ASCO’s Report on Progress Against Cancer

his year marks the 40th anniversary ofthe National Cancer Act and places a more prominent focus on how much progress against cancer has been made over

the past 4 decades. In the past year alone, significant advances have been made in cancer prevention and screening, hard-to-treat cancers, and reducing cancer recur-

rence. Clinical Cancer Advances 2011: ASCO’s Annual Report on Progress Against Cancer documents the year’s most important clinical cancer research.

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

THE

ROLE

About the CCA Report Every year ASCO appoints an editorial board of renowned oncologists in the field to undertake the compilation and publishing of Clinical Cancer Advances (CCA). Now in its seventh year, the report continues to document the advances that have significantly altered the way a cancer is understood or had a direct effect on patient care. The CCA report also covers the full scope of patient care, including cancer disparities, advanced cancer care, prevention, screening, and survivor care.

I N T E G R I N S

in Glioblastoma

Significant advances have been made in cancer prevention and screening, hard-to-treat cancers, and reducing cancer recurrence.

• Gliomas account for approxiately 80% of all malignant brain and central nervous system tumors in adults.1

Specialty editors were selected for each of the disease- and issuespecific sections of the report and the co-executive editors oversaw its development. The editors reviewed research presented at major scientific meetings and studies published in peer-reviewed scientific journals from October 2010 to September 2011 for consideration in this year’s report. They also identified the most promising trends in oncology and provided their insights on where the future of cancer care is heading.

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

Major Advances in Care

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.com, click “Therapies,” then click “Oncology.”

111020-160332

The 2011 CCA features a total of 54 advances in clinical oncology over the past year. Twelve of the studies are noted as “major” advances, meaning they have the greatest potential impact on patients’ lives. Highlights of these major developments include: ■■ The first conclusive evidence that an aromatase inhibitor reduced the risk of a first breast cancer, making exemestane an option for postmenopausal women who are at high risk for the disease

ASCOPost.com | DECEMBER 15, 2011

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Direct from ASCO

■■ A phase III trial showing that a new combination of chemotherapy drugs, busulfan (Busulfex, Myleran)/melphalan, improved survival for children with highrisk, metastatic neuroblastoma ■■ Two phase III studies showing improved survival for patients with advanced melanoma: Vemurafenib (Zelboraf), which targets a common mutation in melanoma in the BRAF gene, improved overall survival compared to standard chemotherapy. Ipilimumab (Yervoy), an im-

mune therapy that activates the immune system’s T cells, combined with the standard chemotherapy drug dacarbazine improved overall survival by 2 months in patients with previously untreated metastatic melanoma. ■■ A new standard of care for children and young adults with acute lymphoblastic leukemia— giving the common chemotherapy drug methotrexate in large, consistent doses rather than in the gradually increasing doses of the standard regimen

Cancer Policy Priorities A new feature in this year’s report is the “Year in Review,” which describes key cancer policy developments and ASCO policy initiatives from the past year that are likely to influence cancer care over the coming years. Some of the important topics covered in this section include the growing problem of oncology drug shortages, ASCO’s recommendations to transform clinical cancer research, an analysis of the potential impact of health-care reform on cancer disparities, the United Nations

High-Level Meeting to address noncommunicable diseases, and potential solutions for oncology workforce shortages. Clinical Cancer Advances 2011: ASCO’s Annual Report on Progress Against Cancer was published online in the Journal of Clinical Oncology (www.jco.org) on December 5. The full color report and additional resources are available at www.cancer.net/clinicalcanceradvances.

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Journal of Oncology Practice Explores Use of Palliative Care in Practice

recent issue of the Journal of Oncology Practice features a special series of articles on palliative care and end-of-life issues in the oncology practice setting. Articles explore the integration of palliative care services in ambulatory settings, unique delivery mechanisms for palliative care, the impact of public policy and reimbursement on palliative care services, measurement of outcomes and quality measures, and more. Articles of interest include: ■■ Documentation and Discussion of Preferences for Care among Patients with Advanced Cancer: In a prospective study, researchers explored the frequency, timing, and documentation of conversations about end-of-life preferences between physicians and patients

with advanced cancer, to identify patterns of palliative care and hospice use at a Veterans Administration facility in Los Angeles. They found that the majority of patients had some documentation of care preferences recorded. In addition, more than half of all patients and almost three-quarters of decedents had had a palliative care consultation. Researchers concluded that physicians may benefit from more prompts to advise patients about appropriate palliative care services earlier in the course of their care. ■■ Palliative Care Needs of Patients with Cancer Living in the Community: The authors of this study explore palliative care needs of patients with advanced cancer who are treated in the community

setting and are not yet ready to transition to hospice care. They identified several important gaps in care, including the management of severe symptoms, development of advanced directives, and identification of health-care surrogates. The authors conclude that early palliative care intervention could improve outcomes, but will require a clearer understanding of this population’s needs and greater care coordination between inpatient and outpatient settings, and between oncologists and palliative care providers. ■■ Building on Individual State and Federal Initiatives for Advance Care Planning, an Integral Component of Palliative and End-of-life Cancer Care:

Researchers explore recent federal and state policies that focus on advance care planning and suggest care delivery improvements and solutions to overcome barriers to quality end-of-life care. They describe examples of legislation in New York and Massachusetts that empower patients to engage in advance care planning, uphold patient autonomy, and support optimal care delivery. The writers also urge a greater emphasis on doctor-patient communication as part of medical training, as a way to ensure that care aligns with patients’ individual goals and preferences.

■

SAVE THE DATE Multidisciplinary Head and Neck Cancer Symposium

Genitourinary Cancers Symposium

January 26-28, 2012

February 2-4, 2012

Arizona Biltmore Phoenix, Arizona

San Francisco Marriott Marquis San Francisco, California

ASCO ‘12 Annual Meeting June 1-5, 2012 McCormick Place Chicago, Illinois

Important Safety Information WARNINGS AND PRECAUTIONS: • Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D)

ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%). Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%),

and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%), 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.

INDICATIONS • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy • 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.

THE FIRST AND ONLY DRUG APPROVED IN BOTH PTCL AND CTCL

T:14”

B:14.25”

S:13”

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.

The ASCO Post | DECEMBER 15, 2011

PAGE 40

FDA Update

FDA Approves First Drug to Treat Myelofibrosis

he FDA has approved ruxolitinib ( Jakafi), the first drug approved to specifically treat patients with the bone marrow disease myelofibrosis. Myelofibrosis is a disease in which the bone marrow is replaced by scar

tissue resulting in blood cells being made in organs such as the liver and the spleen. This disease is marked by an enlarged spleen, anemia, decreased white blood cells and platelets, and myelofibrosis-related symptoms. Symptoms include fatigue, abdominal

discomfort, pain under the ribs, satiety, muscle and bone pain, itching, and night sweats.

Mechanism of Action Ruxolitinib, taken orally twice daily, inhibits the enzymes JAK 1 T:7”

Only

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

and JAK 2, which are involved in regulating blood and immunologic functioning. Myelofibrosis is associated with the deregulation of JAK 1 and JAK 2. “Jakafi represents another example of an increasing trend in oncol-

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)

ASCOPost.com | DECEMBER 15, 2011

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FDA Update

ogy where a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The clinical trials leading to this ap-

proval focused on problems that patients with myelofibrosis commonly encounter, including enlarged spleens and pain.”

Two Clinical Trials The safety and effectiveness of ruxolitinib was evaluated in two T:7”

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

disease-related symptoms. Patients in the studies were selected to receive treatment with ruxolitinib, placebo, or best available therapy (hydroxyurea, a chemotherapy agent, or glucocorticoids). A greater percentage of patients receiving ruxolitinib experienced continued on page 42

T:9.875”

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

clinical trials with 528 patients. Patients in both trials were resistant or refractory to available myelofibrosis therapy or ineligible for allogeneic bone marrow transplantation. All patients had splenomegaly and were in need of treatment as a result of

The ASCO Post | DECEMBER 15, 2011

PAGE 42

FDA Update

FDA Approves Ruxolitinib continued from page 41

more than a 35% reduction in spleen size compared to patients receiving placebo or best available therapy. Similarly, a greater proportion of patients receiving ruxolitinib saw more than a 50% reduction in myelofibrosis-related symptoms, including ab-

dominal discomfort, night sweats, itching and bone or muscle pain, than was the case in patients receiving placebo. The most serious side effects seen in patients treated with ruxolitinib include thrombocytopenia, anemia, fatigue, diarrhea, dyspnea, headache, dizziness, and nausea. T:7”

(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.

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. 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.

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

view goal date under the Prescription Drug User Fee Act and has been designated as an orphan drug, which identifies the disease as affecting fewer than 200,000 people in the United States. The agent is manufactured by Incyte Corp of Wilmington, Delaware.

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510(k) Clearance Granted for OncoTrac

ranslational Sciences Corporation announced that it has received FDA 510(k) clearance for commercialization of its OncoTrac medical imaging software. OncoTrac is designed for efficient quantitative assessment of treatment response of metastatic tumors including those of the breast, lung, colorectal, prostate, and lymphoma. The OncoTrac family of products provides a structured workflow solution for cancer practitioners and researchers to report precise measurements of solid and metastatic tumors for routine clinical care and cancer drug trials. As a vendor-neutral platform, OncoTrac software architecture is suitable for use in daily radiology practice, and can be integrated into most existing picture and archive communications systems (PACS) environments without any product customization. OncoTrac enterprise software facilitates tumor response assessment using widely accepted standards such as RECIST 1.0, RECIST 1.1, and WHO, as well as emerging standards such as the Choi criteria. Reports can be exported and stored in both a PACS system and in an electronic medical record. T:9.875”

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.

Ruxolitinib was reviewed under the FDA’s priority review program, an expedited 6-month review of drugs that may offer significant advances in treatment over available therapy or that provide a treatment when no adequate therapy exists. The treatment was approved ahead of the drug’s December 3 re-

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Send Us Your News Send your news of new appointments, awards, or significant events to The ASCO Post. Write to editor@ASCOPost.com. All submissions will be considered for publication.

ASCOPost.com | DECEMBER 15, 2011

PAGE 43

2011 European Multidisciplinary Cancer Congress Male Breast Cancer Differs from Breast Cancer in Women, but Little Data Informs Treatment By Alice Goodman

lthough a rare occurrence, men do get breast cancer, and when they do, it has a distinct biology from that of female breast cancer. About 90% of cases most closely resemble postmenopausal female invasive ductal carcinoma, and 10% are ductal carcinoma in situ (DCIS), which accounts for 25% of breast cancer cases in women. Lobular breast cancer is not found in men, noted Florian Otto, MD, of the Tumor and Breast Center (ZeTuP) in St. Gallen, Switzerland. Dr. Otto described male breast cancer at the European Multidisciplinary Cancer Congress in Stockholm.

Florian Otto, MD

Male breast cancer is usually close to the nipple and manifests as a hard nontender mass. Skin ulceration can occur, and lymph node involvement is more frequent in male breast cancer than in females. Mean tumor size at diagnosis is 24 mm, Dr. Otto said. “The diagnosis of male breast cancer is made the same way [as female breast cancer],” he said. Mammography and then further workup with ultrasound and fine-needle aspiration can establish the diagnosis.

Epidemiologic Background

Overview of Male Breast Cancer Male breast cancer accounts for about 2,000 new cases per year in the ■■ Male breast cancer is rare, with an annual incidence of 1.1 in 100,000. United States vs 230,480 cases of fe■■ The presentation of breast cancer differs in males and females. In men, it male breast cancer. The annual inciis usually found near the nipple and is a hard nontender mass, with more dence is 1.1 per 100,000. Mean age at frequent involvement of lymph nodes. diagnosis is 67 years. ■■ The biology of the disease differs in men and women as well. Male breast cancer “For males, the incidence of breast is mainly invasive ductal carcinoma, and lobular cancer is not found in men. cancer increases with age, while for fe■■ No randomized trials have been conducted to guide therapy. males, it plateaus at around age 60,” Dr. Otto continued. ■■ In the absence of hard data, diagnosis and treatment mostly follow that Men with risk factors such as the of female breast cancer. BRCA2 mutation, the CHEK2 gene, and Klinefelter syndrome (charactermuscle invasion or skin involvement. ized by narrow shoulders, wide hips, cancers are HER2-positive, compared “There are no data on anti-HER2 female-type pubic hair, gynecomaswith 18% to 20% of female breast cantherapy in male breast cancer. No tia, and smaller testicles) should be cers. drugs are registered for this indicascreened with monthly self-exam and Neglected Disease tion,” Dr. Otto said. semiannual clinical exam, and base“Male breast cancer is a neglected In the absence of randomized, conline mammogram followed by annual area, with little data to inform treattrolled trials, treatment of metastatic mammogram for gynecomastia. Other ment selection. We have no randombreast cancer in males can only be risk factors include conditions and ized trials with guided by case reports, he continued. procedures resultenough patients to Choices for hormone receptor–posiing in an altered About 90% of [male guide treatment,” tive cases include tamoxifen, aromaestrogen-to-testosbreast cancer] cases he said. Surgery tase inhibitors, fulvestrant (Faslodex), terone ratio, such and adjuvant cheor gonadotropin-releasing hormone as orchiectomy, most closely resemble motherapy are (GnRH) agonists. There is no standard congenital hernia, postmenopausal female the mainstays of therapy for hormone receptor–negaliver cirrhosis, and treatment; breasttive cases or for antihormonal therobesity. invasive ductal carcinoma, conserving surapy–resistant disease. Trastuzumab “The BRCA2 and 10% are ductal gery is not done (Herceptin) should be used in HER2mutation accounts in men, and it is positive disease. for about 5% to carcinoma in situ. Disclosure: Dr. Otto reported no potential not clear which 15% of male breast conflicts of interest. adjuvant therapies cancer, and this are preferred. “Any adjuvant therapy mutation confers a fivefold greater risk Reference appears to improve overall survival,” of prostate cancer,” he said. 1. Otto F: Male breast cancer—nehe noted. From 80% to 90% of cases of male glected tumour disease. Teaching lecture. Postoperative radiotherapy is given breast cancer are estrogen receptor– 2011 European Multidisciplinary Cancer to men with at least three positive lymph and progesterone receptor–positive. Congress. Presented September 26, 2011. nodes, and/or large tumor size with About 16% of cases of male breast

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American Society of Hematology Elects New Officers

he American Society of Hematology announced the election of three new members to its Executive Committee, the governing body of the organization, for terms to begin in January 2012. Linda J. Burns, MD, will serve a 1-year term as Vice President, followed by successive terms as PresidentElect and President. New Councillor Joseph M. Connors, MD, and new Councillor in Clinical Practice John C. Winkelmann, MD, will serve 4-year terms. Dr. Burns is a Professor of Medicine

Linda J. Burns, MD

Joseph M. Connors, MD

in the Division of Hematology, Oncology and Transplantation; Senior Fellowship Program Director, Department of Medicine; Fellowship Program Direc-

John C. Winkelmann, MD

tor, Division of Hematology, Oncology and Transplantation; Director, Inpatient Blood and Marrow Transplant (BMT) Unit; Director, Hematologic Malignan-

Leadership

cy BMT Interdisciplinary Site-Specific Teams; and attending physician in the BMT Program at the University of Minnesota in Minneapolis. Dr. Connors is a Clinical Professor in the Department of Medicine, Division of Medical Oncology, at the University of British Columbia and the Clinical Director of the BC Cancer Agency Centre for Lymphoid Cancer in Vancouver, BC. Dr. Winkelmann is a physician in private practice at Oncology Hematology Care in Cincinnati, Ohio. He specializes in hematologic malignancies.

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Her struggle is fresh, but she can

move on with new confidence.

with the administration of systemic steroids, circulatory support measures, and temporarily withholding GLEEVEC • Bullous dermatologic reactions (eg, erythema multiforme and StevensJohnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose with or Important Safety Information without concomitant corticosteroids or antihistamines following resolution • GLEEVEC is often associated with edema and occasionally serious fluid or improvement of the bullous reaction retention. Patients should be weighed and monitored regularly for signs and • Clinical cases of hypothyroidism have been reported in thyroidectomy symptoms of fluid retention, which can be serious or life-threatening, and patients undergoing levothyroxine replacement during treatment with be advised to report any rapid, unexpected weight gain. The probability of GLEEVEC. TSH levels should be closely monitored in such patients edema tended to be increased among older patients (>65 years) or those • Consider potential toxicities—specifically liver, kidney, and cardiac toxicity— taking higher doses of GLEEVEC. If severe fluid retention occurs, manage and immunosuppression from long-term use with diuretic therapy and withhold GLEEVEC until the event has resolved and then resume depending on the initial severity of the event • Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant • Cytopenias have been reported. Complete blood counts should be while taking GLEEVEC tablets and to avoid breast-feeding while taking performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). GLEEVEC tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use Dose reduction or treatment interruption may be required for severe adequate contraception. If the patient does become pregnant while taking neutropenia or thrombocytopenia (see full Prescribing Information for dose GLEEVEC, the patient should be advised of the potential hazard to the fetus adjustment recommendations) • Growth retardation has been reported in children and pre-adolescents • Severe congestive heart failure and left ventricular dysfunction have receiving GLEEVEC. The long-term effects of prolonged treatment with occasionally been reported. Most of the patients with reported cardiac GLEEVEC on growth in children are unknown; therefore, monitoring of events have had other comorbidities and risk factors, including advanced growth in children taking GLEEVEC is recommended age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, • Cases of tumor lysis syndrome (TLS), including fatal cases, have been and any patient with signs or symptoms consistent with cardiac failure reported. The patients at risk of TLS are those with tumors having a high should be evaluated and treated proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken • Hepatotoxicity, occasionally severe, may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with • In the Phase 2 unresectable or metastatic GIST trial (400 mg/day; both short-term and long-term use of GLEEVEC. Assess liver function before 600 mg/day), severe (NCI Grades 3/4) lab abnormalities—including initiation of treatment and monthly thereafter or as clinically indicated. anemia (3%; 9%) and neutropenia (10%; 11%)—were reported among Monitor liver function when combined with chemotherapy known to be patients receiving GLEEVEC. In Phase 3 unresectable or metastatic associated with liver dysfunction. A 25% decrease in the recommended GIST trials (400 mg/day; 800 mg/day), severe adverse reactions (NCI dose should be used for patients with severe hepatic impairment. If severe Grades 3/4/5), including abdominal pain (14%; 12%), edema (9%; 13%), hepatotoxicity occurs, GLEEVEC should be withheld until the event has fatigue (12%; 12%), nausea (9%; 8%), vomiting (9%; 8%), diarrhea resolved and then resumed depending on the initial severity of the event (8%; 9%), rash (8%; 9%), and myalgia (6%; 4%), were reported among patients receiving GLEEVEC • In the Phase 3 unresectable or metastatic GIST studies, 13% of patients reported (NCI Grades 3/4) hemorrhage at any site. In the Phase 2 • In the adjuvant treatment of GIST trials (GLEEVEC; placebo), severe unresectable or metastatic GIST study, 5% of patients were reported (NCI Grades 3 and above) lab abnormalities—increase in liver enzymes to have severe gastrointestinal (GI) bleeds and/or intratumoral bleeds. (ALT) (3%; 0%), (AST) (2%; 0%), decreased neutrophil count (3%; 1%), GI tumor sites may have been the source of GI bleeds and decrease in hemoglobin (1%; 0%)—and severe adverse reactions (NCI Grades 3 and above), including abdominal pain (3%; 1%), diarrhea • In patients with hypereosinophilic syndrome and cardiac involvement, (3%; 1%), rash (3%; 0%), fatigue (2%; 1%), nausea (2%; 1%), vomiting cardiogenic shock and left ventricular dysfunction have been associated (2%; 1%), white blood cell count decreased (1%; 0%), and periorbital with initiation of GLEEVEC. The condition was reported to be reversible

GLEEVEC® (imatinib mesylate) tablets are indicated for adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. Approval is based on recurrence-free survival with a median follow-up of 14 months. Clinical benefit has not been demonstrated by a long term effect on recurrence-free survival or survival.

GLEEVEC for adjuvant therapy in KIT+ GIST

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With a median follow-up of 14 months, more than double the number of patients in the placebo arm experienced disease recurrence compared with those in the GLEEVEC arm (HR=0.398 [95% CI: 0.259, 0.610], P<0.0001): GLEEVEC 30/359=8.4%, placebo 70/354=19.8%1 Some serious adverse reactions may occur, including severe congestive heart failure, left ventricular dysfunction, hepatotoxicity, edema, hemorrhage, GI perforation, and hypothyroidism1 The most frequently reported adverse reactions at the time of discontinuation were edema, GI disturbances, fatigue, decreased hemoglobin, and rash1

GLEEVEC Significantly Improves RFS vs Placebo1 100

Patients with RFS (%)

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ACTIVE TREATMENT PERIOD

NONTREATMENT FOLLOW-UP GLEEVEC (n=359)

Placebo (n=354)

0 0

Time to recurrence (months) Patients at risk: GLEEVEC

359

258

207

166

105

Placebo

354

243

186

138

A Phase 3, randomized, double-blind study of adjuvant GLEEVEC vs placebo was conducted in 713 patients following resection of primary KIT+ GIST. The efficacy end point of the study was recurrence-free survival (RFS), defined as the time from date of randomization to the date of recurrence or death from any cause.

edema (1%; 0%), were reported among patients receiving adjuvant treatment with GLEEVEC • There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation • GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Significant reductions in imatinib concentrations may occur when GLEEVEC is administered concomitantly with agents that are strong CYP3A4 inducers such as rifampin, St. John’s wort, and enzyme-inducing anti-epileptic drugs, eg, phenytoin. The use of concomitant strong CYP3A4 inducers should be avoided. If patients must be administered a strong CYP3A4 inducer, the dosage of GLEEVEC should be increased by at least 50% and clinical response should be carefully monitored. Caution is recommended when GLEEVEC is administered with CYP3A4 inhibitors such as ketoconazole, with CYP2D6 substrates that have a narrow therapeutic window, or with CYP3A4 substrates that have a narrow therapeutic window. Other examples of commonly used drugs that may significantly interact with GLEEVEC include acetaminophen, warfarin, erythromycin, and metoprolol. Grapefruit juice should also be avoided in patients taking GLEEVEC. (Please see full Prescribing Information for other potential drug interactions) • Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. GLEEVEC should be used with caution in patients with severe renal impairment

Common Side Effects of GLEEVEC Tablets • Almost all patients who received GLEEVEC in the Phase 3 unresectable or metastatic GIST studies experienced adverse reactions at some time. Overall, the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema and rash/related terms, which were reported more frequently in the 800-mg group. The most frequently reported adverse reactions (400 mg/day; 800 mg/day) (all Grades) were edema (77%; 86%), fatigue (69%; 75%), nausea (58%; 65%),

abdominal pain (57%; 55%), diarrhea (56%; 58%), rash and related terms (56%; 70%), vomiting (37%; 41%), myalgia (32%; 30%), anemia (32%; 35%), anorexia (31%; 36%), and arthralgia (14%; 12%). Therapy with GLEEVEC was discontinued for adverse reactions in 5% of patients at both dose levels studied* • In the adjuvant treatment of GIST trials, almost all GLEEVEC- and placebo-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include (GLEEVEC; placebo) (all Grades) diarrhea (59%; 29%), fatigue (57%; 41%), nausea (53%; 28%), periorbital edema (47%; 15%), decreased hemoglobin (47%; 27%), peripheral edema (27%; 15%), rash (26%; 13%), vomiting (26%; 14%), abdominal pain (21%; 22%), anorexia (17%; 9%), arthralgia (15%; 15%), and myalgia (12%; 12%)* • In the adjuvant GIST trial, drug was discontinued for adverse events in 17% of GLEEVEC- and 3% of placebo-treated patients. Edema, GI disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation* • Supportive care may help reduce the severity of some mild-to-moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary • For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron • GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation • Patients should be informed to take GLEEVEC exactly as prescribed, and not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose *For more detailed study information, please see full Prescribing Information. Please see brief summary of Prescribing Information on the following pages.

Reference: 1. GLEEVEC (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2011. ®

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

Printed in USA

9/11

GLI-1030100

GLEEVEC (imatinib mesylate) tablets for oral use Initial U.S. Approval: 2001 BRIEF SUMMARY: The following information refers to adult patients with Kit-positive GIST. Experience with other indications may differ. Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.8 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. 1.9 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. Approval is based on recurrence-free survival with a median follow-up of 14 months. Clinical benefit has not been demonstrated by a long term effect on recurrence-free survival or survival. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Fluid Retention and Edema Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1) in the full prescribing information]. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Gleevec dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. Severe fluid retention was reported in 9% to 13.1% of patients taking Gleevec for GIST [see Adverse Reactions (6.11)]. 5.2 Hematologic Toxicity Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy [see Dosage and Administration (2.11) in the full prescribing information]. 5.3 Severe Congestive Heart Failure and Left Ventricular Dysfunction Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients taking Gleevec. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated. 5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.3)]. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Gleevec. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with Gleevec interruption and/or dose reduction [see Dosage and Administration (2.10) in the full prescribing information]. When Gleevec is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended. 5.5 Hemorrhage In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. 5.6 Gastrointestinal Disorders Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation. 5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec should be considered at the initiation of therapy. 5.8 Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon re-challenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines. 5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients. 5.10 Toxicities from Long-Term Use It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally

suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Nonneoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals. 5.11 Use in Pregnancy Pregnancy Category D Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec. Sexually active female patients taking Gleevec should use adequate contraception. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area. [see Use in Specific Populations (8.1)] 5.12 Children and Adolescents Growth retardation has been reported in children and pre-adolescents receiving Gleevec. The long term effects of prolonged treatment with Gleevec on growth in children are unknown. Therefore, close monitoring of growth in children under Gleevec treatment is recommended. [see Postmarketing Experience (6.13)] 5.13 Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL and eosinophilic leukemia receiving Gleevec. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. 6.2 Hematologic Toxicity Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses ≥750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease. In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 4 and 5 in the full prescribing information). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5 in the full prescribing information). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively. These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Gleevec, but in rare cases require permanent discontinuation of treatment. 6.3 Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5 in the full prescribing information) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients. 6.5 Adverse Reactions in Other Subpopulations In older patients (≥65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation. 6.11 Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials the majority of Gleevec-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec [see Dosage and Administration (2.10) in the full prescribing information]. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%). Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec are shown in Table 9. Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group. Table 9 Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg Imatinib 800 mg N=818 N=822 All Grades All Grades Grades 3/4/5 Grades 3/4/5 Reported or Specified Term % % % % Edema 76.7 9.0 86.1 13.1 Fatigue/lethargy, malaise, asthenia 69.3 11.7 74.9 12.2 Nausea 58.1 9.0 64.5 7.8 Abdominal pain/cramping 57.2 13.8 55.2 11.8 Diarrhea 56.2 8.1 58.2 8.6 Rash/desquamation 38.1 7.6 49.8 8.9 Vomiting 37.4 9.2 40.6 7.5 Myalgia 32.2 5.6 30.2 3.8 Anemia 32.0 4.9 34.8 6.4 Anorexia 31.1 6.6 35.8 4.7 Other GI toxicity 25.2 8.1 28.1 6.6 Headache 22.0 5.7 19.7 3.6 Other pain (excluding tumor related pain) 20.4 5.9 20.8 5.0 Other dermatology/skin toxicity 17.6 5.9 20.1 5.7 Leukopenia 17.0 0.7 19.6 1.6 Other constitutional symptoms 16.7 6.4 15.2 4.4 Cough 16.1 4.5 14.5 3.2 (continued)

Table 9 Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg Imatinib 800 mg N=818 N=822 All Grades All Grades Grades 3/4/5 Grades 3/4/5 Reported or Specified Term % % % % Infection (without neutropenia) 15.5 6.6 16.5 5.6 Pruritus 15.4 5.4 18.9 4.3 Other neurological toxicity 15.0 6.4 15.2 4.9 Constipation 14.8 5.1 14.4 4.1 Other renal/genitourinary toxicity 14.2 6.5 13.6 5.2 Arthralgia (joint pain) 13.6 4.8 12.3 3.0 Dyspnea (shortness of breath) 13.6 6.8 14.2 5.6 Fever in absence of neutropenia 13.2 4.9 12.9 3.4 (ANC <1.0 x 109/L) Sweating 12.7 4.6 8.5 2.8 Other hemorrhage 12.3 6.7 13.3 6.1 Weight gain 12.0 1.0 10.6 0.6 Alopecia 11.9 4.3 14.8 3.2 Dyspepsia/heartburn 11.5 0.6 10.9 0.5 Neutropenia/granulocytopenia 11.5 3.1 16.1 4.1 Rigors/chills 11.0 4.6 10.2 3.0 Dizziness/lightheadedness 11.0 4.8 10.0 2.8 Creatinine increase 10.8 0.4 10.1 0.6 Flatulence 10.0 0.2 10.1 0.1 Stomatitis/pharyngitis (oral/pharyngeal mucositis) 9.2 5.4 10.0 4.3 Lymphopenia 6.0 0.7 10.1 1.9

T:14”

B:14.25”

S:13”

Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 10. Table 10 Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial 400 mg 600 mg (n=73) (n=74) % % CTC Grades1 Grade 3 Grade 4 Grade 3 Grade 4 Hematology Parameters – Anemia 3 0 8 1 – Thrombocytopenia 0 0 1 0 – Neutropenia 7 3 8 3 Biochemistry Parameters – Elevated Creatinine 0 0 3 0 – Reduced Albumin 3 0 4 0 – Elevated Bilirubin 1 0 1 3 – Elevated Alkaline Phosphatase 0 0 3 0 – Elevated SGOT (AST) 4 0 3 3 – Elevated SGPT (ALT) 6 0 7 1 1CTC Grades: neutropenia (Grade 3 ≥0.5-1.0 x 109/L, Grade 4 <0.5 x 109/L), thrombocytopenia (Grade 3 ≥10-50 x 109/L, Grade 4 <10 x 109/L), anemia (Grade 3 ≥65-80 g/L, Grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), albumin (Grade 3 <20 g/L) Adjuvant Treatment of GIST The majority of both Gleevec and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Gleevec and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin and rash were the most frequently reported adverse reactions at the time of discontinuation. Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Gleevec are shown in Table 11. Table 11 Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1) All CTC Grades CTC Grade 3 and above Gleevec Placebo Gleevec Placebo (n=337) (n=345) (n=337) (n=345) Preferred Term % % % % Diarrhea 59.3 29.3 3.0 1.4 Fatigue 57.0 40.9 2.1 1.2 Nausea 53.1 27.8 2.4 1.2 Periorbital Edema 47.2 14.5 1.2 0 Hemoglobin Decreased 46.9 27.0 0.6 0 Peripheral Edema 26.7 14.8 0.3 0 Rash (Exfoliative) 26.1 12.8 2.7 0 Vomiting 25.5 13.9 2.4 0.6 Abdominal Pain 21.1 22.3 3.0 1.4 Headache 19.3 20.3 0.6 0 Dyspepsia 17.2 13.0 0.9 0 Anorexia 16.9 8.7 0.3 0 Weight Increased 16.9 11.6 0.3 0 Liver enzymes (ALT) Increased 16.6 13.0 2.7 0 Muscle spasms 16.3 3.3 0 0 Neutrophil Count Decreased 16.0 6.1 3.3 0.9 Arthralgia 15.1 14.5 0 0.3 White Blood Cell Count Decreased 14.5 4.3 0.6 0.3 Constipation 12.8 17.7 0 0.3 Dizziness 12.5 10.7 0 0.3 (continued)

Table 11 Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1) All CTC Grades CTC Grade 3 and above Gleevec Placebo Gleevec Placebo (n=337) (n=345) (n=337) (n=345) Preferred Term % % % % Liver Enzymes (AST) Increased 12.2 7.5 2.1 0 Myalgia 12.2 11.6 0 0.3 Blood Creatinine Increased 11.6 5.8 0 0.3 Cough 11.0 11.3 0 0 Pruritus 11.0 7.8 0.9 0 Weight Decreased 10.1 5.2 0 0 Hyperglycemia 9.8 11.3 0.6 1.7 Insomnia 9.8 7.2 0.9 0 Lacrimation Increased 9.8 3.8 0 0 Alopecia 9.5 6.7 0 0 Flatulence 8.9 9.6 0 0 Rash 8.9 5.2 0.9 0 Abdominal Distension 7.4 6.4 0.3 0.3 Back Pain 7.4 8.1 0.6 0 Pain in Extremity 7.4 7.2 0.3 0 Hypokalemia 7.1 2.0 0.9 0.6 Depression 6.8 6.4 0.9 0.6 Facial Edema 6.8 1.2 0.3 0 Blood Alkaline Phosphatase Increased 6.5 7.5 0 0 Dry skin 6.5 5.2 0 0 Dysgeusia 6.5 2.9 0 0 Abdominal Pain Upper 6.2 6.4 0.3 0 Neuropathy Peripheral 5.9 6.4 0 0 Hypocalcemia 5.6 1.7 0.3 0 Leukopenia 5.0 2.6 0.3 0 Platelet Count Decreased 5.0 3.5 0 0 Stomatitis 5.0 1.7 0.6 0 Upper Respiratory Tract Infection 5.0 3.5 0 0 Vision Blurred 5.0 2.3 0 0 (1)All adverse reactions occurring in ≥5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. 6.12 Additional Data from Multiple Clinical Trials The following adverse reactions have been reported during clinical trials of Gleevec. Cardiac Disorders: Estimated 0.1%-1%: congestive cardiac failure, tachycardia, palpitations, pulmonary edema, Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion Vascular Disorders: Estimated 1%-10%: flushing, hemorrhage Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynauds phenomenon, hematoma, Clinical Laboratory Tests: Estimated 0.1%-1%: blood CPK increased, blood LDH increased, Estimated 0.01%-0.1%: blood amylase increased Dermatologic: Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, nail disorder, purpura, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, erythema multiforme, leucocytoclastic vasculitis Digestive: Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis, Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease, General Disorders and Administration Site Conditions: Estimated 1%-10%: weakness, anasarca, chills Estimated 0.1%-1%: malaise Hematologic: Estimated 1%-10%: pancytopenia, febrile neutropenia Estimated 0.1%-1%: thrombocythemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia Hepatobiliary: Estimated 0.1%-1%: hepatitis, jaundice Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1 Hypersensitivity: Estimated 0.01%-0.1%: angioedema Infections: Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0.01%-0.1%: fungal infection Metabolic and Nutritional: Estimated 1%-10%: weight decreased Estimated 0.1%-1%: hypophosphatemia, dehydration, gout, increased appetite, decreased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia Estimated 0.01%-0.1%: hyperkalemia, hypomagnesemia Musculoskeletal: Estimated 1%-10%: joint swelling Estimated 0.1%-1%: joint and muscle stiffness Estimated 0.01%-0.1%: muscular weakness, arthritis Nervous System/Psychiatric: Estimated 1%-10%: paresthesia, hypesthesia Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis

Renal: Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive: Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema Respiratory: Estimated 1%-10%: epistaxis Estimated 0.1%-1%: pleural effusion Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage Special Senses: Estimated 1%-10%: conjunctivitis, vision blurred, eyelid edema, conjunctival hemorrhage, dry eye Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss Estimated 0.01%-0.1%: papilledema1, glaucoma, cataract 1Including some fatalities 6.13 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of Gleevec. 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. Nervous system disorders: cerebral edema1 Eye disorders: vitreous hemorrhage Cardiac disorders: pericarditis, cardiac tamponade1 Vascular disorders: thrombosis/embolism, anaphylactic shock Respiratory, thoracic and mediastinal disorders: acute respiratory failure1, interstitial lung disease Gastrointestinal disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation1 [see Warnings and Precautions (5.6)], diverticulitis Skin and subcutaneous tissue disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome Musculoskeletal and connective tissue disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/ myopathy, growth retardation in children Reproduction disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst 1Including some fatalities 777DRUG INTERACTIONS 7.1 Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold, which significantly (p<0.05) decreased mean Cmax and AUC. Similar findings were observed in patients receiving 400-1200 mg/day Gleevec concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED. Concomitant administration of Gleevec and St. John’s Wort led to a 30% reduction in the AUC of imatinib. Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Gleevec doses up to 1200 mg/day (600 mg BID) have been given to patients receiving concomitant strong CYP3A4 inducers. [see Dosage and Administration (2.9) in the full prescribing information]. 7.2 Agents Inhibiting CYP3A Metabolism There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when Gleevec was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering Gleevec with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations. 7.3 Interactions with Drugs Metabolized by CYP3A4 Gleevec increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by Gleevec. Particular caution is recommended when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus). Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolobenzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin. 7.4 Interactions with Drugs Metabolized by CYP2D6 Gleevec increased the mean Cmax and AUC of metoprolol by approximately 23% suggesting that Gleevec has a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window. 7.5 Interaction with Acetaminophen In vitro, Gleevec inhibits the acetaminophen O-glucuronidate pathway (Ki 58.5 μM). Co-administration of Gleevec (400 mg/day for eight days) with acetaminophen (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen. Gleevec pharmacokinetics were not altered in the presence of single-dose acetaminophen. There is no pharmacokinetic or safety data on the concomitant use of Gleevec at doses >400 mg/day or the chronic use of concomitant acetaminophen and Gleevec. 888USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.11)]. Gleevec can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses ≥100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by either early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤30 mg/kg (one-third the maximum human dose of 800 mg). There are no adequate and well-controlled studies with Gleevec in pregnant women. Women should be advised not to become pregnant when taking Gleevec. 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.

8.3 Nursing Mothers Imatinib and its active metabolite are excreted into human milk. Based on data from three breastfeeding women taking Gleevec, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight. Because of the potential for serious adverse reactions in nursing infants from Gleevec, 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. 8.5 Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema [see Warnings and Precautions (5.1)]. The efficacy of Gleevec was similar in older and younger patients. In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis. In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Gleevec was similar in patients older than 65 years and younger patients. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment (Table 12) at imatinib doses ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function [see Dosage and Administration (2.10) in the full prescribing information]. Table 12 Liver Function Classification Liver Function Test Normal Mild Moderate Severe (n=14) (n=30) (n=20) (n=20) Total Bilirubin ≤ULN >1.0-1.5x ULN >1.5-3x ULN >3-10x ULN SGOT ≤ULN >ULN (can be Any Any normal if Total Bilirubin is >ULN) ULN=upper limit of normal for the institution 8.7 Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment (Table 13) at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment. The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment. Two patients with severe renal impairment were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Dose reductions are necessary for patients with moderate and severe renal impairment [See Dosage and Administration (2.9) in the full prescribing information]. Table 13 Renal Function Classification Renal Dysfunction Renal Function Tests Mild CrCL = 40-59 mL/min Moderate CrCL = 20-39 mL/min Severe CrCL = <20 mL/min CrCL = Creatinine Clearance 108OVERDOSAGE Experience with doses greater than 800 mg is limited. Isolated cases of Gleevec overdose have been reported. In the event of overdosage, the patient should be observed and appropriate supportive treatment given. Adult Overdose 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain. 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases. 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of Gleevec daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of Gleevec daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of Gleevec on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy. Pediatric Overdose One 3 year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhea and anorexia and another 3 year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhea. 16 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container, USP. T2011-40 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

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ASCO HIT/EHR Symposium Improving Quality and Safety with Health Information Technology By Ronald Piana

well-documented flaw in paperbased health care is the propensity for medical errors. According to Blackford Middleton, MD, MPH, MSc, implementing clinical decision support software can decrease medical error, improve outcomes, and lower the costs of care. Presenting a session titled “Improving Quality Through HIT” at the recent ASCO HIT/EHR [Health Information Technology/

Blackford Middleton, MD, MPH, MSc

T:14”

B:14.25”

S:13”

Electronic Health Records] Symposium in Atlanta, Dr. Middleton led off with a slide of an actual hand-written prescription. He asked an audience member to identify the drug and dose. When the doctor called out the answer, Dr. Middleton said, “Wrong— that’s the first medical error of the day.” Dr. Middleton is Corporate Director of Clinical Informatics Research & Development at Partners Healthcare System, and Assistant Professor of Medicine at Brigham and Women’s Hospital, Harvard Medical School, and of Health Policy and Management at the Harvard School of Public Health.

The High Cost of Paper The seminal 1999 Institute of Medicine report, To Err is Human,1 exposed the prevalence and effect medical errors have on our health-care system. More than a decade later, the problem

still exists. HIT might offer solutions, Dr. Middleton maintained. “Paper-based medicine has served a purpose over the millennia. However, it is prone to error, and while it collects a lot of information, it offers no platform for data analyses or communication. And since it doesn’t integrate with e–health care, paper will not be part of the transformation of our health-care system,” Dr. Middleton noted. Citing research from several large health-care institutions and publications in the literature, Dr. Middleton highlighted the extent of medical errors. For instance, he offered these statistics from the outpatient setting: For every 1,000 patients receiving care, about 14 life-threatening or serious adverse drug events are reported; out of 1,000 written prescriptions, about 40 contain medical errors; and out of 1,000 women with a marginally abnormal mammogram, approximately 360 women will not receive follow-up care. “On the inpatient side, there is an estimated error rate of about 10.7 per 1,000 patient-days. Moreover, we see estimates of serious medication error at 5.3% of admissions in New York teaching hospitals,” Dr. Middleton said, stressing that medication errors occur in approximately 1 of every 20 admissions. “Medication error is seen in a wide variety of medical activities. However, nearly 50% of errors happen in the ordering process, after the diagnostic and therapeutic decisions are made. About 26% of errors take place in the administration/management cycle. So we need to think of ways to address the vulnerable areas in the process, because the costs are substantial,” Dr. Middleton said. Studies show that it costs about $2,462 per adverse drug

Reducing Medical Errors with Health Information Technology ■■ Failure to apply best evidence at the point of care results in frequent

medical error, often when doctors are deciding what management strategy to follow.

■■ Costs related to error may justify investment in health information

technology such as a computerized physician order entry system and clinical decision support software.

■■ Such programs may decrease medical errors, improve clinical outcomes,

and lower the total costs of care, but may also have unintended consequences, including system rigidity, alert fatigue, and alternative error potential.

ton and his colleagues found that for an “average” provider, an advanced CPOE system SEE PAGE 68 would prevent: ■■ 9 adverse drug events per year ■■ 6 adverse drug event–related office visits ■■ 4 adverse drug event–related hospital admissions ■■ 3 life-threatening adverse drug events “We calculated that the savings from the CPOE system in this study was worth about $44 billion in the HIT Reduces Costs aggregate when you roll it up against One advantage of a clinical deci1.1 billion outpatient health-care sion support sysvisits per year,” tem is that it is For every 1,000 patients he commented. integrated into the According to Dr. receiving care, about 14 clinical workflow Middleton, most rather than as a life-threatening or serious of these models separate login or are most sensiadverse drug events are screen, allowing tive to prospective the system to inpayment or the reported. teract at the point degree of capitaof care, where tion in a particular many of the prescribing errors ocdelivery environment. “This makes cur. “The literature is rife with studgood sense,” he continued, “Because ies making the case for adoption of often he who pays for health-care IT clinical decision support software, is not he who gains. In our models citing evidence that this software infor ambulatory CPOE, the benefit is creases adherence to guideline-based actually distributed 89% to the payer, care and offers enhanced surveiland the rest of the benefit goes to the lance and monitoring, which leads provider, which is directly related to to decreased medication errors,” Dr. the percentage of capitation or at-risk Middleton observed. contracts you have.” Myriad examples in the literature Testing the Hypothesis demonstrate that employing the variDr. Middleton’s work showed that ous iterations of HIT can save the computerized physician order entry health-care system money, he pointed was effective, largely because the phyout. For instance, the effects of elecsician is at the order entry point. He tronic health records, computerized postulated that decision support for physician order entry, health informaphysicians might be even more effection exchanges, telehealth, and pertive if applied throughout the cycle of sonal health records reduce medical the physician-patient encounter or a errors, hospitalizations, redundancy of hospitalization. tests and procedures, and administraTo test the hypothesis, Dr. Middletive costs. ton and his associates built a system “In one study we did at Partners called the CAD/DM SmartForm for Healthcare and Harvard Medical coronary artery disease and diabetes School, we summarized the evidence mellitus. (A SmartForm is a problembase for the value of an ambulatory oriented, documentation-based cliniCPOE system. After a thorough literacal decision support system that acture evaluation, we built a large simutively engages clinicians during patient lation model with about a thousand visits.) different variables and estimated the “Instead of providing decision supimpact of a CPOE system on the amport at the point of order entry, this bulatory outpatient visits,” Dr. Middlesystem provides support throughout ton said. continued on page 50 Based on their model, Dr. Middleevent and about $4,555 per preventable adverse drug event, he observed. “These figures exclude the costs of injuries to patients, malpractice suits, and admissions due to adverse drug events. The data indicate that a large percentage of medication errors occur at the point of care, when doctors are deciding what management strategy to follow,” Dr. Middleton said. Moreover, the costs related to error justify investment in a computerized physician order entry (CPOE)/clinical decision support software package, he maintained.

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ASCO HIT/EHR Symposium Health Information Technology continued from page 49

the chart review, previsit, and the visit itself, thoroughly documenting the encounter. In this system, we key up the appropriate data and documentation of the encounter to review, but most importantly, we provide an assessment of what the patient needs,” he explained. Dr. Middleton and associates concluded that SmartForms address quality deficiencies by delivering actionable decision support to the point of care,

with rigorous attention to clinician workflow. These novel tools work together to increase the self-evident value of EHRs to clinicians and improve the quality of medical care. He noted that one downside is the cost of the more sophisticated system. “We had a couple of hundred different rules working at all times. So the knowledge engineering costs of this level of advanced decision support is actually pretty high and might currently be beyond the capacity of most institutions across the country.”

Conclusions In summary, Dr. Middleton balanced the pros and cons of current health information technology relating to clinical decision support. Clinical decision support systems can decrease medical errors, particularly around medications. The systems can improve clinical processes and outcomes and lower the total costs of care. “However, we also need to be concerned about possible unintended consequences of clinical decision support systems, such as rigidity of the system, alert fatigue, and poten-

tial for errors. Further research should focus on improving the relevance of clinical decision support software and knowledge sharing,” Dr. Middleton concluded.

■

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

Reference 1. Kohn LT, Corrigan JM, Donaldson MS (eds): To Err Is Human: Building a Safer Health System. Washington, DC; National Academies Press; 2000. Available at http://www.nap.edu/openbook. php?isbn=0309068371. Accessed November 17, 2011.

Oncologists Need Hands-on Approach in Developing Next Generation of EHRs

A health information technology (HIT) innovator advises oncologists to take an active part in their electronic health record (EHR) development process. By Ronald Piana

he electronic health record system offered by vendors is more like a filing cabinet, not the sophisticated, interactive database needed by busy oncologists, according to Kevin S. Hughes, MD, FACS, Co-Director, Avon Comprehensive Breast Evaluation Center, Massachusetts General Hospital, who presented a session titled “Beyond the EHR,” at the recent ASCO HIT/EHR symposium in Atlanta.

Kevin S. Hughes, MD, FACS

Specialty-specific Interfaces Needed “The promise of the EHR is to increase efficiencies, reduce costs, and increase quality. However, those goals can be accomplished only if the software takes into account the specific needs of oncology workflow and data collection,” Dr. Hughes explained. “Every specialist needs a specialtyspecific interface; EHR vendors do not have the wherewithal to create thousands of specific interfaces while trying to build the basic infrastructure,” Dr. Hughes commented, add-

ing, “Moving forward, each medical specialty should help build their own specific EHR interfaces that complement the practice’s office flow and patient data needs.”

Talking to Each Other To avoid creating a massive HIT Tower of Babel, EHRs from across oncologic disciplines need to be able to “talk to each other.” But Dr. Hughes contended that depending on EHRs that are designed and built as proprietary products by vendors that want to protect their investments would ultimately make it harder to interoperate across the oncology community. “We need to ensure that EHRs are built with a relatively open data structure that allows one to seamlessly access and interact with the information. This is doable on a large scale across oncologic disciplines. Its going to take considerable time and investment, and it has to be done by a large number of vendors supplying nimble EHRs and working closely with the specialists who use them,” Dr. Hughes said. As examples of successful central databases working with interoperable software packages, Dr. Hughes pointed to the breast imaging, anesthesia, and pathology communities. These specialties have set up their own databases and interfaces to deal with their unique needs. They generate and send free text reports into the EHR, as the basic document management systems lack the ability to accept these data.

EHR in Oncology ■■ Electronic health record (EHR) systems can increase efficiencies,

reduce costs, and improve quality, but the software must meet the specific needs of workflow and data collection for a given specialty (eg, oncology).

■■ Oncology EHRs need to be developed with an eye toward seamless

access and interaction across and between systems, which should be done in cooperation with the oncologists who use them.

■■ The core component of EHR-driven quality care is clinical decision

support functionality. Existing software that helps identify and manage women at high risk for hereditary breast cancer (HughesRiskApps Breast Surgery Module) may serve as a prototype for other systems and modules.

“These disciplines have developed specialty-specific software that is database-driven. The oncology community could definitely build these types of interoperable systems at whatever level an existing EHR can manage, but currently that level tends to be pretty taxed,” Dr. Hughes commented. He posited that future e–health care would be comprised of a large number of specialty-specific software packages that connect to a central EHR, which becomes the community database, a nexus for clinical communication.

Quality Outcomes/Clinical Decisions The core component of EHR-driven quality care is the clinical decision support functionality. “Current EHRs succeed in being a document repository that allows practitioners to view information from multiple areas. But

EHRs cannot move to the next level of communication until they adopt a clinical decision support functionality,” Dr. Hughes said. Dr. Hughes stressed that the physicians using the EHRs are the only ones capable of implementing the clinical decision support functions. Major vendors cannot set the standards for how to care for the complex needs of patients with cancer. To that end, Dr. Hughes along with several collaborators designed a cancer risk assessment software system (HughesRiskApps Breast Surgery Module) for clinical decision support that helps identify and manage women at high risk for hereditary breast and ovarian cancer. “The module, which is in use throughout the country, separates out the clinical pieces and makes those pieces interoperable,” Dr. Hughes said. “We’re trying to show that surcontinued on page 51

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PAGE 51

Perspective

Need for Data Capture Crucial, Now and After ‘Meaningful Use’ By Cindy Chavez

t’s never enough. Whether it is (1%–5%) will affect claims for all of a the Centers for Medicare & Medphysician’s Medicare patients. icaid Services (CMS), other payers, Will other payers follow? Probpharmaceutical manufacturers, or ably. And just having a certified EHR specialty companies, one can never in place isn’t enough for this initiaprovide enough data. When will it all tive. There are no fewer than 20 measures that must end? The problem, be reported, rangor the opportunity In order for physicians ing from actions for many, is that and their staff to be as simple as usit won’t end. The ing ePrescribing need for discrete successful today, they consistently for data to accomplish need the tools to capture patients, to formal even basic reimquality criteria inbursement today this vital data. volving the docuis compoundmentation of speing daily and will cific oncology-related details. never go away. Physicians cannot just provide a basic set of charge codes, Other Ramifications diagnosis codes, and a dictated note Meaningful use measures will also to fully support their practice in the envelop the launching of online “pamost efficient and prosperous way tient portals” for practices. Beyond anymore. They have to go further, and the valuable services, information, this involves harnessing a full range of and efficiencies that can and will be technology to assist them. achieved for the improvement of care At the core of this technology is the and engagement with patients, clinielectronic health records (EHR) solucal information (ie, lab results and tion, which is pivotal to a robust and vivisit summaries) will be provided to brant oncology practice today. “Meanpatients as well. It will be critically ingful use”—the CMS-incentivized important that the information being implementation of EHR technology in provided is up to date, complete, and ways that can be measured significantly accurate. in quality and quantity—is now upon Again, will other payers follow suit us. Not only is there an opportunity to and try to affect physician reimbursegain $44,000 in incentive payments, ment by the successful certification but this will be a requirement by 2015, of meaningful use? Plan on it. Addiwhen CMS reimbursement penalties

tionally, the Quality Oncology Practice Initiative (QOPI®), developed by ASCO, is not just “nice to have” in practices today. Payers are now setting expectations of QOPI certification by oncologists as a benchmark to reimbursement. This involves a core set of metrics to be reported on, mostly separate from the meaningful use measures, and wholly focused on oncology care. While QOPI is a great reporting initiative for measuring the health of clinical practices, many other quality mechanisms need to be provided to practices, involving clinical dashboards, and robust reporting—all to improve the quality and efficiency with which physicians care for patients. Clinical research is another vast landscape begging for complete and robust data. In order to better identify patients who may be eligible for participation in clinical research, proactive measures, such as the harnessing of technical reporting tools, must be in place to help physicians target patients in their practice immediately for enrollment. These reporting tools can only be successful if they embrace data from physicians’ current patient populations and generally within the domain of their EHR.

Next Generation of EHRs

ture of the patient’s real-time status. The clinician then does further editing and enhancement of the information, inputting data that only doctors would know,” Dr. Hughes said.

continued from page 50

gery-specific interfaces and specialty-specific decision support can be created and made HL7-compliant so they can interact with other software packages.” [Editor’s Note: Health Level Seven International (HL7) is the global authority on standards for interoperability of health information technology, with members in more than 55 nations. HL7 promotes the use of informatics to increase clinical effectiveness.]

Breast Model as Prototype “Although we follow a relatively simple method, few others around the nation seem to be doing it. Rather than a physician taking a history ver-

bally and then transcribing the patient information into the EHR, we begin with the patient entering her own information on a user-friendly tablet PC questionnaire,” Dr. Hughes said.

Reportable Data Data is important. The data, however, must also be provided in a man-

Following this simple but thorough pathway … creates a relatively seamless course that reduces labor and costs, and increases the ability of busy doctors to deliver high-quality care. He explained that they also use data that is already stored in the EHR, including a problem list of medication alerts and other pertinent clinical issues. “When you mix the stored data with the patient’s input, you get a fairly comprehensive clinical pic-

“The patient/doctor and EHRstored data are aggregated into a package. We then run clinical decision support on that package to individualize a surgical management strategy for that particular patient. We still live in a world that needs

Cindy Chavez

ner that can be reported. Today, dictation and typing into the EHR solution are not ways in which one can pull the relevant data out of electronic records. Whether it is for meaningful use, QOPI, research, or payer contracting, the reporting to support such initiatives must be in a structured format. That generally means “point and click” or “check the box.” In order for physicians and their staff to be successful today, they need the tools to capture this vital data. Physicians should be aware that embracing and adopting EHR solutions, practice management systems, and patient portals are necessary for a successful and vibrant practice, and I expect, one day will be viewed as a requirement by patients and their referring physicians.

■

Disclosure: Ms. Chavez is Senior Director of Operations, Oncology and Multispecialty Customer Products, McKesson Specialty Health.

documentation, so at this point, we generate all the necessary orders and documents,” Dr. Hughes commented. “Following this simple but thorough pathway … creates a relatively seamless course that reduces labor and costs, and increases the ability of busy doctors to deliver high-quality care. We developed this breast surgery module as the prototype, but we plan to move into other disciplines that treat breast cancer, as there is significant overlap of data and, ideally, it will serve as a module to any EHR,” Dr. Hughes said.

■

Disclosure: Dr. Hughes is the inventor of HughesRiskApps, a freeware software system. He receives salary support from this effort and potentially will receive royalties for commercial use of the software.

Can you tell which patient has ALK-positive NSCLC? Molecular testing is increasingly important in lung cancer In a study of 420 patients with adenocarcinoma non-small cell lung cancer (NSCLC), more than 50% of tumors tested positive for a predictive biomarker.1 About 3% to 5% of patients with advanced NSCLC harbor a genetic alteration known as the anaplastic lymphoma kinase (ALK) fusion gene.2-9 The EML4-ALK fusion gene is believed to be a key oncogenic driver that contributes to cell proliferation and tumor survival.6, 10-12

Approval of the first ALK-directed therapy is a compelling reason to start testing patients for the ALK fusion gene Now, XALKORI (crizotinib)—the first ALK-directed therapy—may offer new potential for locally advanced or metastatic NSCLC patients. XALKORI is an inhibitor of the ALK receptor tyrosine kinase and is believed to block growth and survival mechanisms in tumor cell lines, potentially leading to regression or stabilization of tumors.7 Testing is necessary to identify patients for whom XALKORI may be appropriate. An FDA-approved test should be used to determine which patients have ALK-positive NSCLC.

Clinical characteristics should not be used exclusively to determine which patients to test In XALKORI registration studies, the ALK fusion gene was identified in patients of varying age, ethnicity, gender, and smoking status. In addition, while the ALK fusion gene was identified predominantly in patients with adenocarcinoma, it was also seen in other histological types. Thus, simultaneous testing for all clinically relevant biomarkers—including ALK—prior to treatment initiation may help guide therapeutic decisions.13 References: 1. Johnson BE, Kris MG, Kwiatkowski D, et al. Clinical characteristics of planned 1000 patients with adenocarcinoma of lung (ACL) undergoing genomic characterization in the US Lung Cancer Mutation Consortium (LCMC). 14th World Conference on Lung Cancer. July 3-7, 2011; Amsterdam, the Netherlands. Abstract O16.01. 2. Garber K. ALK, lung cancer, and personalized therapy: portent of the future? J Natl Cancer Inst. 2010;102:672-675. 3. Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008;14:6618-6624. 4. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-567. 5. Palmer RH, Vernersson E, Grabbe C, Hallberg B. Anaplastic lymphoma kinase: signalling in development and disease. Biochem J. 2009;420:345-361. 6. Mossé YP, Wood A, Maris JM. Inhibition of ALK signaling for cancer therapy. Clin Cancer Res. 2009;15:5609-5614. 7. Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46:1773-1780. 8. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14:4275-4283. 9. Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009;115:1723-1733. 10. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non–small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-4253. 11. Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Natl Rev Cancer. 2008;8:11-23. 12. Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A. 2008;105:19893-19897. 13. Pérez-Soler R. Individualized therapy in non-small cell lung cancer: future versus current clinical practice. Oncogene. 2009;28(Suppl 1):S38-S45.

Not without testing.

SELECTED SAFETY INFORMATION XALKORI has been associated with severe, life-threatening or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Other causes of pneumonitis should be excluded. XALKORI should be permanently discontinued in patients with treatment-related pneumonitis. Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. Safety of XALKORI was evaluated in 255 patients with locally advanced or metastatic ALK-positive NSCLC in 2 single-arm clinical trials (Studies A and B). The most common adverse reactions (â&#x2030;Ľ25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3/4 adverse reactions in â&#x2030;Ľ4% of patients in both studies included ALT increased and neutropenia.

Please see additional Important Safety Information on the next page and accompanying brief summary of Prescribing Information. For more information, please visit www.xalkorihcp.com.

Please see accompanying brief summary of Prescribing Information. For more information, please visit www.xalkorihcp.com.

CRI00206/290208

Printed in USA/November 2011

ASCOPost.com | DECEMBER 15, 2011

PAGE 55

Year in Review

Reflections from The ASCO Post

he editors gratefully acknowledge all contributors to The ASCO Post and thank the columnists who contributed to Volume 2, January–December 2011: ■■ Al B. Benson III, MD, FACP ■■ Richard Boxer, MD, FACS

■■ ■■ ■■ ■■ ■■ ■■ ■■

Carlton G. Brown, RN, PhD, AOCN Barrie R. Cassileth, PhD E. David Crawford, MD Emil J. Freireich, MD, DSc (Hon) John Goodman, PhD Jimmie Holland, MD Gabriel N. Hortobagyi, MD

■■ ■■ ■■ ■■ ■■ ■■ ■■

Nora A. Janjan, MD, MPSA, MBA Hagop M. Kantarjian, MD Theodore S. Lawrence, MD, PhD Mary S. McCabe, RN, MA Derek Raghavan, MD, PhD Elizabeth Reed, MD Eliezer Robinson, MD

■■ ■■ ■■ ■■ ■■ ■■ ■■ ■■

George W. Sledge, Jr, MD Thomas J. Smith, MD, FACP Joshua Spendlove, MD Deb Stewart, BSN, RN, CBCN, BPNC-IC Marvin J. Stone, MD, MACP Daniel A. Vorobiof, MD Congresswoman Deborah Wasserman Schultz (D-FL) Stanley Winokur, MD

Selected thoughts published over the past year in The ASCO Post appear here. We invite readers to visit the complete archive online at ASCOPost. com.

On ASCO “The power of ASCO is that its members are usually the best doctors in each country.” —Eduardo L. Cazap, MD, PhD Volume 2, Issue 17 “Today, thanks to a vigorous International Affairs Committee, ASCO influences oncology services on all four corners of the world.” —Gabriel N. Hortobagyi, MD Volume 2, Issue 8

On Being an Oncologist “When you combine human kindness with scientific drive, you pave the road for unlimited success.” —Alexandra Levine, MD, MACP Volume 2, Issue 17 “American physicians will use their … limitless commitment to excellence to continue to improve healthcare quality, service, and patient outcomes.” —Richard Boxer, MD Volume 2, Issue 15 “Patients always come first.” —George W. Sledge, Jr, MD ASCO President, 2010-2011 Volume 2, Issue 8 “You can learn almost everything you want to know about human behavior by sitting at a patient’s bedside and listening. My life has become bigger and richer by sharing these intimate times with people from all walks of life I otherwise would never have known.” —Alexandra Levine, MD, MACP Volume 2, Issue 17 continued on page 61

The ASCO Post | DECEMBER 15, 2011

PAGE 56

2011 European Multidisciplinary Cancer Congress Twitter Dominates Social Media Buzz at Stockholm Meeting By Caroline Helwick

here was a time when clinical For example, attendees with iPads trial results were disseminated and smartphones could navigate via mainly through peer-reviewed jourthe meeting App rather than tote nals that appeared in your mailbox. around the program book. Every exComputers and prompt reporting hibitor displayed QR codes, which from medical conferences changed drove visitors to other resources on that, and same-day postings on meditheir phone or tablet devices. For cal websites brought “breaking news” Novartis-sponsored studies, QR a step closer. But codes allowed atthe evolution has tendees to downTwitter was a huge continued, and load PDF copies today the boom in success, with 3,192 tweets of posters. social media—esA designated during the Congress. pecially Twitter— “Social Media” area has led to realnear the exhibits —Niels Bramsen time data delivery invited attendees straight from the to log on to three conference hall to mobile devices social networking sites—Twitter, anywhere in the world. Facebook, and LinkedIn—and three oncology-related websites—those for Multimedia Experience the European Cancer Organisation At the 2011 European Multidis(ECCO), the conference, and eCanciplinary Cancer Congress (EMCC) cerHub (www.ecancerhub.eu), a new in Stockholm, organizers for the first integrated platform serving providers, time took steps to encourage conferscientists, patients, and policymakers ence attendees to invest in the social across Europe. media experience. From Twitter, video An article in the conference newsblogs, and QR codes (see page 68), to paper extolled the value of “chatting to an official Congress App, new commuthe neighbours” via social media, urgnications tools were pervasive. ing oncologists to ramp up their virtual

Tweets from the @OncEd Twitter Page during EMCC 2011 OncEd BOLERO-2: Everolimus in combination with exemestane for advanced breast cancer Phase III trial #emcc2011 OncEd BOLERO-2: Significant improvement in Progression Free Survival (PFS 2.8 m 6.9 m HR -.43 P = highly significant. Very striking! #emcc2011 OncEd BOLERO-2: Does this change our standard of care for metastatic HR+ breast cancer...very likely. Still need to await mature data #emcc2011

connections, not only to colleagues but to their patients as well. “It is about time the professionals caught up,” the editor noted. Indeed, Twitter hung in the air at the meeting—quite literally, as several well-placed screens aggregated the Twitter conversation throughout the day.

Over 3,000 Tweets in the Air Niels Bramsen, Communication and Marketing Coordinator for ECCO, which oversaw the Social Media kiosk, observed that attendees were “tweeting quite a lot on iPhones, iPads, and Androids….“Twitter was a huge success, with 3,192 tweets during the Congress continued on page 58

Patient Advocates Form Huge Presence at EMCC 2011 Social Media Has ‘Real Value’

atient advocate and two-time breast cancer survivor Kathi Apostolidis from Greece spoke at a session on patients’ and physicians’ use of social media. “Social media is not a fad. It has real value,” she said. She uses social media to connect with oncologists and policymakers across the globe, and to stay in tune with the experience of patients with cancer. “What is new is the rise of individual patient advocates, patients who, due to the nature of their disease, have scouted the internet to find new therapies, to connect with other patients with the same disease, and who want to share what they learned on their journey with others,” she noted. “They are not yet in great numbers in Europe, but the impact of these ‘epatients’ is growing. They blog, are invited to speak at conferences, and are very active in social media. They are

Kathi Apostolidis

Jan Geissler,

connectors.” Follow her on Twitter: @ kgapo and @opnhealth.

Reaching the Advocacy Community Jan Geissler, cofounder of Leukaemie-online.de, a German online patient advocacy community, as well as CMLadvocates.net, a global social media platform for patient advocates, moderated a session on social media at the meeting. “I use Twitter to report what’s happening in my session and to follow what’s happening in the other sessions. Lots of people—here at the meeting and outside—thanked me for reporting from the patient advocacy and eth-

Ronnie Lassiaille

Denis Costello

ics track of the conference because they could not be there,” he said. He noted that his 350 followers do not constitute a large group, “but I think with key opinion leaders following me, I have a reach in the advocacy community.” Follow him on Twitter: @jangeissler.

Be Part of the Conversation Ronnie Lassiaille, Head of Web and Data Services for the European Society for Medical Oncology (ESMO), was tweeting membership-related information, scientific information, and press releases. “And we are retweeting journalists’ tweets,” she said. “Of all the congresses I have attended, this is the one where information is really flow-

ing—and we will definitely aim to do even better at next year’s ESMO Congress. There is so much good information out there, and we are trying to be part of the conversation.” Follow her on Twitter: @RonnieLass.

A Digital Story-telling Platform Denis Costello, Web Communications Manager for EURORDIS and RareConnect.org, a patient advocacy site devoted to rare diseases, sees social media as a “digital story telling platform” that “aggregates the mass of conversation.” From the meeting, he is blogging “how the drug development industry is changing, how it engages patients, how a new model is emerging, moving toward a multi-stakeholder platform,” he said. Follow him and his colleagues on Twitter: @eurordis.

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Disclosure: Ms. Apostolidis, Ms. Lassialle, Mr. Geissler, and Mr. Costello reported no potential conflicts of interest.

The case for Vectibix® QQ2W dosing schedule1

– The recommended dose of Vectibix® is 6 mg/kg every 14 days

660-minute infusion1

– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

PPremedication not standardized1

– The use of premedication was not standardized in the clinical trials – The utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown

NNo loading dose1

– No loading dose is required

11% severe infusion reactions reported1

– Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3-4) – Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion – Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions

INDICATION:

Vectibix® is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal cancer with these mutations. Important Safety Information, including Boxed WARNINGS: WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. [See Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)]. In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported. Withhold or discontinue Vectibix® for severe or life-threatening dermatologic toxicity and monitor for inflammatory or infectious sequelae. Terminate the infusion for severe infusion reactions.

occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Cases of fatal and non-fatal interstitial lung disease (ILD) have been observed in patients treated with Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, Vectibix® therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, Vectibix® should be permanently discontinued and the patient should be treated appropriately. In patients with a history or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® must be carefully considered. In clinical studies, patients with a history of, or evidence of, interstitial pneumonitis or pulmonary fibrosis were excluded. In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed. Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose. Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis. Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women. Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®. The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized clinical trial, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in patients treated with Vectibix® included rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); Please see brief summary of stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC Reference: 1. Vectibix® (panitumumab) grade 3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® prescribing information, Amgen. (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®. In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea

Prescribing Information on next page.

08-11 G61228-R1-V1

The ASCO Post | DECEMBER 15, 2011

PAGE 58

2011 European Multidisciplinary Cancer Congress Twitter Dominates Social Media Buzz in Stockholm continued from page 56

under the hashtag #emcc2011,” he reported. This included 382 tweets related to gastrointestinal malignancies, 320 for breast, 134 for prostate, and 122 for lung. Among the most active and influential Twitter users for the #EMCC2011

hashtag was well known scientist and oncology commentator Sally Church, PhD (@MaverickNY on Twitter), of Icarus Consultants, Jersey City, New Jersey. With over 6,000 followers, she “live tweeted” several sessions from the EMCC 2011 meeting and offered Trim: 7.875” curated conference tweets via her Live: 6.75” Pharma Strategy Blog page (http://

Vectibix (panitumumab) Injection for intravenous Infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. ®

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions]. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Twitter Hashtags

he hashtag (#) symbol is used on Twitter to mark keywords or categories in a post (or “tweet”) to facilitate searches. Clicking on a word with a hashtag in front of it will automatically show all recent tweets containing the hashtagged word.

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Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Dermatitis Acneiform 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0. Body System Body as a Whole

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibixtreated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported. Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration]. Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%). For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies. No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions has been identified during post-approval. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or established a causal relationship to drug exposure: • Skin and subcutaneous tissue disorders: Angioedema [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Skin and subcutaneous tissue disorders: Skin necrosis • Immune system disorders: Anaphylactoid reaction [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.7)] DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with Vectibix. USE IN SPECIFIC POPULATIONS Pregnancy – Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll. Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients. Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration, Warnings and Precautions and Adverse Reactions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations]. Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations]. This brief summary is based on the Vectibix® prescribing information v12, 06/2011 Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, and 7,807,798 as well as other patents or patents pending. ©2006-2011 Amgen Inc. All rights reserved.

MC46026-F

able interest, too,” Mr. Bramsen added. “Having launched our LinkedIn groups from scratch a few weeks ago, we received 238 members in the general ECCO group and good numbers of new members in specific track groups.” Over 2,200 attendees downloaded the ECCO App, opening 69,000 pages of Congress content, he added. But while some attendees embraced Twitter and other forms of virtual communication, most oncologists received the Congress news the old-fashioned way: by sitting through sessions, Mr. Bramsen acknowledged. By following the tweets, he said, “We have the impression these are mostly patient advocates (see sidebar on page 56), journalists, and industry. It seems doctors are not tweeting as much.”

Tweeting…and Much More Not so for Sunil Verma, MD, a medical oncologist at Sunnybrook Regional Cancer Center in Toronto. He and his colleague Scott Berry, MD, sent more than 100 tweets from EMCC 2011 sessions to almost 350 followers via the @ OncEd Twitter page (see sidebar, page 56)—and also expanding the data on their website, www.oncologyeducation. com, a multidimensional site they created “by physicians, for physicians,” Dr. Verma told The ASCO Post. “Scott and I are interested in using Web-based technology to inform clinicians. We take the data, synthesize it, and provide our own perspective within a week of a conference. And we are getting hits from 140 countries,” he said. “People at the meeting can’t be everywhere at once, and they want to know the results of the key trials,” he said. EMCC 2011 was the “pilot” for what will become a full-on tweeting opportunity at the next ASCO Annual Meeting, he added, when Drs. Verma and Berry will enlist other physicians for comprehensive meeting coverage. Trim: 10.75” Live: 9.75”

INDICATIONS AND USAGE Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14) in Full Prescribing Information]. The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progressionfree survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations. [see Clinical Studies (14) in Full Prescribing Information]. DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions. Dose Modifications for Infusion Reactions [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix. • If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose. – If toxicities recur, permanently discontinue Vectibix. – If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached. Do not administer Vectibix as an intravenous push or bolus. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported. Withhold Vectibix for severe or life-threatening dermatologic toxicity. [see Boxed Warning, Adverse Reactions, and Dosage and Administration]. Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCICTC grade 3–4). Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [see Boxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. [see Dosage and Administration]. Increased Toxicity With Combination Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCICTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Severe diarrhea and dehydration which may lead to acute renal failure and other complications have been observed in patients treated with Vectibix in combination with chemotherapy. Pulmonary Fibrosis: Cases of fatal and non-fatal interstitial lung disease (ILD) have been observed in patients treated with Vectibix. In the event of acute onset or worsening of pulmonary symptoms, Vectibix therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, Vectibix should be permanently discontinued and the patient should be treated appropriately. In patients with a history or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix must be carefully considered. In clinical studies, patients with a history of, or evidence of, interstitial pneumonitis or pulmonary fibrosis were excluded. Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed. Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix. Ocular Toxicities: Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix therapy for acute or worsening keratitis. EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Assessment for EGFR expression 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 specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and 174 received Vectibix in combination with chemotherapy [see Warnings and Precautions]. The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

pharmastrategyblog.com). Stephen Dunn, a journalist for Brandcast Health, a digital, video, and social media health-care agency, kept track of pharma activity, noting that the most mentions were for Novartis at 612, followed by Roche at 49 tweets. Mr. Dunn can be found on Twitter at @brandcasthealth. “LinkedIn was shown consider-

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Disclosure: Mr. Bramsen and Drs. Verma and Berry reported no potential conflicts of interest.

ASCOPost.com | DECEMBER 15, 2011

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2011 European Multidisciplinary Cancer Congress Researchers Find Remarkable Heterogeneity in Sarcomas By Alice Goodman

oes one size fit all for the treatment of sarcoma? The answer is a resounding “no,” according to JeanYves Blay, MD, Department of Medicine, Université Claude Bernard, and Unité INSERM (National Institute of Health and Medical Research Unit), Lyon, France. Researchers have been able to classify sarcomas into subtypes according to driving molecular alterations, and the identification of these abnormal pathways has led to the development of targeted agents for these subtypes—some quite effective, he explained. Another boon attributable to the identification of driving molecular alterations is that sarcomas represent optimal models for the development of targeted therapy.

Jean-Yves Blay, MD

Over 100 Subtypes “Sarcoma is a heterogeneous group of more than 50 histotypes, without taking grading into account, and there are probably more than 100 molecular subtypes, Dr. Blay told listeners at the recent European Multidisciplinary Cancer Congress in Stockholm. Although these discoveries are exciting, adapting treatment of sarcomas according to histology is still controversial for most subtypes at present, Dr. Blay noted. He and his colleagues are presently working on two large sets of research projects in this area. One is testing new treatments that target a protein or pathway that is driving a particular tumor subtype. In addition,

the group is studying sarcomas without known driving forces—those with complex genetic alterations—and looking for additional mutations that may be responsible for tumor growth.

Sarcoma Subgroups Five subgroups of sarcomas have been identified: ■■ Sarcomas with specific translocations and fusion oncogenes (Ewing’s sarcoma, synovial sarcoma, alveolar rhabdomyosarcoma, and desmoplastic small round cell tumor) ■■ Sarcomas with tyrosine kinase mutations (KIT in gastrointestinal stromal tumor [GIST]) ■■ Sarcomas with deletion of tumor suppressor genes (rhabdoid tumors) ■■ Sarcomas with a single genetic alteration (well-differentiated or dedifferentiated liposarcomas) ■■ Sarcomas with complex genetic alterations (leiomyosarcomas, malignant fibrous histiocytoma, undifferentiated and pleiomorphic sarcomas, osteosarcomas); these tumors have chromosome instability and are associated with a worse prognosis “The ability to subclassify sarcomas gives us the opportunity to determine which subsets predict for response to adjuvant and neoadjuvant therapy for a very complex group of diseases,” Dr. Blay continued.

Treatment Considerations For localized sarcomas, surgery and radiation are standard of care, resulting in cure rates of about 50%. Of the remaining patients, about 60% have metastatic disease. Despite surgery, radiation, and chemotherapy, overall survival for patients with metastatic sarcoma treated with first-line doxorubicin plus ifosfamide is about 12

Update on Sarcoma Treatment ■■ Sarcomas are a heterogeneous group of tumors, and one size does not fit all as far as treatment goes.

■■ As with other types of cancers, the future of treating sarcoma is based on identifying molecular abnormalities that drive the sarcoma subtype and developing therapies targeted to those abnormalities.

■■ The use of imatinib for the treatment of gastrointestinal stromal tumor

and dermatofibrosarcoma protuberans represents a “home run” for this approach.

EXPERT POINT OF VIEW

istorically, studying sarcoma has been problematic for several reasons. Sarcomas represent only about 1% of all adult cancers, and there are many subtypes, so getting a group of patients with one type of sarcoma together for a clinical trial in a single institution can be challenging. In the past, studies grouped several types of sarcomas together and that confounds the literature, because response rates and outcomes vary depending on Edwin Choy, MD subtypes accrued, said Edwin Choy, MD, Assistant Professor at Harvard Medical School and Massachusetts General Hospital, Boston. “Now the world of sarcoma research is more interconnected. The [Sarcoma Alliance for Research through Collaboration] makes it easier to conduct multi-institutional trials and ask meaningful sarcoma questions. These sarcomas are truly different diseases. Ewing sarcoma, for example, is an entirely different entity from gastrointestinal stromal tumor [GIST], just as breast and lung cancers are different. The correct way to study sarcomas is to identify the molecular driver of these malignancies and develop therapies targeted to those aberrations,” Dr. Choy stated. “The hope of the future and the current strategy for drug development is based on teasing out these molecular differences and targeting them.”

Advantages in Sarcoma Research This strategy may be easier to apply in sarcomas than in other tumor types, because the sarcoma setting is thought to have some advantages. Many types occur in young people before they have been exposed to environmental carcinogens, and these types may have only a single molecular aberration to target. “We know that some types of sarcomas are genetically more straightforward than other tumor types. We know that GIST, dermatofibrosarcoma protuberans, and clear cell sarcomas are genetically simpler compared to carcinomas or other types of malignancies,” Dr. Choy said.

■

Disclosure: Dr. Choy is a paid consultant for Amgen and sanofi-aventis and receives research support from Novartis, Pharmacyclics, and AstraZeneca.

months. A variety of chemotherapies have been studied. One debate concerns how best to deploy doxorubicin and ifosfamide— in combination or as single-agent therapy. The ongoing EORTC 62012 study, completed in 2010, should answer that question. The study is comparing doxorubicin vs the combination of full-dose doxorubicin plus full-dose ifosfamide as first-line therapy for softtissue sarcoma in about 400 patients. Dr. Blay emphasized that disease stabilization is probably a more important endpoint than response rates in clinical trials. “About 5% of all patients with soft-tissue sarcomas will be longterm survivors, with no progression at 5 years. These patients probably will not relapse, even if they had only partial response or stable disease. This is an important piece of information,” he said.

Another important finding emerged from an analysis of the randomized phase II study on trabectedin (STS-201) given every week vs every 3 weeks. Every-3-week treatment achieved better time to progression, progression-free survival, and a trend toward improved overall survival, leading to approval of the drug in Europe. Retrospective study showed that response to trabectedin differed according to histologic and molecular subtypes. “This leaves us with three registered drugs for treatment of soft-tissue sarcomas: doxorubicin, ifosfamide, and trabectedin,” he said. “For histotypes, nothing has been shown superior to single-agent doxorubicin for first-line treatment in advanced-phase disease, when survival is considered. For synocontinued on page 60

The ASCO Post | DECEMBER 15, 2011

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2011 European Multidisciplinary Cancer Congress Heterogeneity in Sarcoma continued from page 59

vial sarcomas, ifosfamide can be added to doxorubicin, with a slightly superior overall response rate but no durable progression-free survival and no demonstrated survival advantage. These drugs may be more effective in specific subtypes,” he theorized.

Other drugs have been studied in phase II trials. Paclitaxel showed activity in angiosarcoma. Gemcitabine plus docetaxel showed limited activity in relapsed leiomyosarcoma, and gemcitabine monotherapy appears to be preferred over the combination in leiomyosarcoma. In other subtypes, the combination has been shown to

be superior over gemcitabine in a randomized trial conducted by the Sarcoma Alliance for Research through Collaboration (SARC) group.

Targeted Therapy “Despite these choices, we need to approach the question of targeted therapy for sarcomas. A major target is

What role may MUC1 play in NSCLC

MUC1 (mucin 1) is a transmembrane glycoprotein that is normally found on the apical surface of most simple secretory epithelial cells and is associated with a number of diverse cellular functions.1 The functions of the extracellular domain of MUC1 are largely dictated by the extent of its glycosylation.1,2 The cytoplasmic tail of MUC1 can serve as a scaffold for interactions with intracellular proteins that affect cell survival and proliferation and can have direct effects on transcription within the nucleus.1,2

110718-140032

Select functions of MUC1 in normal cells • Lubricates epithelial surfaces3 • Acts as a physical barrier against microbes3 • Protects against proteolytic degradation3 • Involved in adaptive immunity against pathogens4 • Mediates normal T-lymphocyte responses and regulates T-lymphocyte proliferation5 • Involved in signal transduction, which regulates cell survival and proliferation2 • Can directly affect transcription within the nucleus1 Overexpression, altered distribution, and aberrant glycosylation of MUC1 have been observed in a variety of cancers, including non-small cell lung cancer (NSCLC).1,2,6 Aberrant overexpression of MUC1 by tumor cells is associated with several mechanisms of tumor cell survival.6-8 Overexpression of MUC1 may play a role in

abnormal cell signaling through interactions with regulatory proteins, such as with EGFR.2,7 In addition, the cytoplasmic tail of MUC1 can be targeted to the nucleus, where it interacts with transcription factors for genes related to invasion, angiogenesis, and metastasis.7,8 Furthermore, cells overexpressing tumor-associated MUC1 may escape the host immune response by suppression of the T-cell proliferation response and by failure to process and present MUC1 on class II major histocompatibility complexes.9,10 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC. Visit www.emdserono.com to learn more about EMD Serono Oncology.

■

Disclosure: Dr. Blay has received research support and honoraria from Novartis, Pfizer, Roche, GlaxoSmithKline, and PharmaMar. 1. Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol. 2008;70:431-457. 2. Bafna S, Kaur S, Batra SK. Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells. Oncogene. 2010;29(20):2893-2904. 3. Carson DD. The cytoplasmic tail of MUC1: a very busy place. Sci Signaling. 2008;1(27):pe35. 4. McAuley JL, Linden SK, Png CW, et al. MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. J Clin Invest. 2007;117(8):2313–2324. 5. Agrawal B, Longenecker BM. MUC1 mucin-mediated regulation of human T cells. Int Immunol. 2005;17(4):391-399. 6. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816. 7. Ahmad R, Raina D, Joshi MD, et al. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69(17):7013-7021. 8. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42):5667-5677. 9. Agrawal B, Krantz MJ, Reddish MA, Longenecker BM. Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2. Nat Med. 1998;4(1):43-49. 10. Hiltbold EM, Vlad AM, Ciborowski P, Watkins SC, Finn OJ. The mechanism of unresponsiveness to circulating tumor antigen MUC1 is a block in intracellular sorting and processing by dendritic cells. J Immunol. 2000;165:3730-3741.

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EMD Serono Oncology | Combination is key™

EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

003296_emddsa_de_muc1_lv_fa1.indd 1

the expression and activation of mechanisms driving the tumor cell, and this has led the way to research in sarcomas,” he explained. For example, KIT and PDGFR mutations comprise the initial molecular event in GIST. Beyond that, further molecular characterization of GIST tumors shows that tumors with KIT exon 11 and 9 mutations require a double dose of imatinib (Gleevec). “The mutational status of GIST seems to be the most important prognostic factor,” he said. Other drugs that target a molecular abnormality assumed to drive sarcoma subtype have been studied. These agents include figitumumab in Ewing sarcoma, imatinib in dermatofibrosarcoma protuberans and pigmented villonodular synovitis, crizotinib (Xalkori) in inflammatory myofibroblastic tumors, mTOR inhibitors in angiolipomas and perivascular epithelial cell tumors, RG7128 targeted to liposarcomas with MDM2 amplification, and denosumab (Prolia, Xgeva) for giant cell tumors of the bone, a rare entity with well understood biology, he said. Despite these examples, “it is not a piece of cake to identify good treatments. We have many examples of failure, such as gefitinib [Iressa] in synovial sarcoma, which targets a protein that is overexpressed in this subtype but most likely plays no role in the neoplastic process. It will therefore be important not only to characterize mutations in sarcomas, but also to characterize their genuine role in the proliferation and survival of tumor cells to guide therapeutic development in specific molecular subtypes. The successes achieved in this group of orphan diseases have validated the relevance of this comprehensive approach.”

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Perspective

Year in Review continued from page 55

On Cost of Care

“The cuts to oncology being proposed have little effect on the overall budget … but will hamper an already fiscally challenged cancer care delivery system.” —Shelagh Foster Director of Government Relations ASCO, Volume 2, Issue 15 “We need a new payment model that promotes quality of care instead of the current system that promotes quantity of care.” —Diane Meier, MD, FACP Volume 2, Issue 14

On the Oncology Drug Shortage “The greatness of a civilized society is measured by how well it treats its weakest members—the sick and the poor.” —Hagop M. Kantarjian, MD Volume 2, Issue 17 “The gains in the curable malignancies have resulted from a hard-fought war, and now it is particularly galling to see the slow, steady, and continued emergence of a national travesty—the shortage of cytotoxic drugs, which will certainly lead to an epidemic of avoidable deaths.” —Derek Raghavan, MD, PhD Volume 2, Issue 13

On Disparities “A cancer diagnosis is no longer the death sentence it used to be, and the statistics are only getting better. But our health-care system is still rife with disparities that prevent these advances from reaching everyone.” —Congresswoman Debbie Wasserman Schultz Volume 2, Issue 15

On Research “Where is the evidence that protons can be used to safely to deliver a higher dose of radiation than photons to, for example, the prostate?” —Theodore S. Lawrence, MD, PhD Volume 2, Issue 14

Visit

The Art and Grace of Just Letting Go Options after a career in oncology By Richard Boxer, MD, FACS

be forced to retire early due to the ravike a breeze rippling across a lake, ages of malignancies and their complithe end of your career is approachcations, but I was ready. I built my sail ing and you cannot escape its path. You for the oncoming winds of change and can see it coming, and before you know Richard Boxer, MD, FACS was able to take advantage of even the it the inexorable movement will rush unexpected dire circumstances. I am past you. You have two choices: Build a Other Opportunities recommending the same to you. sail so that you can capture the energy There are also financially productive and move with it, or remain unprepared The Value of Teaching and professionally adventurous routes and be left behind as it sweeps by. Teaching has always been a responby which to expand your horizons The trick is to seamlessly move from sibility of physicians. Whether we teach just as your practicing medical profull-time practice to the next chapour patients or teach students and/or fessional career is in its denouement. ter in your life, while fulfilling your residents, we fulfill our oath and satisfy The knowledge and experience that philosophical, physical, and emotional an inner longing to pass our knowledge, is gained during the 30 to 40 years of goals and going to your strengths. It experience, judgment, and wisdom to practice allows you to effortlessly prois an enormous waste of wisdom for those who follow us. This is our duty to vide value to businesses that engage in doctors who have gathered decades the health industry. of knowledge and Since 16% of the experience to simWhether we teach our patients or teach student American econoply walk away from and/or residents, we fulfill our oath and satisfy an inner my is derived from medicine. It is actuhealth care, the ally a public health longing to pass our knowledge, experience, judgment, and opportunities are disaster. For the wisdom to those who follow us. vast. first 30 to 40 years Decisions that of your life, you would take weeks were educated to ourselves, our teachers, and the patients of focus by the uninitiated, nonphycare for the public, and the payoff for who will be treated in the future. As in sician executive would have immedisociety was an equal number of years the Hippocratic oath we swore upon reate clarity to an experienced physiof service. However, if there are opceiving our medical degree: cian. Furthermore, there is a greater portunities for the doctor to continue I swear by Apollo, the healer, Asclepichance that you—as opposed to the to give back to society for another 10 us, Hygieia, and Panacea, and I take to nonphysician businessman—would years, that payoff increases by 25%. witness all the gods, all the goddesses, make the correct decision based on Planning for Transition to keep according to my ability and your judgment. That is why so many Every physician knows that a promy judgment, the following Oath and businesses understand the value of agreement: To consider dear to me, as fessional career must come to an end. physician executives. The doctor my parents, him who taught me this art; Some hang on longer than is safe for needs to recognize his/her strengths to live in common with him and, if necthem or their patients. They hang on in this context as well and provide a essary, to share my goods with him; To because of the fear of the future. There compelling argument to prospective look upon his children as my own brothers, is an art but also honor and grace in just employers. to teach them this art [italics added]. letting go. However, with planning— Your responsibility to yourself and There is a medical school, a teachwhich should start years if not decades family is to build a sail that is ready to ing Veterans Administration hospibefore the inevitable transition—the take you to the next chapter of your tal, or a community clinic (federally plans become a natural extension of life. Get ready; the wind is coming qualified or not) within 50 miles of life rather than an abruption of it. your way. Disclosure: Dr. Boxer reported no potential almost all physicians. It is very satIn my particular situation, I became conflicts of interest. isfying to teach and care for those involved with national politics 20 years who are underinsured or uninsured, before my forced retirement. I planned Dr. Boxer is Professor of Clinical Urology at whether for compensation or as a for a seamless shift from urology private the University of Miami and Clinical Profesvolunteer. It is a graceful and dignipractice and public policy to consultsor at the University of Wisconsin, Madison, fied exit from a career that has been ing exclusively in public health policy. I and the Medical College of Wisconsin. the pride of your professional life. did not know at the time that I would

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PAGE 62

In the Literature

Emerging Clinical Data on Cancer Management RENAL CELL CARCINOMA Significantly Longer Survival with Axitinib Compared to Sorafenib in Patients with Renal Cell Carcinoma A phase III study comparing the vascular endothelial growth factor receptor (VEGFR) inhibitors axitinib and sorafenib (Nexavar) as second-line therapy in patients with metastatic renal cell carcinoma found that axitinib produced significantly longer progression-free survival. Published in The Lancet, the study appears to be the first reported phase III randomized trial comparing the effectiveness of one targeted agent against another in patients with renal cell carcinoma. A total of 723 patients in 22 countries were randomly assigned to receive axitinib at 5 mg twice daily (n = 361) or sorafenib at 400 mg twice daily (n = 362). Patients who did not experience hypertension or adverse reactions to axitinib higher than grade 2 were allowed dose increases to 7 mg, and then to 10 mg, twice daily. Participants were not masked to study treatment. All patients were aged 18 years or older with confirmed renal clear cell carcinoma that progressed despite first-line therapy containing sunitinib (Sutent), bevacizumab (Avastin) plus interferon alfa, temsirolimus (Torisel), or cytokines.

Median progression-free survival was 6.7 months with axitinib compared to 4.7 months with sorafenib. In patients who had previously received cytokines, median progression-free survival rose to 12.1 months in the axitinib group and 6.5 months in the sorafenib group.

Discontinuation Rates Patients received axitinib for a median duration of 6.4 months (range = 0.03–22) and sorafenib for 5.0 months (range = 0.03–20). By the data cutoff date, 61% of the axitinib treatment group and 71% of the sorafenib group had discontinued study treatment. This was primarily due to disease progression, which occurred among 160 patients in the axitinib group and 180 in the sorafenib group. The second most common reason for discontinuation was adverse events, including treatment-related adverse events in 14 (4%) of the patients treated with axitinib and 29 (8%) of the patients treated with sorafenib. The most common adverse events were diarrhea, hypertension, and fatigue in the axitinib arm, and diarrhea, palmar-plantar erythrodysesthesia, and alopecia in the sorafenib arm. Data showing that axitinib led to a “statistically significant and clinically meaningful increase” in progressionfree survival “support the hypothesis that biochemically more potent inhibition of the VEGFR, as achieved

with axitinib, produces a more robust clinical effect” and “establish axitinib as a treatment option for second-line therapy of advanced renal cell carcinoma,” the investigators concluded. “An ongoing phase III trial is comparing axitinib and sorafenib in patients with metastatic renal cell cancer and no previous systemic first-line therapy or progressive disease after one previous systemic first-line regimen for metastatic disease containing sunitinib, cytokine(s), or both.” The study was funded by Pfizer, which developed axitinib. Rini B I, et al: Lancet, Nov. 4, 2011 (early release online).

BREAST CANCER Significant Neurologic and Executive Function Impairment among Breast Cancer Survivors Women who survive breast cancer show significant neurologic impairment, with outcomes appearing to be significantly poorer for those treated with chemotherapy, according to a report in the Archives of Neurology. Investigators at Stanford University School of Medicine in California conducted an observational study to determine whether profiles of brain activation differ among breast cancer survivors treated with or without chemotherapy, compared with healthy control women. The study included 25 women with breast cancer who received chemotherapy, 19 women with breast cancer who did not receive chemotherapy, and 18 healthy female controls, all matched for age and other demographic variables. The women were asked to perform card-sorting tasks, and the researchers used functional MRI to measure activation in several areas of the brain.

Areas of Deficit

The results showed that women who had breast cancer “demonstrated significantly reduced activation in the left middle dorsolateral prefrontal cortex and premotor cortex compared with healthy controls,” the authors reported. “The chemotherapy group also demonstrated significantly reduced left caudal lateral prefrontal cortex activation and increased perseverative errors and reduced process-

ing speed compared with the other two groups,” they added. “Reduced left caudal lateral prefronSEE PAGE 68 tal cortex activation was significantly correlated with higher disease severity and elevated subjective executive dysfunction in the chemotherapy-treated women.” The study also found that the effects of chemotherapy on brain function may be exacerbated by such factors as increased age and lower educational level. Although primary breast cancer has not been associated historically with neurologic problems, “a growing body of evidence suggests that patients are at increased risk for altered brain structure and function,” the authors noted. “This study provides further evidence that primary [breast cancer] may cause measurable brain injury,” they stated in their conclusion. “Women treated with chemotherapy may show additional prefrontal deficits and have difficulty compensating for neurobiological changes such that they also show impaired executive function. The left caudal lateral prefrontal region may be particularly vulnerable to the effects of chemotherapy and/or disease severity and may represent a novel biomarker of subjective or subclinical executive dysfunction in chemotherapy-treated women.” Kesler SR, et al: Arch Neurol 68:14471453, 2011.

LUNG CANCER Evidence of Improved Survival for Lobectomy vs Limited Resection in Early-stage Lung Cancer “Evidence is statistically inconclusive but suggestive that lobectomy, compared with limited resection, is associated with increased long-term survival for early-stage lung cancer,” according to a study reported in the Journal of the National Cancer Institute. The study analyzed data from 679 patients diagnosed with stage I or II non–small cell lung cancer (NSCLC) in a variety of regions and hospitals in the United States. Patients were mostly elderly, male, and white, and more than continued on page 66

Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

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

DECODE

metastatic melanoma

Indication and Usage ZELBORAF™ (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information Cutaneous squamous cell carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF. The incidence of cuSCC in ZELBORAF-treated patients in the Phase III study was 24%. The median time to first appearance of cuSCC was 7 to 8 weeks. Potential risk factors included age ≥65 years, prior skin cancer, and chronic sun exposure. All patients should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months following discontinuation of ZELBORAF. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe reactions may include generalized rash and erythema or hypotension. Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including 1 case of Stevens-Johnson syndrome and 1 case of toxic epidermal necrolysis in the Phase III study. ZELBORAF treatment should be permanently discontinued in patients who experience a severe hypersensitivity or dermatologic reaction. QT prolongation Exposure-dependent QT prolongation has been observed in patients treated with ZELBORAF, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes.

Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval. ECG and electrolytes should be monitored before initiating treatment with ZELBORAF and after dose modification and routinely during treatment (15 days after treatment initiation then monthly for first 3 months of treatment and every 3 months thereafter or as clinically indicated). If the QTc exceeds 500 ms, ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values. Liver laboratory abnormalities Liver laboratory abnormalities have occurred with ZELBORAF. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Lab abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials. While taking ZELBORAF, all patients should be advised to avoid sun exposure and, when outdoors, to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30). For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions In the Phase III study, 5 cases of uveitis were reported in patients treated with ZELBORAF.

EXTEND

survival

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

P<0.0001

OS=overall survival HR=hazard ratio CI=confidence interval * Median follow-up was 6.2 months (95% CI, 0.4-13.9) for ZELBORAF patients vs 4.5 months (95% CI <0.1-11.7) for those taking dacarbazine. † There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms respectively at the time of analysis.3

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

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

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, 5 cases each of blurry vision and iritis and 6 cases of photophobia were reported in the Phase III study. One case of retinal vein occlusion was reported in the Phase II study. New Primary Malignant Melanoma Eight skin lesions in 7 patients were reported as new primary malignant melanoma in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitoring for skin lesions should occur as outlined above [see cuSCC]. Use in Pregnancy: Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If ZELBORAF is used during pregnancy or if the patient becomes pregnant while taking ZELBORAF, the patient should be apprised of the potential hazard to a fetus. BRAF Testing Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for the selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common adverse reactions of any grade (≥30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was predefined as a grade 3 event.

Please see Brief Summary of Prescribing Information on the following page. References: 1. Smalley KS, Sondak VK. Melanoma—an unlikely poster child for personalized cancer therapy. N Engl J Med. 2010;363:876-878. 2. Flaherty KT. Next generation therapies change the landscape in melanoma. F1000 Med Reports. 2011; 3:1-4. doi:10.3410/M3-8. 3. Data on file. Genentech, Inc.

www.zelboraf.com

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In the Literature

Emerging Clinical Data in Cancer Management continued from page 62

85% were current or former smokers. Most patients (524, or 77%) had lobectomy, but 155 (23%) had limited resection. The authors noted that the while “lobectomy is considered the standard

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.

histology between the two groups of patients and most patients in each group had adenocarcinoma. Patients in the limited resection group had greater severity of lung disease and were more likely to have a history of heart failure, stroke, and obesity. “Increasing severity of lung disease and a history of stroke were associated

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 Pruritis 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)]. Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action. Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women. Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus. Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established. Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly disorders patients (≥ 65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine. Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC†# 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. disorders Cough Injury, poisoning and procedural complications Sunburn

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

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

with receipt of limited resection, indicating that sublobar resections can serve as an alternative approach for those unable to tolerate lobectomy,” the authors noted.

Key Data Patients were observed for a median of 55 months. “Over the course of the study, a non-statistically significant trend toward improved long-term survival was evident for lobectomy, compared with limited resection, in adjusted analyses (hazard ratio of death = 1.35 for limited resection, 95% CI = 0.99 to 1.84, P = .05),” the researchers reported. A survey of physicians identified by study patients found that the surgeons of patients in the limited resection group “tended more often to be thoracic surgeons compared with surgeons of patients in the lobectomy group (81% vs 72%, P = .09) and they tended to perform a higher number of lung resections per month” (median = 6 vs 4, P = .07). Other factors reported to be independently associated in adjusted analysis with limited resection were “Medicare, Medicaid, lack of or unknown type of insurance, small tumor size, increasing severity of lung disease, and history of stroke.”

■

Billmeier SE, et al: J Natl Cancer Inst 103:1621-1629, 2011. Safety:10"

ZELBORAF™ (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about TRADENAME. 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

treatment for early-stage NSCLC,” the relatively high frequency of limited resection “likely reflects both the extent of comorbidity seen in patients with lung cancer and ongoing disagreement concerning the appropriate role for limited resection in the treatment of NSCLC.” Safety:7" There was no difference in tumor

Are You Being Affected by the Oncology Drug Shortage?

To report on how the oncology drug shortage is affecting your practices, contact: ■■ ASCO: publicpolicy@asco. org or 571-483-1368

■■ FDA: drugshortages@fda. hhs.gov

■■ American Society

of Health-System Pharmacists: http://www. ashp.org/DrugShortages/ Report/

ASCOPost.com | DECEMBER 15, 2011

PAGE 67

In the News

Solid Organ Transplant Recipients Have Increased Risk for Broad Range of Malignancies But most patients do not develop cancer. By Charlotte Bath responding to an excess absolute risk … attributable to transplantation of approximately 0.7% per year,” the researchers reported in the Journal of the American Medical Association.1 “ Risk was increased for 32 different malignancies, some related to known infections (eg, anal cancer, Kaposi sarcoma) and others unrelated (eg, melanoma, thyroid, and lip cancers),” the investigators stated. The most comhe Transplant Cancer Match mon malignancies with elevated risk Study, a large investigation linking were non-Hodgkin lymphoma and transplant and cancer registries, concancers of the kidney, liver, and lung, firms and expands on previous studcorresponding to three commonly ies showing an increased cancer risk transplanted organs. Together, these among recipients of solid organ transfour malignancies “comprised 43% of plantation. But these results need to be all cancer cases in transplant recipients considered in the context of transplancompared with 21% in the U.S. general tation’s proven value in saving lives, population,” the authors stated. according to Eric Engels, MD, MPH, “Elevated risk of liver cancer was lead author of the Transplant Cancer observed only among liver transplant Match Study rerecipients. The export and Senior traordinary risk in Cancer is one Investigator, Dithe first 6 months vision of Cancer after liver transcomplication [of Epidemiology and plant is probably transplantation], but Genetics at NCI. an artifact of de“Transplant is layed recognition in the great majority of one of the great or reporting of liver cases, patients don’t success stories of cancer,” the aumedicine. It helps thors wrote, adding get cancer. That’s a patients with sethat they “suspect good piece of news that vere medical illthat the vast majornesses live, in many ity of early cancers can be taken from a cases, a normal and were prevalent study like this. largely healthy life. cases from the exCancer is one complanted liver.” plication that we As Dr. Engels focus on, and we hope to reduce the explained, “We wrote that text very risk of cancer, but in the great majorcarefully to try to convey what we ity of cases, patients don’t get cancer. thought was going on. We do think That’s a good piece of news that can be that a lot of those early cancers are taken from a study like this as well,” Dr. an artifact of the way our study was Engels said in an interview with The conducted. We identified cancers by ASCO Post. linking databases together, and if the dates are off slightly in those databases, Overall Cancer Risk Increased then it could look like the cancer ocTwofold curred after the transplant. But what The Transplant Cancer Match we think happened was that the cancer Study used linked data from the nawas present before the transplant. And tional Scientific Registry of Transplant when the liver was taken out to do the Recipients and 13 population-based transplant, it was discovered then that cancer registries in the United States cancer was in the liver, or it was reportfrom 1987 to 2008 to evaluate cancer ed at that time. So that would show up as a cancer diagnosis just after transrisk in a cohort of 175,732 transplant plant, but really the cancer was present recipients. “We observed a 2-fold before the transplant.” overall increased risk of cancer, corIn the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

Expect Questions from Your Patients

atients concerned about an increased risk of cancer among recipients of organ transplantation need to know that “in the great majority of cases, patients don’t get cancer,” according to Eric Engels, MD, MPH, lead author of the Transplant Cancer Match Study report and Senior Investigator, Division of Cancer Epidemiology and Genetics at NCI. “Patients who are on the wait list for a transplant know that transplantation is a potentially lifesaving therapy. They are eager to get a transEric Engels, MD, MPH plant, and that is the correct way to think about it,” Dr. Engels said. But these patients also need to think about ways to minimize their overall risks of cancer, “and that would be true both before and after the transplant,” Dr. Engels added. Considerations involve general cancer reduction strategies, such as not smoking. Candidates for and recipients of organ transplants “should undergo routine screening for cancer based on their age,” Dr. Engels advised, such as cervical cancer screening and mammography for women and colon cancer screening for both men and women. “Transplant recipients also have an increased risk for some virus-related cancers. So they should be evaluated for prevention and screening of those cancers,” Dr. Engels said. “They should get the hepatitis B vaccine if they are not already hepatitis B immune.”

Screening of Transplanted Organs? Screening for recipients of transplanted organs, such as lungs, kidneys, and livers, where the study showed cancer is more likely to develop, “probably varies across the country, from transplant center to transplant center, but it is not a general part of clinical care to do screening,” Dr. Engels said. “I think that is something we would like people to consider. I don’t think we are at the point in our studies and analyses where we can strongly advocate for that, but I think the findings do raise it as a possibility.” The risk for non-Hodgkin lymphoma risk was highest in the first year after transplants, then decreased and increased again to a plateau at 4.5 years after transplant. “There is no widely accepted way to screen those patients,” Dr. Engels said. “Some transplant centers screen people using a blood test for Epstein-Barr virus to look for evidence that the virus is reactivated. I think there is a recognition in the field that tests like that need to be further developed and standardized, and then they could be applied clinically.”

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The cancer was not in the newly transplanted liver. “I know that the centers where the organs are procured do a careful review of the donor’s medical history and examine the organs for any evidence of disease,” Dr. Engels said. The study also found that the risk was decreased for breast cancer and to a lesser extent prostate cancer. “We scratched our heads about that,” Dr. Engels said. “We don’t really know why the risk is decreased. We speculated that it could be due to screening

practices—transplant candidates are screened in advance for those cancers, and anybody who has those cancers would not get a transplant. Maybe that helps reduce the risk after transplant. We don’t have another explanation for that.”

Medications Could Cause or Protect against Cancer “Medications that are used in transplant recipients could have cancer-causing effects,” Dr. Engels continued on page 68

The ASCO Post | DECEMBER 15, 2011

PAGE 68

Patient’s Corner

Cancer Risk in Organ Transplant Recipients continued from page 67

said, stressing that evidence is not yet available to support this hypothesis. “We are not the first people to speculate about that possibility,” he noted. “The medicines are designed to suppress the immune system, but they may have other effects. It is difficult to sort that out, but it is something that I think people are thinking about. Even though we think that some of these drugs potentially have cancer-causing effects, that hasn’t been shown. Most patients don’t get cancer and get benefit from these drugs for their transplant.” Some immunosuppressive drugs are being used in the treatment of cancer, such as everolimus (Afinitor) to overcome resistance to hormonal therapy in advanced breast cancer (as reported in The ASCO Post in November).2 “These drugs are used in some cases outside of transplant,” Dr. Engels explained. “They are used for people with autoimmune diseases, for example, and may actually have protective anticancer effects. But in all these cases, one has to weigh the benefits of the drug in helping people with severe medical illness against the possible risks. Somebody with metastatic cancer who is being considered for a trial of an immunosuppressive drug needs to recognize that there could be risks, but that the benefits are hopefully going to greatly outweigh the risks,” he said. Dr. Engels and his coauthors stated, “future analyses will focus on specific cancers that occur excessively and examine associations with medical conditions and individual immunosuppressive medications.” The investigators are looking at specific cancers, including non-Hodgkin lymphoma, but do not yet have any results to share, Dr. Engels said. Another study is looking at the risks associated with intensive induction immunotherapy given at the time of transplant.

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

References 1. Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al: Spectrum of cancer risk among US solid organ transplant recipients. JAMA 306:1891-1901, 2011. 2. Goodman A: Everolimus overcomes resistance to hormonal therapy in advanced breast cancer. The ASCO Post 2(16):1, November 1, 2011.

My Cancer Is Incurable, but My Future Is Limitless By Veronica Cappalonga, as told to Jo Cavallo

Looking Forward

ancer has nearly always been part of my life. When I was 6 years old, I was diagnosed with acute lymphoblastic leukemia. The doctors told my parents that unless I was treated immediately, I wouldn’t live longer than a month. Over the next 3 years, I underwent intensive courses of chemotherapy and heavy doses of cranial and full-body radiation. The therapy put me in a 7-month remission, but soon after, I was diagnosed with acute myeloid leukemia. An autologous bone marrow transplant finally cured me of leukemia, and for the next 12 years I lived a fairly normal life. I was able to return to school and played soccer, a sport I love.

In October, I passed the 6-year mark since that last diagnosis, and I’m still looking ahead. Although my tumor was considered inoperable when I was first diagnosed, because it had quadrupled in size within just a few days of the diagnosis, my surgeon removed as much of the cancer he could without further damaging my brain. Even before the surgery, however, the glioblastoma had left me weakened on my right side and my speech slurred. After the surgery I was completely paralyzed on my right side and I couldn’t speak. Intensive physical and speech therapy have improved my ability to speak and helped strengthened my legs, so I’m not completely dependent on my wheelchair and can usually get around with the use of a cane. Now, I’m determined to finish college. My mother, Rocio, is my lifeline.

Veronica Cappalonga

to help raise awareness of brain cancer and money for research.

Living My Future

I realize how serious my condition is. But even with all my physical setbacks, emergency trips to the hospital, and delayed dreams, my experience with cancer starting when I was just a New Challenges young child has taught me that nothAfter graduating from high school, I ing is set in stone—not the dire preattended Santa Monica College, where dictions from some doctors and not I studied communications. the physical limitations from My goal since my illness was my cancer. I’m still here. I’m still Patients deserve to have the gift of to help other children diagplanning to have as full a life as hope, whether their life expectancy nosed with cancer—to be possible. Bevacizumab is keeptheir voice and to let them ing my brain tumor manageable, is a few months, days, or even hours. know that they were not and speech and physical rehaMiracles happen. I’ve experienced them. alone in fighting this disease. bilitation are making me stronBut before I could finish my Cancer may be a challenge in my life, but ger. Now, I’m looking toward my education, at the age of 22, I future. my spirit is intact and my life is joyful. was diagnosed with grade 4 I would not have gotten to glioblastoma multiforme. Acwhere I am without faith, famcording to my doctors, this was probily, community, and the major support She attends classes with me, taking ably the result of the high doses of craof my doctors and nurses. Patients denotes and helping me get around camnial radiation I received as a child. serve to have the gift of hope, whether pus, and she’s with me as I train to I was put on a regimen of chemotheir life expectancy is a few months, make the swimming team for the 2012 therapy that included bevacizumab days, or even hours. Miracles happen. U.S. Paralympics Games in London. (Avastin) and given conformal radiaI’ve experienced them. Cancer may be Whether I qualify for the team or not, tion therapy. But even with treatment, a challenge in my life, but my spirit is I plan on being at the games to cheer the prognosis was grim—my life exintact and my life is joyful. on my teammates. I’ll also continue to pectancy was about a year-and-a-half, be involved in events like the Heroes of Ms. Cappalonga, 28, lives in Los Angeles. said my doctors. Hope Race for Brain Tumor Research

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Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

Fareston helps reduce the guess work FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

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Important safety information: FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. FARESTON is contraindicated in patients with known hypersensitivity to the drug. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively. References: FARESTON® Prescribing Information, 2011. Data on file, GTx, Inc.

Please see brief summary of prescribing information including boxed warning on the following page. For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

BRIEF SUMMARY OF PRESCRIBING INFORMATION WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions]. INDICATIONS AND USAGE FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. DOSAGE FORMS AND STRENGTHS Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side. CONTRAINDICATIONS Hypersensitivity to the Drug FARESTON is contraindicated in patients with known hypersensitivity to the drug. QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia. WARNINGS AND PRECAUTIONS Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions and Clinical Pharmacology]. Hypercalcemia and Tumor Flare As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued. Tumorigenicity Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology]. General Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia. Laboratory Tests Periodic complete blood counts, calcium levels, and liver function tests should be obtained. Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. 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 [see Use in Specific Populations]. Women of Childbearing Potential FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study FAR60 n = 221

TAM20 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below. Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies]. Adverse Reactions Cardiac Cardiac Failure Myocardial Infarction Arrhythmia Angina Pectoris Ocular* Cataracts Dry Eyes Abnormal Visual Fields Corneal Keratopathy Glaucoma Abnormal Vision/Diplopia Thromboembolic Pulmonary Embolism Thrombophlebitis Thrombosis CVA/TIA Elevated Liver Tests** AST Alkaline Phosphatase Bilirubin Hypercalcemia

North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) 2 2 -

(1) (1)

1 (<1) 3 (1.5) -

1 1

22 20 8 4 3 -

(10) (9) (4) (2) (1.5)

16 (7.5) 16 (7.5) 10 (5) 2 (1) 2 (1) -

1 -

4 1

(2)

2 (1) 2 (1) 1 (<1) -

1 1 1 -

(<1) (<1) (<1)

4 24 4 6

30 16 2 1

(19) (10) (1) (<1)

(<1)

11 (5) 41 (19) 3 (1.5) 6 (3)

(2) (11) (2) (3)

(<1) (<1)

(<1)

1 (<1) 2 (1) -

2 (1) 3 (1.5) 1 (<1)

3 (1.5) 1 (<1) 1 (<1) 2 (1)

3 (1.5)

5 (3) 1 (<1) 1 (<1) -

(<1)

4 (2) 3 (1.5) 4 (2)

1 (<1) 3 (1.5) 4 (2) 4 (2)

22 (15) 13 (9) 1 (<1) -

32 (15) 18 (8) 2 (1) -

35 (17) 31 (15) 3 (1.5) -

1 1

(<1)

* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: AST >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. Post-marketing Experience The following adverse reactions were identified during post approval use of FARESTON. 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. Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge. DRUG INTERACTIONS Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. Agents that Prolong QT The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions]. Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum. Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions]. Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%. Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely. Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure). USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. 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. In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly. Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits. In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero. Nursing Mothers It is not known if toremifene is excreted in human milk. Toremifene is excreted in 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 from FARESTON, 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 There is no indication for use of FARESTON in pediatric patients. Geriatric Use The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. Renal Impairment The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. Hepatic Impairment The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Race The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted. OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement. Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

CLINICALPHARMACOLOGY Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Pharmacodynamics Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). Effects on Cardiac Electrophysiology The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions]. Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions]. Table 1: QTc Prolongation in Healthy Male Volunteers Treatment Arm Toremifene 20 mg (N = 47) Toremifene 80 mg (N = 47) Toremifene 300 mg (N = 48)

Mean (90% CI) ΔΔQTc, ms 7 (0.9, 13.6) 26 (21.1, 31.2) 65 (60.1, 69.2)

ΔQTc > 60 ms (n, %) 0 2 (4.3%) 43 (89.6%)

QTc > 500 ms (n, %) 0 0 5 (10.4%)

Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks. Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin. Metabolism – Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies. Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. Renal insufficiency – The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function. Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food. Race – The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks. PATIENT COUNSELING INFORMATION Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions and Use in Specific Populations]. Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions]. Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions, and Clinical Pharmacology]. Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment. Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of coadministered drugs [see Drug Interactions]. Distributed by GTx, Inc. Memphis, TN 38103, USA Product covered by Orion Product Patents and related patent numbers. © 2011 GTx, Inc. All rights reserved. 2E Rev. 03/2011

ASCOPost.com | DECEMBER 15, 2011

PAGE 71

Opinion

Medicare Reimbursement to Physicians: Déjà Vu All Over Again By Nora Janjan, MD, MPSA, MBA, and John Goodman, PhD

n February 2011, The ASCO Post published an opinion piece (“Congress and the ‘Doctor Fix’: Looking Back, Looking Ahead”) about the ping-pong of legislative continuing resolutions to avert a 21.3% cut in physician reimbursement. These continuing resolutions were necessary because the Affordable Care Act, signed into law on March 25, 2010, did not address physician reimbursement and the sustainable growth rate in order

to meet Congressional Budget Office constraints. Also in response to the Act’s budget targets, at least $500�� billion was cut from Medicare despite the baby boomer population entering its ranks. A separate piece of legislation, Senate Bill (SB) 1776, known as the “Doctor Fix,” was introduced October 21, 2009 in exchange for American Medical Association (AMA) support of the Act. While eliminat-

KEY DATES IN THE MEDICARE PHYSICIAN REIMBURSEMENT SAGA October 21, 2009: SB 1776 (“the Doc Fix”) is introduced in the Senate [but fails to pass]

April 1, 2010: CMS notifies contractors to delay physician pay cuts by 10 business days

November 19, 2009: House of Representatives passes HR 3961 (the Medicare Physician Payment Reform Act) [but Senate fails to pass]

April 15, 2010: Senate passes HR 4851 (Continuing Extension Act), retroactively reinstating physician payments for Medicare patients in April, and postponing the 21.3% cut until June 1, 2010

December 19, 2009: Congress passes Department of Defense appropriations bill (HR� �� 3326), �� providing 2-month reprieve from cuts to the Medicare physician fee schedule that was due to become effective January 1, 2010 December 24, 2009: Senate passes the Patient Protection and Affordable Care Act

June 18, 2010: Senate passes an amended version of HR 3962 (Preservation of Access to Care for Medicare Beneficiaries and Pension Relief Act), providing a 2.2% Medicare physician payment update from June 1 until November 30, 2010

March 1, 2010: CMS notifies contractors to hold Medicare physician claims for 10 business days

December 15, 2010: HR 4994 is passed and signed into law, providing a 1-year delay for the sustainable growth rate cuts in physician reimbursement by Medicare

March 2, 2010: House and Senate pass HR 4691 (Temporary Extension Act), extending a wide range of expiring programs and postponing the sustainable growth rate cuts until April 1, 2010

April 15, 2011: Rep. Paul Ryan introduces House Congressional Resolution 34, which would reserve funds for Medicare reimbursement of physicians over the next 10 years

March 10, 2010: Senate passes HR 4213 (American Workers, State, and Business Relief Act), which includes a provision delaying physician reimbursement cuts until October 1; because the House passed a similar version of this bill on December 9, 2009 (without any health-related provisions), the House and Senate need to reconcile the language before it can be signed into law, but fail to do so before spring recess March 25, 2010: President Obama signs the Patient Protection and Affordable Care Act into law

May 25, 2011: Senate votes down the Ryan proposal on a straight party-line vote September 15, 2011: Medicare Payment Advisory Committee presents a proposal to repeal the sustainable growth rate using budgetary offsets, including a freeze on primary care reimbursement and a 5.9% cut for all other specialties for each of the next 3 years, followed by a 7-year freeze [but the AMA opposes the proposal, citing an existing 20% gap between reimbursement rates and practice expenses]

ing the sustainable growth rate formula, this legislation would have frozen physician payments for 10 years. Although not indexed to inflation, physicians were willing to trade a decade of certain Medicare reimbursement for the recurring crises caused by Congressional inaction about the sustainable growth rate issue. However, SB 1776 failed to pass because it was purportedly not compliant with the “pay-as-you-go” Congressional provisions. Enacting a series of temporary patches to the problem, Congress has continued its wrangling over the issue, leading to three delays in Medicare reimbursement in 2010, for more than a month of delayed physician reimbursement without interest (see sidebar).

Nora Janjan, MD, MPSA, MBA

and the veto is not overridden, the Secretary is required to implement the Independent Payment Advisory Board.

Bleak Future for Reimbursement

Yogi Berra was right—it’s déjà vu all over again. While sustainable growth rate fixes have been addressed over more than a decade, the pingLooming Crisis pong process over the past 3 years is Once again, a crisis looms. A 29.5% unprecedented. As of this writing, the cut in Medicare is scheduled to occur fix has been addressed only in the curJanuary 1, 2012, on the cusp of a presirent House of Representatives. With dential election year. Now that the the Thanksgiving deadline for deficit Joint Select Committee on Deficit Rereduction, it is doubtful that this issue duction has been unable to trim $1.2 will be addressed, as with previous extrillion in federal spending, it will result perience, until the deadline. in an additional 2% reduction in physiWhile a 2-year sustainable growth cian reimbursement. When added to rate fix will be approved for politithe scheduled cut, this would result in cal reasons, physicians and patients a total reduction of should face the 31.5% in Medicare reality of an adMuch is at stake in reimbursement for ministration, if physicians. reelected, that the upcoming year for The Obama adwill no longer physicians, the practice ministration now face another elecindicates support of medicine, our patients, tion challenge or for a 2-year susrespond to politiand for the nation tainable growth cal pressure. The rate fix. This fits physician reimas a whole. the timeline for the bursement cuts implementation of recently proposed the authority of the Medicare Indeby the Medicare Payment Advisory pendent Payment Advisory Board. Committee and the extensive level of The advisory board, with a $15�� mil�� Medicare savings required of the Inlion appropriation for 2012 alone, dependent Payment Advisory Board has the authority to limit the growth in approximately 2 years portend a of Medicare spending. By September bleak future for Medicare reimburse1, 2013, the advisory board must subment of physician services. mit draft proposals to limit Medicare Physicians, unlike any other govspending to the Medicare Payment ernment contractor, have routinely Advisory Committee and the Secrefaced a 20% to 30% cut in reimbursetary of Health and Human Services. ment for their services. Meanwhile, By August 15, 2014, the Secretary the federal government has grown by must implement the advisory board more than 25% over the past 3 years, proposal, unless Congress enacts an and the total compensation package alternative that achieves the required of federal workers has increased dralevel of Medicare savings. If Congress matically and is twice that of workers does not pass such legislation, or if in the private sector. While physicians continued on page 72 the President vetoes the legislation

The ASCO Post | DECEMBER 15, 2011

PAGE 72

Opinion

Medicare Reimbursement continued from page 71

Political Weakness of Physicians

made between the AMA and the administration; in exchange for supporting the Act, the administration promised passage of a favorable sustainable growth rate fix for the AMA. The fix failed passage in the Senate as Republicans and retiring Senate Democrats voted against the legislation.

The weakness of physicians in FOCUS FORTY the political process was clearly UNDER demonstrated during the process of

repeatedly have gone hat in hand to Congress and the President to avert sustainable growth rate cuts, very little of the additional $4 trillion in debt over the past 3 years has been paid to physicians caring for a burgeoning Medicare and Medicaid population.

the passage of the Affordable Care Act. This weakness of the physician political lobby was confirmed through the poorly negotiated deal

The month-long extensions that averted cuts in reimbursement were a purposeful manipulation to prove once again how dependent physicians are upon the federal government for their livelihood. In oncology, where 70% of patients treated are insured by Medicare, there is a de facto single-payer system. Much is at stake in the upcoming year for physicians, the practice of medicine, our patients, and for the nation as a whole.

■

Disclosure: Dr. Janjan is Senior Fellow in Healthcare Policy. Dr. Goodman is President and CEO, National Center for Policy Analysis, a nonprofit think tank established in 1983 and headquartered in Dallas.

Each year, more than 70,000 adolescents and young adults are diagnosed with cancer. YTRO FOCUS F

SUCO FORTY F

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Melanoma Melanoma is one of the frequently diagnosed cancers in this population. Learn about the new treatments that are now available as well as unique issues that are associated with caring for adolescent and young adult patients.

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Spotlight on Research

Neural Stem Cell Transplantation May Improve Cognitive Function in Brain Cancer

Laboratory research is showing promising results in restoring cognition following radiation. By Jo Cavallo

Charles L. Limoli, PhD

he potentially devastating long-term consequences on cognitive function in patients with brain cancer following cranial irradiation led Charles L. Limoli, PhD, Professor of Radiation Oncology, University of California, Irvine, to study neural stem cell transplantation and how the procedure may prevent cognitive decline in this setting. Although an effective treatment for brain cancers, radiation therapy can sometimes induce debilitating side effects, including disruptions in memory and concentration and in the ability to carry out executive functions such as planning and multitasking, severely limiting quality of life. The amount of cognitive destruction on still-developing brains is especially troubling. “Pediatric cancer patients, who have perhaps decades to live following successful treatment, can experience a loss of up to 3 IQ points per year,” says Dr. Limoli. Since 2007, Dr. Limoli and his colleagues have been studying the effects of intrahippocampal transplantation of human neural stem cells in irradiated laboratory rats and then measuring their cognitive performance. The results of their study, published in the July 15, 2011, issue of Cancer Research,1 showed significant improvement in cognitive function in irradiated rats that received the neural stem cell transplants. The ASCO Post talked with Dr. Limoli about his research.

Radiation and Cognitive Impairment Explain how cranial irradiation damages cognitive function. We use radiation on patients with brain cancer because outside of surgical resection, it’s really the only effective treatment that forestalls the growth of primary and metastatic lesions in the

brain. Typically, radiation-induced late normal tissue injury in the brain, such as necrosis and edema, manifest at higher doses (> 40 Gy) and at protracted times (> 6 months) after radiotherapy is completed. However, at much lower doses (≤ 10 Gy) radiosensitive populations of neural stem cells are depleted, thereby limiting their capability to undergo neurogenesis, a naturally occurring process that contributes new brain cells to the hippocampus and helps to maintain cognitive health throughout life. Importantly, the depletion of these stem cells and the resulting cognitive deficits occur in the absence of any overt histologic or radiographically visible damage.

riod of familiarization, the rats were reintroduced into the same testing arena 5 minutes or 24 hours later, but after the position of the blocks had been moved to a different location. The capability of the rats to recognize and explore the object at the new location provides a very sensitive test for hippocampal memory. What we found is that the animals that were given the human neural stem cells explored the new location of the block and the rats that were irradiated and not engrafted with hNSCs did not. The rats engrafted with hNSCs acted indistinguishably from unirradiated control rats. When we sacrificed the rats to ana-

The field of regenerative medicine in radiation oncology holds a great deal of promise for the rehabilitation of many cancer survivors. Nevertheless, a significant amount of rigorous scientific work clearly remains to establish safety and efficacy in humans. After survival, the next most important consideration for evaluating clinical outcome in cancer survivors may well be the quality-of-life issues related to cognitive function. The adverse effects of radiotherapy on the brain and cognition are progressive and difficult to reverse, and to date, there are no satisfactory long-term solutions for this serious clinical problem.

Study Specifics How was your study conducted, and what were the results? First, we selected a human neural stem cell (hNSC) that was derived from an embryonic stem cell and grew it to mass culture for transplantation. Then we irradiated athymic nude rats to induce cognitive deficits, and 2 days later, we stereotactically injected 100,000 stem cells into four sites in each hippocampus, for a total of eight injections in the brain (800,000 cells/animal). At 1 and 4 months following transplantation, we subjected these animals to cognitive testing by giving them novel place recognition tasks to assess spatial recognition memory. Basically, the recognition task consisted of placing rats in a box containing two Lego blocks and allowing them to explore the location of these objects. After a pe-

lyze their brains, we found that the hNSCs survived at significantly higher levels than we had anticipated. Unbiased stereology showed that 23% and 12% of the cells survived 1 and 4 months after transplantation, respectively. Immunohistochemistry was used to determine how these cells differentiated, and we found a significant number of new neurons and astroglial cell types. These data indicated that surviving engrafted cells turned into new neurons, new astrocytes, and new oligodendrocytes and that this combination of engrafted cells was able to restore cognition following irradiation. We also found that while the stem cells migrated throughout the hippocampus, they tended to home to the very spot where normal neural stem cells exist, and migrated to the neurogenic niche within the brain. When we stained for activity regulated cytoskeleton-associated protein (Arc), which is a molecular determinant of memory, we found that our transplanted cells expressed Arc, suggesting that they had functionally integrated into the hippocampal circuitry. The presence of the Arc-positive cells suggested that the restoration of cognition was at least in part due to the functional replacement of cells lost or damaged as a consequence of irradiation.

In terms of how they were used in your study, are neural stem cells preferable to embryonic stem cells? Our data does not indicate any significant differences between them, although there is a lower risk of teratoma formation with the human neural stem cells.

Next Steps Do you plan to study this procedure in human clinical trials? Yes. I’m hoping to launch a phase I trial of this stem cell therapy in glioblastoma patients within the next 2 years. The protocol would be to transplant stem cells following brain tumor surgery and radiation treatments to assess safety and to restore cognitive function. Are there applications for this procedure in other illnesses? Absolutely. We recognized many years ago that this strategy might be an effective means to ameliorate “chemobrain,” a condition that is reported frequently in a growing population of cancer survivors subjected to a wide range of chemotherapeutic agents. These patients routinely exhibit a variety of cognitive impairments, believed, in part, to be caused by damage to the stem cells in the brain. We are actively engaged in determining the potential efficacy of using hippocampal stem cell transplants to reverse the adverse effects of chemobrain in this large cohort of patients. Studies are also underway using hNSC transplantation to restore cognitive function following brain trauma, and evidence suggests the strategy may be beneficial in the treatment of Alzheimer’s disease and for alleviating side effects in any normal tissue subjected to radiation exposure. While the field of regenerative medicine in radiation oncology is still very new, it holds a great deal of promise for the rehabilitation of many cancer survivors. Nevertheless, a significant amount of rigorous scientific work clearly remains to establish safety and efficacy in humans.

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

Reference 1. Acharya MM, Christie LA, Lan ML, et al: Human neural stem cell transplantation ameliorates radiation-induced cognitive dysfunction. Cancer Res 71:4834-4845, 2011.

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AVASTIN® (bevacizumab)

Opinion

Solution for intravenous infusion Initial U.S. Approval: 2004

Prostate Cancer Screening Reconsidered continued from page 2

of Screening For Prostate Cancer (ERSPC) trial. This study included eight countries and involved the random assignment of over 182,000 men to either screening or usual care. After almost 9 years of follow-up, no significant reduction in prostate cancer mortality was observed between the two groups, but there was a difference in mortality seen in a subset of patients between the ages of 55 and 69. This difference amounted to an absolute reduction of 0.71 prostate cancer deaths per 1,000 men.4 After cancer is diagnosed the majority of men feel compelled to receive treatment, and as already noted, physicians remain unable to determine with any certainty those men who will die from prostate cancer and those who will die with the disease. This inevitably leads to overtreatment, unnecessarily subjecting men to side effects such as incontinence and erectile dysfunction. From the ERSPC trial, we learned that 48 men need to be treated before 1 death from prostate cancer is prevented.4

Conclusions So what conclusions can we draw regarding prostate cancer screening? The U.S. Preventive Services Task Force recently updated their review of evidence on screening and treatments for prostate cancer, concluding that PSA-based screening “results in small or no reduction in prostate cancer– specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary.”5 On the other hand, the American

Urological Association recommendation is to start screening at age 40 instead of 50, as early PSA levels are more indicative of future prostate cancer occurrence than family history1 and can help establish a baseline PSA level with which to compare. The utility of screening and diagnosing prostate cancer clearly deteriorates with increasing age. In a population over age 65, approximately 200 men need to be treated for at least 12 years before 1 prostate cancer death is prevented.6

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Disclosure: Dr. Crawford is Chairman of the National Prostate Conditions Education Council. Dr. Spendlove reported no potential conflicts of interest.

References 1. Carroll P, Albertsen P, Greene K, et al: Prostate-specific antigen best practice statement: 2009 update. American Urological Association Education and Research, 2009. Available at www.auanet.org. Accessed October 27, 2011. 2. Welch HG, Black WC: Overdiagnosis in cancer. J Natl Cancer Inst 102:605613, 2010. 3. Thompson IM, Pauler DK, Goodman PJ, et al: Prevalance of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med 350:2239-2246, 2004. 4. Croswell JM, Kramer BS, Crawford ED: Screening for prostate cancer with PSA testing: Current status and future directions. Oncology (Williston Park) 25:452-460, 2011. 5. Chou R, Croswell JM, Dana T, et al: Screening for prostate cancer: A review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. October 7, 2011 (early release online). 6. Wong YN, Mitra N, Gudes G, et al: Survival associated with treatment vs observation of localized prostate cancer in elderly men. JAMA 296:2683-2693, 2006.

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

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2‑negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. 1.4 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).] 1.5 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.

AVASTIN® (bevacizumab) Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% 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).] 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 4024 patients with CRC, non‑squamous NSCLC, MBC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) 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 59), 41% male and 85.1% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients

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AVASTIN® (bevacizumab)

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 7, 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).]

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)

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%).

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).]

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), Warnings and Precautions (5.6).]

Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3‑4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥30 mIU/mL and a negative serum β‑HCG pregnancy test)was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n=84 or with Avastin (n=95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

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

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

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

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

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.

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

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

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

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

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 4. Table 4 NCI‑CTC Grades 1−5 Adverse Events in Study 9 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

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%). Metastatic Breast Cancer (MBC) Only Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥ 2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%). Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/ hypotension (2). Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥ 5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3. Table 3 NCI‑CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

Body as a Whole Asthenia Headache Pain Cardiovascular Hypertension Digestive Stomatitis Metabolic/Nutrition Weight loss Musculoskeletal Myalgia Respiratory Dyspnea Epistaxis Skin/Appendages Exfoliative dermatitis Urogenital Albuminuria

Capecitabine (n = 215)

Capecitabine + Avastin (n = 229)

47% 13% 25%

57% 33% 31%

24%

19%

25%

14%

18% 1%

27% 16%

75%

84%

22%

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 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

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%

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 4: 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 immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

T:13"

Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, 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 9). [See Warnings and Precautions (5.8).]

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

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 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%.

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109)

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients. 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.

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 (reported from unapproved use for treatment of various ocular disorders): Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual disturbances; Ocular hyperemia; Ocular pain and/or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia 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 9, 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

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

In combination with IV 5-FU–containing chemotherapy in first- and second-line MCRC…

Think Avastin

Because overall survival matters The only FDA-approved biologic with significant overall survival (OS) benefits in first- and second-line MCRC1-4 4.7-month increase in median OS with Avastin plus IFL in pivotal first-line Study 21072,4

Percentage Surviving

100

First-line median OS:

20.3 vs 15.6 months

(HR=0.66 [95% CI, 0.54–0.81], P<0.001)

60 40 20

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

0 6

IV=intravenous; 5-FU=5-fluorouracil; MCRC=metastatic colorectal cancer; IFL=5-FU/leucovorin (LV)/ irinotecan; HR=hazard ratio; CI=confidence interval; FOLFOX4=5-FU/LV/oxaliplatin.

Indication 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.

Boxed WARNINGS and additional important safety information 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 dehiscence 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 and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control

AVA0000402600

Printed in USA.

18 12 OS (Months)

OS in second-line Study E3200: 13.0 months with Avastin plus FOLFOX4 vs 10.8 months with FOLFOX4 alone (HR=0.75, [95% CI, 0.63–0.89] P=0.001)1,3 included hypertension (grade 3–4, 5%–18%) and 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 The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were 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 Based on animal data, Avastin may cause fetal harm and may impair fertility. 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 The most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy– sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. References: 1. Avastin Prescribing Information. Genentech, Inc. February 2011. 2. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 3. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544. 4. Data on file. Genentech, Inc.

(05/11)