TAP Vol 3 Issue 9 by Harborside Press LLC

Chemotherapy-induced Nausea/Vomiting 9

BRAF and MEK Inhibition in Melanoma

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VOLUME 3, ISSUE 9

Bone Metastasis in Prostate Cancer 64

JUNE 15, 2012

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

2012 ASCO Annual Meeting

T-DM1 Proves More Effective, Less Toxic Than Standard Treatment for Metastatic Breast Cancer

ASCOPost.com

Radiotherapy in Early-stage Hodgkin Lymphoma

By Caroline Helwick

ositive results conT-DM1 in Metastatic Breast Cancer tinue to be reported for trastuzumab emtansine ■■ The phase III EMILIA trial demonstrated a 3.2-month improvement in (T‑DM1), the antibodyprogression-free survival for patients receiving the novel antibody-drug drug conjugate linking conjugate T-DM1. trastuzumab (Herceptin) ■■ Progression-free survival was 9.6 months, vs 6.4 months with capecitabine/ to a cytotoxic agent. Early lapatinib (P < .0001). results of the international ■■ Overall survival favored T-DM1 (HR = 0.621) but did not cross the interim phase III EMILIA study, analysis efficacy stopping boundary for statistical significance. presented at the 2012 ASCO ■■ T-DM1 was very well tolerated, with a small percentage of patients Annual Meeting, showed experiencing transient elevations in liver function tests and a 35% reduction in risk of thrombocytopenia. progression among patients with advanced HER2-overthis is a breakthrough,” said lead author Kimberly expressing breast cancer L. Blackwell, MD, of Duke Cancer Institute at who received T-DM1, compared to standard treatment Duke University, Durham, North Carolina. with capecitabine (Xeloda) and lapatinib (Tykerb).1 Dr. Blackwell was referring not only to the ‘Breakthrough’ Results 3.2-month improvement in progression-free sur“For patients facing metastatic breast cancer, continued on page 3 Technology

Decoding the Genetic Blueprint of Cancer Cells: Findings in Multiple Myeloma and Breast Cancer By Jo Cavallo

dvances in next-generation DNA sequencing technologies are allowing scientists to decipher the whole genome or whole exome (ie, the coding region of the genome) of cancer specimens more quickly and inexpensively than ever before. And the results are revealing genes that had not previously been associated with cancer as well as multiple genetic mutations that disrupt common pathways and trigger cancer-related changes in a cell.

Findings in Multiple Myeloma

Todd R. Golub, MD, Director of the Cancer Program at the Broad Institute, Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber Cancer Institute, is a coauthor of the first large-scale study to compare the entire genomes of malignant cells and normal cells from 38 patients with multiple myeloma. Dr. Golub and co-investigators at the Broad Institute and Dana-Farber Cancer Institute, Boston, found mutations in the nuclear factor (NF)-kappaB pathway, We learned from this study how to start an important transcripthinking about the complex analysis of tional regulator in multiple myeloma. Although not just seeing that a mutation exists in a researchers had suspected tumor but learning to recognize whether a that this pathway was involved in the development given mutation is likely to be important. of the disease, they did — Todd R. Golub, MD not understand the chain

By Andreas Engert, MD

he treatment of patients with Hodgkin lymphoma is one of the major success stories in medical oncology. Depending on clinical stage, clinical risk factors, and the treatment given, 60% to 90% of all patients can be cured of their malignancy long-term. Hodgkin lymphoma survivors represent one of the largest groups of cancer survivors in Western countries. This is in part due to the young age of most patients and the excellent outlook after treatment. However, Hodgkin survivors are at high risk of treatment-related side effects including secondary cancers, organ damage, infertility, fatigue, and psychosocial problems. Since these sequelae can occur up to 30 years after treatment, finding the right balance between toxicity and cure is the main goal in Hodgkin lymphoma. continued on page 87

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

MORE IN THIS ISSUE Oncology Meetings Coverage ASCO Annual Meeting �� 3, 6, 8, 9, 10, 15, 83 American Association for Cancer Research �� 19, 20, 34 American Society of Breast Surgeons �� 27, 28–31 European Lung Cancer Conference �� 38 Direct from ASCO �� 45 Kathy Giusti on Multiple Myeloma �� 49 FDA Update �� 60–63, 68 Letters to the Editor �� 94–95

continued on page 25

A Harborside Press® Publication

The ASCO Post | JUNE 15, 2012

PAGE 2

Erratum

Editorial Board James O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

Associate Editors

William T. McGivney, PhD Philadelphia, Pennsylvania

Joseph S. Bailes, MD Texas Oncology

James L. Mulshine, MD Rush University Medical Center

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

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

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

Jay S. Cooper, MD Maimonides Medical Center

Lynn D. Wilson, MD Yale University School of Medicine

John Cox, DO Texas Oncology

Stanley H. Winokur, MD Singer Island, Florida

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

photo of Michael Gordon, MD, University of Arizona Cancer Center. We regret the error. The correct photo appears above.

George W. Sledge, MD Indiana University

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

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

Leo I. Gordon, MD

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

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

E. David Crawford, MD University of Colorado

n the print edition of our May 1 issue, the article entitled “NCCN Clinical Practice Guidelines: Important Updates for 2012” included an incorrectly identified photograph on page 13. The picture identified as Leo I. Gordon, MD, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, who addressed lymphomas at the National Comprehensive Cancer Network 17th Annual ConferSee Page 90 ence, was actually a

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

The ASCO Post

Wants to Hear from You The Editors encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press® Publishing Staff

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2012 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $235; Individual International: $290; Institutional Domestic: $290; Institutional International $370. Contact subscriptions@harborsidepress.com.

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Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. 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 | JUNE 15, 2012

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2012 ASCO Annual Meeting

continued from page 1

vival, but to the tolerability of the novel agent, which disrupts HER2 signaling and delivers the cytotoxic DM1 component intracellularly. Co-investigator David Miles, MD, of Mount Vernon Hospital in London, United Kingdom, emphasized the favorable toxicity profile of T-DM1 in an interview with The ASCO Post. “The issue with capacitabine/lapatinib is toxicity. You have a 20% incidence of very difficult-to-manage diarrhea, whereas with T-DM1 this was a negligible issue in the trial. From a patient point of view, in terms of side effects and quality of life, the outcomes are greatly superior with T-DM1,” Dr. Miles said.

David Miles, MD

EMILIA Trial Details EMILIA investigators randomly assigned 991 patients with HER2-positive locally advanced or metastatic breast cancer who had previously received a taxane and trastuzumab. Patients received T-DM1 (3.6 mg/kg IV every 3 weeks) or a combination regimen dubbed XL (capecitabine, 1,000

EXPERT POINT OF VIEW

“S

tated simply, T-DM1 really works in this patient population,” said Louis Weiner, MD, Director of the Georgetown-Lombardi Cancer Center in Washington, DC, and the invited discussant of the presentation. “It is an important new weapon in the therapeutic armamentarium for breast cancer.” While future confirmatory studies will be important, especially to elucidate the mechanisms Louis Weiner, MD of tumor control with T-DM1, he maintained that “the very clean design and institution of this study, coupled with the compelling results, make it unlikely that additional studies will fail to confirm these important findings.” Dr. Weiner predicted that a statistically significant improvement in overall survival will eventually be observed, which he said would be “particularly notable since effective palliative treatment has rarely been associated with improved survival in the metastatic setting.”

Looking Ahead Looking to the future, Dr. Weiner predicted that pairing T-DM1 with different classes of agents will broaden the range of treatment efficacy. “And this is happening,” he reported, noting that 17 T-DM1–based clinical trials are accruing or in progress, some with chemotherapy and others with targeted agents. “Needless to say, T-DM1 merits evaluation for previously untreated HER2-overexpressing metastatic breast cancer and ultimately may find utility in adjuvant and neoadjuvant management, and perhaps in other HER2-overexpresssing cancers,” he added. “Such trials are planned or in progress.”

■

Disclosure: Dr. Weiner reported serving in a consulting or advisory role for Abbott Laboratories, Celldex, Johnson and Johnson, Merrimack, Samsung Advanced Institute of Technology, Symphogen; owning stock in Celldex and Merrimack; receiving honoraria from Bristol-Myers Squibb; and receiving research funding from Samsung Advanced Institute of technology.

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

mg/m2 twice daily on days 1–14 every 3 weeks, plus lapatinib, 1,250 mg daily) every 3 weeks until progression. Patients progressing on standard therapy were allowed to cross over to T-DM1. By independent review after a median follow-up of approximately 1 year, T-DM1 delayed disease progression by 9.6 months in contrast to 6.4 months with capecitabine/ lapatinib. This represented a 35% reduction in the risk of progression (P < .0001), which was also seen by investigator review, Dr. Blackwell reported at the ASCO Plenary Session. “There was a consistency of effect,” she added. “Essentially no subgroup favored capecitabine/lapatinib treatment.” Only in women ≥ 65 years old was T-DM1 not superior to standard treatment. Median overall survival was not reached with T-DM1, and was 23.3 months with capecitabine/lapatinib, for a 38% reduction in mortality risk (P = .0005). “However, the interim statistical stopping boundary based on number of deaths was not met,” she pointed out. Therefore, the difference is not yet statistically significant. © ASCO/Todd Buchanan 2012

T-DM1 in Metastatic Breast Cancer

Kimberly L. Blackwell, MD

Despite lacking statistical significance, Dr. Blackwell maintained, “there is an apparent survival benefit with T-DM1.” More than 65% of the T-DM1 recipients were alive at the time of analysis, compared with 47.5% of the capecitabine/lapatinib group. Objective response rates were 44% with T-DM1 and 31% with capecitabine/lapatinib, and median response duration was almost doubled with the antibody-drug conjugate: 12.6 vs 6.5 months. Patient-

reported outcomes according to the FACT-Breast Trial Outcome Index and symptom progresSee Page 90 sion were also significantly better with T-DM1, Dr. Blackwell reported.

Additional Data An equally striking difference between the arms was observed in tolerability. Dose reductions were required for only 16.3% of the T-DM1 arm, compared to 53.4% with capecitabine and 27.3% with lapatinib. Median dose intensity was 99.9% with T-DM1, compared with 77.2% for capecitabine and 93.4% with lapatinib. The most common adverse events of at least grade 3 for T-DM1 included thrombocytopenia (12.8% vs 0.2%) and transient elevations in alanine aminotransferase (2.9% vs 1.4%) and aspartate aminotransferase (4.3% vs 0.8%). As expected, capecitabine/lapatinib was associated with significantly more diarrhea, hand-foot syndrome, and vomiting.

■

Disclosure: Drs. Blackwell and Miles reported no potential conflicts of interest.

Reference 1. Blackwell KL, Miles D, Gianni L, et al: Primary results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. 2012 ASCO Annual Meeting. Abstract LBA1. Presented June 3, 2012.

2012 ASCO Annual Meeting

ee pages 3 through 15 of this issue for more highlights from this year’s ASCO Annual Meeting, and watch for continued comprehensive coverage of the conference in future issues of The ASCO Post.

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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.

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

HEAD AND NECK

[9%]

TRUNK

[19%] RETROPERITONEUM

[15%]

EXTREMITIES

[60%]

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

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

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

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

The ASCO Post | JUNE 15, 2012

PAGE 6

2012 ASCO Annual Meeting Genitourinary Oncology

Encouraging Results with Neoadjuvant Therapy for High-risk Prostate Cancer By Alice Goodman

se of the CYP17 inhibitor abiraterone acetate (Zytiga) in combination with leuprolide and prednisone prior to radical prostatectomy achieved pathologic complete response or near complete response in one-third of men with high-risk, localized prostate cancer. Abiraterone is FDA-approved for metastatic prostate cancer unresponsive to chemotherapy, and this is the first trial to study this agent upfront in the neoadjuvant setting.

Mary-Ellen Taplin, MD

“These patients were an extremely high-risk cohort, so results are particularly amazing,” said lead author MaryEllen Taplin, MD, of Harvard Medical School and Dana-Farber Cancer Institute, Boston, in an interview with The ASCO Post. The phase II See Page 90 study was presented at the 2012 ASCO Annual Meeting.1 She cautioned that larger randomized trials are needed to validate this finding, and said that additional trials in the neoadjuvant setting

are open or being planned to evaluate other prostate cancer agents now used for advanced cancer.

Study Design Men diagnosed with high-risk prostate cancer frequently experience biochemical failure (rising prostatespecific antigen [PSA]) following primary treatment with radical prostatectomy or radiation plus hormones and require salvage therapy. The rationale for the neoadjuvant trial was to determine if giving abiraterone plus other hormonal therapy (leuprolide) prior to surgery would improve the prognosis for these patients. “To date, no neoadjuvant or adjuvant therapy has shown a benefit for high-risk prostate cancer,” said Dr. Taplin. The study enrolled 58 patients with high-risk disease, defined as having one or more of the following features: bulky stage T3-T4 disease on physical examination (present in 24% of participants); PSA > 20 ng/mL (19%); Gleason score 8–10 (71%); or high PSA velocity (a rise in PSA of > 2 ng/ mL between any two time points within 12 months preceding the initial diagnostic prostate biopsy [16%]). About one-third of patients also had lymph node involvement. Patients were randomly assigned to 3 months of abiraterone, leuprolide, and low-dose prednisone (5 mg per day) or 3 months of leuprolide. Prostate biopsy was done at 3 months to assess prostate tissue androgen levels. All patients in the study received another 3 months of neoadjuvant ther-

Neoadjuvant Abiraterone for Prostate Cancer ■■ Neoadjuvant therapy with abiraterone plus leuprolide achieved encouraging responses in high-risk prostate cancer.

■■ This is one of the first trials to show eradication of prostate cancer in the neoadjuvant setting.

EXPERT POINT OF VIEW

“T

his is one of the first, if not the first, study to show that a treatment can make prostate cancer in the prostate gland itself disappear in a reproducible number of patients, and it is an exciting step forward,” said Nicholas Vogelzang, MD, moderator of the pre–ASCO Annual Meeting press conference where the results of the neoadjuvant abiraterone study by Dr. Taplin and colleagues were first released. Dr. Vogelzang is Chair of ASNicholas Vogelzang, MD CO’s Communications Committee, and Chair of Genitourinary Oncology for US Oncology. Neoadjuvant therapy is now standard for the treatment of other cancers, including breast, rectal, and bladder cancer, Dr. Vogelzang continued. “In breast cancer, a complete disappearance in primary disease leads to better long-term survival. We have seen this in bladder cancer, where complete response to chemotherapy prior to surgery improves long-term survival.” The study by Taplin and colleagues “is the first time we have seen this degree of complete response in prostate cancer with neoadjuvant therapy,” Dr. Vogelzang concluded.

■

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

apy with abiraterone, leuprolide, and prednisone. After a total of 6 months of neoadjuvant therapy, radical prostatectomy was performed and surgical specimens were evaluated for pathologic response, prostate androgen levels, and androgen-receptor signaling.

Key Data The total pathological response rate was 34% in patients treated with abiraterone for 6 months vs 15% in those who started out on leuprolide alone and then received 3 months of combination therapy. The pathological complete response rate and near complete response rate favored abiraterone, but the difference between groups was not statistically significant. “It is rare to eliminate prostate cancer with hormone therapy,” Dr. Taplin commented. “The typical pathologic complete response with older hormone therapy is < 5%. Response rates [in this trial] are impressive given these high-

risk features, with one-third of patients having positive lymph nodes,” she sated. Treatment with abiraterone was well tolerated. Grade 3 adverse events included elevated liver enzymes in 9% and hypokalemia in 5%. Dr. T aplin said that low-dose prednisone was able to minimize side effects associated with abiraterone therapy, and that the dose of 5 mg given in this trial is half the usual dose used in patients with advanced disease.

■

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

Reference 1. Taplin M-E, Montgomery RB, Logothetis C, et al: Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study. 2012 ASCO Annual Meeting. Abstract 4521. Presented June 2, 2012.

Visit The ASCO Post website at ASCOPost.com

Antibody-drug conjugates (ADCs):

Can an ADC be greater than the sum of its parts?

Antibody-drug conjugates: Taking targeted therapy to the next level ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic agent. ADCs are designed to deliver potent anticancer agents to tumors in a targeted manner to limit systemic exposure.1-5

Monoclonal antibody

Stable linker

Cytotoxic agent

targets antigens that are preferentially or exclusively expressed on the surface of cancer cells and may retain anticancer effects1,3,6-8

designed to allow an ADC to remain inactive while in circulation1,2,7-9

incorporated into an ADC, may be up to 1000-fold more potent than currently used chemotherapies7

These investigational ADCs have multiple proposed mechanisms of action, including antibody-mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic agent.6

Visit www.ResearchADCs.com to learn more References:

1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146. 3. Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932. 5. Ghose T, Blair AH. Antibody-linked cytotoxic agents in the treatment of cancer: current status and future prospects. J Natl Cancer Inst. 1978;61:657-676. 6. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169. 7. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107. 8. Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180. 9. Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptidelinked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852.

The ASCO Post | JUNE 15, 2012

PAGE 8

2012 ASCO Annual Meeting Pediatric Oncology

Crizotinib Yields Benefits in Aggressive Pediatric Tumors

Complete responses were observed in most patients with anaplastic large cell lymphoma. By Caroline Helwick

he value of the targeted agent crizotinib (Xalkori) may not be restricted to the 5% of patients with non– small cell lung cancer who have abnormalities in the ALK gene. In a phase I study conducted by the C hildren’s Oncology Group consortium, crizotinib halted tumor growth and, in some cases, eradicated See Page 90 all signs of cancer in children with anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumors, and aggressive forms of neuroblastoma, investigators reported at the 2012 ASCO Annual Meeting.1 Abnormalities in the ALK gene are common in these pediatric cancers, being found in 80% to 95% of anaplastic large cell lymphomas, 50% of inflammatory myofibroblastic tumors, and up to 15% of aggressive neuroblastomas.

Yael Mosse, MD

The study’s principal investigator, Yael Mosse, MD, of the Children’s Hospital of Philadelphia, noted, “It’s remarkable that this targeted oral medication provided such a substantial benefit in these children with highly aggressive cancers, most of whom had already un-

dergone every available therapy. Now that we know much more about the drivers of some pediatric cancers, we can target those changes and treat patients in a much smarter and potentially safer way.”

Patient Outcomes The phase I dose-escalation study included 70 children (median age 10 years) with refractory solid tumors and ALCL. Patients received one of six different doses of crizotinib (100– 365 mg/m2 per dose twice daily) in 28‑day cycles as long as tolerated. By disease, the outcomes were as follows: Anaplastic large cell lymphoma: 8 patients were enrolled; 7 of 8 achieved complete responses. Inflammatory myofibroblastic tumor: 7 patients were enrolled; 1 of 7 had a partial response, 1 had a minor response (tumor shrinkage falling short of an objective response), and 5 are at a point too early to evaluate. Neuroblastoma: 35 patients were enrolled, 27 are evaluable; of 8 with known ALK mutations, 1 had a complete response, 1 had a minor response, and 1 had stable disease as the best response. Of 19 patients whose ALK status is unknown, 1 had a complete response and 6 had prolonged stable disease. Dr. Mosse noted that many of the responses were highly durable, and some patients have been on treatment for 18 months to 2 years or longer without disease progression.

‘Dramatic Potential’ Nicholas J. Volgelzang, MD, Chair of ASCO’s Cancer Communications

Crizotinib in Pediatric Cancers ■■ Several pediatric tumors—anaplastic large cell lymphoma, inflammatory myofibroblastic tumors, and aggressive forms of neuroblastoma—often harbor abnormalities in the ALK gene.

■■ In a phase I study, treatment with the ALK-inhibitor crizotinib led

to complete responses in 88% of patients with anaplastic large cell lymphoma, and produced some complete and partial responses in patients with the other tumor types.

■■ The drug is well tolerated, and many patients remain on treatment for 2 years or longer.

EXPERT POINT OF VIEW

ichael P. Link, MD, 2011–2012 President of ASCO and a pediatric oncologist himself (at Stanford University School of Medicine and the Lucile Salter Packard Children’s Hospital at Stanford), said the crizotinib study by Mosse and colleagues has far-ranging implications. “The molecular driver (ALK) is present in very different and sometimes unrelated tumor types, and thus this ALK inhibitor may work in very different Michael P. Link, MD cancers,” he predicted. “It may turn out to be even more effective in this form of non-Hodgkin lymphoma than it is in lung cancer.” Furthermore, he added, “we have a glimpse at a new paradigm of understanding cancer and drug development—that it will someday not be sufficient to identify tumors by their histology or organ of origin, but will be necessary to understand the tumor’s heterogeneity and molecular drivers in order to select treatment. If you understand this, you can choose the appropriate inhibitor, and you have the prospect of seeing dramatic responses.”

■

Disclosure: Dr. Link is currently negotiating for research support from Pfizer for a follow-up study of crizotinib in tumors with genetic events in the ALK gene.

Committee and Chair of Genitourinary Oncology for US Oncology, said he witnessed a dramatic response to crizotinib in an adult with ALK-positive ALCL treated by his colleague Fadi Braiteh, MD, in a clinical trial. “The patient was very, very ill. She achieved a complete response with crizotinib and was able to receive a transplant. So this drug does have dramatic potential in older patients as well and in patients with other tumors,” he commented. Elaborating on the study’s outcomes, Dr. Mosse noted that having seven complete responses in anaplastic large cell lymphoma “already meets the bar for what we look for in phase II.” The consortium will soon be studying crizotinib in combination with chemotherapy in ALCL, hoping not only to improve outcomes but also to reduce the toxicity associated with standard therapy. In neuroblastoma, the benefit of the drug is less clear, but there is proof-of-concept that some patients with these tumors can benefit, and a phase II trial will further distinguish which patients are likely to benefit from this drug.

The recommended phase II dose will be 280 mg/m2 per dose twice daily, and additional studies will look for markers of sensitivity and resistance to inform future study designs.

Further Implications Crizotinib was very well tolerated, with virtually all adverse events being low-grade. At the highest dose level, one patient developed elevated liver enzymes and another had a low neutrophil count, but this was reversible. Dr. Mosse said the findings have implications beyond these pediatric cancers. “With next-generation sequencing, we may discover that the ALK gene is relevant to multiple human cancers,” she suggested.

■

Disclosure: Drs. Mosse and Vogelzang reported no potential conflicts of interest.

Reference 1. Mosse YP, Balis FM, Lim MS, et al: Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: A Children’s Oncology Group phase I consortium study. 2012 ASCO Annual Meeting. Abstract 9500. Presented June 2, 2012.

ASCOPost.com | JUNE 15, 2012

PAGE 9

2012 ASCO Annual Meeting Supportive Care

Antipsychotic Effectively Controls Chemotherapy-induced Breakthrough Nausea and Vomiting By Alice Goodman

lanzapine (Zyprexa), an FDAapproved antipsychotic, effectively controlled chemotherapy-induced nausea and vomiting (CINV) in patients who failed to respond to guideline-recommended antiemetic therapy in a phase III trial presented at the ASCO Annual Meeting.1

(32%), a difference that was statistically significant (P < .001). Nausea was eliminated in 28 (67%) patients in the olanzapine arm vs 9 (24%) in the

metoclopramide arm, again a statistically significant difference (P < .01). Disclosure: Dr. Navari reported no potential conflicts of interest.

Reference 1. Navari RM, Nagy CK, Gray SE: 2012 ASCO Annual Meeting. Abstract 9064. Presented June 2, 2012.

Rudolph M. Navari, MD, PhD

“This is the first randomized trial to demonstrate an effective treatment for breakthrough CINV, which typically occurs within 2 to 4 days despite guideline-directed prophylaxis. Olanzapine was significantly better than metoclopramide in controlling breakthrough CINV, and the study suggests that olanzapine will be very useful in these patients, who can be debilitated from their symptoms,” said lead author Rudolph M. Navari, MD, PhD, Harper Cancer Institute, Indiana University School of Medicine in South Bend, Indiana.

Study Data The double-blind, randomized, controlled, phase III trial enrolled 205 chemotherapy-naive patients who were treated with highly emetogenic chemotherapy, including cisplatin, doxorubicin, and cyclophosphamide. All patients were given standard guidelineSee Page 90 recommended antiemetic therapy. Of the 205 patients, 80 developed breakthrough CINV despite recommended therapy and were randomly assigned to 72 hours of treatment with either oral olanzapine at 10 mg/d or oral metoclopramide at 10 mg/d (3 times a day for 3 days). During 72 hours of monitoring, 30 of the 42 patients in the olanzapine arm (71%) had no vomiting vs 12 of the 38 patients assigned to metoclopramide

Our world centers around theirs ACTION PURPOSE IMPACT

As cancer researchers, we dare to advocate uncharted paths in science and research. We engage and execute with a vision, collaborating with the oncology community to deliver personalized and measurable outcomes that improve and extend lives. We strive to advance the fight against cancer, continuously applying research to clinical practice and targeting the individual needs of people living with cancer.

This is our pledge. This is GSK Oncology. Learn more at the new GSKoncology.com

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The ASCO Post | JUNE 15, 2012

PAGE 10

2012 ASCO Annual Meeting Skin Cancer

Dual BRAF and MEK Inhibition Is Active in Advanced Melanoma Minimum skin toxicity with the combination By Caroline Helwick

Jeffrey S. Weber, MD, PhD

n advanced melanoma, combination therapy with two investigational drugs—one targeting BRAF and the other the MEK pathway—achieved a median progression-free survival of 7.4 months, which rose to 10.8 months in patients who were optimally dosed, reported Jeffrey S. Weber, MD, PhD, Director of the Donald A. Adam Comprehensive Melanoma Research Center at H. Lee Moffitt Cancer Center, Tampa. Importantly, these outcomes were achieved with far less dermatologic toxicity than is normally observed with either of the investigational agents alone, Dr. Weber reported at See Page 90 the 2012 ASCO Annual Meeting.1

100% Disease Control Rate The combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib was tested in varying doses in 125 patients with advanced melanoma and the V600E BRAF mutation. The current efficacy analysis focused on 77 patients who had received no prior BRAF-targeted therapy and thus had demonstrated no resistance to BRAF inhibitors. In the expanded phase Ib trial, investigator-assessed best responses included complete responses in 8%, partial responses in 49%, and stable disease in 39%, for an overall disease control rate of 96% among the 77 pa-

tients. However, among the 24 patients receiving dabrafenib, 150 mg twice daily, plus trametinib, 2 mg/d, 100% of patients achieved disease control or better, including complete responses in 8%, partial responses in 54%, and stable disease in 38%, with no patients progressing. “Certainly this is an impressive record by any assessment,”Dr. Weber suggested, adding that the waterfall plot showing responses was “as good as or better than any I’ve seen in a [melanoma] trial.”

Dermatologic Toxicity Was Rare The combination was not only very active, but was associated with little skin toxicity. Hyperproliferative skin lesions, including squamous cell carcinoma and actinic keratosis, are wellknown side effects of vemurafenib treatment, occurring in up to 25% of patients, Dr. Weber noted. With dabrafenib/trametinib, however, 13% of the 135 patients in the overall study developed skin toxicity ≥�� grade 2; only 3% developed squamous cell carcinoma, 5% developed actinic keratoses, 2% developed skin papillomas, and 22% developed rash, which is a common side effect of MEK inhibitors. “We did see rashes, but the acneiform rash we often see with MEK inhibitors was almost absent in this study,” he said. “It’s fascinating to find such promising effects with this combination regimen,” Dr. Weber said. “Not only are the two drugs causing shrinkage of the cancer, but we’re seeing that a second anticancer therapy may actually suppress the side effects of the first. There is a significant diminution of the dermatologic toxicities, such as just 3% squamous cell carcinoma, which can favorably be compared to the 15%

Trametinib/Dabrafenib in Metastatic Melanoma ■■ Combination therapy with the investigational MEK inhibitor trametinib and BRAF inhibitor dabrafenib had an acceptable safety profile, with a lower incidence of rash and hyperproliferative skin lesions compared with the single agents.

■■ Among patients with V600 BRAF–mutant advanced melanoma, the clinical activity of dabrafenib/trametinib was encouraging, and a phase III trial is ongoing.

EXPERT POINT OF VIEW

ommenting on the trial of combined BRAF and MEK inhibition in advanced melanoma, Michael K.K. Wong, MD, PhD, Professor of Medicine at Keck School of Medicine, University of Southern California, Los Angeles, called the findings “nothing short of extraordinary” and a potential “game changer.” “Inducing complete responses in melanoma is impressive, and a near universal overall disease control rate is outstanding,” he told The ASCO Post. Michael K.K. Wong, MD, PhD “In what other cancer do we see 100% disease control rates, especially in a phase I/II trial? These are game-changing results in any cancer, let alone melanoma. They change the way we think about this disease.” The 3% rate of squamous cell carcinoma was particularly striking to Dr. Wong, who treats the disease himself and worries that the skin manifestations could be a harbinger of internal squamous cell carcinoma lesions. While this is only an unproven possibility, he said, “These drugs have not been out long enough to know the full extent of the impact of these squamous cell carcinomas.”

Underlying Mechanism? The rare skin toxicity with the dabrafenib/ trametinib combination suggests to him that (1) these lesions may flow through the MEK pathway, perhaps as a consequence of some pressure exerted by BRAF inhibitors, and (2) it is possible that squamous cell carcinomas might be amenable to treatment via MEK pathway inhibition. “As a drug developer,” he said, “I wonder if we should pursue MEK inhibitors for squamous cell carcinoma.” Regarding the encouraging outcomes in patients with melanoma, Dr. Wong issued the usual caveat—that long-term follow-up is needed—but emphasized that this is especially true for treatment with BRAF and MEK inhibitors, whose biggest drawback has been that responses are frequently short-lived. “The big unknown here is whether these responses will be durable,” he said. “Or will this be yet another example of how the plasticity of gene expression within cancer cells ends up finding a way around the obstruction put in its path by these inhibitor-type drugs?” He continued, “The larger phase III trial will definitively prove or disprove the idea that this is a very active combination. If it is, we will be using dual inhibitors at some cost. To consume resources to this degree, we don’t just want to shrink tumors; we want to have them not recur.”

■

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

to 25% frequency seen with this drug alone or with other BRAF inhibitors.”

Other Side Effects On the other hand, 52% of patients had pyrexia, and while just 8% of cases were grade 3 or higher, 23% had doses reduced or delayed because of fever, he added. Fatigue, nausea, and chills occurred at rates similar to those seen with BRAF inhibitors alone. The phase II randomized portion of the study is currently ongoing, and the phase III testing of the “150/2” dose has begun, he said, adding, “Obviously

we must be cautious, but we find these results extremely encouraging.”

■

Disclosure: Dr. Weber has received honoraria from and served on advisory boards for GlaxoSmithKline.

Reference 1. Weber JS, Flaherty KT, Infante JR, et al: Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. 2012 ASCO Annual Meeting. Abstract 8510. Presented June 4, 2012.

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

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

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

IMPORTANT SAFETY INFORMATION

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

Hypocalcemia

Osteonecrosis of the Jaw (ONJ)

• XGEVA® can cause severe hypocalcemia. Correct preexisting hypocalcemia prior to XGEVA® treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

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

www.XGEVA.com

SUPERIORITY XGEVA® (denosumab) delayed the median time to first SRE by 8.2 months in a prespecified integrated analysis across 3 head-to-head studies vs zoledronic acid1,2

PERCENTAGE OF PATIENTS WITHOUT SRE

Time to first SRE, evaluated in more than 5,600 patients2 XGEVA® 120 mg Q4W (n = 2,862) zoledronic acid 4 mg Q4W (n = 2,861)

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: 19.4 months

40 30

17%

Median time: 27.7 months

20 10

RISK REDUCTION

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

0 0

Reduction in risk of ﬁrst SRE in 3 individual studies • Breast cancer: 18% vs zoledronic acid (P = 0.010, superiority)1 • Prostate cancer: 18% vs zoledronic acid (P = 0.008, superiority)1 • Other solid tumors*/multiple myeloma: 16% vs zoledronic acid (P < 0.001, noninferiority; P = 0.060, NS for superiority)1 – Subanalysis of other solid tumors*: 19% vs zoledronic acid (P = 0.034, superiority)2 – XGEVA® is not indicated for the prevention of SREs in patients with multiple myeloma *Excluding breast and prostate cancer. † P value for superiority.

STUDY MONTH

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

NO DOSE ADJUSTMENTS

PRECISE ACTION

SUBCUTANEOUS INJECTION

XGEVA® is not cleared by the kidneys and does not require dose adjustments, regardless of renal function2-5

XGEVA® acts precisely to bind to RANK Ligand, a key mediator of bone resorption, to inhibit osteoclast activity1

XGEVA® is administered once every 4 weeks as a single, 120 mg subcutaneous injection1

Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.2 • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. • Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea.

• The most common serious adverse reaction in patients receiving XGEVA® was dyspnea. • The most common adverse reactions resulting in discontinuation of XGEVA® were osteonecrosis and hypocalcemia. Please see brief summary of Prescribing Information on the following page.

ASCOPost.com | JUNE 15, 2012

PAGE 15

2012 ASCO Annual Meeting Survivorship

Better Information Needed for Primary Care Providers Who Treat Cancer Survivors By Alice Goodman

any primary care providers are unaware of the late effects of chemotherapy, according to survey results presented at the ASCO Annual Meeting.1 For three out of four commonly used chemotherapy agents, medical oncologists performed well on the survey, but 29% to 38% of medical oncologists were unable to correctly identify two possible late side effects of cyclophosphamide.

Larissa Nekhlyudov, MD

Problem Created by Success “Oncologists often identified late effects of commonly used chemotherapy, while primary care providers did not,” said lead author Larissa Nekhlyudov, MD, MPH, Associate Professor at Harvard Medical School and internist at Harvard Vanguard Medical Associates, Boston. “With more than 12 million cancer survivors, the transition from oncologists to primary care needs to be improved. Patients should be aware of the side effects of the drugs they receive, but it is vitally important that oncologists relay this information to patients’ primary care providers so

their risks can be appropriately managed throughout their lives “In some sense, this study represents a positive message, because this is a problem [long-term survivorship] created by our successes,” said 2011–2012 ASCO President Michael P. Link, MD, Lydia J. Lee Professor of Pediatric Hematology/Oncology at Stanford University School of Medicine, Palo Alto, California. “Our patients return to primary care. Patients and primary care providers need summaries of their treatment history and guidelines for survivorship care. This situation makes a good case for electronic medical records. We need to make sure that the ball does not get dropped in the transition from oncologists’ offices to primary care providers.”

Knowledge Gap for Late Effects The Survey of Physician Attitudes Regarding the Care of Cancer Survivors was completed by 1,072 primary care providers and 1,130 medical oncologists who treat breast and colorectal cancers. Physicians were asked to select which of five late effects of four widely used cancer drugs—doxorubicin, paclitaxel, oxaliplatin, and cyclophosphamide—they had observed or seen reported. For doxorubicin, 55% of primary care providers and 95% of medical oncologists correctly identified cardiac dysfunction as a late effect. For paclitaxel, 26% of primary care providers and 97% of medical oncologists cor-

Intersection of Primary Care and Cancer Survivorship ■■ A large survey revealed a huge knowledge gap between primary care

providers and oncologists regarding late effects of four commonly used chemotherapy drugs.

■■ There is room for improvement in this regard among medical oncologists as well.

■■ The growing number of cancer survivors makes it imperative to provide

good survivorship planning that can be used following the transition from oncology practices to primary care providers.

rectly identified peripheral neuropathy as a late effect. For oxaliplatin, 22% of primary care providers and 96% of medical oncologists correctly identified peripheral neuropathy as a late effect. The knowledge gap for late effects of cyclophosphamide was evident for oncologists as well; 15% of primary care providers and only 71% of medical oncologists correctly identified premature menopause as a late effect, and 17% of primary care providers and only 62% of medical oncologists correctly identified secondary malignancy as a late effect. Only 6% of primary care providers and 65% of oncologists correctly identified the late effects of all four drugs. In an adjusted analysis, being boardcertified in oncology and spending more time in patient care increased the likelihood of correctly identifying late effects of all four drugs.

Need for Improvement “These findings emphasize the need for ongoing education among all phy-

sicians who care for cancer survivors about potential late effects. In the transition of patients from oncology to primary care settings, primary care providers should be informed about the late effects of cancer treatment so that they may be better prepared to recognize and address these effects among the cancer survivors in their care,” Dr. Nekhlyudov said. “Whether this may See Page 90 be achieved with the development and use of survivorship care plans needs to be evaluated,” she added.

■

Disclosure: Drs. Nekhlyudov and Link reported no potential conflicts of interest.

Reference 1. Nekhlyudov L, Aziz N, Lerro CC, Virgo K: Oncologists’ and primary care providers’ awareness of late effects of cancer treatment: Implications for survivorship care. 2012 ASCO Annual Meeting. Abstract 6008. Presented June 2, 2012.

National Cancer Survivors' Day Sunday, June 3, 2012, was National Cancer Survivors' Day and events were held around the United States in recognition of the more than 12 million survivors of cancer. In Chicago, the Robert H. Lurie Comprehensive Cancer Center held its 19th Annual Cancer Survivors' Celebration & Walk in tribute to cancer survivors and the advances being made in cancer treatment and research. Save the Date for the 20th Anniversary Survivors' Celebration and Walk, June 2, 2013. Visit www.cancer.northwestern.edu. Photo credit: Randy Belice

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

NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION*

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

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

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

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

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

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page. *The reconstituted concentration for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL). † Melphalan+prednisone. ‡ HR=0.695 (95% CI, 0.57-0.85); p<0.05. § VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated MM. The primary endpoint was time to progression (TTP). Secondary endpoints were complete response (CR), overall response rate (ORR), progression-free survival (PFS), and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. In an updated analysis at a median follow-up of 36.7 months, the overall survival advantage was sustained despite subsequent treatments.

Living Proof

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

003410_3_milpro_ascopt_fa2.indd 2

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

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

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Expert’s Corner

At More than a Century Old, American Association for Cancer Research Continues to Evolve A Conversation with Margaret Foti, PhD, MD (hc) By Barbara Boughton

Margaret Foti, PhD, MD (hc)

argaret Foti, PhD, MD (hc), has been Chief Executive Officer of the American Association for Cancer Research (AACR) since 1982, and has been instrumental in launching some of the most seminal efforts of the cancer research organization. Over the past 4 years, she has helped spearhead the AACR’s scientific partnership with Stand Up To Cancer, as well as the AACR’s production of the Cancer Progress Report of 2011, which chronicled advances in cancer research over the past 40 years. At 24 years old, Dr. Foti began her meteoric rise through the ranks of the AACR when she became the country’s youngest managing editor of a scientific journal, Cancer Research, then the flagship publication of AACR. During her tenure as CEO, the AACR’s budget has grown from about $1 million to $74 million and its membership has spiraled from 3,000 to over 33,000 basic, translational, and clinical scientists in more than 90 countries. In a recent interview with The ASCO Post, Dr. Foti looked back on her career in scientific publishing and association management at the AACR, to provide perspective on how the field of prevention research has changed over the years.

Women in Science How was the work of editing scientific journals back when you started on Cancer Research different from today, and how were women received when you first started working at AACR? Cancer Research was then one of the

few cancer journals in the world, and it was very small. It’s still the most highly cited cancer journal in the world. But now the editors and staff at the journal review 6,000 manuscripts per year, whereas back then there were just several hundred. The journal, of course, was much thinner then, and the editorial work was less complex. I was very lucky in that all my mentors (including Cancer Research editor Sidney Weinhouse, PhD, at the time Dr. Foti became managing editor) took me under their wing and gave me great support. There was no discrimination. I think women in scientific publishing should get help from those whose expertise they need to develop profession-

gy, Biomarkers & Prevention to address the increasing interest in cancer prevention. Five years ago, our journals did not include many papers on the basic science of prevention. We knew that the impact of basic science on prevention would be very important going forward, so the journal Cancer Prevention Research was designed to include the full spectrum of science in this field, from lab to clinical research, including new data on genomics, imaging, and biomarkers. Cancer Discovery provides one-stop shopping for cancer researchers who want to keep abreast of what’s going on in their field and in other exciting areas of cancer research.

New technologies are being brought to bear on cancer research in general and translational research in particular. A lot of issues are of concern to us, such as how to intercept cancer at earlier stages, how to treat and prevent precancers, and how to manage all the new genomic data. —Margaret Foti, PhD, MD (hc)

ally; it shouldn’t matter whether these mentors are women or men. When I became CEO of AACR, however, there were very few female CEOs of scientific or medical organizations—now there are many more of us out there, which is a good thing.

Newer Journals The AACR now publishes seven journals containing a total of more than 27,000 scientific pages. What was the impetus behind the establishment of some of its newest journals, such as Cancer Prevention Research (begun 5 years ago) and Cancer Discovery (established last year)? The AACR has been involved in and supportive of cancer prevention for the past 100 years. One of our founding fathers in 1907 was a cancer prevention scientist. In 1991, we published the journal Cancer Epidemiolo-

Earlier in my career, I thought scientists wanted to do their own thinking about the scientific literature. It is now clear, especially because of the burgeoning literature in cancer research, that scientists want the latest developments in the field brought to them with analysis and commentary from thought leaders. So Cancer Discovery has the best papers in all areas of cancer research and also has news articles and commentary. The manuscript acceptance rate is very low—we aim to keep the quality very high so that it has a high impact factor.

Chief Priorities What do you view as some of the chief priorities for the AACR in addressing gaps in cancer prevention research? We have to continue to strengthen the basic science of cancer prevention research and translate that science to the clinic. Nine physicians and two ba-

sic scientists founded our organization in 1907, but basic scientists now make up about half of our membership. New technologies are being brought to bear on cancer research in general and translational research in particular. A lot of issues are of concern to us, such as how to intercept cancer at earlier stages, how to treat and prevent precancers, and how to manage all the new genomic data. One of the questions we are facing is: How do you train people to analyze the voluminous genomic data? In the future, we’ll see a great deal of progress in areas such as genomic imaging of biomarkers and information technology for analysis of genomic data sets.

Changing with the Times How has the AACR changed since you became CEO, and what recent projects of the organization do you view as significant, both now and in the future? We have built the AACR into a multifaceted cancer prevention organization that not only publishes cancer science and medicine, but also one that holds very important meetings in the field. We are now much more proactive in identifying scientific priorities than in the past, as well as holding think tanks and workshops that identify these priorities. We’ve increased our capacity as a research grant-giving organization through projects such as Stand Up To Cancer and others. We also view the Cancer Progress Report—first issued in 2011—as very important, and we will continue to put it out annually. At parties, one can always hear comments and questions from the lay public about what is happening in cancer research. The big question is always: Are we going to achieve the cure? Or more accurately, will we see cures of the many diseases that we call cancer? There’s an enormous amount of education needed among the lay public, and we’re committed to helping with that effort through projects such as the Cancer Progress Report and a revamped website for the public.

■

Disclosure: Dr. Foti is Chief Executive Officer of the American Association for Cancer Research.

The ASCO Post | JUNE 15, 2012

PAGE 20

2012 AACR Annual Meeting Genomics

Can Whole-genome Sequencing Predict Cancer Risk and Improve Public Health? By Charlotte Bath

f, as expected, the cost of whole-genome sequencing continues to drop, perhaps down to the $1,000 vicinity, it may become an alluring option for consumers who want to know about their risks for cancer and other diseases. But can genome sequencing really provide practical information about individual risks and influence risk-reduction strategies that could improve public health? If consumers obtain whole-genome sequencing in hopes that “it will to alert them to a risk that they don’t necessarily know about, then they will likely be satisfied, because there are risks for which these tests can in fact alert them. We estimate that at least half of individuals, once all the research is done, will get such a result,” remarked Bert Vogelstein, MD, coauthor of a study published in Science Translational Medicine1 on the potential of personal genome sequencing to predict the risks of cancer and other diseases.

Bert Vogelstein, MD

“However, if individuals want to get tested because they think that this will be a crystal ball to tell them what their medical history will be, they will be disappointed. It will not do that,” Dr. Vogelstein said. Updating the caveat, let the buyer beware, he said, “Let the buyer understand what they are paying for, what information they are going to get. How useful that information will be is up to the consumer.” Dr. Vogelstein, who presented the research findings at the American Association for Cancer Research (AACR) Annual Meeting, is Clayton Professor of Oncology at the Johns Hopkins Kimmel Cancer Center, Co-director of the Hopkins’ Ludwig Center for Cancer Biology Research in Baltimore, and investigator at the Howard Hughes Medical Institute in Chevy Chase, Maryland.

Important Distinction While costs in excess of $10,000 are

currently curbing demand for wholegenome sequencing, discussants at a press conference where Dr. Vogelstein presented his findings in advance of the AACR meeting, agreed that it is important to properly frame the issues concerning whole-genome sequencing in anticipation of increased demand.

Olufunmilayo I. Olopade, MD

“We have to implement genome technologies correctly and for the public good,” stated Olufunmilayo I. Olopade, MD. Dr. Olopade is Professor of Medicine and Human Genetics and Director of the Cancer Risk Clinic

whether these mutations change your risk, but rather, is the knowledge of these mutations going to change your behavior, your medical actions, your preventive strategies? Does it change something about the way you will act as a result of having that knowledge? Then it presumably would have value in being tested,” said Timothy Rebbeck, PhD, Professor of Epidemiology, University of Pennsylvania Perelman School of Medicine in Philadelphia. “I think that the number of situations where that is the case right now is very small, but the number of situations where we can actually act on genetic information in a positive way by changing our behavior, by changing our prevention strategies, is extremely limited. As those grow, as we have more of those options available to us, based on genetic information, then these genetic tests will become more and more valuable.” Thomas Sellers, PhD, MPH, Executive Vice President and Director of the Moffitt Research Institute in Tam-

To me, the concept is not just about whether these mutations change your risk, but rather, is the knowledge of these mutations going to change your behavior, your medical actions, your preventive strategies? —Timothy Rebbeck, PhD

at the University of Chicago School of Medicine. Whole-genome sequencing and related issues of tumor heterogeneity and personalized medicine were

Timothy Rebbeck, PhD

also discussed by speakers at other sessions of the Annual Meeting, attended by nearly 17,000 physicians, researchers, health-care professionals, cancer survivors, and patient advocates. “To me, the concept is not just about

pa, Florida, noted that the article coauthored by Dr. Vogelstein made a very important distinction between genome sequencing to predict risk and for personalized medicine. “Once you have disease, having a full sequence could be extremely valuable,” Dr. Sellers stated. Identification of mutations can inform treatment, such as how a patient might respond to a particular drug, but to know if there is a mutation or not, “you need to know what the normal germline sequence is,” Dr. Sellers pointed out. “So in that situation, knowing the complete sequence of an individual is going to have to be part of the exercise of doing personalized treatment if we are going to provide proper therapy for a particular cancer.”

Quantitative Framework The research findings reported by

Thomas Sellers, PhD, MPH

Dr. Vogelstein were based on data on the incidence of 24 diseases, including cancer, autoimmune, and other diseases, among 53,666 pairs of identical twins entered into registries worldwide. Johns Hopkins researchers developed mathematic models to predict minimum and maximum risk distributions compatible with the twin data and used these distributions to estimate the capacity of whole-genome sequencing to identify individuals at clinically significant risk for the 24 diseases. “Identical twins share the same genome, and if the genome were the determining factor for common diseases, then the prevalence of a specific disease in an individual whose twin has that disease can be used to determine how well whole-genome sequencing could predict an individual’s disease risk. What we hope to do in this study is to put the debate about the value of whole-genome sequencing and its relevance to personalized medicine in a quantitative framework,” Dr. Vogelstein explained. “Each of us contains about 4½ million variants that distinguish us one from another,” he said, and “trying to figure out the way these variants interact with one another to cause or reduce the risk of disease is really a Herculean task.” He added, “the functional significance of almost all these variants is currently unknown.”

Clinically Actionable Results A positive test result, “something that we thought was clinically actionable,” Dr. Vogelstein explained, was defined as a 10% risk of disease, meaning 1 in 10 people would develop the disease from all factors combined. “A negative test result and its usefulness is in the eye of the beholder, but in order to be really useful—that is, actionable to change people’s behavior or their continued on page 22

Stimulating

Possibilities

The potential of Dendritic Cell Mediated Immunotherapy (DCMI) in advanced NSCLC

BINDS

PROPOSED MECHANISM OF ACTION: Orally administered DCMIs are thought to bind in the gut epithelium and interact with dendritic cells in the gut wall 1,2

STIMULATES

Binding produces an immunostimulatory cytokine cascade in the gut, stimulating the migration and maturation of tumor antigen-presenting dendritic cells2,3

ACTIVATES Matured dendritic cells present tumorassociated antigens to T lymphocytes and activate them2,3

INFILTRATES These effector T lymphocytes then make their way to distal tumors, where they infiltrate and inhibit tumor growth2,3

There is an unmet need for treatments in advanced NSCLC that work in a broad range of patients, regardless of tumor histology or mutation status.4 Agennix is investigating a novel oral DCMI in advanced NSCLC. Learn more at www.discoverDCMI.com

DCMI

References: 1. Suzuki YA et al. Biochem. 2001;40:15771-15779. 2. Spadaro M et al. Cancer Res. 2007;67:6425-6432. 3. Varadhachary A et al. Int J Cancer. 2004;111:398-403. 4. Kelly RJ, Giaccone G. Expert Opin Biol Ther. 2010;10:1379-1386.

The ASCO Post | JUNE 15, 2012

PAGE 22

2012 AACR Annual Meeting Whole-genome Sequencing

Strong Family History

continued from page 20

Whole-genome sequencing can be extremely valuable for identifying the genetic basis of monogenetic diseases—those caused by a single defect in a single gene—and management of families with a strong history of these diseases, Dr. Vogelstein said. “That will of course be dependent on understanding all the kinds of variations that occur and what their influence is, but on monogenetic diseases, that certainly is a good possibility for many families,” he added. “I agree completely that that is where the greatest value will be,” Dr. Sellers said, “but there are limitations.” Some people may not know their family history either because of adoption, separation, or lack of communication. Another limitation is that “family history is not a static event.

medical care—you probably want to have that risk much less than the general population,” Dr. Vogelstein added. The study found that most patients would receive negative tests for most diseases, and the predictive value of the negative tests would be small. “On the positive side,” the researchers wrote, “our results show that, at least in the best-case scenario, the majority of patients might be alerted to a clinically meaningful risk for at least one disease through whole-genome sequencing.” As an example, Dr. Vogelstein presented the study data for ovarian cancer. “At most, 1 in 50 women will get a positive result. That could be very useful to those women, because it would suggest that they should be candidates for intense surveillance, he said. But for the 49 out of 50 who test negative, the result “is not that informative,” Dr. Vogelstein stated. “It shows only that they have a risk that is slightly lower than the general population.” Instead of the estimated 1.4% risk of ovarian cancer for women in the United States today, having a negative test would mean the risk “is somewhere about 1.3% or 1.2% at best,” he noted. “The point about medically actionable information is critical,” Dr. Rebbeck stated. “We have often been treating genetic risk equally across all diseases, but some diseases and some genetic risks are going to be more medically actionable than others,” he said. “A 10% increased risk where there is no medical intervention might be thought of very differently than a 10% increased risk that could be easily addressed” by preventive actions, such as staying out of the sun, he said. “So we may need to think about whether a particular level of risk has a medically actionable intervention and not treat all of these increased risks the same.” Dr. Olopade pointed out that receiving a positive result predicting a high risk for ovarian cancer can be “an actionable item” or an anxiety-creating dilemma, depending on a woman’s circumstances. A woman who is done having children may choose to have her ovaries removed, but a woman in her 20s concerned about marriage and future childbearing could have “so much anxiety over that information that it in fact does more harm than good.”

vention at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School in Boston.

Genes, Environment, and Bad Luck “Cancer is a mixture of genetic and nongenetic effects,” Dr. Vogelstein explained, but many people think nongenetic effects refer only to the lifestyle and environmental factors. “That’s only a small part of the picture. Much more important in some cases are stochastic, or random, influences. Cancers, as we now know, are caused by the sequential accumulation of mutations, almost all of them occurring after birth. These mutations occur strictly by chance as cells divide,” he explained. “We do know that when it comes

One of the issues that comes up concerns how good our history-taking is and whether it is important to use family history as it gets easier to identify alterations using these specific technologies. — Judy E. Garber, MD, MPH

It’s dynamic,” he noted. A person may not have a family history, then suddenly a family member develops cancer and the other family members are now in a different risk category. “That raises the question about when you do sequencing for family history,” Dr. Sellers said. In her AACR Presidential Address, Judy E. Garber, MD, MPH, noted that genome sequencing may reveal alterations in genes that were not suspected based on the patient’s history. “One of the issues that comes up in this context concerns how good our history-taking is—we have certainly relied on such interviews to identify individuals and families for testing— and whether it is important to use family history as it gets easier and easier to identify alterations using these specific technologies,” Dr. Garber said. “Clinically, most of us would still argue that it is critically important to have context for your analysis.” Dr. Garber, who completed her term as AACR President during the Annual Meeting, is Director of the Center for Cancer Genetics and Pre-

to cancer, it is genes, it is the environment, and it is also bad luck,” Dr. Sellers agreed. He said that the study by Dr. Vogelstein and colleagues emphasizes the relative contributions of those three components. “For the vast majority of individuals, whole-genome sequencing will never be a crystal ball that can reliably predict future health,” Dr. Vogelstein said. He explained that for males in the United States, a negative test would reduce their risk of developing some type of cancer from 45% to between 32% and 42%; for females, the risk would be reduced from 38% to between 27% and 36%. “A fortune teller with a crystal ball this precise would soon go out of business,” he said. For those who test positive, meaning they have a 10% risk for disease, “this does not imply that the disease will be the person’s major health problem,” Dr. Vogelstein added. “Perhaps most important, from a public health perspective, whole-genome sequencing can certainly be useful in certain patients but cannot substitute for conventional risk management strate-

gies, including routine checkups, lifestyle optimization, and so forth.”

Prevention and Detection Interventions Dr. Vogelstein cited a review article by Colditz el al,2 also published in Science Translational Medicine, “showing that over half of cancers can be prevented by applying the knowledge that we have today,” he reported. “Effective risk management will have to involve the entire population, not just a genetically predisposed subset in order to make a real dent in disease incidence,” he said. Going back to his ovarian cancer example, he noted that while the estimated percentage of women in the United States who will develop ovarian cancer is only 1.4%, this represents about 2.2 million women. If every woman had whole-genome sequencing, “you could conceivably identify a predisposition in 500,000 of them,” Dr. Vogelstein said. “That leaves 1.7 million of the 2.2 million who will get the disease unalerted to their condition. We have to make surveillance and early detection available to all, not just those who are at high risk.” It’s similar with pancreatic cancer, he said. Whole-genome sequencing conducted among all men and women in the United States could at best identify a predisposition among just 230,000 of the 4.5 million who will eventually develop the disease. “We’re specifically not trying to say that whole-genome sequencing will or won’t be useful,” Dr. Vogelstein replied in response to a question. “We are simply trying to do a reality check. How many people benefit? How many people will get information that won’t really help them understand their risk?” Also citing the Colditz article,2 Dr. Sellers stressed the importance of cancer prevention, particularly by reducing smoking, obesity, and use of tanning beds. “We are not doing a good enough job convincing the public that they need to do these things. We need to create the incentives to adopt those healthy lifestyles,” he said. “We now have vaccines that can prevent human papillomavirus (HPV) infection, which would have a very large impact on eliminating cancers, and the only behavior change there—much easier than the others—is just to get the vaccine, but the uptake is nowhere near where it should be,” he added. Dr. Sellers noted that the HPV vaccine was important for both males and females.

ASCOPost.com | JUNE 15, 2012

PAGE 23

2012 AACR Annual Meeting Clinician’s Perspective “I am the clinician in the room,” said Dr. Olopade, explaining her perspective and focus on the individual patient. “What I think the genome has really allowed us to appreciate is how each individual’s genome is different from every other person’s,” she said. “Unless we actually do a lot more sequencing of genomes, we’re not going to know the different variations of the genomes that explain the heterogeneity that we see among patients who come into the clinic,” she added. “For those of us who are doctors and have to prevent or treat illness, the more understanding we have of individual genomes, the better.” Reading the study reported by Dr. Vogelstein, Dr. Olopade said, “I remembered the arguments and the discussions we had almost 20 years ago, when we started talking about the clinical implications of genetics for regular oncology practice. The debate at that time was about whether we were going to offer BRCA1 and BRCA2 testing and whether anyone would want to know that information because there was nothing they could do about it. We had passionate discussions and debate among ethicists, among patient advocates, and among geneticists who thought nothing good could come out of that sort of research. But 20 years later, the oncology community in fact has adopted widespread testing for BRCA1 and BRCA2 because we came to realize there were many women who died of ovarian cancer unnecessarily, and we could have prevented that if we knew they had the genetic mutation.”

Preparing Patients Dr. Garber had also addressed early BRCA1 and BRCA2 testing in her talk the previous day. “We found that most people who sought to learn the results handled the information fine, as long as it was provided carefully,” she said. Whole-genome sequencing “may not be different, but preparing patients for what they may learn is a much more complicated task.” Dr. Garber noted that there has already been a shift from testing for BRCA1 and BRCA2 to testing for a panel of mutations that might indicate increased risk of ovarian cancer. “Individuals will say, ‘If you are going to look at some of my genes, why not all of them?’ So why not all of them?” Dr. Olopade called on her medical colleagues to embrace the challenge of genome sequencing, to look at lifestyle, social, and cultural influences that can alter the genome, “and then we’ve got to figure

out those so-called stochastic events.” Perhaps patients who knew that they were at increased cancer risk due to genetic and random events might be more motivated to make healthy lifestyle changes. “What I always ask my patients is, ‘Are you asking about the risk of dying from cancer or risk of being diagnosed with cancer?’ I think from a public health

perspective, the better our tools to help patients survive cancer and not have untoward side effects, the more the public will adopt public health interventions that will help them beat the odds of dying or suffering from cancer.”

■

Disclosure: Drs. Vogelstein, Olopade, Rebbeck, Sellers, and Garber reported no potential conflicts of interest.

References 1. Roberts NJ, Vogelstein JT, Parmigiani G, et al: The predictive capacity of personal genome sequencing. Sci Transl Med 4:133ra58, 2012. 2. Colditz GA, Wolin KY, Gehlert S: Applying what we know to accelerate cancer prevention. Sci Transl Med 4:127rv4, 2012.

FOR A DIFFERENT PERSPECTIVE IN RENAL CELL CARCINOMA, DISCOVER…

THE OTHER SIDE OF RCC

In the United States, RCC is the 9th most common malignancy and accounts for 2% to 3% of all adult cancers.1,2 Incidence rates continue to rise; however, the reason for this increase is unknown.2 The American Cancer Society estimates that there will be 64,770 new cases and 13,570 deaths in 2012.3

Studies have demonstrated the importance of sustained drug levels; however, these levels can be compromised when toxicities lead to dose modifications, interruptions, or discontinuations.3,6,7 In the Phase III trials of targeted agents, 30% to 40% of patients required dose modifications, and in the community setting this percentage may be higher.5 Treatment modifications require significant monitoring by healthcare professionals, and may potentially compromise treatment exposure and patients’ daily living.3,6

Is good enough, enough? Today’s RCC patients are often active, with busy lifestyles and families. With a median age at diagnosis of only 64, quality of daily living on therapy is critical.1 While the introduction of targeted therapy has improved the management of advanced disease and the outlook for patients, new challenges and existing unmet needs may compromise not only patients’ everyday life, but overall outcomes.2,3

Furthermore, in addition to dose modifications deemed necessary by a physician, patients themselves may choose not to adhere to their dosing regimen due to discomfort or dissatisfaction with the toxicity of therapy, among other factors.6

There may be opportunities to improve patient care

Therapy for advanced RCC has evolved, but…

Proactive monitoring, early detection, and prompt management of side effects are important for optimal patient management. Additionally, open communication between patients and healthcare professionals can be crucial to avoid premature treatment discontinuations or adverse impacts on patients’ everyday lives.3,6

Each therapeutic class of agents is associated with distinct adverse events. Despite recent advances in treatment, side effects remain an important issue in patient management.4 Research has shown that a substantial proportion of patients—both in clinical trials and everyday clinical practice—may not receive the full dose of their therapy due to adverse event management.5,6

Go behind the scenes to learn more at www.WhyCompromiseRCC.com.

AVEO and Astellas are uncompromising in their commitment to RCC patients References: 1. Centers for Disease Control and Prevention. http://apps.nccd. cdc.gov/uscs/toptencancers.aspx. Accessed January 27, 2012. 2. National Comprehensive Cancer Network. http://www.nccn.org. Published October 18, 2011. Accessed January 27, 2012. 3. American Cancer Society. Atlanta: ACS; 2012. 4. Cowey CL, Hutson TE. Clin Adv Hematol Oncol. 2010;8(5):357-364. 5. Hudes GR, Carducci MA, Choueiri TK, et al. J Natl Compr Canc Netw. 2011;9(suppl 1):S-1-S-30. 6. Appleby L, Morrissey S, Bellmunt J, Rosenberg J. Hematol Oncol Clin N Am. 2011;25(4):893-915. 7. Rini BI. J Clin Oncol. 2009;27(19):3225-3234. 8. Ravaud A. Ann Oncol. 2009;20(suppl 1):i7-i12. 9. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Cancer Chemother Pharmacol. 2010;66(2):357-371. doi:10.1007/s00280-009-1170-y.

An Uncompromising Commitment to RCC

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PAGE 24

Journal Spotlight Hematology

Maintenance Lenalidomide Improves Progression-free Survival and Time to Progression in Patients with Multiple Myeloma By Charlotte Bath

hree phase III, double-blind, multicenter, randomized studies showed that lenalidomide (Revlimid) maintenance therapy for patients with multiple myeloma significantly improved progression-free survival or time to progression, the primary endpoints of the studies published in The New England Journal of Medicine.1-3

Newly Diagnosed Disease Among newly diagnosed patients aged 65 years or older, melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance (MPR-R) “significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age.” These results reported by Antonio Palumbo, MD, of the University of Turin, Italy, and colleagues were culled from 82 centers in Europe, Australia, and Israel.1 The study was funded by Celgene. Progression-free survival was significantly longer among the 152 patients receiving MPR-R (31 months) than among the 153 patients receiving melphalan, prednisone, and lenalidomide (MPR) or the 154 patients receiving melphalan plus prednisone (MP) followed by placebo MPR (14 months). Response rates were superior with MPR-R (77%) and MPR (68%) compared with MP (50%). “In the present study, the major influence on progression-free survival was associated with lenalidomide maintenance therapy,” the researchers wrote. “A landmark analysis showed that lenalidomide maintenance reduced the rate of progression among all patients, regardless of age, by 66% as compared with placebo,” the authors reported. The median followup was 30 months. See Page 90 “Longer follow-up is required to evaluate an overall survival benefit,” the authors stated. The most frequent adverse events during induction therapy were hematologic, with grade 4 neutropenia reported by 35% of the patients in the MPRR group, 32% in the MPR group, and 8% in the MP group. The 3-year rate of second primary tumors was 7% with MPR-R and MPR and 3% with MP.

After Stem Cell Transplant In two of the studies, lenalidomide was administered after autologous stem cell transplantation. Patients who began receiving lenalidomide maintenance therapy at day 100 after hematopoietic stem cell transplantation had significantly longer time to disease progression and significantly improved overall survival than those receiving placebo, but more toxicity and second cancers, according to a study reported by Philip L. McCarthy, MD, of Roswell Park Cancer Institute, Buffalo, New York, and other investigators.2 The study was conducted at multiple U.S. sites and funded by NCI. More grade 3 or 4 hematologic adverse events and grade 3 nonhematologic events occurred in patients who received lenalidomide (P < .001 for both comparisons), the researchers reported. “Second

some patients, and the discontinuation of maintenance therapy.

Second Post-transplant Study In the study by Michel Attal, MD, of the Hopital Purpan, Toulouse, and other investigators,3 lenalidomide maintenance after transplantation significantly prolonged progression-free and eventfree survival compared to placebo, but 4 years after randomization, overall survival was similar in the two study groups. “Our study was not designed to show an overall survival advantage, and the number of deaths is still low (25% rate of death),” the investigators noted. “The probability of surviving 4 years after randomization was high for both groups. This result might be related to the intensive strategy we used (reinforced induction, a second

As myeloma evolves from an ‘incurable’ cancer to a chronic disease, physicians are faced with the task of maximizing available treatments not only to improve survival but also to maintain their patients’ quality of life. – Ashraf Z. Badros, MB, ChB

primary cancers occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%).” The 460 study participants were younger than 71 years of age and had stable disease or a marginal, partial, or complete response after stem-cell transplantation. After a median followup of 18 months, 44% of the patients in the placebo group had progressive disease or had died, compared to 20% in the lenalidomide group. “The increase in time to progression led to early study unblinding, and despite the crossover, benefits with respect to progression and overall survival were seen in patients receiving lenalidomide maintenance therapy, especially those who had received lenalidomide-based induction therapy,” the authors reported. The authors noted that the study reported by Attal et al (see below) did not show an overall survival benefit, which could be due to differences in induction and consolidation before transplantation, the use of lenalidomide consolidation in both groups after transplant, the use of two transplants in

transplantation in patients who did not have a complete or very good partial response after the first transplantation, and consolidation) and to the activity of new agents that were used to treat relapses…. A longer follow-up is still required to assess the role of lenalidomide maintenance on overall survival.” The French study, funded by the Programme Hospitalier de Recherche Clinique and others, involved 614 patients under age 65 with nonprogressive disease after first-line transplantation. Lenalidomide maintenance therapy improved median progression-free survival to 41 months vs 23 months with placebo. This benefit was seen across all subgroups. “The incidence of second primary cancers was 3.1 per 100 patient-years in the lenalidomide group vs 1.2 per 100 patient-years in the placebo group (P = .002),” the authors noted. Median eventfree survival was significantly improved with lenalidomide (40 vs 23 months; P < .001). Grade 3/4 peripheral neuropathy rates were similar in the two groups. “Together with the findings reported by McCarthy et al, our data support

the use of lenalidomide maintenance therapy after high-dose chemotherapy and autologous hematopoietic stemcell transplantation in patients with myeloma, but the impressive benefits must be weighed against the increased risks,” the authors concluded.

Critical Questions “These studies provide compelling evidence of improvement in progression-free survival; however, the results raise several critical questions,” according to an editorial accompanying the articles.4 These questions concern whether progression-free survival is the appropriate primary endpoint in maintenance if it doesn’t result in improved overall survival; whether lenalidomide maintenance therapy is safe, considering the adverse side effects and incidence of second cancers of 4%; and the cost, which can exceed $160,000 per year. The editorial by Ashraf Z. Badros, MB, ChB, of the University of Maryland School of Medicine, Baltimore, also points out that pomalidomide and bortezomib (Velcade) are currently being tested in trials of maintenance therapy and both appear to have efficacy in the setting of resistance to lenalidomide. “As myeloma evolves from an ‘incurable’ cancer to a chronic disease, physicians are faced with the task of maximizing available treatments not only to improve survival but also to maintain their patients’ quality of life,” Dr. Badros said.

■

Disclosure: Dr. Palumbo has received honoraria for board membership, consultancy, and speakers bureau activities from Celgene and Janssen Cilag. Dr. McCarthy has received honoria for consultancy and speakers bureau activities from Celgene and Onyx. Dr. Attal has received grants from Celgene and serves on advisory boards for Celgene and Janssen. Dr. Badros has received research grants from Pfizer, AOI, Onyx, Bristol-Myers Squibb, BioInvent, Geron, and Lilly.

References 1. Palumbo A, Hajek R, Delforge M, et al: Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366:1759-1769, 2012. 2. McCarthy PL, Kouros O, Hofmeister CC, et al: Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770-1781, 2012. 3. Attal M, Lauwers-Cances V, Marit G, et al: Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1782-1791, 2012. 4. Badros AZ: Lenalidomide in myeloma. N Engl J Med 366:1836-1838, 2012.

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Technology

Genetic Blueprint continued from page 1

of events that turned the pathway on. The study, published last year in the journal Nature,1 found that 11 different genes involved in the NF-kappaB pathway were altered in at least one tumor sample. In addition, mutations were found in genes that are involved in two cellular processes in normal cell function: RNA processing and protein folding. About half of the multiple myeloma samples sequenced had defects in one or more of these genes, including FAM46C, which had never before been linked to cancer. Another surprising discovery was that a small number of multiple myeloma patients (just 4%) had BRAF V600E gene mutations—the same mutation found in some types of melanoma and colon cancer, which had not previously been associated with the development of multiple myeloma.

Driver vs Passenger Mutations “We learned from this study how to start thinking about the complex analysis of not just seeing that a mutation exists in a tumor but learning to recognize whether a given mutation is likely to be important … because we know that probably the majority of the mutations observed in any individual tumor—the so-called passenger mutations—are not going to be diagnostically important, they are not going to point to good treatment strategies. And so there is a need for approaches to sort out the difference between the driving events—the mistakes that drive cells toward becoming cancerous—and the passenger mutations— genetic alterations that are just along for the ride,” said Dr. Golub. One way to accomplish that goal, said Dr. Golub, is to develop sophisticated algorithms to establish the statistical significance of mutation frequency in a specific gene, a complicated process because the mutation rate is not the same across the various tumor types. Additional analysis of the myeloma samples is also showing a difference in the mutation rates among the subtypes of the cancer. “And we are now discovering that the mutation rate even within a single sample may be different across the genome. We did not appreciate that in our initial study,” said Dr. Golub.

ing cancerous from passenger mutations, thousands of myeloma tumors will be needed for genomic analysis, said Dr. Golub. It may be possible to analyze such a vast number of tumors over the next 2 years, as the cost of genomic sequencing continues to come down. Currently, Dr. Golub is completing the genomic sequencing

of 250 additional multiple myeloma tumors. The next year, said Dr. Golub, will be spent analyzing how the new genes discovered in multiple myeloma contribute to the development of the disease and whether they represent new therapeutic targets for the cancer. “Simply identifying the existence of

a mutation does not make for a treatment of the disease. It’s going to take time for the scientific community to understand what these mutations mean and what they do to the cell, and figure out if there is a therapeutic opportunity. But at least now people know what to work on,” said Dr. Golub. continued on page 26

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The use of the Caris Target Now service, the use or interpretation of any information prov ro ided d as a part art of su such ch ser servic vice, e, and and/or /or th the e sele selecti ction on of any dr drug ug age agents nts is so solel lelyy at at and and wit within hin th the e discretion of the treating physician’s independent medical judgment. The Caris Target Now w services are perf erform ormed ed by Car Caris is Lif Life e Scie Science ncess, a C CLIA LIA-ce -certi rtifi fied ed llabo aborat ratory ory op opera eratin ting g unde underr the U.S. Clinical Laboratory Amendment Act of 1988 and in compliance with all releva v nt U.S. state and n fed f eral rregu ulations. s None of the e Caris r Targe rget Now services have e been n re evie i wed w by the United States Food and Drug Administration. Persons depicted are models and used for illustrative purposes only. y ©201 2 2 Cari r s Life Scien i ces an a d affi ffiliaates. All right h s rese erved. CTN051512AP

The ASCO Post | JUNE 15, 2012

PAGE 26

Technology

Genetic Blueprint continued from page 25

Rare Mutations in Breast Cancer

A large-scale genomics investigation of breast cancer tumors is also revealing genes never before associated with the disease. Using DNA samples taken from 50 patients with luminal (estrogen receptor– and/or progesterone receptor–positive), HER2-negative breast cancer enrolled in a clinical trial and comparing them to the patients’ healthy cells, researchers from the Genome Institute at Washington University in St. Louis found over 1,700 mutations. Most of these mutations were unique to the individual patient and involved single-nucleotide variations, frame shifts, translocations, and deletions. Similar to what has been published in earlier studies, the researchers found two relatively common mutations: PIK3CA, which was present in 50% of the tumors, and TP53, found in about 20% of the tumors. However, mutations in the tumor-suppressor gene MAP3KI, found in about 15% of ERpositive breast cancers, represented a significant new discovery.

not appreciated before, because a lot of sequencing focused on cell lines or in higher-grade breast cancers, so mutations associated with low-grade breast cancers were missed.” Because breast cancer is so common, discovering rare but drug-sensitive gene mutations that occur in as few as even 1% or 2% of all breast cancers is crucial, because those small percentages still translate to between 2,000 and 4,000 patients a year in the United States. Dr. Ellis’ research was presented at last year’s annual meeting of the American Association for Cancer Research.2 This study has been expanded by the Washington University team to

Bradley A. Ozenberger, PhD

their own data sets,” said Bradley A. Ozenberger, PhD, Program Director, The Cancer Genome Atlas. The next phase of total genomic sequencing, said Dr. Ozenberger, is application in the clinic with analyses that match a patient’s specific tumor

Genomic Sequencing of Cancer Cells ■■ Advances in DNA sequencing have enabled faster and less costly decoding of cancer cell genomes and exomes, leading to new discoveries of genes and mutations that trigger cancer-related changes.

■■ In the first large-scale study to compare entire genomes of malignant vs

normal cells, Boston investigators found that 11 different genes involved in the NF-kappaB pathway were altered in at least one tumor sample from 38 patients with multiple myeloma.

■■ Using DNA samples from 50 patients with luminal, HER2-negative breast

cancer, St. Louis researchers found over 1,700 mutations, most of which were unique to the individual patient, but some relatively common (eg, in PIK3CA, TP53, and MAP3KI).

■■ The Cancer Genome Atlas, a joint effort of the National Human Genome

Research Institute and the NCI, is aiming to complete the sequencing of 22 cancer genomes over the next 2 years.

Matthew J. Ellis , MD, PhD

“The MAP3KI suppressor gene was hitherto unknown in breast cancer,” said Matthew J. Ellis, MD, PhD, Professor of Medicine and Chief of Breast Oncology at Washington University, St. Louis, and lead investigator of the study. “MAP3KI is a stress kinase. It becomes activated when cells are responding to stress, including chemotherapeutic stress, and when activated, triggers cell death. The interesting clinical association is that MAP3KImutant tumors are associated with lower-grade histology. It is the opposite of what you see with mutant P53. The significance of this mutation was

77 patients and has documented 3,355 mutations. The complete findings of the genomic analysis of Dr. Ellis’ new study were presented at the ASCO Annual Meeting.3

Making Personalized Medicine a Reality On a national level, The Cancer Genome Atlas (TCGA), a joint effort of the National Human Genome Research Institute and the NCI, is now sequencing the genomes of 22 cancers with the goal of completing its analysis in 2 years. “Although we may not finish evaluating every one of the 500 samples of each of the 22 tumor types by 2014, we will have a large data set that will be available to researchers so they can begin their own investigations and make their own discoveries combined with

biomarkers with targeted therapies to inhibit cancer growth. And genomic analysis of malignant tumor samples is already starting to have an impact in the clinic. Some large cancer institutions are offering genomic testing for certain malignancies, including lung cancer and multiple myeloma, although more needs to be understood before clinicalgrade genomic sequencing becomes standard of care for these patients, said Dr. Golub.

Much to Learn “There is still much to learn about how to interpret the data and learn what aspects of it are actually clinically useful vs just a curiosity,” Dr. Golub said. “That all still needs to be worked out, but I think it is no longer a matter of when genomic sequencing will enter the clinic, because the when is now.

It is going to be a matter of the pace at which it becomes used routinely in clinical research and in routine clinical care,” he added. “Many of the mutations that we are uncovering from genomic sequencing are mysterious, but I think that the first use for some of them will be in predictive and prognostic medicine with respect to standard-of-care drugs” Dr. Ellis commented. “What we may find is that some of the mutations are quite predictive of lack of response to standard therapy. I think that some of these mutations we are uncovering in luminal breast cancer will be resistance markers, probably not only to endocrine therapy but also to chemotherapy.” Because whole-genome sequencing is still a complex process, achieving true personalized medicine for individual patients with cancer is still years away from becoming a reality. In the meantime, “progress will be made in subsets of patients, one mutationdefined cancer subset at a time,” said Dr. Ellis.

■

Disclosure: Dr. Golub is an advisor to Foundation Medicine, Inc., which is developing sequencing-based diagnostic tests for cancer. Drs. Ellis and Ozenberger reported no potential conflicts of interest.

References 1. Chapman MA, Lawrence MS, Keats JJ, et al: Initial genome sequencing and analysis of multiple myeloma. Nature 471:467-472, 2011. 2. Ellis MJ, Ding L, Shen D, et al: Analysis of luminal-type breast cancer by massively parallel sequencing. American Association for Cancer Research 102nd Annual Meeting. Abstract LB-87. Presented April 3, 2011. 3. Ellis, MJ Ding L, Shen D, et al: whole genome sequencing to characterize luminal-type breast cancer, 2012 ASCO Annual Meeting. Abstract 503. Presented June 3, 2012.

Multiple Myeloma Genomics Portal Data from the genomic study of multiple myeloma cells can be accessed through the Multiple Myeloma Genomics Portal at Broadinstitute.org/mmgp/home. Researchers can search, download, and analyze data sets generated by The Cancer Genome Atlas at Tcga-data.nci.nih.gov/tcga.

FOR PATIENTS WITH ADVANCED BCC

IS IT TIME FOR A CHANGE? The first and only FDA-approved Hedgehog pathway inhibitor

Turn the page to see more... Indication Erivedgeâ&#x201E;˘ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS See full prescribing information for complete boxed warning. Erivedge can result in embryo-fetal death or severe birth defects. Verify pregnancy status prior to initiation of Erivedge. Advise male and female patients of these risks. Advise females of the need for contraception and advise males of the potential risk of Erivedge exposure through semen. Please see additional Important Safety Information, including BOXED WARNING, on following page and Brief Summary of Prescribing Information on back.

Simulated image based on locally advanced BCC patient at Week 24. Indication Erivedge™ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

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

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

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

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

TRANSFORM THE TREATMENT OF ADVANCED BCC Erivedge— a unique treatment option • Systemic therapy that targets dysregulated Hedgehog pathway signaling, a known driver of BCC1,2 • One 150-mg capsule a day until disease progression or unacceptable toxicity1 • Erivedge reduced lesions in patients with advanced BCC1 Objective response rates (ORR) by IRF from ERIVANCE1* laBCC (n=63) ORR (95% CI) Complete response

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

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

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

Median response duration (months) (95% CI)

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

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

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

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)

MedDRA Preferred Term2 Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)]. 1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

73858ge_a.indd 3

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

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

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

All aBCC1 Patients (N = 138) All Grades 3 Grade 3 Grade 4 (%) (%) (%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

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

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

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

ERIVEDGE™ [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832300

4/23/12 3:27 PM

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American Society of Breast Surgeons 13th Annual Meeting

Postsurgical Local Breast Cancer Therapies Compared in Two Large Studies By Caroline Helwick

study presented at the 13th Annual Meeting of the American Society of Breast Surgeons suggested that accelerated partial-breast irradiation (APBI) using brachytherapy might control the tumor bed better than whole-breast irradiation (WBI), while another study suggested that radiofrequency ablation might effectively substitute for radiation therapy in some patients with breast cancer. The studies were highlighted at a press briefing during the meeting, which was held May 2–6 in Phoenix.

Peter D. Beitsch, MD

In a study of 1,444 patients with early breast cancer in the MammoSite Registry Trial,1 rates of local recurrence 60 months after lumpectomy were 3.5%, and only 1.1% were considered tumor-bed failures, reported Peter D. Beitsch, MD, a surgical oncologist who directs the Dallas Breast Center. Specifically, 50 patients treated who underwent accelerated partialbreast irradiation (3.5%) developed an ipsilateral tumor recurrence, 14 (1.1%) at the initial tumor site and 36 (2.6%) elsewhere in the breast. Of these recurrences, 28% were in the tumor bed and 72% occurred elsewhere. This was not a controlled study, but Dr. Beitsch noted that in historical controls, whole-breast irradiation has been associated with recurrence rates in the tumor bed of 2% to 7.1%—about double the rates of recurrences elsewhere in the breast (1.9% to 3.8%). Proportionally, 69% of these are tumor bed recurrences and 31% recur elsewhere. This is essentially the reverse of what investigators found in the current MammoSite Registry study, Dr. Beitsch pointed out. “These data suggest that although tumor control in the breast appears to be similar for APBI and WBI, disease control at the initial tumor site may be better with APBI,” he commented, adding, “I believe APBI improves care.

My feeling is that there is something unique in its ability to control the tumor bed.”

Conflicting Results The findings of the MammoSite Registry Trial contrast with those recently reported from investigators at The University of Texas MD Anderson Cancer Center,2 which was a larger retrospective analysis of nearly 93,000 women in a Medicare billing claims database, 7% of whom had accelerated partial-breast irradiation and 93%, mastectomy. It found accelerated partial-breast irradiation to be associated with a higher risk for complications and double the rate of subsequent mastectomy, compared with wholebreast irradiation. Dr. Beitsch commented on the discrepant findings, noting that it is unclear why women subsequently underwent mastectomies in the MD Anderson study, and that it was not necessarily because of local recurrences. “We radiate the breast to control undetectable cancer cells left behind around the lumpectomy cavity. Common sense would say internally

Misti H. Wilson, MD

therapy as a way to rid the cavity of residual disease.3 The study, one of the first published long-term studies to examine postlumpectomy outcomes, was reported by Misti H. Wilson, MD, of the University of Arkansas for Medical Sciences, Little Rock. Radiofrequency ablation can create an additional disease-free zone around the cavity, and can extend this zone sufficiently to eliminate the need for repeat surgery to achieve clear tumor margins. Some 20% to 75% of patients required second or even third surgeries to accomplish this. “We hypothesized that excision followed by [radiofrequency ablation] to extend the margin by 1 cm may decrease the reexcision rate and

Therapy after Breast Cancer Surgery ■■ The MammoSite Registry Trial showed that early breast cancer had a low

likelihood of tumor bed recurrence when treated with accelerated partialbreast irradiation, which appeared comparable to outcomes with wholebreast irradiation.

■■ These results contradicted findings from a much larger retrospective

analysis, in which accelerated partial-breast irradiation was associated with a higher risk for complications and double the rate of subsequent mastectomy, vs whole-breast irradiation.

■■ A long-term study of radiofrequency ablation administered to the

lumpectomy site showed the technique to be an effective alternative to postsurgical external-beam radiation therapy, comparably preventing local tumor recurrence.

targeted radiation would be the best method to kill these cells,” he suggested. “We now have strong data to support that, and we showed the complication rate is very low from this form of therapy.”

Radiofrequency Ablation Prevents Local Recurrence In another study presented at the meeting, investigators suggested that radiofrequency ablation of the lumpectomy site may be an effective alternative to external-beam radiation

provide therapeutic benefit similar to [that of external-beam radiotherapy] at the time of the initial operation,” Dr. Wilson said. Because of the ablation-extended margins, only patients with grossly positive margins on pathology or residual calcifications on postoperative mammography would require additional excision of the tumor bed, she explained. The study included 73 patients with tumors ≤ 3.0 cm and clinically negative lymph nodes who under-

went lumpectomy and excision followed by radiofrequency ablation without external-beam radiotherapy. Pathology reports indicated that 19 patients had close or focally positive margins, and 16 (84%) were spared reexcision after undergoing initial excision and radiofrequency ablation. Only 3 patients of 73 (4%) required a second surgery, she reported. At a median follow-up of 55 months, there was one local recurrence in the tumor bed (1.7%) and three recurrences elsewhere. The recurrence rate for lumpectomy with radiation is 1% per year for the first 5 years, then about 0.5% thereafter, which suggests that the excision followed by radiofrequency ablation technique is as protective as radiotherapy, Dr. Wilson said.

V. Suzanne Klimberg, MD

“Without the side effects of radiation, [radiofrequency ablation] is an extremely appealing choice. The ablated tissue remains in the breast, so less breast mass is lost and post-treatment tissue shrinkage is not a problem,” she said. “The cosmetic results are excellent. Often, you can barely tell the patient has had surgery.” The study found good to excellent cosmesis in 90% of patients. Principal investigator V. Suzanne Klimberg, MD, the Muriel Balsom Chair in Surgical Oncology at the University of Arkansas for Medical Sciences, and President of the American Society of Breast Surgeons, noted, “for patients in rural areas, radiotherapy—the standard of care following lumpectomy surgery—simply isn’t an option if a therapy center is not located nearby. Today, these patients have no choice but mastectomy.” Another advantage of excision followed by radiofrequency ablation is that patients receive complete treatment before discharge. continued on page 28

The ASCO Post | JUNE 15, 2012

PAGE 28

American Society of Breast Surgeons 13th Annual Meeting

Epidemiology, Diagnosis, and Treatment of Breast Cancer Explored at the American Society of Breast Surgeons Meeting By Caroline Helwick

ver 1,300 breast surgeons attended the 13th Annual Meeting of the American Society of Breast Surgeons, held May 2–6 in Phoenix. Presentations included investigations on recurrence after lumpectomy, gender differences in breast cancer, and the potential role of infrared thermography in diagnosing the disease.

ally, there has been reluctance to use breast conservation for women with locally advanced cancers, especially in women with significant tumor

remaining after presurgical chemotherapy,” said lead author Elizabeth Cureton, MD. “We wanted to evaluate the local recurrence rates from the

CD30-directed therapy

Lumpectomy for High-risk Locally Advanced Breast Cancer High-risk breast tumors that respond well to neoadjuvant chemotherapy can be safely treated with lumpectomy, according to University of California, San Francisco, researchers, who determined that tumor biology dictates recurrence in this group, and that local recurrence was low regardless of surgical procedure.1 See Page 90 “ Tr a d i t i o n -

Postsurgical Local Therapies continued from page 27

Based on these results, excision followed by radiofrequency ablation is being examined in the multicenter ABLATE (Radiofrequency Ablation after Breast Lumpectomy Added to Extend Intraoperative Margins) trial.

■

Disclosure: Drs. Beitsch, Wilson, and Klimberg reported no potential conflicts of interest. The study by Wilson et al was funded by grants from angioDynamics, the Fashion Footwear Association of New York, and ZVC.

References 1. Beitsch P, Vicini F, Whitworth P, et al: Improved tumor bed control with MammoSite® accelerated partial breast irradiation. American Society of Breast Surgeons Annual Meeting. Abstract 58. Presented May 4, 2012. 2. Smith GL, Xu Y, Buchholz TA, et al: Association between treatment with brachytherapy vs whole-breast irradiation and subsequent mastectomy, complications, and survival among older women with invasive breast cancer. JAMA 307:1827-1837, 2012. 3. Wilson M, Korourian S, Boneti C, et al: Long-term results of excision followed by radiofrequency ablation as the sole local therapy for breast cancer. American Society of Breast Surgeons Annual Meeting. Abstract 136. Presented May 4, 2012.

I-SPY TRIAL, a multicenter neoadjuvant study, because we know that patients and physicians are often afraid to use breast-conserving surgery, be-

Important Safety Information BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS™ (brentuximab vedotin).

Contraindication:

Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.

Warnings and Precautions:

• Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly. • Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted. • Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. • Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.

CT SCANS confirmed responses in relapsed patients Mx8000 Ex: CT080100137 Se: 8002/4 Im: 130/208 Ax: 1623.9 120.0 kV 280.0 mA 1.3 mm/-0.5:1 Tilt: 0.0 0.0s Lin:DCM/ Lin:DCM/id:ID W:200 L25

ASCOPost.com | JUNE 15, 2012

PAGE 29

American Society of Breast Surgeons 13th Annual Meeting cause they believe that more surgery will be better for an aggressive tumor,” she said. “But this was not the case,” she reported. “The I-SPY TRIAL has shown that tumor characteristics such as gene expression, advanced stage, and poor response to neoadjuvant therapy itself were the major predictors of cancer

recurrence, and more surgery is not, therefore, necessarily better.” The report, part of the I-SPY 1 trial, examined 206 patients, 90% of whom were classified as high-risk on the basis of the 70-gene expression profile. After neoajduvant chemotherapy, 90 women underwent lumpectomy (78 with radiation) and 116 had mastecto-

my (92 with radiation). In the overall group, after 3.9 years median followup, 45 (22%) had distant recurrences and 14 (7%) had local recurrences. Of the distant recurrence group, 10 also had local recurrences; only 4 of the 10 with local recurrences had no distant recurrences during the study. Tumor size and lymph node status

After multiple failures,

single-agent response Indicated for the treatment of:

Important Safety Information (continued)

• Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

HL: 73% objective response rate (ORR) (95% CI: 65%-83%)

32%

complete remission (95% CI: 23%-42%)1

40%

partial remission (95% CI: 32%-49%)1

N = 102, 15-77 years (median: 31 years)1

• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1

sALCL: 86% ORR (95% CI: 77%-95%)

57%

complete remission (95% CI: 44%-70%)1

29%

partial remission (95% CI: 18%-41%)1

N = 58, 14-76 years (median: 52 years)1

The indications for ADCETRIS™ (brentuximab vedotin) are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

2011 August 19 Acq Tm: 14:05:52

Adverse Reactions:

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

Drug Interactions:

Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

512x512 B

A R

• Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS™ (brentuximab vedotin)– treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with newonset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. • Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. • Use in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

L Vp

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; 2012. US/BVP/2011/0104f

855.4SEAGEN (855.473.2436) SeaGenSecure.com

at diagnosis and at the time of surgery were significantly associated with recurrence. Women with poor response to neoadjuvant chemotherapy were also more likely to have recurrent disease. By treatment type, local recurrence rates were low in both the lumpectocontinued on page 30

The ASCO Post | JUNE 15, 2012

PAGE 30

American Society of Breast Surgeons 13th Annual Meeting Epidemiology, Diagnosis, and Treatment of Breast Cancer continued from page 29

my group as well as the mastectomy group. These data were also no different in the setting of an excellent response to neoadjuvant chemotherapy or in the setting of residual disease.

Co-investigator Laura Esserman, MD, Co-leader of the Breast Oncology Program at UCSF Helen Diller Family Comprehensive Cancer Center, emphasized that distant metastatic disease, not local recurrence, is the major risk for this patient population. She noted that the I-SPY 1 data have shown that excellent tumor re-

Five-year local/distant recurrencefree survival was 79% with breastconserving surgery and 72% with mastectomy. Surgical treatment was not randomized, and more patients with extensive disease were treated with mastectomy. Importantly, with multimodal therapy, local recurrence was not a significant problem.

Laura Esserman, MD

Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS™ (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

Contraindications Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia

Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

ADCETRIS™ (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactions In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Effect of other drugs on ADCETRIS

CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in specific populations Pregnancy

Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers

It is not known whether brentuximab vedotin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Renal impairment

The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment

The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Dosage and administration

Use in pregnancy

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

General dosing information

Dose modification

Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

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

US/BVP/2011/0150b

sponse to neoadjuvant chemotherapy is a strong predictor that the disease will not recur locally. “Therefore, women who respond well to presurgical chemotherapy may not require other aggressive local treatment and may do well with lumpectomy instead of mastectomy,” she said. Dr. Cureton added that if radiation is indicated, lumpectomy should be attempted as it carries less risk for complications than when paired with mastectomy.

Male Breast Cancer Is More Fatal An analysis of male breast cancers from the National Cancer Data Base (NCDB) found that men have a significantly lower breast cancer survival rate than women, particularly for earlystage disease.2 This is the largest study ever conducted on gender differences in breast cancer. The study compared 13,457 male and 1,439,866 female breast cancer

Notable Findings from the 2012 ASBS Meeting ■■ High-risk breast tumors that

respond well to neoadjuvant chemotherapy can be safely treated with lumpectomy rather than mastectomy, according to data showing that biology, not surgical procedure, dictates recurrence in this group.

■■ A study on gender differences

in breast cancer found that men have a significantly lower breast cancer survival rate than women, particularly for earlystage disease.

■■ Infrared thermography is not a

reliable breast cancer screening tool, according to a study of women with abnormal results on mammography, ultrasound, or MRI who were scanned using a thermography system, with results compared to pathology findings.

ASCOPost.com | JUNE 15, 2012

PAGE 31

American Society of Breast Surgeons 13th Annual Meeting cases entered from 1998 to 2007 in the NCDB. The study found that 5-year survival rates were 83% for women compared to 74% for men (P < .0001), reported Jon Greif, DO, FACS, of the Carol Ann Read

Jon Greif, DO, FACS

Breast Health Center at Alta Bates Summit Medical Center in Oakland, California. The differences were most pronounced for early-stage disease (0, I, and II). There was little difference in survival for stages III and IV. Men presented with significantly larger tumors (median, 20 vs 15 mm), more frequent lymph node involvement (42% vs 33%), and more distant metastases (4% vs 3%). Differences in survival, in tumor size, and in regional and systemic involvement may be attributed to a lack of awareness of breast cancer in men and therefore delay in diagnosis. Among male breast cancers, 88.3% were estrogen receptor–positive, yet only 41% of men were recorded as having been offered or taken hormonal therapy. “If these numbers are accurate, more liberal

use of estrogen-blocking medication such as tamoxifen might improve outcomes,” Dr. Greif suggested.

Infrared Thermography Not a Useful Breast Cancer Screening Tool Infrared thermography, a non– radiation-based imaging modality that measures thermal abnormalities in breast tissue, is not a reliable breast cancer screening tool, according to a study conducted at the Comprehensive Breast Cancer at Bryn Mawr Hospital, Bryn Mawr, Pennsylvania.3 The study examined 178 women with abnormal results on mammography, ultrasound, or magnetic resonance imaging (MRI) who underwent minimally invasive breast biopsy. The affected breasts were

Cara Marie Guilfoyle, MD

scanned using the No Touch Breast Scan (NTBS) system prior to biopsy, and the results were compared with pathology findings. “The NTBS high-specificity mode missed 50% of all cancers, while the high-sensitivity mode

delivered an unacceptable number of false-positives,” reported Cara Marie Guilfoyle, MD. Initially, patients were evaluated using a high-specificity computerized analysis setting, which attempts to minimize the number of false-positive cancer results. Because this modality failed to detect many patients with positive pathology findings, the researchers switched to the highsensitivity mode to optimize cancer detection from that point on. Scans from the early part of the study were reanalyzed using the high-sensitivity mode and both sets of results were reported. In the high-specificity mode, 52 patients were found to have cancer, and infrared imaging failed to detect 26 cases (sensitivity 50%). Of 132 negative biopsies, 42 had positive findings on infrared (specificity 67%). The positive predictive value of infrared thermography was only 37%, and negative predictive value was 77%. In the high-sensitivity mode, infrared thermography correctly identified 44 of the 46 positive breast biopsies (sensitivity 87%). Of the 116 negative biopsies, 61 were incorrectly identified as positive (specificity 48%). The positive predictive value of infrared thermography was 40%, and the negative predictive value was 90%. Lead researcher Andrea Barrio, MD, commented, “These findings fail to point out a useful role for infrared thermography in our patient

Andrea Barrio, MD

population and, therefore, show that infrared thermography cannot be used as a successful adjunct to mammography. For screening, mammography remains the gold standard.”

■

Disclosure: Drs. Cureton, Esserman, Greif, Guilfoyle, and Barrio reported no potential conflicts of interest.

References 1. Cureton E, Alvarado MD, Yau C, et al: Biology, not choice of mastectomy versus lumpectomy, dictates recurrence in high-risk breast cancer. 2012 American Society of Breast Surgeons. Abstract 260. Presented May 4, 2012. 2. Greif J, Pezzi C, Klimberg S, et al: Gender differences in breast cancer: Analysis of 13,000 male breast cancers from the National Cancer Data Base. 2012 American Society of Breast Surgeons. Abstract 104. Presented May 4, 2012. 3. Guilfoyle CM, Collett AE, Christoudias MK, et al: Does infrared thermography predict the presence of malignancy in patients with suspicious radiologic breast abnormalities? 2012 American Society of Breast Surgeons. Abstract 92. Presented May 4, 2012.

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The ASCO Post | JUNE 15, 2012

PAGE 34

2012 AACR Annual Meeting Pediatric Oncology

Risk Stratification and Targeted Therapy, Abetted by Collaboration, Improve Outcomes for Children with Cancer By Charlotte Bath

utcomes for children with cancer have “improved over the course of the years incrementally, mostly not from the development of new drugs, because virtually all the drugs that we use now in leukemia were available in the 1970s. It is really through better understanding of the heterogeneity of the disease and therefore more appropriate risk stratification, giving more intensive therapy (and, occasionally, targeted therapy for patients at highest risk of relapse), and wherever possible, modifying therapy to reduce the side effects of therapy for patients who have a very good prognosis,” 2011–2012 ASCO President Michael P. Link, MD, told participants at the AACR/ASCO Presidential Symposium presented during the American Association for Cancer Research (AACR) Annual Meeting.1 The symposium was co-chaired by Dr. Link and 2011–2012 AACR President Judy E. Garber, MD, MPH. “This is the path for improving the outcome in children with acute lymphoblastic leukemia (ALL)”—stratifying risk according to molecular classification and basing our therapeutic decisions on these classifications. “It is certainly true in neuroblastoma … and acute myeloid leukemia (AML) as well,” said Dr. Link, who is Professor of Pediatrics, Division of Pediatric Hematology/Oncology at Stanford University School of Medicine in Palo Alto, California. Many of the lessons learned from treating children with cancer can also be applied to treating

tion, through the understanding of multidisciplinary care,” he said in an interview with The ASCO Post. “Collaboration is going to become more important than ever as tumor classifications become more precise in defining subsets of common cancers.”

‘One of the Great Success Stories’ “ALL is the most common malignancy in the pediatric population, and [its treatment] is really one of the great success stories in all of cancer therapies,” noted James R. Downing, MD, Scientific Director and Deputy Director of St. Jude Children’s Research Hospital in Memphis. “Today, if a child comes into the hospital with ALL, there is a greater than a 90% chance of survival,” Dr. Downing said.

James R. Downing, MD

“What is responsible for that? It really is the effective use of combination chemotherapy, figuring out how to use it, how to deliver intensive therapy, how to add maintenance therapy, and supportive care. A major influence, though, has been risk stratification into

Pediatric cancer has been the poster child for what can be accomplished through collaboration, through the understanding of multidisciplinary care. — Michael P. Link, MD

adults, he added. Progress in treating childhood cancers owes a lot to “a tremendous willingness to collaborate and to share,” Dr. Link acknowledged. “Pediatric cancer has been the poster child for what can be accomplished through collabora-

genetic subgroups and then, based on those, adjusting the intensity of therapy for those patients,” Dr. Downing explained. “Over the past 5 years, using genome-wide approaches,” Dr. Downing said, “we have made a number of

Genomics in Pediatric Cancer ■■ Advances in the management of pediatric cancers are largely attributable to risk stratification by molecular classification and therapies based on these classifications, as well as extensive collaborations in research and multidisciplinary care.

■■ The Pediatric Cancer Genome Project is generating prognostic markers and therapeutic targets through whole-genome sequencing and the identification of disease-specific mutations.

■■ The Total Therapy protocols at St. Jude Children’s Research Hospital

use immunologic and molecular assays to measure the level of minimal residual disease after induction of remission and increase the precision of risk-directed therapy.

■■ Nearly 80% of childhood cancer survivors experience long-term toxicities

from therapy, and 40% have severe or life-threatening long-term treatment-related complications; efforts to reduce morbidity and mortality in this population are under investigation.

discoveries, as have a number of other laboratories around the world, that have provided new diagnostic and prognostic markers. What we showed was that 60% of ALL patients actually had genetic lesions in genes that regulate normal B-cell development.” These mutations appear with very high frequency in high-risk leukemias, and studies are being developed to look at how to therapeutically target them.

Pediatric Cancer Genome Project In 2010, St. Jude Children’s Research Hospital initiated the Pediatric Cancer Genome Project as a joint project with Washington University School of Medicine in St. Louis. The goal was to sequence 600 diagnostic and 600 germline samples over a 3-year period, “to develop a foundational effort that would provide a database for all investigators working in pediatric or adult cancer,” Dr. Downing said. “The frequency of mutations across the cancer types varies markedly,” Dr. Downing reported. “There are particular pediatric cancers, such as osteosarcoma, that have more mutations than seen in almost any adult cancer. There are other pediatric cancers, like infant acute lymphoblastic leukemia, that have exceedingly few mutations.” Data on these genomes can be explored at the project’s website: explore .pediatriccancergenomeproject.org. “We are generating prognostic markers, … and there are therapeutic targets that are coming out of this,” Dr. Downing noted. “But there are a num-

ber of lessons that we need to keep in mind. First, whole-genome sequencing will be required to really identify all mutations. Clonal heterogeneity is an issue. We are going to need sensitive methods to detect the rare clones. Relapse often arises from that rare clone being selected in response to chemotherapy,” he said. Even with whole-genome sequencing, much of the “large landscape of the genome remains uncharacterized,” Dr. Downing said. “There is going to be lots of work over the next several years to really look at those areas of the genome, to decipher exactly what mutations mean, and how they impact and transform the phenotype.”

Total Therapy Trials To minimize morbidities and improve quality of life for children being treated for ALL, the Total Therapy XV protocol at St. Jude uses immunologic and molecular assays to measure the level of minimal residual disease after induction of remission to increase the precision of risk-directed therapy. “Final risk classifications are really based on the response to the treatment,” Ching-Hon Pui, MD, said. “We know the depth of remission affects the ultimate treatment outcome.” Dr. Pui is Chair of the Department of Oncology and Co-Leader of the Hematological Malignancies Program at St. Jude. With the whole-genome analysis, 100% of the ALL population can now be classified into prognostically and therapeutically relevant subgroups, Dr. Pui said. “We found it is important to individualize the drug dosages based

ASCOPost.com | JUNE 15, 2012

PAGE 35

2012 AACR Annual Meeting on pharmacokinetics, pharmacogenetics, and pharmacodynamics,” he noted. Although prophylactic cranial irradiation had been standard treatment for high-risk leukemia, “up to 20% of patients will eventually develop radiation-induced second cancers, many brain tumors, after 20 years or more,” Dr. Pui said. “So in Total Therapy XV, we totally omitted the use of prophylactic cranial irradiation regardless of the presenting features.” Triple intrathecal chemotherapy with methotrexate, hydrocortisone, and cytarabine was used, with patients at high risk of CNS relapse receiving more intensified intrathecal therapy, Dr. Pui explained. The protocol also limited the use of cyclophosphamide because of its negative effect on fertility, and of anthracyline because of its link to cardiomyopathy, and omitted etoposide entirely because of safety concerns.

at the price of a high morbidity,” according to Smita Bhatia, MD, MPH, Director of the Center for Cancer Survivorship and of Outcomes Research at the City of Hope in Duarte, California. Data from survivors followed for 30 years show that “close to 80% are going to have long-term toxicity, and

close to 40% of them have severe or life-threatening long-term treatmentrelated complications,” she said. These conditions include steroid-related osteonecrosis; radiation-related musculoskeletal deformities, lung cancer, breast cancer, brain tumors, and pulmonary dysfunction; and chemother-

apy-related leukemia and cardiac complications. In the 1980s, when these late events and complications became apparent, “we stopped throwing the kitchen sink at our patients and started tailoring therapy to risk factors,” Dr. Bhatia said. continued on page 36

Throughout the course of castration-resistant prostate cancer (CRPC)

T HE ROOT OF T U M OR G ROWTH A N D R O G E N R E C E P TO R S I G N A L I N G

Ching-Hon Pui, MD

“Using this approach,” Dr. Pui said, “we are achieving 10-year event-free survival of 86% and 10-year survival of 91%,” but 2% of patients develop isolated CNS relapse. Following salvage therapy, patients with CNS relapse “have all been in second remission for 7 to 10 years. In all likelihood, they are cured. In the past 12 years at St. Jude, we have not lost a single patient from isolated CNS relapse although none of the patients received prophylatic cranial irradiation,” Dr. Pui said. Under a new protocol—the Total Therapy Study XVI—triple intrathecal therapy is used upfront (and intensified for high-risk patients who can be clearly identified), because based on the results of Total Therapy XV, patients at high risk of CNS relapse can be identified, Dr. Pui said. “In the past 5 years, we have treated over 260 patients and we have not had a single patient with CNS relapse,” he added. “So we can push event-free survival to 94% today.”

Long-term Survival Issues “One in 900 individuals is a childhood cancer survivor, but this comes

Despite low or undetectable levels of testosterone, androgen receptor signaling persists. 1,2

Androgen receptor signaling promotes tumor growth and drives prostate cancer progression. 1,3,4

Visit www.TargetAR.com to learn more. REFERENCES: 1. Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Nat Clin Pract Urol. 2009;6:76-85. 2. Chen Y, Clegg NJ, Scher HI. Lancet Oncol. 2009;10:981-991. 3. Knudsen KE, Scher HI. Clin Cancer Res. 2009;15:4792-4798. 4. Sawyers CJ, Tran C, Wongvipat J, et al. Poster presented at: ASCO 2007 Prostate Cancer Symposium; February 22-24, 2007; Miami, FL.

The ASCO Post | JUNE 15, 2012

PAGE 36

2012 AACR Annual Meeting Risk Stratification and Targeted Therapy continued from page 35

“In the 1990s, we started understanding the relationship of dose of radiation and chemotherapeutic agents to these late effects, and we started initiating efforts to track and educate our survivors,” she continued. The emphasis is now on the etiology and pathogenesis of these treatment-related adverse events, identifying patients at highest risk, and intervening to reduce morbidity and mortality.

dergoing autologous transplant for lymphoma. In patients who would eventually develop therapy-related leukemia, we saw changes in gene expression that are associated with the development of leukemia, but they could be identified as early as the time the peripheral blood stem cells were procured, Dr. Bhatia said. “Then we

Reducing Morbidity and Mortality “We need to start working on interventions to reduce morbidity and mortality,” Dr. Bhatia said. “There is a clear dose-response relationship—even at low doses—between anthracycline and cardiomyopathy,” she noted, that “is begging for a targeted intervention

In the 1990s, we started understanding the relationship of dose of radiation and chemotherapeutic agents to these late effects, and we started initiating efforts to track and educate our survivors. —Smita Bhatia, MD, MPH

Smita Bhatia, MD, MPH

Second Cancers Second cancers can result from the combination of inefficient detoxification of genotoxic insults that can be caused by chemotherapy and inefficient repair of DNA damaged by these agents, Dr. Bhatia explained. A small proof-of-principle study found that “patients either repair their DNA damage or have apoptosis. If there is DNA repair, which is complete, you have recovery. If it is really bad DNA repair, you have apoptosis, but sometimes in between you develop therapy-related leukemia,” she said. Another study looked at geneexpression changes in CD34-positive cells among patients who were un-

looked at the time of development of therapy-related leukemia and, again, … the changes in gene expression associated with the development of therapy-related leukemia were present in the bone marrow stem cells of those patients,” she explained. “This speaks to the personalized therapy that Dr. Pui is talking about,” Dr. Bhatia noted, “because if we can discern that at the time of transplant that a group of patients is at a very high risk of therapy-related leukemia, instead of offering them autologous transplant, we can offer them allogeneic transplant or other methods of treatment.” In a study of genomic instability, as measured by telomere length, “we found that patients who eventually developed therapy-related leukemia showed attrition in telomere lengths, as opposed to those who eventually did not develop therapy-related leukemia,” Dr. Bhatia reported.

for those at increased risk of cardiomyopathy.” One approach being tried is the use of beta-blockers to reduce the risk of anthracycline-related congestive heart failure. “We know clearly that radiation for unrelated cancer increases the risk of breast cancer. Among girls who received radiation, by the time they are 40 years of age, 20% of them are going to develop breast cancer,” Dr. Bhatia said. “We have developed a low-dose tamoxifen trial that we hope will reduce the risk of radiation-related breast cancer.” The risk of adverse outcomes with therapeutic exposures is modified by the patient’s age and gender, viral infections, lifestyle exposures, and genetic predisposition. “These factors can be used to identify those who have the highest risk of developing adverse outcomes. We can modify our therapies, provide personalized

therapies, or screen those at highest risk,” she concluded.

‘Boatload’ of Information The future practice of oncology and truly personalized medicine will “not only have to consider the tumor genome, but will have to consider the host genome as well,” taking into account a “boatload” of information, Dr. Link said. “Sophisticated informatics will be crucial if we are going to be able to utilize all of this information to deliver personalized medicine” while continuing to take into account patient needs and desires, he noted. There are also implications for clinical trials. “We need highly annotated tissues,” Dr. Link said. “We can identify very small subsets of patients within a cancer type that are better defined by sequencing, but these smaller subgroups make robust clinical trials much more difficult to accomplish. We need broader trials. In pediatrics, international collaboration is the rule in order to recruit sufficient numbers of patients. We need new regulatory considerations for licensing new agents. We need novel endpoints,” he added. “And we need incentives for developing agents that will be applicable for a diminished target population.”

■

Disclosure: Drs. Link, Bhatia, Downing, and Pui reported no potential conflicts of interest.

Reference 1. Pediatric Cancer in the Age of Genomics—Lessons from Our Children. American Association for Cancer Research Annual Meeting. AACR/ASCO Presidential Symposium. Presented April 2, 2012.

Cancer Survivors Stand Up, Give Thanks, and Give Back By Charlotte Bath

“I

have me back,” is how breast cancer survivor Jeanette Daniel of Memphis described her life after being treated on a clinical trial at Vanderbilt-Ingram Cancer Center in Nashville. Being conducted by the Stand Up To Cancer P13K Dream Team, whose leader discovered the PI3K pathway, the trial combines letrozole with the PI3K inhibitor BKM120 or the PI3K/ mTOR inhibitor BEZ235. Aberrant activation of the P13K pathway has been associated with several malignancies, including breast, ovarian, and endometrial cancer. Ms. Daniel spoke

at the Annual Meeting of Stand Up To Cancer’s scientific partner, the American Association for Cancer Research (AACR).1 Ms. Daniel was diagnosed with stage IIIA breast cancer in 2006, and despite 2 years of radiation and chemotherapy and six different protocols, the cancer progressed and invaded her spine, hips, skull, and ribs. She could no longer go to work and had to use a pain pump. By early 2011, she was told “in about 6 months, the cancer would just use me up,” she said. “Then we found

a study,” she continued, and instead of being used up, “was lifted up and just swept along with incredible out-ofthe-box thinkers.” Several months ago, Ms. Daniel was told “there is no evidence of active disease in your body,” she reported. “Doing what you are doing is keeping me alive,” she told the AACR meeting participants. “I owe you the genuine debt of my life.” While scientific presentations and research reports dominated the AACR Annual Meeting, Ms. Daniel was not the only cancer survivor to share her

personal experiences. Several poster presentations also related to cancer survivorship and advocacy.

Helping the Homeless “Street Smarts” is a cancer education and outreach program to provide breast cancer screening and follow-up for homeless women in Birmingham, Alabama. The program was created by C ynthia Ryan, PhD, following a yearlong immersion in the homeless community for an article about cancer among the homeless for the fall 2010 iscontinued on page 37

ASCOPost.com | JUNE 15, 2012

PAGE 37

2012 AACR Annual Meeting Cancer Survivors Give Back continued from page 36

sue of the AACR consumer publication CR (now known as Cancer Today).2 Dr. Ryan is Associate Professor, Department of English, University of Alabama at Birmingham, and a breast cancer survivor. “The many appeals for women to have their breasts examined and to be aware of these things don’t work for this population, because the prospect of being sick and dying is often not the most pressing fear in their lives,” Dr. Ryan explained in an interview with The ASCO Post.

Cynthia Ryan, PhD

“Findings from a focus group consisting of homeless women diagnosed with stage IV breast cancer revealed competing values (poor self-esteem and body image and negative encounters with the health-care system) preventing individuals in this population from seeking diagnosis or treatment for cancer, even when options are available free-of-charge. Street Smarts brings together members of this underserved community for a day of pampering while educating them about breast cancer screening and health-care alternatives,” Dr. Ryan reported in her poster presentation.3 The pampering includes treating the women to lunch, facials, manicures, and haircuts. Breast cancer survivors from the streets assist in the breast education sessions and serve as mentors for the participants. “The women leave with a tote bag displaying a message that these women have devised,” Dr. Ryan said. That message is, “Be street smart and survive.” The bag is filled with personal hygiene products, and for these homeless women, the bag itself is a “big deal,” Dr. Ryan noted. Street Smarts is funded in partnership with the Susan G. Komen for the Cure North Central Alabama Affiliate.

Taking It to the Streets The first program was conducted at a church, and although oncology nurses were present, “we did not of-

fer screening because many of these women would not have shown up,” Dr. Ryan said. To recruit participants, “we took to the streets,” she continued. “We went into the parks. I got in front of them at the mission church where I had originally met members of the local homeless population.” Nearly 100 women did show up for

the first program. Dr. Ryan reported that several women raised their hands and asked where they could go for screening. “We did not expect that,” she said. “They were attentive. They were excited. Someone was paying attention to them.” Screening will be part of a second session scheduled for June at the county hospital, Cooper Green Mercy

Hospital. The women will also be registered at the county hospital when this occurs so that they will then have the return services if they need them, Dr. Ryan reported. “If they are in the system at Cooper Green, then we are going to know if they followed up, if they come back. Some of them will

AMG 386: Phase III Clinical Trials in Ovarian Cancer

continued on page 38

Trials Now Enrolling

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

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

Primary Endpoint: • Progression-free survival (PFS)

Primary Endpoint: • Progression-free ee survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

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

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

AMG 386 IV QW + Paclitaxel IV QW (3 on/1 off)

ENDPOINTS Primary

PFS Key Secondary

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

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

AMG 386 IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

AMG 386 IV QW Monotherapy

Primary

PFS

2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

ENDPOINTS

Placebo IV QW Monotherapy

Key Secondary

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

AMG 386 is an investigational agent that has not been approved by the FDA for the use under investigation for this trial.

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

AMG 386 is an investigatio i tigational agent that at has not been approved ed by the FDA for the use se underr investigatio tigation forr this ttrrial.

For Additional Informat Information on: • Amgen Call Center: (866) 57-AMGEN • www w.Amgen .AmgenT Trials.com T rials.com (20101129) • www.ClinicalTrials.gov Trials.gov T rials.gov (NCT01493505)

The ASCO Post | JUNE 15, 2012

PAGE 38

European Lung Cancer Conference Thoracic Oncology

Study Validates Prognostic Role of Tumor Lymphocytic Infiltration in Resectable Non–Small Cell Lung Cancer

he benefit from platinum-based adjuvant chemotherapy in non– small cell lung cancer (NSCLC) was demonstrated in four randomized trials (International Adjuvant Lung Cancer Trial [IALT], Canadian JBR.10 trial, Cancer and See Page 90 Leukemia Group B [CALGB] 9633 trial, and Adjuvant Navelbine International Trialist Association [ANITA] trial).1-4 Central histopathologic review by one or two specialized pathologists on 1,587 NSCLC cases showed the following histology distribution: 624 adenocarcinoma, 727 squamous cell carcinomas, and 236 other types of NSCLC. Concurrently with histology, the LACE-Bio team assessed the presence of lymphocytic infiltration, which has been shown as a borderline favorable prognostic factor on overall survival in the IALT study. Therefore, the LACEBio group performed a validation of the results concerning the prognostic role of lymphocytic infiltration on the ANITA, JBR.10, and CALGB 9633 trials. The study was presented by Elisabeth Brambilla, MD, PhD, of Grenoble Uni-

versity Hospital, Grenoble, France, at the 3rd European Lung Cancer Conference.5

tion of lymphocytic infiltration with other covariables. Since there was no evidence of a different prognostic role in the chemotherapy and control arms in the IALT study, the prognostic values were studied for validation in all patients with adjustment for the treatment arm. Prognostic analyses were performed with Cox models stratified by studies and adjusted for treatment, sex, age, performance status, type of

NSCLC (P =.001). No correlation was found with the other covariates. Intense lymphocytic infiltration was correlated with longer overall survival (P =.01) and disease-free survival (P = .0005) without heterogeneity among trials. The authors concluded that the results are consistent across all trials in the validation set. Intense lymphocytic infiltration, found in only a minority of tumors, was validated as a favorable

Cancer Survivors Give Back

L. Fornia and other members of the Ovarian Cancer Alliance of Oregon and Southwest Washington, based in Portland and Vancouver, are back in the classroom, but this time it is to help future health-care practitioners learn to recognize risks and symptoms of ovarian cancer so they will be able to diagnose the disease in its early stages.4 Twenty-eight percent of women diagnosed in late stages (stage III and IV) will survive 5 years. “We are speaking to nursing students, nurse practitioners, medical students, pharmacy students, basically telling our personal stories, so that it humanizes the vague symptoms—such as bloating, pelvic or abdominal pain, difficulty eating or feeling full quickly, and urinary urgency or frequency—that a woman can have. If these symptoms are unusual for you and occur almost daily for more than a few weeks, see your doctor, preferably a gynecologist,” Ms. Fornia told The ASCO Post.

The program—Survivors Teaching Students: Saving Women’s Lives— was developed by the Ovarian Cancer National Alliance. In addition to implementing this program at the local level, the Ovarian Cancer Alliance of Oregon and Southwest Washington also participates in community health fairs and other events. According to Ms. Fornia, their overall message is, “Listen and pay attention to your body. If you’ve got some vague symptoms that are hanging on for a month or 6 weeks, then you need to see a doctor.”

continued from page 37

not. Some of them will not agree to be screened, and that’s the way it goes.” Dr. Ryan was able to arrange many of the services provided by Street Smarts because “I network,” she said. “I write a lot of op-eds, a lot of magazine articles, so people are familiar with me.” She already knew some of the oncology nurses at the hospital because she often accompanies homeless women to appointments there. “I am kind of their facilitator. I help to clarify information for them and make sure their questions are answered,” Dr. Ryan said. “I am in the process of waiting for the trademark for the program so that we can spread it across the country,” Dr. Ryan reported. What the program requires, she said, “is that you look at these folks like they’re real people. You make associations with them and say, ‘I am going to help you through this.’”

Survivors Teaching Students Ovarian cancer survivor Judith

Prognostic Role of Lymphocytic Infiltration The study authors considered lymphocytic infiltration to be intense, mimicking lymph node lymphocytic density, or not intense (null, mild, or moderate). A logistic model, stratified on trial, was used to study the correla-

surgery, stage, and histology. Among 804 analyzed patients, 763 were valuable for lymphocytic infiltration assessment. Intense lymphocytic infiltration was observed in 6% of patients in the validation set, compared to 11% in the IALT study. Lymphocytic infiltration was associated with histology—10% in squamous cell carcinoma and approximately 4% in adenocarcinoma and other histologic types of

Lymphocytic infiltration was associated with histology—10% in squamous cell carcinoma and approximately 4% in adenocarcinoma and other histologic types of NSCLC.

Capturing the Passion To increase awareness of clinical trials available in West Michigan, cancer survivors share their own experiences with clinical trials by serving on the Grand Rapids Clinical Oncology Program’s Patient Advisory Board for Clinical Research. According to the AACR presentation by Patrick Gavin, the Patient Advisory Board “was formed to capture the passion

prognostic factor for survival in patients with resectable NSCLC.

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Disclosure: This research was made possible by unrestricted grants from the Ligue Nationale Contre le Cancer (France) and Sanofi-Aventis.

References 1. Arriagada R, Durant A, Pignon JP, et al: Long-term results of the International Adjuvant Lung Cancer Trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol 28:35-42, 2010. 2. Butts CA, Ding K, Seymour L, et al: Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II nonsmall-cell lung cancer: Updated survival analysis of JBR.10. J Clin Oncol 28:29-34, 2010. 3. Strauss GM, Herndon JE 2nd, Maddaus MA, et al: Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer. J Clin Oncol 26:5043-5051, 2008. 4. Douillard JY, Rosell R, De Lena M, et al: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer. Lancet Oncol 7:719-727, 2006. 5. Brambilla E, Domerg C, Lantuejoul S, et al: LACE-BIO: Validation of the prognostic role of tumour lymphocyte infiltration in resectable non-small cell lung cancer. 3rd European Lung Cancer Conference, Abstract 77O. Presented April 20, 2012.

that clinical trial participants possess in searching for a cure for a disease that has personally affected them.” 5

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Disclosure: Dr. Ryan, Ms. Fornia, Ms. Daniel, and Mr. Gavin reported no potential conflicts of interest.

References 1. Daniel J: Stand Up To Cancer press event. 2012 American Association for Cancer Research Annual Meeting. Presented April 1, 2012. 2. Ryan C: Homeless with cancer. CR (newly named Cancer Today), Fall 2010. 3. Ryan C: Street smarts: Cancer education and outreach in the homeless community. 2012 American Association for Cancer Research Annual Meeting. Abstract LB-50. Presented April 1, 2012. 4. Fornia JL: Real people—real stories: Survivors teaching students. 2012 American Association for Cancer Research Annual Meeting. Abstract LB-45. Presented April 1, 2012. 5. Gavin P: Cancer clinical trials: Real answers, real options, real miracles, right here in west Michigan. 2012 American Association for Cancer Research Annual Meeting. Abstract LB-53. Presented April 1, 2012.

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

Choose TASIGNA first

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

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

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

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

0.7%

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17 6%

TASIGNA 300 mg bid (n=282)

Imatinib 400 mg qd (n=283)

TASIGNA

Imatinib

(n=282)

(n=283)

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

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

IMPORTANT SAFETY INFORMATION ■

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

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

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

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

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

AM7-1033710

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

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

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

At 24 months

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

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

5.13 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels, including the lipid profile, should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments [see Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion. 5.14 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations (8.1) in the full prescribing information]. 6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert [see Boxed Warning, Warnings and Precautions (5)]. Myelosuppression [see Warnings and Precautions (5.1)] QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)] Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)] Elevated serum lipase [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly diagnosed Ph+ CML-CP The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 25 months (range 0.1 – 35.4 months). The median actual dose intensity was 594 mg/day in the nilotinib 300 mg twice daily group. The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 2.5% of patients. Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec while on study drug. The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (17%), neutropenia (15%) and anemia (7%). See Table 7 for Grade 3/4 laboratory abnormalities. Discontinuation due to adverse events regardless of causality was observed in 9% of patients. Resistant or intolerant Ph+ CML-CP and CML-AP In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1-1096) and 264 (range 2-1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151–1110) and 780 mg/day (range 150-1149), respectively and corresponded to the planned 400 mg twice daily dosing. The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1-345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1–234). In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (≥1% and <10%) were thrombocytopenia, neutropenia and anemia. In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (≥1% and <10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.4) in the full prescribing information]. Discontinuation due to drug-related adverse reactions was observed in 16% of CML-CP and 10% of CML-AP patients. Most Frequently Reported Adverse Reactions Tables 5 and 6 show the percentage of patients experiencing non-hematologic adverse drug reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least one dose of Tasigna are listed. Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Imatinib 400 mg once daily groups)a Patients with Newly Diagnosed Ph+ CML-CP TASIGNA Imatinib TASIGNA Imatinib 300 mg 400 mg 300 mg 400 mg twice daily once daily twice daily once daily N=279 N=280 N=279 N=280 Body System and Preferred Term All Grades (%) CTC Gradesb 3 / 4 (%) Skin and subcutaneous Rash 37 18 <1 2 tissue disorders Pruritus 20 7 <1 0 Alopecia 11 6 0 0 Periorbital edema <1 15 0 0 Gastrointestinal Nausea 20 39 1 1 disorders Constipation 17 6 0 0 Diarrhea 14 40 <1 2 Vomiting 11 24 0 <1 Abdominal pain upper 15 11 <1 <1 Abdominal pain 14 10 1 0 (continued)

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

Fatigue Pyrexia Asthenia Edema, peripheral Myalgia

32 22 16 15 19

3 <1 0 <1 2

23 28 14 12 16

<1 2 1 0 <1

Musculoskeletal and connective tissue disorders

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

26 13 14 20 17 11

2 <1 <1 2 2 <1

16 15 15 18 15 12

0 0 2 1 <1 1

Respiratory, thoracic and mediastinal disorders

Cough Dyspnea Oropharyngeal pain

27 15 11

<1 2 0

18 9 7

0 2 0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

Metabolism and nutritional disorders

Anorexia

Psychiatric disorders

Insomnia

Vascular disorders

Hypertension

aExcluding bNCI

laboratory abnormalities Common Terminology Criteria for Adverse Events, Version 3.0

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

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

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

CML-CP

CML-AP

TASIGNA 300 mg twice daily N=279 (%)

Imatinib 400 mg once daily N=280 (%)

TASIGNA 400 mg twice daily N=321 (%)

TASIGNA 400 mg twice daily N=137 (%)

10 12 4

9 21 5

301 312 11

423 424 27

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

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

18 12 17 7 4 6 7 2 3 4 2

18 6 15 9 4 4 7 9 2 3 5

0 0

<1 <1

1 <1

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

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

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

ASCOPost.com | JUNE 15, 2012

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Direct from ASCO

Best of ASCO® Meetings Deliver Top Annual Meeting Abstracts and Select Educational Sessions in an Intimate Setting This Year Expanding to the Midwest

f you have to miss the Annual Meeting this year, don’t worry. ASCO also offers Best of ASCO Meetings, which feature 2 days of presentations on the top scientific abstracts from the Annual Meeting, complemented by select education sessions. “The Best of ASCO Meeting provides an opportunity for practicing oncologists to review the best studies from the ASCO Annual Meeting,” said Kathy Miller, MD, Chair of the Best of ASCO Planning Committee, breast cancer expert, and Associate Professor at the Indiana University Simon Cancer Center. “As identified by leaders in the field, these important studies will give Best of ASCO participants the knowledge to provide their patients with the best care,” Dr. Miller said.

A Third Meeting Launched: Chicago This year, in addition to its East Coast meeting in Boston (August 3–4 at the Renaissance Boston Waterfront Hotel) and its West Coast meeting in San Diego (August 10–11 at the Manchester Grand Hyatt), ASCO will hold a Best of ASCO Meeting in Chicago (July 12–13 at the Hyatt Regency Chi-

Four Educational Sessions Are Included

cago). Attendees can choose from any of these three convenient locations and experience the same engaging program. The Chicago location was added, in part, because Midwestern ASCO members who were unable to attend the Annual Meeting were asking for a Best of ASCO Meeting closer to home.

Intimate Meeting Size Equals More Opportunities for Q&A The Best of ASCO Meetings are small, which is one of the key features attendees like about these events. Attendees can take advantage of the meetings’ smaller size to more easily network with peers and faculty. The meetings’ size also allows for interactive sessions with faculty. A popular part of the meetings are the question

and answer case sessions that allow attendees to spend half an hour discussing difficult cases with expert faculty. This year, the Best of ASCO Planning Committee has expanded these sessions so that they are held on both days of the meeting. Each Best of ASCO Meeting— whether San Diego, Boston, or Chicago—offers the same dynamic content. Abstracts chosen for presentation and discussion reflect the foremost research and strategies in oncology that will directly impact patient care. The program features a variety of session topics that focus on the latest scientific findings in primary disease sites and practice-changing advances in cancer prevention and treatment. Each Best of ASCO Meeting has different faculty.

In addition to presentation and discussion of important new abstracts, this year’s Best of ASCO Meetings will offer summaries of four educational sessions: Developing a Targeted Therapy: Issues in the Age of Personalized Medicine; Early Drug Development: Casting a Wide Net Versus Preselecting a Narrow Audience; Adjuvant Therapy for Older Adults; and Treatment of Older Patients with Advanced Cancer: Balancing Efficacy with Toxicity.

Register by June 20 and Save All Best of ASCO attendees will receive access to the Best of ASCO Virtual Meeting. The Virtual Meeting will include sessions captured at the Best of ASCO Meeting in Chicago and allows attendees to view those meeting sessions on a number of different devices. For more information about Best of ASCO Meetings, to register, and to reserve housing, visit boa2012.asco.org. The Housing and Early Registration Deadline for all three meeting locations is June 20, 2012, at 11:59 PM (EDT).

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Lance Armstrong Foundation Provides Grant to Conquer Cancer Foundation to Support New Video Series for Young Adults with Cancer

he Conquer Cancer Foundation and the Lance Armstrong Foundation have something in common: both are on a mission to empower millions of people living with cancer by sharing knowledge and providing resources that address some of the most critical issues they will face. Thanks to a grant from the Lance Armstrong Foundation to the Conquer Cancer Foundation, which supports Cancer.Net, ASCO’s patient information website, a new video series for young adults with cancer has just been launched. A joint project of ASCO

and the Lance Armstrong Foundation, the series “Moving Forward: Perspectives from Survivors and Doctors” will present 13 companion videos for young adults that provide insight from survivors and information from doctors on important topics, and help young adults better understand and cope with challenges related to their diagnosis.

Much-needed Resource for Young Adult Patients “When I was first diagnosed with cancer at age 19, I was frustrated by the lack of resources available to me,” said Doug Ulman, Lance Armstrong Foundation President and CEO. “As both a young adult survivor and cancer advocate, I’m thrilled that this new video series can serve as a much-needed resource for

young adults with cancer. By supporting the series through the Conquer Cancer Foundation and collaborating with ASCO, we can ensure that heath-care professionals are offering their young adult patients this additional support to help them in their cancer journey.” Released on www.cancer.net/movingforward and on the Foundation’s YouTube site (bit.ly/LIVESTRONGmovingforward) are the first four video pairs in the series, including an introduction and information on fertility, fear of recurrence, and bills and medical expenses. Each month new videos featuring ASCO members will be paired with survivor vignettes addressing issues such as body changes, dating and sexuality, diet and exercise, family and friends, fear of dying, health insurance, pain and

swelling, and school and work. The Conquer Cancer Foundation works to ensure that vital information for physicians, patients, and families is available and easily accessible wherever and whenever it’s needed. To help the Foundation continue its support of programs such as See Page 90 this, please consider making a donation online www.conquercancerfoundation.org/SupportPatientEducation.

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The ASCO Post | JUNE 15, 2012

PAGE 46

Direct from ASCO

Full Membership: What It Means, What It Offers, and Why It’s Essential

s part of our series explaining cialty training program. The disthe benefits of ASCO’s various counted dues savings, coupled with membership categories, in this issue resources tailored to early-career we focus on the Full Membership oncologists, make ASCO an essenCategory tial resource for the professional just Involvement in ASCO—the starting out in cancer care. largest and most inclusive profesSarah Foster Adams, MD, sional organization in oncology— has been a Full Member with disallows those involved in cancer care counted dues for 2 and a half years to chart the very course of the field, now. She is Assistant Professor of advancing the frontiers of research, Obstetrics and Gynecology at the defining the standards of practice University of Pennsylvania’s Perelfor clinical care, and influencing man School of Medicine and pracpublic policy. tices at the Joan Karnell Cancer Today, most of the members Center. of ASCO belong to the category “Membership in ASCO is a great of Full Member, which comprises thing for people new to the practice more than 22,000 oncology proof medicine, and the fact that ASCO fessionals, 2,800 of whom are in offers us a discount when we’re just the first 3 years of their career and starting out is really helpful,” Dr. Adare offered discounted dues. Full ams said. Members make up 70% of ASCO’s Updates on Research, total membership. Valuable Networking, The Full Member category is Leadership Skills available to experienced licensed Colin D. Weekes, MD, PhD, physicians or other health profesAssistant Professionals at the sor in the Dividoctoral level of Membership for sion of Medical any nation who Oncology at the devote a majorme means access to University of ity of their proupdated information Colorado School fessional activity on how to treat of Medicine, has to cancer patient care and/or repatients. It’s also a nice been a member since 1999, startsearch or educatool for meeting other ing out in the cattion in the biolegory of Member ogy, diagnosis, physicians who in Training, then prevention, or may have interests progressing to Full treatment of huMember with disman cancer. similar to mine. counted dues, and Reflecting —Colin D. Weekes, MD, PhD now Full Member. its belief that a “Membership multidisciplinary for me means access to updated inapproach to care is central to the formation on how to treat patients,” future of oncology, ASCO encomsaid Dr. Weekes, a gastrointestinal passes all oncology subspecialties; oncologist and clinical investigator membership is available to medical with his own lab. “It’s also a nice oncologists, hematologic oncolotool for meeting other physicians gists, radiation oncologists, surgiwho may have interests similar to cal oncologists, pediatric oncolomine.” gists, and gynecologic oncologists. Dr. Weekes commented that Discounts for Early-career when a patient of his relocates, Professionals he uses ASCO to help find a colFull membership was one of league to care for that patient in ASCO’s original membership cathis or her new location. ASCO ofegories when the organization was fers many ways for members to get founded in 1964. In 1999 ASCO to know other professionals, from began offering discounted dues to attendance at the Annual Meeting physicians for the first 3 years after and Symposia to the organization’s completion of an oncology subspesocial networking resources, free

ASCO Tumor Boards, and participation in one of more than 100 committees, subgroups, and working groups. “Membership is career enhancing,” added Dr. Weekes, who has served on several ASCO committees and for the last 3 years has sat on the Scientific Program Committee. “It has provided a very valuable way to gain leadership skills. As an example, I’ve given talks at ASCO meetings.”

Registration Discounts, Advanced Housing Access One of the most recognized membership benefits that has been

Volume 29, Issue 15

May 20, 2011

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

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

www.jco.org

cited by ASCO members is the 20% to 60% savings off the nonmember registration rate at the ASCO Annual Meeting and ASCO Symposia. In addition, advance access to members-only housing and registration gives members access to the most sought-after hotels for the Annual Meeting. Full Members have an exclusive benefit at the Annual Meeting in that only ASCO Full Members may sponsor more than one abstract. Thus, Full Members may sponsor their own meeting abstracts as well as the work of their colleagues for presentation at the meeting.

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

What’s Hot in

JCO

JCO.org Dual Blockade of Epidermal Growth Factor Receptor– Induced Pathways: A New Avenue to Treat Metastatic Colorectal Cancer

Refining the Use of Endocrine Therapy for Ductal Carcinoma in Situ

Is Adjuvant Chemotherapy Useful for Women With Luminal A Breast Cancer?

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

Estrogen Receptor in Breast Ductal Carcinoma in Situ: Good Cop, Bad Cop?

ASCOPost.com | JUNE 15, 2012

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Direct from ASCO

Free Journals, Practice Support, Educational and Clinical Products Free print subscriptions and online access to the Journal of Clinical Oncology and the Journal of Oncology Practice are significant benefits enjoyed by individuals in the Full Member category. Additionally, members have access to Cancer in the News and receive ASCO Express, The ASCO Post, and ASCO Connection. ASCO’s educational products offer important resources for oncology professionals. Members save 20% to 50% on all of these products and resources, such as ASCO’s Maintenance of Certification modules and the full library of images and illustrations in the Oncology Slide Library from ASCO University. ASCO’s clinical guidelines and practice management and reimbursement resources also represent significant benefits of membership. These resources provide information and tools to improve

Patient-friendly News from the ASCO Annual Meeting

o to Cancer.Net to find the latest news for patients from the 2012 ASCO Annual Meeting. At www.cancer.net/ascoannualmeeting, patients can listen to expert-led podcasts, watch disease-specific videos, read research summaries, and get recaps of each day’s highlights. The information here was updated throughout the meeting and helps put the breaking research into context for patients. Follow Cancer.Net on Facebook (www.facebook.com/CancerDotNet) and Twitter (www.twitter. com/CancerDotNet) to find updates in real time.

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quality and efficiency in practice. Among these valuable programs are the Quality Oncology Practice Initiative (QOPI ®), the Coding and Reimbursement Service, and ASCO’s Clinical Practice Guidelines, which are supported by slide

sets, decision aids, and patient guides. Retention in the Full Member category is very high because B:8.625” members find value in what ASCO T:7.625” offers. To learn more about S:6.75” the benefits available to Full Members and Full

Members with discounted dues, as well as the benefits in other ASCO membership categories, please visit benefits.asco.org.

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

COMET-1

COMET-2

PRIMARY ENDPOINT

Overall Survival

Confirmed Pain Response CRPC (N=246)

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

Cabozantinib (60 mg qd) Randomization Prednisone

Randomized, double-blind, controlled trial

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

Cabozantinib (60 mg qd) Randomization Mitoxantrone + Prednisone

Randomized, double-blind, controlled trial

The ASCO Post | JUNE 15, 2012

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Direct from ASCO

Markers in Cancer 2012, to be Held October 11–13, Will Seek to Move the Field of Biomarkers to the Next Phase

here are hundreds and hundreds of papers published on biomarkers in cancer each year, but very few make it over the hurdles necessary to be used in actual patient care, said James L. Abbruzzese, MD, Chair of the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center.

Walter M. Stadler, MD, Chair of the meeting’s Scientific Committee, Fred C. Buffett Professor of Medicine and Surgery, Associate Dean for Clinical Research, and Director of the Genitourinary Program at the University of Chicago Medicine. “At almost any conference you go to now, everyone talks about personalized cancer care, and the only way to do that is with biomarkers, and yet we don’t have a lot of rigorous discussion on how to move biomarker science forward.”

Audience Has Expanded

James L. Abbruzzese, MD

Overcoming those hurdles will be the main focus at Markers in Cancer 2012, to be held in Hollywood, Florida, on October 11–13. The theme: Bridging the Translational Divides. “Speakers will provide critical thinking on developing a road map for translating marker research to patient care through improved study design and better statistics, giving almost a cookbook, providing a series of strides that need to be made in order to get FDA approval,” said Dr. Abbruzzese, Chair of the Organizing Committee for the meeting.

Especially Important for Clinical and Translational Researchers The meeting, which alternates between being held in the United States and Europe, is sponsored by ASCO, the European Organisation for Research and Treatment of Cancer (EORTC), and NCI. Formerly known as the ASCO-NCI-EORTC Annual Meeting on Molecular Markers in Cancer, the conference presents the latest advances in cancer markers to assess drug efficacy, improve prognostic and predictive evaluations and imaging, and enhance clinical trial development. “In many ways, this is becoming an increasingly more important conference, especially for clinical and translational researchers,” said

The NCI and EORTC recognized the importance of biomarker science in 2000 with the first Molecular Markers Meeting held in Copenhagen. The explosion of new biomarker information and pharmacotherapeutics now mandates a meeting that is more inclusive of the basic, preclinical, and clinical researcher. Thus, the conference is now designed for clinicians, pathologists, laboratory scientists, statisticians, representatives from the pharmaceutical industry, regulatory agencies who are interested in cancer, and those that specialize in molecular diagnostics. The hope this year, said Dr. Abbruzzese, is that some consensus can be reached on which way to go. “As technology has developed, the sequencing, imaging and specific physiological underpinnings of cancer have become a much more robust area for research,” he said. “The problem is that everyone has their favorite biomarker or lab technique, and is busy trying to apply it to a small number of patients, and yet somehow we never get to the goal of getting this to help manage a large number of patients. We need to come together on this.” The meeting will be structured as educational talks followed by dedicated time for discussion with speakers. Other features are oral presentations of top abstracts, poster sessions, and ample opportunities for networking. “Attendees can look forward to a set of internationally recognized speakers, as well as a lot of time built

Walter M. Stadler, MD

in for scientific interaction and collaboration,” said Dr. Stadler.

Premeeting Session for Early-career Oncologists A Diagnostic Development Tutorial will take place prior to the start of the meeting, on October 10 and 11. The two-day tutorial is an interactive seminar designed to help selected early-career oncolo-

gists and industry and regulatory representatives learn about biomarker development, from discovery through validation and clinical trials. Interested academic and industry participants can apply at markersincancer.org. The deadline for academic applicants is June 22; the deadline for industry applicants is September 5.

Register and Reserve Housing Today The housing and early registration deadline for Markers in Cancer 2012 is September 5 at 11:59 PM (EDT). View the program agenda, register, or reserve housing at markersincancer. org.

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ASCO Participates in Two FDA Meetings on Improving Clinical Trials

SCO recently took part in two public meetings at the U.S. Food and Drug Administration (FDA) that had the broad goal of improving clinical trials and, ultimately, treatment for cancer patients. Then ASCO President Michael P. Link, MD, served as a panelist on a workshop sponsored by FDA and ASCO, along with the American Society of Hematology and the American Association for Cancer Research, to discuss the use of minimal residual disease as a biomarker for evaluating new drugs for the treatment of acute lymphoblastic leukemia. In addition, ASCO members Stephen Hunger, MD, and Gregory Reaman, MD, served as Co-Chairs of the “Minimal Residual Disease as a Surrogate Endpoint in Acute Lymphoblastic Leukemia Workshop,” held April 18 at FDA headquarters in Silver Spring, Maryland. Workshop materials and presentations are available from www.fda.gov/Drugs/NewsEvents/

ucm294931.htm. Dr. Christine Chung, MD, a member of ASCO’s Cancer Research Committee, testified on behalf of ASCO at an FDA public hearing on “Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice,” held April 23 at the FDA White Oak Campus in Silver Spring, Maryland. Dr. Chung, a medical oncologist at the Sidney Kimmel Comprehensive Cancer Center and an Associate Professor of Oncology at the Johns Hopkins University, spoke about several topics, including the importance of greater consistency in federal regulations and guidance. ASCO supports efforts to create a clear and transparent regulatory system to help modernize the regulation of clinical trials. Webcast recordings from the meeting are available on the FDA’s website, www.fda.gov.

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ASCOPost.com | JUNE 15, 2012

PAGE 49

Expert’s Corner Hematology

Multiple Myeloma Research Foundation Initiatives Are Leading to More Effective Targeted Treatments

A Conversation with Kathy Giusti, Founder and CEO of the Multiple Myeloma Research Foundation By Jo Cavallo therapies have been FDA-approved for myeloma: bortezomib (Velcade), lenalidomide (Revlimid), thalidomide (Thalomid), and liposomal doxorubicin (Doxil). Through its research network (the MMRC), the MMRF has helped to accelerate development of two more agents, carfilzomib and pomalidomide, both of which could be approved by FDA later this year. Four more treatments are in late-stage clinical trials. While a better understanding of the genomics of myeloma cells Kathy Giusti and the development of more effective n 1996, at just 37, the last thing novel agents have extended median Kathy Giusti expected to hear was overall survival from 3 to 7 years, the that she had the fatal blood cancer 5-year relative survival rate remains multiple myeloma. An executive at one of the lowest of all cancers, at just Searle Pharmaceuticals and the moth39%. er of an 18-month-old daughter, GiIn 2006, Ms. Giusti underwent a usti was told she probably had 3 years syngeneic stem cell transplant using to live. At the time, treatments for the donor cells from her identical twin sisdisease were limited to the same alkylter Karen Andrews, a cofounder of the ating agents availMMRF, and she able in the 1950s, remains in remisWe look at myeloma and stem cell transsion. Last year, Ms. plantation was just Giusti was named drug development as emerging as a poone of Time Magaa portfolio. We tend tential therapy. zine’s 100 Most Into look at the next Diagnosed with fluential People in the smoldering generation of drugs that the World. form of multiple The ASCO Post we know are effective. myeloma, Ms. Gitalked with Ms. usti was given infuGiusti about the —Kathy Giusti sions of pamidroprogress being nate disodium and made in multiple put on a watch-and-wait approach. myeloma and new research initiaA graduate of the Harvard Business tives launched by the MMRF. School, Giusti used her knowledge Origins of the Foundation of the pharmaceutical industry and Why did you launch the Multiple Myher business skills to launch the Muleloma Research Foundation? tiple Myeloma Research Foundation Coming from the pharmaceutical (MMRF) in 1998. To propel the industry, my hope was that we could development of new drugs for the attract scientists to the field of muldisease, Ms. Giusti founded the Multiple myeloma, and the only way to tiple Myeloma Research Consortium do that was to provide funding for (MMRC) 6 years later. them. I wanted to extend my life long The results in money raised for enough to see my daughter go to kinresearch in multiple myeloma and dergarten or at least to remember success in new drug development me. for the disease are unprecedented. Since its inception, the MMRF has Novel Agents raised $195 million for research, What are some drugs in developfunding more than 80 laboratories ment that look effective for multiple worldwide and 11 pharmaceutical myeloma? and biotech companies. We look at myeloma drug deOver the past 9 years, four new

Success of the Multiple Myeloma Research Consortium

ince its founding in 2004, the Multiple Myeloma Research Consortium (MMRC) has grown from a handful of member institutions to 16 such academic centers and has launched 38 phase I and phase II clinical trials. Six of the drugs studied in those investigations are currently in phase III trials. And those trials are launching 60% faster than comparable clinical trials in oncology, according to data from MMRC metrics, decreasing the amount of time from the development and finalization of a trial’s protocol design to patient enrollment by an average of 100 days. In addition to initiating clinical studies, the MMRC has also established a tissue bank, which has accrued more than 3,500 samples from myeloma patients. Last year, scientists from the Broad Institute decoded the whole genomes and whole exomes of 38 multiple myeloma patients using tissue samples donated from the MMRC. The findings, published in Nature,1 revealed genes never before associated with cancer.

More Genomic Sequencing The study also found that a small percentage of myeloma patients—just 4%—had BRAF V600E gene mutations, the same mutation found in some types of melanoma and colon cancer, which had been previously unknown in the development of multiple myeloma. Currently, the Broad Institute is completing the genomic sequencing of 250 additional multiple myeloma tumors with samples supplied from the MMRC tissue bank. Once sequencing is completed, scientists will analyze how the new genes discovered in myeloma contribute to disease onset and whether they represent new therapeutic targets. Information on all current MMRC-launched clinical trials will be available later this year on the Multiple Myeloma Research Consortium website at themmrc.org. Grant opportunities for researchers can be found at the Multiple Myeloma Research Foundation website at themmrf.org, and data from the genomic study of multiple myeloma cells can be accessed through the MMRC Multiple Myeloma Genomics Portal at broadinstitute.org/mmgp/ home.

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Reference 1. Chapman MA, Lawrence MS, Keats JJ, et al: Initial genome sequencing and analysis of multiple myeloma. Nature 471:467-472, 2011.

velopment as a portfolio. We tend to look at the next generation of drugs that we know are effective, such as the proteasome inhibitors, like bortezomib, and the immunomodulatory drugs, like thalidomide and lenalidomide. Carfilzomib is another effective proteasome inhibitor, and there is an additional one from Millennium called MLN9708, which is in phase II trials. The MMRC is facilitating a clinical trial of that drug in combination with lenalidomide and dexamethasone for newly diagnosed patients. Building off of the immuno-

modulatory drugs, we have helped to support Celgene with its agent pomalidomide. There are other classes of drugs that we are testing that have been found to be synergistic with the two mainstay classes of proteasome inhibitors and immunomodulatory drugs. For example, the histone deacetylase inhibitors panobinostat and vorinostat (Zolinza), monoclonal antibodies like elotuzumab (HuLuc63) and Akt inhibitors like perifosine (KRX-0401). What we are really trying to do now is understand a lot about our disease continued on page 50

The ASCO Post | JUNE 15, 2012

PAGE 50

Expert’s Corner

Kathy Giusti

CoMMpass Study

continued from page 49

The MMRF has just launched CoMMpass (Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile), a longitudinal study of 1,000 newly diagnosed patients. How many patients are enrolled so far, and what are the goals of the study?

and the different pathways involved in disease onset and progression.

Building a Community How is the MMRF able to be so effective in getting new drugs developed and fast-tracked for FDA approval? The MMRF has been very successful at building a community. We are only as good as the partners that work with us, and we know that. And the partners that work with us are the pharmaceutical companies and biotech firms who look at our research models and understand the benefits they offer in speed and efficiency; the academic centers that have the scientists; and fellows, who we continually fund and bring into these models that we are constantly developing. In addition to the academic centers, we’re partnering with the community centers because—and this has been a big shift for us—so many patients are now being treated at the community level. We are working on our 3-year strategic plan, and these plans are highly scientific, highly clinical, and highly translational. We build out how we raise our money and how we spend our money efficiently, because the question we are always asking is, what is going to have the greatest impact toward a cure?

Unique Organization How is the MMRF structured differently from other disease foundations? There are not a lot of foundations that have an MD as its Chief Medical Officer (as is the MMRF’s Dr. Michael N. Needle) and a team of experts with PhDs. But the big difference with us is that we actually design, build, and run the research models that we develop, and we’re constantly measuring them to see if the models are effective. An example would be the Multiple Myeloma Research Consortium. We designed it, we built it, we brought everyone together, and we continue to fund it to make sure that the infrastructure for success is in place. Right now, the MMRC is overseeing more than 20 trials. We are opening clinical trials faster, and we always ask, are we accruing patients to them quickly enough? If not, we figure out what’s slowing us down—is it the protocol development or the contracting, and how do we fix it?

We have 120 patients enrolled already, and we’re open in 40 study sites (themmrf.org/research-programs/ commpass-study). The CoMMpass study is collecting and analyzing tissue samples and genetic information from newly diagnosed patients who will be followed over a 5-year period. The tricky

LITTLE THINGS MAY SEEM INSURMOUNTABLE FOR PATIENTS WITH CHEMOTHERAPY-INDUCED ANEMIA

part of CoMMpass is that we’re asking patients to give us that very first clean bone marrow aspirate before beginning treatment. There’s this window of time when patients are first diagnosed that can be challenging. Asking them to give bone marrow, enroll in the trial, and sign the consent forms can be difficult.

ASCOPost.com | JUNE 15, 2012

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Expert’s Corner

That’s why it’s really important to work with community centers: They’re seeing those patients in that window of time. We’ve come to understand that myeloma is not one disease; it’s a number of diseases. So we’re trying to understand the disease based on the molecular biomarkers of our patients’

tumor cells. And because we’re following these patients for a long time and sequencing their genomics at early diagnosis, at remission, and at relapse/ progression, our hope is that we will start to understand why some patients relapse and become resistant to treatment. From there, we can look at what

new drug targets and pathways might eventually emerge.

Looking Ahead What does the future look like for patients with myeloma? What we are starting to see is that a considerable number of patients don’t

ACTIVE MANAGEMENT OF CANCER-RELATED ANEMIA MAY HELP REDUCE ITS OVERALL IMPACT ANEMIA IS COMMON IN CANCER PATIENTS RECEIVING CHEMOTHERAPY In patients

receiving chemotherapy, anemia (Hb < 11 g/dL) was present in over 50% of those with ovarian, breast, and non-small cell lung cancer and approximately 40% of those with colorectal and head and neck cancer.* Anemia also was observed in approximately half of patients receiving platinum-, anthracycline-, taxane-, or gemcitabine-based chemotherapy regimens.*1

SYMPTOMS OF ANEMIA ARE OFTEN DUE TO THE HYPOXIA-RELATED EFFECTS ON ORGAN FUNCTION Signs and symptoms include

pallor of the skin and mucous membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.2,3

HEMOGLOBIN LEVELS AND PERFORMANCE SCORES ARE CORRELATED The European

Cancer Anaemia Survey, a prospective observational survey that enrolled patients regardless of disease status or cancer treatment, showed a significant correlation between Hb level and performance status at enrollment (n = 14,912 evaluable).† Though poor performance status was observed in all Hb level groups (< 8 g/dL to ≥ 12 g/dL), the lower the Hb level, the more likely patients would be ambulatory but unable to work, would stay in bed or chair more than 50% of the day, or would be totally confined to bed or chair.4,5

Hb levels significantly correlate with performance status†4,5

% OF PATIENTS

WHO score at enrollment:

n = ‡

90 80 70 60 50 40 30 20 10 0

0–1 2 (eg, ambulatory but unable to work) 3 (eg, in bed/chair > 50% of the day) 4 (eg, bed/chair bound)

84.0

75.2 60.0 49.2

8750

Mean (SD) 0.8 (0.8) WHO score

10.1

5.0 0.5

2.3 0.2 ≥ 12.0

27.7

19.3

13.5

10.0 – 11.9

8.0 – 9.9

26.7 16.0 2.2

HEMOGLOBIN LEVELS (g/dL)

< 8.0

4214

1242

187

1.0 (0.8)

1.4 (1.0)

1.7 (1.1)

8.0

PATIENTS CAN BECOME ANEMIC WITHIN THE FIRST 2 CYCLES OF CHEMOTHERAPY

When data from 1,821 patients with cancer who began receiving chemotherapy at Hb ≥ 12 g/dL were analyzed to determine relative risk for anemia, 62% of patients experienced a Hb decline of 1.5 g/dL within a median of 6.1 to 7.2 weeks and 51% had a Hb decline of 2 g/dL within a median of 7.3 to 8.9 weeks.6 Low Hb levels have been associated with an increased likelihood of chemotherapy dose delays and dose reductions.7 How might clinicians reduce the overall impact of anemia?

respond to the treatments that we have today. We would consider those patients to be at high risk. Then there are the patients who might only respond for a short period of time—they are high-risk in a different way. We don’t know why a drug only works for high-risk patients for a limited amount of time, so we need to understand that piece of the puzzle too. There are many subtypes of myeloma. Each type has a different level of risk and may require a different combination of approaches, and we just don’t know the answers to that dilemma yet. Our hope is that the CoMMpass study will help generate the hypotheses that will lead us in the right direction, not just to more effective treatments for all patients, but also to a cure.

■

Disclosure: Ms. Giusti is founder and CEO of the Multiple Myeloma Research Foundation.

Contact

The ASCO Post

PATIENT EDUCATION IS AN IMPORTANT ASPECT OF ACTIVE ANEMIA MANAGEMENT

NCCN recommends that Hb levels ≤ 11 g/dL or ≥ 2 g/dL below baseline prompt an evaluation of anemia in order to characterize the anemia and correct any underlying comorbidities. At this point, a detailed history, physical, and further laboratory tests are suggested, which include a CBC with indices, onset of symptoms (eg, syncope, dyspnea, headache, fatigue), comorbidities, and exposure to antineoplastic drugs and radiation.8 ASCO/ASH recommends that clinicians also discuss the benefits and harms of therapeutic options with patients undergoing myelotoxic chemotherapy who become anemic.9

For more information about chemotherapy-induced anemia, please visit anemia.com/professional/cia. *N (anemia patients evaluated) = 42,923. Data from January 1, 2000, through December 31, 2007, from a retrospective, observational, cohort study of 47,159 adult patients with cancer were obtained through electronic medical records at community and hospital-affiliated clinical oncology practices throughout the United States. The mean baseline Hb prior to initiating chemotherapy was 12.4 g/dL across all tumor types. †Observational, prospective, multisite survey of patients with solid or hematological tumors. Survey enrollment was conducted from January to July 2001, with data collected for up to 6 data points or 6 months of scheduled clinic visits. ‡Missing data for n = 519. References: 1. Wu Y, Aravind S, Ranganathan G, Martin A, Nalysnyk L. Clin Ther. 2009;31:2416-2432. 2. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Available at: http://evs.nci.nih.gov/ ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Accessed March 30, 2011. 3. Ludwig H, Strasser K. Semin Oncol. 2001;28:7‐14. 4. Ludwig H, Van Belle S, Barrett-Lee P, et al. Eur J Cancer. 2004;40:2293-2306. 5. World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. 1979. Available at: http://whqlibdoc.who.int/offset/WHO_OFFSET_48. pdf. Accessed February 17, 2011. 6. Barrett-Lee J, Ludwig H, Birgegård G. Oncology. 2006;70:34-48. 7. Repetto L. Crit Rev Oncol Hematol. 2009;72:170-179. 8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Cancer- and Chemotherapy-Induced Anemia. v2.2012. Available at: http://www.nccn.org. Accessed September 28, 2011. 9. Rizzo DJ, Brouwers M, Hurley P, et al. J Clin Oncol. 2010;28:4996-5010.

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

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The ASCO Post | JUNE 15, 2012

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Journal Spotlight Hematology

Marrow Cells in Secondary Acute Myeloid Leukemia Are Highly Clonally Derived, Raising Implications for Treatment Strategies By Matthew Stenger

yelodysplastic syndromes (MDS) often evolve into secondary acute myeloid leukemia (AML), but the genetic changes underlying this evolution have not been well understood. Using next-generation sequencing, Walter and colleagues from Washington University in St. Louis, Missouri, have shown that nearly all bone marrow cells in patients with MDS and secondary AML are clonally derived, regardless of myeloblast count, and that evolution to secondary AML is characterized by multiple cycles of clonal selection and mutation acquisition.1 As noted by the investigators, one potential clinical implication of the study’s finding that the dominant secondary AML clone was always derived from an MDS founding clone is that targeting therapies at early mutations present in these clones “might be the most effective strategy for eliminating disease-propagating cells and improving the rate of response to traditional chemotherapy for patients with secondary AML.”

Clonal Architecture Defined In this study, whole genome sequencing was used in samples of bone marrow from seven subjects with secondary AML to identify somatic mutations specific to secondary AML. Marrow samples obtained from each subject during the preceding MDS phase were then genotyped to determine the presence or absence of specific somatic mutations. Recurrent mutations in coding genes were identified, and the clonal architecture of each pair of samples from See Page 90 the MDS and secondary AML stages was defined using an allele burden comprising hundreds of mutations. The researchers found that approximately 85% of unfractionated bone marrow cells (up to 92.7%) were clonal in the MDS and secondary AML samples, irrespective of myeloblast count and even when myeloblast count was less than 5% in MDS samples. Although it has been observed previously that myeloblast count can underestimate the size of clonal populations in MDS, the current study

suggests that when the entire genome is interrogated for mutations, clonal hematopoiesis involving most of the marrow is “the rule” in MDS even at an early stage.

Recurrent Mutations The secondary AML samples contained mutations in 11 recurrently mutated genes, including 4 not previously implicated in either MDS or AML. In all cases, progression to secondary AML was marked by the persistence of an antecedent founding clone containing 182 to 660 somatic point mutations and the emergence of at least one daughter subclone, with subclones having as many as hundreds of new mutations. Only two samples were monoclonal at the MDS stage. All founding clones and subclones contained at least one mutation in a coding gene. Genes with recurrent mutations that have been previously reported in MDS or AML and that were observed

Evolution of Secondary Acute Myeloid Leukemia ■■ Most bone marrow cells in patients with myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML) are clonally derived.

■■ Genetic evolution of secondary AML is characterized by multiple cycles of clonal selection and mutation acquisition.

■■ The ability to identify patterns of pathogenic mutations and their clonality should improve diagnostic and prognostic assessment in patients with MDS and secondary AML.

tions and a second that contained all these mutations and 83 additional mutations. When this patient’s disease progressed to AML, both of the original clones persisted and three new subclones emerged containing all the preexisting mutations and 57 to 263 new mutations. The findings indicate that evolution of the tumor proceeded sequentially from cells in a founding clone to cells in daughter subclones, with each new clone carrying forward all preexisting mutations, whether pathogenic or nonpathogenic. Changes in six other tumors from

We anticipate that next-generation sequencing results from hundreds to thousands of patients with MDS and secondary AML will allow us to improve prognostic algorithms and ultimately influence the therapeutic choices available for individual patients. —Timothy A. Graubert, MD

in secondary AML samples in the current study included NPM1, PTPN11 (not observed in MDS sample), RUNX1 (one of two mutations in this gene not observed in MDS sample), STAG2, TP53, U2AF1, and WT1 (not observed in MDS sample). Genes with recurrent mutations that have not been previously associated with MDS or AML and that were observed in secondary AML samples in the study consisted of CDH23 (not observed in MDS sample), SMC3, UMODL1 (two mutations, both also observed in MDS sample), and ZSWIM4. As an example of the clonal architecture identified in these samples, one subject had five distinct mutation clusters that defined the clonal genetic progression of the tumor. The MDS sample contained two clones, one with 323 somatic muta-

this patient also conformed to a linear model of clonal evolution. As expected, the proportion of mutations that were secondary AML– specific was smaller (7% vs 38%) in subjects with rapid progression to secondary AML (< 6 months) than in subjects with slower progression (>�� 20�� months). The spectrum of transition and transversion mutations in the founding clone was similar in all seven subjects, with the most common substitution being a CG→TA transition, as has been observed in other cancer genomes. A significant increase in the frequency of secondary AML–specific C→G transversions was observed in MDS samples of two subjects receiving decitabine (Dacogen) treatment prior to conversion to secondary AML compared with two subjects who did not receive decitabine.

As noted by the authors, it is characteristic of leukemia that hematopoietic cells freely mix and recirculate between the peripheral blood and marrow. Clones that expand over time must retain the capacity for selfrenewal, and mutations in new daughter clones must be associated with a competitive growth advantage relative to their ancestral clones. Thus, “The result is that these secondaryAML samples are not monoclonal but are instead a mosaic of several genomes with unique sets of mutations; this mosaic is shaped by the acquisition of serial mutations and clonal diversification.”

Clinical Implications This study has shown that the proportion of neoplastic marrow cells is virtually identical in both MDS and secondary AML, indicating that MDS is as clonal as secondary AML, even when the myeloblast count is 0. The study’s findings have a number of clinical implications. First, secondary AML is currently distinguished from MDS on the basis of manual counting of bone marrow myeloblasts, with treatment decisions frequently resting on diagnosis of secondary AML in this manner. The ability to identify patterns of pathogenic mutations and their clonality should improve diagnosis and assessment of prognosis. As noted by the authors in this regard, two of the subjects in the study had progression to secondary AML within 1 month based on increases in myeloblast count from 7% to 66% and from 13% to 43%. However, there was no change in the number of clones in these tumors (two in each case) and a minimal increase in the number of point mutations (< 2% gain). Further, as noted above, the finding that the continued on page 54

ASCOPost.com | JUNE 15, 2012

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Journal Spotlight

FOCUSED ON YOUR

PATIENTS

February 2012

ZOM-1036266

The ASCO Post | JUNE 15, 2012

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JCO Spotlight

Strong Biomarker Candidates for Predicting Clinical Response to Bevacizumab By Charlotte Bath

lasma vascular endothelial growth factor A (VEGF-A) and tumor neuropilin-1 “are strong biomarker candidates for predicting clinical outcome in patients with advanced gastric cancer” after treatment with bevacizumab (Avastin). This was the conclusion of a mandatory biomarker program following up on AVAGAST study findings that adding bevacizumab to chemotherapy in patients with advanced gastric cancer improves p ro g re s s i o n - f re e survival and tumor response, but not overall survival. The results of the See Page 90 AVAGAST trial were reported in the Journal of Clinical Oncology in 2011 and the biomarker evaluation was published by JCO online in May 2012.1 Using plasma samples available from 712 patients (92%) and tumor samples available from 727 patients (94%), researchers identified baseline plasma VEGF-A levels and tumor neuropilin-1 expression as potential predictors of bevacizumab efficacy. “Patients with high baseline plasma VEGF-A levels showed a trend toward improved overall survival” compared to patients with low VEGF-A levels, the authors reported. “Patients with low baseline expression of neuropilin-1 also showed a trend toward improved overall survival” compared to patients with high neuropilin-1 expression. “For both biomarkers, subgroup analyses demonstrated significance only in patients from non-Asian regions,” the researchers noted.

Earlier Studies “Pretreatment levels of circulating VEGF-A have been previously studied as a biomarker for VEGF-targeted therapies, but have been shown to be primarily prognostic rather than predictive,” the authors wrote. “In AVAGAST, we demonstrate that high plasma VEGF-A levels are associated with worse prognosis in metastatic gastric cancer. In addition, we demonstrate that high plasma levels of VEGF-A at baseline are associated

with a trend toward a larger bevacizumab effect in terms of overall survival, progression-free survival, and overall response rate. These benefits were not evident in patients with low baseline VEGF-A levels. The potential predictive role of plasma VEGF-A identified in AVAGAST is supported by two other recent independent biomarker analyses performed in patients with metastatic breast cancer (AVADO study) and pancreatic cancer (AViTA study).” In the AVAGAST study, “patients with low levels of neuropilin-1 expression appeared to derive more benefit from bevacizumab therapy than patients with higher levels of expression in terms of overall survival, progression-free survival, and overall response rate,” the researchers reported. “These observations are consistent with two recent retrospective, exploratory biomarker analyses in colorectal cancer (NO16966 study) and breast cancer (AVF2119g study), although different antibodies and methodologies were used in all studies.” AVAGAST, a global, randomized, double-blind, phase III study, randomly assigned patients with previously untreated, locally advanced or metastatic gastric cancer to bevacizumab or placebo (387 in each group) in combination with cisplatin plus capecitabine (Xeloda), or fluorouracil in patients unable to take oral medications. “Although bevacizumab was associated with a significantly longer progression-free survival vs placebo (median, 6.7 vs 5.3 months; HR = 0.80; P = .0037) and higher overall response rate (46.0% vs 37.4%; P = .0315), the difference in overall survival, the primary study endpoint, did not reach statistical significance (12.1 vs 10.1 months; HR, 0.87; P = .1002),” the researchers reported.

■

Reference 1. Van Cutsem E, de Haas S, Kang YK, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial J Clin Oncol. May 7, 2012 (early release online).

Marrow Cells in AML continued from page 52

dominant secondary AML clone was derived from an MDS founding clone in all cases suggests that targeting early mutations in these clones could prove to be a successful treatment strategy. In addition, as stated by the investigators, “It is possible that disease progression … is driven not only by the presence of recurrent mutations…but also by the clone (ie, founding vs daughter) in which they arise. Coupling genotyping of MDS samples for prognostically important mutations with analysis of clonal architecture may yield more informative biomarkers and a better understanding of the pathogenesis of MDS.” Timothy A. Graubert, MD, a lab leader in the Stem Cell Biology Sec-

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

tion of the Division of Oncology at Washington University, and a coauthor of the study, stated “Analysis of changes in the clonal architecture of these tumors following specific treatments may help us understand the heterogeneity of responses to these treatments. We anticipate that nextgeneration sequencing results from hundreds to thousands of patients with MDS and secondary AML will allow us to improve prognostic algorithms and ultimately influence the therapeutic choices available for individual patients.”

■

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

Reference 1. Walter MJ, Shen D, Ding L, et al: Clonal architecture of secondary acute myeloid leukemia. N Engl J Med 366:10901098, 2012.

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

What’s Hot in

JOP

JCO.org esponse to a Treatment Summary and Care Plan Among Adult R Survivors of Pediatric and Young Adult Cancer

roductivity Assessment of Physician Assistants and Nurse P Practitioners in Oncology in an Academic Medical Center

Trends in Twitter Use by Physicians at the American Society of Clinical Oncology Annual Meeting, 2010 and 2011

Effects of Funding Policy Changes and Health Warnings on the Use of Erythropoiesis-Stimulating Agents

Providing Care for Cancer Survivors in Integrated Health Care Delivery Systems: Practices, Challenges, and Research Opportunities

ASCOPost.com | JUNE 15, 2012

PAGE 55

Appointments

Egidio Del Fabbro Named Program Director of Palliative Care at Virginia Commonwealth University Massey Cancer Center

gidio Del Fabbro, MD, has been named program director of palliative care at Virginia Commonwealth University (VCU) Massey Cancer Center, effective May 1, 2012.

training,” said Steven R. Grossman, MD, PhD, Chair of the Division of Hematology, Oncology and Palliative Care at VCU Massey Cancer Center.

“Dr. Del FabbroB:8.375” brings valuable knowledge and experience to an imT:7.875” portant leadership role at VCU Massey S:7” Cancer Center,” said Gordon D.

Ginder, MD, Director of VCU Massey Cancer Center. “He will significantly contribute to the Center’s excellence in cancer care, research and education.”

Egidio Del Fabbro, MD

A nationally recognized expert in palliative care, Dr. Del Fabbro comes to VCU Massey from The University of Texas MD Anderson Cancer Center in Houston, where he was Associate Professor in the Department of Palliative Care and Rehabilitation Medicine. He was also Director of the Outpatient Cachexia Clinic and Associate Director of the Palliative Care Fellowship Training Program. Dr. Del Fabbro will also serve as an Associate Professor of Internal Medicine within the Division of Hematology, Oncology and Palliative Care of the Department of Internal Medicine at the VCU School of Medicine. His specific clinical and research interests include cancer-related fatigue and cachexia. “We are delighted to have Dr. Del Fabbro join us to lead our Thomas Palliative Care Program. His addition is integral to the Program’s long-term growth and continued success as one of the world’s foremost leaders of palliative care treatment, research and

The ASCO Post Follow us on

@ASCOPost

Is there more to

angiogenesis than VEGF-A? VEGF-A DOES NOT ACT ALONE As tumors grow, other angiogenic factors such as VEGF-B and placental growth factor (PlGF) can also contribute to angiogenesis.1-3 Inhibiting additional angiogenic factors beyond VEGF-A has become an important area of oncology research. For additional information about the role of VEGF-A, VEGF-B, and PlGF in angiogenesis, go to www.VEGFandBeyond.com. Sanofi and Regeneron are investigating the potential impact of broad blockade of angiogenic growth factors, including VEGF-A, VEGF-B, and PlGF.

References: 1. Zhang F, Tang Z, Hou X, et al. VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. PNAS. 2009;106:6152-6157. 2. Taylor AP, Rodriguez M, Adams K, et al. Altered tumor vessel maturation and proliferation in placenta growth factor-producing tumors: potential relationship to post-therapy tumor angiogenesis and recurrence. Int J Cancer. 2003;105:158-164. 3. Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131:463-475. US.AFL.12.03.002 4/12 Printed in U.S.A. © 2012 sano-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.

■

The ASCO Post | JUNE 15, 2012

PAGE 56

News

International Photodynamic Medicine Symposium: Shedding New Light on an Old Therapy By Susan Reckling

his past May, a collaborative think tank of researchers was convened at The Ohio State University, Columbus, to share their expertise in a somewhat older treatment that is reemerging on many fronts: photodynamic therapy.

Patrick Ross, Jr, MD, PhD

Participants from the United States, Great Britain, and Japan took part in the inaugural International Photodynamic Medicine Symposium, hosted by Patrick Ross, Jr, MD, PhD, Chief of the Division of Thoracic Surgery; John Wilson, PhD, Associate Director; and Michael Caligiuri, MD, CEO of The Ohio State University Comprehensive Cancer Center‒James Cancer Hospital and Solove Research Institute. Clinicians from thoracic surgery, otolaryngology, gastroenterology, neurology, dermatology, radiation oncology, and hepatology joined immunologists, physicists, biochemists, and photobiologists to explore the clinical application of photodynamic therapy and review state-of-the-art research, focusing on the interplay between the laboratory and the clinic. Speakers from Great Britain represented the University of Leeds, Yorkshire Laser Center, and the University College of London. Speakers from the United States represented the University of Pennsylvania, Ro-

swell Park Cancer Institute, Medical College of Wisconsin, University of Miami, Harvard Medical School, Children’s Hospital of Los Angeles, Wayne State University, Mayo Clinic, Tufts University, and Weill Cornell Medical College, along with The Ohio State University. Supported by an unrestricted educational grant from Pinnacle Biologics, Inc, the symposium was intended as a forum to stimulate a collaborative exchange of ideas for research projects, developing concepts for clinical trials, and new applications for both diagnosis and therapy for a variety of malignancies. Featuring the most recent and relevant advances in our understanding of photodynamic therapy, the proceedings of this symposium will be published in a supplement to the Journal of the National Comprehensive Cancer Network later this year. The Ohio State University is a charter member of the National Comprehensive Cancer Network (NCCN).

Current Status Although approved in Japan since the 1990s, photodynamic therapy is being performed today in approximately 45 medical centers in the United States, according to Dr. Ross, and one photosensitizer—porfimer sodium (Photofrin)—is currently approved here. The technique has been approved for treating early and late endobronchial non–small cell lung cancers as definitive therapy for symptom management and for managing symptoms associated with advanced esophageal cancers that are not suitable for other treatment. Moreover, photodynamic therapy has been approved for treating Barrett’s

Snapshot of Photodynamic Therapy ■■ Photodynamic therapy (PDT) is currently available at approximately 45 medical centers in the United States, for use with one FDA-approved photosensitizer, porfimer sodium (Photofrin).

■■ The technique is approved to treat endobronchial non–small cell lung

cancers, esophageal cancer symptoms, and Barrett’s esophagus with highgrade dysplasia in patients who are not candidates for other treatments.

■■ PDT can be used alone but may prove most useful in conjunction with other cancer treatments.

■■ The technique is being investigated in a variety of other cancers, and phase III studies in prostate cancer are pending.

Photodynamic Therapy for Cancer

hotodynamic therapy is a two-step treatment that includes a photosensitizing agent and a light source. In the first step, the photosensitizing agent (porfimer sodium) is injected into the bloodstream and absorbed by all cells. Over 24 to 48 hours, the drug is concentrated in cancer cells. In the second step, tumor is eliminated with a laser at 630 nm; the site of treatment dictates the length of exposure, which can be 8 to 12 minutes in the airway. The light activates the photosensitizing agent, producing an active form of oxygen, which destroys nearby cancer cells. The light is directed through thin fiber optic cables. These fiber optic cables are then passed through an endoscope for esophageal tumors or a bronchoscope for lung tumors. For surface tumors such as skin cancer, other light sources may include light-emitting diodes. Not only does photodynamic therapy directly kill cancer cells, it also seems to damage the blood vessels in the tumor and may activate an immune reaction to attack the tumor cells.

Drawbacks and Advantages The one noted side effect of photodynamic therapy is photosensitivity, which may last for at least 30 days after treatment. After undergoing photodynamic therapy, it is necessary to avoid bright indoor lights and direct sunlight. Sunscreen is not protective in this case, as the photosensitivity is caused by visible light, not ultraviolet light. Some indoor light is good, however, to help break down the drug in the skin. Although photosensitivity is a concern after photodynamic therapy, with the proper precautions, nursing assistance, and patient education, it is a manageable, temporary side effect. Generally, photodynamic therapy is performed as an outpatient procedure and can be repeated. Photodynamic therapy can be used alone or in conjunction with other cancer treatments, such as surgery, radiotherapy, or chemotherapy. Ongoing studies with photodynamic therapy are focusing on how best to employ this technology as well as ways to improve its effectiveness; one promising option is to join the photosensitizing agent with a targeted chemotherapy drug. Research continues to center on refining the photosensitizing agents for a more powerful, tumor-specific result; developing light sources that can penetrate tissue and treat deeper tumors; and improving equipment and light delivery.

■

esophagus with high-grade dysplasia in patients who are not candidates for esophagectomy. It is also used to treat superficial basal cell carcinomas. Although the technique can be used alone, it may prove most useful in conjunction with other cancer treatments, such as surgery, radiotherapy, or chemotherapy. Various investigational uses of photodynamic therapy have been receiving more attention of late. For instance, speakers at this symposium shared their experiences with photodynamic therapy for superficial oral and laryngeal tumors, as an adjunct to stenting for inoperable cholangiocarcinomas, and as part of lung-sparing surgery for mesothelioma. Along with mesothelioma, other areas for which current treatment

options are few and/or ineffective include high-grade gliomas of the brain, for which photodynamic therapy is under investigation. In addition, phase III studies of photodynamic therapy for prostate cancer are pending. Other ongoing areas of research in photodynamic therapy include its immunologic effects, which are being seen in photodynamic therapy vaccines that may improve antitumor immunity. This new area of photoimmunotherapy is of particular interest to both research scientists and clinicians.

Keynote Presentation One of the highlights of the symposium was the opening keynote continued on page 58

Bristol-Myers Squibb Immuno-Oncology

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News

Photodynamic Therapy continued from page 56

presentation by the internationally renowned leader in the study of photodynamic therapy: Harubumi Kato, MD, PhD, Professor, Department of Surgery, Tokyo Medical University, Japan. Dr. Kato’s research focus has been on the detection and treatment of early-stage lung cancer. In 1980, he was the first person in the world to apply photodynamic therapy clinically to the treatment of lung cancer; since then, Dr. Kato says there has been “much progress” in photodynamic therapy. For years, Dr. Kato has used photodynamic therapyto treat early-stage centrally located squamous cell carcinoma. “We can see a central tumor by endoscope but not a peripheral cancer,” he explained. Dr. Ross added that perhaps with improvements in the light delivery system, photodynamic therapy may prove to be a useful treatment of peripheral lung tumors in the future as well. “Selection of patients for photodynamic therapy is extremely important,” reported Dr. Kato. In cases of early-stage lung, esophageal, cervical, head and neck, or skin cancer, photodynamic therapy may offer a curative benefit. Dr. Ross and Dr. Kato agreed that not all patients

Harubumi Kato, MD, PhD

with lung cancer are candidates for surgery and radiation therapy. Therefore, photodynamic therapy offers these patients a possible curative alternative with no apparent long-term side effects.

Rerouting the Thinking of Oncologists There are several reasons why photodynamic therapy has not yet moved from a niche option to a more mainstream treatment. For both Drs. Kato and Ross, the main issue may center on perspective. Dr. Kato believes that many oncologists like to treat patients with drugs, although the most effective cancer drug is about 30% effective, he said. In select patients, photodynamic therapy may represent an effective, less expensive alternative than many of the newer targeted agents. Dr. Ross agreed, adding that oncologists need to recognize the value of

this intervention, in curative, multidisciplinary, and palliative settings. In addition, many medical oncologists are not used to thinking about mechanical treatments, such as photodynamic therapy, Dr. Ross explained. “Advances in medical therapies are often based on investment,” Dr. Ross revealed. “And investment comes only when medical companies recognize a downstream market. Utilization drives research, which drives innovation, which drives investment.” The criticisms surrounding photodynamic therapy include photosensitivity for perhaps 1 month after the procedure. Although this concern is valid, many presenters at the symposium, including Dr. Ross, agree that with the proper precautions, nursing assistance, and patient education, it is a manageable side effect. Also, the long-term efficacy of photodynamic therapy has been questioned. Although long-term outcomes with this treatment are as yet unclear, Dr. Kato noted that the 5-year survival rate is 94% in cases of early superficial bronchial lung cancer. Although the medical literature contains many reports on the use of photodynamic therapy, and the majority of speakers at this symposium have obtained positive results with it for many malignancies, more formal

Scan this QR code to access a video on photodynamic therapy and how it See Page 90 works, from the Information Television Network.

phase�� III randomized, controlled trials comparing photodynamic therapy with standard treatment options are needed.

Looking Ahead In closing, the future of photodynamic therapy appears bright, particularly with this premier group of experts continuing to share emerging research findings and clinical implications of this treatment alternative. The Ohio State University organizers of this symposium hope that it will become an annual event that continues to include more proponents of photodynamic therapy from the laboratories and the surgical suites, all sharing their expertise, refining techniques, joining in clinical trials, and spreading the word.

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Disclosure: Dr. Ross is Chairman of the Scientific Advisory Board, Pinnacle Biologics. Dr. Kato reported no potential conflicts of interest.

Narratives in Oncology A Special Supplement to The ASCO Post Narratives in Oncology is a special edition of The ASCO Post and features personal profiles about oncology leaders who have made an important contribution to the clinical research and care of patients with cancer. This issue will be the first of a planned annual special edition of The ASCO Post profiling leaders in oncology.

See Page 90

Look for your copy of the supplement with this issue of The ASCO Post or visit ASCOPost.com

Now Enrolling

The Medical Division at Lilly Oncology is currently enrolling patients in a phase 3 trial of the VEGF receptor-2 antagonist ramucirumab (IMC-1121B)

REACH*: A Second-line Hepatocellular Carcinoma (HCC) Trial

Randomization

• H CC after progression on or intolerance to first-line sorafenib • C hild-Pugh score of <9 (Child-Pugh A or B [B7 or B8]) • A t least 1 measurable or evaluable viable lesion not previously treated with locoregional therapy

N=~544

Best supportive care + blinded ramucirumab 8 mg/kg IV infusion every 2 weeks

Best supportive care + blinded placebo 8 mg/kg IV infusion every 2 weeks

Treat until progressive disease, intolerable toxicity, noncompliance, withdrawal of consent, or investigator decision

Study Objectives Primary endpoint:

Secondary endpoints:

• Overall survival (OS)

• Progression-free survival (PFS)

• Safety profile of ramucirumab

• Best objective response rate (ORR)

• Ramucirumab serum concentrations

• Time to radiographic progression

• Pharmacodynamics of ramucirumab

• P atient-reported outcome (PRO) measures of disease-specific symptoms and health-related quality of life

• Immunogenicity of ramucirumab

For further information, please contact ImClone Systems by e-mail at ClinicalTrials@imclone.com or visit www.clinicaltrials.gov (identifier number NCT01140347). Note that, for an investigator to participate, the study must be approved by the investigator’s country competent health authority. Ramucirumab (IMC-1121B) is an investigational new drug. The safety and efficacy of ramucirumab have not been established for the use under investigation. There is no guarantee that ramucirumab will receive regulatory approval and become commercially available for the use under investigation.

* REACH: A Multicenter, Randomized, Double-blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) versus Placebo and BSC as Second-line Treatment in Patients With Hepatocellular Carcinoma Following First-line Therapy With Sorafenib

The ASCO Post | JUNE 15, 2012

PAGE 60

FDA Update

Drug Safety Communication Issued Regarding Lenalidomide and Risk of New Malignancies

he FDA recently released a safety announcement about an increased risk of second primary malignancies in patients with newly diagnosed multiple myeloma who received treatment with lenalidomide (Revlimid). Clinical trials conducted after lenalidomide was approved showed that newly diagnosed patients treated with the drug had an increased risk of developing second primary malignancies compared to similar patients who received a placebo. Specifically, these trials showed there was an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma. This safety information has been added to the Warnings and Precautions section of the lenalidomide drug label. The patient Medication Guide accompanying lenalidomide prescriptions is also being updated to inform patients about this risk. Health-care professionals should consider both the potential benefit of lenalidomide and the risk of second primary malignancies when decid-

FDA Approves Drugs Faster than Canadian and European Counterparts

ccording to a study published online in The New England Journal of Medicine (May 16, 2012), the FDA approved more new drugs in less time—about 15% faster—than the European Medicines Agency and Health Canada. The analysis compared drug review performance for the three agencies from 2001 to 2010. The majority of the new agents were first approved for use in the United States. “[T]he vast majority of the novel therapeutics first received approval for use in the United States,” the investigators reported. “Furthermore, both first-review and total review times at the FDA were essentially the same for applications submitted during the [Prescription Drug User Fee Act (PDUFA)] III and PDUFA IV periods. These findings contradict recent criticisms of the speed of review by the FDA and question whether review speed is justified as an emphasis for PDUFA V, particularly since the FDA continues to outpace its European and Canadian peers.”

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ing to treat patients with this drug, and monitor patients for this risk. In April 2011, FDA announced an ongoing safety review to evaluate

the possible increased risk of second primary malignancies with Revlimid. FDA performed a comprehensive review of this safety issue.

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TREANDA® is her chemo.

This is her therapy.

ASCOPost.com | JUNE 15, 2012

PAGE 61

FDA Update

Aflibercept Granted Priority Review for Metastatic Colorectal Cancer

anofi and Regeneron Pharmaceuticals, Inc, recently announced that the FDA has granted Priority Review of the Biologics License Application (BLA) for the investigational agent aflibercept (Zaltrap) concentrate for solution for infusion

in combination with irinotecan/fluoropyrimidine–based chemotherapy in patients with metastatic colorectal cancer previously treated with an oxaliplatin-containing regimen. Under Priority Review, the target date for an FDA decision on the

aflibercept BLA is August 4, 2012. The filing was based on the phase III VELOUR study in 1,226 patients with metastatic colorectal cancer previously treated with an oxaliplatin-containing regimen. Aflibercept, also known in the scientif-

Single-agent TREANDA tripled median PFS in patients with CLL*

Survival distribution function

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

• TREANDA was generally well tolerated in the pivotal phase 3 trial

6 months median PFS

P<.0001

• The most common non-hematologic adverse reactions (frequency ≥15%) were pyrexia (24%), nausea (20%), and vomiting (16%) (n=153). The most common hematologic abnormalities (frequency ≥15%) were anemia (89%), thrombocytopenia (77%), neutropenia (75%), lymphopenia (68%), and leukopenia (61%) (n=150)

HR†=0.27 (95% CI‡: 0.17, 0.43)

• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatmentnaïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301). Patients were scheduled to receive either TREANDA 100 mg/m2 intravenously on Days 1 and 2 (n=153) or chlorambucil 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles

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

Single-agent TREANDA produced a 74% ORR§ in patients with indolent B-cell NHL that had progressed ORR§: INDOLENT B-CELL NON-HODGKIN’S LYMPHOMA (NHL) THAT HAS PROGRESSED

57%

PR (n=57)

17%

CR/CRu (n=17)

74%

Total ORR

(95% CI: 64.3, 82.3)

100

Patients responding (%) §

Overall response rate (ORR) was defined as a best response of a complete response (CR), unconfirmed complete response (CRu), or partial response (PR) during the study (ORR=CR+CRu+PR). Independent Review Committee assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be ≥20 mm.

• TREANDA was evaluated in a single-arm pivotal study of 100 patients with indolent B-cell NHL that had progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Patients were scheduled to receive TREANDA 120 mg/m2 on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles • TREANDA was generally well tolerated in 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176) • The most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%) (N=176). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%)

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Selected Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment. Myelosuppression is frequently severe and should be expected when treating patients with TREANDA • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA

Discover the elements of efficacy and safety LEARN MORE AT TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

ic literature as VEGF Trap, is an investigational angiogenesis inhibitor with a unique mechanism of action. This fusion protein binds multiple forms of vascular endothelial growth factor-A (VEGF-A), as well as VEGF-B and placental growth factor.

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The ASCO Post | JUNE 15, 2012

PAGE 62

FDA Update

FDA-led Research Team Discovers Autoimmune Mechanism for Drug-induced Adverse Reactions

team of researchers led by the FDA has discovered a new mechanism for identifying and understanding drug-related autoimmune reac-

tions. In an article available online in the journal AIDS, the team reported that in certain at-risk patients, the antiHIV drug abacavir (Ziagen) causes

the immune system to “see” a patient’s own healthy tissues and proteins as a foreign invader. The effect is similar to what happens when the immune sys-

Brief Summary of Prescribing Information INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table 4). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration] Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

tem recognizes a viral or bacterial protein during an infection. Abacavir is known to cause allergic reactions in certain, at-risk pa-

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued) Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study

Laboratory Abnormality Hemoglobin Decreased Platelets Decreased Leukocytes Decreased Lymphocytes Decreased Neutrophils Decreased

TREANDA (N=150) All Grades Grade 3/4 n (%) n (%) 134 (89) 20 (13) 116 (77) 16 (11) 92 (61) 42 (28) 102 (68) 70 (47) 113 (75) 65 (43)

Chlorambucil (N=141) All Grades Grade 3/4 n (%) n (%) 115 (82) 12 (9) 110 (78) 14 (10) 26 (18) 4 (3) 27 (19) 6 (4) 86 (61) 30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two singlearm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) System organ class Preferred term Total number of patients with at least 1 adverse reaction Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia Gastroesophageal reflux disease Dry mouth Abdominal pain upper Abdominal distension General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain

Number (%) of patients* All Grades Grade 3/4 176 (100) 94 (53) 13 (7)

132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 18 (10) 15 (9) 8 (5) 8 (5)

7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0

101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5)

19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; JUNE 15, 2012

PAGE 63

FDA Update

tients. These reactions can range from mild skin reactions to severe allergic shock and even death. Abacavir interacts with human leukocyte antigens (HLAs), specifically HLA-B*5701, which help the body to distinguish â&#x20AC;&#x153;self â&#x20AC;? vs â&#x20AC;&#x153;foreignâ&#x20AC;? proteins. The drug can cause HLA-B*5701 to present for

the first time certain â&#x20AC;&#x153;self â&#x20AC;? proteins that the body has not seen before. Because the body has not previously recognized these â&#x20AC;&#x153;self â&#x20AC;? proteins, it mistakenly treats them as foreign, resulting in the body trying to destroy its own tissues. HLA-B*5701 is known to be a risk factor for serious

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) (continued) System organ class Number (%) of patients* Preferred term All Grades Grade 3/4 Infections and infestations Herpes zoster 18 (10) 5 (3) Upper respiratory tract infection 18 (10) 0 Urinary tract infection 17 (10) 4 (2) Sinusitis 15 (9) 0 Pneumonia 14 (8) 9 (5) Febrile Neutropenia 11 (6) 11 (6) Oral Candidiasis 11 (6) 2 (1) Nasopharyngitis 11 (6) 0 Investigations Weight decreased 31 (18) 3 (2) Metabolism and nutrition disorders Anorexia 40 (23) 3 (2) Dehydration 24 (14) 8 (5) Decreased appetite 22 (13) 1 (<1) Hypokalemia 15 (9) 9 (5) Musculoskeletal and connective tissue disorders Back pain 25 (14) 5 (3) Arthralgia 11 (6) 0 Pain in extremity 8 (5) 2 (1) Bone pain 8 (5) 0 Nervous system disorders Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) 0 Psychiatric disorders Insomnia 23 (13) 0 Anxiety 14 (8) 1 (<1) Depression 10 (6) 0 Respiratory, thoracic and mediastinal disorders Cough 38 (22) 1 (<1) Dyspnea 28 (16) 3 (2) Pharyngolaryngeal pain 14 (8) 1 (<1) Wheezing 8 (5) 0 Nasal congestion 8 (5) 0 Skin and subcutaneous tissue disorders Rash 28 (16) 1 (<1) Pruritus 11 (6) 0 Dry skin 9 (5) 0 Night sweats 9 (5) 0 Hyperhidrosis 8 (5) 0 Vascular disorders Hypotension 10 (6) 2 (1) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category. Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients All Grades Grade 3/4 99 94 94 56 88 11 86 60 86 25

Hematology Variable Lymphocytes Decreased Leukocytes Decreased Hemoglobin Decreased Neutrophils Decreased Platelets Decreased

reactions to abacavir. â&#x20AC;&#x153;This discovery is a new step towards understanding how and why certain drugs cause severe allergic reactions in some patients,â&#x20AC;? said Janet Woodcock, MD, Director of FDAâ&#x20AC;&#x2122;s Center for Drug Evaluation and Research. â&#x20AC;&#x153;We hope that, in the future,

TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant â&#x2030;ĽÂ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to â&#x2030;¤Â Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) â&#x2030;ĽÂ 1 x 109/L, platelets â&#x2030;ĽÂ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant â&#x2030;ĽÂ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to â&#x2030;¤Â Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) â&#x2030;ĽÂ 1 x 109/L, platelets â&#x2030;ĽÂ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. s !SEPTICALLY RECONSTITUTE EACH 42%!.$! VIAL AS FOLLOWS s MG 42%!.$! VIAL !DD M, OF ONLY Sterile Water for Injection, USP s MG 42%!.$! VIAL !DD M, OF ONLY Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. s !SEPTICALLY WITHDRAW THE VOLUME NEEDED FOR THE REQUIRED DOSE BASED ON MG M, CONCENTRATION and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2â&#x20AC;&#x201C;0.6 mg/ mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture SHOULD BE A CLEAR AND COLORLESS TO SLIGHTLY YELLOW SOLUTION s 5SE 3TERILE 7ATER FOR )NJECTION 530 for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown TO BE COMPATIBLE s 0ARENTERAL DRUG PRODUCTS SHOULD BE INSPECTED VISUALLY FOR PARTICULATE MATTER AND discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8Â°C or 36-47Â°F) or for 3 hours when stored at room temperature (15-30Â°C or 59-86Â°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25Â°C (77Â°F) with excursions permitted up to 30Â°C (86Â°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in â&#x2030;Ľ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. PostMarketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 50

DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ÂŠ2008-2010 Cephalon, Inc., or its affiliates. TRE-2487 (Label Code: 00016287.06) This brief summary is based on TRE-006 TREANDA full Prescribing Information.

March 2012

health-care professionals will be able to identify people who are at high risk of developing serious reactions to various drugs, and offer them alternative treatments.â&#x20AC;? The research teamâ&#x20AC;&#x2122;s work will provide the FDA with new tools to analyze the safety of drugs that have the potential to cause severe allergic reactions. This latest discovery will advance the FDAâ&#x20AC;&#x2122;s ability to approve therapies that are personalized for safety. The results also may give biopharmaceutical companies and other research organizations new methods to identify early in the development process drugs with the potential to cause severe adverse drug reactions. This may also serve as a model for future research to predict drug reactions in different populations of at-risk patients.

â&#x2013;

New Breast Biopsy System with Vacuum Technology Approved

evicor Medical Products, Inc, announced that it has received 510(k) clearance from the FDA for the Mammotome elite Biopsy System, a tetherless single-insertion, multiplesample, vacuum-assisted biopsy device featuring proprietary vacuum technology. Devicor also announced the commercial launch of the device. The new system provides a vacuum that achieves nearly the same suction power of the traditional Mammotome vacuum-assisted biopsy system, enabling the device to capture large, high-quality tissue samples. The Mammotome elite Biopsy System will be used to aid in the detection and treatment of breast cancer in ultrasound-guided breast and axillary lymph node biopsies. The system includes a reusable holster, a charging base, and a single-patient-use disposable 13-gauge probe with a bladed insertion tip. This tip is designed to move easily through tissue while allowing physicians to maintain control of the needle even in problematic dense breast tissue. The new lightweight ergonomic design of elite provides superior control for precise needle placement and easy insertion.

â&#x2013;

The ASCO Post | JUNE 15, 2012

PAGE 64

Journal Spotlight Genitourinary Oncology

Denosumab Delays Time to First Bone Metastasis in Men with Castration-resistant Prostate Cancer By Charlotte Bath

enosumab (Xgeva) significantly delayed time to first bone metastases among men with nonmetastatic castration-resistant prostate cancer enrolled in a phase III randomized, placebo-controlled trial. The time to first bone metastasis was 33.2 months among the 716 patients randomly assigned to receive subcutaneous denosumab vs 29.5 months for an equal number of patients randomly assigned to placebo (P = .032). Denosumab significantly increased bone metastasis–free survival (defined as the time to either the first metastasis or death) by a median of 4.2 months (P = .028), but not overall survival, which was 43.9 months among patients receiving denosumab vs 44.8 months for those receiving placebo (P = .91).

Unmet Clinical Need

“Prostate cancer patients who develop bone metastases usually have poor outcomes, so preventing the development of metastasis has been a major unmet clinical need,” stated Matthew Smith, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, the lead author of the study report published in The Lancet.1 “This first demonstration of a treatment that can meet that goal is a significant accomplishment that should lead to better treatment strategies,” he said.

Matthew Smith, MD, PhD

“Our findings also provide the first direct clinical evidence for the important role of the bone microenvironment and RANKL signaling in the development of bone metastases in men with prostate cancer,” the investigators reported. RANKL is “an essential mediator of osteoclast formation, function, and survival,” the investigators noted, and denosumab, a fully hu-

man monoclonal antibody, specifically binds and inactivates RANKL. “The trial was extremely well conducted,” Christopher J. Logothetis, MD, said in an interview with The ASCO Post. Dr. Logothetis is Chair of the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, and wrote a comment2 accompanying the article by Dr. Smith and colleagues. “For the first time, they have demonstrated that there is a delay in the time to detectable bone metastases, but they provide no evidence that denosumab impacts overall survival,” Dr. Logothetis noted.

Denosumab Discontinuation All study patients received a bilateral orchiectomy or continuous androgen-deprivation therapy with a gonadotropin-releasing hormone agonist or antagonist for at least 6 months before starting the study. Total serum testosterone had to be lower than 1.72 nmol/L (50 ng/dL), and the men had to be castration-resistant with three consecutive increasing prostatespecific antigen (PSA) tests, the last two 1.0 μg/L or higher. All the men were considered at high risk for bone metastases, characterized by “PSA of 8.0 μg/L or higher within 3 months before randomization or PSA doubling time of 10 months or less, or both,” the authors wrote. Subcutaneous denosumab at 120 mg or subcutaneous placebo (sterile saline) was administered every 4 weeks. (The FDA has approved denosumab as two different products, one for treating osteoporosis [Prolia] and the other for the prevention of skeletal-related events in patients with solid tumors and bone metastases [Xgeva]. Both brand name formulations are marketed by Amgen, which funded the study.) “Patients were discontinued from treatment when bone metastasis occurred so that they could receive standard treatment for bone metastasis per investigator discretion,” the authors reported. Discontinuation of denosumab was required by the study protocol, and this requirement, the investigators stated, “restricted our ability to evaluate overall survival with

denosumab, since about 80% of the deaths occurred in patients who had discontinued investigational product. With a median time from bone metastasis to death of 19 months, a treatment effect of denosumab on overall survival would be difficult to identify, particularly in the context of all other prostate cancer therapies used during that period that could affect survival. This same requirement also limited our ability to establish when asymptomatic bone metastases became symptomatic, since patients were removed from the study once a bone metastasis was detected and symptoms might not yet have occurred,” they added. “If they were looking for greater impact,” Dr. Logothetis said, the investigators should have continued giving denosumab to patients even after evidence of metastases. “If there is one criticism of the study,” he added, it is that both arms of the study should have been continued to see if the benefit from denosumab extended out further.

Dilemma Related to Timing The dilemma, according to Dr. Logothetis, concerns whether there is sufficient evidence to recommend denosumab for patients who have high-risk features as defined in the study. “[T]he delay in time to metastases documented by Smith and colleagues is similar to the delay in time to skeletal-related events reported in a comparison of denosumab against zoledronic acid in men with metastatic castration-resistant prostate cancer,” he wrote in The Lancet, citing a study by Fizazi et al.3 “Because the duration of benefit is similar in both the premetastatic and metastatic settings with no prolongation of survival in either group, deferral of treatment until metastases are evident is the preferred approach,” Dr. Logothetis commented. “Despite differences in the study design, the magnitude of benefit attributed to denosumab is approximately equal in the premetastatic and (previously reported) metastatic settings. This similarity challenges the notion that benefit will be lost if deno-

Christopher J. Logothetis, MD

sumab therapy is delayed,” he told The ASCO Post. “The next question is, how do we address this dilemma?” Dr. Logothetis said. Rather than using “the blunt instrument of a bisphosphonate,” distinct agents that target specific molecular pathways are being developed, and theoretically, it should be possible to select the patients likely to benefit. “We have to work toward better identifying subsets most likely to benefit, with an impact on survival.” Markers for identifying these subsets of patients do not currently exist, “but we are all in a hurry working on them,” Dr. Logothetis said. “Candidate markers are being considered,” he noted, but “they are not ready for prime time.” Smith and colleagues “provided the first proof of principle that you can target a molecular pathway to prolong survival [in this setting],” Dr. Logothetis added. “So if we understood better how to select patients based on that molecular pathway, theoretically, we would get a greater advantage.”

■

Disclosure: Drs. Smith and Logothetis reported no potential conflicts of interest.

References 1. Smith MR, Saad F, Coleman R, et al: Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: Results of a phase 3, randomised, placebo-controlled trial. Lancet 379:39-46, 2012. 2. Logothetis CJ: Treatment of prostate cancer metastases: More than semantics. Lancet 379:4-6, 2012. 3. Fizazi K, Carducci M, Smith M, et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study. Lancet 377:813-822, 2011.

Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

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

DECODE

metastatic melanoma

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

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

EXTEND

survival

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

P<0.0001

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

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

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

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

Please see Brief Summary of Prescribing Information on the following page. References: 1. Smalley KS, Sondak VK. Melanoma—an unlikely poster child for personalized cancer therapy. N Engl J Med. 2010;363:876-878. 2. Flaherty KT. Next generation therapies change the landscape in melanoma. F1000 Med Reports. http://f1000.com/reports/m/3/8. Published April 1, 2011. Accessed July 14, 2011. 3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.

zelboraf.com

The ASCO Post | JUNE 15, 2012

PAGE 68

FDA Update

New Drug Application Submitted for Regorafenib for the Treatment of Metastatic Colorectal Cancer

ayer HealthCare announced that it has submitted a New Drug Application (NDA) to the FDA seeking approval for the oral

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.

the pivotal, global phase� �� III COR� RECT (Colorectal Cancer Treated with Regorafenib or Placebo after Failure of Standard Therapy) trial.

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

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

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

Results from the study were first pre� sented at the Gastrointestinal Can� cers Symposium in January 2012 and were subsequently presented at the ASCO Annual Meeting in Chicago this month.

CORRECT Study The CORRECT study was an international, multicenter, random� ized, double-blind, placebo-con� trolled phase III study that enrolled 760 patients with metastatic colorec� tal cancer whose disease had pro� gressed during or within 3 months following last administration of ap� proved standard therapies. Patients who had withdrawn from standard treatment due to unacceptable tox� icity warranting discontinuation of treatment and precluding retreat� ment with the same agent prior to progression of disease were also al� lowed into the study. Patients were randomized to re� ceive either regorafenib plus best supportive care or placebo plus best supportive care. Treatment cycles consisted of 160 mg of regorafenib (or matching placebo) once daily for 3 weeks on/1 week off plus best sup� portive care. The study was conducted in North America, Europe, China, Japan, and Australia. Safety:10"

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

multikinase inhibitor regorafenib for the treatment of patients with metastatic colorectal cancer. The submission Safety:7" is based on the results of

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

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PAGE 69

2012 Oncology Meetings June

July

World Conference on Interventional Oncology June 14-17 • Chicago, Illinois For more information: www.wcio2012.org

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

Emerging Strategies in Treatment of Non-Small Cell Lung Cancer and Head & Neck Cancer June 16 • Atlanta, Georgia For more information: http://cancernetus.com 8th Central European Oncology Congress: Best of ASCO 2012 June 17-20 • Opatija, Croatia For more information: www.penta-pco.com/ceoc2012

Cancer Vaccines & Active Immunotherapeutics: 3rd Annual Summit June 26-28 • Boston, Massachusetts For more information: http://cancervaccines-meeting.com MASCC/ISOO International Symposium on Supportive Care in Cancer June 28–30 • New York, New York For more information: www.kenes.com/mascc

Health Effects of Chernobyl Catastrophe: A Quarter of a Century September 1-2 • Kiev, Ukraine For more information: www.nbscience.com/20.html

10th International Congress on Targeted Therapies in Cancer August 10-12 • Washington, DC For more information: http://cancerlearning.onclive.com

Multidisciplinary Symposium in Thoracic Oncology September 6-8 • Chicago, Illinois For more information: http://thoracicsymposium.org

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

Melanocytes and Melanoma: From Basic Science to Clinical Applications June 18-20 • Malmö, Sweden For more information: www.melanoma2012.org 4th Molecular Diagnostics for Cancer Drug Development June 25-28 • Boston, Massachusetts For more information: http://moleculardiagnosticscancer.com

September

Best of ASCO® San Diego August 10-11 • San Diego, California For more information: http://boa2012.asco.org

Pan Pacific Lymphoma Conference July 17-20 • Lahaina, Maui, Hawaii For more information: unmc.edu/panpacificlymphoma

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

17th International Conference on Cancer Nursing September 9–13 • Prague, Czech Republic For more information: www.isncc.org/ conference/17th_ICCN

Pan Pacific

2012

Lymphoma Conference

5th Latin American Lung Cancer Conference July 25-27 • Rio De Janeiro, Brazil For more information: www.lalca2012.org

Tuesday-Friday Tuesday-Friday

July July 17-20, 17-20, 2012 2012 Hyatt Hyatt Regency Regency Maui Maui Resort Resort & & Spa Spa Lahaina, Lahaina, Maui, Maui, Hawaii Hawaii

A A comprehensive comprehensive conference conference by by internationally internationally recognized recognized speakers speakers presenting presenting the the most most recent recent developments developments in in lymphoma lymphoma and and transplantation. transplantation.

Conference Directors James James O. O. Armitage, Armitage, MD MD

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

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

9th Asia Pacific Musculoskeletal Tumor Society Meeting September 6-9 • Kuala Lumpur, Malaysia For more information: apmsts2012.com

continued on page 70

13th International Lung Cancer Congress July 19-22 • Huntington Beach, California For more information: http://cancerlearning.onclive.com

11th International Congress on the Future of Breast Cancer July 26-28 • Coronado, California For more information: http://cancerlearning.onclive.com

8th International Jordan Oncology Society Conference September 6-8 • Amman, Jordan For more information: http://jo-events.com/jos-conference

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

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

CALL CALL FOR FOR ABSTRACTS: ABSTRACTS: April April 16, 16, 2012 2012

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2012 Oncology Meetings 2012 Oncology Meetings continued from page 69

9th International Symposium on Melanoma and Other Cutaneous Malignancies September 12 • Chicago, Illinois For more information: http://cancerlearning.onclive.com 2012 Breast Cancer Symposium September 13-15 • San Francisco, California For more information: http://breastcasym.org 32nd Congress of the European Society of Clinical Oncology September 19-21 • Valencia, Spain For more information: www.ecco-org.eu

American Society of Head and Neck Radiology 46th Annual Meeting October 3-7 • Miami Beach, Florida For more information: www.ashnr.org

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

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

9th Annual School of Breast Oncology October 25-28 • Atlanta, Georgia For more information: http://cancerlearning.onclive.com

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

3rd International Conference on Stem Cells and Cancer October 27-30 • New Delhi, Delhi, India For more information: www.iscc.in IASLC 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

Congress of Oncologists September 20-22 • Sudak, Ukraine For more information: http://nbscience.com/congress-ofoncologists 8th Annual Symposium on Controversies and Clinical Challenges in Myeloma, Lymphoma, and Leukemia September 21-23 • Pasadena, California For more information: http://cancerlearning.onclive.com Sydney Cancer Conference September 27-28 • Sydney, Australia For more information: sydney.edu.au/cancer-research/ SCC2012 37th ESMO Congress September 28-October 2 • Vienna, Austria For more information: www.esmo.org

October 27th Annual Critical Issues in Tumor Microenvironment, Angiogenesis, and Metastasis October 1-4 • Cambridge, Massachusetts For more information: http://steele.mgh.harvard.edu ACCC National Oncology Conference October 3-6 • San Antonio, Texas For more information: http://accc-cancer.org

32nd Annual Oncology Nurses Symposium October 7-10 • San Diego, California For more information: www.scripps.org

ASTRO’s 54th Annual Meeting October 28-31 • Boston, Massachusetts For more information: www.astro.org

Chemotherapy Foundation Symposium XXX November 6-10 • New York, New York For more information: http://chemotherapyfoundation symposium.org 7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org 17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com

3rd International Breast Cancer Prevention Symposium October 10-12 • Lafayette, Indiana For more information: www.purdue.edu/breastcancer

RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/

Western Neuroradiological Society 44th Annual Meeting October 18-21 • Sedona, Arizona For more information: www.wnrs.org

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

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

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

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

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

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

In the treatment of myelofibrosis What does

REGULATING JAK mean for your patients?

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

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*Intermediate or high-risk MF.

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

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

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

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

150

40 20 0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

100 50 0 -50

IMPROVEMENT WORSENING

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

-100

50% Improvement Upper 50th Percentile

Placebo (n = 153)

Upper 50th Percentile

Jakafi (n = 145)

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

Placebo (n = 145)

Worsening of TSS is truncated at 150%.

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

Visit www.jakafi.com/regulate

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

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

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

b Symptom

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

References: 1. Jakafi Prescribing Information. Incyte Corporation. November 2011. 2. Data on file. Incyte Corporation.

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

JAK targeted to make a difference

NC007 JK0 BS 12P_Layout 1 11/16/11 9:16 AM Page 1

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

ASCOPost.com | JUNE 15, 2012

PAGE 75

Issues in Oncology

ASCO Reexamines the Oncology Workforce Shortage By Jo Cavallo

study commissioned by ASCO in 2006 predicted a significant shortage of medical and gynecologic oncologists in the United States by 2020. As a result, the organization created the Workforce Implementa� tion Group to develop recommenda� tions to stem the projected workforce shortfall and ensure ongoing care for the rising number of cancer sur� vivors. The study, published the fol� lowing year in the Journal of Oncology Practice,1 forecasted a looming perfect storm of events that included an ag� ing and growing population, increas� ing numbers of cancer survivors, and an aging and retiring oncology work� force, which together would result in a shortage of between 2,550 and 4,080 oncologists by the next decade—ap� proximately one-quarter to one-third of the supply of oncologists in 2005.

Workforce Shortage Projections Today, new indicators are show� ing that while demand for health-care services may be increasing, the way it is delivered is changing, possibly al� tering the future shortfall projections of oncologists. “When we published our first study, we were trying to get

a snapshot of what was going on in the oncology world. This established a baseline from which we set up a da� tabase that now allows us to be aware of changes in real time, and thus, to be more proactive,” said Michael A. Goldstein, MD, Co-chair of ASCO’s Workforce Advisory Group and Workforce in Oncology Task Force, and an oncologist at Beth Israel Dea� coness Medical Center in Boston. “Since that time, there has been a shift in where and how clinical care is delivered. A lot of small practices have amalgamated or been bought out by hospitals, and some have actu� ally closed. So the distribution of on� cologists has changed, and we don’t yet know whether those changes will bring increased or diminished effi� ciency and capacity.” The financial recession, which be� gan in late 2007 and still lingers today, is also having an effect on the oncology workforce, possibly rendering the ear� lier projections obsolete. “At the time the study was published, the economic decline hadn’t yet started. A lot of phy� sicians who were going to retire have not retired, and some have even come back into the workforce for financial

Choosing Wisely® Campaign

SCO recently published a detailed review of the “Top Five” opportunities to improve the quality and value of cancer care by curbing use of common tests and treatments that are not supported by clinical evidence. Published in the Journal of Clinical Oncology,1 the article coincided with the announcement of several Top Five lists as part of the Choosing Wisely® campaign, which is sponsored by the American Board of Internal Medicine Foundation. The JCO article summarizes each element of the oncology Top Five list, which includes: unnecessary use of chemotherapy for patients with advanced cancers who are unlikely to benefit; use of advanced, costly imaging technolo� gies for staging of early breast and prostate cancers and for detection of breast cancer recurrence; and overuse of drugs to stimulate white blood cell produc� tion in patients receiving chemotherapy. Lowell E. Schnipper, MD, lead author of the JCO article and chair of ASCO’s Cost of Care Task Force, said “By tackling the overuse of treatments and tests for some of the most common cancers, we hope to achieve substan� tial improvements in the quality of cancer care in the U.S. The Top Five list is just the first step in an ongoing ASCO effort to help physicians and patients implement these recommendations.” For more information on the Choosing Wisely campaign and ASCO’s ef� forts to improve cancer care, visit asco.org/topfive.

■

Reference 1. Schnipper LE, Smith TJ, Raghavan D, et al: American Society of Clinical Oncol� ogy Identifies Five Key Opportunities to Improve Care and Reduce Costs: The Top Five List for Oncology. J Clin Oncol. April 3, 2012 (early release online).

In the model going forward, the oncologist is going to be more of a supervisor overseeing care delivered by other people. The oncologist will deal with the more stressful, more acute, or more serious cases. —Michael A. Goldstein, MD

reasons, so the supply projections are probably inaccurate,” said Michael P. Kosty, MD, a member of the Work� force Advisory Group and Director of the Scripps Green Cancer Center in La Jolla, California. Advances in treatment, such as oral cancer medications, which patients ad� minister themselves, and the increas� ing use of nonphysician practitioners in oncology practices, are also eas� ing demand on oncologists’ time. “In both formal and informal canvassing of oncologists around the country, we found that very few practices are in a situation where they are overrun with patients and the waiting times are ex� orbitant. I think there is a feeling that there still will be a shortage of oncol� ogy specialists, but the magnitude might be different from even the most optimistic projection in the 2007 pa� per,” said Dr. Kosty.

activities, work hours, and patient visit rates to the use of nurse practitioners and physician assistants.

How Medical Care Is Delivered To get an updated picture of what the future supply and demand for on� cologists may be over the next decade, ASCO is launching a new survey and expects to have some results in about 18 months. ASCO has also established an oncology database to track the number of practicing oncologists in real time. Currently, ASCO puts that number at approximately 14,000.

Temporary Reprieve Although the economic downturn may be keeping physicians in the work� force longer than they had planned, the lull in a projected workforce shortage may be short-lived. “At the time of the study, we did not contemplate a scenar� io where the economy was in such bad condition, so it is plausible that physi� cians are staying in practice longer than they have in the past due to the eco� nomic situation,” said Clese Erikson, Director of the Center for Workforce Studies at the Association of Ameri� can Medical Colleges (AAMC). “But presumably the economy is going to re� cover, and we may have a lot of pent up demand to retire,” she added. The AAMC conducted ASCO’s 2006 Survey of Practicing Oncologists, which collected data from practicing oncologists, oncology fellows, and on� cology fellowship program directors. The questions on the survey explored issues ranging from current practice

Clese Erikson

Even if the predicted workforce shortages in the coming years come true, better coordination in how on� cology care is delivered through ini� tiatives such as team-based medical homes and Choosing Wisely (see side� bar)—which calls for the reduction of unnecessary procedures and tests— may help mitigate the problem. “We are seeing dramatic changes in the personnel involved in delivering health care,” said Dr. Goldstein. “The study we did about the use of nonphysician pro� viders in oncology practices showed that [nonphysician practitioners] are widely employed.2 They increase efficiency and are very well accepted by both physicians and patients, so in the model going for� ward, the oncologist is going to be more of a supervisor overseeing care delivered by other people. The oncologist will deal continued on page 76

The ASCO Post | JUNE 15, 2012

PAGE 76

Issues in Oncology

Oncology Workforce Shortage continued from page 75

with the more stressful, more acute, or more serious cases.”

Further Uncertainties Adding to the uncertainty over the future supply and demand of oncology services in the United States is the impact of the Patient Protection and Affordable Care Act, which will expand health-care coverage to 32 million previously uninsured Americans by 2014. (A decision by the U.S. Supreme Court on the constitutionality of the law is anticipated this month.) Although the greatest workforce shortfall is expected to come in the number of primary care physicians— the AAMC is predicting a shortage of 27,200 primary care physicians in 2014; rising to 45,400 by 2020—the impact may trickle down to other medical specialties, including oncology. “If you look at the specialties people go into after their internal medical residencies, cardiology is number 1 and hematology/oncology and gastroenterology are numbers 2 and 3, depending on the year. ASCO and those of us in medical oncology are doing what we can to make oncology an attractive career choice,” said Dr. Kosty. “But one of the consequences of that is unless more people go into internal medicine and then subspecialize, we’re going to be creating a potential shortage in other medical specialties.” The Workforce Advisory Group realized early on that it would need a multifaceted approach to solve a potential future deficit in the number of practicing oncologists and help physicians remain active longer. Thus, the group is examining how strategies such as job sharing and part-time employment might be appealing to oncologists as they move through different stages in their careers and look to balance work and private life. “More women are going into oncology, and one of the consequences of that is they take time off to have children and raise families. In general, both men and women going into medicine today have a different outlook on life and are less willing to sacrifice everything for their career. We have to become more creative in [accommodating different lifestyle needs],” said Dr. Kosty.

Joint Initiatives The Workforce Advisory Group is also engaging in joint initiatives with nonphysician oncology professionals and general practice physicians to

study the workforce shortage problem and come up with solutions. “We now have close relationships with the American Academy of Physician Assistants and the Oncology Nursing Society and interact with oncology nurse practitioners, so we have a much more team-oriented approach. We’re

also validating the demand projection to see if it’s still on the same curve as originally predicted. I think it’s much more of an organic and ongoing process than just taking a snapshot in time with a survey,” said Dr. Goldstein.

■

Disclosure: Drs. Goldstein and Kosty and Ms. Erikson reported no potential conflicts of interest.

References 1. Erikson C, Salsberg E, Forte G, et al: Future supply and demand for oncologists: Challenges to assuring access to oncology services J Oncol Pract 3:79-86, 2007. 2. Towle E, Hanley A: Examining the role of nonphysician practitioners in oncology practice. Oncology Metrics, 2011.

ASCOPost.com | JUNE 15, 2012

PAGE 77

In the Clinic Hematology

Newest Indication for Rituximab as Maintenance Treatment in Non‑Hodgkin Lymphoma By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommen-

dations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication

he CD20-directed monoclonal antibody rituximab (Rituxan)

was recently approved for single-agent maintenance therapy in patients with previously untreated follicular, CD20positive, B-cell non-Hodgkin lymphoma (NHL) who achieved a complete or partial response to rituximab in combination with first-line chemotherapy.1,2 Rituximab has prior NHL indications in relapsed or refractory lowgrade or follicular CD20-positive Bcell NHL as a single agent; previously untreated follicular CD20-positive B-cell NHL in combination with firstline chemotherapy; nonprogressing low-grade CD20-positive B-cell NHL as a single agent after first-line CVP chemotherapy (cyclophosphamide, vincristine, and prednisone); and previously untreated diffuse large B-cell CD20-positive NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or other anthracycline-based regimens. Rituximab also has indications in chronic lymphocytic leukemia, as well as in rheumatoid arthritis, Wegener’s granulomatosis, and microscopic polyangiitis. Approval of rituximab as maintenance therapy was based on an open-label randomized trial (Primary Rituximab and Maintenance [PRIMA] study) comparing rituximab maintenance (n = 505) vs observation (n = 513) for 2 years in 1,018 patients continued on page 78

Maintenance Rituximab in Non-Hodgkin Lymphoma ■■ With its most recent expanded indication, rituximab was approved for single-agent maintenance therapy in previously untreated follicular, CD20-positive, B-cell nonHodgkin lymphoma after a complete or partial response to rituximab plus first-line chemotherapy.

■■ The recommended dose

of rituximab for singleagent maintenance therapy is 375 mg/m2 given as IV infusion starting 8 weeks after completion of rituximab plus chemotherapy and continuing every 8 weeks for 12 doses.

The ASCO Post | JUNE 15, 2012

PAGE 78

In the Clinic

Maintenance Rituximab in Non-Hodgkin Lymphoma continued from page 77

with previously untreated follicular lymphoma with high tumor burden who achieved response to a first-line chemotherapy including rituximab (R).3 Induction therapy consisted of R-CHOP in 75% of patients, R-CVP in 22%, and R-FCM (fludarabine, cy� clophosphamide, mitoxantrone) in 3%. Progression-free survival at a me� dian 36 months of follow-up in the

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

PRIMA study was 75% in the ritux� imab group vs 58% in the observation group, yielding a 45% reduction in risk for progression (HR = 0.55, P < .0001). At 2 years, 71.5% of rituximab patients and 52% of observation patients were in complete or unconfirmed complete remission (P = .0001). There was no difference between groups in overall survival (HR = 0.87, 95% CI = 0.51– 1.47).

How It Works Rituximab binds specifically to the antigen CD20 (human B lympho� cyte–restricted differentiation antigen, Bp35) located on pre-B and mature B lymphocytes. The CD20 antigen is expressed on greater than 90% of B-cell NHL cells, but is not found on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. CD20 regulates early steps in the activation process for cell-cycle initiation and dif� ferentiation and may also function as a calcium ion channel. CD20 is not shed from the cell surface and does not in� ternalize upon antibody binding, and free CD20 antigen is not found in the circulation.

How It Is Given The recommended dose of ritux� imab as single-agent maintenance ther� apy is 375 mg/m2 given as IV infusion (not bolus or push) starting at 8 weeks following completion of rituximab plus chemotherapy and continuing every 8 weeks for 12 doses. Patients should be premedicated with acetaminophen and an antihistamine. Rituximab is not recommended for use in patients with severe, active infection.

Safety Profile Rituximab carries a boxed warning for fatal infusion reactions, tumor ly� sis syndrome, severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy. Fatal reactions within 24 hours of rituximab infusion have been reported, with approximate� ly 80% of these occurring after the first infusion. Severe mucocutaneous reactions and progressive multifocal leukoencephalopathy have resulted in deaths. In the trial supporting approval of rituximab, safety data collection was limited to grade 2 or higher infections and grade 3 or higher adverse events. Grade 2 to 4 infection occurred in

39% of rituximab re� cipients and 24% of those in the observa� tion arm (P < .0001). Grade 3 or 4 adverse See Page 90 events occurred in 24% and 17%, respectively (P = .0026). Grade 3 or 4 adverse events occurring at a higher incidence (≥ 2%) in the ritux� imab group were infections (4% vs 1%) and neutropenia (4% vs < 1%).

■

References 1. RITUXAN® (rituximab) for injec� tion prescribing information. Genentech Inc, April 2011. Available at http://www. gene.com/gene/products/information/ pdf/rituxan-prescribing.pdf. Accessed January 18, 2012. 2. U.S. Food and Drug Administration: Rituximab 2011. Available at http://www. fda.gov/AboutFDA/CentersOffices/ Officeof MedicalProductsandTobacco/ CDER/ucm241928.htm. Accessed Janu� ary 18, 2012. 3. Salles G, Seymour JF, Offner F, et al: Rituximab maintenance for 2 years in pa� tients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): A phase 3, ran� domised controlled trial. Lancet 377:4251, 2011.

What You Need to Know About Glucarpidase Injection for Toxic Methotrexate Levels in Renal Impairment By Matthew Stenger

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

Indication

n January 2012, glucarpidase injec� tion (Voraxaze) was approved for the treatment of toxic plasma metho� trexate concentrations (> 1 μmol/L) in patients with delayed methotrexate clearance due to impaired renal func� tion.1 Owing to the potential risk of subtherapeutic exposure to metho� trexate, glucarpidase is not indicated for use in patients exhibiting the ex�

OF NOTE High-dose methotrexate may re� sult in impaired renal function. Glucarpidase converts methotrex� ate to inactive metabolites that can be eliminated nonrenally.

pected clearance of methotrexate (concentrations within 2 standard de� viations of the mean methotrexate ex� cretion curve specific for the adminis� tered dose of methotrexate) or in those with normal or mildly impaired renal function.2 Approval was based on efficacy as� sessment in 22 patients with delayed methotrexate clearance (more than 2 standard deviations above the aver� age on standard nomograms) second� ary to renal dysfunction.2 Evaluable patients had pre- and post-treatment plasma samples measured by high performance liquid chromatogra� phy. Patients received a single dose of glucarpidase at 50 U/kg by IV in� jection over 5 minutes; those with initial methotrexate concentrations > 100 μmol/L were to receive a sec� ond dose 48 hours later. Patients had a median age of 15.5 years (range, 5–84 years), 59% were male, and the most common underlying cancers were osteogenic sarcoma (50%) and leukemia/lymphoma (45%). All pa�

Glucarpidase for Methotrexate Toxicity ■■ Glucarpidase (Voraxaze) was approved for the treatment of toxic plasma methotrexate concentrations (> 1 μmol/L) in patients with delayed methotrexate clearance due to impaired renal function.

■■ Glucarpidase is given as a single IV bolus injection of 50 U/kg over 5 minutes.

tients received IV hydration, urinary alkalinization, and leucovorin rescue. Initial methotrexate concentra� tions were > 1 to 50 μmol/L in 13 patients, > 50 to 100 μmol/L in 2, and > 100 μmol/L in 7. The study end� point was achievement of a concentra� tion ≤ 1 μmol/L within 15 minutes of glucarpidase administration that was maintained for 8 days. This response occurred in 10 patients (45%) overall, all with initial methotrexate concentra�

OF NOTE Leucovorin should not be admin� istered within 2 hours before or after a glucarpidase dose.

tions ≤ 50 μmol. However, all patients exhibited a > 95% rapid reduction in methotrexate levels that was main� tained for 8 days. A second dose of glucarpidase in 6 patients with initial methotrexate levels > 100 μmol/L did not result in response in any of the 4 patients with levels > 1 μmol/L.

How It Works Glucarpidase is a recombinant bac� terial enzyme that hydrolyzes the car� boxyl-terminal glutamate residue from folic acid and such classical antifolates as methotrexate.2,3 The agent converts methotrexate to inactive metabolites, providing an alternate non-renal path� way for methotrexate elimination.

ASCOPost.com | JUNE 15, 2012

PAGE 79

In the Clinic

How It Is Given Glucarpidase is given as a single IV bolus injection of 50 U/kg over 5 min� utes. It is important to note that meth� otrexate concentrations within 48 hours of glucarpidase administra� tion can be reliably measured only by a chromatographic method.2 An inactive methotrexate metabolite (DAMPA) resulting from glucarpi� dase treatment interferes with mea� surement of methotrexate by immu�

(22%) of 18 receiving two doses. Glucarpidase carries a warning/ precaution for serious allergic reac� tions, including anaphylaxis, and a warning against use of immunoassays to measure methotrexate concentra� tions within 48 hours after a glucarpi� dase dose.

■

References 1. U.S. Food and Drug Administration: Glucarpidase. Available at www.fda.gov/ Drugs/InformationOnDrugs/Approved� Drugs/ucm288016.htm. Accessed March B:8.375” 19, 2012. 2. VORAXAZE® (glucarpidase) for T:7.63” injection prescribing S:6.875” information. BTG

International Inc, January 2012. Avail� able at www.accessdata.fda.gov/drugsatf� da_docs/label/2012/125327lbl.pdf. Ac� cessed March 19, 2012. 3. Patterson DM, Lee SM: Glucarpi� dase following high-dose methotrexate: Update on development. Expert Opin Biol Ther 10:105-111, 2010.

OF NOTE Measurement of methotrexate levels using immunoassays is not accurate for 48 hours after admin� istering glucarpidase. noassays, resulting in overestimation of methotrexate levels during this period. Leucovorin should not be admin� istered within 2 hours before or after a glucarpidase dose, since it is a sub� strate for glucarpidase.2 Otherwise, the dose of leucovorin during the first 48 hours after glucarpidase ad� ministration should be the same as that before glucarpidase administra� tion. After 48 hours, the leucovorin dose should be based on the mea� sured methotrexate concentration. Leucovorin should be continued for at least 3 days after the methotrexate level has dropped below the leucovo� rin treatment threshold, and it should not be stopped on the basis of a single methotrexate measurement below this threshold.

Safety Profile Safety data are from 290 patients in two single-arm trials of glucarpidase in patients with markedly delayed meth� otrexate clearance due to renal dys� function.2 Patients had a median age of 17 years (range, 6 months to 85 years), 64% were male, 32% had osteogenic sarcoma/sarcoma, and 63% had leu� kemia/lymphoma. The most common adverse reactions (incidence ≥ 1%) were paresthesias (2%), flushing (2%), nausea/vomiting (2%), hypotension (1%), and headache (1%). Of 98 pa� tients evaluated, 16 (17%) developed ant ig l u c ar p i da s e antibodies after glu� carpidase adminis� tration, including 12 (15%) of 78 receiv� See Page 90 ing one dose and 4

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The ASCO Post | JUNE 15, 2012

PAGE 80

In the News Breast Cancer

Will Study Showing Increased Complications Compared to Whole-breast Irradiation Put the Brakes on Brachytherapy? By Charlotte Bath

In the News focuses on media re� ports that your patients may have questions about at their next visit. This continuing column will pro� vide summaries of articles in the popular press that may prompt such questions, as well as com� ments from colleagues in the field.

lder women treated for invasive breast cancer with brachythera� py following lumpectomy were more likely to have complications and sub� sequent mastectomies compared to women treated with whole-breast irra� diation following lumpectomy, accord� ing to a retrospective population-based study of more than 92,000 women. The authors of the study, published in the Journal of the American Medical not� Association,1 ed that the use of brachytherapy as an alternative to wholebreast irradiation af� See Page 90 ter lumpectomy has increased substan� tially in recent years, and expressed concern that the number of women “experiencing excess harm associated with brachytherapy may grow pro� portionally.” But might this study and the coverage it received by consumer and health and medical media put the brakes on brachytherapy for treating breast cancer? “Our data have caused me to con� sider the strengths and limitations of brachytherapy in the treatment of breast cancer and to weigh these is� sues when discussing treatment op� tions with my patients,” Benjamin D. Smith, MD, corresponding author for the JAMA article, said in an interview with The ASCO Post. Dr. Smith is As� sistant Professor, Department of Ra� diation Oncology, The University of Texas MD Anderson Cancer Center in Houston. His coauthors are also from MD Anderson and from the Center for Health and Social Sciences at the Uni� versity of Chicago. “Our work helps to highlight some of the potential tradeoffs between brachy� therapy and whole-breast irradiation,” Dr. Smith stated, and that information can be discussed with patients in decid� ing what form of radiation to use follow� ing lumpectomy (see sidebar).

Risk of Complications and Subsequent Mastectomies The study included 92,735 women aged 67 years or older with incident in� vasive breast cancer identified through the national Medicare data set, which includes all Medicare beneficiaries throughout the United States, the authors noted. Following lumpecto� my, 6,952 patients were treated with brachytherapy and 85,783 with wholebreast irradiation. “This study has almost 7,000 pa� tients treated with brachytherapy, and to my knowledge, this is the larg� est number of patients treated with brachytherapy in any study in the world’s literature,” Dr. Smith said. “Just the sheer size of this study and its com� prehensive nature—including all older Medicare beneficiaries in the U.S. from 2003 to 2007—make our work an im� portant and unique contribution to the literature,” Dr. Smith said.

“Patients were classified as treated with [whole-breast irradiation] vs breast brachytherapy if claims indicat� ing [such] treatment were recorded within 12 months of diagnosis,” the au� thors stated. Patients were diagnosed between 2003 and 2007, and during that time, the use of brachytherapy among the study population increased from 3.5% to 12.5%. “Breast brachytherapy was associ� ated with a higher risk of infectious and noninfectious postoperative com� plications” experienced within 1 year of lumpectomy by 27.6% of patients treated with brachytherapy, compared to 16.9% of patients receiving wholebreast irradiation, the researchers re� ported. Patients receiving brachythera� py also had a higher 5-year incidence of postradiation complications—25.0% vs 18.8% for patients receiving wholebreast irradiation. These complications included breast pain (experienced by

Benjamin D. Smith, MD

14.6% of patients receiving brachy� therapy vs 11.9% of patients receiving whole-breast irradiation), fat necrosis (8.3% vs 4.1%), and rib fracture (4.5% vs 3.6%). Five-year overall survival was similar—87.7% for patients treated with brachytherapy vs 87.0% for those treated with whole-breast irradiation. Women treated with brachytherapy had a higher 5-year cumulative inci� dence of mastectomy (4.0% vs 2.2% in women treated with whole-breast irra� continued on page 82

Expect Questions from Your Patients

“O

ur study provides critical interim companion data to awaited randomized trials and may help clinicians and patients quantify the risk-benefit ratio of brachythera� py compared with standard therapy,” Benjamin D. Smith, MD, said of a study comparing lumpectomy and either whole-breast irradiation or brachytherapy as treatment for inva� sive breast cancer in older women. “Having some of these data and putting the two treatments side-byside enables us to show people some of the differences in complications and in mastectomy rates,” said Dr. Smith. “That can be the basis upon which you can have a conversation with your pa� tients about some of the tradeoffs.”

What Are the Tradeoffs? The study found that over 5 years, women receiving brachytherapy were more likely to have subsequent mas� tectomies, 4.0% vs 2.2% for those re� ceiving whole-breast irradiation. Brachytherapy was also associated with a higher risk of postoperative skin or soft-tissue infections, experi� enced within year 1 by 16.2% treated with brachytherapy compared with

10.3% treated with whole-breast irra� diation. Noninfectious postoperative complications occurred among 16.3% of patients treated with brachytherapy compared to 9.0% of patients treated with whole-breast irradiation. Five-year overall survival was es� sentially the same—87.7% vs 87.0% for patients treated with whole-breast irradiation. “Compared with [whole-breast ir� radiation], brachytherapy irradiates less breast tissue and requires a much shorter course of treatment,” the re� searchers reported in the JAMA study. “I have some patients for whom the convenience of radiation therapy is the most important aspect of the choice in treatment they’ll receive, and those patients often end up receiving some type of partial-breast radiation strat� egy, either brachytherapy or nonin� vasive external-beam approaches to finish radiation therapy in a week,” Dr. Smith said. “There are other patients who would much prefer to have the treat� ment that is potentially associated with the very best long-term tumor control or has the very best long-term random� ized data demonstrating its safety and

effectiveness. Those patients typically choose some type of whole-breast ir� radiation,” he continued. “I think it would be overly pater� nalistic for us to look at these small differences and then make a sweeping value judgment to say that all patients should receive this or all patients should receive that. But I do think these data will be helpful in contextu� alizing some of the tradeoffs between the two different treatments and then helping patients decide what is most important to them.”

What About Younger Women? The study involved only women aged 67 years or older. In addition, a consensus statement on partial-breast irradiation published by the Ameri� can Society for Radiation Oncology (ASTRO) in 2009 defined suitable patients for brachytherapy as those aged 60 years and older and “recom� mends being cautious about using brachytherapy for women between the ages of 50 and 60,” Dr. Smith said. In the JAMA article, the authors not� ed that future studies are required “to validate findings in younger patients with other insurance status.”

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Resistance to CML therapy may occur. In some cases, repeatedly. Even today, with a number of available options for treating refractory CML, a gap in therapy exists. One post-imatinib study found 65% of patients discontinued dasatinib as a second-line therapy after 5 years.1 Another post-imatinib study found 70% of patients discontinued nilotinib after 4 years. 2 Additionally, a small study showed approximately a quarter of patients responded when treated sequentially with 2 second-generation tyrosine kinase inhibitors (TKIs) after imatinib. But in those patients that did respond, the median response rate was 16 months.3 It’s clear that for refractory patients, unmet medical needs persist.

Visit CMLResponseProject.com to learn more. References: 1. Shah NP, Cortes JE, Schiffer CA, et al. Five-year follow-up of patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2011; Chicago, IL. 2. Le Coutre PD, Giles FJ, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or -intolerant patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 48-month follow-up results of a phase 2 study. Poster presented at: 53rd ASH Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. 3. Garg RJ, Kantarjian H, O’Brien S, et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood. 2009;114(20):4361-4368. ©2012 ARIAD Pharmaceuticals, Inc. All rights reserved. 5344912

The ASCO Post | JUNE 15, 2012

PAGE 82

In the News

Whole-breast Irradiation and Brachytherapy continued from page 80

diation). “For every 56 women treated with brachytherapy in our cohort, 1 ex� tra mastectomy happened that wouldn’t have happened if all those 56 women had been treated with whole-breast ir� radiation instead,” Dr. Smith said. The Medicare data did not indi� cate why the mastectomies were per� formed, and the authors noted that cancer recurrence was not confirmed. “It certainly is possible that a mastec� tomy could be done to manage a se� vere complication from either brachy� therapy or whole-breast radiation,” Dr. Smith noted. “When we excluded pa� tients with any code for any toxicity— and this actually wasn’t in our manu� script, but it was a subsidiary analysis that we conducted—we still found about the same risks of mastectomy in patients with brachytherapy compared to whole-breast irradiation. So I don’t think toxicity was driving this differ� ence, but it is an important limitation of our study, and we can’t really know for sure what the reasons for mastec� tomy were.”

Suitable vs Unsuitable Candidates Dr. Smith pointed out that the study included women treated with brachytherapy who would not be considered suitable candidates, ac� cording to a consensus statement on partial-breast irradiation published by the American Society for Radia� tion Oncology (ASTRO) in 2009.2 “I happen to be the first author on that guideline,” noted Dr. Smith, who is Vice Chair of ASTRO’s Clinical Guidelines Committee. The state� ment “defined patients suitable for brachytherapy as patients age 60 and older with estrogen receptor–posi� tive, stage I breast cancer treated with lumpectomy with negative margins and negative lymph nodes,” Dr. Smith said. “The majority of the patients in our study would have had stage I breast cancer, but some of them could have been patients with higher-stage disease as well.” Although patients in the study

Visit

who were treated with brachyther� apy were less likely to have axillary lymph node involvement, those who did were at particularly high risk of subsequent mastectomy. The ASTRO consensus statement says “brachytherapy should only be done in the context of a clinical trial if a patient has node-positive breast can� cer,” Dr. Smith pointed out. “Having a node-positive breast cancer indi� cates that there is probably a higher burden of disease in the breast and also that the cancer had to travel to the lymph nodes through the breast tissue itself. So it is likely that it could be a marker for residual breast cancer cells present elsewhere in the breast tissue that would not be en� compassed by partial-breast brachy� therapy,” he explained.

Awaiting Randomized Trials “Our results underscore existing controversy over appropriateness of widespread adoption of breast brachytherapy as the sole radiation treatment modality following lumpec� tomy, because few data are available to quantify benefits and harms of brachytherapy in direct comparison

Difference between Efficacy and Effectiveness

ne of the reasons large population-based studies are important is based on the “difference between efficacy—does a treatment work in a highly controlled setting of a phase III randomized clinical trial—and effectiveness— does a treatment work in general practice,” according to Benjamin D. Smith, MD. Dr. Smith is corresponding author of a retrospective population-based study of more than 92,000 older women with invasive breast cancer treated with lumpectomy followed by either whole-breast irradiation or brachythera� py. “It is important to understand the effectiveness of a treatment approach in addition to its efficacy,” he said. Dr. Smith noted that the study also adds to a considerable volume of previ� ous work looking at large population-based data sets with women similar to those in the study cohort, treated with either lumpectomy alone or lumpec� tomy plus conventional whole-breast radiation therapy. “We found previously that women who receive conventional whole-breast irradiation have about a threefold reduction in their risk of subsequent mastectomy, suggesting that whole-breast irradiation is an effective treatment. Indeed, it is effective when used widely in the community setting,” he said.

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been replaced by newer catheters and devices.3 “Our study was specifically de� signed to look at brachytherapy as it was used in the U.S. between 2002 and 2007, but there are other ran� domized clinical trials that are evalu� ating different types of partial-breast radiation,” Dr. Smith said. “There’s

Many women across the country are receiving brachytherapy before we have any strong randomized data to tell us that it is a good treatment. —Benjamin D. Smith, MD

with standard [whole-breast irradia� tion],” the authors commented. Dr. Smith said “many women across the country are receiving brachytherapy before we have strong randomized data to tell us that it is a good treat� ment.” High-quality case control studies or matched-pair analyses of patients treated with whole-breast ir� radiation vs the type of brachytherapy commonly used now are also lacking, he said. One of the criticisms of the cur� rent study cited in the press was that the only form of brachytherapy in use during the study period was a single-catheter device that has largely

a large randomized trial in Canada, which is comparing whole-breast to partial-breast irradiation, and in that study the partial-breast irradiation is given with external-beam approaches. A large ongoing study in Italy is look� ing at intraoperative radiation thera� py, which is a type of brachytherapy given at the time of surgery, compared to standard treatments. And other studies are ongoing as well. So several different techniques are being stud� ied in different parts of the world,” he pointed out. “To address persistent questions,” the authors noted, the ongoing Ra� diation Oncology Therapy Group

(RTOG)/National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39 trial is comparing partial-breast irradiation to whole-breast irradia� tion. “If patients are randomly as� signed to partial-breast irradiation, the physician can choose to treat them with either brachytherapy or external-beam radiation therapy,” Dr. Smith said. “There are some poten� tial technical differences in those two treatments.” Patient accrual began in 2005 and is expected to be completed later this year.

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Disclosure: Dr. Smith has received research funding from Varian Medical Systems, a maker of equipment for both whole-breast irradiation and brachytherapy.

References 1. Smith GL, Xu Y, Buchholz TA, et al: Association between treatment with brachytherapy vs whole-breast irradia� tion and subsequent mastectomy, com� plications, and survival among older women with invasive breast cancer. JAMA 307:1827-1837, 2012. 2. Smith BD, Arthur DW, Buchholz TA, et al: Accelerated Partial Breast Ir� radiation Consensus Statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 74:987-1001, 2009. 3. Mulcahy N: Breast brachytherapy takes a hit (or not). Medscape Today News. May 1, 2012. Available at www. medscape.com. Accessed May 22, 2012.

website at ASCOPost.com

ASCOPost.com | JUNE 15, 2012

PAGE 83

2012 ASCO Annual Meeting Studies Report Findings in Patient-centered Care

ew studies highlighting findings that will lead to improvements in the patient experience and identify� ing potential risks for development of cancers in the future were reported at a press briefing held during the 2012 ASCO Annual Meeting in Chicago. “In this era of sophisticated research advances, these studies are a reminder of how we need to be thinking about ev� ery aspect of patent care, from managing costs and painful side effects to monitor� ing patients long after their treatment has ended,” said news briefing modera� tor Nicholas Vogelzang, MD, Chair of ASCO’s Cancer Communications Com� mittee and Chair and Medical Director, Developmental Therapeutics Commit� tee, US Oncology, Comprehensive Can� cer Centers of Nevada.

Young Women Treated for Childhood Cancer: A study finds that female survivors of childhood cancer treat� ed with radiation to the chest had a high risk of developing breast cancer at a young age, comparable to that of BRCA1/2 mutation carriers.

■■ ASCO Tests New Quality Measures to Encourage Improved Capture of Family Histories and Referral to Genetic Counseling: A study reported findings of the Quality Oncology Practice Initia� tive pilot that tested new measures to evaluate the practice of family history-

taking and referral for genetic counsel� ing and testing in patients with either breast cancer or colorectal cancer. Watch future issues of The ASCO Post for coverage of these reports and more from the 2012 ASCO Annual Meeting.

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Nicholas Vogelzang, MD

“As oncologists, we need to collabo� rate with our patients and colleagues across the medical field to put this evi� dence into practice,” Dr. Vogelzang said.

Key Studies Important findings presented at the 2012 ASCO Annual Meetings include: ■■ Newer, More Costly Drugs No Better than Standard First-line Therapy for Locally Advanced or Metastatic Breast Cancer: A phase III randomized trial found weekly admin� istration of either of two newer and sig� nificantly more costly agents was not superi� See Page 90 or to standard weekly dosing of paclitaxel as first-line therapy for locally advanced or metastatic breast cancer. ■■ Serotonin–Norepinephrine Reuptake Inhibitor Antidepressant Is First Effective Treatment for Chemotherapy-induced Peripheral Neuropathy: A phase III study found that the antidepressant duloxetine (Cymbalta) is effective in treating painful chemotherapy-in� duced peripheral neuropathy. ■■ Low Levels of Radiation Therapy Can Increase Risk of Breast Cancer Among

Unified in our uncompromising commitment to improving patient care in renal cell carcinoma For more information visit www.aveopharma.com or www.astellas.com.

011L-073-4740

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The ASCO Post | JUNE 15, 2012

PAGE 84

Integrative Oncology Barrie R. Cassileth, PhD, Guest Editor

he use of dietary supplements by patients with cancer has risen signifi� cantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supple� ments can be daunting. Patients typically rely on family, friends, and the Inter� net, often receiving misleading information. To facilitate the availability of evidence-based information on alterna� tive and complementary therapies commonly used by patients with can� cer, The ASCO Post launches this series on Integrative Oncology, guest edited by Barrie R. Cassileth, PhD. Our first installment addresses the popular supplement Acai Berry.

Acai Berry Scientific Name: Euterpe oleraceae Common Names: Acai palm, cabbage palm, palm berry

Overview

A small berry that grows on a palm tree, acai is native to Central and South America, particularly the Amazon re� gion. It is consumed as food, raw or in the form of a juice. Acai is also used in tradi� tional medicine to treat heart problems, infections, urinary ailments, and schisto� somiasis, a disease transmitted by snails. In Brazil, the largest producer of acai berries, they are referred to as “superfruits” or “purple gold” and con� sumed as an ice cream flavor or a juice. In the 1990s, acai was promoted as “su� perfood for age-defying beauty,” thus turning it into a global phenomenon. It is also marketed to treat heart disease, flu, and arthritis, to lower high choles� terol, for weight loss, to reverse aging, and as an anticancer agent. Acai is sold in the form of juice, energy drinks, tablets, and as an ingre� dient in cosmetics. However, quality control is a major concern, as many

OF NOTE Despite unsubstantiated claims of benefits, acai berry is widely pro� moted for weight loss, to lower cholesterol, to treat cardiovascular disease, and as a cancer cure. Oncol� ogists should be aware of the safety concerns surrounding acai products and their possible interactions with standard cancer treatments.

products contain preservatives, added sugar, and hidden chemicals.1 Acai has also been the subject of many Internet scams in recent years. In 2009, a lawsuit was filed against 50 companies for us� ing famous televi� sion personalities without their per� mission to endorse products contain� ing acai. Ingesting acai fruits that were contaminated with insects carrying the protozoan Try� panosoma cruzii, a causative agent of Chagas disease, re� sulted in 178 cases of acute illness.2 The pulp and skin of acai fruit are rich in anthocyanins, proanthocyani� dins, and other fatty acids.3 A few in vitro and in vivo studies show that acai has anti-inflammatory, apop� totic4-7 and antioxidant effects.8-10 It inhibits nitric oxide production11 and cyclooxygenases 1 and 2,9 and induces apoptosis in HL-60 leukemia cells via caspase 3 activation.4 Human studies have not yet been conducted.

Acai/Drug Interactions

Because of its antioxidant effects, acai may interfere with some chemothera� peutic agents and with radiotherapy.12

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Disclosure: Dr. Cassileth and Ms. Gubili reported no potential conflicts of interest.

References 1. U.S. Food and Drug Administra� tion: Public notification: “Acai berry soft gel ABC” contains undeclared drug

ingredient. October 18, 2011. Available at www.fda.gov/Drugs/ResourcesFo� rYou/Consumers/BuyingUsingMedi� cineSafely/MedicationHealthFraud/ ucm276098.htm. Accessed May 2, 2012. 2. Nóbrega AA, Garcia MH, Tatto E, et al: Oral transmission of Chagas disease by consumption of açaí palm fruit, Brazil. Emerg Infect Dis 15:653-655, 2009. 3. Schauss AG, Wu X, Prior L, et al: Phytochemical and nutrient composition of the freeze-dried amazonian palm berry, Euterpe oleraceae mart (acai). J Agric Food Chem 54:8598-8603, 2006. 4. Del Pozo-Insfran D, Percival SS, Talcott ST: Acai (Euterpe oleracea Mart.) polyphenolics in their glycoside and agly� cone forms induce apoptosis of HL-60 leukemia cells. J Agric Food Chem 54:12221229, 2006. 5. Pacheco-Palen� cia LA, Talcott ST, et al: Absorption and biological activity of phytochemical-rich extracts from açai (Euterpe oleracea Mart.) pulp and oil in vitro. J Agric Food Chem 56:3593-3600, 2008. 6. Mertens-Talcott SU, Rios J, JilmaStohlawetz P, et al: Pharmacokinetics of anthocyanins and antioxidant effects after the consumption of anthocyaninrich acai juice and pulp (Euterpe oleracea Mart.) in human healthy volunteers. J Ag� ric Food Chem 56:7796-7802, 2008.

7. Jensen GS, Wu X, Patterson KM, Barnes J, et al: In vitro and in vivo antioxi� dant and anti-inflammatory capacities of an antioxidant-rich fruit and berry juice blend. Results of a pilot and randomized, double-blinded, placebo-controlled, cross� over study. J Agric Food Chem 56:83268333, 2008. 8. Rodrigues RB, Lichtenthaler R,Zimmermann BF, et al: Total oxidant scavenging capacity of Euterpe oleracea Mart. (acai) seeds and identification of their polyphenolic compounds. J Agric Food Chem 54:4162-4167, 2006. 9. Schauss AG, Wu X, Prior RL, et al: Antioxidant capacity and other bioactivi� ties of the freeze-dried Amazonian palm berry, Euterpe oleraceae mart. (acai). J Agric Food Chem 54:8604-8610, 2006. 10. Hassimotto NM, Genovese MI, Lajolo FM: Antioxidant activity of dietary fruits, vegetables, and commercial frozen fruit pulps. J Agric Food Chem 53:29282935, 2005. 11. Matheus ME, de Oliveira Fer� nandes SB, Silvera CS, et al: Inhibitory effects of Euterpe oleracea Mart. on nitric oxide production and iNOS expression. J Ethnopharmacol 107:291-296, 2006. 12. D’Andrea GM: Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA Cancer J Clin 55:319-321, 2005. Compiled by Barrie Cassileth, PhD, and Jyothi Gubili, MS, Memorial Sloan-Kettering Cancer Center. The About Herbs website is managed by K. Simon Yeung, PharmD, MBA, LAc, Memorial Sloan-Kettering Cancer Center.

ntegrative Oncology is guest edited by Barrie R. Cassileth, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial SloanKettering Cancer Center, New York. The Integrative Medicine Service at Memo� rial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, Barrie R. Cassileth, PhD minerals, and other dietary supplements, and un� proven anticancer treatments. Each of the 255 and growing number of entries offers health-care professional and patient ver� sions, and entries are regularly updated with the latest research findings.

Visit the About Herbs website at www.mskcc.org/aboutherbs

Endocrine therapy may be a challenge in some postmenopausal breast cancer patients if: • There are concerns about genetic CYP2D6 variations • Patients are receiving other medications that have known drug interactions with their endocrine therapy • Patients are experiencing intolerable side effects with current endocrine therapy

Fareston may be the answer 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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In multiple clinical studies, less than 1% of women stopped taking Fareston due to joint pain

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Black box warning and 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

FARESTON® (toremifene citrate) 60 mg Tablets oral administration Initial U.S. Approval: [1997] 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. © 2012 GTx, Inc. All rights reserved. 2E Rev. 03/2011

ASCOPost.com | JUNE 15, 2012

PAGE 87

Opinion

Radiotherapy in Early-stage Hodgkin Lymphoma continued from page 1

Ongoing Controversies The scientific discussion among those caring for Hodgkin patients has been highly controversial at times. The questions most often addressed by opinion leaders, cooperative groups, and patient advocates have been: Is combined-modality treatment the op� timal compromise between toxicity and efficacy? Is chemotherapy-only an alternative? Should we abandon radiotherapy altogether in this patient population? Should we strive for the best tumor control with first-line treat� ment and use BEACOPP (bleomycin, etoposide, doxorubicin, cyclophos� phamide, vincristine, procarbazine [Matulane], and prednisone) instead of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or do we have a second shot that is effective enough? Even after more than 30 years of clinical trials and tens of thousands of patients studied, these questions are still not fully answered. One of the most controversial and emotional discussions has been about the role of radiotherapy in Hodgkin lymphoma. We can refer to a vast number of rel� evant clinical trials of differing qual� ity, registry data, and personal expe� rience, all of which makes it difficult to maintain an unclouded view. From this hodgepodge of information, it is important to stick to the hardest data available, ie, those data generated within high-quality prospective, ran� domized trials.

HD.6 Trial A clinical trial recently published by Meyer and coworkers in The New England Journal of Medicine has again sparked the discussion on the role of radiotherapy in early Hodg� kin lymphoma.1 In this trial (HD.6) conducted by the National Cancer Institute of Canada Clinical Trials Group, 405 previously untreated stage IA or IIA nonbulky Hodgkin lymphoma patients were randomly assigned to chemotherapy (ABVD) alone or a large-field radiothera� py–containing treatment strategy. In the group that was assigned to radiation, a favorable cohort of 64 patients received subtotal nodal ir� radiation (STNI) only and the un� favorable cohort of 125 patients was treated with two cycles of ABVD followed by STNI. Those assigned

to ABVD who responded to treat� ment received four cycles of of the chemotherapy, and those with less than a complete remission had a to� tal of six cycles of ABVD. The HD.6 study was closed pre� maturely in April 2002, after results emerged from the EORTC H8-F trial reporting excellent outcomes with combined-modality treatment that included involved-field radia� tion therapy. The trial committee felt that continuing with a protocol that included STNI would be inappropri� ate. The initial report of this trial at a median follow up of 4.2 years had re� ported no difference in overall surviv� al. At 12 years, however, overall sur� vival was 94% among those receiving ABVD alone, compared with 87% for those receiving STNI or ABVD plus STNI. In patients treated with ABVD

ever, when large-field radiation was combined with chemotherapy, a 2.5fold increased risk of leukemia was observed in patients receiving com� bined-modality treatment compared with those treated with chemothera� py only. In female Hodgkin patients, the risk of breast cancer was significantly increased only after radiation doses of 38.5 Gy or higher and was not ob� served at lower doses. In other stud� ies, the significant dose-response relationship between the radiation dose and the risk of breast cancer was limited to women who received radiation therapy alone and was not observed among women who re� ceived both chemotherapy and ra� diation therapy. This is very likely due to the effect of chemotherapy on ovarian function.

One of the most controversial and emotional discussions has been about the role of radiotherapy in Hodgkin lymphoma. —Andreas Engert, MD

alone, a total of 12 patients had died, compared with 24 of those who had received STNI as part of their initial treatment. This final report underscores the impact of sufficient follow-up par� ticularly in the group of Hodgkin lymphoma patients with the best prognosis, ie, early favorable disease. Not surprisingly, this trial has also attracted a number of substantial cri� tiques, including objections to the outdated large-field radiotherapy used and the questionable statistics reported.

Long-term Side Effects What are the long-term side ef� fects of radiotherapy in Hodgkin lymphoma, and who is at risk? Years after realizing that improved radia� tion techniques could indeed induce long-lasting remissions in early-stage Hodgkin lymphoma, reports began to emerge about severe late effects including secondary malignancies, thyroid abnormalities, and cardiovas� cular disease.2 Side effects were cor� related with radiation dose and field size. For instance, in carefully per� formed case-control studies, the addi� tion of limited-field radiation therapy to chemotherapy did not significantly increase the risk of leukemia. How�

In other case studies, a radiation dose > 4 Gy to the breast was asso� ciated with a 3.2-fold higher breast cancer risk compared to women who received lower doses of radiotherapy and had no alkylating agent–based chemotherapy. The risk increased to 8-fold for women who received > 40 Gy to the breast.

Other Adverse Effects As far as treatment-related cardio� vascular disease is concerned, there is a clear correlation with medias� tinal radiotherapy in Hodgkin lym� phoma survivors. Cardiac mortality in dose-related fashion was reported in patients who had received more than 30 Gy to the mediastinum. More recent studies show that with longer follow-up, the relative risk of cardiac mortality was significantly elevated at 12.1. Of note, patients who received ABVD chemotherapy without medi� astinal irradiation also had a signifi� cantly elevated relative risk of cardiac mortality at a factor of 7.8. Importantly, the peak incidence of cardiac mortality in this study was 15 to 19 years after treatment and re� mained significant up to at least 25 years. There is a clear need to careful� ly monitor particularly young Hodg� kin lymphoma patients who have re�

ceived higher doses of anthracyclines. Major side effects of radiotherapy such as secondary cancers or cardio� vascular disease are mainly confined to the original radiation field. Thus, major reductions in field size and dose over the past 20 years represent an important step toward reducing the overall risk of radiation-related side effects. While subtotal-nodal or extended-field techniques were used historically, this has changed to the more frequent use of involved-field technology, which reduces the non� specific irradiation of healthy tissue by up to 10-fold. Sufficiently powered prospective randomized trials from cooperative groups have clearly shown that sub� total-nodal and extended fields are not needed when combined-modality therapy is used. As few as two cycles of ABVD combined with 20 Gy of involved-field radiotherapy can cure more than 90% of Hodgkin patients in early favorable stages.3 In addition, field size of radiotherapy in Hodg� kin lymphoma has been further re� duced more recently to the so-called involved-node radiation field, in which only a rather small margin around the initially involved lymph node is ad� dressed.

Clinical Trials The major problem in the con� troversy of combined-modality or chemotherapy-only strategies in early-stage Hodgkin lymphoma is the lack of randomized trials. Few trials have used identical numbers of chemotherapy cycles that would allow for a proof of principle of che� motherapy-alone concepts. When chemotherapy was compared with combined-modality treatment, me� ta-analyses found significant differ� ences in terms of tumor control and overall survival favoring combined modalities in early-stage Hodgkin lymphoma patients. In addition, more recent ran� domized trials clearly send a note of caution to those who believe in chemotherapy-only approaches. In the EORTC-GELA H9 trial for early favorable Hodgkin lym� phoma, the failure-free survival at 5 years was significantly reduced in patients who did not receive addi� tional radiotherapy after six cycles of chemotherapy (EBVP [epirubi� cin, bleomycin, vinblastine, predni� sone]). continued on page 88

The ASCO Post | JUNE 15, 2012

PAGE 88

In the Literature

Emerging Clinical Data on Cancer Management PAIN AND DISTRESS Pain Remains Prevalent and Often Inadequately Treated among Cancer Outpatients “Pain is as prevalent in ambula� tory oncology patients with common solid tumors as it was more than 20 years ago, despite the fact that opioid prescribing in the United States has increased more than 10-fold since 1990,” according to results of a study among 3,023 ambulatory patients with cancer identified to be at risk for pain. The patients were being treat� ed for invasive cancer of the breast (50%), colon/rectum (21%), pros� tate (10%), or lung (19%) and were enrolled onto the prospective study regardless of phase of care or stage of disease. “This study is the largest prospec� tive evaluation of pain and other symptoms in outpatient oncology in the United States,” the researchers re� ported. “The distribution of the four solid tumors is typical for outpatient cancer care, including the low relative proportion of patients with prostate cancer.”

Design and Results Patients completed a 25-item measure of pain, functional interfer� ence, and other symptom at initial assessment and 4 to 5 weeks later. “Providers recorded analgesic pre� scribing. The pain management index was calculated to assess treat� ment adequacy,” the researchers noted. Among the 2,026 (67%) reported having pain or requiring analgesics at initial assessment, “670 (33%)

Radiotherapy in Early-stage Hodgkin Lymphoma continued from page 87

Very recent reports from the EORTC-GELA-IIL H10 study in pa� tients with early favorable and unfavor� able disease provided additional rele� vant data. In this PET-guided trial, the chemotherapy-only arms in patients who were PET-negative after two cycles of ABVD had to be closed due to significantly more events, in both early favorable and early unfavorable disease. These data ague against the uncritical use of chemotherapy only in

were receiving inadequate analgesic prescribing,” the researchers found. There was no difference in treat� ment adequacy between the initial and follow-up visits. Multivariable analysis revealed that the odds of a non-Hispanic white patient having inadequate pain treatment were ap� proximately half those of a minority patient after adjusting for other ex� planatory variables. “Other significant predictors of inadequate pain treatment were hav� ing a good performance status, be� ing treated at a minority treatment site, and having nonadvanced disease without concurrent treatment,” the researchers wrote. “The present study corroborates others’ findings about the inequality of pain treatment ad� equacy between minority patients and non-Hispanic white patients and shows that these findings persist at short-term follow-up,” the authors noted. Of the 584 patients with moderate or severe pain at initial assessment, 241 (41%) were not receiving an opi� oid. “Twenty percent of the patients in severe pain were not receiving any analgesic. The most commonly prescribed nonopioids were acet� aminophen (35%) and nonsteroidal anti-inflammatory agents (19%),” the researchers reported.

Gap in Pain Treatment “Patients with nonadvanced can� cer who were not receiving cancerdirected treatment were especially likely to be undertreated for pain. This disparity may be explained in part by the fact that nearly 50% of these patients experienced symp� toms that oncologists believed were early-stage Hodgkin lymphoma out� side of clinical trials.

Conclusions We should be cautious not to overinterpret studies such as the re� cent Canadian HD.6 investigation, given the rather small subgroups of patients included, the outdated ra� diotherapy used, and the problem� atic statistics. What we would really need to change the current standard approach of combined-modality treatment in early-stage Hodgkin lymphoma are sufficiently powered

not attributable to cancer or cancer therapy and thus were not treated ag� gressively. This potential gap in pain treatment could be bridged with im� proved coordination of care between oncologists and nononcology pro� viders,” the authors wrote. “Finally, the availability of effec� tive pain medication that is not per� ceived to interfere with driving, work performance, social interactions, or bowel habits could improve adher� ence to pain treatment,” the authors suggested.

Fisch MJ, et al: J Clin Oncol, April 16, 2012 (early release on line).

Screening for Distress and Unmet Needs in Patients with Cancer In the past decade, “screening for distress has been positioned as the sixth vital sign in cancer care, in addition to the first five, which are measurements of pulse, respiration, blood pressure, temperature, and pain,” according to a review article in the Journal of Clinical Oncology. Although distress is not a precise clinical term, “it is part of the clini� cal significance criterion that is a qualifier for several mood disorders, including major depression and adjustment disorder,” the authors wrote. “One reason for its adoption in cancer care is that the term distress is often more useful for cancer cli� nicians than psychiatric terms such as anxiety or depression. It is easily understood by the lay person and does not carry the stigma often as� sociated with diagnostic labels and terms such as psychiatric, psycho� social, and emotional problems. It prospectively randomized trials of high quality. There are simply too many well performed studies today demonstrat� ing that the combination of small-field radiotherapy and a few cycles of che� motherapy currently is the best avail� able choice of treatment for patients in these risk groups. In addition, emerg� ing data show that the actuarial risk as� sociated with ABVD—both acute and long-term—might have been underes� timated.

■

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

is usually well understood by non– mental-health clinicians, facilitating quick assessment with simple verbal enquiry or patient self-report,” the authors noted.

Effects of Screening Uncertain Research is inconclusive about how effective screening for distress is in improving recognition and treatment of distress and associated problems, “but screening seems to improve communication between patients and clinicians and may en� hance psychosocial referrals. Direct effects on quality of life are uncer� tain, but screening may help improve discussion of quality-of-life issues,” the authors noted. Introducing screening programs requires enlisting administrative support, properly training staff, and ongoing support. “To ensure con� tinuity of care, it is important that screening is linked with follow-up care and appropriate treatment. It is also important to follow screening triage guidelines and algorithms, but not at the expense of clinical flexibil� ity,” the authors wrote. “Patient input is also crucial to help evaluate pilot screening pro� grams and protocols from the per� spective of the recipient of care. To maximize reach, we also recommend reviewing to what extent the screen� ing program is acceptable to older pa� tients, those who are medically frail, and minority/underserved groups such as people new to a community for whom English may be a second language.” Carlson LE, et al: J Clin Oncol 30:11601177, 2012.

continued on page 96

References 1. Meyer RM, Gospodarowicz MK, Connors JM: ABVD alone versus radia� tion-based therapy in limited-stage Hodg� kin’s lymphoma. N Engl J Med 366:399408, 2012. 2. Ng A, Travis L: Acute and long-term complications of radiotherapy for Hodg� kin Lymphoma, in Specht L, Yahalom J (eds): Radiotherapy for Hodgkin Lym� phoma. New York, Springer, 2011, pp 183196. 3. Engert A, Plütschow A, Eich HT, et al: Reduced treatment intensity in patients with early stage Hodgkin lymphoma. N Engl J Med 363:640-652, 2010.

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The ASCO Post | JUNE 15, 2012

PAGE 90

Patient’s Corner

Surviving the Aftermath of Cancer

Although cancer-free for over 3 decades, I still live with the remnants of my disease and its treatment every day. By Sheila Leatherwood, as told to Jo Cavallo

ith medical information now just a click away, it’s difficult to imagine a time before the Inter� net existed, when finding answers to questions about serious diseases was nearly impossible. When I was di� agnosed with liposarcoma 33 years ago, there was only one oncologist in my hometown of Tyler, Texas, and he didn’t know anything about the prognosis of this rare cancer. There were no books about liposarcoma in the public library and no patient pamphlets in medical centers for me to turn to for information. I was so young at the time—just 24—and so removed from thinking I could have a serious illness that when the doctor said I had a stage II malignant tumor in the deep fat tissues in my left thigh, I didn’t realize that “malignant” meant cancerous. Even after traveling 2 hours from my home to the MD Anderson Can� cer Center in Houston for a second opinion, I kept thinking this was all a mistake and that my biopsy re� sults from the tumor that had been removed had gotten mixed up with someone else’s. When my oncologist told me I would need adjuvant radia� tion therapy and that with it I had an 80% chance of being cured of the can� cer, I thought, ‘I want a 100% chance of being cured.’ And refused the treat� ment. That’s how naive I was about understanding what I was facing.

When the liposarcoma came back a-year-and-half later in the exact same area, I was ready to do whatever my doctors recommended. By then I had two young children and I wanted to live. I had surgery to remove the second tumor, followed by 6 weeks of radiation therapy. X-rays—there were no MRIs or CT scans back then—showed the area was clear of any tumors.

Coping with Treatment Side Effects Although I’ve remained cancerfree since 1980, I’ve had to battle years

rod worked its way out of my hipbone and had to be replaced. When the surgeon cut into my leg, he found the area filled with rice bodies. Although they were removed, the wound from the surgery never quite healed. After two life-threatening infections, sev� eral surgeries, and several months of IV antibiotics, the rod was removed, and my doctors are trying to mend the bone by filling it with calcium. In the meantime, I have to use crutches, and I may need to use a walking cane for the rest of my life. I know that’s a small price to pay for my life. But with more and more

With more and more patients surviving their cancer, I’m wondering whether doctors are paying attention to the long-term and late side effects from treatment that survivors often face. Who is monitoring their overall care, looking for signs of treatment side effects or cancer recurrence once they’ve returned to their primary care physician? —Sheila Leatherwood

of horrific side effects from the radia� tion therapy I was given. The femur in my left leg snapped one day as I was walking; the bone was so brittle and damaged, I had to have a metal rod in� serted into the femur and attached to my hip and knee. Three years ago, the

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

patients surviving their cancer, I’m wondering whether doctors are pay� ing attention to the long-term and late side effects from treatment that sur� vivors often face. Who is monitoring their overall care, looking for signs of treatment side effects or cancer recur�

Sheila Leatherwood

rence once they’ve returned to their primary care physician?

Helping Survivors I’ve been told by every doctor I’ve seen that my problems are rare, but I’m sure I’m not that unique given the amount of radiation I received so long ago. I don’t know—and no one has been able to tell me—if I’m vulnerable to other health problems from late ef� fects yet to come. With all the medical and profes� sional networking websites that are so easily accessed today, it shouldn’t be difficult for physicians to work more closely together to help each other—and survivors—learn about potential health risks from treatment late effects, especially for rare cancers. By doing that, physicians will help survivors achieve a better quality of life for many years after their cancer diagnosis.

■

Sheila Leatherwood lives in Tyler, Texas.

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ASCOPost.com | JUNE 15, 2012

PAGE 91

Lab Notes

Ongoing Molecular Research in the Science of Oncology OUTCOME PREDICTORS Pretreatment Tumor Hypoxia Predicts Biochemical Failure after Radiotherapy for Prostate Cancer Hypoxia often occurs early in solid tumor development as a result of imbal� ances between oxygen supply and con� sumption and may lead to genetic and molecular signaling that influences the biology and clinical behavior of tumors and response to treatment. Milosevic and colleagues from Princess Margaret Hospital and Ontario Cancer Institute in Toronto recently showed that hypoxia is an independent predictor of biochemical recurrence of prostate cancer after radio� therapy alone or together with neoadju� vant and concurrent hormonal therapy.

Early Failure Preferentially Predicted In this study, direct oxygen measure� ments were made prior to treatment in 247 patients with clinically localized prostate cancer who were followed for over 6 years. When added to a base� line clinical model consisting of Glea� son score and prostate-specific antigen level, hypoxia was an independent pre� dictor of early biochemical relapse-free survival. Its effect as a predictor was even more pronounced when analysis was limited to 142 patients with bulk tumor at the oxygen measurement site. As noted by the investigators, this finding contributes to other emerging evidence “indicating that early biologic and clinical behavior [of the tumor] is determined by the dominant focus of disease in the prostate gland and less so by secondary more indolent foci.” On univariate analysis, the effect of hypoxia on biochemical relapse-free survival was greatest earlier in follow-up and diminished with increasing time. Patients with hypoxic tumors were more likely than those with well-oxy� genated tumors to develop biochemi� cal failure within the first 48 months of completing treatment but not at longer durations after the end of treatment. Hypoxia was the only factor predictive of local recurrence in 70 patients who had biopsies conducted during followup, with the effect again being greatest early after completing treatment. These findings support the hypoth� esis that hypoxia influences clinical outcome after radiotherapy in interme� diate-risk prostate cancer and provide

a rationale for studying the combina� tion of radiotherapy with new hypox� ia-targeted treatment approaches. As stated by the investigators, “New treat� ment approaches for high-risk patients with hypoxic tumors might consist of

further radiation dose-escalation, the use of hypoxic cell sensitizers or cyto� toxins in combination with radiothera� py, or molecular therapeutic strategies that either alter the balance between oxygen supply and consumption or

exploit the molecular consequences of hypoxia to enhance radiation response, tumor control, and patient survival.”

Milosevic M, et al: Clin Cancer Res 18:2108-2114, 2012.

continued on page 92

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www.oncotypeDX.com *This analysis included 912 patients with node-negative, ER-positive, early-stage invasive breast cancer. †Patients with unclear treatment decisions were excluded from this meta-analysis. Additionally, patients who did not want CT, those with poor performance status, and those who could not tolerate CT were excluded. ‡CT=chemotherapy; HT=hormone therapy. Reference: 1. Hornberger J, et al. Poster P2-09-06. Presented at: San Antonio Breast Cancer Symposium; 2010. Genomic Health, Oncotype DX, Recurrence Score, and Uncover the Unexpected are trademarks of Genomic Health, Inc. © 2012 Genomic Health, Inc. All rights reserved. GHI10100_0112

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The ASCO Post | JUNE 15, 2012

PAGE 92

Lab Notes

Ongoing Molecular Research

synergistic effect in reducing growth of BRAF-mutant xenografts was found when metformin was combined with a small-molecule VEGF receptor inhibi� tor (axitinib [Inlyta]), a neutralizing VEGF antibody (bevacizumab [Avas� tin]), or stable expression of a VEGF-A short hairpin RNA. These findings have potential im� plications for both the treatment of diabetic patients with melanoma and treatment of BRAF-mutant cancers. As stated by the investigators, “Metfor� min inhibits the growth of most tumor cells, but BRAF-mutant melanoma cells are resistant to metformin in vi� tro, and metformin accelerates their growth in vivo. Unexpectedly, VEGF inhibitors and metformin synergize to suppress the growth of BRAF-mutant tumors, revealing a combination of drugs that may be effective in these pa� tients.”

continued from page 91

TARGETED THERAPY Complex Relationship between Metformin and BRAF-mutant Tumors The antidiabetic drug metformin appears to lower cancer risk in diabetic patients and has shown antitumor activity in preclinical studies. Sup� pression of mTOR signaling via AMP kinase (AMPK)-dependent TOR complex 1 (TORC1) inhibition is one of the proposed mechanisms by which metformin appears to suppress cancer cell growth. In recent studies, Martin and col� leagues from the University of Man� chester in the UK showed that BRAFmutant (but not NRAS-mutant) melanoma cells were resistant to met� formin on the basis of constitutive TORC1 activation mediated by RSK (ribosomal S6 kinase) that occurred despite AMPK activation. Metfor� min accelerated the angiogenesis and growth of BRAF-mutant melanoma xenografts in association with upregu� lation of vascular endothelial growth factor A (VEGF-A). Upregulation of VEGF-A was shown to result from increased ERK activity caused by AMPK-mediated degradation of the dual-specificity pro� tein phosphatase DUSP6. However, a

Martin MJ, et al: Cancer Discov 2:344355, 2012.

Gab2 Promotes Characteristics of Epithelialto-Mesenchymal Transition in Ovarian Cancer Ovarian cancer is often diagnosed at a late stage, when cancer cells have already migrated and invaded other tissues and organs. Wang and col� leagues from the University of Colo� rado Denver and the Dana-Farber Cancer Institute in Boston, showed

that Gab2—a scaffolding adaptor protein that is overexpressed in a sub� set of ovarian tumors and in other cancers—can act to increase migra� tion and invasion and turn on the epithelial-to-mesenchymal program through activation of the PI3K-Zeb1 pathway in ovarian cancer. These investigators showed that overexpression of Gab2 in ovarian cancer cells with normally low Gab2 expression resulted in increased cell migration and invasion and downreg� ulation of expression of E-cadherin, an epithelial cell marker involved in cell-cell contact. Knockdown of Gab2 expression in cells with high Gab2 expression inhibited migration and invasion and upregulated E-cadherin expression. Studies of wild-type Gab2 and mutants defective in activation of the PI3K and Shp2-Erk pathways showed that Gab2 inhibited E-cadherin ex� pression and increased the expression of Zeb1—a transcription factor in� volved in epithelial-to-mesenchymal transition (EMT) and cell migration and invasion—through the activation of the PI3K pathway. Knockdown of Zeb1 blocked Gab2-induced down� regulation of E-cadherin expression and increased cell invasion. PI3K in� hibitors and rapamycin (an inhibitor of the PI3K downstream target mTOR) acted to reverse the effects of Gab2 on migration and invasion.

Quality Care

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This exciting new ASCO conference will bring together top leaders in the field to share new strategies, methods and technologies for measuring and improving the quality of cancer care. Abstracts are currently being accepted in the following categories: • Quality Measurement • Quality Improvement - Guideline Recommendation Compliance and its Effects on Quality • The Use of IT to Improve Quality • Involving Patients in Quality Care - Patient-Reported Outcomes - Communication and Decision-Making

Wang Y, et al: Oncogene 31:2512–2520, 2012.

COMBINATION THERAPY Anti-EpCAM Antibody-Drug Conjugate Shows High Activity against Pancreatic Cancer Human epithelial cell adhesion molecule (EpCAM) is overexpressed in many cancers. Although anti-Ep� CAM antibodies have shown promise in preclinical studies, early-phase clini� cal evaluation of these antibodies has been disappointing. To determine whether the antitu� mor activity of anti-EpCAM antibody could be improved, Moldenhauer and colleagues from the German Can� cer Research Center in Heidelberg, Germany, constructed a novel conju� gate consisting of a chimerized antiEpCAM monoclonal antibody and α-amanitin, a toxin that inhibits DNA transcription. The conjugate reduced cell proliferation in human pancreatic, colorectal, breast, and bile duct cancer cell lines. A single dose of the conjugate sig� nificantly reduced subcutaneous pan� creatic carcinoma xenograft growth in immunocompromised mice compared with the antibody alone. At higher doses of α-amanitin in the conjugate, complete tumor regression was seen in 90% of tumors, with increased apopto� sis and reduced cell proliferation ob� served in all animals. As stated by the investigators, these findings suggest that “anti-EpCAM antibody conjugates with α-amanitin have the potential to be highly effec� tive therapeutic agents for pancreatic carcinomas and various EpCAM-ex� pressing malignancies.”

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Moldenhauer G, et al: J Natl Cancer Inst 104:622-634, 2012. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

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As stated by the investigators, “Our finding reveals that Gab2 overexpres� sion contributes to activation of the PI3K pathway and promotes EMT in a subset of ovarian cancer…. Con� sidering [that PI3K inhibitors] or ra� pamycin can reduce Gab2-enhanced cell migration and invasion of ovar� ian cancer cells, drugs that target the PI3K/mTOR pathway can be poten� tially used to treat Gab2-overexpressed ovarian cancer in combination with standard chemotherapy.”

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The ASCO Post | JUNE 15, 2012

PAGE 94

Letters to the Editor

The Semantics of Palliative Care

he interview with Thomas J. Smith, MD (The ASCO Post, April 15, 2012), the lead author of the ASCO Palliative Care Provisional Clinical Opinion, was timely. Howev� er, it left many clinical terms and issues unclear. A significant percentage of mod� ern medicine, including cancer care, is palliative. Cancer is often a chronic disease, as many patients are not cured but live with cancer after we minimize the tumor burden and relieve the symptoms caused by the disease. In that sense, palliative care is part and parcel of good patient care. What is generally understood from the words “palliative care” is symptom management. Every illness—par� ticularly the serious ones like a heart attack or cancer—is accompanied by a host of physical, psychosocial, spiritual, financial, and emotional symptoms, which need to be relieved if one is to “heal” the patient and not just “cure” or “stabilize” the illness. Thus, “palliation” should begin at the moment the illness is diagnosed. The palliation in this context is not “endof-life care,” although palliation does play a major role in the end-of-life set� ting. The establishment of “pallia� tive care” as a specialty has become

necessary only because of fragmen� tation of medical care into subspe� cialization, time constraints, reim� bursement issues, and a shift away from the primary and family care models. Dr. Smith is quoted as saying that “palliative care is all about honor�

I would ask the ASCO panel to con� sider renaming palliative care, instead using a term such as symptom manage� ment or an abbreviation such as SYM� CARE. For example, the discharge summary could state that the patient was treated successfully for myocardial infarction and all of the SYMCARE

What is generally understood from the words “palliative care” is symptom management. Every illness … is accompanied by a host of physical, psychosocial, spiritual, financial, and emotional symptoms, which need to be relieved if one is to ‘heal’ the patient and not just ‘cure’ or ‘stabilize’ the illness. Thus, ‘palliation’ should begin at the moment the illness is diagnosed. ing people’s choices.” That is true in principle, but most people do not know what choices to make since they have not had this conversation with their physicians and their loved ones. Dr. Smith points to the Cancer Care Outcomes Research and Surveil� lance Consortium (CanCORS) study, which showed that 60 % of oncologists (let alone primary care physicians) do not have such discussions with their patients. Hospice is truly the end-of-life care where palliation plays a major role.

issues were properly addressed. This model of care should be integrated into the care of every patient with any seri� ous (and particularly, life-threatening) illness. This type of care should not be palliative in the sense that it cannot be aggressive. Symptom manage� ment should be as aggressive as the primary treatment for the given ill� ness. If the treating physician is un� able to fulfill that role, then another physician and/or a team of profes� sionals with specific expertise in

symptom management should be called in for consultation. Hospice care should continue to be defined as care of those who have 6 months or less to live. If, in that setting, a short course of radiation therapy (eg, 1 fraction rather than 10 fractions) or chemotherapy, a course of antibiotics, or a blood transfusion is deemed nec� essary to decrease symptoms and im� prove quality of life, then it should be covered by insurance. To talk about advance directives when someone is sick and/or is be� ing hospitalized is precisely the worst time to do so. The core principle of advance directives is self-autonomy and the right to make personal choic� es in health care. The issues of death and dying are frightening and should be relegated to footnotes in such dis� cussions. I believe that education about ad� vance directives should begin in high schools, as teenagers become young adults, when they are healthy and in the prime of their lives. The concept should be reinforced repeatedly in community settings such as church� es, synagogues, mosques, commu� nity centers, PTA meetings, and so forth. —Khalid L. Rehman, MD, FACP New York Medical College Valhalla, New York

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CHIEF MEDICAL OFFICER The American Society of Clinical Oncology (ASCO) is seeking an accomplished oncology leader to serve as their inaugural Chief Medical Officer. This new physician leader will apply medical knowledge and experience to further ASCO’s mission, particularly in four areas: cancer communications, cancer policy, quality cancer care, and charitable fundraising. The distribution of effort across these four areas will vary over time, depending on the organization’s needs and special skill set of the incumbent. The CMO will assist the volunteer leadership and the CEO in communicating and carrying out the strategic priorities of the Society. He or she will serve as a collaborative resource for development and implementation of programs and products across a matrix organization. Ideal experience for this exciting new position includes experience as an oncology leader with a deep passion for, commitment to and track record of accomplishments in cancer clinical medicine. A prior leadership role with ASCO in a volunteer capacity is strongly desired as is an in-depth understanding of the current trends and issues affecting oncology clinical practice today, including reimbursement and electronic tools. The successful candidate must possess outstanding communication skills, both oral and written.

Spencer Stuart has been retained to assist ASCO with this important recruitment. Spencer Stuart and ASCO respect the importance of maintaining confidentiality. As such, letters of application, with curriculum vitae/resume and letters of nomination should be submitted by email to: Alexis H. Stiles at astiles@spencerstuart.com. Or by mail to: Spencer Stuart, c/o Alexis H. Stiles One Commerce Square, 2005 Market Street, Suite 2350,Philadelphia, PA 19103

ASCOPost.com | JUNE 15, 2012

PAGE 95

Letters to the Editor

Physicians Need to Be Involved in Reducing Costs

am so proud of ASCO for participat� ing in the American Board of Internal Medicine Foundation’s Choosing Wise� ly campaign (see The ASCO Post, May 1, page 19; and page 75 of this issue). I am the Associate Medical Direc� tor for a 280-physician multispecialty group in the Hudson Valley of New York, which was recently granted status as an Accountable Care Organization by the Centers for Medicare & Medic� aid Services. I have reached the conclu� sion that if physicians are not involved in the process of reducing health-care costs, it will not happen in a way that will protect our patients. I am con� vinced that physicians can reduce costs without impairing care and quality. It was painful to see that I routinely violate one of ASCO’s Top Five recom� mendations: I have been dependant on surveillance serologic markers for my patients with breast cancer, even though I know the data are not supportive. I need to rethink that practice and begin explaining the change to my patients.

Regional Disparities in Cancer Mortality

was interested to see an article about the continuing declines in cancer death rates featured in the April 15 issue of The ASCO Post (page 94), as I have just published a paper on breast cancer mortality rates.1 Although overall breast cancer mortality rates have decreased significantly, a much smaller decline was seen in medically undeserved areas such as Appalachian counties (17.5%) com� pared with non-Appalachian counties in 13 Appalachian states (30.5%), and compared with non-Appalachian coun� ties in the United States overall (28.3%). So I’d like to remind readers of The ASCO Post that there are probably enor� mous regional disparities in the decline of overall cancer mortality rates. —Nengliang Yao, MS Dept of Health Policy and Administration College of Health and Human Development Pennsylvania State University University Park, Pennsylvania

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Reference 1. Yao N, Lengerich EJ, Hillemeier MM: Breast cancer mortality in Appa� lachia. J Health Care Poor Underserved 23:715-725, 2012.

I feel now is an opportune time to address the issue of liability reform. The Federal government needs to grant liability relief for physicians and spe� cialties that follow practice guidelines outlined in the Choosing Wisely cam� paign. Only by moving forward togeth�

■

er will this effort succeed. The time for political battles and disagreements has past; catastrophic consequences await us all if this effort is not successful. Thank you for highlighting this is� sue in The ASCO Post. It has become my favorite newspaper, and I read it

regularly from cover to cover. —Thomas J. Lester, MD Associate Medical Director Mount Kisco Medical Group Chief, Hematology and Medical Oncology Northern Westchester Hospital Mount Kisco, New York

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Collaborating to Conquer Cancer

The ASCO Post | JUNE 15, 2012

PAGE 96

In the Literature

Emerging Clinical Data continued from page 88

THYROID CANCER Low-dose Radioiodine as Effective as High-dose in Thyroid Ablation Two studies in The New England Journal of Medicine found that lowdose radioiodine is as effective as a high-dose strategy in treating pa� tients with thyroid cancer and that recombinant human thyrotropin (thyrotropin alfa [Thyrogen]) and thyroid hormone withdrawal had similar efficacy in preparing patients for radioablation. In both studies, thyrotropin alfa was administered by intramuscular injection of 0.9 mg on 2 consecutive days; the low dose of radioiodine was 1.1 GBq and the high dose was 3.7 GBq. A randomized noninferiority trial conducted at 29 centers in the Unit� ed Kingdom and funded by Cancer Research UK compared low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation, in patients with tu� mor stage T1 to T3 differentiated thyroid cancer and possible spread to nearby lymph nodes but without metastasis. Among 421 evaluable patients, “success rates were 85.0% in the group receiving low-dose radioiodine vs 88.9% in the group receiving the high dose, and 87.1% in the thyrotropin alfa group vs 86.7% in the group under�

going thyroid hormone withdrawal,” the authors reported. “Similar results were found for low-dose radioio� dine plus thyrotropin alfa (84.3%) vs high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or highdose radioiodine plus thyrotropin alfa (90.2%),” they added.

Important Advantages “The use of a reduced dose of ra� dioiodine has important advantages. Patients, many of whom are women with children, would spend less time in hospital isolation and have fewer side effects,” the authors noted. In this study, fewer patients in the low-dose group were hospitalized for at least 3 days—13% compared with 36.3% for the high-dose group (P < .001). “The proportions of patients with adverse events were 21% in the low-dose group vs 33% in the high-dose group (P = .007) and 23% in the thyrotropin alfa group vs 30% in the group undergo� ing thyroid hormone withdrawal (P = .11),” they reported. The authors concluded, “Our study answers two central questions involv� ing radioiodine ablation of thyroid remnants after surgery for differentiat� ed thyroid cancer: namely, that the effi� cacy of low-dose radioiodine is similar to that of high-dose radioiodine, and that the efficacy of low-dose radioio� dine ablation is not compromised by the use of thyrotropin alfa instead of thyroid hormone withdrawal.”

Similar Study They noted that the study con� ducted at 24 centers in France was

similar to their study, but excluded patients with stage T3 tumors or stage T2 tumors with lymph node involvement. The study funded by the French National Cancer Institute and the French Ministry of Health also found equivalent ablation rates with low-dose and high-dose radio� iodine and the use of thyroid hor� mone withdrawal or recombinant human thyrotropin. “For the 684 patients who could be evaluated, a follow-up study was performed between 6 and 10 months (average, 8.3±1.6 months) after 131I administration; there were no sig� nificant differences in the time after 131 I administration in the four groups receiving treatment (two 1.1-GBq groups and two 3.7-GBq groups),” the researchers wrote. “On the basis of the local thyroglobulin determina� tions, thyroid ablation was consid� ered complete in 631 (92%) of the 684 patients,” they stated. “This study shows similar rates of thyroid-remnant ablation among patients with thyroid cancer, with� out evidence of residual disease after surgery, when either 1.1-GBq or 3.7GBq 131I is used and when the pa� tient is prepared by means of either recombinant human thyrotropin or withholding of thyroid hormone,” the authors summarized. “A simi� lar ongoing study reached the same conclusions. Thus, the use of recom� binant human thyrotropin and a low dose of 131I for postoperative radioio� dine ablation represents an effective and attractive option for the manage� ment of low-risk thyroid cancer that reduces the amount of whole-body irradiation and maintains the quality of life. Future randomized studies in patients with low-risk thyroid cancer should be permitted to restrict ra� dioablation to patients in whom it is beneficial.” Schlumberger M, et al: N Engl J Med 366:1663-1673, 2012. Mallick U, et al: N Engl J Med 366:16741685, 2012.

HODGKIN LYMPHOMA Panobinostat Produces Objective Responses in Patients Refractory to Autologous Transplant

Panobinostat produced objective responses in 27% and tumor reduc� tions in 74% of 129 patients enrolled in “the largest, prospective, multi�

center, international trial conducted in heavily pretreated patients” with Hodgkin lymphoma who relapsed or were refractory to autologous stem cell transplantation, according to results published in the Journal of Clinical Oncology. Among 35 patients achieving objective responses in the phase II trial, 30 had partial respons� es and 4 had complete responses. The median duration of response was 6.9 months. “An additional 71 patients demonstrated a best response of sta� ble disease, for a disease control rate (complete and partial responses plus stable disease) of 82%,” the research� ers reported. The estimated overall survival rate was 78%. Panobinostat, a pan-deacetylase in� hibitor, was administered three times per week orally at a dose of 40 mg to patients who had already received two to seven courses of chemotherapy. The patients were aged 18 years or older from 45 sites across 13 countries. “The population also had many poor prog� nostic features: 74 patients (57%) had primary refractory disease (did not re� spond to first-line therapy or relapsed within 3 months) and 85 (66%) re� lapsed less than 12 months after their first [stem cell transplant],” the authors noted.

Notable Myelotoxicity Patients who responded to panobi� nostat were as heavily pretreated as the overall patient population, and 41% of responders to panobinostat had not responded to their most recent prior therapy. The most common drug-re� lated grade 3 to 4 adverse events “were hematologic and included thrombo� cytopenia (79%), anemia (21%), and neutropenia (21%),” the authors re� ported. “This order of myelotoxicity would certainly limit the ability to combine panobinostat with other myelotoxic drugs,” according to an accompanying editorial. “The relatively low response rate and its toxicity will diminish the enthusiasm for this drug.” The study’s authors reported that “thrombocytopenia was manageable, commonly through dose or schedule adjustment or study drug interruption, with only seven patients (5%) discon� tinuing because of thrombocytope� nia.” They concluded that not only did panobinostat demonstrate promising single-agent activity, but “because pan� obinostat modulates several cellular mechanisms that regulate lymphoma cell survival, angiogenesis, and immu�

ASCOPost.com | JUNE 15, 2012

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In the Literature

nity, it has the potential of enhancing the activity of other agents when used in combination.” Younes A, et al: J Clin Oncol April 30, 2012 (early release online). Canellos GP: J Clin Oncol April 30, 2012 (early release online).

younger than 6 years of age with pre� cursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72% ± 5% when treated with chemotherapy only.

Differences among Study Groups “Treatment strategies for patients

with induction failure differed among the study groups,” the authors noted. “Seven study groups assigned these patients to the highest-risk treatment group, whereas other study groups enrolled such patients in an alterna� tive trial of leukemia therapy or treated them with individualized therapy. Al�

though the indications for allogeneic transplantation during the first period of complete remission varied among the study groups, induction failure was a consensus indication for alloge� neic transplantation. HLA-matched, related-donor transplantation was continued on page 98

ACUTE LYMPHOBLASTIC LEUKEMIA Pediatric ALL with Induction Failure Is Highly Heterogeneous with Varying Outcomes While failure of remission-induc� tion therapy is rare in children and adolescents with acute lymphoblastic leukemia (ALL), when it does occur it is highly adverse and heterogeneous, according to a study in The New England Journal of Medicine. “Patients who have T-cell leukemia appear to have a better outcome with allogeneic stemcell transplantation than with chemo� therapy, whereas patients who have precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy,” the authors reported. “We identified induction failure, defined by the persistence of leukemic blasts in blood, bone marrow, or any extramedullary site after 4 to 6 weeks of remission-induction therapy, in 1,041 of 44,017 patients (2.4%) 0 to 18 years of age with newly diagnosed ALL who were treated by a total of 14 cooperative study groups between 1985 and 2000,” they stated. “Patients with induction failure frequently presented with high-risk features, including older age, high leu� kocyte count, leukemia with a T-cell phenotype, the Philadelphia chromo� some, and 11q23 rearrangement,” they reported. At a median follow-up pe� riod of 8.3 years, the 10-year estimated survival was 32% ± 1%. Factors associated with a particu� larly poor outcome were an age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction ther� apy. Allogeneic stem-cell transplanta� tion from matched, related donors was associated with improved outcomes in T-cell leukemia. Factors associated with a favorable outcome in patients with precursor Bcell leukemia were high hyperdiploidy (a modal chromosome number > 50) and an age of 1 to 5 years. Children

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The ASCO Post | JUNE 15, 2012

In the Literature

Emerging Clinical Data continued from page 97

generally the preferred method among various alternatives to chemotherapy alone,” the study authors reported. “A key finding is that the prognos� tic value of various clinical and bio� logic features of ALL at diagnosis also holds true within the microcosm of ALL induction failure,” an editorial ac� companying the article noted. “These data also highlight the complex inter� relationship between disease biology and early treatment response—that is, inferior initial responses to therapy por� tend different outcomes within unique biologic subgroups.” The superiority of chemotherapy to stem-cell transplanta� tion in children younger than 6 years of age with precursor B-cell ALL (without MLL rearrangement) “is striking and may substantially affect current prac� tice, since stem-cell transplantation has generally been accepted as the preferred treatment for all cases of induction fail� ure,” according to the editorial. “The general insights obtained in this study apply not just to induc� tion failure, but to ALL overall,” the editorial continued. “From this re� markable collaborative effort we learn that induction failure is not a single entity with a uniform prognosis but rather exhibits biologic and prognos� tic heterogeneity. It is possible that sophisticated risk stratification and risk-directed treatment may lead to improved outcomes.” Schrappe M, et al: N Engl J Med 366:1371-1381, 2012. Rabin KR: N Engl J Med 366:14451446, 2012.

OVARIAN CANCER Scoring System Based on DNA Repair Pathways Predicts Outcomes and Response to Platinum Therapy A potentially important tool to identify patients with advanced-stage ovarian cancer likely to benefit from platinum-based chemotherapy and re� direct those with poor predicted out� comes to alternative treatments was developed using gene-expression data and validated in two independent da� tasets. While the scoring system still needs to be tested prospectively in a clinical trial, the developers believe “the score is ready for such testing, which must be performed before more widespread adoption in ovarian can� cer patients as a prognostic tool,” they

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004

wrote in an article published in the Journal of the National Cancer Institute. “Gene expression data was extract� ed from The Cancer Genome Atlas (TCGA) database for 151 DNA repair genes from tumors of serous ovar� ian cystadenocarcinoma patients (n = 511). A molecular score was generated based on the expression of 23 genes involved in platinum-induced DNA damage repair pathways.” Patients were divided into low-score (0–10) and high-score (11–20) groups, and overall survival was analyzed by Ka� plan–Meier method, the authors ex� plained. “Results were validated in two gene expression microarray datasets.” Patients in the high-scoring group had 5-year overall survival of 40% vs 17% in the low-scoring group (P < .001) and results were reproduced in the validation datasets (P < .05). “The score positively correlated with com� plete response rate, recurrence-free survival, and progression-free surviv� al,” the investigators stated. Development of the ability to predict overall survival and outcomes to che� motherapy using prognostic markers is critical, particularly in patients with ovar� ian cancer, because there are currently no good clinical measures to predict response to standard platinum-based chemothera� py. “Although 30% of patients receive no benefit from standard platinum-based chemotherapy, many patients undergo multiple cycles of futile, potentially toxic treatment,” the authors noted. “With further validation, the score can become an important tool that can be used in such advanced-stage ovar� ian cancer patients before initiation of first-line therapy to help direct them toward treatments with the greatest benefit/risk ratio. Patients in the low� est scoring category of 7 or less, with a median [overall survival] of 2.1 years, stand to benefit the most from alter� nate therapies, such as enrollment in phase I clinical trials or treatments that target alternate DNA repair pathways, such as radiation,” they continued. “Conversely, patients in the highest scoring category of 14 and above derive the greatest most durable benefit from platinum and taxane chemotherapy.” The authors also hypothesized that pa� tients in the highest-scoring category would benefit most from poly-ADP ri� bose polymerase (PARP) inhibitors.

■

Kang J, et al: J Natl Cancer Inst 104:670681, 2012.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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

AVASTIN® (bevacizumab) 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 3795 patients with CRC, non‑squamous NSCLC, MBC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] Data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, an indication for which Avastin is not approved. The population was aged 18‑88 years (median 59), 43.2% male and 85.3% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 5, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab) Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

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).]

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

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

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

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

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

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

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

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

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

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

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

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.

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

55% 55% 19%

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

Adverse events were encoded using MedDRA, Version 10.1.

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

AVASTIN® (bevacizumab)

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

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

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

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

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/ carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/ carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 7, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 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).] 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.

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 21071,2,4

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

18 12 OS (Months)

OS in second-line Study E3200: 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.

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.4%) — Proteinuria including nephrotic syndrome (<1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)

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

AVA0000402601

Printed in USA.

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

Pregnancy warning Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother 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. September 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.

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