TAP Vol 4 Issue 8 by Harborside Press LLC

Molecular Testing for Lung Cancer

| Targeted Therapy for Breast Cancer

| Transformed Follicular Lymphoma

VOLUME 4, ISSUE 8

MAY 15, 2013

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

ASCOPost.com

Journal Spotlight

Profound and Rapid Molecular Remission with CD19-targeted T Cells in Relapsed B-cell ALL By Matthew Stenger

s was recently reported in Science Translational Medicine, Renier J. Brentjens, MD, and colleagues at Memorial Sloan-Kettering Cancer Center, New York, found that profound molecular remission was rapidly induced in patients with relapsed B-cell acute lymphoblastic leukemia (ALL) using autologous T cells targeting the B-cell CD19 antigen.1 The autologous T cells were modified to express a CD19–specific CD28/CD3ζ second-generation dualsignaling chimeric antigen receptor (CAR) termed 19-28z (19-18z CAR-modified T cells). Promising outcomes have been reported using CD19targeted autologous T cells in patients with low-grade Bcell tumors, but to date there had been no reports of outcomes using CD19targeted adoptive T-cell therapy in patients with relapsed B-cell ALL, which is more aggressive and associated with a worse prognosis.

By Laurence H. Baker, DO

Study Details In the study, five patients with relapsed B-cell ALL who had not previously received allogeneic hematopoietic stem cell transplantation, and independent of remission status after salvage chemotherapy, were treated with the adopRenier J. Brentjens, MD tive T-cell therapy after conditioning therapy with cyclophosphamide. Treatment consisted of infusion of 1.5 to 3 × 106 autologous 19-28z+ T cells/kg. Due to ethical reasons, and according to study protocol, eligible patients subsequently underwent allogeneic stem cell transplantation. This limited the time for follow-up observation of the persistence of modified continued on page 18

Issues in Oncology

Sequestration’s Impact on Cancer Care

Budget cuts are jeopardizing patient access to care and threatening progress in scientific research.

n a recent issue of The ASCO Post, I counted 14 expert commentaries where the authority who wrote or was interviewed for the piece reported “no potential conflicts of interest.” I wondered how likely that was. We need to be clearer on the meaning of potential conflicts of interest. How often have you seen an important speaker read a list of potential conflicts as if he or she were a tobacco auctioneer, speaking so fast that the disclosure is obscured by the speed of its delivery? How often have you read an expert opinion where he or she claims no conflicts to declare? Given continued on page 27

Dr. Baker is Collegiate Professor of Oncology Developmental Therapeutics and Professor in the Departments of Medicine and Pharmacology at the University of Michigan, Ann Arbor.

MORE IN THIS ISSUE

By Jo Cavallo

On the Potential for Conflicts of Interest

n March 1, the deficit-budget mechanism known as sequestration took effect, triggering $85 billion in across-the-board cuts to most federal agencies over the remaining 7 months in fiscal year 2013. The total federal deficit reduction budget under the Budget Control Act of 2011 calls for $1.2 trillion

over the next 8 years. And the reverberations of the effects of those cuts across medical care for patients and scientific research were immediately felt. The National Institutes of Health (NIH), the world’s largest supporter of biomedical research,1 was originally slated to lose $1.55 billion out of its $31 billion budget as a result of sequestration, which translated to a decrease to the In the end, it is the patient with cancer National Cancer Institute fighting for his or her life who is going (NCI) budget of about $219 million. However, to feel the most profound impact from on March 26, President these budget reductions in clinical cancer Obama signed into law the research, slowdowns in FDA drug reviews, continuing budget resolution—the Consolidated and physician reimbursement. and Further Continu—Sandra M. Swain, MD, FACP ing Appropriations Act,

Oncology Meetings Coverage NCCN Conference�� 3, 106, 107, 115 SIR Conference�� 12, 14, 17 AACR Meeting �� 40-43, 70, 72, 123 Heart Effects of Breast Radiotherapy �� 49-54 Mario E. Lacouture, MD, on Dermatologic Toxicity �� 69 Direct from ASCO �� 86-90 Medical Education and Debt �� 99 Lynch Syndrome and Endometrial Cancer �� 124 Hagop Kantarjian, MD, and Elihu Estey, MD, on AML �� 137 In Memoriam: Emil Frei III, MD�� 169

continued on page 24

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Inside This Issue

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

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Michael P. Link, MD Stanford University Medical Center

Associate Editors Joseph S. Bailes, MD Texas Oncology Laurence H. Baker, DO University of Michigan Comprehensive Cancer 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 Wisconsin School of Medicine and Public Health Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD National Comprehensive Cancer Network Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology

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

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

George D. Demetri, MD Dana-Farber Cancer Institute

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland

John A. Fracchia, MD New York Urological Associates

David Khayat, MD Pitie-Salpetriere Hospital, Paris, France

Louis B. Harrison, MD Continuum Cancer Centers of New York

Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel

Mario E. Lacouture, MD Memorial Sloan-Kettering Cancer Center

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

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

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

Harborside Press® Publishing Staff Conor Lynch, Executive Editor Conor@harborsidepress.com

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Sarah McGullam, Assistant Editor Sarah@harborsidepress.com

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Contributing Writers: Charlotte Bath, Jo Cavallo, Alice Goodman, Caroline Helwick, Susan

London, Caroline McNeil, Eileen O’Gara-Kurtis, Ronald Piana, Matthew Stenger, Marian Wiseman

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations. Disclosure information available at ASCOPost.com.

James O. Armitage, MD, on Stem Cell Transplantation in Follicular Lymphoma see page 66

Lynn D. Wilson, MD Yale University School of Medicine

International Editors

Bishoy Morris Faltas, MD Weill Cornell Medical College

Jose Baselga, MD, PhD, and Targeted Therapies for Breast Cancer see page 56

George W. Sledge, MD Indiana University

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

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

Fred R. Hirsch, MD, PhD, on Personalized Therapy for Lung Cancer see page 32

James L. Mulshine, MD Rush University Medical Center

E. David Crawford, MD University of Colorado

Paul F. Engstrom, MD Fox Chase Cancer Center

Don’t Miss These Important Reports in This Issue of The ASCO Post

Eileen O’Reilly, MD, on S-1 in Pancreatic Cancer see page 127

Visit The ASCO Post online at ASCOPost.com The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2013 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 27,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $259; Individual International: $499; Institutional Domestic: $319; Institutional International $559. Contact subscriptions@harborsidepress.com. Correspondence: Address general inquiries to Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” 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.

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National Comprehensive Cancer Network Annual Conference

NCCN Clinical Practice Guidelines in Oncology: 2013 Updates By Caroline Helwick

t the 18th Annual Conference of the National Comprehensive Cancer Network (NCCN), representatives of NCCN Guidelines panels presented two new sets of guidelines along with updates for several tumor types, summarized in this issue of The ASCO Post.

New NCCN Guidelines for Survivorship

“The survivorship guidelines are intended as a library of tools for a provider to use when assessing a cancer survivor.” —Crystal S. Denlinger, MD

To better address the issues faced by cancer survivors and their families and to offer practical recommendations for clinical use, the NCCN Guidelines Panel for Survivorship Care created its inaugural practice guidelines, said Note: For a more complete listing of these and other updates, visit www.nccn.org.

Crystal S. Denlinger, MD, of Fox Chase Cancer Center, Philadelphia. Subtopics covered in the initial version of the guidelines are anxiety and depression, cognitive function, exercise, immunizations/infections, fatigue, pain, sexual function, and sleep disorders. “These survivorship guidelines are meant to be a companion to the disease guidelines,” said Jennifer Ligibel, MD, of Dana-Farber Cancer Institute, Boston, who with Dr. Denlinger reviewed several of the topics. The guidelines recommend physical activity and return to daily activities as soon as possible after cancer treatment, tailored to the individual’s abilities and preferences. The general recommendation is at least 150 minutes of moderate-intensity activity a week, coupled with strength training and stretching. NCCN also includes an assessment pathway. Clinicians are advised to evaluate the patient’s risk for exerciseinduced adverse events, as high-risk patients should avoid physical activity. Practical advice for specific populations (such as those with lymphedema, transplant, ostomy, peripheral neuropathy, and bone loss/metastases) is provided. The guidelines give examples of light, moderate, and vigorous exercise, and strategies to increase physical activity. General principles about cognitive dysfunction as a complication of cancer treatment are presented, with the acknowledgement that evidence-

based guidance is lacking. The guidelines include an evaluation pathway that indicates the need to screen for reversible contributing factors, specific assessments, and practical interventional strategies that center on patient/family education and counseling. Vaccinations are encouraged based on age and medical condition as part of standard practice. Vaccines considered safe for cancer and transplant survivors include influenza, pneumonia, meningitis, and hepatitis; live attenuated vaccines such as for measles, mumps, and rubella are contraindicated or advised with caution. Patients should be vaccinated at least 3 weeks prior to initiating cancer treatment, in order to receive the full benefit of immunity. Patients should be assessed for disease status, prior and current treatments, time from treatment completion, exposure to endemic infections or epidemics, and overall immune system viability. Principles for herpes zoster (shingles) vaccination in cancer or transplant survivors are provided. General assessments for sexual dysfunction should focus on the level of sexual activity (past and present), the impact of cancer therapy, sexual concerns or symptoms, comorbidities, risk factors, and psychosocial factors. The guidelines include validated tools for assessment: a brief sexual symptom checklist for women and a sexual health inventory for men. “We tried hard to minimize the interventions to things an oncology provider could do

vs things that need to be referred,” Dr. Denlinger noted.

New NCCN Guidelines for Penile Cancer

“With 5-FU or imiquimod, you can get excellent outcomes.” —Philippe E. Spiess, MD

New NCCN Guidelines were issued for penile cancer, which is diagnosed in about 1,250 men each year and constitutes 0.4% to 0.6% of all malignancies. Management of penile cancer has been very heterogeneous; therefore, these guidelines were clearly needed, said Philippe E. Spiess, MD, of the H. Lee Moffitt Cancer Center, Tampa, Florida. “The standard of care in the management of primary penile tumors remains complete tumor excision and continued on page 8

Visit The ASCO Post at the ASCO Annual Meeting May 31 - June 4, 2013 The ASCO Post BOOTH 12096 • Harborside Press BOOTH 13096 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

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.

The ASCO Post | MAY 15, 2013

PAGE 8

National Comprehensive Cancer Network Annual Conference NCCN Guidelines continued from page 3

eradication with negative margins,” he said, but less invasive or even noninvasive management is sometimes appropriate. Radical surgery (partial or total penectomy with a negative surgical margin) is the primary recommendation for invasive disease, but less invasive options can being considered based on the stage and grade of the primary penile tumor. In the new guidelines, the algorithm for primary treatment of superficial lesions (Tis or Ta) includes topical treatment with either imiquimod 5% or fluorouracil (5-FU) cream (category 2A, ie, based on lower-level evidence, with uniform NCCN consensus that the intervention is appropriate) or wide local excision with circumcision; laser therapy and complete glansectomy are less evidence-based options. For more extensive tumors (T1), grade dictates treatment, the spectrum of which includes wide local excision, laser, radiation therapy, glansectomy, and partial/total penectomy. Penile-preserving surgery maintains function and quality of life in a select cohort of patients, but “clinical stage consideration is critical,” Dr. Spiess said. This approach is indicated only for patients with small lesions, where negative margins can be obtained. “The treatment paradigm for bulky nodal disease is clearly evolving to a multimodal approach,” he noted. Good outcomes with neoadjuvant chemotherapy followed by surgical resection led to its recommendation as a preferred approach for palpable inguinal lymph nodes > 4 cm. For diagnostic workup, the guidelines support the use of a nomogram to predict metastatic lymph node involvement, which outperforms the conventional clinical risk categories. Dynamic sentinel node biopsy has low sensitivity and remains an insufficient way to detect occult inguinal disease at most centers with limited experience with this technique. For patients with nonpalpable inguinal nodes considered at low risk, surveillance is indicated; inguinal lymph node dissection is recommended for those at high risk and is the gold standard for aggressive primary tumors. For palpable nodes (nonbulky disease), the size of the unilateral lymph node dictates the subsequent workup.

Nonchemotherapy Option for Acute Promyelocytic Leukemia

“For the first time, the NCCN Guidelines have taken chemotherapy out of the upfront treatment for APL.” —Margaret R. O’Donnell, MD

The NCCN Guidelines for acute promyelocytic leukemia (APL) were changed as a result of a study presented at the 2012 Annual Meeting of the American Society of Hematology,1 which compared the gold standard for newly diagnosed non‒high-risk APL—simultaneous all-trans retinoic acid (ATRA) and chemotherapy (idarubicin)—with the chemotherapy-free combination of ATRA and arsenic trioxide (Trisenox). Complete responses were observed in 97% of each arm, but 2-year event-free survival was higher in the nonchemotherapy arm (97%) vs controls (87%). For treatment induction of patients with low- or intermediate-risk APL, ATRA in two divided doses plus arsenic trioxide is recommended until bone marrow remission, according to Margaret R. O’Donnell, MD, of City of Hope Comprehensive Cancer Center, Duarte, California.

New Agents in Multiple Myeloma

“We have wonderful new agents, at least a log more potent than priorgeneration drugs.” —Kenneth C. Anderson, MD

Upon the approval of the secondgeneration proteasome inhibitor carfilzomib (Kyprolis), the guidelines for transplant candidates were updated to include the triplet of carfilzomib/ lenalidomide (Revlimid)/dexamethasone as an initial treatment option under “other regimens.” This joins a growing list of triplets that greatly increase response rates, according to Kenneth C. Anderson, MD, of Dana-Farber Cancer Institute, Boston. The 2013 update also includes carfilzomib as a preferred salvage therapy option for relapsed/refractory disease, as well as the new immunomodulatory drug pomalidomide (Pomalyst) plus low-dose dexamethasone. The improved activity and safety profiles of carfilzomib and pomalidomide over older agents in their respective classes has elicited enthusiasm about using them together, he added.

Updates in Bone Cancer

Intralesional excision with the use of a high-speed burr is preferred over more extensive surgery requiring skeletal reconstruction. The typically high recurrence rate after surgery has been greatly reduced with the use of adjuvant therapy, either thermal or chemical. In patients with unresectable or recurrent tumor, denosumab (Xgeva) is active and has become an emerging component of treatment. Denosumab can help restore the skeletal architecture to allow a joint-conserving procedure, or avoidance of surgery altogether, Dr. Biermann noted. The recommended workup includes history, physical examination, cross-sectional imaging of the primary site, chest imaging, and biopsy, with optional bone scan. For localized disease, excision is recommended; if resection carries unacceptable morbidity or the tumor is unresectable, options include serial embolization, denosumab, interferon, pegylated interferon, and/or radiotherapy (as a last resort).

Updates in Thyroid Cancer

“Giant cell tumor of bone has a 2% incidence of metastasis, and that together with the significant local morbidity is why it deserves special treatment.” —J. Sybil Biermann, MD

New treatment pathways for giant cell tumor of bone and chordoma debuted in the updated version of the guidelines for bone cancer, joining those for osteosarcoma, nonmetastatic Ewing’s sarcoma, and chondrosarcoma. These are especially important, given the rarity of these neoplasms and most clinicians’ lack of familiarity with them, said J. Sybil Biermann, MD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor. Although considered a benign disease, “Giant cell tumor of bone has a 2% incidence of metastasis, and that together with the significant local morbidity is why it deserves special treatment,” Dr. Biermann suggested.

“Two new drugs have become available for metastatic disease. These are exciting times in thyroid cancer.” —Robert I. Haddad, MD

When thyroid cancer patients become refractory to radioactive iodine, there have been few effective treatment options, but the availability of multitargeted tyrosine kinase inhibitors is changing this. In medullary thyroid cancer, cabozantanib (Cometriq) and vandetanib (Caprelsa), both recently FDA-approved for advanced or metastatic disease, have more than doubled progression-free survival. The guidelines now list both drugs as category 1 treatments for unresectable disease that is symptomatic or asymptomatic and structurally progressive. continued on page 10

NOW ENROLLING – A RANDOMIZED PHASE lll STUDY

A Phase III study of the pan-PI3K inhibitor buparlisib (BKM120) with fulvestrant in patients with HR+/HER2−, aromatase inhibitor-treated, locally advanced or metastatic breast cancer who progressed on or after mTOR inhibitor Postmenopausal women with HR+/HER2–, inoperable, locally advanced or metastatic breast cancer previously treated with an aromatase inhibitor (N≈615) Evidence of progression on or after mTOR inhibitor-based therapy No more than one prior line of chemotherapy for metastatic disease Archival tumor tissue for analysis of PI3K pathway activation

Molecular pre-screening*

ECOG Performance Status ≤2

Randomization (2:1)

Additional inclusion/exclusion criteria apply.

Buparlisib + fulvestrant

Placebo + fulvestrant

Primary endpoint: Progression-free survival Key secondary endpoint: Overall survival *Molecular pre-screening for PI3K activation status can occur at any time prior to randomization after obtaining pre-screening informed consent.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

Buparlisib (BKM120) is an investigational new drug. Efficacy and safety have not been established. There is no guarantee that buparlisib will become commercially available. For more information Contact your local Novartis representative. Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (USA only). Visit www.clinicaltrials.gov (NCT01633060). Visit the PRI3M program website at www.pri3m.com or scan the QR code.

Pioneering Research of PI3K inhibitors in Malignancies

www.pri3m.com Novartis Pharmaceuticals Corporation East Hanover, NJ 07936-1080

February 2013

G-BKE-1061803

Novartis Pharma AG CH-4002, Basel, Switzerland

The ASCO Post | MAY 15, 2013

PAGE 10

National Comprehensive Cancer Network Annual Conference NCCN Guidelines continued from page 8

While not FDA-approved for thyroid cancer, other small-molecule tyrosine kinase inhibitors (sorafenib [Nexavar], sunitinib [Sutent], and pazopanib [Votrient]) can be considered, said Robert I. Haddad, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, Boston.

New Agents in Colorectal Cancer

first progression, in combination with FOLFIRI, irinotecan, FOLFOX (leucovorin, 5-FU, oxaliplatin) or CapeOx (capecitabine [Xeloda], oxaliplatin). Regorafenib was added to the guidelines as a treatment option after first, second, or third progression, depending on previous lines of therapy, based on the 1.4-month survival advantage seen in the CORRECT trial.3

Melanoma: No Sentinel Lymph Node Biopsy for Thin Lesions

New Drugs in Prostate Cancer

“We have learned a lot in the past 10 years about the importance of androgen signaling, even in castration-resistant prostate cancer.” —Philip W. Kantoff, MD

“We had hoped ziv-aflibercept would be the next step forward, but in the registration study it provided only a 1.4-month overall survival benefit.” —Leonard Saltz, MD

Two new agents recently approved for metastatic colorectal cancer are now included in the NCCN Guidelines: zivaflibercept (Zaltrap, a fusion protein that blocks all human VEGF-A isoforms, VEGF-B, and placental growth factor) and regorafenib (Stivarga), a multikinase inhibitor. Unfortunately, while they were shown to improve overall survival, the benefit is small, according to Leonard Saltz, MD, of Memorial Sloan-Kettering Cancer Center, New York. In the VELOUR trial, ziv-aflibercept plus FOLFIRI (leucovorin, 5-FU, irinotecan) as second-line treatment improved overall survival from 12.06 to 13.50 months (P � .0032), � .0032), .0032), .0032), and progression-free survival from 4.7 to 6.9 months (P � .0007).2 This benefit is similar to what is seen when bevacizumab (Avastin) is added to chemotherapy, but the newer drug is more expensive and potentially more toxic, Dr. Saltz noted. In the updated guidelines, zivaflibercept is acceptable when added to FOLFIRI or irinotecan, but should not be used as a single agent, in combination with FOLFIRI after failure of FOLFIRI-bevacizumab (or vice versa), or added to a failed regimen. Bevacizumab was also added as an option after

“The Panel tried to set a threshold for the practitioner, and we have said that thin melanomas do not warrant sentinel lymph node biopsy.” —Daniel G. Coit, MD

The most recent updates in melanoma pertain not to treatment but to the diagnosis and workup of new patients, especially the indication for sentinel lymph node biopsy. According to the updated guidelines, sentinel lymph node biopsy is not warranted for thin lesions, ie, those ≤ 0 .75 mm. “That is a big change in the guidelines,” said Daniel G. Coit, MD, of Memorial Sloan-Kettering Cancer Center, New York. Since nearly three-quarters of primary melanomas are < 1 mm, “this change in the guidelines has the potential to affect many patients,” he said. Conventional risk factors such as ulceration, high mitotic rate, and lymphovascular invasion are quite uncommon in these very thin melanomas, but, when present, sentinel lymph node biopsy may be considered. Patients with lesions ≤ 0 .75 mm without these features can proceed to wide excision. For lesions 0.76 to 1.0 mm, a sentinel lymph node biopsy can be considered. For lesions > 1 mm, sentinel lymph node biopsy is recommended.

New drugs in prostate cancer take advantage of the persistence of androgen receptor expression, even in castrationresistant disease. Two drugs targeting this pathway were recently approved—abiraterone acetate (Zytiga), an androgen synthesis inhibitor, and enzalutamide (Xtandi), an antiandrogen—and these have changed the treatment landscape, said Philip W. Kantoff, MD, of the Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston. The NCCN Guidelines include abiraterone/prednisone as a category 1 recommendation in both the pre- and postchemotherapy settings, and enzalutamide as a category 2A recommendation for docetaxel-naive men and a category 1 recommendation postchemotherapy. “These drugs have a clinically meaningful impact on survival,” Dr. Kantoff said.

Updates in Non-Hodgkin Lymphoma

“The combination of lenalidomide plus rituximab is very encouraging in relapsed/refractory follicular lymphoma.” —Jeremy S. Abramson, MD

For follicular lymphoma that is lowgrade but has a high tumor burden, the combination of bendamustine plus rituximab (Rituxan) now carries a category 2A recommendation and is expected to become a category 1 ranking (ie, based on high-level evidence) in future updates. New to the guidelines for the second-line treatment of stage I/II disease is lenalidomide with or without rituximab, which has a category 2A ranking, said Jeremy S. Abramson, MD, Massachusetts General Hospital Cancer Center, Boston. In mantle cell lymphoma, rituximab maintenance received a category 1 recommendation following R-CHOP therapy in older adults not considered candidates for intensive therapy. For young, fit patients, the role of induction therapy with a cytarabine-containing treatment program followed by high-dose chemotherapy with autologous stem cell transplant was reviewed based on phase II and recent phase III data. For chronic lymphocytic leukemia, first-line therapy now includes lenalidomide (continuous or intermittent dosing) as a treatment option, and bendamustine with or without rituximab. For relapsed/refractory disease, lenalidomide with or without rituximab is a treatment option. n

Disclosure: Drs. Spiess, Denlinger, Ligiel, Saltz, Abramson, Kantoff, and Coit reported no potential conflicts of interest. Dr. Anderson is an advisor for Celgene, Onyx, Sanofi-Aventis, and Gilead; and is a scientific founder of Acetylon and OncoPep.

References 1. Lo-Coco F, Avvisati G, Orlando SM, et al: ATRA and arsenic trioxide versus ATRA and idarubicin for newly diagnosed, non-high-risk acute promyelocytic leukemia: Results of the phase III, prospective, randomized, intergroup APL0406 study by the Italian-German Cooperative Groups Gimema-SALAMLSG. Blood 120:Abstract 6, 2012. 2. Van Cutsem E, Tabernero J, Lakomy R, et al: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer. J Clin Oncol 30:3499-3506, 2012. 3. Grothey A, Van Cutsem E, Sobrero A, et al: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicenter, randomized, placebo-controlled, phase 3 trial. Lancet 381:303-312, 2013.

ASCOPost.com | MAY 15, 2013

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Announcements

In Chicago for ASCO?

Join the Robert H. Lurie Comprehensive Cancer Center of Northwestern University for the 20th Annual Cancer Survivors’ Celebration & Walk—and New 5K Run.

obert H. Lurie Comprehensive Cancer Center of Northwestern University is celebrating the 20th Annual Cancer Survivors’ Celebration with a first! Join the Lurie Cancer Center for a timed 5K run along the lakefront on Sunday, June 2. The run will start in Chicago’s Grant Park at 7:15 AM, before the 20th Annual Cancer Survivors’ Celebration & Walk begins.

Register Today Register online today or visit Northwestern Medicine at ASCO’s Annual Meeting on Saturday, June 1, Booth 2062, to register in person. The run is limited to 500

June 2 is National Cancer Survivors’ Day

participants. Run registration fee of $50 per person includes special 20th Anniversary dri-fit shirt and registration for the

Celebration & Walk. Participants must sign up for the Walk when registering for the Run. Registration fee for Celebration & Walk only is $15 in advance

and $25 on June 2. Registration and event details at cancer.northwestern.edu/walk or 312.695.1300. n

The ASCO Post | MAY 15, 2013

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Society of Interventional Radiology Refractory Liver Metastases Yield to Yttrium-90 Radioembolization By Caroline Helwick

n patients with unresectable hepatic metastases from metastatic melanoma and neuroendocrine tumors, radioembolization led to good outcomes in studies from Emory University School of Medicine reported at the 38th Society of Interventional Radiology Annual Scientific Meeting, held recently in New Orleans.

Metastatic Melanoma Study “Systemic chemotherapy for metastatic melanoma to the liver is largely ineffective, and median survival after diagnosis generally ranges from 2 to 7 months,” according to Hasmukh J. Prajapati, MD, a Senior Associate in Radiology at Em-

Hasmukh J. Prajapati, MD

ory. The extent of metastases generally renders surgery or ablation ineffective, but a survival advantage has been reported after yttrium-90 radioembolization therapy in this patient population, he said. The study included 24 consecutive patients who received a total

of 42 yttrium-90 procedures over a 9-year period at Emory.1 Bilobar disease was present in 92%; index lesion size was 3–7 cm in 42% and > 7 cm in 42%; 29% had > 8 liver lesions, 8% had portal vein thrombosis, and 75% had additional extrahepatic metastases. The primary tumor was ocular in 60%, cutaneous in 40%. The median survival from the time of first yttrium-90 procedure was 13.4 months (range, 1 month to 7 years). Median survival from initial melanoma diagnosis was 121.4 months, and from a diagnosis of liver metastases was 19.9 months. Tumor response was significantly associated with progression-free survival, which was 19.6 months for the 12.5% of patients with a partial response, 10.3 months for the 62.5% with stable disease, but only 1.3 months for the 25% of nonresponders, Dr. Prajapati reported. For patients who received one cycle of treatment (92%), median survival was 12.9 months, while those with repeat cycles (8%) had a median survival of 21.3 months (P � .06). The investigators evaluated factors that were significantly related to improved survival after yttrium-90 radioembolization, and found survival to be highest in patients with Child Pugh class A (15.1 months), < 8 liver lesions (17.7 months), and an absence of extrahepatic metastases (21.4 months).

Radioembolization for Liver Metastases ■ A study of yttrium-90 radioembolization therapy in patients with

unresectable metastatic melanoma to the liver demonstrated a median survival of 12.9 months for patients who received one cycle of treatment and 21.3 months for those who received repeat cycles.

■ A retrospective analysis of yttrium-90 radioembolization for hepatic

metastases from neuroendocrine tumors found that the treatment doubled median survival (4.2 years vs 2.0 years in an untreated group, P = .005).

Visit

Neuroendocrine Tumors Emily B. McIntosh, a medical student at Emory, reported the results of a retrospective analysis that compared patients with neuroendocrine tumors and hepatic metastases treated with (n � 46) and without (n � 113) yttrium-90 radioembolization.2 The 159 patients were identi-

“Independent prognostic factors for survival from hepatic metastases were treatment with yttrium-90, treatment with [octreotide], tumor burden, and bilirubin,” she said. The Cox proportional hazards

Independent prognostic factors for survival from hepatic metastases were treatment with yttrium-90, treatment with [octreotide], tumor burden, and bilirubin. —Emily McIntosh

fied from the Emory Cancer Registry and were treated between 2003 and 2012. A few baseline differences were noted between the two groups. Patients treated with yttrium-90 had a longer time to the development of hepatic metastases, were more likely to have at least 10 hepatic lesions, had lower bilirubin levels, and were more likely to have received octreotide acetate (Sandostatin) as a previous treatment. “The median overall survival after treatment with yttrium-90 was 1.3 years,” Ms. McIntosh reported. Interestingly, patients treated with yttrium-90 had a greater number of liver lesions than patients not receiving this treatment. They also had a longer interval between the primary diagnosis and hepatic metastasis as well as lower bilirubin levels. From the time of the initial diagnosis, median survival time was essentially doubled among patients treated with yttrium-90: 4.2 years compared with 2.0 years in the untreated group (P � .005). From the time of diagnosis of hepatic metastases, median survival was significantly improved: 2.8 years compared with 1.7 years, respectively (P � .02).

model, controlled for time from primary diagnosis to hepatic metastases, identified the following hazard ratios: number of hepatic lesions > 10 (2.51), treatment with yttrium-90 (0.53), treatment with octreotide (0.43), elevated bilirubin (1.17), and size of largest hepatic lesions (1.07). She added that while octreotide was independently associated with a survival benefit, previous studies have not shown this. n

Disclosure: Dr. Prajapati and Ms. McIntosh reported no potential conflicts of interest.

References 1. Prajapati HJ, Dawson DH, Kim HS: Selective internal yttrium-90 radioembolization therapy in patients with unresectable metastatic melanoma to liver, refractory to systemic therapy: Analysis of imaging findings, survival and factors associated with prolonged survival. Society of Interventional Radiology Annual Scientific Meeting. Abstract 64. Presented April 15, 2013. 2. McIntosh EB, El-Rayes B, Kauh J, et al: Resin-based yttrium-90 radioembolization for metastatic neuroendocrine tumors in a single-center cancer registry. Society of Interventional Radiology Annual Scientific Meeting. Abstract 65. Presented April 15, 2013.

website at ASCOPost.com

Visit ASCO Booth #22036

NOW ENROLLING A Phase 2 Trial of Rindopepimut in Patients With Relapsed EGFRvIII-Positive Glioblastoma • Rindopepimut is an investigational therapeutic vaccine. It targets EGFRvIII, a constitutively activated deletion mutant that is found only in tumors. About a third of glioblastoma patients express EGFRvIII, and its presence has been linked to poor long-term survival1-3 • ReACT is a phase 2 study being conducted in the United States that will evaluate if rindopepimut is effective in extending progression-free survival in patients with relapsed EGFRvIII-expressing glioblastoma, when added to standard bevacizumab

1:1 Randomization

Blinded Rindopepimut Group 1 Bevacizumab Naïve (n=70)

1st or 2nd relapse EGFRvIII-positive GB

Bevacizumab Blinded KLH Control

Bevacizumab

Treat until tumor progression, intolerance, or withdrawal of consent

Rindopepimut

Group 2 Bevacizumab Refractory

Bevacizumab

(n=25) N=95

Key Inclusion Criteria

Key Exclusion Criteria

• Previous treatment must include surgery (biopsy, partial resection, or full surgical resection), conventional radiation therapy, and temozolomide

• Presence of diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial disease

• First or second relapse of glioblastoma. Patients enrolling into group 2 must have progressed while receiving bevacizumab

• Clinically significant increased intracranial pressure, uncontrolled seizures, or requirement for immediate palliative treatment

• Documented EGFRvIII-positive tumor status. A tumor sample from either the initial diagnosis or more recent relapse will be acceptable. Only patients with the EGFRvIII mutation can participate in the trial

• History, presence, or suspicion of metastatic disease

Key Trial Endpoints • Primary: Progression-free survival (PFS) rate at 6 months (PFS 6) • Secondary: Objective response rate, overall PFS, and overall survival

For more information visit www.celldextherapeutics.com or e-mail info@celldextherapeutics.com—see more at booth #22036.

1. Pelloski CE et al. J Clin Oncol. 2007;25(16):2288-2294. 2. Sampson JH et al. J Clin Oncol. 2010;28(31): 4722-4729. 3. Sampson JH et al. Neuro Oncol. 2011;13(3):324-333. ©2013 Celldex Therapeutics Inc.

J3A

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The ASCO Post | MAY 15, 2013

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Society of Interventional Radiology Early Data Promising for Concurrent Sorafenib Plus Embolization in Metastatic Liver Cancer By Caroline Helwick

f sorafenib (Nexavar) and local ablation techniques are both effective in the treatment of metastatic hepatocellular carcinoma, could they deliver an

Jean-Francois (Jeff) H. Geschwind, MD

even greater punch when combined? The concurrent use of interventional radiology approaches and sorafenib for metastatic hepatocellular carcinoma is being evaluated at major cancer centers, with research presented at the Society of Interventional Radiology 38th Annual Scientific Meeting.

Sorafenib plus Chemoembolization Potential benefit for sorafenib plus doxorubicin-eluting bead-transarterial chemoembolization (DEB-TACE) was demonstrated in the final analysis of a phase II trial presented at the meeting by Jean-Francois (Jeff) H. Geschwind, MD, Professor of Radiology, Surgery, and Oncology and Director of the Division of Vascular and Interventional Radiology at Johns Hopkins University, Baltimore.1 The study’s first author was Allen Feng, a medical student at Hopkins. Dr. Geschwind explained the rationale for the combination, noting that large clinical trials have established the survival benefit of sorafenib, while DEB-TACE is considered superior to conventional TACE, a common approach to metastatic hepatocellular carcinoma. “This is why we used DEBTACE and sorafenib together,” he said. The first prospective study of this combination included 50 patients with Child Pugh A to B7, Barcelona Clinic Liver Cancer (BCLC) class A to C, and good performance status. Patients with partial portal vein thrombosis and asymptomatic extrahepatic disease were allowed to enroll (whereas they were excluded in the SPACE trial, which evaluated this strategy and showed a statistically significant, though clini-

cally small, benefit).2 “These were the typical patients we see in a tertiary care center,” Dr. Geschwind noted. Patients received sorafenib at 800 mg/d beginning 1 week prior to DEB-TACE and underwent as many as four DEB-TACE treatments over 6 months. Aside from safety, the primary endpoint was time to untreatable progression, defined as the interval from the initiation of sorafenib until the patient was unable to receive further intra-arterial therapy. Outcomes were stratified according to whether patients were classified as BCLC A/B or BCLC C.

with thrombosis (P � .03). Interestingly, median overall survival, stratified according to the duration of sorafenib use, showed that BLCL C patients who received at least 6 months of the drug lived much longer than those who received less than 6 months (21.0 vs. 6.8 months; P < .01). .01). However, duration of sorafenib was inconsequential for BLCL A/B patients (28.2 vs 24.6 months; P � .52). “These are promising survival outcomes,” Dr. Geschwind observed. “The addition of DEB-TACE to sorafenib for BCLC C C patients may lead to improvements in survival.” Safety was acceptable, and the “vast

Sorafenib plus Embolization in Metastatic Liver Cancer ■ In a prospective phase II trial, sorafenib plus doxorubicin-eluting bead-

transarterial chemoembolization achieved a disease control rate of 100% at 6 months, with a median time to untreatable progression of 15.4 months for the overall population.

■ In a 19-patient retrospective trial, sorafenib combined with yttrium-90

radioembolization achieved local response in all patients, and increased overall and progression-free survival compared to prior studies of sorafenib alone in patients with similar disease status.

Key Results The DEB-TACE/sorafenib concurrent treatment yielded a disease control rate of 98% at 1 month and 100% at 6 months, months, by both Response Evaluation Criteria in Solid Tumors (RECIST) and European Association for the Study of the Liver (EASL) criteria. “We were able to achieve a 100% disease control rate at 6 months, which is quite promising,” Dr. Geschwind commented. Median time to untreatable progression was 15.4 months for the overall population. For BCLC A/B patients, median time to untreatable progression reached 29.1 months, whereas it decreased to 6.2 months for BCLC C patients (P < .001). “We viewed this as encouraging, even in the C group,” he commented. Median overall survival was 20.4 months for the study population, including 32.4 months for BCLC A/B patients and 8.0 months for BCLC C patients (P < .001). When BCLC C patients were stratified by portal vein thrombosis, median overall survival was 17.1 months in those without this complication, and 7.2 months in those

majority” of patients were able to stay on sorafenib, he said. The incidence of dose cessation requiring exit from the study was 27%. “The imaging data support this combination,” Dr. Geschwind said. “Safety was established, and the efficacy data are promising, but we acknowledge that this is a single-arm, single-center trial with no comparator. Nevertheless, it appears that the addition of DEB-TACE to sorafenib may improve survival, especially in BLCL C patients.”

Sorafenib plus Radioembolization Sorafenib is also being studied in combination with yttrium-90 radioembolization. Results from a retrospective analysis of this approach in a study led by Armeen Mahvash, MD, Associate Professor, and Ravi Murthy, MD, Professor, at The University of Texas MD Anderson Cancer Center, Houston, were reported at the meeting by Sameer Gadani, MD, an interventional oncology fellow at MD Anderson.3 Dr. Mahvash and colleagues asked

whether the addition of yttrium-90 resin microspheres to sorafenib could improve tumor response without adding toxicity in patients with advanced or multifocal hepatocellular carcinoma. They retrospectively examined 19 patients with BCLC class B/C and Child Pugh class A0 to B7 treated between 2008 and 2010. Most patients were Child Pugh class A (n � 16) and BCLC C (n � 13). All patients were on sorafenib prior to and following yttrium-90 treatment. Sorafenib was stopped 1 week prior to radioembolization and restarted after 1 week. Median follow-up was 19 months. “We found that a local response (partial response, stable disease) was achieved in all patients, and overall survival and progression-free survival were increased as compared to prior studies of sorafenib alone in patients with similar disease status,” Dr. Gadani reported. The partial response rate was 19%

Sameer Gadani, MD

by RECIST criteria and 42% by EASL criteria; stable disease was observed in 81% and 58%, by these respective assessments. Median overall survival was 19.5 months for the overall population, 54.9 months for BCLC B patients and 12.1 months for BCLC C patients. Median hepatic disease progression-free survival was 7.8, 9.3, and 6.9 months, respectively, for the above population, while extrahepatic disease progression-free survival was 8.9, 38.0, and 7.5 months, respectively. The addition of yttrium-90 in patients receiving standard- or reduceddose sorafenib did not increase the continued on page 16

The case for Vectibix® QQ2W dosing schedule1

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

660-minute infusion1

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

PPremedication not standardized1

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

NNo loading dose1

– No loading dose is required

IInfusion reactions1

– Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience – Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion – Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions

DDermatologic toxicity1

– Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy – Withhold Vectibix® for dermatologic toxicities that are ≥ grade 3 or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix® – If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than 2 doses of Vectibix®, treatment may be resumed at 50% of the original dose - If toxicities recur, permanently discontinue Vectibix® - If toxicities do not recur, subsequent doses of Vectibix® may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached

INDICATION:

Vectibix® (panitumumab) is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®. Vectibix® is not indicated for the treatment of patients with KRAS mutation-positive mCRC or for whom KRAS mCRC status is unknown. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. IMPORTANT SAFETY INFORMATION WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Severe diarrhea and dehydration, which may lead to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Patients with a history or evidence of interstitial pneumonitis, pulmonary fibrosis, were excluded from most clinical trials. Therefore, the estimated risk in a general population that includes such patients is uncertain. Cases of interstitial lung disease (ILD), including fatalities, have been reported in patients treated with Vectibix®. Interrupt Vectibix® therapy for the acute onset or worsening of pulmonary symptoms. Discontinue Vectibix® therapy if ILD is confirmed. In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed. Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose. Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis. Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll. Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®. The most common adverse reactions (≥ 20%) of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, diarrhea, including diarrhea resulting in dehydration, and constipation. The most serious adverse reactions of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix® administration. Terminate the infusion for severe infusion reactions. Vectibix® is not indicated for use in combination with chemotherapy. In a phase 3 study of patients with KRAS mutation-positive mCRC (n = 440) evaluating Vectibix® in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared to FOLFOX alone as first-line therapy for mCRC, shortened overall survival time was observed in the mutant KRAS mCRC population after 294 deaths (HR = 1.24, 95% CI: 0.98–1.57). Please see brief summary of Prescribing Information on next page. In an interim analysis of Study 2, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% Reference: 1. Vectibix® (panitumumab) vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®- prescribing information, Amgen. treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/ mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). 04-13 NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs ©2013 Amgen Inc. All rights reserved. G61228-R2-V2 61007-R2-V2 4%) and included fatal events in three (< 1%) Vectibix®-treated patients.

The ASCO Post | MAY 15, 2013

PAGE 16

Society of Interventional Radiology Metastatic Liver Cancer

LookingBrand: Ahead Vectibix

selection bias was possible, since pa- ASCOPost Publication: DuringClient: theAMGEN presentation, Dr. tients were already on sorafenib beIssue: 2013-May15_IP4C-PI 10109634 Trim: 7.875in x 10.75in incidence of grade 4 adverse events Gadani Job#: acknowledged the limitafore the yttrium-90 treatment. Nev10109634_AMGEN-Vectibix_ASCOPost_2013-May15_IP4C-PI.pdf Bleed: 7.875in x 10.75in (none were observed). There were tions of the study: It was a retrospecertheless, he said, the encouraging four grade 3 adverse events (21%), tive evaluation of a small number of results warrant future prospective including gastrointestinal ulcer, lympatients, the treatment effect could studies. phopenia without life-threatening be confounded by multiple other Robert K.W. Ryu, MD, of NorthT: 7.875” infection, mucositis, and abdominal treatments the patients received western University, Chicago, who pain/nausea/vomiting. before and after this approach, and moderated the radioembolization continued from page 14

Robert K.W. Ryu, MD

Vectibix® (panitumumab) Injection for intravenous Infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix monotherapy [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].

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

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation.The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibixtreated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported. Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration]. Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. As monotherapy: The incidence of binding antibodies (excluding pre-existing and transient positive patients) was 0.4% (3/717), as detected by the acid dissociation ELISA, and 3.8% (27/717) as detected by the Biacore® assay. The incidence of neutralizing antibodies (excluding pre-existing and transient positive patients) was 1% (7/717). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix. In combination with irinotecan- or oxaliplatin-based chemotherapy: The incidence of binding antibodies (excluding pre-existing positive patients) was 1% (11/1124) as detected by the acid dissociation ELISA and 0.8% (9/1123) as detected by the Biacore assay. The incidence of neutralizing antibodies (excluding pre-existing positive patients) was 0.2 % (2/1124). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions has been identified during post-approval use of Vectibix. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or established a causal relationship to drug exposure: • Skin and subcutaneous tissue disorders: Skin necrosis, angioedema [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Immune system disorders: Anaphylactoid reaction [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions] DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with Vectibix. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology (13.3) in Full Prescribing Information]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll. Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients. Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration, Warnings and Precautions, and Adverse Reactions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations]. This brief summary is based on the Vectibix® prescribing information v17, 03/2013 Rx Only Patent: http://pat.amgen.com/vectibix/ ©2006-2013 Amgen Inc.All rights reserved.

73846-R1-V1

session, commented that the combined drug/embolization strategy is an active research area. “There are a number of ongoing studies. At Northwestern, we are sponsoring a singlecenter study of yttrium-90 with or without sorafenib,” he noted. Much of the current data come from retrospective studies, and prospective data are necessary to confirm the efficacy of this approach, he said. “It’s too early to tell, but the general feeling is one of optimism about the potential synergy between these two treatment modalities.” n

Disclosure: Dr. Geschwind received grant support from NIH/NCI (RO1, KL2, R21), Abdulrahman Abdulmalik Research Fund Charles W. Pratt Foundation for Liver Cancer Research RSNA, SIR Foundation, and the Department of Defense, and pharmaceutical support from Genentech, Biocompatibles/BTG, Philips Healthcare, Nordion, Guerbet, and Bayer Healthcare. He is also a consultant for Bayer Healthcare, Genentech, Biocompatibles/BTG, Nordion, and Guerbet, and is CEO and founder of PreScience Labs. Dr. Gadani reported no potential conflicts of interest. Dr. Ryu is a consultant for IORAD. T: 10.75”

INDICATIONS AND USAGE Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14.1) in Full Prescribing Information]. The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progressionfree survival [see Clinical Studies (14.1) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. Vectibix is not indicated for the tratment of patients with KRAS mutation-positive mCRC or for whom KRAS mCRC status is unknown. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13 [see Warnings and Precautions, Clinical Pharmacology (12.1) and Clinical Studies (14.3) in Full Prescribing Information]. DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration (2.2) in Full Prescribing Information]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions. Dose Modifications for Infusion Reactions [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix. • If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose. – If toxicities recur, permanently discontinue Vectibix. – If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached. Do not administer Vectibix as an intravenous push or bolus. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix. Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning, and Adverse Reactions]. Dose modifications for Vectibix concerning dermatologic toxicity are provided in the product labeling [see Dosage and Administration]. Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCI-CTC grade 3-4). Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [see Boxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. [see Dosage and Administration]. Increased Mortality or Toxicity with Vectibix in Combination with Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In a randomized, open-label study enrolling 440 patients with KRAS mutation-positive mCRC; evaluating Vectibix in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared to FOLFOX alone as first-line therapy for mCRC, shortened overall survival time was observed in the mutant KRAS mCRC population after 294 deaths (HR=1.24, 95% CI: 0.98-1.57). In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCICTC grade 3 diarrhea was 25%. Severe diarrhea and dehydration, which may lead to acute renal failure and other complications, have been observed in patients treated with Vectibix in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD): Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Patients with a history or evidence of interstitial pneumonitis, pulmonary fibrosis, were excluded from most clinical trials. Therefore, the estimated risk in a general population that includes such patients is uncertain. Cases of ILD, including fatalities, have been reported in patients treated with Vectibix. Interrupt Vectibix therapy for the acute onset or worsening of pulmonary symptoms. Discontinue Vectibix therapy if ILD is confirmed. Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed. Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix. Ocular Toxicities: Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix therapy for acute or worsening keratitis. EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Increased Mortality or Toxicity of Vectibix in Combination with Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis/ILD [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and 174 received Vectibix in combination with chemotherapy [see Warnings and Precautions]. The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1)

References 1. Feng A, Reyes D, Kamel I, et al: Prospective phase II trial of sorafenib combined with doxorubicin eluting beadtransarterial chemoembolization for patients with unresectable hepatocellular carcinoma: Efficacy analysis. Society of Interventional Radiology Annual Scientific Meeting. Abstract 134. Presented April 16, 2013. 2. Lencioni R, Llovet JM, Han G, et al: Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediate-stage hepatocellular carcinoma (HCC): Phase II, randomized, double-blind SPACE trial. 2012 Gastrointestinal Cancers Symposium. Abstract LBA154. Presented January 20, 2012. 3. Gadani S, Mahvash A, Avritscher R, et al: Yttirum-90 resin microspheres as an adjunct to sorafenib in patients with unresectable HCC: A retrospective study for evaluation of survival benefit and adverse events. Society of Interventional Radiology Annual Scientific Meeting. Abstract 62. Presented April 15, 2013.

ASCOPost.com | MAY 15, 2013

PAGE 17

Society of Interventional Radiology Interventional Radiologists Report Novel Approaches for Metastatic Lesions By Caroline Helwick

or the treatment of metastases to the liver and the lung, interventional radiologists reported early success with two novel approaches at the Society of Interventional Radiology (SIR) 38th Annual Scientific Meeting, held recently in New Orleans.

enrolled 40 patients with pulmonary metastatic lesions (up to five lesions ≤ 3.5 cm) who were not candidates for resection. The primary tumors were mainly colon (40%) and renal cell (23%) cancers. General anesthesia was used in 67% of patients, and conscious sedation in 33%. About 15% of patients received chest tubes.

Minimally Invasive Ablation Techniques ■ A study of cryoablation for pulmonary metastases yielded a disease control rate of 100% at 3 months and 95% at 6 months, with minor side effects and short recovery time.

■ A study of irreversible electroporation ablation showed the technique to

be safe and potentially beneficial in treating challenging metastatic lesions in the liver, soft tissue, and lung, and tumors near the colon and elsewhere.

Promising Results

David A. Woodrum, MD, PhD

Cryoablation of Lung Tumors For patients with metastatic lung/ pleura tumors, cryoablation provided excellent short-term local tumor control in the first results of the ECLIPSE trial, which is the first prospective multicenter study of this intervention.1 “Cryoablation has potential as a treatment for metastatic cancer and could prolong the lives of patients who have limited options,” said David A. Woodrum, MD, PhD, of the Mayo Clinic in Rochester, Minnesota. The ECLIPSE trial (Evaluating Cryoablation of Metastatic Lung/Pleura Tumors in Patients—Safety and Efficacy)

Cryoablation, performed under computed tomography guidance, was performed on 62 tumors, yielding a disease control rate (responses plus stable disease) of 100% at 3 months and 95% at 6 months (with one local failure). Two patients followed for 12 months are still stable, Dr. Woodrum reported. “We think these results are very promising,” he said. “Cryoablation offers an opportunity to treat patients with few options, but we acknowledge that longer follow-up is needed.” Adverse events (with per-procedure rates) included pneumothorax (50%), pleural effusion (21%), chest or back pain (13%), hemorrhage (8%), and cough (6%). Three grade 3 events were reported: noncardiac chest pain, pneumothorax, and arteriovenous fistula thrombosis. Patients in the study had progressive disease while on chemotherapy, or had recurred after surgical resection, thus making them candidates for this intervention. They discontinued chemother-

EXPERT POINT OF VIEW

ddressing the studies on cryoablation and irreversible electroporation ablation at a Society of Interventional Radiology press briefing, Charles E. Ray, Jr, MD, PhD, Chief of Interventional Radiology at University of Colorado, told The ASCO Post that these novel approaches to metastases are interesting, but noted that there have been obstacles to their adoption. “Cryoablation predates everything else” in the Charles E. Ray, Jr, MD, PhD field of ablation therapy, he noted. “Back when this was an open procedure, surgeons used a 24 French device, which is huge. Now we use a 17-gauge probe, which makes a big difference. But because of the concerns of 20 years ago, such as liver fractures from using such large devices, people are still nervous about cryoablation,” he said. “As for irreversible electroporation,” he continued, “you can ask why this [approach] hasn’t taken off. It’s probably because it is challenging. You need two electrodes, perfectly placed. There’s a learning curve.” In both studies, he added, it is difficult to separate out the effects of the intervention from the effects of the chemotherapy. Most patients were receiving systemic treatment before and after these procedures. n Disclosure: Dr. Ray reported no potential conflicts of interest.

apy about 2 weeks prior to cryoablation, but could restart chemotherapy later. Dr. Woodrum emphasized that cryoablation is intended for patients who are not candidates for resection. He added that the side effects were mostly minor, and the recovery time was short.

Irreversible Electroporation Other researchers at the SIR meeting reported encouraging results with irreversible electroporation, a form of tumor ablation that uses microsecond electrical pulses to create permanent holes in the cell membrane.2 Strong electric fields applied across a cell can cause irreversible permeabilization of the membrane, leading to a disruption of the balance between the molecules inside and outside the cell. This results in cell death without damaging healthy adjacent tissue, according to Constantinos T. Sofocleous, MD, of Memorial Sloan-Kettering Cancer Center, New York, who presented the results at a press briefing. The study’s first author was Mikhail Silk, MD, also of Memorial Sloan-Kettering. Irreversible electroporation is nonthermal and results in little scar tissue. It is structurally protein-sparing (ie, it allows for the healing of nerves and bile ducts in the area of ablation). Moreover, there is no “heat sink” effect (ie, the electric pulses are not affected by blood flow), and this limits the potential for recurrences for treated tumors located near blood vessels. And the mechanism of cellular killing avoids damage to the extracellular matrix, Dr. Sofocleous said. “Unlike thermal ablation, [irreversible electroporation] can be performed in close proximity to bile ducts, major vessels, bladder, rectum, and nerves, with an acceptable safety profile. [The technique] may be especially beneficial in treating liver, lung, and pancreatic lesions, as well as lesions that are close to sensitive structures,” he said. The procedure involves the placement of at least two parallel electrodes, spaced 1.5 to 2 cm apart, through which

the energy is delivered. According to Dr. Sofocleous, while the technique is technically challenging, it is far less morbid than traditional surgery and thermal ablation.

Study Details The study involved 28 patients with 65 metastatic lesions to the liver, soft tissue, and lung. The primary tumors originated mostly in the colon, although eight different tumor types were included. The mean tumor size was 1.9 cm (range, 1–4 cm). Most patients had exhausted all other treatment options, he said. The interventional radiologists used irreversible electroporation instead of thermal ablation on these patients due to the location of their lesions, near critical structures that could be negatively affected by surgery or thermal ablation, Dr. Sofocleous explained. Six months after the procedure, the rate of complete ablation was 92%. One patient has had no evidence of tumor for 778 days, and another patient has had no recurrence for 565 days, he reported. The procedure was safe, with one arrhythmia and one portal vein thrombosis occurring among the 28 patients. Dr. Sofocleous suggested that the technique might be further enhanced by directing a lethal agent to the reversible zone that surrounds the area of irreversible electroporation, or by delivering chemotherapy or genes through the pores. n

Disclosure: Drs. Woodrum, Sofocleous, and Silk reported no potential conflicts of interest.

References 1. De Baere T, et al: Evaluating cryoablation of metastatic lung/pleura tumors in patients. Society of Interventional Radiology. Abstract 33. Presented April 14, 2013. 2. Silk M, et al: Safety of irreversible electroporation treatment for metastatic disease in humans. Society of Interventional Radiology. Abstract 29. Presented April 14, 2013.

The ASCO Post | MAY 15, 2013

PAGE 18

Journal Spotlight

Adoptive T-cell Therapy continued from page 1

T cells and long-term molecular remissions in the study patients. Patients ranged in age from 23 to 66 years. Of the five patients, two had persistent chemotherapy-refractory disease following salvage therapy

(63% and 70% blasts in bone marrow). Two others had achieved morphologic complete remission during salvage therapy with evidence of minimal residual disease (MRD-positive) on deep sequencing polymerase chain reaction and fluorescence-activated cell sorting. The remaining patient was

MRD-negative after salvage therapy.

Results After adoptive T-cell therapy, all patients were MRD-negative on deepsequencing polymerase chain reaction (showing loss of detectable malignant clone IgH rearrangements).

Of the two patients with persistent refractory disease after salvage therapy, one achieved morphologic complete remission by day 11 after T-cell infusion and MRD-negative status by day 59, and the other achieved both morphologic complete remission and continued on page 23

Proof of Principle for Adoptive T-cell Therapy in Cancer A Conversation with Renier J. Brentjens, MD By Matthew Stenger

n a recently published study, Memorial SloanKettering Cancer Center investigators demonstrated the considerable antitumor efficacy of 19-28z chimeric antigen receptor (CAR)-modified T cells in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). The ASCO Post asked lead author Renier J. Brentjens, MD, of Memorial SloanKettering Cancer Center, New York, about techniques used in the study and the implications of the results.

Generating the T Cells How do you generate the CD19-targeted T cells used as treatment in the study? We have generated an artificial T-cell receptor specific to the CD19 antigen expressed on the surface of most B-cell tumors, including B-cell ALL, chronic lymphocytic leukemia (CLL), and B-cell non-Hodgkin lymphoma. The gene for the receptor is cloned into a retroviral vector, a replication incompetent virus. Then, patient T cells are isolated and activated; once the T cells are proliferating, the viral vector with the 19-28z CAR gene is added to the culture to allow for transfer and expression of the gene in the T cells. The T cells are then expanded in culture to the dose needed for patient treatment. This work is done in the Memorial Sloan-Kettering Cancer Center Gene Transfer Facility, directed by Isabelle Riviere, PhD. When the target dose of T cells is achieved, the cells, which are now able to recognize the CD19 protein on the surface of the tumor cells, are infused back into the patient.

Striking Findings What were the most striking findings in the study? The rapidity with which these CAR-modified T cells eradicated even large numbers of tumor cells and the fact that we could achieve molecular remissions in all patients were both very striking findings. From a more global perspective, the study provided proof of principle that T cells genetically modified to recognize tumor-associated antigens could induce potent antitumor efficacy and validated the application of immune cell-based therapies for cancer. There is no doubt that other therapies using adoptive cell techniques for cancer will now be tested. But our findings serve as a benchmark indicating that immune cell-based therapies warrant further serious investigation and funding, and that further preclinical and clinical studies should be done.

Can you comment The study provided proof of principle on the relatively rapid resumption of normal Bthat T cells genetically modified to cell lymphopoiesis seen in recognize tumor-associated antigens study patients? The rapidity of norcould induce potent antitumor efficacy mal bone marrow recovand validated the application of immune ery we observed points to the targeted nature cell-based therapies for cancer. of this therapy; this is in —Renier J. Brentjens, MD contrast to conventional chemotherapy, wherein normal bone marrow function requires a significantly er strategy to investigate in attempting to optimally longer time to recover. Our observation with respect apply this technology to the clinical setting. to normal B-cell recovery in these patients may be related to limited persistence of CAR-modified T cells Looking Ahead Is there a possibility that CAR-modified T-cell treattargeting the CD19 antigen, and this may in part be associated with the need for high-dose lymphotoxic ste- ment alone can completely eradicate malignant clones roid therapy in several patients to reverse symptoms and provide cure in B-cell ALL? We don’t yet know the answer to the question about related to the observed “cytokine storms” mediated by the CAR-modified T cells. Alternatively, limited per- whether CAR-modified T-cell treatment can achieve sistence of our CAR-modified CD19-targeted T cells, cure, but enrollment and treatment of additional pawhich nevertheless allowed for molecular remissions, tients in the study may provide some guidance. It may in turn avoid potential long-term infections re- would be of particular interest to follow patients for whom bone marrow transplantation is not an option lated to persistent B-cell aplasias. and observe whether a single infusion or multiple infuAvoiding Cytokine-mediated Toxicities sions of the CAR-modified T cells could achieve optiRelapse after achieving minimal residual disease–neg- mal remission or potential cure of their disease. ative status was observed in one patient, possibly related to the need for high-dose lymphotoxic steroid treatment for What are the next steps in studying CAR-modified cytokine-mediated toxicities. Are there any potential strat- T-cell approaches to treatment? egies for avoiding or modulating this effect? With regard to the CD19-targeted T-cell apAs we point out in the article, these toxicities appear proach, we are expanding the current phase I trial to correlate to the degree of tumor bulk at the time of in B-cell ALL into a phase II trial, expanding the modified T-cell therapy. To this end, we propose infu- application of this approach to patients with B-cell sion of CAR- modified T cells at earlier time points fol- lymphoma, and continuing enrollment on an open lowing salvage chemotherapy, when tumor load is at a clinical trial that treats patients with relapsed CLL. nadir. Future studies are needed to validate this hypothWith regard to other applications, the current esis and assess whether earlier infusion of T cells may study serves as proof of principle for the CAR-modavoid observed cytokine-mediated toxicities. ified T-cell approach to cancer. We believe that these Additional studies by the group at University initial clinical outcomes validate expanding this apof Pennsylvania further suggest that some of these proach to targeting other cancers. We have thus toxicities may be ameliorated by infusion of an an- expanded our preclinical studies to include investiti-interleukin-6 monoclonal antibody. This would gation of this adoptive therapy approach in lung canbe a potential alternative approach regarding man- cer, mesothelioma, ovarian cancers, prostate cancer, agement of cytokine-related toxicities. Again, this and other solid tumors. We currently have an open approach will need to be studied prospectively for clinical trial in prostate cancer. n Disclosure: Dr. Brentjens has intellectual property in further validation. Finally, the use of multiple timed chimeric antigen receptors: patent number US 7,446,190, which modified T-cell infusions when most of the tumor covers the 19-28z receptor. bulk has been previously eradicated would be anoth-

When hemoglobin fallsâ&#x20AC;Ś

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

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

®1-4

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

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

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

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

RBC = red blood cell

Hb = hemoglobin

Q3W = once every three weeks

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

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

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

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

CONTRAINDICATIONS

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

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

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

ADVERSE REACTIONS $MJOJDBM 5SJBM &YQFSJFODF #FDBVTF DMJOJDBM USJBMT BSF DPOEVDUFE VOEFS XJEFMZ WBSZJOH DPOEJUJPOT BEWFSTF reaction rates observed in the clinical trials of a drug cannot be directly compared UP SBUFT JO UIF DMJOJDBM USJBMT PG PUIFS ESVHT BOE NBZ OPU SFnFDU UIF SBUFT PCTFSWFE in practice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tudy Adverse Reaction 5ISPNCPFNCPMJD "EWFSTF 3FBDUJPOT O

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

"MM 1MBDFCP controlled Studies

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

DRUG INTERACTIONS

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

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

OVERDOSAGE

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

Aranesp Placebo Aranesp Placebo O O O O

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

Aranesp┬о EBSCFQPFUJO BMGB

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

ASCOPost.com | MAY 15, 2013

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Journal Spotlight

Adoptive T-cell Therapy continued from page 18

MRD-negative status by day 8. Of the two other MRD-positive patients, one achieved MRD-negative status by day 28 and the other was MRD-negative at day 30 and remained MRDnegative up to the time of allogeneic transplant at 122 days after T-cell treatment. In total, four of the five patients underwent allogeneic transplant at 1 to 4 months after T-cell therapy. One patient, who was ineligible for allogeneic transplant and additional T-cell therapy, relapsed at 90 days after Tcell therapy after receiving high-dose steroid therapy for cytokine-mediated toxicities.

Cytokine Levels Correlated with Disease Burden Treatment with CD19-targeted CAR-modified T cells has been associated with high fever, hypotension, and elevated proinflammatory cytokine levels in patients with chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma. Thus, serum cytokine levels were monitored in the five study patients. The two patients with the highest tumor burden at the start of T-cell therapy showed the highest cytokine elevations (including elevations of soluble interleukin-2 receptor α, interferon-γ, interleukin 6, and interferon-inducible protein 10) beginning at 5 days after Tcell infusion. These patients also had the highest numbers of detectable CARmodified T cells after treatment. Cytokine elevations were markedly smaller or undetectable in the other patients,

Key Abbreviations in This Article ALL = acute lymphoblastic leukemia CAR = chimeric antigen receptor MRD = minimal residual disease

suggesting that the degree of cytokine elevation was correlated with the bulk of residual disease at the time of T-cell therapy. Three of the five patients experienced transient fevers after T-cell infusion. Two, those with the greatest disease burden at the time of treatment, had increased fever severity and persistence along with hypotension and mental status changes. Both were treated with high-dose lymphotoxic steroid therapy starting on day 6 and tapered slowly thereafter, with constitutional symptoms rapidly improving and cytokine levels becoming normalized.

New Approach to Relapsed B-cell ALL ■ After adoptive T-cell therapy for relapsed/refractory B-cell ALL, all patients were minimal residual disease–negative on deep-sequencing polymerase chain reaction.

■ The new technique showed marked antitumor efficacy, producing major

molecular remissions that could set up curative therapy with subsequent allogeneic stem cell transplantation.

CAR-modified T cells, and recovery of normal B-cell lymphopoiesis.

Potential for Retreatment Of the four patients undergoing allogeneic stem cell transplant, one died of suspected pulmonary embo-

Considering these clinical outcomes, the addition of 19-28z CAR-modified T cells for inclusion into currently upfront adult [B-cell] ALL treatment protocols warrants serious consideration. —Renier J. Brentjens, MD

The ability to measure persistence of the CAR-modified T cells was limited by the performance of allogeneic stem cell transplant relatively soon after treatment in four patients and the need for high-dose steroid therapy in two. Overall, the CARmodified T cells were detectable by polymerase chain reaction or fluorescence-activated cell sorting in the blood and bone marrow 3 to 8 weeks after infusion. In vivo expansion of the CAR-modified T cells, measured by determining peak levels, was correlated with tumor burden at the time of T-cell therapy. Although loss of malignant clones was observed in all patients with persistent disease at the time of T-cell therapy, the investigators concomitantly observed recovery of normal B-cell clones in all patients, consistent with the waning persistence of the

lism at 2 months after transplantation while in complete remission with no evidence of disease. At the time of the report, the other three patients remained in complete remission at 6 weeks to 18 months after transplant. One of the patients with high disease burden after salvage therapy was ineligible for allogeneic transplant due to multiple preexisting comorbidities. As noted, this patient had relapse at 90 days after T-cell therapy and after receiving high-dose steroid therapy for cytokine-mediated toxicities. The relapsed tumor cells exhibited the same malignant IgH rearrangement as the initial malignant clone, expressed target CD19 antigen at the same levels as prior to T-cell treatment, and retained sensitivity to lysis by the autologous CD19-targeted T cells. It thus appears that relapse in this patient after achievement of

MRD-negative status was not due to escape from the effects of the CARmodified T cells, but was due at least in part to the limited persistence of these T cells resulting from the highdose steroid therapy. The investigators wrote, “Whether additional infusions with CARmodified T cells in this patient may have changed the clinical outcome remains to be and will be investigated in future … patients similarly ineligible for additional therapy with allogeneic [hematopoietic stem cell transplantation].” They concluded, “These results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory [B-cell] ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allogeneic HSCT.” They further noted, “[C]onsidering these clinical outcomes, the addition of 19-28z CARmodified T cells for inclusion into currently upfront adult [B-cell] ALL treatment protocols warrants serious consideration.” n

Disclosure: Dr. Brentjens has intellectual property in chimeric antigen receptors: patent number US 7,446,190, which covers the 19-28z receptor.

Reference 1. Brentjens RJ, Davila ML, Riviere I, et al: CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5:177ra38, 2013.

Narratives in Oncology

A Special Supplement to The ASCO Post

Narratives in Oncology is a special edition of The ASCO Post featuring personal profiles about oncology leaders who have made an important contribution to the clinical research and care of patients with cancer. Watch for your issue of Narratives in Oncology mailing with the June 10, 2013* issue of The ASCO Post. Or visit The ASCO Post at ASCO’s Annual Meeting, booth 12096, for your advance copy of this limited special edition. *The ASCO Post will be published two times next month, June 10 and June 25.

The ASCO Post | MAY 15, 2013

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Issues in Oncology

Sequestration continued from page 1

2013—which funds the federal government through the end of September 2013, restoring a modest amount to NIH and NCI funding ($7 million and $10 million, respectively).

Reduced Grant Funding The NIH and the NCI have not yet announced detailed plans for how they will manage the funding loss. However, in a February 1 letter to Senator Barbara Mikulski (D-MD), Secretary of Health and Human Services Kathleen Sebelius wrote that the cuts, “would delay progress on the prevention of debilitating chronic conditions that are also costly to society and on the development of more effective treatments for common and rare diseases affecting millions of Americans… NIH grant funding within states … will likely be reduced due to both reductions to existing grants and fewer new grants.” Those reductions, according to an analysis of 2012 NIH data by United for Medical Research, a coalition of research institutions, patient advocates, and private industry, will result in a loss of 20,500 jobs in the life sciences sector and $3 billion in economic output.2 “The number of grants funded by the NIH has declined every year since 2004, and a lot of that funding goes to salaries for research staff and investigators. That will have an immediate impact on employment and local economies,” said ASCO President Sandra M. Swain, MD, FACP, Medical Director of the Washington Cancer Institute at MedStar Washington Hospital Center. “Importantly,” she continued, “the sequester will discourage very young, bright, talented researchers from working in cancer research and making new discoveries. The budget cuts will also cause investigators to limit the scope of their clinical trials, because a lot of the research commitments of the NIH and the NCI go on for several years. It is likely that these agencies will have to delay the launch of new clinical trials, and this will directly impact the time it takes to develop new treatments.”

Consequences for Medicare Patients Although the full impact of the funding reductions in basic research and clinical studies—and how they may impede future cancer breakthroughs—is still being analyzed, a

more immediate concern is their impact on current cancer patients. On April 1, a 2% ($11.08 billion) cut to Medicare went into effect, which directly affects payments to hospitals and physicians and imposes new cuts on reimbursement for chemotherapy drugs. (Medicaid and the Veterans Health Administration are exempt from the reduction.) Drugs for Medicare patients are usually covered under Medicare Part D, which is not affected by the Budget Control Act. But because chemotherapies must be administered by a physician, they are paid for under Part B and subject to the sequester cut. Moreover, since Medicare adds 6%

When you talk to oncologists about the sequester… many are saying, ‘I’m gone soon because I can’t continue to spend so much time fighting the system.’ —Ted Okon

to the average sales price of a chemotherapy drug to cover operational expenses (such as the cost of storing the agent, inventory, waste, and disposal), the effect of the 2% cut is a relative reduction of 28%, explained Ted Okon,

How Is Sequestration Affecting Health Care?

he Budget Control Act of 2011, which calls for $1.2 trillion in federal funding cuts in national defense and nondefense programs, went into effect on March 1. The acrossthe-board cuts affect 21 agencies and programs directly involved in the health-care sector, including: Centers for Disease Control and Prevention (CDC)— The effective reductions to the CDC are between 8% and 10% (about $303 million) for the rest of this year and will mean 424,000 fewer HIV tests (it funded 3.16 million in 2010), 50,000 fewer immunizations for adults and children (from a baseline of about 300 million), eliminating tuberculosis programs in 11 states, closing the National Healthcare Safety Network (which monitors health-care–associated infections), and eliminating the Cities Readiness Initiative.1 Food and Drug Administration (FDA)—According to ASCO President Sandra M. Swain, MD, FACP, the sequestration cuts to the FDA will seriously hinder the nation’s ability to move the many safe, effective, and innovative medicines currently in the review pipeline to patients whose lives depend on them. “ASCO remains concerned that sequestration will force the FDA to put improvements in the drug development process and regulatory science initiatives on hold. These forward-looking efforts speed approval without compromising rigor, prepare FDA for timely review of cutting-edge therapies, and provide a more predictable process for companies, spurring investment in new areas of therapy, clinical trial designs, and treatment methodologies,” said Dr. Swain. Medicare—Funding has been cut by 2% ($11.08 billion) through reductions in reimbursements to Medicare providers, health plans, and drug plans, which will now be reimbursed at 98 cents on the dollar for their services to Medicare beneficiaries. National Institutes of Health (NIH)—Budget cuts to the NIH and NCI this year will result in delays to new clinical trials and to the development of new cancer therapies. Social Services—The Substance Abuse and Mental Health Services Administration plans to cut the Mental Health Block Grant Program, eliminating services for 373,000 seriously mentally ill adults and children. The Indian Health Service (IHS), which usually covers about 48,000 inpatient admissions and 12.8 million outpatient visits per year to tribal hospitals and clinics, will provide about 3,000 fewer inpatient admissions and 804,000 fewer outpatient visits. The Health Resources and Services Administration estimates that 7,400 fewer patients will have access to HIV medications. n

Reference 1. McDonough JE: Budget sequestration and the U.S. health sector. N Engl J Med 368:1269-1271, 2013.

Executive Director of the Community Oncology Alliance (COA). “While the 2% cut for services seems relatively small, on the drug side it has a profound financial effect. So it is really not surprising that some community oncology practices won’t be able to treat their patients in their offices or clinics. Patients will have to be treated at the hospital instead,” said Mr. Okon. And that is exactly what appears to be happening. According to a story published in The Washington Post,3 several cancer clinics nationwide have already limited the number of Medicare patients they accept, and others are planning to close satellite clinics in rural areas. In a joint statement released by ASCO, COA, the International Oncology Network/AmerisourceBergen, and the US Oncology Network, the organizations warned that unless the Centers for Medicare & Medicaid Services (CMS) modifies implementation of sequestration to exclude Part B drugs, the cuts “will actually jeopardize patient access to cancer care.” The additional cuts to Medicare are also threatening the financial solvency of community oncology practices, potentially further limiting access to cancer care if practices have to shut down completely. In a national poll of community oncology physicians conducted by COA, 72% of respondents said that if the sequestration reductions remain in place, they may be forced to stop seeing new Medicare patients, not treat any Medicare patient without secondary insurance, or send Medicare patients elsewhere for treatment. The net effect, said Mr. Okon, is that many physicians will close their doors. “When you talk to oncologists about the sequester craziness as well as the constant hurdles that are put in front of them by insurance companies and CMS in the treatment of cancer patients, many are saying, ‘I’m gone soon because I can’t continue to spend so much time fighting the system,’” said Mr. Okon. continued on page 26

The ASCO Post | MAY 15, 2013

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Issues in Oncology

Sequestration continued from page 24

According to Mr. Okon, rather than having the desired effect of shaving billions off the sky-high deficit, the indiscriminate sequester cuts will actually cost Medicare approximately $2 billion annually due to a shift to more expensive cancer care in the hospital setting. “Sequestration, which was put in place to cut federal spending without any thought of the consequences, makes absolutely no sense from an economic standpoint,” he added.

The Ripple Effect While each of the 27 NIH institutes and centers face 5.1% in budget reductions, other federal agencies, including the Centers for Disease Control and

Prevention (CDC), are slated for even steeper cuts of about 8%. For the CDC, which is still recovering from deep budget reductions in 2011, the funding loss will mean drastically curtailing the number of free HIV tests and immunizations for adults and children conducted by the CDC’s health department grantees, potentially imperiling the health of millions of Americans. The continuing resolution passed in March restored $74 million to the U.S. Food and Drug Administration (FDA) budget of about $2.38 billion in fiscal year 2013, which was less than the $2.5 billion in government funding in 2012. Nevertheless, the reduction will seriously undermine the agency’s mission to review new cancer treatments while maintaining stringent safety and

efficacy standards, according to Dr. Swain (see “How Is Sequestration Affecting Health Care?,” on page 24.) “In the end, it is the patient with cancer fighting for his or her life who is going to feel the most profound impact from these budget reductions in clinical cancer research, slowdowns in FDA drug reviews, and physician reimbursement,” said Dr. Swain.

Taking Action To stay current on the steps that ASCO is taking to make Congress and the Obama Administration aware of how sequestration is impacting access to cancer care and limiting progress in medical research, and for information on how ASCO members can get involved in efforts to repeal

ASCO Announces New Conflict of Interest Policy

the 2% cut to Medicare reimbursement and reinstate federal funding to the NIH, visit the ASCO in Action website (ASCOaction.ASCO.org). n

Disclosure: Dr. Swain and Mr. Okon reported no potential conflicts of interest.

References 1. National Institutes of Health: Impact of NIH research. Available at nih.gov/ about/impact. 2. United for Medical Research: Looming sequestration cuts to medical research threaten more than 20,000 jobs. Available at unitedformedicalresearch.com. Posted February 6, 2013. 3. Kliff S: Cancer clinics are turning away thousands of Medicare patients. Blame the sequester. Washington Post. Available at washingtonpost.com. Posted April 3, 2013. JCO Spotlight

By Jo Cavallo

n April, ASCO released its updated conflict of interest policy in the development and presentation of scientific research and educational content. The revised policy is designed to increase transparency in financial relationships between individuals and health-care companies and impose new restrictions for authors of original research who publish in or present at ASCO forums.

Policy Background Published in the Journal of Clinical Oncology (JCO),1 the American Society of Clinical Oncology Policy for Relationships with Companies provides new conflict of interest guidelines for individuals who take part in the planning, authorship, peer review, or presentation of programs or content through ASCO channels. This includes ASCO members and volunteers, and the Society’s affiliates, including the Conquer Cancer Foundation and the Institute for Clinical Excellence, and for content appearing in JCO and the Journal of Oncology Practice (JOP) or at ASCO scientific meetings. In a 2009 Institute of Medicine (IOM) report,2 which presented principles for analyzing financial conflicts of interest in medical research, education, and practice, conflict of interest is defined as “not an actual occurrence of bias or a corrupt decision, but, rather, a set of circumstances that past experience and other evidence have shown poses a risk that primary interests may be compromised by secondary interests.” ASCO first enacted a conflict of inter-

est policy in 1994 and released revised versions in 1996, 2002, and 2005. The new policy builds on the requirements established in the 2005 policy to increase transparency in relationships with companies. It comes at a time when many other health-care organizations, including research facilities and teaching hospitals have improved their conflict of interest policies and some states and the federal government have enacted regulations requiring the public reporting of payments to physicians by companies.

allows the gathering of a range of information regarding an individual’s interactions with companies. The information to be disclosed includes eight areas of financial relationships with companies: compensation received for employment, leadership positions, consulting activities, speaking engagements, and expert testimony; as well as ownership interests, research funding, either to the individual or the institution, and licensing fees and royalties associated with intellectual property interests.

In adopting this new conflict of interest policy, ASCO’s goal is to recognize beneficial collaborations that advance scientific progress, while remaining vigilant about the potential for bias in science and professional education. —Sandra M. Swain, MD, FACP

Promoting Independence ASCO’s Policy for Relationships with Companies applies to all individuals who engage in ASCO volunteer activities, present research findings through ASCO’s continuing medical education programs, and develop ASCO clinical practice guidelines, and authors who submit abstracts and publish in JCO and JOP. Unlike the 2005 policy, which required authors, presenters, and ASCO volunteers to complete a separate disclosure for each ASCO activity, the new conflict of interest policy establishes a “general disclosure” requirement that

While the article published in JCO outlining the details for ASCO’s new policy states that the restrictions on certain relationships with companies “does not create a presumption of impropriety in the existence of these relationships,” it reiterates that “ASCO’s policy is that certain financial relationships give rise to conflicts of interest that are not capable of being effectively managed and are, in fact, inconsistent with actual and perceived independence. Individuals who are free of these relationships should play a key role in the authorship of original research submitted to ASCO meetings or to JCO and JOP.”

Policy on Original Research To promote objectivity and balance in the research that is presented at ASCO educational and scientific meetings and published in JCO and JOP, the new guidelines also require that first, last, and corresponding authors of original research meet a clear standard of financial independence from commercial funders of their research. The new policy regarding original research in ASCO educational or scientific programs is as follows: Abstracts and articles concerning original research are not eligible for inclusion if the first, last, or corresponding author has: ■ Participated in a speakers’ bureau (on any subject) on behalf of the company sponsor of that original research at any time during the 2 years before submission of the abstract ■ Held an employment relationship with the company sponsor of that research at any time during the 2 years before submission of the abstract ■ Held a significant ownership interest in the company sponsor of that research at any time during the 2 years before submission of the abstract The same stipulations for first, last, or corresponding author apply to manuscripts, including articles and abstracts, concerning original research published in JCO or JOP. There is a narrow exemption to the authorship restrictions for certain types of articles in JOP. These submissions will be monitored through disclosure, peer continued on page 27

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Perspective

Laurence H. Baker, DO, on Conflicts of Interest continued from page 1

that, by definition, the statement must emphasize the potential for conflict, do all these experts truly have no conflicts of interest to mention? Consider the term “key opinion leader,” a designation so ingrained in the pharmaceutical industries that these individuals are commonly referred to as KOLs. Is this the recognition of an expert from whom a company would want to obtain opinions, or more like a marketing tool that uses an iconic athlete or celebrity to endorse sneakers? Are drug sales increased because prominent clinicians are associated with a drug?

Public Perception Some may say that all this concern over potential conflicts of interest is political correctness gone amok. But consider the words of Dr. Ezekiel Emanuel, who recently published his viewpoint on the future of biomedical research: “Complicating matters are the recurring episodes of well-paid scientists embroiled in financial conflicts of interest. The result is a depiction of the scientific establishment as just another interest group looking out for itself rather than the public good.”1 We can join rallies to get public support for increased funding of medical research, but they will only be effective if ordinary people perceive us to be truly interested in the public good. Indeed, it should also be recognized that interactions between physicians and the pharmaceutical industry have contributed to the development of some effective therapeutics that have improved individual patient outcomes and thus have contributed to the greater good of society.

Clinical Trials Publically funded clinical trials programs such as those of the NCI have been

New ASCO COI Policy continued from page 26

review, and editorial management. Although ASCO’s new conflict of interest policy became effective on April 22 with the publication of the guidelines online in JCO, the author restrictions on original research come into effect on April 22, 2014, and will only apply to original research initiated after that date.

Potential Sanctions Failure to comply with the new policy requirements may result in sanctions,

under scrutiny. Some argue that all trials should be funded by the pharmaceutical industry. I, and others, have strongly disagreed. Of course, if I do not remind you that I have been privileged to be Chair of the Southwest Oncology Group (SWOG) for the past 8 years, might my opinion be construed as in conflict? During my years as Chair, a major portion of my salary was funded by NIH grants to SWOG, I was given a large and luxurious suite every time the group met at an upscale hotel, and I was a “Big Man on Campus” at my institution. (Of course, I was not as big as Denard Robinson, quarterback of the football team, or

Meaning of ‘Potential’ As Dr. Emanuel reminded us, the public accepts that we benefit from clinical trials. But if we do not declare potential conflicts, we lose important moral ground. Much of the problem lies in the definition of “potential” for conflict of interest. Different institutions seem to use variations based on differing legal opinions. At the University of Michigan, a conflict is noted if I report that I serve unfunded on the board of a nonprofit organization and I am an elected officer, in part because of the potential for me to engage in fundraising for the non-

What if we defined potential for conflict of interest with the purpose of being declarative and fair to those whose opinion might differ? I posit that such a declaration makes a presenter’s argument stronger, not weaker. —Laurence H. Baker, DO

Mitch McGary, center on the basketball team.) Now that the position has ended and I no longer have such a large salary, large office, and presidential suites as a perk, does my endorsement of a publically funded clinical trials network matter more or less to you? When considering expert opinions on clinical trial results, we need to remember that various parties might have unstated motivations for endorsing a study’s conclusions. A few years ago, Dr. Sean Tunis, who established the Center for Medical Technology Policy, provided me with a slide that noted, “almost everyone except the patient gains from a low efficacy bar,” including the clinical investigator, statisticians, drug companies, NCI, FDA, health-care providers, insurers, journals with advertising, and cancer centers. including exclusion from submitting abstracts or presenting at Society CME activities; exclusion from publishing in ASCO publications; exclusion or removal from participation on ASCO committees, editorial boards, clinical practice guideline panels, and other volunteer positions; and censure, suspension, or revocation of ASCO membership. “As a leading source of evidencebased cancer information worldwide, ASCO deeply values the trust of its members, the wider oncology community, and the public,” said

profit at the expense of the University. What if we defined potential for conflict of interest with the purpose of being declarative and fair to those whose opinion might differ? I posit that such a declaration makes a presenter’s argument stronger, not weaker. If we are less declarative or ambiguous, might Freud think we are somewhat ashamed?

Lollapaloozanib vs Standarddruginib Consider the following scenario.… In a prestigious medical journal, Dr. Yukenfutz reports on the efficacy of the new drug lollapaloozanib in treatment of carcinoma of the lens. Dr. Heimidinkle is a KOL on cancer of the lens and has published his ASCO President Sandra M. Swain, MD, FACP. “In adopting this new conflict of interest policy, ASCO’s goal is to recognize beneficial collaborations that advance scientific progress, while remaining vigilant about the potential for bias in science and professional education. ASCO remains committed to maintaining an objective voice in all of its scientific and educational pursuits. We look forward to working with the oncology community in fully implementing this new policy.”

study of standarddruginib. As a result, Heimidinkle is invited to join the expert advisory board of the manufacturer of standarddruginib. Heimidinkle is also asked to write an expert opinion on the work of Yukenfutz in The ASCO Post. Heimidinkle opines that standarddruginib is still better than lollapaloozanib because in the Yukenfutz study there was no eligibility requirement to demonstrate disease progression prior to entry (as there was in the Heimidinkle study). Both studies were randomized, prospective, placebo-controlled trials with progressionfree survival as the endpoint. Heimidinkle suggests that the other study may have permitted a bias in the results by not controlling for evidence of progression at entry. However, he does not think his work with a competitor drug is a conflict worth noting. Knowing of Heimidinkle’s failure to report a potential for conflict, the reader should ask if the criticism is more or less valid. Of course, we understand that the entire case is a fabrication. There is no cancer of the lens! Why cancers do not occur in the ocular lens is a mystery, and the question was first posed by Dr. Stanley Balcerzak, former Division Chief of Hematology/Oncology at Ohio State. New insights into cancer causation could result from investigation of this mystery. And, of course, such investigation would more likely be publicly funded. n

Disclosure: Dr. Baker has received grant support from the National Institutes of Health and the Gates Foundation. Hyatt Corporation provides a suite, but no grant support. He is President of the Board of the Hope Foundation and on the data safety monitoring board for CytRx and Morphotek. He also served on advisory boards for Merck and Millenium.

Reference 1. Emanuel EJ: The future of biomedical research. JAMA 309:1589-1590, 2013.

To learn more about the new ASCO Policy for Relationships with Companies, visit asco.org/rwc. n References 1. American Society of Clinical Oncology: Policy for relationships with companies. J Clin Oncol. April 22, 2013 (early release online). 2. Institute of Medicine: Conflict of interest in medical research, education, and practice. Released April 21, 2009. Available at iom.edu/reports/2009/conflictof-interest-in-medical-research-educationand-practice.aspx.

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FDA Update

Ibrutinib Receives Third Breakthrough Therapy Designation from the FDA

harmacyclics, Inc, announced that the FDA has granted an additional Breakthrough Therapy Designation for the investigational oral agent ibrutinib as monotherapy for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma with deletion of the short arm of chromosome 17 (deletion 17p). Patients harboring a deletion within chromosome 17 generally have poor re-

development and review of a potential new drug for serious or lifethreatening diseases where “preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing

therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” PharS:6.75” macyclics and Janssen are working with the FDA to determine the

implications of this Breakthrough Therapy Designation to the ongoing and planned development and the FDA filing requirements for the use of ibrutinib in CLL patients with deletion 17p. n

COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

NOW APPROVED sponse to chemoimmunotherapy and have limited treatment options. The presence of deletion 17p is one of the worst prognostic factors in patients with CLL. In February 2013, the FDA granted Breakthrough Therapy Designations for ibrutinib as a monotherapy for the treatment of patients with relapsed or refractory mantle cell lymphoma and as a monotherapy for the treatment of patients with Waldenstrom’s macroglobulinemia, both of which are also B-cell malignancies. Ibrutinib is jointly being developed by Pharmacyclics and Janssen for treatment of B-cell malignancies.

Clinical Studies The new designation for ibrutinib in patients with CLL with deletion 17p was based on data from preclinical and clinical studies where ibrutinib as a monotherapy was used to treat patients with this disease. In addition, Pharmacyclics and Janssen have recently initiated a single-arm, open-label, multicenter phase II study of ibrutinib in patients with CLL deletion 17p (RESONATE™ -17), which uses ibrutinib as a monotherapy in patients who have deletion 17p and who did not respond to or relapsed after at least one prior CLL treatment, a high unmet need population. The primary endpoint of the study will be overall response rate. The study began recruiting this year and Pharmacyclics plans to enroll 111 patients worldwide. The Breakthrough Therapy Designation is intended to expedite the

COMETRIQ inhibits the activity of tyrosine kinases including RET, MET and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. IMPORTANT SAFETY INFORMATION BOXED WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQtreated patients. Discontinue COMETRIQ in patients with perforation or fistula. Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. ADDITIONAL IMPORTANT SAFETY INFORMATION Gastrointestinal (GI) perforations (3%) and GI fistulas (1%), all serious, were reported with COMETRIQ, including 1 (<1%) fatal GI fistula. Non-GI fistulas including tracheal/esophageal were reported (4%), including 2 (1%) fatal events. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events

was higher with COMETRIQ (3%) than with placebo (1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Increased incidence of thrombotic events (venous thromboembolism: 6% vs 3%; arterial thromboembolism: 2% vs 0%) was reported with COMETRIQ vs placebo, respectively. Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication. Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ ≥28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Increased incidence of treatment-emergent hypertension, stage 1 or 2 (modified JNC† criteria), was identified with COMETRIQ (61% vs 30% with placebo). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose.

†Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

B:17

T:1

15”

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FDA Update

Breakthrough Therapy Designation for Lambrolizumab for the Treatment of Advanced Melanoma

erck has announced that the U.S. Food and Drug Administration (FDA) has designated lambrolizumab (MK-3475) as a Break-

through Therapy for the treatment of patients S:6.75” with advanced melanoma. Lambrolizumab is Merck’s investigational antibody therapy

targeting the programmed death receptor (PD-1) that is currently being evaluated for the treatment of patients with advanced melanoma

and other tumor types. The designation of an investigational drug as a Breakthrough continued on page 30

COMETRIQ demonstrated significant efficacy in a phase 3 trial (N=330) in metastatic MTC patients with radiographically confirmed disease progression.* Progression-free survival (PFS) COMETRIQ (n=219) Placebo (n=111) HR=0.28 95% CI: 0.19, 0.40 P<0.0001

1.0 0.9 0.8 PFS Probability

7.5”

ASCOPost.com | MAY 15, 2013

0.7 0.6 0.5 0.4

4.0

0.3

11.2

months

0.2 0.1 0

12 2

2 0

21 22

Months

Patients at risk: COMETRIQ Placebo

219 111

121 35

78 11

55 6

31 3

1 0

> Significantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) —Median PFS was 11.2 months with COMETRIQ vs 4.0 months with placebo > Objective response rate (ORR) was 27% with COMETRIQ vs 0% with placebo (P<0.0001) —Median duration of tumor response was 14.7 months (95% CI: 11.1, 19.3) > Adverse reactions occurring in ≥25% of patients treated with COMETRIQ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation; the most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Palmar-plantar erythrodysesthesia syndrome (PPES) occurred (50%) with COMETRIQ and was severe (Grade ≥3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including 1 with nephrotic syndrome, compared with 0 patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

COMETRIQ.com

Please see brief summary of full Prescribing Information, including Boxed Warning, on next page.

B:11.25”

Osteonecrosis of the jaw (ONJ) occurred with COMETRIQ (1%). ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for ≥28 days prior to scheduled surgery, if possible.

Reversible posterior leukoencephalopathy syndrome (RPLS) occurred in 1 (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. The COMETRIQ dose was reduced in 79% of patients vs 9% for placebo.

S:9.75”

Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

T:10.25”

*Results of the international, multicenter, randomized, double-blind EXAM study in patients (N=330) with progressive, metastatic MTC. Primary endpoint: PFS; secondary endpoints: ORR and overall survival (OS). OS data are not yet mature.

The ASCO Post | MAY 15, 2013

PAGE 30

FDA Update

Lambrolizumab continued from page 29

Therapy is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the

drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

About Lambrolizumab Lambrolizumab is an investigational antibody therapy designed to disrupt the action of the immune

COMETRIQ™ (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2) 1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; reversible posterior leukoencephalopathy syndrome. In Patients with Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop

checkpoint protein PD-1 and therefore inhibit the ability of some cancers to evade the body’s immune system. The agent is being studied in multiple cancer types including melanoma and non-small cell lung cancer. In November 2012, early interim results from a single-arm,

an acute myocardial infarction or any other clinically significant arterial thromboembolic complication 5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) of patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. 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. 6. 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 safety of COMETRIQ was evaluated in 330 patients with progressive medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥ 25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia hypocalcemia, fatigue hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving

open-label phase Ib study of lambrolizumab administered to 85 patients with advanced (inoperable and metastatic) melanoma were presented at the Society for Melanoma Research of the 9th International Congress of the Society for Melanoma Research in Hollywood, California. n

placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose. Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)1 or ≥ 2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0

ASCOPost.com | MAY 15, 2013

PAGE 31

FDA Update

Novel Cancer Immunotherapy Set to Enter Clinical Trials

DS Biotechnology Corporation has announced that its Investigational New Drug application for the novel cancer immunotherapy agent PDS0101 has been granted by the FDA, allowing the agent to be evaluated in human patients. PDS0101 is

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade All Grade Grades 3-4 Grades 3-4 CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension. National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation 3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia 4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain 5 Palmar-plantar erythrodysesthesia syndrome 1

based on the company’s Versamune nanotechnology vaccine platform.

Promising Safety Data PDS0101 is a first-in-class immunotherapy being developed to treat cancers and diseases caused

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ Placebo HYPERTENSION, JNC1 STAGE N=2113 (%) N=1073 (%) Normal: Grade 0: Systolic 4 15 < 120 mmHg and Diastolic < 80 mmHg Pre-hypertension: Systolic 34 54 ≥ 120 mmHg or Diastolic ≥ 80 mmHg Stage 1: Systolic ≥ 140 mmHg 46 25 or Diastolic ≥ 90 mmHg Stage 2: Systolic ≥ 160 mmHg 15 5 or Diastolic ≥ 100 mmHg Malignant: Diastolic 0 0 ≥ 120 mmHg Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003: 289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose 1

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased singledose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased singledose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentin, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be

by infection with the human papillomavirus such as cervical cancer, head and neck cancer, and cervical intraepithelial neoplasia. Frank Bedu-Addo, PhD, President and CEO of PDS Biotechnology, presented the highly promising preclin-

apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are 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 COMETRIQ, 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. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. Distributed by Exelixis, Inc. 12/2012 © 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 12/12 [24523]

ical efficacy and safety data demonstrating eradication of the tumors without the safety drawbacks typical of the current immunotherapy technologies.

PDS0101 is designed to prime the immune system to recruit cells of the body’s own immune system to specifically recognize, target and kill the cancer cells. The agent is also designed to reduce the population of certain immune suppressive cells which prevent our immune systems from detecting and attacking the cancer cells. “Should the preclinical results be replicated in the clinical setting, this will be a giant leap forward in the development of safe and effective cancer therapies,” said Dr. Bedu-Addo. n

FDA Approves Antiemetic Drug for New Line of Prefilled Generic Injectables

D Rx Inc, announced that the FDA has approved metoclopramide hydrochloride, an injectable antiemetic, as the second drug to be offered in the recently launched BD Simplist line of ready-to-administer prefilled generic injectables. BD Simplist prefilled injectables are designed to help improve patient care and safety by decreasing the number of steps in the traditional vial and syringe injection sequence to approximately 12 steps, reducing the potential risk of medication error. Metoclopramide hydrochloride is indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stress, prophylaxis of vomiting associated with emetogenic cancer chemotherapy, and the prophylaxis of postoperative nausea and vomiting in those circumstances where nasogastric suction is undesirable. n

The ASCO Post | MAY 15, 2013

PAGE 32

Journal Spotlight Thoracic Oncology

New Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitor Treatment By Matthew Stenger

new guideline for molecular testing to select lung cancer patients for treatment with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors has been jointly developed by the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.1 The guideline, recently published in Archives of Pathology and Laboratory Medicine, provides evidence-based recommendations on which patients and samples should be tested and how testing should be performed. The recommendations are based on a review of literature published between January 2004 and February 2012. Co-chairs and writing and advisory panels consisted of members of all three societies. Expert opinion was also solicited from representatives of FDA, ASCO, the National Cancer Institute, and the National Comprehensive Cancer Network. The recommendations are framed as answers to 14 questions on individual topics, as summarized below. “Recommendations” are supported by grade A or B evidence. “Suggestions” are supported by grade C evidence. “Expert consensus opinion” was used to designate guidance for which grade C or better evidence is lacking.

When Should Molecular Testing of Lung Cancer Be Performed? Which patients should be tested for EGFR mutations and ALK rearrangements? It is recommended that EGFR and ALK molecular testing be used to select patients for EGFR- and ALK-targeted tyrosine kinase inhibitor treatment and that patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics (Recommendation). For resection specimens, testing is recommended for adenocarcinomas and mixed lung cancers

with an adenocarcinoma component regardless of histologic grade; for fully excised specimens, testing is not recommended in lung cancers that lack any adenocarcinoma component (Recommendation). For more-limited specimens (biopsy, cytology), testing may be performed in cases showing squamous

or small cell histology (Recommendation). Primary tumors or metastatic lesions are equally suitable for testing (Recommendation). Separate primary lung tumors in an individual patient may be tested separately (Expert consensus opinion).

When should a specimen be tested? EGFR mutation (Recommendation) and ALK rearrangement (Suggestion) testing should be ordered at time of diagnosis of patients with advanced-stage disease (stage IV) or at the time of recurrence or progression in patients initially precontinued on page 34

The Tissue Is the Issue: Choosing Therapy for Lung Cancer By Fred R. Hirsch, MD, PhD

he new guidelines from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology (CAP/IASLC/AMP) are a significant step toward personalized therapy of patients with lung cancer. More than 226,000 new patients per year are

2004 to 2012. They provide a wide range of recommendations covering tissue acquisition, processing, analysis, reporting, and timeline for analysis. Although the guidelines focus on only the two biomarkers that currently have therapeutic implications, they also pave the way for future biomarker testing for other poten-

Successful implementation of the guidelines into clinical practice should significantly improve clinical care and secure for many patients the most optimal therapeutic options. —Fred R. Hirsch, MD, PhD

diagnosed with lung cancer in the United States. Therapy with EGFR and ALK tyrosine kinase inhibitors for patients with advanced non–small cell lung cancer (NSCLC) has led to significant improvement in response and progression-free survival for the subgroups of patients with tumors harboring EGFR and ALK abnormalities compared with conventional chemotherapy. Thus, molecular testing is now crucial for choosing therapy in patients with advanced NSCLC.

Paving the Way for Future Testing The new guidelines are based on a thorough review of evidence from numerous studies published in the period Dr. Hirsch is Professor of Medicine and Pathology, University of Colorado Cancer Center, Aurora.

tial targets and agents, some of which are already being evaluated in clinical trials. Of specific importance is the multidisciplinary approach to biomarker testing and individualized therapy and the importance of establishing multidisciplinary teams including pathologists, diagnostic interventionists, and medical oncologists. “The tissue is the issue” is a strong theme in the guidelines. They recommend that pathologists should determine the quality of the tumor tissue by assessing cancer cell content and DNA quantity and quality. The quality control of the tumor specimens should be initiated as soon as possible and, most optimally, on site in order to avoid the need for extra or later biopsies from the same patient. It is also important to pay attention to the 2-week timeline (10 working days) for biomarker testing and reporting recommended in the guidelines. The

fact that we are dealing with patients with advanced cancer makes it crucial that the biomarker testing does not delay the initiation of effective therapy.

Who Should Be Tested? The guidelines recommend molecular testing of all advanced NSCLC patients with a tumor containing an adenocarcinoma component—which seems to be a reasonable and feasible recommendation, although some patients with nonadenocarcinomatous tumors might have either an EGFR mutation or ALK rearrangement. It is important to emphasize that no patients with an adenocarcinoma component should be excluded from specific targeted therapy based on clinical characteristics, unless the patient’s clinical situation makes targeted therapy “not possible.” In such situations, the omnipresent need for good communication between the clinical care team and the testing laboratory is particularly evident.

EGFR Testing EGFR mutation testing should be performed by a validated EGFR testing method. The guidelines do not specify the assay methodology. However, the guidelines emphasize the importance of quality controls of the testing laboratory through proficiency testing (CLIA-certified) and they recommend use of methodologies that can detect mutations in specimens with at least 50% tumor cells and preferably those able to detect mutations in specimens with as little as 10% cancer cells. Again, these recommendations call for stringent quality control of the tumor tissue before processing for mutation analysis. Mutation testing should be able continued on page 36

A new opportunity FDA-approved Marqibo

(vinCrIStine sulfate lIPoSomE injection)

For the treatment of adult patients with Philadelphia chromosome–negative (Ph–) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following 2 or more antileukemia therapies. This indication is based on overall response rate. Clinical benefit such as improvement in overall survival has not been verified.

• 15.4% (10/65) CR/CRi in patients who all received multiple prior therapies − 100% had previously received nonliposomal (standard) vincristine − 48% had undergone prior hematopoietic stem cell transplant (HSCT) − 51% had received 3 or more prior therapies − 45% were refractory to their immediate prior therapy − 85% had precursor B-cell ALL and 15% had precursor T-cell ALL − 100% were not eligible for immediate HSCT at enrollment − 34% did not receive asparaginase products • Marqibo® is sphingomyelin/cholesterol-based liposome– encapsulated vincristine − Plasma clearance of Marqibo® is slow, which contributes to a high plasma concentration in contrast to the rapid clearance of nonliposomal vincristine, which results in low plasma concentrations − Extended plasma circulation time contributes to a much higher AUC • The recommended dose of Marqibo® is 2.25 mg/m2 intravenously over 1 hour every 7 days. This dose delivers 2.25 mg/m2 of vincristine WARNING • For Intravenous Use Only—Fatal if Given by Other Routes • Death has occurred with intrathecal administration • Marqibo® (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vincristine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage IMPORTANT SAFETY INFORMATION Contraindications • Marqibo® is contraindicated in patients with demyelinating conditions, including Charcot-Marie-Tooth syndrome; in patients with hypersensitivity to vincristine sulfate or any of the other components of Marqibo®; and for intrathecal administration Warnings and Precautions • Marqibo® is for intravenous use only—fatal if given by other routes. Intrathecal use is fatal. Extravasation causes tissue injury. If extravasation is suspected, discontinue infusion immediately and consider local treatment measures • Sensory and motor neuropathy are common and cumulative. Monitor patients for peripheral motor and sensory, central and autonomic neuropathy and reduce, interrupt, or discontinue dosing. Patients with preexisting severe neuropathy should be treated with Marqibo® only after careful risk-benefit assessment Please see Brief Summary of Prescribing Information, including Boxed Warning, on adjacent pages. Please see Prescribing Information at www.marqibo.com.

• Neutropenia, thrombocytopenia, or anemia may occur. Monitor blood counts prior to each dose. Consider dose modification or reduction as well as supportive care measures if Grade 3 or 4 myelosuppression develops • Anticipate, monitor for, and manage tumor lysis syndrome • A prophylactic bowel regimen should be instituted with Marqibo® to prevent constipation, bowel obstruction, and/or paralytic ileus • Severe fatigue can occur requiring dose delay, reduction, or discontinuation of Marqibo® • Fatal liver toxicity and elevated levels of aspartate aminotransferase have occurred. Monitor liver function and modify or interrupt dosing for hepatic toxicity • Marqibo® can cause fetal harm. Advise women of potential risk to fetus Adverse Events • The most commonly reported adverse reactions (incidence >30%) in clinical studies include constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia (32%) • A total of 75.9% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included febrile neutropenia (20.5%), pyrexia (13.3%), hypotension (7.2%), respiratory distress (6.0%), and cardiac arrest (6.0%) • Twenty-eight percent of patients experienced adverse reactions leading to treatment discontinuation. The most common adverse reactions that caused treatment discontinuation were peripheral neuropathy (10%), leukemia-related (7%), and tumor lysis syndrome (2%) • Deaths occurred in 23% of patients in study 1. The nonleukemia-related causes of death were brain infarct (1), intracerebral hemorrhage (2), liver failure (1), multisystem organ failure (2), pneumonia and septic shock (3), respiratory failure (4), pulmonary hemorrhage (1), and sudden cardiac death (1) Drug Interactions • Marqibo® is expected to interact with drugs known to interact with nonliposomal vincristine sulfate, therefore the concomitant use of strong CYP3A inhibitors or the use of potent P-glycoprotein inhibitors or inducers should be avoided Use in Specific Populations • The safety and effectiveness of Marqibo® in pediatric patients have not been established • It is not known whether Marqibo® is excreted in human milk

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Molecular Testing of Lung Cancer continued from page 32

senting with lower-stage disease. EGFR and ALK testing at diagnosis of stage I, II, or III disease is encouraged, but the decision should be made locally by each laboratory in collaboration with its oncology

team (Expert consensus opinions). Tissue should be prioritized for EGFR and ALK testing (Recommendation). How rapidly should test results be available? EGFR and ALK results should be available within 2 weeks (10 working days) of receipt of the specimen in the

testing laboratory. Laboratories with longer average turnaround times need to make a more rapid test available in cases of clinical urgency. Laboratory departments should establish processes to ensure that specimens with a final histopathologic diagnosis are sent to outside molecular pathology laboratories within 3 working days or to in-

Marqibo® (vinCRIStine sulfate LIPOSOME injection) BRIEF SUMMARY Please see the Marqibo package insert for full Prescribing Information. WARNING • For Intravenous Use Only—Fatal if Given by Other Routes. • Death has occurred with intrathecal administration. • Marqibo (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vinCRIStine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage. INDICATIONS AND USAGE Adult All in Second or Greater relapse Marqibo ® is indicated for the treatment of adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies. This indication is based on overall response rate. Clinical benefit such as improvement in overall survival has not been verified. DOSAGE AND ADMINISTRATION For Intravenous Use Only. Fatal if Given by Other Routes. Marqibo (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vincristine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage. recommended Dosage The recommended dose of Marqibo is 2.25 mg/m2 intravenously over 1 hour once every 7 days. Marqibo is liposome-encapsulated vincristine. Dose modifications: Peripheral Neuropathy Marqibo is contraindicated in patients with demyelinating conditions including Charcot-Marie-Tooth syndrome [see Contraindications ]. Patients with preexisting severe neuropathy should be treated with Marqibo only after careful risk-benefit assessment [see Warnings and Precautions ]. For dose or schedule modifications guidelines for patients who experience peripheral neuropathy, see Table 1. Table 1. recommended Dose modifications for marqibo-related Peripheral Neuropathy Severity of Peripheral Neuropathy Signs and Symptomsa

modification of Dose and regimen

If the patient develops Grade 3 (severe symptoms; limiting self-care activities of daily living [ADL]b) or persistent Grade 2 (moderate symptoms; limiting instrumental ADLc) peripheral neuropathy:

Interrupt Marqibo. If the peripheral neuropathy remains at Grade 3 or 4, discontinue Marqibo. If the peripheral neuropathy recovers to Grade 1 or 2, reduce the Marqibo dose to 2 mg/m2.

If the patient has persistent Grade 2 peripheral neuropathy after the first dose reduction to 2 mg/m2:

Interrupt Marqibo for up to 7 days. If the peripheral neuropathy increases to Grade 3 or 4, discontinue Marqibo. If the peripheral neuropathy recovers to Grade 1, reduce the Marqibo dose to 1.825 mg/m2.

If the patient has persistent Grade 2 peripheral neuropathy after the second dose reduction to 1.825 mg/m2:

Interrupt Marqibo for up to 7 days. If the peripheral neuropathy increases to Grade 3 or 4, discontinue Marqibo. If the toxicity recovers to Grade 1, reduce the Marqibo dose to 1.5 mg/m2.

a b c

Grading based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Self-care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. Instrumental ADL: refers to preparing meals, shopping for groceries and clothes, using telephone, managing money, etc.

Preparation and Handling Items Required by the Pharmacy to Prepare Marqibo • Marqibo Kit • Water batha • Calibrated thermometera (0°C to 100°C) • Calibrated electronic timera • Sterile venting needle or other suitable device equipped with a sterile 0.2 micron filter • 1 mL or 3 mL sterile syringe with needle, and • 5 mL sterile syringe with needle. a

The manufacturer will provide the water bath, calibrated thermometer, and calibrated electronic timer to the medical facility at the initial order of Marqibo and will replace them every 2 years.

Preparation Instructions for Marqibo (vinCRIStine sulfate LIPOSOME injection), 5 mg/31 mL (0.16 mg/mL) Procedures for handling and disposal of anticancer drugs should be followed [see References ]. Call [1 888 292 9617] if you have questions about the preparation of Marqibo. Marqibo takes approximately 60 to 90 minutes to prepare. The preparer should have dedicated uninterrupted time to prepare Marqibo due to the extensive monitoring of temperature and time required for the preparation. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in Marqibo. The preparation steps of Marqibo that involve mixing the Sodium Phosphate Injection, Sphingomyelin/Cholesterol Liposome Injection, and VinCRIStine Sulfate Injection must be done in a biological safety cabinet or by established pharmacy safety procedures for the preparation of sterile injectable formulations and hazardous drugs. However, the preparation steps that involve placement of the vial in the water bath must be done outside of the sterile area. Do not use with in-line filters. Do not mix with other drugs. 1. Fill a water bath with water to a level of at least 8 cm (3.2 inches) measured from the bottom and maintain this minimum water level throughout the procedure. The water bath must remain outside of the sterile area. 2. Place a calibrated thermometer in the water bath to monitor water temperature and leave it in the water bath until the procedure has been completed. 3. Preheat water bath to 63°C to 67°C. Maintain this water temperature until completion of the procedure using the calibrated thermometer. 4. Visually inspect each vial in the Marqibo Kit for particulate matter and discoloration prior to preparation, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. 5. Remove all the caps on the vials and swab the vials with sterile alcohol pads. 6. Vent the Sodium Phosphate Injection vial with a sterile venting needle equipped with a sterile 0.2 micron filter or other suitable venting device in the biological safety cabinet. Always position venting needle point well above liquid level before adding Sphingomyelin/Cholesterol Liposome Injection and VinCRIStine Sulfate Injection. 7. Withdraw 1 mL of Sphingomyelin/Cholesterol Liposome Injection. 8. Inject 1 mL of Sphingomyelin/Cholesterol Liposome Injection into the Sodium Phosphate Injection vial. 9. Withdraw 5 mL of VinCRIStine Sulfate Injection. 10. Inject 5 mL of VinCRIStine Sulfate Injection into the Sodium Phosphate Injection vial. 11. Remove the venting needle and gently invert the Sodium Phosphate Injection vial 5 times to mix. DO NOT SHAKE. 12. Fit Flotation Ring around the neck of the Sodium Phosphate Injection vial. 13. Confirm that the water bath temperature is at 63°C to 67°C using the calibrated thermometer. Remove the Sodium Phosphate Injection vial containing VinCRIStine Sulfate Injection, Sphingomyelin/Cholesterol Liposome Injection, and Sodium Phosphate Injection from the biological safety cabinet and place into the water bath for 10 minutes using the calibrated electronic timer. Monitor the temperature to ensure the temperature is maintained at 63°C to 67°C.

tramural laboratories within 24 hours (Expert consensus opinions).

How Should EGFR Testing Be Performed? How should specimens be processed for EGFR testing? Pathologists should use formalin-fixed, paraffin-embedded speci-

14. IMMEDIATELY after placing the Sodium Phosphate Injection vial into the water bath, record the constitution start time and water temperature on the Marqibo Overlabel. 15. At the end of the 10 minutes, confirm that the water temperature is 63°C to 67°C using the calibrated thermometer. Remove the vial from the water bath (use tongs to prevent burns) and remove the Flotation Ring. 16. Record the final constitution time and the water temperature on the Marqibo Overlabel. 17. Dry the exterior of the Sodium Phosphate Injection vial with a clean paper towel, affix Marqibo (vinCRIStine sulfate LIPOSOME injection) Overlabel, and gently invert 5 times to mix. DO NOT SHAKE. 18. Permit the constituted vial contents to equilibrate for at least 30 minutes to controlled room temperature (15°C to 30°C, 59°F to 86°F). 19. Marqibo (vinCRIStine sulfate LIPOSOME injection) contains 5 mg/31 mL (0.16 mg/mL) vincristine sulfate. ONCE PREPARED, STORE AT CONTROLLED ROOM TEMPERATURE (15°C to 30°C, 59°F to 86°F) FOR NO MORE THAN 12 HOURS. 20. Swab the top of the vial now containing Marqibo with a sterile alcohol pad and return the vial back into the biological safety cabinet. 21. Calculate the patient’s Marqibo dose based on the patient’s actual body surface area (BSA) and remove the volume corresponding to the patient’s Marqibo dose from an infusion bag containing 100 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection. 22. Inject the dose of Marqibo into the infusion bag to result in a final volume of 100 mL. 23. Complete the information required on the Infusion Bag Label and apply to the infusion bag. 24. Finish administration of the diluted product within 12 hours of the initiation of Marqibo preparation. 25. Empty, clean, and dry the water bath after each use. 26. Deviations in temperature, time, and preparation procedures may fail to ensure proper encapsulation of vincristine sulfate into the liposomes. In the event that the preparation deviates from the instructions in the above steps, the components of the kit should be discarded and a new kit should be used to prepare the dose. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. CONTRAINDICATIONS Marqibo is contraindicated in patients with demyelinating conditions including Charcot-Marie-Tooth syndrome. Marqibo is contraindicated in patients with hypersensitivity to vincristine sulfate or any of the other components of Marqibo (vinCRIStine sulfate LIPOSOME injection). Marqibo is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS For Intravenous Use only Fatal if Given by Other Routes. Death has occurred with intrathecal use. Extravasation Tissue Injury Only administer through a secure and free-flowing venous access line. If extravasation is suspected, discontinue infusion immediately and consider local treatment measures. Neurologic Toxicity Sensory and motor neuropathies are common and are cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, hyporeflexia, areflexia, neuralgia, jaw pain, decreased vibratory sense, cranial neuropathy, ileus, burning sensation, arthralgia, myalgia, muscle spasm, or weakness, both before and during treatment. Orthostatic hypotension may occur. The risk of neurologic toxicity is greater if Marqibo is administered to patients with preexisting neuromuscular disorders or when other drugs with risk of neurologic toxicity are being given. In the studies of relapsed and/or refractory adult ALL patients, Grade ≥3 neuropathy events occurred in 32.5% of patients. Worsening neuropathy requires dose delay, reduction, or discontinuation of Marqibo [see Dosage and Administration]. myelosuppression Monitor complete blood counts prior to each dose of Marqibo. If Grade 3 or 4 neutropenia, thrombocytopenia, or anemia develops, consider Marqibo dose modification or reduction as well as supportive care measures. Tumor lysis Syndrome Tumor lysis syndrome (TLS) may occur in patients with ALL receiving Marqibo. Anticipate, monitor for, and manage. Constipation and Bowel obstruction Ileus, bowel obstruction, and colonic pseudo-obstruction have occurred. Marqibo can cause constipation [see Adverse Reactions ]. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction, and/or paralytic ileus, considering adequate dietary fiber intake, hydration, and routine use of stool softeners, such as docusate. Additional treatments, such as senna, bisacodyl, milk of magnesia, magnesium citrate, and lactulose may be considered. Fatigue Marqibo can cause severe fatigue. Marqibo dose delay, reduction, or discontinuation may be necessary. Hepatic Toxicity Fatal liver toxicity and elevated levels of aspartate aminotransferase have occurred. Elevated levels of aspartate aminotransferase of Grade ≥3 occurred in 6-11% of patients in clinical trials. Monitor hepatic function tests. Reduce or interrupt Marqibo for hepatic toxicity. Embryofetal Toxicity Marqibo can cause fetal harm when administered to a pregnant woman. Vincristine sulfate liposome injection was teratogenic or caused embryo-fetal death in animals. Women of childbearing potential should avoid becoming pregnant while being treated with Marqibo. There are no adequate and well-controlled studies of Marqibo in pregnant women and there were no reports of pregnancy in any of the clinical studies in the Marqibo clinical development program. 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 ]. ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the labeling: • For intravenous use only [see Warnings and Precautions ] • Extravasation tissue injury [see Warnings and Precautions ] • Peripheral Neuropathy [see Warnings and Precautions ] • Myelosuppression [see Warnings and Precautions ] • Tumor lysis syndrome [see Warnings and Precautions ] • Constipation and bowel obstruction [see Warnings and Precautions ] • Fatigue [see Warnings and Precautions ] • Hepatic toxicity [see Warnings and Precautions ] Clinical Trials Safety 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. Integrated Summary of Safety in Relapsed and/or Refractory Ph- Adult Acute Lymphoblastic Leukemia Marqibo, at a dose of 2.25 mg/m2 weekly, was studied in a total of 83 patients in two trials: study 1 and study 2. Adverse reactions were observed in 100% of patients. The most common adverse reactions (>30%) were constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia (32%).

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mens or fresh, frozen, or alcoholfixed specimens for polymerase chain reaction (PCR)-based EGFR tests. Other tissue treatments should be avoided. Cytologic samples are suitable for EGFR and ALK testing, with cell blocks preferred over smear preparations (Expert consensus opinions).

What are the specimen requirements for EGFR testing? Pathologists should determine the adequacy of specimens by assessing cancer cell content and DNA quantity and quality. Each laboratory should establish the minimum proportion and number of cancer cells needed for mutation

Adverse reactions of Grade 3 or greater were reported in 96% of patients. Adverse reactions of Grade 3 or greater and occurring in ≥5% of patients are summarized in Table 2. Table 2. most Commonly reported (>5%) Gradea 3 or Greater Adverse reactions among 83 Patients receiving the Clinical Dosing regimen Adverse reactions ≥3

Study 1 and 2 (N=83) n (%)

Blood and Lymphatic System Disorders Febrile Neutropenia Neutropenia Anemia Thrombocytopenia

47 (56.6) 26 (31.3) 15 (18.1) 14 (16.9) 14 (16.9)

Infections Pneumonia Septic Shock Staphylococcal Bacteremia

33 (39.8) 7 (8.4) 5 (6.0) 5 (6.0)

Neuropathyb Peripheral Sensory and Motor Neuropathy Constipation Ileus, Colonic Pseudo-Obstruction Asthenia Muscular Weakness

27 (32.5) 14 (16.7) 4 (4.8) 5 (6.0) 4 (4.8) 1 (1.2)

Respiratory Thoracic and Mediastinal Disorders Respiratory Distress Respiratory Failure

17 (20.5) 5 (6.0) 4 (4.8)

General Disorders and Administration Site Condition Pyrexia Fatigue Pain

31 (37.3) 12 (14.5) 10 (12.0) 7 (8.4)

Gastrointestinal Disorders Abdominal Pain

21 (25.3) 7 (8.4)

Investigations Aspartate Aminotransferase Increased

20 (24.1) 6 (7.2)

Vascular Disorders Hypotension

8 (9.6) 5 (6.0)

Psychiatric Disorders Mental Status Changes

9 (10.8) 3 (3.6)

Cardiac Disorders Cardiac Arrest

9 (10.8) 5 (6.0)

Renal and Urinary Disorders Musculoskeletal and Connective Tissue Disorders

6 (7.2) 7 (8.4)

a b

National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Including neuropathy-associated adverse reactions.

A total of 75.9% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included febrile neutropenia (20.5%), pyrexia (13.3%), hypotension (7.2%), respiratory distress (6.0%), and cardiac arrest (6.0%). Dose reduction, delay, or omission occurred in 53% of patients during the treatment. Twenty-eight percent of patients experienced adverse reactions leading to treatment discontinuation. The most common adverse reactions that caused treatment discontinuation were peripheral neuropathy (10%), leukemia-related (7%), and tumor lysis syndrome (2%). Adverse reactions related to neuropathy and leading to treatment discontinuation were decreased vibratory sense, facial palsy, hyporeflexia, constipation, asthenia, fatigue, and musculoskeletal pain, each reported in at least 1 patient. Deaths occurred in 23% of patients in study 1. The non-leukemia related causes of deaths were brain infarct (1), intracerebral hemorrhage (2), liver failure (1), multi system organ failure (2), pneumonia and septic shock (3), respiratory failure (4), pulmonary hemorrhage (1), and sudden cardiac death (1). DRUG INTERACTIONS No formal drug interaction studies have been conducted with Marqibo. Marqibo is expected to interact with drugs known to interact with non-liposomal vincristine sulfate. Simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included non-liposomal vincristine sulfate have been reported to reduce blood levels of phenytoin and to increase seizure activity. CYP3A Interactions Vincristine sulfate, the active agent in Marqibo, is a substrate for cytochrome P450 3A isozymes (CYP3A); therefore, the concomitant use of strong CYP3A inhibitors should be avoided (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). Similarly, the concomitant use of strong CYP3A inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort). P-glycoprotein Interactions Vincristine sulfate, the active agent in Marqibo, is also a substrate for P-glycoprotein (P-gp). The effect of concomitant use of potent P-gp inhibitors or inducers has not been investigated; it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of Marqibo. Therefore the concomitant use of potent P-gp inhibitors or inducers should be avoided. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions ] Based on its mechanism of action and findings from animal studies, Marqibo can cause fetal harm when administered to 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. In an embryofetal developmental study, pregnant rats were administered vincristine sulfate liposome injection intravenously during the period of organogenesis at vincristine sulfate doses of 0.022 to 0.09 mg/kg/day. Drug-related adverse effects included fetal malformations (skeletal and visceral), decreases in fetal weights, increased numbers of early resorptions and post-implantation losses, and decreased maternal body weights. Malformations were observed at doses ≥0.044 mg/kg/day in animals at systemic exposures approximately 20-40% of those reported in patients at the recommended dose.

detection during validation. A pathologist should assess the tumor content of each specimen and perform (or guide a trained technologist in performing) microdissection for tumor cell enrichment as needed (Expert consensus opinions). How should EGFR testing be performed?

Nursing mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Marqibo in pediatric patients have not been established. Geriatric Use Safety and effectiveness in elderly individuals have not been established. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. renal Impairment The influence of renal impairment on the safety, efficacy, and pharmacokinetics of Marqibo has not been evaluated. Hepatic Impairment Non-liposomal vincristine sulfate is excreted primarily by the liver. The influence of severe hepatic impairment on the safety and efficacy of Marqibo has not been evaluated. The pharmacokinetics of Marqibo was evaluated in patients with moderate hepatic dysfunction (Child-Pugh B) secondary to melanoma liver metastases. The dose-adjusted maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of Marqibo in patients with moderate hepatic impairment was comparable to the Cmax and AUC of patients with ALL who had otherwise normal hepatic function. OVERDOSAGE When Marqibo (vinCRIStine sulfate LIPOSOME injection) was administered at a dose of 2.4 mg/m2, severe toxicities including motor neuropathy of Grade 3, grand mal seizure of Grade 4, and elevated aspartate aminotransferase and hyperbilirubinemia of Grade 4 were reported in 1 patient each. There is no known antidote for overdosage. NONCLINICAL TOXICOLOGY Carcinogenesis, mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with Marqibo or non-liposomal vincristine sulfate. Based on the mechanism of action and genotoxicity findings in nonclinical studies conducted with non-liposomal vincristine sulfate, Marqibo may be carcinogenic. No genotoxicity studies have been conducted with Marqibo. Non-liposomal vincristine was genotoxic in some in vitro and in vivo studies. The single- and repeat-dose animal toxicology study results indicate that Marqibo can impair male fertility, consistent with the literature on non-liposomal vincristine sulfate. Administration of vincristine liposome injection causes testicular degeneration and atrophy, and epididymal aspermia in rats. Gonadal dysfunction has been reported in both male and female post-pubertal patients who received multi-agent chemotherapy including non-liposomal vincristine sulfate. The degree to which testicular or ovarian functions are affected is age-, dose-, and agent-dependent. Recovery may occur in some but not all patients. Animal Toxicology and/or Pharmacology In a repeat-dose comparative toxicology study in rats, vincristine sulfate liposome injection or non-liposomal vincristine sulfate was administered to animals intravenously once per week for 6 weeks. Clinical signs of toxicity consistent with neurotoxicity were greater with vincristine sulfate liposome injection than with non-liposomal vincristine sulfate at equal vincristine sulfate doses of 2 mg/m2 /week and included uncoordinated movements, weakness, reduced muscle tone, and limited usage of the limbs. Neurological testing indicated drug-induced peripheral neurotoxicity with both drugs. Based on the histopathology examination after 6 weekly doses, vincristine sulfate liposome injection induced greater peripheral neurotoxicity (nerve fiber degeneration) and secondary skeletal muscle atrophy than the equal dose of non-liposomal vincristine sulfate. In a separate tissue distribution study in rats, administration of 2 mg/m2 of intravenous liposomal or non-liposomal vincristine sulfate showed greater accumulation of vincristine sulfate in sciatic and tibial nerves (as well as the lymph nodes, spleen, and bone marrow) of the animals following vincristine sulfate liposome injection. PATIENT COUNSELING INFORMATION Physicians are advised to discuss the following with patients prior to treatment with Marqibo: Extravasation Tissue Injury: Advise patients to report immediately any burning or local irritation during or after the infusion [see Warnings and Precautions ]. Ability to Drive or operate machinery or Impairment of mental Ability: Marqibo may cause fatigue and symptoms of peripheral neuropathy. Advise patients not to drive or operate machinery if they experience any of these symptoms [see Warnings and Precautions ]. Gastrointestinal/Constipation: Patients receiving Marqibo may experience constipation. Advise patients how to avoid constipation by a diet high in bulk fiber, fruits and vegetables, and adequate fluid intake as well as use of a stool softener, such as docusate. Instruct patients to seek medical advice if they experience symptoms of constipation such bowel movement infrequency, abdominal pain, bloating, diarrhea, nausea, or vomiting [see Warnings and Precautions ]. Pregnancy/Nursing: Advise patients to use effective contraceptive measures to prevent pregnancy during treatment with Marqibo [see Warnings and Precautions ]. Instruct patients to report pregnancy to their physicians immediately. Advise patients that they should not receive Marqibo while pregnant or breastfeeding. If a patient wishes to re-start breastfeeding after treatment, she should be advised to discuss the appropriate timing with her physician [see Use in Specific Populations ]. Concomitant medications: Advise patients to speak with their physicians about any other medication they are currently taking [see Drug Interactions ]. Peripheral Neuropathy: Advise patients to contact their physicians if they experience new or worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the feet or hands [see Warnings and Precautions ]. other: Instruct patients to notify their physicians if they experience fever, productive cough, or decreased appetite [see Warnings and Precautions ]. REFERENCES 1. NIOSH Alert: Preventing occupational exposure to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html. 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. (2006) 63:1172-1193. 4. Polovich M, White JM, Kelleher LO (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. Distributed by: Talon Therapeutics, Inc., 400 Oyster Point Boulevard, Suite 200, South San Francisco, CA 94080 ©2012 Talon Therapeutics, Inc. Marqibo ® is a registered trademark of Talon Therapeutics, Inc. All rights reserved. October 2012. Printed in the USA. MRQ005 TALONtx.com

Laboratories may use any validated EGFR testing method with sufficient performance characteristics (Recommendation). Test methods that detect mutations in specimens with at least 50% cancer cell content should be used, although laboratories are strongly encouraged to use tests able to detect mutations in specimens with as little as 10% cancer cells (Expert consensus opinion). Mutation testing should be able to detect all mutations that have been reported with a frequency of at least 1% in lung adenocarcinomas (Expert consensus opinion). Neither immunohistochemistry for total EGFR nor EGFR copy number analysis (eg, fluorescence [FISH] or chromogenic [CISH] in situ hybridization) is recommended for selection of EGFR tyrosine kinase inhibitor therapy (Recommendations). What is the role of KRAS analysis in selecting patients for EGFR tyrosine kinase inhibitor therapy? KRAS mutation testing is not recommended as a sole determinant of EGFR tyrosine kinase inhibitor therapy (Recommendation). What additional considerations are important in the setting of secondary or acquired EGFR tyrosine kinase inhibitor resistance? Tests should be able to detect the secondary EGFR T790M mutation in as few as 5% of cells (Recommendation).

How Should ALK Testing Be Performed? What methods should be used for ALK testing? Labs should use an ALK FISH assay with dual-labeled break-apart probes for selecting patients for ALK tyrosine kinase inhibitor therapy. If it is carefully validated, ALK immunohistochemistry may be considered for screening to select specimens for ALK FISH testing (Recommendation). Reverse transcriptase PCR is not currently recommended for selecting patients for ALK tyrosine kinase inhibitor treatment (Recommendation). A pathologist should be involved in selecting sections for ALK FISH testing by assessing tumor architecture, cytology, and specimen quality, and a pathologist should participate in interpretation of ALK FISH slides by performing the analysis directly or reviewing the interpretation of cytogeneticists or technologists with specontinued on page 36

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Molecular Testing of Lung Cancer continued from page 35

cialized training in solid tumor FISH analysis (Expert consensus opinions).

Fred R. Hirsch, MD, PhD, on Choosing Therapy continued from page 32

to detect all EGFR mutations that have been reported with a frequency of at least 1%, including the “resistant” mutation T790M. The guidelines give strict recommendations in this regard, although the clinical significance of many rare mutations is not entirely established.

ALK Testing It is recommended that ALK testing be done with ALK fluorescence in situ hybridization (FISH) for eligibility in clinical trials, since this test is currently the only FDA-approved companion diagnostic. However, the question is what to use for a screening test for ALK rearrangement. Numerous studies over the past several years have compared immunohistochemistry (IHC) to FISH and found good sensitivity (~80%–95%) and specificity (90%–100%) with IHC, depending somewhat on methodology and antibody used. The guidelines state that ALK IHC, if carefully validated, may be considered as a screening methodology to select specimens for ALK FISH testing. The ALK FISH test is still costly and very much skill-dependent, whereas IHC is readily clinically applicable and performed in every pathology department. However, as noted, further validation of the ALK IHC assay is needed, and the assay is not yet FDA-approved for therapeutic applications. Although the ALK FISH assay with specific criteria defined as “positive” is the gold standard, some case reports have already been published concerning patients with tumors that are ALK FISH-negative but IHC-positive and show significant response to ALK inhibition. Thus, it may be that the future will call for a combined diagnostic paradigm including both IHC and FISH.

Clinical Practice Now that molecular testing of patients with advanced NSCLC is required and guidelines are established, the next step will be the implementation of these guidelines into clinical practice. According to the most optimistic reports, only 60% to 70% of patients with advanced NSCLC undergo molecular testing, more commonly in the academic envi-

Testing for secondary ALK mutations associated with acquired resistance to ALK inhibitors is not currently required for clinical management (Expert consensus opinion). ronment than in community practices. In order to capture all the patients who will benefit from personalized therapy, a wide range of educational activities have to be implemented. While molecular testing for patients with advanced NSCLC is already implemented in many places in the United States and many other countries, the new guidelines should have a significant impact on the overall future management of all patients with lung cancer, since they cover a broad range of crucial aspects of molecular testing. It is important to emphasize that molecular testing is complex. Standardization in testing is crucial if patients are to be able to take advantage of

Should Other Genes Be Routinely Tested? Are other molecular markers suitable for testing in lung cancer? Testing for EGFR should have patients with advanced NSCLC often have only very small biopsy or cytology specimens, making testing difficult or impossible, particularly if the sparse material has already been exhausted for routine diagnostic purposes. Despite the fact that technology is rapidly evolving and assays become more and more applicable to small biopsies and cytology specimens, there will still be some patients for whom molecular profiling will not be possible and for whom standard chemotherapy is the only option. The implementation of the new guidelines will in many cases lead to a tough prioritization of sparse available tumor material—although ongoing develop-

therapeutic progress; “failed” molecular testing or false-negative results can lead to a detrimental effect in individual patients. And while the new guidelines are expected to lead to a significant improvement in patient care, their success in this regard is entirely dependent on success in establishing a multidisciplinary team approach to the management of patients with lung cancer—also stressed by the new guidelines. With the continued rapid movement toward personalized medicine, such guidelines will need to be continuously monitored and modified as diagnostic and therapeutic progress occurs.

Barriers to Implementation The implementation of the new guidelines carries some financial implications. However, the prices for molecular testing and the applied assays have dropped significantly over the past several years and continue to drop. In any case, costs of testing must be viewed in the context of the price associated with offering a patient ineffective or less-effective therapy due to lack of testing or failed testing due to lack of guidelines and/or standardization. Another potential barrier for molecular testing is the fact that many

priority over testing for other molecular markers in lung adenocarcinoma (Recommendation), and testing for ALK, after testing for EGFR, should take priority over testing for proposed markers (Suggestion). Published evidence is currently insufficient to support development of testing guidelines for other proposed markers.

How Should Molecular Testing Be Implemented and Operationalized? Must all adenocarcinomas be tested for both EGFR and ALK? Simultaneous testing is difficult to implement due to high costs and labor requirements. Laboratories may implement step-wise testing algorithms to enhance efficiency of molecular testing, provided the overall turnaround time requirements are met (Expert consensus opinion). How should EGFR and ALK test results be reported? Reports should include a results and interpretation section that can be readily understood by oncologists and nonspecialist pathologists (Expert consensus opinion).

ment of multiplex technologies covering several biomarkers will help remedy this situation in the future. It needs to be emphasized that the prioritization of sparse tumor material should be addressed based on a multidisciplinary approach.

How should EGFR and ALK testing be validated? EGFR and ALK testing validation should follow the same guidelines as for other molecular diagnostics ad FISH tests (Expert consensus opinion).

Conclusion

How should quality assurance be maintained? Laboratories should follow quality control and quality assurance policies for EGFR and ALK testing similar to those for other clinical laboratory assays. Laboratories performing such testing for tyrosine kinase inhibitor therapy should enroll in proficiency testing, if available. n

The new CAP/IASLC/AMP guidelines for molecular testing represent a significant step toward standardization and implementation of personalized medicine for patients with lung cancer. Successful implementation of the guidelines into clinical practice should significantly improve clinical care and secure for many patients the most optimal therapeutic options. Further, the guidelines provide an important framework for incorporating the new recommendations and standards that will be needed as progress toward personalized medicine continues. n Disclosure: Dr. Hirsch has participated in advisory boards for Pfizer, Boehringer-Ingelheim, Roche/Genentech; his laboratory has (through University of Colorado) research funding from Genentech, Lilly/Imclone, Ventana-Roche; and he is a member of Board of Directors for The International Association for the Study of Lung Cancer (IASLC) and has been advisor for the guidelines.

Reference 1. Lindeman NI, Cagle PT, Beasley MB, et al: Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors. Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. April 3, 2013 (early release online).

ASCOPost.com | MAY 15, 2013

PAGE 37

JCO Spotlight Thoracic Oncology

Greater Prediagnosis Soy Food Consumption Associated with Improved Survival in Women with Lung Cancer By Matthew Stenger

s recently reported by Gong Yang, MD, MPH, Research Associate Professor at Vanderbilt University School of Medicine, Nashville, and colleagues in the Journal of Clinical Oncology,1 higher prediagnosis consumption of soy food was associated with improved overall survival in Chinese women with lung cancer in the Shanghai Women’s Health Study. In a prior analysis in the Shanghai Women’s Health Study, the investigators found a significant inverse association between soy intake and lung cancer risk among nonsmoking women.2 Estrogen signaling has been found to promote lung cancer progression, and various data show increased risk of death from lung cancer among patients using hormone replacement therapy and reduced risk with use of antiestrogens. Plant-derived estrogens, including the isoflavones found mainly in soy foods, appear to act as natural selective estrogen receptor modulators, and preclinical studies have indicated that soy and soy isoflavones can inhibit cancer cell transformation, induce apoptosis, and inhibit angiogenesis and metastasis.

Study Details The current analysis involved 444 Chinese women with incident lung cancer identified in the Shanghai Women’s Health Study between 1997 and 2010. Prediagnosis soy food intake was assessed at enrollment into the study and 2 years later. Patients had a mean age of 66 years at diagnosis, and 92% were “neversmokers.” Mean daily soy intakes were 18.0 g for dry weight soy food, 8.8 g for soy protein, and 30.3 mg for isoflavones. Soy food intake was not associated with age at diagnosis, smoking, obesity, family history of

lung cancer, tumor stage, treatment regimens, or time between baseline dietary assessment and disease diagnosis. Of the 444 patients, 318 died during follow-up, including 301 patients in whom lung cancer was the primary cause of death. The median follow-up from time of diagnosis for censored patients was 36 months. Data on tumor stage and treatment were not available for a large proportion of patients. On multivariable analysis of demographic and clinical characteris-

total mortality (P � .04 for overall significance) on multivariable analysis adjusting for age at diagnosis, education, cigarette smoking, body mass index, menopausal status, history of lung cancer in first-degree relatives, intakes of total calories and fruit and no-soy vegetables, interval between first food intake questionnaire and lung cancer diagnosis, and use of NSAIDs and vitamin supplements. Compared with the 50th percentile of soy food intake in dry weight (16.0 g/d), women in the

Among all 444 patients, soy food intake was significantly associated with risk for total mortality (P = .04 for overall significance) on multivariable analysis. —Gong Yang, MD, MPH and colleagues

tics among 301 patients (including 231 who had died) who had data available for both clinical and nonclinical variables, increasing age and advanced tumor stage were significantly associated with increased risk of overall mortality and receipt of chemotherapy was significantly associated with reduced risk. No significant associations were observed for education, cigarette smoking, overweight/obesity, receipt of surgery or radiation therapy, or adenocarcinoma vs nonadenocarcinoma.

Findings in Total Population Soy food and isoflavone intakes were categorized by 10th, 30th, 50th, 70th, and 90th percentiles. Among all 444 patients, soy food intake was significantly associated with risk for

Prediagnosis Soy Intake and Lung Cancer ■ Women with lung cancer who had higher prediagnosis intake of soy foods had lower risk of overall mortality, with similar findings for isoflavone intake.

■ Risk reduction was maximal at about the 70th percentile of soy food intake (21.4 g/d of dry weight soy food), with no additional benefit observed with greater intake.

10th percentile (6.3 g/d) had a 42% increased risk of mortality (hazard ratio [HR] � 1.42, 95% confidence interval [CI] � 1.08–1.87) and those in the 30th percentile (11.5 g/d) had a 15% increased risk (HR � 1.15, 95% CI � 1.03–1.28), whereas those in the 70th percentile (21.4 g/d) had an 8% decreased risk (HR � 0.92, 95% CI � 0.85–0.99) and those in the 90th percentile had a 7% decreased risk (HR � 0.93, 95% CI � 0.75–1.14). Isoflavone intakes were 10.2, 18.8, 26.5, 37.9, and 53.5 mg/d for the 10th through 90th percentiles. Hazard ratios for isoflavone intake percentiles were similar to those for soy intake percentiles, but the overall trend was only borderline significant (P � .06 for overall significance).

Adjustment for Tumor Stage and Treatment A second multivariable analysis involved only the 301 patients with data on clinical characteristics and adjusted for tumor stage and receipt of chemotherapy, surgery, and radiation therapy in addition to the

factors included in the first multivariable analysis. On this analysis, the strength of the significant association between soy food intake and mortality was increased (P � .004 for overall significance). Compared with the 50th percentile, women in the 10th percentile had an 81% increased risk for mortality (HR � 1.81, 95% CI � 1.26–2.59) and those in the 30th percentile had a 25% increased risk (HR � 1.25, 95% CI � 1.09–1.42), whereas those in the 70th percentile had a 12% decreased risk (HR � 0.88, 95% CI � 0.80–0.97) and those in the 90th percentile had an 11% decreased risk (HR � 0.89, 95% CI � 0.68–1.16). Thus, risk of death decreased with increasing soy food intake until intake reached approximately the 70th percentile, with further increase in intake appearing to confer no additional benefit. Results for isoflavone intake were similar: Hazard ratios relative to the 50th percentile were 1.76 for the 10th percentile, 1.24 for the 30th percentile, 0.87 for the 70th percentile, and 0.89 for the 90th percentile. The overall trend was significant (P � .007). The effect of soy food intake was stronger in never-smokers, in whom hazard ratios relative to patients in the 50th percentile were 2.40 in the 10th percentile, 1.42 in the 30th percentile, 0.85 in the 70th percentile, and 0.92 in the 90th percentile (P � .002 for overall significance). Additional analysis by soy food intake tertile in the 301 patients (1st tertile, > 20.6 g/d; 2nd, 12.4–20.6 g/d; 3rd, ≤ 12.3 g/d) showed that the adjusted 12-month survival rate was 60% for women in the highest tertile and 50% for those in the lowest tertile. As noted by the authors, since dietary assessments occurred before cancer diagnosis, no inferences on the effect of postdiagnosis diet can be made; they cite the need for investigation of the potential effects of postdiagnosis soy food intake

continued on page 38

The ASCO Post | MAY 15, 2013

PAGE 38

JCO Spotlight

Soy Food Consumption and Lung Cancer continued from page 37

and lung cancer outcomes, particularly in patients with early-stage disease, in whom any postdiagnosis intervention, including diet modification, might be expected to have the greatest impact. They also note that since the study was conducted among women with a low prevalence of cigarette smoking and postmenopausal hormone use, it would be useful to study the effects of soy diet among smokers and women using hormone replacement therapy. The investigators concluded:

[T]his…study provides the first evidence that soy food consumption before cancer diagnosis may favorably affect clinical outcomes of lung cancer in women. More epidemiologic studies are needed to confirm this finding and provide support for launching randomized trials. Given that the incidence of lung cancer among women is increasing

steadily worldwide and that soy can be readily incorporated into most diets, our findings, if confirmed by future studies, could potentially contribute to the development of new strategies for control and management of this fatal malignancy. n Disclosure: The study authors reported no potential conflicts of interest.

References 1. Yang G, Shu X-O, Li H-L, et al: Prediagnosis soy food consumption and lung cancer survival in women. J Clin Oncol. March 25, 2013 (early release online). 2. Yang G, Shu XO, Chow WH, et al: Soy food intake and risk of lung cancer: Evidence from the Shanghai Women’s Health Study and a meta-analysis. Am J Epidemiol 176:846-855, 2012.

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The ASCO Post

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

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

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

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

Blood Donation

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

Nursing Mothers

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

Trim:

ASCOPost.com | MAY 15, 2013

PAGE 39

ASCO Statement

Congress Must Reverse Devastating Budget Cuts to Cancer Care

andra M. Swain, MD, FACP, ASCO President, issued the following statement on April 27, 2013: “Today, out of concern for public safety, Congress provided the Federal :15.5” Aviation Administration enhanced flexibility in application of sequestra-

tion related cuts, including reversal of furlough requirements imposed on air traffic controllers. Individuals with cancer deserve no less. “ASCO, along with others in the oncology community, has called upon the Secretary of Health and Human Services

to apply sequestration cuts in a way that protects access to cancer care for America’s elderly. More than 120 Members of Congress have signed a letter asking the Secretary to exercise any authority she has to reverse the cuts and to make it a high priority. “Secretary Sebelius has indicated

she does not have authority to apply reductions selectively, and that cuts must apply across the board. “We urge Congress to take action now and pass H.R. 1416, bipartisan legislation which would preserve access to care by exempting cancer drugs from sequester.” n

ORAL, ONCE-DAILY THERAPY1

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

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

ORR (95% CI)

Median response duration (months) (95% CI)

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

Adverse Reactions

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

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

Trim:10.75”

Complete response

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

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

The ASCO Post | MAY 15, 2013

PAGE 40

American Association for Cancer Research Annual Meeting Tobacco Use in Cancer Patients: Often Overlooked but Critical to Address By Alice Goodman

ne would hope that the importance of treatment for tobacco dependence would be well recognized as a cornerstone of standard care for cancer patients. However,

a policy statement released by the American Association for Cancer Research (AACR) at its recent Annual Meeting revealed some surprising and disappointing findings T:7”

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont) All aBCC Patients (N = 138) Grade 3 Grade 4 All Grades 3 (%) (%) (%) 1

MedDRA Preferred Term

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

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].

All aBCC1 Patients (N = 138) MedDRA Preferred Term

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

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

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

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

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

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

ical cancer trials. The AACR statement, published in Clinical Cancer Research,1 calls on the oncology community to provide evidence-based tobaccodependence treatment for all cancer and cancer-screening patients and to evaluate tobacco as a confounding factor in cancer clinical trial outcomes.

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). t "EWJTF QBUJFOUT UIBU &3*7&%(& FYQPTVSF EVSJOH QSFHOBODZ DBO cause embryo-fetal death or severe birth defects. t *OTUSVDU GFNBMF QBUJFOUT PG SFQSPEVDUJWF QPUFOUJBM UP VTF B IJHIMZ effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t *OTUSVDU BMM NBMF QBUJFOUT FWFO UIPTF XJUI QSJPS WBTFDUPNZ UP VTF condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. t *OTUSVDU QBUJFOUT UP JNNFEJBUFMZ DPOUBDU UIFJS IFBMUIDBSF QSPWJEFS if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. t *OTUSVDU QBUJFOUT UP JNNFEJBUFMZ SFQPSU BOZ QSFHOBODZ FYQPTVSF UP ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. t *OGPSN GFNBMF QBUJFOUT PG UIF QPUFOUJBM GPS TFSJPVT BEWFSTF reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. t "EWJTF QBUJFOUT OPU UP EPOBUF CMPPE PS CMPPE QSPEVDUT XIJMF UBLJOH ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t "EWJTF QBUJFOUT UP TXBMMPX &3*7&%(& DBQTVMFT XIPMF BOE OPU UP crush or open the capsules.

ERIVEDGE ® [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0001559500 HED0000832301

Stark Statistics

T:10”

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

related to the paucity of services and interventions for tobacco dependence in oncology practices and the lack of documentation of smoking status by oncologists and in clin-

Here are some of the findings: A survey of NCI-designated cancer centers found that only 38% of responding centers document smoking status as a vital sign and less than 50% have dedicated personnel for tobacco-dependence treatment, while 78% of the same centers have dedicated nutrition personnel. A recent large survey of oncologists showed that while 90% believe that tobacco use affects cancer outcomes and that tobacco-dependence treatment should be included as standard of care, only 40% provided routine assistance for treating tobacco dependence. Only 33% of lung cancer specialists considered themselves adequately trained in smoking cessation. A recent evaluation of 155 NCI Cooperative Group trials demonstrated that only 29% of registered

Roy Herbst, MD, PhD

trials assessed tobacco use during follow-up. Less than 5% of these trials included follow-up on subsequent tobacco use status. In 2010, about 69% of smokers in the general public reported a desire to quit smoking, and more than 52% attempted to quit over the previous 12 months. Without use of evidence-based pharmacotherapy and/or counseling support, only

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PAGE 41

American Association for Cancer Research Annual Meeting EXPERT POINT OF VIEW

ichard Hurt, MD, Director of the Nicotine Dependence Center at the Mayo Clinic in Rochester, Minnesota, applauds the new American Association for Cancer Research (AACR) policy recommendations. “It is disappointing that more oncologists are not paying enough attention to tobacco use in their practices,” he commented. “Left untreated, tobacco dependence will kill 60% of smokers in the general population of smokers. There are three good reasons for cancer patients to stop smoking: StopRichard Hurt, MD ping smoking will improve outcomes from chemotherapy and radiation therapy and reduce side effects from these treatments as well as reduce the risk of second cancers.” More attention is paid to nutrition at cancer centers than to tobacco cessation, he continued. “People on the nutritional side have done a better job than we have at educating oncologists and cancer patients about the need to maintain a good nutritional status while undergoing therapy,” Dr. Hurt continued. Documentation of tobacco use is essential in clinical trials, since tobacco use is a major confounding factor, compromising outcomes of a new therapy. “Tobacco use should be assessed at baseline and at every follow-up and be included in the analysis,” he noted.

Tobacco Treatment Specialists The Mayo Clinic Nicotine Dependence Center has trained at least 1,500 people to be Tobacco Treatment Specialists, and these specialists now work at centers around the United States. He pointed out that physician extenders such as nurse practitioners and physician assistants could easily complete the training and are eligible for reimbursement for tobacco dependence interventions. “Every medical center [including oncology practices] should have a trained Tobacco Treatment Specialist. The payback for stopping smoking is immediate in terms of reduced risk of heart disease,” he commented. “Oncology practices and professional societies need to embrace this policy statement and also develop their own policy statements and infrastructure for delivering intervention. Tobacco dependence treatment should be at the top of the agenda for oncologists and other medical specialties,” he emphasized. “Hopefully these guidelines will enlighten oncologists.” n Disclosure: Dr. Hurt reported no potential conflicts of interest.

about 4% to 7% of people are successful at quitting. These percentages are similar in cancer patients, explained Roy Herbst, MD, PhD, Chair of the panel that produced the AACR policy statement on Tobacco Use by Cancer Patients and Facilitating Cessation, and chief of medical oncology at Yale University School of Medicine in New Haven, Connecticut.

Multiple Risks “Although lung cancer first comes to mind as associated with tobacco use, tobacco is implicated in 18 other cancers. A frequent assumption is that once cancer develops, it is fruitless to stop smoking.

This is not true!” he Dr. Herbst emphasized. Even though many cancers have effective treatments, tobacco use complicates treatment and reduces survival in lung, head and neck, breast, prostate, colon, cervical, and endometrial cancer as well as lymphoma, he continued. Tobacco use interferes with drug metabolism, compromises the effects of chemotherapy and radiation, leads to worse side effects from therapy, increases the risk of second cancers, affects wound healing, and exacerbates pain, he added. “Patients who continue to smoke are at greatly increased risk of second cancers and heart disease. In

Smoking and Cancer Care ■ Tobacco use in cancer patients compromises outcomes, worsens side effects of treatment, and leads to second cancers, as well as to heart disease and other comorbidities.

■ Tobacco use in cancer patients is a neglected area in many oncology practices, given short shrift compared with nutrition.

■ Oncologists need to assume responsibility for providing smoking interventions in their practices.

■ These interventions are reimbursable in some states and are addressed by the Affordable Care Act.

■ A new AACR policy statement addresses the shortcomings of current

cancer care delivery related to tobacco use and provides recommendations for critical steps to bridge the gap between services needed and those delivered.

addition to documenting what drugs patients are taking, we also need to document if they are smoking and whether this is related to other health problems they have,” he told the audience. A strong evidence base supports use of pharmacotherapy and nicotine chewing gum, as well as the “5A” approach to treating tobacco users (ie, ask about smoking status, advise people to quit, assess interest in quitting, assist with pharmacotherapy and counseling, and arrange follow-up). Yet many cancer healthcare providers never get beyond the first 2 As, Dr. Herbst said.

AACR Recommendations AACR’s policy statement makes concrete recommendations related to assessment of tobacco use and providing evidence-based treatment for current smokers and recent quitters, as well as all participants in clinical trials of cancer, and cancer screening patients. The statement says that oncology practices are responsible for ensuring that such care is delivered. The statement calls for the repeated documentation of tobacco use in all patients, so that the confounding effects of smoking on treatment, disease progression, and comorbidities can be tracked in clinical trials, starting at registration and through follow-up. Tobacco use should also be documented in all clinical care settings. Universal standardized measurement of tobacco use and exposure is needed to create a meaningful database for information-sharing. Further, evidence-based tobacco

interventions should be incorporated into review criteria for researchers as well as health-care quality and

Carolyn Dressler, MD

accreditation bodies. And tobacco cessation interventions should be valued and supported by health systems, payers, and funding bodies by providing incentives for developing infrastructure and delivering interventions. At a press conference where the policy statement on tobacco use and cancer patients was presented, Carolyn Dressler, MD, Center for Tobacco Products (FDA), Rockville, Maryland, said that the Affordable Care Act stipulates that smoking cessation interventions will be covered by all insurance plans, but this will vary by state and be evidence-based. Electronic medical records, also a new requirement, will track smoking status. n Disclosure: Drs. Dressler and Herbst reported no potential conflicts of interest.

Reference 1. Toll BA, Brandon TH, Gritz ER, et al: Addressing tobacco use by cancer patients and facilitating cessation: An American Association for Cancer Research Policy Statement. Clin Cancer Res 19:1941-1948, 2013.

The ASCO Post | MAY 15, 2013

PAGE 42

American Association for Cancer Research Annual Meeting Novel Approaches to Genetic Testing and Overcoming Treatment Resistance Highlighted at AACR Meeting By Alice Goodman

elow are brief summaries of highlights from the very full, comprehensive collection of studies presented at the American Association of Cancer Research (AACR) Annual Meeting in Washington, DC. The abstracts describe a potential strategy to overcome resistance and genetic characterization of squamous cell carcinoma of the head and neck.

Intermittent Vemurafenib May Overcome Resistance Vemurafenib (Zelboraf ) is considered an advance in the treatment of melanoma, but most patients who respond to the drug develop resistance. Two separate experimental studies suggest that an intermittent dosing strategy has the

Darrin Stuart, PhD

potential to overcome resistance seen with standard continuous dosing.1 At an AACR press conference, the studies were discussed by Darrin Stuart, PhD, Senior Research Investigator at the Novartis

Institutes for Biomedical Research in Emeryville, California. Postdoctoral fellow and first author on the abstract, Meghna Das Thakur, PhD presented the entire body of work as part of the Clinical Trials of Targeted Agents in Solid Tumors Symposium held during the AACR meeting. Previous studies showed that xenografts of BRAF-expressing tumors in mice not only developed resistance to vemurafenib, but were actually dependent on vemurafenib for proliferation. Withdrawal of vemurafenib caused the tumors to stop growing and even regress in some cases. In a human study, Dr. Stuart and colleagues at the Royal Marsden Hospital in London evaluated 42 melanoma patients with vemurafenib-resistant tumors. In 14 of 19 cases in which post-relapse computed tomography scans were available, tumors demonstrated evidence of decreased tumor growth rate. Next, mice were implanted with BRAF(V600E)-expressing tumor xenografts and treated with vemurafenib 4 weeks on and 2 weeks off (intermittent strategy) or continuously. None of the tumors in the intermittent-dosage group developed resistance. Dr. Stuart said that these results suggest a drug holiday with intermittent dosing is a worthy strategy to pursue to overcome resistance to vemurafenib.

Research Highlights from the AACR Annual Meeting ■ Both human and murine data suggest that a drug holiday with intermittent dosing may overcome resistance to vemurafenib in patients with melanoma.

■ Analysis by The Cancer Genome Atlas researchers identified and

characterized four subtypes of squamous cell carcinoma of the head and neck: atypical, classical, mesenchymal, and basal.

More News From AACR in This Issue of The ASCO Post

Genetics of Squamous Cell Carcinoma of the Head and Neck Comprehensive genetic analysis by The Cancer Genome Atlas (TCGA) identified four different subtypes of squamous cell carcinoma of the head and neck.2 Significant mutations were found in the following genes: CDKN2A, TP53, PIK3CA, NOTCH1, HRAS, and NFE2L2. Some of the genetic patterns observed in this analysis overlapped with those seen in squamous cell non–small cell lung cancer and other squamous cell cancers, noted David N. Hayes, MD, MPH, Associate Professor at the University of North Carolina, Chapel Hill. Dr. Hayes said squamous cell carcinoma of the head and neck is the eighth tumor type to be analyzed by the TCGA project. Among the 279 patients with untreated squamous cell carcinoma of the head and neck included in the study, 80% were tobacco-related and 13% were human papillomavirus (HPV)-positive. Dr. Hayes and colleagues described four genetic subtypes of squamous cell carcinoma of the head and neck: 1. atypical subtype with no amplification of EGFR, HPV positive, and a high rate of PI3 kinase (PIK3CA) mutations 2. classical subtype, also seen in squamous cell lung cancer, associated with two key mutations: KEAP1 and NFE2L2 3. mesenchymal subtype, mostly mutations of FGR1 and FGR 4. basal subtype, highly associated with TP63 amplifications and overexpression The study also showed that HPVpositive and other patients have infrequent EGFR gene amplification, and that HPV-positive tumors have a

high rate of PIK3CA gene mutations. HPV-positive patients almost never have p53 alterations. In addition, some potentially actionable or druggable mutational targets for HPVnegative patients were identified, including EGFR, FGR, PIK3CA, HRAS, and CCND1.

David N. Hayes, MD, MPH

“This dataset confirms that there is a clear genetic difference between HPV-positive patients who usually have a better prognosis and are easier to treat than HPV-negative patients,” said Giuseppe Giaccone, MD, PhD, Associate Director for Clinical Research at Georgetown University Medical Center’s Lombardi Comprehensive Cancer Center, Washington, DC, and the Director of Clinical Research for the MedStar Health Cancer Network’s Washington Region. n

Disclosure: Drs. Stuart, Hayes, and Giaccone reported no potential conflicts of interest.

References 1. Thakur MD, Fisher R, Salangsong F, et al: Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. AACR Annual Meeting. Abstract LB-144. Presented April 8, 2013. 2. Hayes DN, Grandis J, El-Naggar AK, et al: Comprehensive genomic characterization of squamous cell carcinoma of the head and neck in the Cancer Genome Atlas. AACR Annual Meeting. Abstract 1117. Presented April 7, 2013.

Promising Phase II Results Continue to Support Ibrutinib in CLL see page 70 Genetically Engineered T Cells in Treating Childhood ALL see page 72 Combinatorial Immunologic Approach Yields Benefit in Recurrent Ovarian Cancer see page 123

ASCOPost.com | MAY 15, 2013

PAGE 43

American Association for Cancer Research Annual Meeting Breast Cancer

Factors Increasing Risk of Death from Breast Cancer Identified By Alice Goodman

everal studies presented at the Annual Meeting of the American Association for Cancer Research in Washington, DC, focused on factors associated with breast cancer mortality. One study found that older women with longer intervals between mammograms had a higher likelihood of dying of breast cancer. A second study had a somewhat surprising finding—that the BRCA1 mutation, but not BRCA2, was associated with a worse prognosis. A third study found that black women had the poorest prognosis regardless of breast cancer subtype.

Older Women and Mammogram Interval An analysis of data from 9,929 women diagnosed with breast cancer in the Women’s Health Initiative during a 12.2-year follow-up found a significant association between mammogram interval and breast cancer mortality, especially in elderly women.1 “We found that for all women with breast cancer, including those aged 75

Michael S. Simon, MD, MPH

and older, a longer interval between the last mammogram and the date of breast cancer diagnosis was associated with a greater chance of dying of breast cancer,” said lead author Michael S. Simon, MD, MPH, Barbara Ann Karmanos Breast Cancer Institute in Detroit. An interval of 5 years or more between the last mammogram and diagnosis of breast cancer was associated with advanced disease in 23%, compared with 20% of women with a shorter interval of 6 months to 1 year (P < .05). This This diff difference erence is statistically significant and could affect large numbers of women, Dr. Simon said. In an adjusted analysis, women with an interval of 5 years or more between mammogram and diagnosis

or who never had a mammogram had a 1.7 times greater risk of breast cancer death compared with women who had an interval of 6 months to 1 year between mammogram and diagnosis (P for trend � .0008). Women aged 75 or older at diagnosis with an interval of 5 years or more between mammogram and diagnosis or who never had a mammogram had a three times greater risk of breast cancer death compared with women who had the shorter interval (P for trend � .0001). This relationship was not seen among younger women. According to Dr. Simon, these findings suggest that regular mammography should be continued for older women every 1 or 2 years.

histochemical markers— with the goal of developing a predictive model, Dr. Schmidt said.

Black Women with Breast Cancer When data were stratified by subtype and adjusted for breast cancer stage and treatment, black women appeared to have worse survival across cancer subtypes compared with other racial and ethnic groups in a prospective cohort of 1,688 breast cancer survivors enrolled in the Life After Cancer Epidemiology and Pathways study.3

BRCA1 vs BRCA2 Mutations A large retrospective study of 5,518 women diagnosed with breast cancer before age 50 at any of 10 clinics in the Netherlands between 1970 and 2002 found a 1.5 times greater risk of 5-year recurrence in women who carried the BRCA1 mutation (2.6% of the population) compared with noncarriers and a 1.2 times greater risk of 15-year death compared with noncarriers.2 “These data are from one of the largest, least-biased BRCA1- and BRCA2-genotyped breast cancer cohorts,” said lead author Marjanka M. K. Schmidt, PhD, Netherlands Cancer Institute in Amsterdam. The proportion of estrogen receptor–positive tumors was similar between patients who were noncar-

Candyce Kroenke, MPH, ScD

“These data suggest that the difference in survival between black women and other racial/ethnic groups cannot be explained entirely by variable subtype diagnosis,” stated lead author Candyce Kroenke, MPH, ScD, Kaiser Permanente Division of Research in Oakland, California. At 6.3 years of follow-up, 499 deaths were reported. Of these, 268 were due to breast cancer. Black women were almost twice as likely to experience breast cancer–related death compared with white women. Black women were less likely to be diagnosed with either luminal A or luminal B subtypes than white women, but were more likely to be diagnosed triple-negative breast cancer, which is the most difficult-to-treat subtype, while luminal A is considered to have the best prognosis, she said.

Study findings included the following: • Black women with any subtype were more likely to die of breast cancer than white women diagnosed with the same subtype. • Black women with luminal A breast cancer were 2.3 times more likely to die than white women. • Black women with luminal B subtype were 2.6 times more likely to die than white women. • Black women with basal-like subtype were 1.3 times more likely to die than white women. • Among women with HER2-positive breast cancer, black women were 2.4 times more likely to die than white women. Dr. Kroenke said that other studies have shown that black women are more likely to die of breast cancer than white women, but the reasons for the mortality gap remain a mystery, since the excess mortality is seen across different subtypes of breast cancer. More research is needed to explore this issue, she said. n

Disclosure: Drs. Simon, Schmidt, and Kroenke reported no potential conflicts of interest.

References 1. Simon MS, Wasserstein-Smoller S, Thompson CA, et al: Mammography interval and breast cancer mortality in the Women’s Health Initiative. AACR Annual Meeting. Abstract 157. Presented April 7, 2013. 2. Schmidt MMK, van den Broek A, Tollenaar RAM, et al: Breast cancer survival of BRCA1/2 carriers compared to non-BRCA1/2 carriers in a large breast cancer cohort. AACR Annual Meeting. Abstract 1338. Presented April 8, 2013. 3. Kroenke C, Kwan M, Bernard P, et al: Race and breast cancer prognosis by PAM50 subtype in the LACE and Pathways studies. AACR Annual Meeting. Abstract 131. Presented April 7, 2013.

Marjanka M. K. Schmidt, PhD

riers and those with a BRCA2 mutation (86% and 81%, respectively), but only 29% of patients with a BRCA1 mutation had estrogen receptor–positive tumors. A more refined analysis of the data is now underway—to look at other tumor characteristics, including tumor grade, tumor type, and immun-

Risk Factors for Breast Cancer Mortality ■ Older women with longer intervals between mammography screening

and breast cancer diagnosis were at increased risk of breast cancer death.

■ The BRCA1 mutation was associated with a higher likelihood of death than nonmutated breast cancer while this association was not observed with the BRCA2 mutation.

■ No matter what type of breast cancer they had, black women were more likely to die of breast cancer compared with white women.

INDICATION: Iclusig™ (ponatinib) is a kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Introducing Iclusig™ (ponatinib) Unlock efficacy for resistant or intolerant CML and Ph+ ALL patients IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY See full prescribing information for complete boxed warning • Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. • Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity. Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, has occurred in Iclusig-treated patients. Overall, 11% of patients experienced an arterial thrombosis event of any grade, and serious arterial thrombosis occurred in 8% of Iclusigtreated patients. 30 of 34 patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors. Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. Hepatotoxicity: Hepatotoxicity that has resulted in liver failure and death occurred in 3 Iclusig-treated patients with BP-CML or Ph+ ALL. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver

function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated. Congestive Heart Failure: Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure (CHF) or left ventricular dysfunction (LVD), with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of CHF or LVD. Monitor patients for signs or symptoms consistent with CHF and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious CHF. Hypertension: Eight patients treated with Iclusig (2%) experienced treatmentemergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations. Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Hemorrhage: Serious bleeding events occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients.

C H R O N I C P H A S E C M L (C P - C M L )

More than half of CP-CML patients resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy achieved MCyR.

(144/267) 95% CI: 48-60

MCyR

% (118/267)

CCyR 95% CI: 38-50 Most patients who achieved MCyR also achieved CCyR.

Median duration of follow-up was 10 months.1

Response rates in CP-CML patients by number of prior TKIs.1

1 prior TKI

75%

MCyR

(12/16) (95% CI: 48-93)

Iclusig is an oral medication taken once daily with or without food.

2 prior TKIs

MCyR

(63/98) (95% CI: 54-74)

≥3 prior TKIs

45%

MCyR

(69/153) (95% CI: 37-53)

Learn more about Iclusig efficacy in the T315I mutation and in all phases of resistant or intolerant CML and Ph+ ALL at Iclusig.com.

Iclusig was evaluated in a single-arm, open-label, international, multicenter trial. All patients were administered 45 mg of Iclusig once daily. Patients were assigned to one of six cohorts based on disease phase (chronic phase CML [CP-CML]; accelerated phase CML [AP-CML]; or blast phase CML [BP-CML]/Ph+ ALL), resistance or intolerance (R/I) to prior TKI therapy, and the presence of the T315I mutation. The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR).

The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage. Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated. Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended. Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy. Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig. The most common non-hematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia. Please see the brief summary of the Prescribing Information on the following pages, including the Boxed Warning. Note: Unless otherwise indicated, data presented are from Iclusig [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2012. Reference: 1. Data on file.

BRIEF SUMMARY Iclusig (ponatinib) Rx only Please consult full Prescribing Information, including Boxed Warning, available at Iclusig.com.

WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY Arterial Thrombosis: • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

required urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Treatment-emergent hypertension occurred in 67% of patients (300/449) [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm Hg). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations. 5.5

Clinical pancreatitis occurred in 6% (28/449) of patients (5% grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). Twenty-two of the 28 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis [see Dosage and Administration (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Hepatotoxicity: • Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. 1

INDICATIONS AND USAGE

5.6

This indication is based upon response rate [see Clinical Studies (14)]. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig. CONTRAINDICATIONS

5.7

WARNINGS AND PRECAUTIONS

5.1

Thrombosis and Thromboembolism Arterial Thrombosis

In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%).

Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients.

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Serious arterial thrombosis occurred in 8% (34/449) of Iclusig-treated patients. Twenty-one patients required a revascularization procedure (16 patients with coronary revascularization, 4 patients with peripheral arterial revascularization, and 1 patient with cerebrovascular revascularization). Overall, fifty-one patients (11%) experienced an arterial thrombosis event of any grade.

5.8

Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. The other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).

Serious cerebrovascular events were reported in 2% (8/449) of Iclusig-treated patients. Two patients experienced hemorrhagic conversion of the initial ischemic event. Four patients developed stenosis of large arterial vessels of the brain (e.g., carotid, vertebral, middle cerebral artery). Serious peripheral arterial events were reported in 2% (7/449) of Iclusig-treated patients. Three patients developed digital or distal extremity necrosis; 2 of these patients had diabetes mellitus and peripheral arterial disease and required amputations. Thirty of 34 Iclusig-treated patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors (e.g., myocardial infarction, coronary artery disease, angina, stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipidemia, and smoking). Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3)].

5.9

5.10 Tumor Lysis Syndrome Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. Both cases occurred in patients with advanced CML. Hyperuricemia occurred in 7% (30/449) of patients, the majority had chronic phase CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig. 5.11 Compromised Wound Healing and Gastrointestinal Perforation No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Hepatotoxicity Hepatotoxicity that has resulted in liver failure and death occurred in Iclusig-treated patients. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts. The incidence of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation was 56% (all grades) and 8% (grade 3 or 4). Iclusig treatment may result in elevation in ALT, AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.

Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing. 5.12 Embryo-Fetal Toxicity Iclusig can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Ponatinib caused embryo-fetal toxicity in rats at exposures lower than human exposures at the recommended human dose. 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. Advise women to avoid pregnancy while taking Iclusig [see Use in Specific Populations (8.1)].

Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)]. 5.3

Congestive Heart Failure Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure or left ventricular dysfunction, with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of congestive heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with congestive heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious congestive heart failure [see Dosage and Administration (2.3)].

5.4

Hypertension Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. These patients

M yelosuppression Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with accelerated phase CML (AP-CML), blast phase CML (BP-CML) and Ph+ ALL than in patients with chronic phase CML (CP-CML). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended [see Dosage and Administration (2.2)].

Venous Thromboembolism Venous thromboembolic events occurred in 3% of Iclusig-treated patients, including deep venous thrombosis (9 patients), pulmonary embolism (4 patients), and 1 case each of portal vein thrombosis, and retinal vein thrombosis. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].

C ardiac Arrhythmias Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. The cardiac rhythms (1 case each) identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain).

Myocardial infarction or worsening coronary artery disease was the most common arterial thrombosis event and occurred in 21 patients (5%) of Iclusig-treated patients. Eleven of these patients developed congestive heart failure concurrent or subsequent to the myocardial ischemic event.

5.2

Fluid Retention Fluid retention events judged as serious occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. Serious fluid retention events in more than 1 patient included: pericardial effusion (6/449, 1%), pleural effusion (5/449, 1%), and ascites (2/449, <1%).

None 5

Hemorrhage Serious bleeding events, occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.9)]. Interrupt Iclusig for serious or severe hemorrhage [see Dosage and Administration (2.3)].

Iclusig™ (ponatinib) is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

P ancreatitis

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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The following adverse reactions are discussed in greater detail in other sections of the prescribing information: • Thrombosis and Thromboembolism [see Warnings and Precautions (5.1)] • Hepatotoxicity [see Warnings and Precautions (5.2) and Dosage and Administration (2.3)] • Congestive Heart Failure [see Warnings and Precautions (5.3)]

• Hypertension [see Warnings and Precautions (5.4)] • Pancreatitis [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)] • Hemorrhage [see Warnings and Precautions (5.6)] • Fluid Retention [see Warnings and Precautions (5.7)] • Cardiac Arrhythmias [see Warnings and Precautions (5.8)] • Myelosuppression [see Dosage and Administration (2.2) and Warnings and Precautions (5.9)] The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily. At the time of analysis, the median duration of treatment with Iclusig was 337 days in patients with CP-CML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg, or 83%, of the expected 45 mg dose. Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 4. Overall, the most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. The rates of treatment-emergent adverse events resulting in discontinuation were 13% in CPCML, 11% in AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse events that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%). Dose modifications (dose delays or dose reduction) due to adverse reactions occurred in 74% of the patients. The most common adverse reactions (≥5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and ALT, AST, or GGT increased (6%). Table 4: Adverse Reactions Occurring in >10% of Patients, Any Group CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) System Organ Class Any CTCAE Any CTCAE Any CTCAE Any CTCAE Grade Grade Grade Grade Grade Grade Grade Grade (%) 3/4 (%) 3/4 (%) 3/4 (%) 3/4 (%) (%) (%) (%) Cardiac or Vascular disorders Hypertension (a) 68 39 71 36 65 26 53 31 Arterial ischemia (b) 13 7 12 6 8 5 3 0 Cardiac Failure (c) 6 4 6 2 15 11 6 6 Gastrointestinal disorders Abdominal pain (d) 49 10 40 8 34 6 44 6 Constipation 37 2 24 2 26 0 47 3 Nausea 23 1 27 0 32 2 22 0 Diarrhea 16 1 26 0 18 3 13 3 Vomiting 13 2 24 0 23 2 22 0 Oral mucositis (e) 10 1 15 1 23 0 9 3 GI hemorrhage (f) 2 <1 8 1 11 5 9 6 Blood and lymphatic system disorders Febrile neutropenia 1 <1 4 4 11 11 25 25 Infections and infestations Sepsis 1 1 5 5 8 8 22 22 Pneumonia 3 2 11 9 13 11 9 3 Urinary tract infection 7 1 12 1 0 0 9 0 Upper respiratory tract infection 11 1 8 0 11 2 0 0 Nasopharyngitis 9 0 12 0 3 0 3 0 Cellulitis 2 1 4 2 11 3 0 0 Nervous system disorders Headache 39 3 28 0 31 3 25 0 Peripheral neuropathy (g) 13 2 8 0 8 0 6 0 Dizziness 11 0 5 0 5 0 3 0 Respiratory, thoracic, and mediastinal disorders Pleural effusion 3 1 11 2 13 0 19 3 Cough 12 0 17 0 18 0 6 0 Dyspnea 11 2 15 2 21 7 6 0 Skin and subcutaneous tissue disorders Rash and related conditions 54 5 48 8 39 5 34 6 Dry skin 39 2 27 1 24 2 25 0 Musculoskeletal and connective tissue disorders Arthralgia 26 2 31 1 19 0 13 0 Myalgia 22 1 20 0 16 0 6 0 Pain in extremity 17 2 17 0 13 0 9 0 Back pain 15 1 11 2 16 2 13 0 Muscle spasms 12 0 5 0 5 0 13 0 Bone pain 12 <1 12 1 11 3 9 3 General disorders and administration site conditions Fatigue or asthenia 39 3 36 6 35 5 31 3 Pyrexia 23 1 31 5 32 3 25 0 Edema, peripheral 13 <1 19 0 13 0 22 0 Pain 8 <1 7 0 16 3 6 3 Chills 7 0 11 0 13 2 9 0 Metabolism and nutrition disorders Decreased appetite 8 <1 12 1 8 0 31 0 Investigations Weight decreased 6 <1 7 0 5 0 13 0 Psychiatric disorders 0 12 0 8 0 9 0 Insomnia 7

Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology Criteria for Adverse Events) for assessment of toxicity. Treatment-emergent, all causality events (a) derived from blood pressure (BP) measurement recorded monthly while on trial (b) includes cardiac, central nervous system, and peripheral arterial ischemia (c) includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure (d) includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort (e) includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration (f) includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage (g) includes burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, polyneuropathy

Table 5: Serious Adverse Reactions (SAR) Cardiovascular disorders Arterial ischemic event Myocardial infarction or worsening coronary artery disease Stroke or TIA Peripheral arterial disease Hemorrhage CNS hemorrhage Gastrointestinal hemorrhage Cardiac failure Effusions* Atrial fibrillation Venous thromboembolism Hypertension Gastrointestinal disorders Pancreatitis Abdominal pain Blood and lymphatic system disorders Febrile neutropenia Thrombocytopenia Anemia Infections Pneumonia Sepsis General Pyrexia

N (%) 34 (8%) 21 (5%) 8 (2%) 7 (2%) 22 (4%) 10 (2%) 10 (2%) 20 (4%) 13 (3%) 11 (2%) 10 (2%) 8 (2%) 23 (5%) 17 (4%) 13 (3%) 13 (3%) 12 (2%) 24 (4%) 11 (2%) 14 (3%)

*includes pericardial effusion, pleural effusion, and ascites

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 6). Table 6: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities Laboratory Test CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) (%) (%) (%) (%) Hematology Thrombocytopenia 36 47 57 47 (platelet count decreased) Neutropenia (ANC decreased) 24 51 55 63 Leukopenia (WBC decreased) 14 35 53 63 Anemia (Hgb decreased) 9 26 55 34 Lymphopenia 10 26 37 22 ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count *Reported using NCI-CTC-AE v 4.0

Table 7: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Laboratory Test Safety Population N=449 Any Grade* Grade 3/4 (%) (%) Liver function tests ALT increased 53 8 AST increased 41 4 Alkaline phosphatase increased 37 2 Albumin decreased 28 1 Bilirubin increased 19 1 Pancreatic enzymes Lipase increased 41 15 Amylase increased 3 <1 Chemistry Glucose increased 58 6 Phosphorus decreased 57 8 Calcium decreased 52 1 Sodium decreased 29 5 Glucose decreased 24 0 Potassium decreased 16 2 Potassium increased 15 2 Sodium increased 10 <1 Bicarbonate decreased 11 <1 Creatinine increased 7 <1 Calcium increased 5 0 Triglycerides increased 3 <1 ALT=alanine aminotransferase, AST=aspartate aminotransferase. *Graded using NCI-CTC-AE v 4.0

DRUG INTERACTIONS Based on in vitro studies ponatinib is a substrate of CYP3A4/5 and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)].

7.1

Drugs That Are Strong Inhibitors of CYP3A Enzymes In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 mg once daily [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

7.2

Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of Iclusig with strong CYP3A inducers was not evaluated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)]. Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.3

Drugs That Elevate Gastric pH Coadministration of Iclusig with drugs that elevate the gastric pH was not evaluated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.4

Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 [also known as BCRP] (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

USE IN SPECIFIC POPULATIONS

8.1

regnancy P Pregnancy Category D Risk Summary Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Iclusig in pregnant women. Advise women to avoid becoming pregnant while taking Iclusig. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis. At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

8.3

Nursing Mothers It is unknown whether ponatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother.

8.4

Pediatric Use The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

8.5

Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Patients of age ≥ 65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6

Hepatic Impairment Iclusig has not been studied in patients with hepatic impairment. As hepatic elimination is a major route of excretion for Iclusig, hepatic impairment may result in increased ponatinib exposure. Avoid Iclusig in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure [see Clinical Pharmacology (12.3)]. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

8.7

Renal Impairment Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

OVERDOSAGE Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally self-administered 165 mg on cycle 1 day 2. The patient experienced fatigue and non-cardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion. In the event of an overdose of Iclusig, stop Iclusig, observe the patient and provide appropriate supportive treatment. Manufactured for: ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street Cambridge, MA 02139-4234 For information contact: 1-855-55-ARIAD (855-552-7423) medinfo@ariad.com PB/0213/0103/US

ASCOPost.com | MAY 15, 2013

PAGE 49

Journal Spotlight Breast Cancer

Risk for Ischemic Heart Disease after Radiotherapy for Breast Cancer By Matthew Stenger

population-based case-control study reported by Sarah C. Darby, PhD, Professor of Medical Statistics in the Clinical Trial Service Unit and Epidemiologic Studies Unit at the

Sarah C. Darby, PhD

University of Oxford, and colleagues in The New England Journal of Medicine indicates that incidental exposure of the heart to radiation in breast cancer treatment is associated with increased risk of ischemic heart disease.1 The investigators found that the risk of major coronary events increased linearly with radiation dose to the heart, with increased risk starting within 5 years after radiotherapy, and that women with preexisting cardiac risk factors have a greater absolute risk than other women. The study involved 2,168 women who underwent radiotherapy for breast cancer between 1958 and 2001 and who were younger than 70 years at the time of breast cancer diagnosis in Sweden or between 1977 and 2000 and who were younger than 75 years at diagnosis in Denmark. The analysis included a total of 963 women with major coronary events, defined as myocardial infarction, coronary revascularization, or death from ischemic heart disease, and 1,205 controls matched for country, age at diagnosis, and year of diagnosis who had no major coronary event prior to an index date defined as the date of breast cancer diagnosis plus time to first major event in the matched case patient. Mean radiation doses to the whole heart and left anterior descending coronary artery were estimated from radiotherapy charts.

Risks for Major Coronary Events Overall, women irradiated for cancer of the left breast had higher major coronary event rates than women with irradiation to the right breast (rate ratio [RR] � 1.32, P � .002). There were no other strong associations between

major coronary events and tumor characteristics or cancer treatments administered in addition to radiotherapy, apart from a borderline significant association with positive nodal status (RR � 1.20, P � .06). The rate ratio for major coronary events among women with a history of ischemic heart disease was 6.67 compared with the rate in women without such history (overall P < .001). .001). Elevated rates of major coronary events were also associated with a history of other circulatory diseases, diabetes, chronic obstructive pulmonary disease, smoking, high body mass index, and history of regular analgesic use. The rate ratio for major coronary events when one or more of these factors was present in the

absence of history of ischemic heart disease was 1.96.

Effects of Radiotherapy The average of the estimated mean doses of radiation to the heart was 6.6 Gy in women with tumors in the left breast, 2.9 Gy in those with tumors in the right breast, and 4.9 Gy overall. The rate of major coronary events increased by 7.4% for each increase of 1 Gy Gy delivered to the heart (P < .001). Compared with the estimated major coronary event rate for no radiation dose to the heart, major coronary event rates increased by 10% for doses < 2 Gy, 30% for doses of 2 to 4 Gy, Gy, 40% for doses of 5 to 9 Gy, and 116% for doses of 10 Gy or more. The percentage increase

per Gy did not differ according to any of the matching factors used in selection of control patients, tumor characteristics (including whether the tumor was in the right or left breast), or cancer treatment in addition to radiotherapy. Although the overall major coronary event rate was higher in women with vs without cardiac risk factors, the percentage increase in rate per Gy was similar for both groups. The percentage increases in major coronary event rate per Gy according to number of years since radiation exposure were 16.3% for 0 to 4 years, 15.5% continued on page 50

Critical Information on Radiation’s Heart Effects By Lori Pierce, MD

he paper by Darby et al provides extremely important information on quantitative estimates of the effect of radiotherapy on coronary events in women with breast cancer.1 The authors have determined a direct relationship between radiation dose and effects on the heart and provide strong evidence that major coronary

Lori Pierce, MD

events increase by approximately 7% for every increase of 1 Gy in the mean heart dose. And although this rate was similar in women with and without cardiac risk factors, as expected, the overall rate was greater in women with preexisting cardiac risk factors. Surprisingly, the increase in events was evident within the first 5 years after radiotherapy, earlier than previous reports have suggested. Dr. Pierce is Professor of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor.

These data further stress the importance of the use of radiotherapy techniques that exclude the heart from the radiation field. Individualized treatment planning techniques that are computed tomography (CT)based are critical when determining the optimal field arrangement. When necessary, planning and treatment modifications such as use of respiratory gating or active breathing control should be incorporated to displace the heart from the treatment field and/or heart blocks inserted to exclude the heart from the radiation beam. This paper also emphasizes the importance of treating other cardiac risk factors to minimize additive risk.

Important Limitation However, the study has an important limitation that needs to be considered when interpreting its findings. Due to the years of treatment, almost all patients were treated in a pre–CTbased treatment-planning era. Therefore, information from the radiation plans was used to reconstruct treatment fields using a CT scan from a single woman of typical anatomy. Body habitus is highly variable, and perfect alignment between the dose delivered and estimated dose is not possible based on planning using a single case. This limitation is most critical when estimating dose in the low-

dose/scatter region. It is not clear that we know, based on these data, that the linear relationship demonstrated at higher doses does in fact extend to the low-dose region. Such an analysis would be possible only with planning and outcome data from patients treated using CT-based individualized plans. To that end, studies are needed to correlate factors such as mean heart dose and other cardiac metrics with cardiac outcomes in patients treated with three-dimensional plans if we are to fully understand the complex dose/ volume relationships.

Reassuring Patients In the meantime, patients should be informed of the potential for increased cardiac risks following radiotherapy but be reassured that all efforts are being taken to protect the heart from the effects of radiation. Furthermore, oncologists—radiation oncologists or otherwise—should increasingly work with internists and primary care physicians to maximize overall cardiac health for our patients. n

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

Reference 1. Darby SC, Ewertz M, McGale P, et al: Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 368:987-998, 2013.

The ASCO Post | MAY 15, 2013

PAGE 50

Journal Spotlight

Radiotherapy and Heart Disease continued from page 49

for 5 to 9 years, 1.2% for 10 to 19 years, and 8.2% for 20 or more years. Findings were similar when this analysis was repeated separately according to age at time of breast cancer diagnosis, presence or absence of preexisting cardiac risk factors, and whether the case patient had died from ischemic heart disease. The estimated mean dose of radiation to the heart was a better predictor of major coronary events (P < .001) than the estimated mean dose to the left anterior descending coronary ar-

tery (P � .001). The estimated mean dose to the heart remained a significant predictor (P � .04) after after adjustment for the estimated mean dose to the left anterior descending coronary artery. The mean dose to the left anterior descending coronary artery was no longer a significant predictor (P � .62) after adjustment for the estimated mean dose to the heart.

Study Limitations Limitations of the study include the fact that computed tomography (CT)-based information on radiotherapy was not available for the women studied, since they were

Radiotherapy and Coronary Events ■ The heart usually receives some incidental radiation exposure during

radiotherapy for breast cancer but, until now, the likely extent of any risk has been unclear.

■ This research suggests that the rate of major coronary events increases by 7.4% per Gy to the heart.

■ This suggests that the risk will be low for most women being irradiated today, and doctors can use this estimate to reassure their patients.

■ The few women for whom radiotherapy poses undue risk—either because it would involve a substantial cardiac dose, or because the woman is already at increased risk of heart disease—can now be identified, and the various options considered.

treated prior to the era of three-dimensional CT-based planning. Fur-

Left-sided Adjuvant Breast Radiotherapy: A Change of Heart? By Andrew D. Seidman, MD

arby and colleagues are to be congratulated for an ambitious population-based case-control study that demonstrates the impact of postoperative adjuvant ionizing radiation for early-stage breast cancer on ischemic heart disease.1 The study examined roughly 1,000 cases and 1,000 controls in Sweden and Denmark from 1958 to 2001.

Sensitive Metrics In a recent report by Chung, Pierce, and colleagues from the University of Michigan Department of Radiation Oncology, serial adenosine stress myocardial perfusion single-

Data in Context Their work must be taken in the context of more recent cohorts that have been treated with improved planning techniques that reduce the volume of cardiac tissue exposed and dose delivered to the heart.2,3 Patt and colleagues reported no significant differences in cardiac morbidity for right- vs left-sided radiotherapy in a larger and more contemporary series of approximately 16,000 patients.2 In a study by Giordano and colleagues (N � 27,000), death from ischemic heart disease was greater in patients with leftsided tumors who were diagnosed in the earliest time period (1973– 1979) as opposed to later time periods.3 Consistent with the notion that time and technique matter, the highest proportional increase in major cardiac events observed in the Darby et al study indeed occurred in the 1970s, although the subset analyses are underpowered to show statistical significance. Dr. Seidman is a medical oncologist at Memorial Sloan-Kettering Cancer Center, New York.

Andrew D. Seidman, MD

photon emission computed tomography (SPECT-CT) scans were employed to assess perfusion defects, ejection fraction, and wall motion abnormalities before and 1 year after left-sided adjuvant radiation.4 The use of three-dimensional conformal radiation therapy or intensity-modulated radiation therapy resulted in low heart doses, with only 3 of 32 patients receiving a mean heart dose greater than 5 Gy (mean dose to heart � 2.82 Gy, range � 1.11–6.06 Gy). Despite the fact that 30 of the 32 subjects received adjuvant anthracycline, there were no significant differences in these very sensitive metrics of cardiac function before vs after radiotherapy. Similarly, in a more contemporary series (N � 1,500), there was no difference in cardiac events among women receiving both an anthracycline and trastuzumab (Herceptin) in NCCTG N9831 as a function of lat-

erality of adjuvant radiotherapy.5

Minimizing Risk Few would argue with the notion that baseline risk factors influence the risk of radiotherapy-related cardiotoxicity. Nevertheless, with longer followup on the more recent large studies, even in the context of potentially cardiotoxic systemic therapies such as anthracyclines and trastuzumab, there is reason to be optimistic that modern and meticulous radiation planning will minimize, though not likely eliminate, what has historically been a significant risk. n

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

References 1. Darby SC, Ewertz M, McGale P, et al: Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 368:987-998, 2013. 2. Patt DA, Goodwin JS, Yong-Fang K, et al: Cardiac morbidity of adjuvant radiotherapy for breast cancer. J Clin Oncol 23:7475-7482, 2005. 3. Giordano SH, Kuo YF, Freeman JL, et al: Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97:419-424, 2005. 4. Chung E, Corbett JR, Moran JM, et al: Is there a dose-response relationship for heart disease with low-dose radiation therapy? Int J Rad Oncol Biol Phys 85:959-964, 2012. 5. Halyard MY, Pisansky TM, Dueck AC, et al: Radiotherapy and adjuvant trastuzumab in operable breast cancer: Tolerability and adverse event data from the NCCTG phase III trial N9831. J Clin Oncol 27:2638-2644, 2009.

ther, the study included few women younger than 40 years at the time of radiotherapy; as noted by the authors, “[C]aution is needed in applying our results to women in this age group, and the possibility of larger increases in the rate of major coronary events per gray of radiation for this group cannot be ruled out.” In addition, few women in the study were treated with anthracyclines and none received taxanes or trastuzumab (Herceptin). All of these drugs are known to have adverse effects on the heart even in the absence of radiotherapy. The authors concluded:

[W]e found that incidental exposure of the heart to radiotherapy for breast cancer increased the rate of major coronary events by 7.4% per gray, with no apparent threshold. The percentage increase per unit increase in the mean dose of radiation to the heart was similar for women with and women without preexisting cardiac risk factors, which indicates that the absolute increases in risk for a given dose to the heart were larger for women with preexisting cardiac risk factors. Therefore, clinicians may wish to consider cardiac dose and cardiac risk factors as well as tumor control when making decisions about the use of radiotherapy for breast cancer. n

Disclosure: The study was supported by funding or grants from Cancer Research UK, British Heart Foundation, UK Medical Research Council, European Commission, UK Department of Health, and Oxford National Institute for Health Research Biomedical Research Centre.

Reference 1. Darby SC, Ewertz M, McGale P, et al: Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 368:987-998, 2013. See page 52 in this issue of The ASCO Post for additional expert perspective from Benjamin D. Smith, MD, of MD Anderson Cancer Center, on reducing incidental cardiac irradiation during breast radiotherapy.

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Perspective

Reducing Incidental Cardiac Irradiation during Breast Radiotherapy By Benjamin D. Smith, MD

n the treatment of breast cancer, a wealth of data from prospective clinical trials and meta-analyses has documented the benefits of radiation to prevent local-regional recurrence and improve survival. Accordingly, important quality indicators in breast cancer care include: (1) receipt of radiation to the breast after breast-conserving therapy for women under the age of 70 with invasive breast cancer, and (2) receipt of radiation to the chest wall and nodal basins after mastectomy for women with stage III breast cancer.

Dramatic Changes in Radiation Oncology Despite the well-documented benefits of radiation, the heart is often an innocent bystander in the path of the radiation beam, resulting in incidental but potentially clinically relevant cardiac irradiation. It has long been known that incidental radiation to the heart has the potential to produce a host of cardiac complications, including ischemic heart disease, heart failure, pericarditis, valvular disease, conduction disease, and cardiac death. The work presented by Darby et al1 could easily be interpreted as providing yet another datapoint in this litany of radiation therapy perils, stoking fears among patients and provoking a defensive posture from radiation oncologists. (See pages 49 and 50 in this issue for a summary of this work and additional expert perspective from the oncology community). Yet, radiation oncology has undoubtedly changed dramatically since the time that patients in the study by Darby et al were treated. In the past decade, the defining advance has been the transition from two-dimensional treatment planning to three-dimensional treatment planning. With twodimensional treatment planning, radiation fields were designed using simple two-dimensional radiographs, which allowed for only a simplistic understanding of the anatomic structures in the path of the radiation beam. For example, with two-dimensional radiographs, it could be determined whether a portion of the cardiac silDr. Smith is Assistant Professor of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Fig. 1: Example of a radiation treatment plan to treat the whole breast in a woman with ductal carcinoma in situ. The prescription dose is 50 Gy in 25 fractions. The colored lines depict the radiation dose received and can be interpreted similarly to a topographic map. All tissue inside the red line receives a dose of at least 50 Gy. All tissue inside the purple line receives a dose of at least 45 Gy. The other doses and their associated colors are as follows: green, 25 Gy; orange, 5 Gy; yellow, 2 Gy; and aquamarine, 1 Gy. Panel A depicts the radiation treatment plan in free breathing, with a mean heart dose of 1.8 Gy. Panel B depicts the radiation treatment plan using deep inspiration breath hold, with a mean heart dose of 0.8 Gy.

Fig. 2: Example of a radiation treatment plan to treat the chest wall and nodal basins (including internal mammary nodes) in a patient with stage III breast cancer. The prescription dose is 50 Gy in 25 fractions. The colored lines depict the radiation dose received and can be interpreted similarly to a topographic map. All tissue inside the red line receives a dose of at least 50 Gy. All tissue inside the purple line receives a dose of at least 45 Gy. The other doses and their associated colors are as follows: green, 25 Gy; orange, 5 Gy; yellow, 2 Gy; and aquamarine, 1 Gy. Panel A depicts the radiation treatment plan in free breathing, with a mean heart dose of 2.8 Gy. Panel B depicts the radiation treatment plan using deep inspiration breath hold, with a mean heart dose of 1.3 Gy.

houette was included in the radiation beam, but the precise proportion of heart irradiated and the dose received by this portion of the heart could not be calculated with certainty. In contrast, with three-dimensional treatment planning, which is now standard in most practices, radiation fields are designed using computed tomography (CT) images. As a result, the complex relationship between dose delivered and volume irradiated for any critical structure can be measured and potentially modified. The mean radiation dose delivered to the heart and the percent of the heart receiving a certain dose can be readily determined. Similar metrics can also be determined for

specific cardiac structures, such as the left-anterior descending coronary artery, pericardium, and valves.

Conflicting Data Despite the impressive descriptive cardiac dose-volume data now readily available, the clinical significance of these metrics has been unclear to date. Further, prior observational epidemiologic data regarding the significance of incidental heart radiation is conflicting. For example, Giordano et al2 concluded that breast radiation delivered in the 1970s yielded an increased risk of cardiac death, but that breast radiation delivered in the 1980s and 1990s did not. Since relatively simple two-

dimensional radiation techniques were still the norm in the 1980s and 1990s, the implication of these findings was that cardiac dose-volume metrics acquired from three-dimensional planning were unlikely to be relevant, since risks were already low with simple two-dimensional treatment planning. However, a study from Darby et al published in 2005,3 using the same population-based data source, reached a different conclusion, finding that leftsided breast radiation was associated with a late increase in cardiac death attributable to radiation. The implication of this study was that cardiac dose must be minimized. It is in the setting of these two conflicting narratives on the relationship

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Perspective

between breast radiation and cardiac risk that the current study from Darby et al provides novel, clinically relevant, and important data to assist radiation oncologists and their patients.1 Specifically, the finding that risk of cardiac events increased linearly with mean cardiac dose, without a threshold, strongly supports the assertion that incidental cardiac radiation during breast cancer treatment must be minimized.

Minimizing Cardiac Irradiation Accompanying dissemination of three-dimensional treatment planning for breast cancer, several techniques have emerged to minimize incidental cardiac radiation. For example, a cardiac block can be used to block out the portion of the radiation beam that would have intersected with the heart. This approach works well for upper-quadrant tumors but runs the risk of creating a geographic miss in patients with lower-quadrant tumors. Another technique is intensity-modulated radiation therapy, which uses sophisticated treatment planning algorithms and multiple radiation beams to bend the radiation dose around the heart. While this approach can be particularly helpful in minimizing high doses of radiation delivered to the heart, the amount of low-dose radiation given to the thorax, including the heart, lung, and contralateral breast, is often increased, with uncertain clinical ramifications. A third approach is the use of deep inspiration breath hold, in which delivery of radiation is synchronized with the patient’s breathing cycle. During deep inspiration, the lingula inflates, displacing the heart inferiorly and posteriorly, outside of the path of the radiation beam. At The University of Texas MD Anderson Cancer Center, we routinely use deep inspiration breath hold to minimize cardiac exposure in patients receiving radiation for left-sided breast cancer.

Deep Inspiration Breath Hold Figs. 1 and 2 depict examples of patients recently treated at our institution in the breast-conserving and postmastectomy settings,

respectively. Panels 1A and 2A demonstrate cardiac exposure that would have resulted from treatment in free breathing. It can be observed that a portion of the heart is irradiated in each of these treatment plans. Nevertheless, the mean heart dose is rela-

tively low, at 1.8 Gy for Fig. 1A and 2.8 Gy for Fig. 2A. In comparison, the mean heart dose was 6.6 Gy for women with left-sided breast cancers included in the Darby et al study.1 B:7.875 in The significantly lower mean T:7.625 in heart doses achievable in our prac-

tice even without advanced technologies such as deep inspiration breath hold illustrates that with careful three-dimensional radiation treatment planning alone, mean heart dose, and accordingly cardiac continued on page 54

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EACH PLAYS AN IMPORTANT ROLE 1-3 Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Schulze H, Senge T. Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. J Urol. 1990;144(4):934-941. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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Perspective

Radiotherapy and Heart Disease continued from page 53

risk, may be considerably lower than that reported by Darby et al. This fact provides reassurance to patients and their physicians that the cardiac risks reported by Darby et al do not necessarily have to be recapitulated in currently treated patients provided that care is taken in designing radiation treatment plans. Figs. 1B and 2B on page 52 illustrate the added benefit derived from implementing deep inspiration breath hold. As can be readily observed, displacement of the heart with deep inspiration breath hold helps to minimize incidental cardiac irradiation. Accordingly, mean cardiac doses with deep inspiration breath hold were 0.8 Gy in Fig. 1B and 1.3 Gy in Fig. 2B. It is important to note that there are no data from prospective randomized trials indicating a clinically measurable benefit from implementation of deep inspiration breath hold in clinical practice. However, if the model presented by Darby et al is accurate, one could infer that deep inspiration breath hold served to reduce the cardiac event risk by 7% for patient 1 and

11% for patient 2. When considering that over 100,000 women receive radiation for breast cancer yearly in the United States, this small incremental individual benefit from deep inspiration breath hold would be likely to exert a significant population-wide benefit if uniformly adopted.

sequently to synchronize delivery of radiation to the respiratory cycle. Second, implementation of deep inspiration breath hold requires increased expertise on the part of radiation therapists and physicists, which may not be readily available. Third, deep inspiration breath

The finding that risk of cardiac events increased linearly with mean cardiac dose, without a threshold, strongly supports the assertion that incidental cardiac radiation during breast cancer treatment must be minimized. —Benjamin D. Smith, MD

Barriers to Implementation Despite the benefits of deep inspiration breath hold, it is not necessarily commonly used in routine community practice across the United States. There are several reasons for this. First, implementation of deep inspiration breath hold typically requires a capital investment to acquire the necessary technology to obtain a gated simulation CT scan and sub-

hold increases daily treatment time per patient by approximately 33%, and thus may not be feasible in centers already operating at capacity. Fourth, deep inspiration breath hold is not currently recognized by any Common Procedural Terminology (CPT) code, and thus, the additional staff effort and machine time may not be economically feasible for many practices.

In Summary The findings from Darby et al go beyond simply adding to the literature regarding late cardiovascular effects of radiation. The study provides the scientific rationale to support ongoing efforts to develop and disseminate technologies that will reduce incidental cardiac irradiation. These efforts should ultimately improve the therapeutic ratio of radiation treatment, thus easing our patients’ fears and illustrating the gains that can be realized through implementation of advanced radiation oncology technologies. n Disclosure: Dr. Smith receives research funding from Varian Medical Systems and is the recipient of an ASCO Career Development Award.

References 1. Darby SC, Ewertz M, McGale P, et al: Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 368:987-998, 2013. 2. Giordano SH, Kuo YF, Freeman JL, et al: Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97:419-424, 2005. 3. Darby SC, McGale P, Taylor CW, et al: Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: Prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 6:557-565, 2005.

University of Michigan Launches New Cardio-oncology Program

he University of Michigan Samuel and Jean Frankel Cardiovascular Center, working with specialists at the University of Michigan (U-M) Comprehensive Cancer Center, has launched Michigan’s first cardio-oncology clinic, a program designed to prevent or minimize heart damage caused by chemotherapy and radiation. Preventing heart disease in cancer patients is gaining more importance as aggressive cancer therapies are used on older patients who may already have heart disease, and researchers identify a growing number of cardiovascular side effects of anti-cancer therapy.

Eliminating Cardiovascular Complications a Key Goal “The goal of the collaboration between cardiologists and oncologists is to eliminate cardiovascular complications as a barrier to effective treatment of cancer patients, by providing prevention and early detection of cardiac

Elina Yamada, MD

complications, cardiovascular monitoring during anticancer therapy, and therapy of cardiovascular disease that develops during chemotherapy,” says University of Michigan cardiologist Elina Yamada, MD. Physicians will use strain imaging with echocardiograms to help detect heart damage in its earliest stages before heart function deteriorates. Radiation to the chest, especially among patients with left-sided breast cancer, leukemia and chest tumors, can lead to inflammation of the heart’s

protective sac, the pericardium, or narrowing and stiffening of heart valves. Current radiation techniques spare the heart much more than earlier treatment approaches, but research is underway at the U-M Comprehensive Cancer Center to further reduce radiation exposure to the heart. Radiation is one of several issues to consider, but cardiotoxicity is also a concern. “The diagnosis of cardiac problems during cancer treatment can be difficult based on symptoms alone, as some of them, such as fatigue, shortness of breath, and swelling, can be caused by the adverse effects of chemotherapy. Therefore, when patients present with these symptoms, it is important to have cardiac evaluation,” says Dr. Yamada. Heart problems linked to cancer treatment include heart failure, chemotherapy-induced hypertension, arrhythmias, thromboembolism (blood clots) or cardiac ischemia, a sudden se-

Monika Leja, MD

vere blockage of a coronary artery that can lead to a heart attack. About one-third of cancer patients who receive cancer drugs such as trastuzumab (Herceptin) and anthracyclines will develop cardiotoxicity. A small percentage of these patients will have to stop therapy because of side effects. “Our goal will be early detection and to protect patients with heart medications,” says Monika Leja, MD, a cardiologist at the University of Michigan. n

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News

Breast Cancer Survivors Not Likely to Maintain Physical Activity Sufficient for Benefits of Exercise

ew breast cancer survivors meet national exercise recommendations during the 10 years after being diagnosed, even though they are among the women who could most benefit from regular physical activity, according to a study by researchers at Fred Hutchinson Cancer Research Center. Prior studies and available evidence show a strong association between physical activity and reduced mortality, extended survival, and higher quality of life among breast cancer survivors.

The predictors of physical activity in this population remain poorly understood, according to the authors. n Disclosure: Funding for the study was

provided by grants from the National Institutes of Health. Coauthors included researchers from the National Cancer Institute, City of Hope National Medical Center, University of Louisville and the University of Washington.

Reference 1. Mason C, et al: Cancer Epidemiol Biomarkers Prev. April 10, 2013 (early release online).

Study Details The current study, published online ahead of print in the journal Cancer Epidemiology, Biomarkers and Prevention, followed an ethnically diverse group of 631 breast cancer survivors ages 18 to 64 from New Mexico, Los Angeles County, and western Washington for 10 years.1 Recreational aerobic activity was ascertained for each woman via interviews and questionnaires the year before diagnosis and again 2, 5, and 10 years after enrollment into the study. U.S. physical activity guidelines call for at least 150 minutes per week of moderate exercise or at least 75 minutes per week of vigorous activity. Prior to diagnosis, 34% of the women met U.S. physical activity guidelines. This percentage remained unchanged 2 years later. The percentage of women who complied with the activity guidelines increased to 39.5% at 5 years but then dropped to 21.4% at 10 years. Overall, researchers found that fewer than 8% of the survivors met U.S. physical activity guidelines at all of the study time points.

Breast Cancer Survivors and Maintenance of Physical Activity ■ Prior to breast cancer diagnosis, 34% of the women in the study met U.S. physical activity guidelines. The percentage of women who complied with the activity guidelines increased to 39.5% at 5 years but then dropped to 21.4% at 10 years.

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed. Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

■ Fewer than 8% of survivors met U.S. physical activity guidelines at all study time points.

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Expert’s Corner Breast Cancer

Breakthroughs in Targeted Therapies for Breast Cancer Are Improving Patient Survival Rates A Conversation with José Baselga, MD, PhD By Jo Cavallo

José Baselga, MD, PhD

or more than 20 years, José Baselga, MD, PhD, has devoted his medical and scientific career to caring for breast cancer patients and the development of novel molecular targeted agents to treat the disease. From 1996 to 2010, he was Head of the Oncology Department of Vall d’Hebron University Hospital in Barcelona, and from 2010 to 2012, he was Chief of the Division of Hematology/Oncology and Associate Director of the Massachusetts General Hospital Cancer Center in Boston. In January, Dr. Baselga began his new position as Physician-in-Chief of Memorial Sloan-Kettering Cancer Center in New York, where he is leading a staff of over 900 attending physicians and overseeing the institution’s clinical and translational research programs. Dr. Baselga’s laboratory investigations of growth factor receptors as targets for breast cancer therapy were instrumental in the development of several molecularly targeted agents, including trastuzumab (Herceptin) and lapatinib (Tykerb). More recently, Dr. Baselga led the clinical development and clinical trials of two new drugs, pertuzumab (Perjeta) in the treatment of HER2-positive metastatic breast cancer and everolimus (Afinitor) in the treatment of advanced hormone receptor–positive HER2-negative breast cancer. In 2012, the therapies received FDA approval in the treatment of advanced breast cancer. Today, Dr. Baselga is focused on the clinical investigation of the next generation of PI3 kinase inhibitors for patients with mutations in the PI3 kinase alpha gene.

A Past President of the European Society for Medical Oncology, Dr. Baselga has served on the Board of Directors of ASCO as well as the American Association for Cancer Research (AACR) and has received ASCO’s Young Investigator and Career Development Awards and AACR’s Rosenthal Family Award. The ASCO Post talked with Dr. Baselga about his goals as Physicianin-Chief, his latest studies of PI3 kinase inhibitors, and the advantages of the team approach to research.

New Role What are your goals as you begin your new role as Physician-in-Chief of Memorial Sloan-Kettering Cancer Center? This is a time of great opportunity in cancer research and in improving patient care. We have plans to expand our clinical programs, and we will be creating additional research and clinical space. Our goal is to bring precision cancer medicine to the forefront. Being at Memorial is also like coming home for me. I completed a medical oncology fellowship here

have amazing data with the checkpoint inhibitors, particularly the anti-CTL4, PD-1, and PD-L1 monoclonal antibodies, in addition to targeting the BRAF pathway in patients with mutations. At Memorial, for example, Jedd D. Wolchok, MD, PhD [Associate Attending Physician], and colleagues are combining checkpoint therapies, including antiCTL4 and anti-PD-1, and they are seeing unprecedented activity. We need to be open to the possibilities in all kinds of cancers. We are making progress in some of them rapidly, and I’m terribly excited about the research going on in breast cancer, lung cancer, melanoma, and leukemia.

Pertuzumab Research In your phase III trial of pertuzumab for metastatic breast cancer, adding the drug to trastuzumab and docetaxel increased median progression-free survival by 6 months. How significant was that result? It was very significant because not only did the study show an improvement in progression-free survival, which is important, it also showed

The dream is to bring precision medicine forward in breast cancer, and whenever possible, to think about reducing the use of chemotherapy. —José Baselga, MD, PhD

and was a young faculty member, so it is a very pleasant feeling to be back at such a fantastic institution with so many colleagues at the cutting edge of the field, and with such a strong commitment to advancing cancer care for our patients and worldwide.

Treatment Progress Do you see progress being made in treatment advances for every cancer? Yes, in every cancer. And we need to be open-minded about the possibility that even the tumors that seem to be the most difficult to treat might be targetable at some point. Just a few years ago, melanoma was very complicated to treat and nothing seemed to work. Now we

an improvement in overall survival. In the initial New England Journal of Medicine paper,1 we showed improvement in progression-free survival. Sandra M. Swain, MD, FACP [ASCO President and Medical Director of the Washington Cancer Institute at MedStar Washington Hospital Center], later presented data at the San Antonio Breast Cancer Symposium showing a remarkable improvement in overall survival as well. Now we are developing other drug combinations that are equally exciting. We are also studying pertuzumab in the adjuvant setting, which could potentially further increase the cure rate in patients with early diagnosed HER2-positive breast cancer.

New Targets Could you talk a little about other targeted therapies being developed in breast cancer? Another emerging target is the PI3K gene, the most frequently mutated gene in breast cancer, as we have learned from The Cancer Genome Atlas effort and others. Close to 50% of the estrogen receptor–positive tumors have a PI3 kinase mutation and it is also frequently mutated in HER2-positive breast cancer. We know that patients with PI3 kinase mutations, downstream of the HER2 receptor, respond less to trastuzumab, pertuzumab, and lapatinib, but now we have PI3K alpha-specific agents, including BYL719 and GDC0032. We presented data at this year’s AACR Annual Meeting,2,3 in which we showed high responses in patients with PI3K alpha mutations. The work done by others with CDK4/6 inhibitors is also very promising. In addition, initial data show that a significant proportion of patients with breast cancer have an overexpression of another receptor, FGFR1, and we are about to launch a clinical trial with patients with FGFR receptor alterations. I can see a landscape in which breast cancer tumors will routinely be genomically sequenced as part of clinical practice. We are already doing that at Memorial. Sequencing not only helps you identify the best treatment approach, it also opens up the possibility for patients to take part in novel clinical trials with agents that are increasingly safe. The dream is to bring precision medicine forward in breast cancer, and whenever possible, to think about reducing the use of chemotherapy.

PI3K Inhibitors You are currently involved in several clinical studies of PI3K inhibitors as single agents and combined with PARP inhibitors. Please talk about those studies. At the AACR meeting, we presented data on PI3 kinase inhibitors as single agents, which showed high activity. This again proved that if there is a driver mutation in a tumor, it is likely that targeting it will

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Expert’s Corner

result in clinical activity. The next question is how are we going to amplify the tumor activity that we are already seeing? There are a number of approaches we can take. One that we are pursuing is to combine PI3 kinase inhibitors with HER2 inhibitors—for example, trastuzumab and pertuzumab. Another approach we are working on is combining PI3 inhibitors with antiestrogen therapy, similarly to how we combined everolimus with an antiestrogen. A third approach is the out-of-box “Dream Team” approach being funded by Stand Up to Cancer (SU2C). We are working in collaboration with Lewis C. Cantley, PhD [Director of the Cancer Center at Weill Cornell Medical College and New York-Presbyterian Hospital], Gordon B. Mills, MD, PhD [Chairman of the Department of Systems Biology, MD Anderson Cancer Center], and Gerburg Wulf, MD, PhD [Assistant Professor of Medicine, Harvard Medical School] on different mouse models combining PI3 kinase inhibitors and PARP inhibitors, and we all came together with the same data. Now the PI3 Kinase Dream Team is conducting a clinical trial with a PI3K inhibitor and a PARP inhibitor in five cancer centers.

tise to the table, while at the same time understanding that the power of individual investigators to work independently is critical to cancer advancements. So I guess it will be a combination of both. n Disclosure: Dr. Baselga has served in a consulting or advisory role for Novartis, Roche, and Chugai.

References 1. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012. 2. Juric D, Krop I, Ramanathan RK, et al: GDC-0032, a beta isoform-sparing B:7.875 in PI3K inhibitor: Results of T:7.625 in a first-inhuman phase Ia doseS:6.625 escalation study. in

AACR Annual Meeting. Abstract LB-64. Presented April 7, 2013. 3. Rodon J, Juric D, GonzalezAngulo AM, et al: Towards defining the genetic framework for clinical response to treatment with BYL719, a PI3Kalpha-specific inhibitor. AACR Annual Meeting. Abstract LB-65. Presented April 7, 2013.

Team Work Will the team approach to cancer research become the norm in the future? This is a complex question. We need to find ways to work together and to learn from each other with everybody bringing their exper-

The ASCO Post

In mCRPC, is it appropriate to

INHIBIT ANDROGEN PRODUCTION BEFORE BLOCKING THE ANDROGEN RECEPTOR?* THIS APPROACH IS AN OPTION FOR TREATMENT IN ADVANCED PROSTATE CANCER.1,2

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Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer. References: 1. Sartor AO, Tangen CM, Hussain MHA, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. 2008; 112(11):2393-2400. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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Expert’s Corner

Women in Oncology: Trending in the Right Direction A Conversation with Sandra M. Swain, MD, FACP By Ronald Piana was enhanced by terrific mentors who happened to be men but recognized my inner drive and dedication to the field, such as Dr. Warren Ross of the University of Florida, Dr. Marc Lippman of NCI, and Dr. Bernard Fisher of the NSABP, to name a few.

Then vs Now

Sandra M. Swain, MD, FACP

ccording to ASCO President Sandra M. Swain, MD, FACP, an important part of her Presidential theme, “Building Bridges to Conquer Cancer,” is finding creative ways to ensure that we have enough oncologists to care for our burgeoning cancer patient population. Adding more women to the oncology workforce is one way to help stave off an impending shortfall of cancer specialists. And it’s a mission close to Dr. Swain’s heart. The ASCO Post recently spoke with Dr. Swain about how her own experiences helped shape her vision of the future of women in oncology.

Medical School and Mentors What was the atmosphere like in medical school, especially for a woman who wanted to pursue oncology? I went to medical school at the University of Florida in the 1980s, and there were few women in my class. Not surprisingly, there were even fewer women in my internal medicine residency program. In fact, I was the only woman in my fellowship group at the NCI. So, I had no female mentors in oncology, but I had some great male mentors who supported me during the early stages of my career, which was invaluable for a young doctor. Naturally, there were some men who didn’t support my career choice, suggesting that I’d be better suited for family practice. That sounds unbelievably paternalistic by today’s standards, but that’s the way it was. Nevertheless, let me be clear about something: A mentor is a mentor, whether it’s a man or woman. My career Dr. Swain is Medical Director, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC.

What is the most notable change since your days in medical school? There are simply more options today for women entering a medical career, and society has certainly become more flexible to the needs of women in medicine. For instance, there are far more opportunities to work part time, or work in an environment with more controlled hours. Also, more men today are stay-at-home dads, which gives women more room to pursue a career in oncology. In all, there are a lot of different choices, and we’re in the midst of a culture change that will benefit everyone.

ing, talks, travel, and research. It’s very demanding. And the pay is less than in private practice, which wasn’t a determining factor for me at the time I made my career decision. However, times have changed. Medical school is incredibly expensive, and young graduating doctors have a debt burden that naturally affects their career choice and their lifestyle. Young doctors might postpone getting married and starting a family until their careers are well underway and they’ve paid off some of their debt. I went to a state school that was very inexpensive, and I graduated with a very small debt. One enters one’s career with a different frame of mind when buried under a mountain of debt. I feel for young doctors today. In my case, my career choices were made out of love for what I was doing, especially my research days at the NCI, when I was working with true giants in the field. So I’m lucky that money has never been a

Recent statistics show a substantial increase in women in oncology fellowships over the past decade but a low proportion of women in leadership roles…. We can help steer this talent into leadership positions. —Sandra M. Swain, MD, FACP

I didn’t marry until I was 40 years old. My career was the driving factor in my life, so I needed to meet someone who not only appreciated that, but also welcomed it. It took a while to find the right man, one who was strong and confident enough to embrace having a successful career-oriented wife. That said, it is very important that women who are looking to assume leadership roles factor in the demands of that type of career with their private life. It can be a difficult balancing act. But it’s worth it, so go for it.

Career Path Medical school debt has been shown to shape career directions. Was it a factor in your career path? No, I’m a hard-driving perfectionist and never satisfied with the status quo, so the academic environment was a better fit than community practice. The heavy workload in academic medicine is compounded by writing and teach-

motivating factor in my career.

Current Trends What does the current picture of women in oncology tell us? It tells us that we’re trending in the right direction. Recent statistics show a substantial increase in women in oncology fellowships over the past decade. However, we continue to see a low proportion of women in leadership roles. This might very well be due to a perception problem; in other words, talented young women might perceive a lack of opportunity in moving up the oncology ladder. It isn’t exactly clear, but it is something we want to work on, so we can help steer this talent into leadership positions. It may also be a timing issue; women may want to wait for their children to get older and then be able to devote more time to their career. On the other hand, not everyone wants to be a leader, so it is just as important to keep all of

these talented, educated women in the workforce at some level.

ASCO Presidency Being one of ASCO’s women presidents must be very satisfying. In the Society’s 49 years, we’ve had 6 women presidents, and yes, I’m very proud to be in that group. It’s worth noting that 4 of the past women presidents took office during the past decade, and 9 of our 19 current board members are women. I’m gratified about the growing influence women have in ASCO. It is a credit to the Society’s constant self-examination and forward-looking vision.

Advice for Young Women If you were addressing a group of young women entering medical school, what reason would you give them to considerer a career in oncology? I would tell them that, from my experience as an oncologist, there is nothing more rewarding than having the honor and privilege of talking to people who are in such a difficult part of their life’s journey after a diagnosis of cancer. I learn something from every patient I see. I would also tell them that although oncology is a demanding career, you can find a balance between your work and your personal life. And the fact that you spend your day caring for patients who need and recognize your humanity and compassion will add to the completeness of your life.

Closing Thoughts Any last comments on women in the oncology workforce? We have problems on a societal level. For example, there is a severe lack of affordable child care in the country. Lacking that one component puts enormous stress on women in medicine. We simply don’t do enough to help young working women who have children. This is a part of our national infrastructure that needs attention. When women are comfortable knowing they have a safe and affordable environment for their children while they’re at work, it has proven benefits for society as a whole. It’s a big question and I don’t have an answer, but it’s something we really need to think about. n

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

Because Endocrine Monotherapy Can Only Take You So Far

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

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

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

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

7.8 months Placebo plus exemestane: 3.2 months

AFINITOR plus exemestane:

PFS Probability (%)

Median PFS: 3.2 months

55%

Median PFS: 7.8 months

reduction in risk of progression or death2

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

0 0

Time (months)

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

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

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

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

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

AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. Important Safety Information. • AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients • There have been reports of noninfectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR, some with

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

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

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

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

also been reported; monitoring of laboratory tests is recommended

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

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

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

• Careful monitoring and appropriate dose adjustments for adverse

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

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

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

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

10/12

AFB-1043056

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

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

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

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

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

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

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

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JCO Spotlight Hematology

Autologous Stem Cell Transplant Improves Survival in Transformed Follicular Lymphoma By Matthew Stenger

s reported by the Canadian Blood and Marrow Transplant Group in Journal of Clinical Oncology,1 patients with transformed follicular lymphoma receiving autologous transplantation have improved survival outcomes compared with patients receiving rituximab (Rituxan)-containing chemotherapy alone. Allogeneic transplantation did not improve outcomes compared with rituximab-containing chemotherapy alone.

Study Details This retrospective cohort study included 172 patients aged 18 to 65 years with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patients undergoing transplant were those treated with autologous or allogeneic transplantation between 1994 and 2010 at transplant centers in Canada. A separate comparison group of patients receiving rituximab-containing

chemotherapy alone was identified using the British Columbia Cancer Agency Centre for Lymphoid Cancer Database. Patients with grades 1, 2, and 3A follicular lymphoma were included, and those with grade 3B lymphoma were excluded. Patients undergoing transplantation for a subsequent diagnosis of Hodgkin lymphoma or T-cell lymphoma and those without biopsy confirmation of transformation were

excluded. All patients received at least one cycle of an anthracycline- or platinum-containing regimen with rituximab for transformation.

Patient Characteristics Of the 172 patients included in the analysis, 22 (13%) received allogeneic stem cell transplantation, 97 (56%) received autologous stem cell transplantation, and 53 (31%) received rituximab-containing chemo-

Role of Stem Cell Transplantation in Follicular Lymphoma By James O. Armitage, MD

he place of either autologous or allogeneic hematopoietic stem cell transplantation in the care of patients with follicular lymphoma has been a point of controversy. However, for patients in whom an effective chemotherapy or chemoimmunotherapy regimen for low-grade follicular lymphoma fails, I believe that transplantation provides the best chance for prolonged failure-free survival. Data on 121 patients from St. Bartholomew’s Hospital in London and the Dana-Farber Cancer Insitute in Boston,1 and the results for 126 patients treated at the University of Nebraska Medical Center (unpublished data), both show a 10year freedom from relapse of lymphoma of approximately 45%. In addition, a European randomized trial showed improved failure-free and overall survival with autotransplant as part of the first salvage regimen.2 A recent report from a GELA/GOELAMS study found that rituximab (Rituxan) as part of primary therapy did not reduce the benefit of autologous transplantation after relapse.3 Allogeneic transplantation yields an even higher freedom from relapse, but has a higher treatment-related mortality and morbidity.4-6

Transformed Lymphoma Villa et al have addressed another issue in the use of autologous or allogeneic transplantation for patients with Dr. Armitage is Joe Shapiro Professor of Medicine and Professor and Chair of Oncology, University of Nebraska Medical School, Omaha.

follicular lymphoma—ie, transplants for patients whose lymphoma has transformed from follicular to diffuse large Bcell lymphoma. In reviewing the data, it is important to remember that patients in whom transformation occurs before therapy for the follicular lymphoma have a better outlook than when trans-

all survival unless these patients can be salvaged by a delayed transplant.

Optimizing Outcomes My experience has been that patients who present with a transformation to diffuse large B-cell lymphoma and have composite low-grade fol-

Patients in whom transformation occurs before therapy for the follicular lymphoma have a better outlook than when transformation occurs after extensive previous treatments for follicular lymphoma. — James O. Armitage, MD

formation occurs after extensive previous treatments for follicular lymphoma. (In the Villa paper, patients in the chemotherapy-alone group were twice as likely to be chemotherapy-naive before transformation.) The authors found a high treatmentrelated mortality rate associated with allogeneic transplantation (ie, 23% vs 5%) that reduced the chance that a presumed graft-vs-cancer effect in the allogeneic group might lead to a better outcome. Although the progressionfree survival curves in the paper were not significantly different among patients undergoing transplant or treatment with chemotherapy and rituximab, many more late progressions in the chemotherapy-alone patients will likely lead, eventually, to a poorer over-

licular lymphoma can often be “cured” of the high-grade lymphoma with regimens like CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, plus rituximab). However, for patients with transformation that occurs after previous treatment for follicular lymphoma, the results with further standard chemotherapy/chemoimmunotherapy have not been satisfactory, and these patients should be offered transplantation if they respond to salvage chemoimmunotherapy. The results by Villa and colleagues suggest that for most patients, autologous transplantation is likely to lead to the best outcome. n

Disclosure: Dr. Armitage is a consultant for Ziopharm, Seattle Genetics, GlaxoSmithKline, Spectrum, Genentech, and Roche; and is on the Board of Directors of Tesaro.

References 1. Rohatiner AZ, Nadler L, Davies AJ, et al: Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: Long-term followup. J Clin Oncol 25:2554-2559, 2007. 2. Schouten HC, Qian W, Kvaloy S, et al: High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: Results from the randomized European CUP trial. J Clin Oncol 21:3918-3927, 2003. 3. Le Gouill S, De Guibert S, Planche L, et al: Impact of the use of autologous stem cell transplantation at first relapse both in naive and previously rituximab exposed follicular lymphoma patients treated in the GELA/GOELAMS FL2000 study. Haematologica 96:11281135, 2011. 4. van Besien K, Loberiza FR Jr, Bajorunaite R, et al: Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 102:3521-3529, 2003. 5. Robinson SP, Goldstone AH, Mackinnon S, et al: Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: An analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 100:4310-4316, 2002. 6. Peniket AJ, Ruiz de Elvira MC, Taghipour G, et al: An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: Allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation. Bone Marrow Transplant 31:667-678, 2003.

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JCO Spotlight

therapy alone (chemotherapy-alone group). Baseline characteristics and risk factors for outcomes were not balanced among groups. At diagnosis, median ages were 44 years in the allogeneic transplant group, 51 years in the autologous transplant group, and 51 years in the chemotherapy-alone group (P = .001 overall); median ages at transformation were 48, 55, and 57 years, respectively (P < .001 overall), with 0%, 26%, and 36%, respectively, being 60 years or older (P = .005 005 overall). A total of 64%, 64%, and 51% of patients were male. Patients in the allogeneic transplant group received a median of two systemic regimens for follicular lymphoma, and those in the other two groups received a median of one (P = .01 01 overall). Overall, 14% of patients receiving allogeneic transplant, 16% of those receiving autologous transplant, and 32% in the chemotherapy-alone group were chemotherapynaive prior to transformation. Two patients in the allogeneic transplant group had received pretransformation autologous transplant. Other significant differences across groups included differences in year of diagnosis of transformation and proportions of patients receiving anthracyclines and platinums. For patients undergoing stem cell transplantation, the median time from transformation to transplant was 6 to 8 months, although time varied widely from several months to several years. Patients in the autologous transplant group were significantly older at transplant than those in the allogeneic transplant group (median, 56 vs 48 years, P < .001) .001) and were significantly more likely to have undergone transplant during 2006 to 2010 (75% vs 50%) compared with 2001 to 2005. Overall, 77% of patients in the allogeneic transplant group and 85% of those in the autologous transplant group had chemosensitive disease. Ap-

proximately half of patients underwent transplant in first complete remission or partial remission and approximately one-third in second complete or partial remission. Conditioning regimens included total-body irradiation in 55% of allogeneic transplant patients and 4% of autologous transplant patients (P < .001 overall). There was also a significant difference in stem cell sources, which included peripheral blood in 77% and 94% of patients, respectively, and bone marrow in 18% and 6%, respectively (P = .02 overall).

Survival Outcomes on Multivariate Analysis Multivariate analysis was performed to adjust for the following factors: female sex, age less than 60 years at transformation, years from diagnosis of follicular lymphoma to transformation, advanced stage at transformation, elevated lactate dehydrogenase at transformation, number of chemotherapy regimens for transformation, anthracycline-containing chemotherapy, platinum-containing chemotherapy, and year of transformation of 2005 or later.

Stem Cell Transplantation in Transformed Follicular Lymphoma ■ Five-year overall survival from time of follicular lymphoma transformation was 46% in the allogeneic transplant group, 65% in the autologous transplant group, and 61% in the rituximab-containing chemotherapy– alone group.

■ On multivariate analysis, overall survival was significantly better in the

autologous transplant group compared with the rituximab-containing chemotherapy–alone group.

Survival Outcomes After a median follow-up of 7.5 years, 5-year overall survival from time of transformation was 46% in the allogeneic transplant group, 65% in the autologous transplant group, and 61% in the rituximab-containing chemotherapy–alone group (P = .24) and 5-year progression-free survival was 46%, 55%, and 40%, respectively (P = .12), with no significant differences observed across treatments. Similarly, there were no differences between the allogeneic transplant group and the autologous transplant group in 5-year post-transplant overall survival (45% and 57%, P = .12) or post-transplant progression-free survival (45% and 55%, P = .52). Transplantation-related mortality rates were 23% in the allogeneic transplant group vs 4% in the autologous transplant group at 1 year (P = .01) and 23% vs 5% at 5 years (P = .001).

On multivariate analysis, patients in the autologous transplant group had significantly improved overall survival from the date of transformation compared with the rituximab-containing chemotherapy–alone group (hazard ratio [HR] = 0.13, P < .001), whereas there was no significant difference for the allogeneic transplant group vs the chemotherapy-alone group (HR = 0.44, P = .12). .12). Th There ere was no signifi significant cant diff differerence for the allogeneic transplant group vs the autologous transplant group with regard to overall survival from time of transplant (HR = 1.5, P = .35). .35). Progression-free survival from the date of transformation was significantly better in the autologous transplant group (HR = 0.09, P < .001) and in the allogeneic transplant group (HR = 0.19, P = .001) compared with the rituximab-containing chemotherapy–alone group. As the authors noted, the study has a number of limitations due to its retrospective, nonrandomized cohort

design, including the fact that multiple known and unknown factors led the study patients to be offered the treatments they received: “This likely generated selection bias, because a higher proportion of patients responding to chemotherapy would have proceeded to autologous [transplant] or allogeneic [transplant] rather than receive rituximab-containing chemotherapy only,” they wrote. Patients in the chemotherapy-only group were also older than those in the transplant groups, which may have led to an overestimation of the benefit of stem cell transplantation. The authors concluded: [O]ur data suggest that eligible patients with transformed follicular lymphoma may benefit from autologous [stem cell transplantation] because it improves [overall survival] compared with rituximab-containing chemotherapy. However, the superiority of autologous [transplant] is modest. Patients with significant comorbidities related to organ dysfunction or age may be best served by treatment with rituximabcontaining chemotherapy. Allogeneic [transplant] may be considered in certain circumstances, particularly if an autologous stem-cell graft cannot be collected or if better strategies emerge to minimize [transplantation-related mortality]. However, relapse and [transplantation-related mortality] remain significant problems in patients with transformation who undergo [stem cell transplantation], even in the rituximab era. Prospective trials will be required to demonstrate the optimal therapy for this aggressive form of nonHodgkin lymphoma. n

Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Villa D, Crump M, Panzarella T, et al: Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: A report of the Canadian Blood and Marrow Transplant Group. J Clin Oncol 31:1164-1171, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Henry T. Lynch, MD, and Carrie L. Snyder, MSN, on Lynch Syndrome and Endometrial Cancer see page 124

Visit The ASCO Post online at ASCOPost.com

Hagop Kantarjian, MD, and Elihu Estey, MD, on Drug Approvals in Acute Myeloiod Leukemia see page 137

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Attaches the cytotoxic agent to the antibody. Seattle Genetics’ linker system is designed to be stable in circulation and release the cytotoxic agent inside targeted cells.1-3

In addition to licensing its ADC technology, Seattle Genetics is developing 7 proprietary ADCs. The company’s robust pipeline of empowered antibody-based therapies and one approved ADC are designed to address significant unmet medical needs.

For more information about our ADC technology and to download an educational slide deck, please visit seattlegenetics.com/technology. REFERENCES: 1. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14(3):154-169. 2. Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235-244. 3. Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the treatment of non–Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6):2358-2364.

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Dermatologic Events in Oncology Prevention and Treatment of Acneiform Rash Caused by EGFR Inhibitors By Mario E. Lacouture, MD

Mario E. Lacouture, MD

Dermatologic Events in Oncology is guest edited by Mario E. Lacouture, MD, an Associate Member in the Division of Dermatology, Department of Medicine, at Memorial Sloan-Kettering Cancer Center, New York. He is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments and the author of many publications, including the recently published Skin Care Guide for People Living With Cancer. The series is intended to offer oncologists guidance in recognizing and treating the skin toxicities associated with anticancer agents.

pidermal growth factor receptor (EGFR) inhibitors block pathway activity in malignant cells as well as normal tissues, such as skin, hair, nails, and gut. They have been approved by regulatory agencies for the treatment of lung, pancreatic, colorectal, head and neck, medullary thyroid, and breast cancers. These agents are either monoclonal antibodies (cetuximab [Erbitux], panitumumab [Vectibix], pertuzumab [Perjeta]) or small molecules (erlotinib [Tarceva], lapatinib [Tykerb], afatinib [investigational], vandetanib [Caprelsa]), and result in an acneiform rash (all grades) in 40% to 90% of patients. Whereas only 10% to 20% of patients develop grade 3 rash, decreased quality of life is seen across all grades of this untoward event.

The mechanism of rash development is primarily inflammatory, but approximately 30% of patients develop secondary bacterial infections, with hallmarks such as purulent discharge and yellow crusting. A correlation between presence and severity of rash and treatment response has been demonstrated, which underscores the need to treat patients with rash, as these are the individuals who could benefit the most from EGFR inhibitor therapy.

Treatment Recommendations The acneiform rash is characterized by erythematous papules and pustules that develop on the face, scalp, and upper trunk within the first month in > 90% of patients. Not only

Prevention of acneiform rash caused by EGFR inhibitors includes topical corticosteroids (hydrocortisone 2.5%, alclometasone) and oral antibiotics (minocycline, doxycy-

Prevention of acneiform rash caused by EGFR inhibitors includes topical corticosteroids (hydrocortisone 2.5%, alclometasone) and oral antibiotics (minocycline, doxycycline, or antibiotics covering skin flora) twice daily for at least the first 6 weeks. —Mario E. Lacouture, MD

does the rash have a cosmetic impact, but it is frequently associated with pain, infections, and pruritus.

Fig. 1: Acneiform rash on the face caused by an EGFR inhibitor. Note the yellow crusting on the nasolabial folds suggestive of bacterial infection. Treatment includes topical corticosteroids and oral antibiotics.

cline, or antibiotics covering skin flora) twice daily for at least the first 6 weeks. This results in a reduction

of grade 2 and greater skin toxicities by more than 50%. In addition, these measures lessen the need to modify the dose of the EGFR inhibitor. For treatment in patients who have already developed grade 1/2 rash, a similar approach, using topical corticosteroids (hydrocortisone 2.5%, alclometasone) and oral antibiotics (minocycline, doxycycline, or antibiotics covering skin flora) twice daily for at least 4 weeks is suggested. In cases where secondary infections are suspected, a bacterial swab culture should be performed in order to institute oral antibiotic therapy based on sensitivities. For grade 3 rash, consider a dose interruption for 2 weeks or until the rash is grade � � 1. In addition, oral corticosteroids (methylprednisolone dose pack or prednisone 0.5 mg/kg for 7 days) may be beneficial. Also for grade 3 rash, topical corticosteroids and oral antibiotics should continue upon rechallenge with EGFR inhibitors. Application of a skin moisturizer and a broad-spectrum sunscreen with an SPF of at least 30 when going outside is recommended in all patients, since the rash is accompanied by dry skin and may be aggravated by sun exposure. n

Disclosure: Dr. Lacouture is a consultant for AstraZeneca, Bayer/Onyx, Pfizer, GlaxoSmithKline, BMS, Roche, Genentech, and Amgen.

Fig. 2: EGFR inhibitor–associated rash on the upper trunk. In the trunk, high-potency topical corticosteroids may be used (ie, fluocinonide, mometasone), in addition to oral antibiotics.

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American Association for Cancer Research Annual Meeting

Promising Phase II Results Continue to Support Ibrutinib in CLL By Alice Goodman

esults from an ongoing phase II study reported at the recent Annual Meeting of the American Association for Cancer Research (AACR) demonstrate impressive activity with the use of ibrutinib in patients with chronic lymphocytic leukemia (CLL) and 17p deletions, which are associated with a poor prognosis.1

Adrian Wiestner, MD, PhD

Growing Body of Evidence This study adds to a growing body of evidence that is highly promising for this novel Bruton’s tyrosine kinase inhibitor in the treatment of CLL. In fact, during the AACR meeting, the U.S. Food and Drug Administration announced that ibrutinib was awarded a “breakthrough designation” for CLL with 17p deletions, suggesting that it is on a fast track for approval. (See the May 1 issue of The ASCO

Post, pages 1 and 24, for more on ibrutinib’s road to approval.) Two phase II studies previously reported at the 2012 American Society of Hematology Annual Meeting demonstrated impressive results in CLL. One study included treatment-naive patients and relapsed/refractory patients, while the other focused on those with high-risk CLL.2,3 The study reported at the AACR meeting focused on CLL with 17p deletion and in a second cohort enrolled patients older than 65. Ibrutinib was well tolerated and highly effective in eradicating tumor cells in both treatment-naive and relapsed/refractory patients with CLL. Treatment with ibrutinib achieved dramatic clearance of tumor burden in the lymph nodes, blood, spleen, and bone marrow, and importantly, responses were durable. According to correlative studies, ibrutinib exerts sustained inhibition of B-cell receptor signaling and nuclear factor–kappaB signaling in both peripheral blood and lymph nodes.

Novel Approach for Challenging Patients “Ibrutinib as a single agent is well tolerated and highly effective in CLL. Responses are durable, and high re-

EXPERT POINT OF VIEW

ommenting on this study, Jan A. Burger, MD, PhD, Associate Professor in the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, and first author of one of the ibrutinib studies presented at the 2012 Annual Meeting of the American Society of Hematology, said that taken together, evidence supporting ibrutinib’s efficacy thus far is impressive. “Ibrutinib is amazingly active, even in high-risk Jan A. Burger, MD, PhD patients, who have few other alternatives. When a patient with 17p deletion relapses, treatment success is limited. These patients die with progressive disease within a year or two, and often within months. With ibrutinib, we still don’t reach median survival after 1 year,” Dr. Burger noted. With about 500 CLL patients treated to date, Dr. Burger is confident that ibrutinib fulfills an unmet medical need. “Suddenly we have a safe oral agent with dramatic results. We hope the drug will be approved by FDA sooner rather than later. Otherwise, patients who need this therapy won’t be able to get it.” Dr. Burger noted that ibrutinib received an FDA breakthrough designation for CLL with 17p deletion, mantle cell lymphoma, and Waldenström’s macroglobulinemia. n Disclosure: Dr. Burger has received research funding from Pharmacyclics and Gilead.

Ibrutinib in Chronic Lymphocytic Leukemia ■ Single-agent ibrutinib achieved dramatic reductions in tumor burden in

the blood, bone marrow, and spleen in patients with chronic lymphocytic leukemia (CLL).

■ These results were seen in patients with 17p deletions, who have a poor

prognosis and few other treatment options, as well as in the elderly, who may not tolerate more aggressive treatment approaches.

■ Ibrutinib has a breakthrough designation from FDA for CLL with 17p deletions.

sponse rates are achieved irrespective of deletion of 17p. The drug achieved rapid disease control in all anatomic sites and rapid and sustained inhibition of BCR signaling. Ibrutinib should be investigated further, possibly as a single agent in CLL,” said lead author Adrian Wiestner, MD, PhD, Head of the Lymphoid Malignancies Section in the Hematology Branch at the National Heart, Lung, and Blood Institute at the NIH in Bethesda, Maryland. The FCR regimen (fludarabine, cyclophosphamide, rituximab [Rituxan]) is a standard of care for CLL in the United States. Although FCR is effective, patients with 17p deletions have a poorer response and so do elderly and frail patients. Ibrutinib represents a novel approach for these difficult-to-treat patients, Dr. Wiestner told listeners. Ibrutinib is a selective inhibitor of Bruton’s tyrosine kinase (BTK), an element of the B-cell receptor signaling pathway implicated in the evolution of CLL.

Study Details The phase II single-center trial included two cohorts of CLL patients who required treatment: elderly patients over age 65 (n = 24, 8 treatment-naive) and those with deletion of chromosome 17p (n = 29, 15 treatment-naive). This study continues to enroll treatment-naive patients with 17p deletion. Patients were treated with singleagent ibrutinib at 420 mg/d in 28-day cycles, with the primary endpoint of response at 6 months. Treatment will be continued and response evaluated every 6 months. Ibrutinib was safe and well tolerated. The most common adverse events were grade 1 or 2 diarrhea, rash, arthralgia, cramps, mouth sores and fatigue. Hematologic adverse events were rare, and no treatment-related

drug discontinuations were reported. Two deaths occurred, both unrelated to the study drug. Rapid disease control was evident at 6 months in the blood, lymph nodes, and spleen. Lymph node disease burden was reduced by at least 50% in 95% of patients; median reduction of splenomegaly was 55%.

Response Data In 26 patients with an available bone marrow biopsy, ibrutinib reduced tumor infiltration by CLL cells by 82%. Absolute lymphocyte count was reduced by a median of 62%. According to standard response criteria for CLL, the rate of partial response was 52%. At 12 months, the estimated event-free survival was 94%. However, nodal responses were seen in 95% of patients. Ibrutinib exhibited on-target effects by inhibiting B-cell receptor signaling in CLL cells in the lymph nodes and blood cells. However, no correlation was observed between the degree of inhibition of B-cell receptor signaling and the degree of clinical response, Dr. Wiestner commented. “The durability of response is noteworthy. However, currently follow-up is short. Existing therapies often fail to eliminate cancer cells effectively in the blood, lymph nodes, spleen, and bone marrow. Ibrutinib is an example of targeted therapy that has the potential to greatly improve patients’ lives,” he stated. n

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

References 1. Wiestner A, et al: AACR Annual Meeting. Abstract LB-141. Presented April 8, 2013. 2. Byrd JC, et al: ASH Annual Meeting. Abstract 189. Presented December 9, 2012. 3. Burger JA, et al: ASH Annual Meeting. Abstract 187. Presented December 9, 2012.

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FDA Update

Daratumumab Receives Breakthrough Therapy Designation in Multiple Myeloma

DA has granted daratumumab breakthrough therapy designation for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory

is expressed. According to FDA, breakthrough therapy designation is intended to expedite the development and review time for a potential new

medicine “to treat a serious or lifethreatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over

existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” n

FOR A DIFFERENT PERSPECTIVE IN RENAL CELL CARCINOMA, DISCOVER…

ANOTHER SIDE OF RCC agent, or who are double refractory to a proteasome inhibitor and immunomodulatory agent. Daratumumab is an investigational human monoclonal antibody with broad spectrum cytotoxic activity. It targets the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells and may also have potential in other cancers on which CD38 is expressed. The drug is currently in Phase I/ II trials for multiple myeloma and has potential applicability against other malignancies on which CD38

More FDA Updates in This Issue of The ASCO Post Ibrutinib Receives Third Breakthrough Therapy Designation See page 28 Lambrolizumab in Advanced Melanoma See page 29 Novel Immunotherapy to Enter Clinical Trials See page 31 New Labeling for Oxycontin See page 97

In the United States, RCC is the 9th most common malignancy and accounts for 2% to 3% of all adult cancers.1,2 Incidence rates continue to rise; however, the reason for this increase is unknown. 2 The American Cancer Society estimates that there will be 64,770 new cases of RCC and 13,570 RCCrelated deaths in 2012. 3

Studies have demonstrated the importance of sustained drug levels; however, these levels can be compromised when toxicities lead to dose modifications, interruptions, or discontinuations. 5,8,9 In the Phase 3 trials of targeted agents, 30% to 40% of patients required dose modifications, and in the community setting this percentage may be higher.7 Treatment modifications require significant monitoring by healthcare professionals, and may potentially compromise treatment exposure and patients’ daily living. 5,8

Is good enough, enough? Today’s RCC patients are often active, with busy lifestyles and families. With a median age at diagnosis of only 64, quality of daily living on therapy is critical. 3 While the introduction of targeted therapy has improved the management of advanced disease and the outlook for patients, new challenges and existing unmet needs may compromise not only patients’ everyday life, but overall outcomes.4,5

Furthermore, patients themselves may choose not to adhere to their dosing regimen due to discomfort or dissatisfaction with the toxicity of therapy. 8 Other factors that may affect adherence include misinterpretation of physician instructions, polypharmacy syndrome and lifestyle distractions (e.g., demands of work and family, lack of support).10

Therapy for advanced RCC has evolved…

There may be opportunities to improve patient care

Each therapeutic class of agents is associated with distinct adverse events. Despite recent advances in treatment, side effects remain an important issue in patient management.6

Proactive monitoring, early detection, and prompt management of side effects are important for optimal patient management. Additionally, open communication between patients and healthcare professionals can be crucial to try to avoid premature treatment discontinuations or adverse impacts on patients’ everyday lives. 5,8

Research has shown that a substantial proportion of patients—both in clinical trials and everyday clinical practice—may not receive the full dose of their therapy due to adverse event management.7,8

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

AVEO and Astellas are uncompromising in their commitment to RCC References: 1. Centers for Disease Control and Prevention. http://apps.nccd. cdc.gov/uscs/toptencancers.aspx. Accessed January 27, 2012. 2. National Comprehensive Cancer Network. http://www.nccn.org. Published October 18, 2011. Accessed January 27, 2012. 3. American Cancer Society. Atlanta: ACS; 2012. 4. Cowey CL, Hutson TE. Clin Adv Hematol Oncol. 2010;8(5):357-364. 5. Hudes GR, Carducci MA, Choueiri TK, et al. J Natl Compr Canc Netw. 2011;9(suppl 1):S-1-S-30. 6. Appleby L, Morrissey S, Bellmunt J, Rosenberg J. Hematol Oncol Clin North Am. 2011;25(4):893-915. 7. Rini BI. J Clin Oncol. 2009;27(19):3225-3234. 8. Ravaud A. Ann Oncol. 2009;20(suppl 1):i7-i12. 9. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Cancer Chemother Pharmacol. 2010;66(2):357-371. doi:10.1007/s00280-009-1170-y. 10. Moore S. Cancer Nurs. 2007;30:112-122.

An Uncompromising Commitment to RCC

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American Association for Cancer Research Annual Meeting Hematology

Preliminary Progress with Genetically Engineered T Cells in Treating Childhood ALL By Alice Goodman

wo small phase I studies at separate centers demonstrated encouraging results in the treatment of children with acute lymphoblastic leukemia (ALL) using reinfused autologous genetically engineered T cells. Results of both studies were presented at the Annual Meeting of the American Association for Cancer Research (AACR) in Washington, DC.1,2 These studies add to a growing body of small early clinical trials suggesting that the technique can achieve complete remission of leukemia in children with limited treatment options.

The treatment, called anti-CD19 chimeric antigen receptor (CAR) Tcell therapy, involves collection of the patient’s own immune cells, which are then genetically modified and expanded in the laboratory to attach to the CD19 protein expressed on the surface of ALL cells. The modified cells are then reinfused into the patient. The technique is under study in children at several centers, including the Pediatric Oncology Branch at the National Cancer Institute, Children’s Hospital of Philadelphia, Memorial Sloan-Kettering Cancer Center, and

Anti-CD19 CAR T cells represent a unique way to attack childhood leukemia. Preliminary evidence suggests that we can induce complete remission in patients refractory to other therapies. — Daniel W. Lee, MD

the Fred Hutchinson Cancer Research Center. Each center employs modifications of the technique related to in vitro expansion and genetic modifica-

Personal Testimonial: CAR-modified T Cells in Adults By Alice Goodman life expectancy was 6 to 10 years without a transplant.

Resistant Disease Over the next 13 years, Dr. Olson underwent several rounds of chemotherapy, each achieving a successively shorter remission, until the last treatment, Douglas Olson, PhD David Porter, MD when his CLL was found welve adults with chronic lym- to be resistant. His oncologist, David phocytic leukemia (CLL) have Porter, MD, Professor of Medicine been treated with CD19-targeted chi- at the Hospital of the University of meric antigen receptor (CAR) T-cell Pennsylvania, suggested a bone martherapy at the University of Pennsyl- row transplant as his best hope for vania in Philadelphia by Carl June, extending survival. But then Dr. PorMD, Richard W. Vague Professor ter offered Dr. Olson enrollment in a in Immunotherapy, and colleagues. phase I trial of the genetically engiThese were all end-stage patients with neered T-cell treatment. no other good treatment options. “Both my wife and I are scientists. Thus far, 9 of the 12 patents have had We believed this treatment could a good response; 3 are in complete re- work. I entered the trial with no resermission, with durable responses. vations. I trusted Dr. Porter, but most At the recent Annual Meeting of importantly, I saw this as an opportuthe American Association for Cancer nity to advance the field,” he said. Research, the adult CLL patient with The procedure to collect and inthe longest remission to date spoke to fuse the T cells was relatively painless. attendees about his experience with Nothing happened for about 2 weeks the therapy. after the procedure, and then Dr. OlDouglas Olson, PhD, a research son experienced severe flu-like sympscientist in the drug industry, first re- toms, suggesting cytokine-release ceived the CLL diagnosis 16 years ago syndrome. when he was 49 years old with a wife “I hoped this meant that the treatand four young children. At the time, ment was working,” he said. The there was no cure for CLL except symptoms persisted for more than a bone marrow transplantation, which week, and then he was hospitalized then had a survival rate of 50%. His for kidney problems, which ultimately

resolved. Meanwhile, Dr. Porter gave him the news that the CAR-modified T cells were populating his bone marrow. “At that time, I became convinced that I would respond to the treatment,” Dr. Olson noted. The following week, Dr. Olson was found to be in complete remission. “Dr. Porter told me, ’We can’t find a single cancer cell in your body. Your bone marrow is completely free of cancer cells.’”

Still Cancer-free “It has now been more than 2.5 years. I am still healthy and cancerfree. I ran my first half marathon a few months ago. I do require intravenous gamma globulin every 3 months to boost my immunity,” Dr. Olson said. “I am just one life, but I am convinced that these scientists have found the key to saving my life and others,” he concluded. Drs. June and Porter emphasize that the treatment is still in its early days and several challenges remain to be overcome. But, thus far, the experience in both children and adults has raised hopes that genetically engineered T cells will be an important breakthrough in the field of hematologic malignancy. n

Disclosure: Dr. Porter has potential financial interest in CART19/CTL19 cells due to “upstream IP and patents” from licensure to Novartis. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight.

tion of the cells, but all the centers are using autologous T cells modified to recognize the CD19 antigen. CAR Tcell therapy is also being explored in adults with chronic lymphocytic leukemia (CLL, see sidebar).

NCI Study The first study1 included four patients aged 10 through 16. Following treatment with the genetically engineered T cells, one of two patients with ALL previously treated with bone marrow transplantation achieved complete responses, while a third child with ALL who had never been in remission despite intensive chemotherapy achieved a minimal residual disease–negative complete response. A fourth child with B-cell non-Hodgkin lymphoma who had a prior bone marrow transplant had progressive disease despite the T-cell therapy. It was too early to evaluate a fifth child who had been treated. Presenting author Daniel W. Lee, MD, Assistant Clinical Investigator in the Pediatric Oncology Branch of the NCI in Bethesda, Maryland, said, “Childhood ALL is the most common malignancy in pediatric patients. The majority of children can achieve remission, but this comes with the price of long therapy, toxicity, and cost, with no guarantee of long-term cure. Children who relapse have limited therapeutic options, and new therapies are sorely needed.” The first four patients to undergo the technique at NCI were treated with fludarabine and cyclophosphamide prior to receiving the CAR T cells. Side effects were temporary and not seen in every patient, Dr. Lee continued. They included fever, low blood pressure, and low blood counts and were easily managed in hospital. No evidence of graft-vs-host disease was observed in the three post-transplant

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American Association for Cancer Research Annual Meeting patients who had undergone previous bone marrow transplantation. “Anti-CD19 CAR T cells represent a unique way to attack childhood leukemia. Preliminary evidence suggests that we can induce complete remissions in patients refractory to other therapies,” Dr. Lee stated.

Philadelphia Study The second study2 treated five pediatric patients with CAR T-cell therapy. Four of the first five patients achieved complete responses, said study coauthor

lymphohistiocytosis, which is part of the cytokine release syndrome—the part most responsible for hypotension and fever. Interrupting macrophage activation syndrome with tocilizumab (Actemra), an antirheumatic drug, can alleviate the toxicity, without potentially interfering with the therapeutic response, Dr. Barrett explained.

“We have seen the success of this therapy sustained and reproduced at other centers,” Dr. Lee stated. “Going forward in children, the technique will be studied as a potential alternative to bone marrow transplantation or some of the harsh conditioning associated with transplant. In the future we hope the technique, along with chemothera-

py, will be studied in newly diagnosed children in an effort to minimize the chance of relapse and the subsequent need for additional chemotherapy or bone marrow transplantation. We are excited to pursue this. Further study is needed to characterize the long-term effects of this therapy because normal continued on page 74

GE Healthcare Clarient Diagnostic Services

David M. Barrett, MD

David M. Barrett, MD, Instructor in Pediatric Oncology at The Children’s Hospital of Philadelphia. Three of these complete responses have been durable, with the longest response being 12 months (range, 2–12 months), and one was transient. The fifth patient did not respond. “The main takeaway message is that this therapy is effective in pediatric ALL. We are learning about the toxicity. The toxicity is significant but manageable. We need to learn more about how the leukemia can escape by removing its CD19 expression.” Dr. Barrett said. “This therapy has the potential to save lives when chemotherapy cannot.” In children, one of the important toxicities is the macrophage activation syndrome, also called hemophagocytic

Anti-CD19 Chimeric Antigen Receptor T-cell Therapy ■ Two small studies add to a

growing body of evidence suggesting that autologous genetically engineered T cells can achieve complete and durable remissions in children with acute lymphocytic leukemia and no other treatment options.

■ Patient numbers are small,

and research is still in an early phase, but investigators hold high hopes for confirmation of long-term efficacy and safety.

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American Association for Cancer Research Annual Meeting Childhood ALL continued from page 73

B cells can also be affected,” he added.

Dream Team Grant The successes of these two studies and other reports from investigators at Memorial Sloan-Kettering Cancer Center and Fred Hutchinson Cancer Center have led to a “dream team” collaboration supported by a grant from SU2C (Stand Up To Cancer) to study immunogenomics and immunotherapy for treatment of high-risk pediatric cancers. “The primary method of delivering immunotherapy is via the chimeric T cells,” Dr. Barrett explained. Part of the SU2C’s dream team grant is for a collaboration among Children’s Hospital of Philadelphia, Pediatric Oncology Branch of the NCI, Fred Hutchinson Cancer Center, Baylor Medical Center, the University of Wisconsin, the Hospital for Sick Children in Toronto, and the University of British Columbia in Vancouver. This joint effort will integrate the experience at these centers

with chimeric receptors and standardize and expand the approach in order to move forward with the treatment in children, Dr. Barrett said. “There has been enough sustained success with the technique that the dream team is now possible. This therapy can put patients into remission who have no other treatment option, and it looks like it can be widely applicable with durable responses. There hasn’t been anything like this to treat cancer in a long time,” he noted. “The biggest parallel I can think of was radiation therapy for central nervous system leukemia, which had a profound and dramatic increase in survival for children with leukemia. Very few discoveries have matched that level of impact,” Dr. Barrett continued. n

Disclosure: Drs. Lee and Barrett reported no potential conflicts of interest.

EXPERT POINT OF VIEW

“T

his is a very exciting breakthrough even though it is preliminary at this point. Previous immune approaches to cancer that initially looked promising have often turned out to have durable responses, therefore we need to study this new technology in controlled clinical trials before it is widely used,” said Richard Bram, MD, PhD, Chair, Division of Pediatric Hematology/Oncology at the Mayo Clinic in Rochester, Minnesota, who was not involved in these studies. Richard Bram, MD, PhD “These investigators are using a very clever manipulation of the immune system. Patients don’t need B lymphocytes to survive, as long as they can get an exogenous supply of antibodies from monthly injections of IgG. The treatment targets CD19 B lymphocytes in normal tissue and in cancer tumors, without hurting most other types of cells, and probably depletes the supply of normal B-cells,” Dr. Bram said. “The efficacy of the chimeric antigen receptor T-cell approach is important, especially in young patients who have no other options. I am cautiously optimistic and very excited, and hope that this novel approach will be rapidly validated and adopted by others,” Dr. Bram stated. n Disclosure: Dr. Bram reported no potential conflicts of interest.

References 1. Lee DW, Shah N, Stetler-Stevenson M, et al: Autologous-collected anti-CD19 chimeric antigen receptor (CAR) T cells for acute lymphocytic leukemia (ALL) and B-cell lymphoma in children who have previously undergone allogeneic hematopoietic

stem cell transplant. AACR Annual Meeting. Abstract LB-138. Presented April 8, 2013. 2. Grupp S, Kalos M, Barrett DM, et al: Use of CD19-targeted chimeric antigen receptor-modified T (CART19) cells in

ALL and CLL produce transient cytokine release syndrome, macrophage activation syndrome, and durable responses. AACR Annual Meeting. Abstract 4574. Presented April 9, 2013.

Nonmelanoma Skin Cancer May Be Associated with Modest Increased Risk of Secondary Cancer: Further Study Needed

prospective study by researchers at Brigham and Women’s Hospital observed an association between risk of second primary cancer and history of nonmelanoma skin cancer in white men and women. The researchers found that people with a history of nonmelanoma skin cancer had a modestly increased risk of getting cancer in the future, specifically breast and lung cancer in women and melanoma in both men and women. The study was published on April 23, 2013 in PLOS Medicine.1

Two Large Cohort Studies The researchers analyzed data from two large United States cohort studies: the Health Professionals Follow-up Study and the Nurses’ Health Study. The researchers followed 46,237 men from June 1986 to June 2008 in the Health Professionals Follow-up Study, and 107,339 women from June 1984 to June 2008 in the

Nurses’ Health Study. The researchers identified 36,102 new cases of nonmelanoma skin cancer and 29,447 new cases of other primary cancers.

cancer associated with an 11% higher risk of other primary cancers in men, and a 20% higher risk of other primary cancers in women.

Key Points ■ Researchers analyzed data from two large US cohort studies: the Health Professionals Follow-up Study and the Nurses’ Health Study.

■ A history of nonmelanoma skin cancer was significantly associated with a 15% higher risk of other primary cancers in men, and a 26% higher risk of other primary cancers in women.

■ Because the study was observational, results should be interpreted cautiously and are insufficient evidence to alter current clinical recommendations.

A history of nonmelanoma skin cancer was significantly associated with a 15% higher risk of other primary cancers in men, and a 26% higher risk of other primary cancers in women. When melanoma was excluded from this analysis, the rates changed slightly, with a history of nonmelanoma skin

After using statistical models to correct for multiple comparisons, looking at individual cancer sites, the researchers found that a history of nonmelanoma skin cancer was significantly linked to an increased risk of breast and lung cancer in women, and an increased risk of melanoma in both men and women.

Continued Investigation Needed According to the researchers, these findings should be interpreted cautiously. “Because our study was observational, these results should be interpreted cautiously and are insufficient evidence to alter current clinical recommendations,” said Jiali Han, PhD, Channing Division of Network Medicine, Department of Medicine and Department of Dermatology, Brigham and Women’s Hospital. “Nevertheless, these data support a need for continued investigation of the potential mechanisms underlying this relationship.” n

Disclosure: This research was supported by the National Institutes of Health (CA87969 and CA055075).

Reference 1. Song F, Qureshe A, Giovannucci EL, et al: Risk of a second primary cancer after non-melanoma skin cancer in white men and women: A prospective cohort study. PLOS Medicine April 23, 2013.

VOTRIENT for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efﬁcacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.

LIGHTING A WAY FORWARD

WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. Please see additional Important Safety Information on adjacent pages. Please see Brief Summary of Prescribing Information, including BOXED WARNING, for VOTRIENT on adjacent pages.

VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efﬁcacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.

VOTRIENT demonstrated significant improvement in PFS in a Phase 3 trial1 PFS in overall study population (N=369)1

1.6 MONTHS 4.6 MONTHS

Proportion progression-free

1.0

Median PFS

VOTRIENT (n=246 ) Placebo (n=123)

Median PFS

HR: 0.35 (95% CI 0.26-0.48) P<0.001

0.8

• VOTRIENT provided a 65% reduced risk of progression or death compared with placebo (HR 0.35; 95% CI 0.26-0.48; P<0.001)1 • The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or GIST has not been demonstrated1

0.6 0.4 0.2 0.0 0

Months

Important Safety Information for VOTRIENT WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

Randomized, double-blind, placebo-controlled, multicenter, Phase 3 trial to evaluate the efﬁcacy and safety of VOTRIENT in patients (N=369) with advanced STS. The Phase 3 trial population excluded patients with adipocytic sarcoma or GIST. Patients were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.1,2

• Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the randomized STS trial, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT had congestive heart failure, which did not resolve in 1 patient. Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Hemorrhagic events have occurred and can be fatal. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thrombotic Events: Arterial thrombotic events have occurred and can be fatal. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thrombotic event in the past 6 months.

• Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures. Treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence.

Please see Brief Summary of Prescribing Information, including BOXED WARNING, for VOTRIENT on adjacent pages.

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In soft tissue sarcoma, a dose decrease or increase should be in 200 mg steps based on individual tolerability • In patients taking VOTRIENT, dose modifications, interruptions, and discontinuations may be required for hepatic impairment, drug interactions, and following adverse events • In the advanced STS clinical trial, 58% of patients on VOTRIENT required a dose interruption; 38% of patients on VOTRIENT had their dose reduced • Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modifications based on drug interactions, please see Section 2.2 of accompanying Brief Summary

• Hypothyroidism: Hypothyroidism was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. • Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT.

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial thrombotic and venous thromboembolic events, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • The most common adverse reactions (≥20%) in patients with advanced soft tissue sarcoma who received VOTRIENT were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, hair color changes, vomiting, tumor pain, dysgeusia, headache, musculoskeletal pain, myalgia, gastrointestinal pain, and dyspnea See below and accompanying Brief Summary for additional Important Safety Information, including Warnings and Precautions.

• Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs 0% in the placebo group). • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.

The most common adverse reactions (≥20%) in patients who received VOTRIENT versus placebo were fatigue (65% vs 48%), diarrhea (59% vs 15%), nausea (56% vs 22%), decreased weight (48% vs 15%), hypertension (42% vs 6%), decreased appetite (40% vs 19%), hair color changes (39% vs 2%), vomiting (33% vs 11%), tumor pain (29% vs 21%), dysgeusia (28% vs 3%), headache (23% vs 8%), musculoskeletal pain (23% vs 20%), myalgia (23% vs 9%), gastrointestinal pain (23% vs 9%), and dyspnea (20% vs 17%). Laboratory abnormalities occurring in >10% of STS patients and more commonly (≥5%) in patients receiving VOTRIENT versus placebo included increases in AST (51% vs 22%), ALT (46% vs 18%), glucose (45% vs 35%), alkaline phosphatase (32% vs 23%), total bilirubin (29% vs 7%), and potassium (16% vs 11%); decreases in albumin (34% vs 21%) and sodium (31% vs 20%); and leukopenia (44% vs 15%), lymphocytopenia (43% vs 36%), thrombocytopenia (36% vs 6%), and neutropenia (33% vs 7%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. 2. Data on file. GlaxoSmithKline, 2011.

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. • Adverse Reactions in the Randomized STS Trial: Fifty-eight percent of patients on VOTRIENT required a dose interruption, 38% of patients on VOTRIENT had their dose reduced, and 14% of patients who received VOTRIENT discontinued therapy due to adverse reactions.

VOTRIENT.com/HCP GSKSource.com

myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thrombotic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. 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. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.10 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.14 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.15 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly

in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.16 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Fourteen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with STS who Received VOTRIENT

Adverse Reactions Fatigue

VOTRIENT

Placebo

(N=240)

(N=123)

All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 % % % % % % 65

Diarrhea

Nausea

Weight decreased

Hypertension

Appetite decreased

Hair color changes

Vomiting

Tumor pain

Dysgeusia

Headache

Musculoskeletal pain

Myalgia

Gastrointestinal pain

Dyspnea

Exfoliative rash

Cough

Peripheral edema

Mucositis

Alopecia

Dizziness

Skin disorderb

Skin hypopigmentation

Stomatitis

Chest pain

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. b 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia. Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus <1%), chills (5% versus 1%), vision blurred (5% versus 2%), nail disorder (5% versus 0%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. a

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with STS who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo

Parameters Hematologic Leukopenia Lymphocytopenia Thrombocytopenia Neutropenia Chemistry AST increased ALT increased Glucose increased Albumin decreased

VOTRIENT Placebo (N=240) (N=123) All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 % % % % % % 4 43 3 3

41 10 63 34

0 0 1 0

1 36 6 7

50 9 0 0

0 2 0 0

5 4 45

15 68 <1

3 2 0

2 1 35

22 82 2

0 1 0

B:14.25”

T:14”

S:13”

Alkaline phosphatase 3 23 0 2 31 0 increased Sodium decreased 3 14 0 2 03 0 Total bilirubin 2 9 1 0 7 2 0 increased Potassium increased 1 61 0 1 10 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the STS clinical trial. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)] 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.16)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile

animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.15)]. 8.5 Geriatric Use: In the STS trials, 24% (93/382) of patients were age ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%) and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT >ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/ moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/ day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration

of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

The ASCO Post | MAY 15, 2013

PAGE 80

Expert’s Corner Late Effects

Managing Female Reproductive Complications after Cancer Treatment in Children and Young Adults A Conversation with Monika L. Metzger, MD, MSc By Charlotte Bath

Monika L. Metzger, MD, MSc

ollow-up care for female patients treated for cancer as children, adolescents, or young adults should include assessment and management of the late effects that therapy may have on reproductive health, as detailed in updated guidelines from the Children’s Oncology Group. “It is important for oncologists to take action, to feel responsible for this aspect of cancer care,” Monika L. Metzger, MD, MSc, the lead author of the guidelines told The ASCO Post. It is also important, she added, “for the general practitioners who take care of these patients after they have gone through cancer treatment to be familiar with the guidelines regarding reproductive health, as well as all other issues of cancer survivorship.” Dr. Metzger is an Associate Member, Department of Oncology, at St. Jude Children’s Research Hospital in Memphis.

Rapidly Evolving Field The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers are evidence-based recommendations for screening and managing the late effects of cancer treatment. The literature updates for the guidelines occur every 2 years though guideline updates based on these reviews occur every 5 years, with the latest version recently published in the Journal of Clinical Oncology.1 “This is a field that has been rapidly evolving,” Dr. Metzger said. She cited the example of oocyte cryo-

preservation—removing eggs from a woman’s body and freezing them for later fertilization and reimplantation. “Oocyte cryopreservation is no longer considered experimental by the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology,” Dr. Metzger noted. Dr. Metzger primarily treats young patients who have lymphomas and whose reproductive health may be affected by chemotherapy or radiotherapy. “Adolescents and young adults have their own fears, questions, and concerns,” she said. Conversely, these young patients can seem “particularly unconcerned, which happens, too,” she said, because they don’t think cancer or

patients or parents might not think of in terms of reproductive health. Does this need to be explained? If the central nervous system needs to be irradiated, then it absolutely needs to be brought up that this may affect reproductive health. Does treatment of hypogonadism with hormone replacement therapy raise concern from patients and parents about risks of hormone replacement itself? Yes, but not going through puberty is probably even harder. We don’t know the answer yet, but at this point there is no reason not to give hormone replacement therapy to a young girl who is not going into puberty.

A cancer survivor will always be a cancer survivor and will always harbor the risks of its treatment. So I think cancer survivors should be followed for the rest of their lives. It doesn’t always have to be with an oncologist. —Monika L. Metzger, MD, MSc

treatment side effects could possibly ever affect them. In an interview with The ASCO Post, Dr. Metzger offered insight into the concerns of young patients and their parents and how oncologists and other health professionals can address those concerns.

Methodical Approach What should initial discussions with young patients about cancer treatment include about possible effects on reproductive health? The most important thing at diagnosis is the location of the cancer and whether that could affect anything about your reproductive potential. Then comes discussion of the therapies—the chemotherapy, the radiotherapy, the surgery—and how do those affect your reproductive health altogether. There needs to be a methodical approach to this. One of the locations mentioned in the guidelines is the hypothalamus, which

Preserving Fertility Are your patients mostly concerned about having children? Yes, they are concerned about whether they are going to be able to have children. Less frequently, some patients who have to go through chemotherapy or radiation therapy will also be concerned about whether their kids are going to be healthy. The guidelines mention that many cancer survivors have unnecessary anxiety about the risk of birth defects, which are not more frequent among their offspring. Yes, that is true. But we also don’t want our patients to become pregnant during chemotherapy because we don’t know how that will affect the fetus. While oocyte preservation is no longer considered experimental by the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology, what are the

options for younger prepubertal patients? Ovarian tissue cryopreservation is still experimental. There has been some success with this technique, but it is still too early to know whether this is a realistic option. It is definitely not something that can be used for every type of cancer. For instance, you wouldn’t use it for leukemia, because leukemia can be harbored in the ovarian tissue, and you would hate to reintroduce the disease into an already cured patient. Is oophoropexy commonly used? How is it determined where to transpose the ovaries to properly shield them? Oophoropexy—surgical fixation or suspension of the ovaries to remove them from the field of irradiation—is used mainly for Hodgkin lymphoma patients. It is done laparoscopically. The ovaries are tacked behind the uterus, and there is no need to reposition them in order for the patient to become pregnant or to continue normal regular menses. How well oophoropexy shields the ovaries will depend on the field of radiation. Sometimes there might also be scattered radiation. The ovaries are extremely sensitive to radiation. The radiation oncologist obviously still needs to be careful when irradiating the iliac inguinal lymph nodes.

Lifelong Follow-up Do female patients treated for cancer when they are young need to have followup assessments of reproductive health throughout their lives, or is there a cutoff, according to either the age of the patient or years posttreatment? A cancer survivor will always be a cancer survivor and will always harbor the risks of its treatment. So I think cancer survivors should be followed for the rest of their lives. It doesn’t always have to be with an oncologist. The medical community needs to be educated that more and more of the population are going to be cancer survivors, and they would continued on page 82

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

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

AND...

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

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

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

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

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

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

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

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

The ASCO Post | MAY 15, 2013

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Expertâ&#x20AC;&#x2122;s Corner

Monica L. Metzger, MD, MSc continued from page 80

do better following guidelines that address the risks of previous treatment. A survey cited in the guidelines found that providers and patients tend

to avoid the topic of sexual dysfunction, â&#x20AC;&#x153;although 80% of women report a desire to discuss sexual issues.â&#x20AC;? The guidelines say, â&#x20AC;&#x153;providers should initiate discussions.â&#x20AC;? Whatâ&#x20AC;&#x2122;s a good way to start those discussions? Health-care providers just need to be very matter of fact. â&#x20AC;&#x153;We were talk-

ing about your vision. We were talking about your hearing. Now we are talking about your sexual function.â&#x20AC;? If the provider is uncomfortable talking about it, then the patient is going to be uncomfortable. n Disclosure: Dr. Metzger reported no potential conflicts of interest.

Reference 1. Metzger ML, Meacham LR, Patterson B, et al: Female reproductive health after childhood, adolescent, and young adult cancers: Guidelines for the assessment and management of female reproductive complications. J Clin Oncol 31:1239-1247, 2013.

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

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

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

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

ASCOPost.com | MAY 15, 2013

PAGE 83

News Hematology

Majority of Children Readmitted to Hospital Following Stem Cell Transplant

early two-thirds of children receiving stem cell transplants returned to the hospital within 6 months for treatment of unexplained fevers, infections, or other problems, according to a study performed at Dana-Farber/Childrenâ&#x20AC;&#x2122;s

Hospital Cancer Center in Boston. Children who received donor cells were twice as likely to be readmitted as children who received their own stem cells, the study indicated. â&#x20AC;&#x153;No one had ever looked at these data

in children,â&#x20AC;? said Leslie E. Lehmann, MD, Clinical Director of Pediatric Stem Cell Transplantation at Dana-Farber/ Childrenâ&#x20AC;&#x2122;s Hospital Cancer Center. â&#x20AC;&#x153;This is very important information and will allow us to counsel families appropriately, Leslie E. Lehmann, MD

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

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

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

as well as try to devise interventions that reduce the rate of readmissions,â&#x20AC;? she said. The study by Dr. Lehmann and Harvard Medical School student David Shulman was presented recently at the 26th Annual Meeting of the American Society of Pediatric Hematology Oncology in Miami.

Study Details A record review of 129 children from 2008 to 2011 revealed that 64% had at least one hospital readmission within 180 days of transplant. The source of the donor cells was a key predictor: 79% of patients receiving transplants from a related or unrelated donor were readmitted compared to 38% who received their own cells (autologous transplant). The mean number of readmissions was 2.4, indicating that for some children, discharge after transplant is just the beginning of a long process characterized by repeated hospital stays. Fever without a documented source of infection accounted for 39% of the readmissions; 24% were for infections, and 15% for gastrointestinal problems. â&#x20AC;&#x153;Most of the patients went on to be successfully treated and ultimately did very well,â&#x20AC;? commented Dr. Lehmann.

Future Goals

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

ONCOLOGY

â&#x20AC;&#x153;We hope these findings can eventually lead to identifying a group of low-risk children who could be managed at local hospitals rather than transplant centers, reducing costs and inconvenience to families,â&#x20AC;? Dr. Lehmann said. Dr. Lehmann said the goal is to identify which patients could be safely treated without requiring an admission to the hospital. n

Disclosure: The study was conducted without outside funding.

Reference 1. Lehman LE, Shulman D: Study presented at the 26th Annual Meeting of the American Society of Pediatric Hematology Oncology. April 2013.

The ASCO Post | MAY 15, 2013

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Issues in Oncology Perspective

Disparities in Cancer Care: How A Deep South Community Overcame Them By Caroline Helwick

acial inequities were a daily observation for Edward E. Partridge, MD, growing up in Alabama during the civil rights era. When he became a physician, he saw that these disparities extended into his own field, gynecologic oncology. He decided to do something about it. Dr. Partridge recently discussed his life’s work in a lecture at the Society of Gynecologic Oncology (SGO) Annual Conference on Women’s Cancers. He then shared his insight in an interview with The ASCO Post. Dr. Partridge is Director of the University of Alabama at Birmingham Comprehensive Cancer Center.

A Collective Challenge “Cancer disparities became obvious once we had either diagnostic or therapeutic procedures that could make a difference in outcomes,” he said. With the development of screening techniques for colorectal and breast cancers in the 1970s, disparities in the uptake of these techniques emerged—by income, insurance status, education— and this impacted mortality rates. The development of more effective treatments came next, and again, these were differentially delivered, he said. “Disparities in cancer care began to raise their ugly head in the 1980s, and by the early 1990s we were fully aware that they existed,” Dr. Partridge said. Disparities exist in areas where more clinicians could be making a difference: tobacco use (with higher education, smoking is less common); screening for breast, colorectal, and cervical cancer (the higher educated and insured populations receive more screening); physical activity and obesity (obesity rates are higher in persons of low income and in African Americans); and the provision of high-quality care for cancer. “These are the areas where we deliver care differentially,” Dr. Partridge said. “If everyone had the same mortality rate as college-educated persons, there would be 216,000 fewer cancer deaths annually in the United States,” he added. “There are no biologic or genetic differences between persons with a college education and those without, but the college-educated person does not smoke, gets age-appropriate screening, consumes a relatively healthy diet, and gets some physical activity every

week. When people in this group do develop cancer, they have insurance and they seek the best care possible,” he explained. “Their lower mortality rate is what is achievable based on our knowledge today,” he said, yet this is an unrealized goal in the general population. “Collectively, [as physicians, we can do better] to deliver what we know to the nation’s population,” Dr. Partridge maintained.

UAB Makes a Commitment Becoming an NCI-designated cancer center in the Deep South in 1972, the University of Alabama at Birmingham expressed a “moral and ethical obligation” to alleviate cancer disparities in 1992, he said. “We began connecting to our African American populations in both the inner city and in the rural Black Belt (named

and to facilitate enrollment for those deemed eligible. With this intervention, clinical trial participation doubled among African Americans, from 11% of all cancer diagnoses to 22%.

Interventions Deliver on Outcomes The various programs described by Dr. Partridge have clearly delivered on health-care outcomes. “Over time, we demonstrated that we eliminated disparities,” he said. Disparities in mammography screening between white and African American women on Medicare were essentially obliterated, reduced from a 16% difference prior to 2000 to a 0.5% difference in 2006. In a second intervention, 71% of women never previously screened obtained mammograms. Cervical cancer screening increased as well, and as a result, mortality from

We can redesign our health-care delivery system to markedly reduce disparities. It’s not complicated. It doesn’t matter how poor that community is. —Edward E. Partridge, MD

for its rich black soil, not its population) of Alabama [eventually moving into the Mississippi Delta as well],” he said. Two-thirds of the population in these regions is African American, and onethird live below the poverty line. Thus was formed the Alabama Partnership for Cancer Control (now the Deep South Network for Cancer Control), a program that capitalized on community spirit and cohesiveness, centered around community health advisors—African American women well trained to promote breast and cervical cancer screening in their underserved communities. The next step was to train community health advisors to be patient navigators. These navigators facilitated access to care and ensured adherence to diagnostic follow-up of positive screens or prescribed cancer treatments. A third program trained lay workers to promote clinical trial participation

this malignancy—which at baseline was twice as high in the Black Belt region vs higher-income areas—by 2005 had become half as likely as in other areas. “All this suggests that volunteers working in a community can actually change behavior within a population,” he said. “This tells me we can redesign our health-care delivery system to markedly reduce disparities. It’s not complicated. It doesn’t matter how poor that community is. There are individuals who want to improve the plight of their community. This is a model of what can be done elsewhere,” he added.

Latest Endeavor “One of the more exciting things we are doing now is based on our experience with the lay navigators in early phases of the cancer continuum—essentially, it is to make our lay navigators

‘nurse extenders’ and use them in the survivorship and end-of-life phases of care,” Dr. Partridge said. Through a $15 million 3-year Innovation Challenge Grant from the Centers for Medicare and Medicaid, the UAB Comprehensive Cancer Center and its 10 affiliated centers will train 35 lay navigators. Their aim is to overcome health system and community barriers in an effort to increase adherence to screening and lifestyle changes in the survivorship phase, to on-pathway treatments and to survivorship/advanced care plans. The program aims not only to improve healthcare outcomes but to reduce costs and demonstrate value. “Every Medicare patient will be assigned a navigator who will be an extension of the physician’s office. The goal is to intervene earlier, during the acute phase of care, to prevent unnecessary use of the emergency room, hospital, and intensive care unit,” he said. “The ‘innovative’ part that is really exciting is this: we are going to train a supportive/palliative care team to have discussions during survivorship about end-of-life choices with the patient and family. The goal is to have patients enter hospice care a month earlier than usual and eliminate chemotherapy during the final 2 weeks of life,” he added. Dr. Partridge estimates that this intervention alone will reduce Medicare expenditures at UAB and its 10 affiliated sites by $50 million a year. “I think we will be able to demonstrate that lay persons can do a great job as nurse extenders, if you will, and this approach will save money,” he said. In closing, he emphasized that what has been done in Alabama and the Delta can be replicated in other underserved areas. Such programs are most likely to be successful, he added, when they “create trust, eliminate bias, and share power.” n Disclosure: Dr. Partridge reported no potential conflicts of interest.

Dr. Partridge recently presented his lecture “Our Failure to Deliver,” as the American Cancer Society Lectureship at the Society of Gynecologic Oncologists (SGO) Annual Meeting on Women’s Cancers in Los Angeles. The comments and opinions expressed herein are those of Dr. Partridge and do not necessarily reflect the opinion of the The ASCO Post, Harborside Press, or ASCO. For more information, visit sgo.org.

NOW ENROLLING

ACUTE LYMPHOBLASTIC LEUKEMIA

INO-VATE ALL INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy A randomized, phase 3 trial in patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) This is a 2-armed, randomized, open-label, phase 3 study designed to evaluate the hematologic remission rate (CR + CRi) with inotuzumab ozogamicin compared with investigators’ choice of FLAG, cytarabine combined with mitoxantrone, or HIDAC.

Selected inclusion criteria • Relapsed or refractory CD22-positive ALL due to receive salvage 1 or salvage 2 therapy • Ph+ ALL patients must have failed treatment with at least 1 second-generation tyrosine kinase inhibitor • Bone marrow involvement with ≥5% lymphoblasts • Aged 18 years or older • ECOG performance status 0-2 • Adequate liver function

Selected exclusion criteria • Isolated extramedullary relapse, Burkitt’s lymphoma or mixed-lineage leukemia, or active central nervous system leukemia • Active heart disease • Prior chemotherapy ≤2 weeks prior to randomization and/or patients not recovered from acute toxicity • Prior treatment with monoclonal antibodies ≤6 weeks before randomization • Prior allogeneic hematopoietic stem cell transplant ≤4 months before randomization • Peripheral lymphoblasts >10,000/µL

Reference: ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01564784. Accessed April 3, 2012.

Inotuzumab ozogamicin is an investigational compound. This information is current as of August 14, 2012.

STW00067B

April 2012

Learn more about INO-VATE (B1931022) For more information about this trial, please visit www.clinicaltrials.gov (NCT01564784) or call: 1-877-369-9753 in the United States and Canada (toll-free) or +1-646-277-4066 outside the United States

The ASCO Post | MAY 15, 2013

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Philanthropy Spotlight

ASCO President’s Personal Philanthropy Honors Founder Jane C. Wright, MD

uring her term as ASCO President, Sandra M. Swain, MD, FACP, of the Washington Cancer Institute has kept a solid focus on her presidential and 2013 ASCO Annual Meeting theme of “Building Bridges to Conquer Cancer.” These bridges take many forms, spanning challenges to be overcome in oncology practice. According to Dr. Swain, some of the most critical challenges that must be overcome include addressing the needs of the global oncology community, closing the gap in health disparities, connecting science with the clinic, and bringing the highest quality care to the patient. As a member of the Conquer Cancer Foundation Board of Directors and as a longtime donor to the Conquer Cancer Foundation, Dr. Swain has contributed to an essential component of each of those bridges—her personal philanthropy. Donations to the Conquer Cancer Foundation are fueling work in each of these key areas, helping to pave the way for a world free from the fear of cancer. The Foundation supports ASCO International through programs that create connections and provide educational opportunities for oncologists in low- and middle-income countries; it is working to combat health disparities through the Diversity in Oncology program; it fosters clinical and translational research through the Grants & Awards Program; and it champions quality care through support of ASCO’s revolutionary learning health system, CancerLinQ™. Through their generosity, donors like Dr. Swain are building bridges to conquer cancer every day.

Honoring Women in Oncology For the past several years, Dr. Swain has personally contributed to the Conquer Cancer Foundation of ASCO Jane C. Wright, MD, Young Investigator Award (YIA), which provides a year of research funding for a promising young in-

vestigator during the challenging transition from training to a cancer research career. The award is named in honor of Dr. Jane Wright, who was one of seven founding members of ASCO—the only woman among the founders—and the Society’s first Secretary/Treasurer. Dr. Wright, who passed away early this spring, was a true trailblazer. At a time when the administration of chemotherapy was largely thought of as experimental, she pioneered the use of anticancer agents and developed new techniques for administrating cancer chemotherapy. And at a time when African American women phy-

en, and the number continues to increase each year as more and more women join the field. Dr. Swain is dedicated to encouraging more women to pursue their passion for improving cancer care. “Throughout the course of my career,

I want to continue the discussion, to honor those women who have paved the way, and to help figure out what we can do to give the future generation of women leaders the tools they will need to meet the evergrowing demands of our field. —Sandra M. Swain, MD, FACP

sicians numbered only a few hundred in the entire United States, she was the highest ranked African American woman at a nationally recognized medical institution. “When I hear the story of Dr. Jane Wright, I am truly amazed at her vision, courage, and fortitude in blazing her own path and advancing the field of oncology in so many ways,” said Dr. Swain. Dr. Wright was just one of the many oncologists celebrated by Dr. Swain, ASCO, and the Conquer Cancer Foundation this year on International Women’s Day. In the last several decades, increasing numbers of women have entered the field of oncology—enrolling in medical school, conducting cancer research, and holding leadership positions in professional societies, cancer treatment centers, academia, government, and industry. Today, more than 30% of ASCO’s 30,000 members are wom-

one issue that has remained close to my heart is encouraging women to pursue careers in medical leadership and clinical practice… And as a shortage in oncology professionals looms over us, it’s only wise to develop all the talent and nurture all the passion that we can find,” she said. “I want to continue the discussion, to honor those women who have paved the way, and to help figure out what we can do to give the future generation of women leaders the tools they will need to meet the ever-growing demands of our field,” she said.

Giving That Inspires For Dr. Swain, the life and career of Dr. Jane Wright are an inspiration that she honors through philanthropic support of the Jane C. Wright, MD, YIA. Many other ASCO Members also choose to support the Foundation in this way, by

making donations in honor of fellow oncologists—mentors, colleagues, and friends—who have inspired them in their careers. Those individuals receive a personalized letter announcing the gift, and are listed as honorees on the Foundation’s website and on banners at the ASCO Annual Meeting. “Giving to an organization like ours is a very personal act of generosity,” said Foundation Executive Director Nancy R. Daly, MS, MPH, “perhaps even more so for ASCO members who see the challenges and opportunities in cancer care up close on a daily basis. That’s why we always want to provide the opportunity for donors to express something personal through their giving—to use their gifts as a way to say ‘Thank you’ or ‘You inspire me’ to someone who has made a difference in their lives or careers.” For Dr. Swain, it all comes back to building bridges, between colleagues, between doctor and patient, and between where we are now as a Society and where we want to be in the future: brick by brick, through ingenuity and generosity. If you would like to make a donation in honor of Dr. Wright and her lifetime commitment to improving cancer care through research, you can do so by supporting the Jane C. Wright, MD, Young Investigator Award. Please help us honor her memory by making a gift today at ConquerCancerFoundation.org/donate. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | MAY 15, 2013

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ASCO President’s Priorities Aim to Build Bridges to Advance Cancer Care

ecognizing the need for greater interconnectivity to accelerate cancer care advances, Sandra M. Swain, MD, FACP, current ASCO President and Medical Director of Washington Cancer Institute MedStar Washington Hospital Center, selected “Building Bridges to Conquer Cancer” as her presidential theme. Major priorities of her term include sharing real-time knowledge to improve patient outcomes, ensuring global health equity, and preparing for the future of oncology.

culled from medical records provided by partner physicians. It will yield detailed information about presenting symptoms, molecular profiles, courses of treatment, side effects, outcomes, and more. In doing so, CancerLinQ will better equip clinicians to provide highly personalized cancer care based on the unique characteristics of each patient’s tumor and physiologic makeup. Once outcome information is aggregated, the information will facilitate the development of guidelines to further improve care quality.

Improving Access to Realtime Decision Support

Reducing Disparities in Cancer Care

To promote the exchange of valuable clinical data that is currently tucked away in millions of medical records across the globe, ASCO is creating a rapid learning system called CancerLinQ. This new tool, which is currently in the prototype stage, will connect oncology practices, measure quality and performance, and provide physicians with decision support in real time. According to Dr. Swain, “The goal is to increase quality care and efficiency by connecting practices’ electronic health records (EHRs) and providing easy access to all information.” CancerLinQ will create a searchable database, composed of information

Meanwhile, Dr. Swain has also prioritized programs designed to bridge the gap in health equity among different racial and economic groups in cancer prevention, diagnosis, and treatment. “Recognizing its responsibility as the leading clinical oncology organization in the world, ASCO has taken deliberate steps to improve global cancer care through its numerous educational offerings and grants,” says Dr. Swain, adding that she hopes to continue building upon that foundation. Signaling a heightened emphasis on this issue, ASCO recently established the Health Disparities Committee,

which was previously a workgroup. Domestically, ASCO is working to eliminate cancer care disparities through programs designed to attract more minority physicians, promote training that equips clinicians to meet the needs of racially and ethnically diverse patients with cancer, improve data collection on cancer disparities, and ensure access to cancer specialists at all federally qualified community health centers. In addition, ASCO has taken an active role advocating for Medicaid and Medicare policies that increase access to high-quality cancer care and clinical trials, including provisions in the Affordable Care Act. Globally, ASCO has long tapped into its worldwide network of members to provide clinicians around the world with resources to help them achieve better care for their cancer patients through programs such as international volunteer opportunities, international training sessions and workshops, and international fellowships and awards. Building upon this foundation, ASCO recently launched ASCO International, an ambitious 4-year expansion of new programs, initiatives, and research opportunities. The goal of ASCO International is to increase awareness of global

cancer care quality disparities, improve practice, and foster innovation in countries around the world, crossing socioeconomic and geographic boundaries.

Preparing to Address Tomorrow’s Challenges As a final area of focus, Dr. Swain is calling upon ASCO to prepare for the future of oncology, which holds challenges such as a growing and aging population, increasing numbers of cancer survivors, and slow growth in the supply of oncologists. To address these issues, ASCO is committed to ongoing initiatives that promote collaborative care and innovative practice models, track trends in the oncology workforce, and train the next generation of oncologists to practice in a time of workforce shortage. Noting the growing number of women in oncology, Swain says, “We need to be creative to find better way to keep them in the workforce.” She adds that the younger generation wants a better lifestyle and that the health care field needs to foster collaborative work environments that allow for work-life balance. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCO Completes Prototype for CancerLinQ™, Marking First Demonstration of a ‘Learning Health System’ to Transform Cancer Care

SCO has completed a prototype of CancerLinQ™, the Society’s groundbreaking health information technology initiative to achieve higher quality, higher value cancer care with better outcomes for patients. The prototype was shown on March 27 at the National Press Club in Washington, DC, during an ASCO-hosted panel discussion on big data in cancer care. With CancerLinQ, ASCO is developing a knowledge-generating computer network that will collect and analyze cancer care data from millions of patient visits, together with expert guidelines and other evidence, to generate real-time, personalized guidance and quality feedback for physicians. “Today we know very little about the experiences of most people with

cancer because their information is locked away in unconnected servers and paper files,” said Sandra M. Swain, MD, President of ASCO. “Only the 3% of patients who participate in clinical trials are able to contribute to advances in treatment. CancerLinQ will transform cancer care by unlocking that wealth of information and enabling every patient to be a cancer knowledge donor.”

Core Functions ASCO built the CancerLinQ prototype to demonstrate the feasibility of such a system and to provide lessons about the technological and logistical challenges involved in fullscale implementation. The prototype includes “de-identified” (ie, anony-

mous) data from 100,000 patients with breast cancer who were treated at leading cancer care institutions around the United States. It reflects more than a year of formative work, including consultation with the oncology and IT communities; efforts to improve oncology data standards; and extensive technology and legal analysis. To build the prototype quickly, ASCO linked together several opensource IT applications. Together, they encompass CancerLinQ’s planned core functions, including: ■ Real-time data collection ■ Clinical decision support ■ Data mining and visualization

■ Quality feedback The prototype will ultimately include data on more than 133,000 cases from oncology practices across the country, far exceeding initial expectations and lending further strength to the lessons that can be drawn from the prototype. ASCO plans to publish its lessons learned over the coming year, and will use them to inform its development of the full CancerLinQ system. For more information, please go to www.asco.org/cancerlinq. n © 2013. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | MAY 15, 2013

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Direct from ASCO

Leading Investigators Honored for Outstanding Contributions to the Field of Oncology

ach year through its Special Awards Program, ASCO recognizes researchers, patient advocates, and leaders of the global oncology community who, through their work, have made significant contributions to enhancing cancer care. These recipients of ASCO’s highest, most prestigious awards collectively represent significant strides in cancer treatment and leadership in the oncology community.

David A. Karnofsky Memorial Award And Lecture Martine J. Piccart, MD, PhD Dr. Piccart is a Professor of Oncology at the Université Libre de Bruxelles and Director of Medicine at the Jules Bordet Institute, Brussels, Belgium. She is a leader in international breast cancer research collaboration and drug development, and serves as the principal or co-principal investigator for numerous clinical trials including HERA, MINDACT, and ALTTO. She is co-founder and Chair of the Breast International Group (BIG), uniting 49 academic research groups from around the world and running over 30 trials under its umbrella.

Science of Oncology Award and Lecture Charles L. Sawyers, MD Dr. Sawyers is Head of the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center, where he works to bring molecularly targeted approaches and molecularly based patient stratification to clinical trials and patient treatment more broadly across tumor types. His laboratory research led to the discovery of BCR-ABL mutations and the development of the secondgeneration ABL inhibitor dasatinib (Sprycel), which overcomes imatinib (Gleevec) resistance.

ASCO–American Cancer Society Award and Lecture Kenneth Offit, MD Dr. Offitt is Chief of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center, a member of the Program in Cancer Biology and Genetics at the SloanKettering Institute, and a Professor of Medicine and Public Health at the Weill College of Medicine of Cornell University. His research group performed the first genome-wide association study of BRCA2 breast cancer, and he is currently using next-generation sequencing to define genomic markers of risk for leukemia, lymphoma, breast, ovarian, and prostate cancers.

medical care, laboratory and clinical research, advocacy, and government; participated in the development of several effective agents including paclitaxel and trastuzumab (Herceptin); and co-invented the Norton-Simon Model of cancer growth, which has broadly influenced cancer therapy.

Pediatric Oncology Award and Lecture Garrett M. Brodeur, MD Dr. Brodeur is an Associate Chair for Research in the Department of Pediatrics at the Children’s Hospital of Philadelphia, an Associate

Volume 29, Issue 15

Official Journal of the American Society of Clinical Oncology

B. J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology Arti Hurria, MD Dr. Hurria is Director of the Cancer and Aging Research Program at City of Hope. She serves as principal investigator on two major grants: one that seeks to identify and develop research methodology that will lead to evidence-based recommendations to improve clinical care for older adults with cancer, and one evaluating clinical and biological predictors of chemotherapy toxicity in older adults with breast cancer.

Gianni Bonadonna Breast Cancer Award and Lecture Larry Norton, MD Dr. Norton is the Deputy Physician-in-Chief for breast cancer programs and Medical Director of the Evelyn H. Lauder Breast Center. He has dedicated his life to the eradication of cancer by activities in

May 20, 2011

JOURNAL 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

Director of the Abramson Cancer Center in the Perelman School of Medicine at the University of Pennsylvania, and holds the Audrey E. Evans Endowed Chair in Pediatric Oncology at the Children’s Hospital of Philadelphia. He played an integral role in the identification of three important genes involved in genomic rearrangements in neuroblastomas: amplification of the MYCN oncogene; deletion of CHD5, a tumor suppressor

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

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gene from 1p36; and mutations of ALK, a gene responsible for most cases of hereditary neuroblastoma.

Distinguished Achievement Award Eduardo L. Cazap, MD, PhD Dr. Cazap is the founder and first President of the Latin American and Caribbean Society of Medical Oncology (SLACOM), the Immediate Past President of the International Union against Cancer (UICC), and the recently designated Deputy Chair of the Developing Countries Task Force of the European Society of Medical Oncology. Dr. Cazap’s leadership has helped push cancer

New ASCO Answers Guides to Breast, Prostate, and Lung Cancer Now Available for Patients

and world health into the international political agenda. In 2011, he served as Co-Chair of the United Nations Civil Society Task Force to advise the President of the United Nations General Assembly during a high-level meeting on noncommunicable diseases.

Special Recognition Award Otis W. Brawley, MD, FACP Dr. Brawley is Chief Medical and Scientific Officer for the American Cancer Society. He serves as a Professor of Hematology, Oncology, Medicine, and Epidemiology at Emory University. Over a career that

For newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer

Oncotype DX reveals the underlying biology that changes treatment decisions 37% of the time ®

37%

changed

63% confirmed

Even when treatment decisions based on traditional measures seem conclusive, Oncotype DX can lead to a different approach • In a meta-analysis, treatment decisions were changed even when definitive treatment decisions had already been made*†1 33% switched from CT + HT to HT alone‡ 4% switched from HT only to CT + HT ‡

he new ASCO Answers guides to cancer are designed to help patients newly diagnosed with cancer understand their disease and treatment options. These comprehensive, patientfriendly booklets contain trusted information about diagnosis, treatment, side effects, and the psychosocial effects of cancer. They also provide space for patients to record details about their diagnosis and treatment plan, a feature that allows patients to easily go back and find the most pertinent information when needed. Each guide can be purchased from the ASCO University Bookstore at www.cancer.net/estore, with a 20% discount for ASCO members. n © 2013. American Society of Clinical Oncology. All rights reserved.

• Only assay incorporated into major clinical practice guidelines to predict chemotherapy benefit 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.

Now available for patients with ductal carcinoma in situ (DCIS) Genomic Health, Oncotype DX, and Uncover the Unexpected are registered trademarks of Genomic Health, Inc. © 2013 Genomic Health, Inc. All rights reserved. GHI10100_0712

has encompassed clinical practice, research, and public policy, Dr. Brawley has championed the American Cancontinued on page 90

The ASCO Post | MAY 15, 2013

PAGE 90

Direct from ASCO

Visit the Conquer Cancer Foundation Donor Lounge at the ASCO Annual Meeting

donors will be given exclusive, complimentary access to light refreshments and a quiet place to relax and meet with friends and colleagues. It also offers multiple computer stations for checking e-mail and accessing the Internet. Not a donor? Not a problem! Stop by the Donor Lounge at any time to make your gift or do so online at ConquerCancerFoundation.org/do-

nate. An annual contribution of $250 or more is appreciated. The Donor Lounge will be located in room S401 of McCormick Place and will be open Friday through Monday from 8:30am to 5:30pm and on Tuesday from 8:30am to noon. n

Photos © ASCO/Todd Buchanan 2012

he work that we do at the Conquer Cancer Foundation would not be possible without the support of generous donors who share our vision to create a world free from the fear of cancer. Conquer Cancer Foundation supporters are invited to visit the Donor Lounge during the ASCO Annual Meeting in Chicago, IL, May 31 to June 4. The lounge will be open throughout the meeting, and

Connect and collaborate with your colleagues in the Conquer Cancer Foundation Donor Lounge.

Special Awards Program continued from page 89

cer Society’s initiatives in tobacco cessation, nutrition, early detection of cancer, and whole-patient care, as well as efforts to eliminate disparities in access to quality cancer care.

Humanitarian Award Bella Kaufman, MD Dr. Kaufman leads the breast cancer unit at The Chaim Sheba Medical Center at Tel Hashomer, Israel, affiliated with Tel Aviv University, and is a founder and leader of the Israeli Consortium for Hereditary Breast Cancer. A longtime volunteer, she is currently a board member for nongovernmental organizations

that promote the right to health equality and provides medical assistance at Physicians for Human Rights-Israel’s clinics, with special attention to underserved cancer patient populations. She goes beyond her daily patient work to care for the underserved populations in her region, including the recent influx of African refugees to Israel and the Palestinian villages of the West Bank.

Partners in Progress Award Howard R. Soule, PhD Dr. Soule is Executive Vice President and Chief Science Officer at the Prostate Cancer Foundation, the leading philanthropic organization in funding and accelerating

prostate cancer research globally. His role in the Prostate Cancer Foundation has greatly contributed to the Foundation’s success in accelerating international research and in increasing public awareness of the disease.

Public Service Award Richard Pazdur, MD Dr. Pazdur is the Director of the Office of Hematology and Oncology Products in the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration. He facilitates coordination of oncology activities across all FDA centers and ensures an ongoing outreach and collaboration between FDA, the National Cancer Institute, and other can-

cer-related organizations within and outside of the government.

Fellows of the American Society of Clinical Oncology (FASCO) The Fellow of the American Society of Clinical Oncology (FASCO) distinction recognizes ASCO members for their extraordinary volunteer service, dedication, and commitment to ASCO. The 2013 recipients of this distinction are: ■ Stephen A. Cannistra, MD ■ Michael A. Carducci, MD ■ Eduardo L. Cazap, MD, PhD ■ Martin J. Murphy, DMedSc, PhD ■ Joan H. Schiller, MD ■ George W. Sledge Jr., MD ■ Everett E. Vokes, MD n © 2013. American Society of Clinical Oncology. All rights reserved.

Up the AntiEGFR Start ERBITUX® (cetuximab) in 1st-Line I N D I C AT I O N S Head and Neck Cancer—ERBITUX is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck Colorectal Cancer—ERBITUX is indicated for the treatment of KRAS mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use, in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer EGFR=epidermal growth factor receptor.

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Approximately 90% of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In 3 patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7 (3%) of the 219 patients with squamous cell carcinoma of the head and neck treated with platinum-based therapy with 5-fluorouracil (5-FU) and European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin — Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks — Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium during and after ERBITUX therapy

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

START WITH THE EXTREME

Regimen

EXTREME=ERBITUX® (cetuximab) in first-line Treatment of REcurrent or MEtastatic head and neck cancer. EXTREME Regimen=EU-approved cetuximab combined with platinum-based therapy with 5-FU.

The First Regimen Approved in 30 Years With Extended Overall Survival for Recurrent Locoregional or Metastatic SCCHN EXTREME REGIMEN (n=222)1

PLATINUM-BASED THERAPY WITH 5-FU (n=220)1

EXTENDED Median Overall Survival

(OS) (Primary Endpoint)

10.1 MONTHS

36% IMPROVEMENT IN OS*

7.4

MONTHS

HR=0.80 (95% CI: 0.64–0.98); p=0.034

IMPROVED Objective Response Rates (Reduced Tumor Size)†

20%

36%

PATIENTS

OR=2.33 (95% CI: 1.50–3.60); p=0.0001

PROLONGED Median Progression-Free Survival

5.5

MONTHS

3.3

MONTHS

HR=0.57 (95% CI: 0.46–0.72); p<0.0001 * Relative improvement in median overall survival for the EXTREME regimen was ([10.1-7.4]/7.4) x 100%=36%.1 †

Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2,3 CI=confidence interval; CT=platinum-based therapy with 5-FU; HR=hazard ratio; OR=odds ratio; SCCHN=squamous cell carcinoma of the head and neck.

The EXTREME Study was an open-label, randomized (1:1), multicenter, controlled clinical trial that compared EU-approved cetuximab + CT versus CT alone. Choice of platinum therapy (cisplatin or carboplatin) was up to the treating physician. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately 15% of the patients in the cisplatin-alone arm switched to carboplatin during the treatment period. In exploratory subgroup analyses of the EXTREME Study by initial platinum therapy (cisplatin or carboplatin), for patients (n=284) receiving cetuximab plus cisplatin with 5-FU compared to cisplatin with 5-FU alone, the difference in median overall survival was 3.3 months (10.6 vs 7.3 months, respectively; HR=0.71 [95% CI: 0.54–0.93]). The difference in median progression-free survival was 2.1 months (5.6 vs 3.5 months, respectively; HR=0.55 [95% CI: 0.41–0.73]). The objective response rate was 39% and 23%, respectively (OR=2.18 [95% CI: 1.29–3.69]). For patients (n=149) receiving cetuximab plus carboplatin with 5-FU compared to carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months (9.7 vs 8.3 months; HR=0.99 [95% CI: 0.69–1.43]). The difference in median progression-free survival was 1.7 months (4.8 vs 3.1 months, respectively; HR=0.61 [95% CI: 0.42–0.89]). The objective response rate was 30% and 15%, respectively (OR=2.45 [95% CI: 1.10–5.46]).1 The EXTREME Study was conducted outside the U.S. using European Union (EU)-approved cetuximab as the clinical trial material. ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab used in these studies; these pharmacokinetic data, together with the results of the EXTREME Study, and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in SCCHN.1

IMPORTANT SAFETY INFORMATION (continued) Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD Select Adverse Reactions ■ The most frequent adverse reactions seen in patients with carcinomas of the head and neck receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) versus CT alone (n=215) (incidence ≥40%) were acneiform rash (70% vs 2%), nausea (54% vs 47%), and infection (44% vs 27%). The most common grade 3/4 adverse reactions for cetuximab in combination with CT (≥10%) versus CT alone included: infection (11% vs 8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX

START WITH THE CRYSTAL

Regimen

CRYSTAL=Cetuximab combined with iRinotecan in first-line therapY for metaSTatic colorectAL cancer. CRYSTAL Regimen=EU-approved cetuximab + FOLFIRI; FOLFIRI=irinotecan, 5-fluorouracil, and leucovorin.

The First and Only Biomarker-Directed Therapy for Newly Diagnosed KRAS Mutation-Negative (Wild-Type) EGFR-Expressing mCRC1 ALL-RANDOMIZED PATIENT POPULATION1 CRYSTAL Regimen (n=608)

Median Overall Survival*

KRAS WILD-TYPE SUBPOPULATION1 P O S T- H O C A N A LY S I S

FOLFIRI alone (n=609)

CRYSTAL Regimen (n=320)

18.5

23.5

(95% CI: 18–21)

(95% CI: 17–20)

(95% CI: 21–26)

MONTHS

HR=0.88 (95% CI: 0.78–1.0)

Objective Response Rates (Reduced Tumor Size)‡

46%

19.5 MONTHS

(95% CI: 17–21)

HR=0.80 (95% CI: 0.67–0.94)†

38%

57%

IMPROVED

39%

PATIENTS

(95% CI: 42–50)

(95% CI: 34–42)

(95% CI: 51–62)

(95% CI: 34–44)

PRIMARY ENDPOINT Median Progression-Free Survival

EXTENDED

19.6 MONTHS

FOLFIRI alone (n=356)

8.9

8.1

9.5

MONTHS

(95% CI: 8.0–9.4)

(95% CI: 7.6–8.8)

PROLONGED

8.1

MONTHS

(95% CI: 8.9–11.1)

(95% CI: 7.4–9.2)

HR=0.85 (95% CI: 0.74–0.99); p=0.0358

HR=0.70 (95% CI: 0.57–0.86)

In all randomized patients, overall survival was not significantly different at the planned, final analysis based on 838 events (HR=0.93 [95% CI: 0.8–1.1]; p=0.327). Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer. •The primary endpoint for the study was progression-free survival in the all-randomized patient population. * Post-hoc updated overall survival analysis based on an additional 162 events.1

Not significantly different.1 Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2,3 § Based on the stratified log-rank test.1 CI=confidence interval; HR=hazard ratio; mCRC=metastatic colorectal cancer.

†

‡

The CRYSTAL Study was a Phase 3, open-label, randomized, multicenter study of 1217 patients with EGFR-expressing mCRC. Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI (the CRYSTAL Regimen) or FOLFIRI alone as first-line treatment. KRAS mutational status was available for 1079/1217 (89%) of the patients: 676 (63%) patients had KRAS mutation-negative (wild-type) tumors. Post-hoc analyses of efficacy data were performed on patient subgroups defined by KRAS mutation status.1 The CRYSTAL Study was conducted outside the U.S. using European Union (EU)-approved cetuximab as the clinical trial material. ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab used in this study; these pharmacokinetic data, together with the results of the CRYSTAL Study, and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in mCRC.1

IMPORTANT SAFETY INFORMATION (continued) Select Adverse Reactions ■ The most frequent adverse reactions seen in patients with KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer treated with EU-approved cetuximab + FOLFIRI (n=317) versus FOLFIRI alone (n=350) (incidence ≥50%) were acne-like rash (86% vs 13%) and diarrhea (66% vs 60%). The most common grade 3/4 adverse reactions (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs <1%), and diarrhea (16% vs 10%). U.S.-licensed ERBITUX provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided above are consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS, on adjacent pages.

UP THE ANTI-EGFR

Dermatologic Toxicities ■ In clinical studies of ERBITUX (cetuximab), dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1-17% of patients —Acneiform rash usually developed within the first 2 weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae —Sun exposure may exacerbate these effects Electrolyte Depletion ■ Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC grades 3 & 4) in 6-17%. In Study 2 the addition of EU-approved cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs 6%) and of grade 3–4 hypomagnesemia (7% vs 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs 4%). No patient experienced grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia, and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy —Replete electrolytes as necessary Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX Adverse Reactions ■ The most serious adverse reactions associated with ERBITUX are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) across all studies were cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection

CONTACT your sales representative or call 1-800-805-1058 (8 AM-8 PM EST, M-F) to receive patient education materials, enrollment information, and forms

Phone 1-800-861-0048 or Fax 1-888-776-2370 8 AM to 8 PM EST, M-F Please see enclosed Full Prescribing Information, including Boxed WARNINGS. References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; March 2013. 2. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer. 1981;47(1):207-214. 3. Van Cutsem E, Köhne C-H, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011-2019.

SCAN QR CODE for more information. By scanning the QR code, you are confirming you are a US Healthcare Professional.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2013 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US13BR00848-03-01

4/13

UP THE ANTI-EGFR

ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4) in Full Prescribing Information, Warnings and Precautions.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing Information.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] K-Ras Mutation-negative, EGFR-expressing Colorectal Cancer: Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2) in Full Prescribing Information, Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]

• i n combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, • in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, • as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information.]

Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Infusion Reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.] Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.] Pulmonary Toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin: In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Erbitux in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of Erbitux resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Erbitux combination arm and 14 patients (3.0%) in the control arm. Nine patients in the Erbitux arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of Erbitux to radiation and cisplatin did not improve PFS. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%. In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary. K-Ras Testing in Metastatic or Advanced Colorectal Cancer Patients: Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2) in Full Prescribing Information, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information]. Perform the assessment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Erbitux. Epidermal Growth Factor Receptor (EGFR) Expression and Response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/ faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 b 15 3 2 0 Infusion Reaction Infection 13 1 9 1 a 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 c 43 2 21 1 Alanine Transaminase, high Aspartate Transaminase, highc 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, highc Respiratory Pharyngitis 26 3 19 4 Skin/Appendages d 87 17 10 1 Acneiform Rash Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux (cetuximab) in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups. Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 2 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89). Table 2:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Recurrent Locoregional Disease or Metastatic SCCHN EU-Approved Cetuximab Platinum-based plus Platinum-based Therapy with Therapy with 5-FU 5-FU Alone (n=219) (n=215) System Organ Class Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Eye Disorders Conjunctivitis 10 0 0 0 Gastrointestinal Disorders Nausea 54 4 47 4 Diarrhea 26 5 16 1 General Disorders and Administration Site Conditions Pyrexia 22 0 13 1 10 2 <1 0 Infusion Reactiona Infections and Infestations b 44 11 27 8 Infection Metabolism and Nutrition Disorders Anorexia 25 5 14 1 Hypocalcemia 12 4 5 1 Hypokalemia 12 7 7 5 Hypomagnesemia 11 5 5 1 Skin and Subcutaneous Tissue Disorders 70 9 2 0 Acneiform Rashc Rash 28 5 2 0 Acne 22 2 0 0 Dermatitis Acneiform 15 2 0 0 Dry Skin 14 0 <1 0 Alopecia 12 0 7 0 a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. b Infection – this term excludes sepsis-related events which are presented separately. c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”. Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm. Colorectal Cancer Study 4: EU-Approved Cetuximab in Combination with FOLFIRI — Study 4 used EU-approved cetuximab. U.S.-licensed Erbitux provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Erbitux in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 3 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4 [see Warnings and Precautions]. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224). Table 3:

Table 3: (Continued)

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFR-expressing, Metastatic Colorectal Cancera EU-Approved Cetuximab plus FOLFIRI FOLFIRI Alone (n=317) (n=350) Grades Grades Grades Body System Grades 1–4b 3 and 4 1–4 3 and 4 Preferred Term % of Patients Skin and Subcutaneous Tissue Disorders d 86 18 13 <1 Acne-like Rash Rash 44 9 4 0 Dermatitis Acneiform 26 5 <1 0 Dry Skin 22 0 4 0 Acne 14 2 0 0 Pruritus 14 0 3 0 Palmar-plantar Erythrodysesthesia Syndrome 19 4 4 <1 Skin Fissures 19 2 1 0 a Adverse reactions occurring in at least 10% of Erbitux (cetuximab) combination arm with a frequency at least 5% greater than that seen in the FOLFIRI arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischaemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”. d Acne-like rash is defined by the events using MedDRA preferred terms and included “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”. Erbitux Monotherapy — Table 4 contains selected adverse reactions in 242 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer who received best supportive care (BSC) alone or with Erbitux in Study 5 [see Warnings and Precautions]. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 17 infusions (range 1–51). Table 4:

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type), EGFR-expressing, Metastatic Colorectal Cancer Treated with Erbitux Monotherapya Erbitux plus BSC BSC alone (n=118) (n=124) Grades Grades Grades Body System Grades 3 and 4 1–4 3 and 4 Preferred Term 1–4b % of Patients Dermatology/Skin Rash/Desquamation 95 16 21 1 Dry Skin 57 0 15 0 Pruritus 47 2 11 0 Other-Dermatology 35 0 7 2 Nail Changes 31 0 4 0 Constitutional Symptoms Fatigue 91 31 79 29 Fever 25 3 16 0 18 3 0 0 Infusion Reactionsc Rigors, Chills 16 1 3 0 Pain Pain-Other 59 18 37 10 Headache 38 2 11 0 Bone Pain 15 4 8 2 Pulmonary Dyspnea 49 16 44 13 Cough 30 2 19 2 Gastrointestinal Nausea 64 6 50 6 Constipation 53 3 38 3 Diarrhea 42 2 23 2 Vomiting 40 5 26 5 Stomatitis 32 1 10 0 Other-Gastrointestinal 22 12 16 5 Dehydration 13 5 3 0 Mouth Dryness 12 0 6 0 Taste Disturbance 10 0 5 0 Infection Infection without neutropenia 38 11 19 5 Musculoskeletal Arthralgia 14 3 6 0 Neurology Neuropathy-sensory 45 1 38 2 Insomnia 27 0 13 0 Confusion 18 6 10 2 Anxiety 14 1 5 1 Depression 14 0 5 0 a Adverse reactions occurring in at least 10% of Erbitux plus BSC arm with a frequency at least 5% greater than that seen in the BSC alone arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related. Erbitux in Combination with Irinotecan — The most frequently reported adverse reactions in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%). Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux (cetuximab) with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions have been identified during post-approval use of Erbitux. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Aseptic meningitis • Mucosal inflammation DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C — There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use: The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

Geriatric Use: Of the 1662 patients who received Erbitux (cetuximab) with irinotecan, FOLFIRI or Erbitux monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

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News

New Labeling for Reformulated OxyContin to Curb Abuse By Keegan Bales

he U.S. Food and Drug Administration has approved updated labeling for the reformulated painkiller OxyContin (controlled-release oxycodone hydrochloride). The new labeling will indicate that the drug has physical and chemical properties that make injection or snorting challenging. This new measure is designed to curb abuse of the drug. The original OxyContin provides the same therapeutic benefits as the reformulated product, but has a greater potential for abuse. Consequently, the FDA has decided that the benefits of the original OxyContin no longer outweigh the risks and will not accept or approve new drug applications for generics that rely on the acceptance and approval of the original OxyContin.

Drug Background The original OxyContin was approved in December 1995. Since then, the product has often been

abused and manipulated in order to release the drug more rapidly, defeating its extended-release properties. This behavior is associated with serious risks, including overdose and death. In April 2010, a reformulated version entered the market and the original form was taken off the shelves by the manufacturer, Purdue Pharma, LP. By essentially banning generics based on the original drug, the FDA is hoping to cut down on dangerous abuse of this powerful opiate. “The development of abuse-deterrent opioid analgesics is a public health priority for the FDA,” said Douglas Throckmorton, MD, Deputy Director for Regulatory Programs in the FDA’s Center for Drug Evaluation and Research. “While both original and reformulated OxyContin are subject to abuse and misuse, the FDA has determined that reformulated OxyContin can be expected to make abuse by injection difficult and is ex-

pected to reduce abuse by snorting compared to original OxyContin.”

Abuse Deterrence The new tablet is more difficult to crush, break, or dissolve. It also forms a viscous hydrogel that cannot easily be injected. While intranasal and intravenous administration of OxyContin is still possible, it is now more difficult. Oral abuse, however, is still feasible. The reformulated product is also intended to reduce incidents of therapeutic misuse. This includes crushing and sprinkling of the product onto food and administering it through a gastric tube. When the FDA is presented with a new formulation that has abuse-deterrent properties, it has the authority to require generics to have these characteristics also. The impact of the reformulated OxyContin and generics is not yet known. The FDA will update its evaluation as new data become available.

The FDA, along with other public health agencies, encourages the development of abuse-deterrent forms of opiates to reduce prescription drug abuse. “At the same time, the FDA remains committed to ensuring that patients with pain have appropriate access to opioid analgesics,” the agency stated. n

Key Points ■ The FDA has approved updated labeling for the reformulated painkiller OxyContin (which is more difficult to inject or snort than the original product), in an effort to curb abuse of the powerful opiate.

■ The agency will no longer

accept or approve new drug applications for generics that rely on the acceptance and approval of the original OxyContin.

The ASCO Post | MAY 15, 2013

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Awards

Cancer Treatment Pioneers to Share Prize in Medicine and Biomedical Research

eter C. Nowell, MD, Janet D. Rowley, MD, and Brian J. Druker, MD, have been named as the recipients of the 2013 Albany Medical Center Prize in Medicine and Biomedical Research, to be officially awarded May 17. The $500,000 award, given to those who have altered the course of medical research, is one of the largest prizes in medicine and science in the United States. James J. Barba, President and CEO of Albany Medical Center and Chairman of the National Selection Committee, said, “These individuals exemplify the extraordinary impact that painstaking research can have on the lives of countless individuals. On behalf of cancer survivors everywhere, I thank Dr. Druker, Dr. Nowell, and Dr. Rowley for their contributions in our fight to eradicate cancer.”

Award Recognizes Significant Outcomes The Albany Medical Center Prize was established in 2000 by the late Morris “Marty” Silverman to honor scientists whose work has demonstrated significant outcomes that offer medical value of national or international importance. A $50 million gift commitment from the Marty and Dorothy Silverman Foundation provides for the prize to be awarded annually for 100 years. Five Albany Prize recipients have gone on to win the Nobel Prize.

Peter C. Nowell, MD Dr. Peter C. Nowell is the Gaylord P. and Mary Louise Harnwell Professor Emeritus, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Dr. Nowell’s research, the first to show that a genetic defect could be responsible for cancer, has led to numerous discoveries into the growth of cells related to cancers and other disorders. In 1960, as a faculty mem-

ber at the University of Pennsylvania School of Medicine, he and graduate student David A. Hungerford of Fox Chase discovered a strange chromosome in blood cells from patients with chronic myeloid leukemia (CML), then an incurable form of leukemia. They further observed that the defective chromosome was found only in malignant blood cells in CML patients and that it was not present in healthy individuals. The results were published in Science. This pivotal discovery of what was later named the Philadelphia chromosome, was the “smoking gun” for a much debated link between cancer and genetics. “Although a number of previous studies had shown chromosomal abnormalities in human cancer, the Philadelphia chromosome was the first documentation of a bona fide genetic signature of malignancy, and this discovery led Dr. Nowell to hypothesize that this genetic alteration

Peter C. Nowell, MD

Janet D. Rowley, MD

chromosomes, including Q-banding, a technique by which scientists could visualize bands of DNA treated with special stains using fluorescent microscopes. Using this technique, Dr. Rowley discovered that Dr. Nowell’s Philadelphia chromosome defect was the result of a “translocation” between chromosomes 9 and 22, where small pieces of these two chromosomes had switched places. “Her finding of the same 9;22 translocation in virtually all bone marrow cells from CML patients, and not in unaffected lymphocytes,

These individuals exemplify the extraordinary impact that painstaking research can have on the lives of countless individuals. —James J. Barba

might somehow provide a growth advantage to the abnormal cells,” said J. Larry Jameson, MD, PhD, dean of the Perelman School of Medicine at the University of Pennsylvania.

Janet D. Rowley, MD Dr. Janet D. Rowley is Professor of Medicine, Blum-Riese Distinguished Service Professor, University of Chicago. Dr. Rowley’s discoveries of consistent chromosome abnormalities in leukemia secured a common agreement by the 1970s among scientists, physicians, and the general public that cancer is, in fact, a genetic disease. In 1973, Dr. Rowley, a geneticist at the University of Chicago, was working on novel approaches to studying

indicated that this chromosomal rearrangement occurs as an acquired genetic change in a single bone marrow cell that is thereby afforded a proliferative advantage which, through clonal expansion, gives rise to leukemia,” explained Dr. Testa. This understanding was critical and Dr. Rowley went on to find other translocations responsible for various blood cancers, giving physicians a new tool to understand how cancer might affect an individual. “For many years, chromosome changes were the best prognostic indicator for leukemia,” said Dr. Rowley. “If you analyzed a patient’s leukemic cells you could have a good estimate of whether that patient would respond well or poorly to treatment.”

Brian J. Druker, MD

Brian J. Druker, MD Dr. Brian J. Druker is Director, Knight Cancer Institute, Associate Dean for Oncology, Oregon Health & Science University, Howard Hughes Medical Institute Investigator, Portland, Oregon. The earlier work of Drs. Nowell and Rowley paved the way for oncologist Dr. Druker to develop a lifesaving treatment for CML that specifically targets the leukemia cells without harming healthy cells. Once scientists understood the chromosomal nature of leukemia, they were able to determine that the malignant cells in CML contain a protein called a tyrosine kinase that essentially “drove” the disease by causing an overproduction of white blood cells. With this knowledge, Dr. Druker began a quest to find a compound that could inhibit the activity of the type of tyrosine kinase that caused CML. Through that research, he and his colleagues identified the compound that ultimately became imatinib (Gleevec). Dr. Druker then led the drug’s clinical trials. During the trials, nearly all CML patients saw their white blood counts return to normal in a matter of weeks with little or no side effects. Patients in hospice facilities, who were expecting to die within days, recovered and began leading normal lives and are still alive today. The trials were so successful that they resulted in the fastest approval by the FDA in its history. “This type of targeted therapy is the future of cancer drug therapy and the future is here,” said Dr. Druker. It’s an exciting time to work in this field.” n

ASCOPost.com | MAY 15, 2013

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Fellow’s Corner Issues in Oncology

Debt and the Oncology Fellow

A Conversation with Matthew Lunning, DO By Ronald Piana

espite today’s challenging economy, health care is one field that offers vast career opportunities. Oncology, with the impending workforce shortage, is especially eager for bright young doctors to join its ranks. But the rising costs of medical school can be a deterrent, leading the best and brightest to pursue other career paths. According to the Association of American Medical Colleges, the median annual cost for tuition is more than $32,000 at public medical schools and more than $50,000 at private institutions. Adding the costs of textbooks, equipment, room, board, and travel, it can bring the cost of a 4-year education to more than $300,000. The ASCO Post recently spoke with Matthew Lunning, DO, a hematology-oncology fellow at Memorial Sloan-Kettering Cancer Center, about the financial stresses faced by today’s young oncologists.

It’s a thought that is always there. I came from a middle-class family. Both of my parents worked hard, but money was often an issue. They fell into the income conundrum of making enough to exclude us from government subsidies, but not enough to be able to help with the burden of medical school tuition and all the extras, which are considerable. Medical school is so challenging that you tend to postpone worrying about what’s going to happen after you graduate until you actually do. I knew my debt would be significant at the end of the medical school tunnel, but I wanted to become an oncologist, so I just swallowed that fact and moved ahead. But debt is a reality. More than 50% of medical students graduate looking at

[Oncology] is a great field. You can make a difference in the lives of cancer patients daily. So the debt is worth the trip, but you need to be prepared to manage it.

Career Path Please tell us about any early experiences that helped shape your career. I’m from Mason City, a relatively small town in northern Iowa. During the summer break after my freshman year at college, I was introduced to oncology by doing clinical trial data collection at our local cancer center. By pure serendipity, Dr. Gerald Marti from the National Institutes of Health (NIH) was visiting our cancer center. Prodded by one of the center’s oncologists, I approached Dr. Marti with an idea for a paper I intended to write. Impressed by my initiative and enthusiasm about oncology, he invited me to the NIH to work in his lab doing research on chronic lymphocytic leukemia (CLL). As an undergrad I spent three summers at NIH, which not only helped my odds of getting into medical school, but also solidified my resolve to become an oncologist. Coming from a state with one allopathic and one osteopathic school, the competition is fierce. I studied at Des Moines University, an osteopathic medical school. It was a terrific experience, but since it was a private medical school, I incurred considerable debt upon graduation.

Debt at the End of the Tunnel Was the prospect of debt something that worried you going into medicine?

In banking terms, your front-end and your back-end status determine your ability to secure a mortgage. In other words, when you sit down with a mortgage officer, they will look at your salary as an oncology fellow or a new attending (front-end), then look at your student debt and other financial commitments (back-end). Recently, evolving regulations after the Fanny Mae/Freddy Mac bust have led to strict lending algorithms, which may make it difficult to get a conventional loan. Here’s an example of the change. I bought a house 7 years ago, before the crash. I simply went to the bank with a promissory letter explaining that I was going to make an intern’s salary at University of Nebraska Medical Cen-

—Matthew Lunning, DO

an excess of $150,000 in loan payments. In my case, I was lucky in that when I came out of medical school I had the ability to consolidate the majority of my federal loans at 2.85%. The current rates for some loans may be up to 6.8%. So a 30-year note for $200,000 at current interest rates—that seems like a long road, especially when you’re watching the balance grow during periods of forbearance.

Impact of Debt As a young oncologist, what were your main concerns about how debt would affect your life and career? First and foremost for me, it is how it may affect your ability to purchase a home straight out of training. Since I entered medical school, and on through training, the housing sector has undergone a huge change. However, the American Dream has not changed; it still begins with the opportunity to own a home to rear your family in. But debt can become an obstacle to attaining that dream.

ter and got a home mortgage. Today, after nearly completing my fellowship, not accruing further sizable debt, and seeing a higher income within reach, I would be put into an algorithm that now would deny me that same mortgage loan. So I would be forced to pursue a more unconventional route. I don’t think that this dilemma is on the radar of fellows who are about to begin their careers. Or if it is, it’s a taboo subject that no one’s willing to talk about. I have not been able to sort out which one it is. But it’s something that needs more attention and perhaps even education.

Future Plans How does debt affect your future plans as a young oncologist? I have a wife and three children. My wife and I met in medical school, but we decided a two-doctor family was not for us, so she left school to be at home to help raise our kids—a sacrifice I will be eternally grateful for. After my fel-

lowship is complete at Memorial SloanKettering, we’re moving back home, otherwise known as Nebraska, where I’ll be an assistant professor at the University of Nebraska Medical Center. I’ve had a great learning experience at Memorial, and I’m confident that will serve me well as I move into the next phase of my career. Needless to say, the cost-of-living is much lower in the Midwest. I’m fortunate to have a good financial advisor who helps put things in perspective. I look at it metaphorically. An oncologist is like a cancer drug in development. A significant amount of money is required in the early stages of development, and the safety profile and effectiveness are untested. You get answers to the above questions as the drug graduates through the clinical trial pipeline and hopefully out into the market as an approved drug. A new oncologist, like a recently approved cancer drug, has to earn enough to repay the investment (in undergraduate and medical school) and earn enough profit to make the education worthwhile. Profit in this context is not just money; it’s the productiveness of the career. Going from being an oncology fellow at Memorial Sloan-Kettering to an assistant professor at the University of Nebraska Medical Center, I see myself in an aggressive debt reduction phase. I now realize that if you don’t put your finances into a workable equation, it could potentially frustrate your view of the future.

Closing Thoughts Any closing thoughts on debt and oncology? It is well vetted that we have an aging population and an impending shortage of oncologists. I wonder whether increasing amounts of debt may poison a decision to become a future oncologist. At least for now, I think oncology has immunity. It has a special allure that draws in the brightest minds that see opportunity for improvement in the ever-evolving oncologic landscape, but are humbled by the sheer impact cancer has on our population. It is a great field. You can make a difference in the lives of cancer patients daily. So the debt is worth the trip, but you need to be prepared to manage it. n

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

What if

engineering the antiBody could iMPRoVE adcc?

Immune Effector Cell

Therapeutic Antibody

Target Cell

*Based on preclinical models.

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

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

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

Sugar Residue

Sugar Removal

Increased Binding

SugarS MaY aY coMproMiSe iMMuNe a

gLYcoeNgiNeeriNg MaY a iNcreaSe aY

gLYcoeNgiNeeriNg couLD LeaD

eFFecTor–aNTiBoDY BiNDiNg

BiNDiNg aFFiNiTY

To iMproVeD aDcc

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

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

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

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

For more information, visit ResearchBcell.com

The ASCO Post | MAY 15, 2013

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Journal Spotlight Technology

eHealth: Caregiver Use of Online System Reduces Symptom Distress in Patients with Non–Small Cell Lung Cancer By Matthew Stenger

he results of a study reported by David H. Gustafson, PhD, Research Professor at the University of Wisconsin-Madison, and colleagues in Cancer suggest that informal caregiver (eg, family member) use of a specifically designed online system to support palliative care reduces symptom distress in patients with non–small cell lung cancer (NSCLC).1

CHESS Components The online support system, known

as CHESS (Comprehensive Health Enhancement Support System), is a noncommercial website created by clinical, communication, and systems scientists at the University of Wisconsin. The CHESS Coping with Lung Cancer site provides organized lung cancer, caregiving, and bereavement information; serves as a channel for communication with and support from peers, experts, clinicians, and users’ social networks; and acts as a coaching tool by providing algorithm-

based feedback in response to information gathered from users. The system includes a clinician report that summarizes caregiver and patient ratings of patient health status and lists questions for the next clinic visit. Clinicians also received email alerts before a scheduled patient visit and alerts whenever a symptom rating exceeded 7 on a scale of 1 to 10.

Study Details In the study, 285 caregiver-patient

pairs were randomly assigned to standard care plus training on and access to either CHESS (n = 144) or Internet use with a list of other lung cancer–specific websites (Internet group, n = 141). Patients had to have stage IIIA, IIIB, or IV NSCLC, be Englishspeaking, and have a perceived life expectancy of at least 4 months. The study interventions continued up to 25 months or for 13 months after the patient’s death, with caregivers having access to bereavement resources after

Lessons of 2 Decades’ Experience with CHESS By David H. Gustafson, PhD

ur work on an Internet-based intervention for lung cancer confirmed what many other studies have shown about technologic interventions for health-care consumers—that such interventions can improve quality of life for caregivers and patients.1 We expected this result in part because of the clinician report in CHESS for lung cancer. This report sends alerts to a patient’s clinical team whenever a patient’s symptoms exceed a preset threshold. In fact, our early finding about the value of the clinician report led us to conduct a separate randomized trial of a system with the clinician report vs a system without it, and this study confirmed the value of the report.2 We believe the power of the clinician report comes from bringing patients and clinicians together, giving them more direct and frequent communication when they need it than they otherwise have, and enabling clinicians to respond to symptoms more effectively.

from such systems as CHESS. We know that not all families benefit equally, but we don’t know which families benefit or under what conditions they benefit.

The Importance of Family We have been developing and testing CHESS programs for cancer and other illnesses and chronic conditions for more than 20 years, yielding extensive evidence not just about the effect of such interventions on patient and caregiver quality of life, but also some evidence that the interventions can reduce costs.3 Our work over the years has consistently

Dr. Gustafson is Emeritus Research Professor and Founder of the Center for Health Enhancement Systems Research and Analysis, University of Wisconsin-Madison.

The Challenge of Dissemination Even though we know that CHESS systems can help patients and their caregivers, we don’t know how to get such systems into wide use. In addition to tests of efficacy, we need studies to

Our work over the years has consistently taught us one lesson in particular: Family members are critically important in the process of caring for patients with serious illnesses. —David H. Gustafson, PhD

Unexpected Finding We did not expect the survival effect we found in the trial of CHESS for lung cancer. This was just one study of a few hundred patients—the finding needs to be confirmed. Although we conducted exploratory analyses of CHESS use that are reported in the paper, we also need to learn more about who benefits most

widely recognized problem, family members matter even more. Their impact on a patient’s outcome can be immense and positive if they get the support and information they need, and that support and information are more readily available through a system like CHESS than any other ways I know of.

taught us one lesson in particular: Family members are critically important in the process of caring for patients with serious illnesses. I learned this myself, as patient rather than researcher, in an experience I described elsewhere,4 and the lung cancer study brought this lesson home to us again. With hospital discharge taking place earlier in the course of patient treatment and hospital readmissions becoming a

learn how best to implement such systems and sustain their use in the real world. We simply don’t know yet how to encourage clinicians and patients to use the system. One obstacle to the widespread dissemination of CHESS specifically is that the programs have been built to answer research questions, not to be widely used as products. In developing CHESS for research tests, we’ve taken

shortcuts that would not hold up in a large-scale implementation of the system. For example, staff members at our research center act as moderators of discussion groups in CHESS systems; we haven’t created tools that enable users to do this themselves. Making the changes to CHESS that would transform it into an efficient, reliable system for widespread use would require both initial and ongoing investments. If an organization has the interest in and resources for doing this, we would make CHESS available and cooperate to make broad dissemination a reality. n

Disclosure: Dr. Gustafson has no potential conflicts of interest to disclose.

References 1. Free C, Phillips G, Galli L, et al: The effectiveness of mobile-health technologybased health behavior change or disease management interventions for health care consumers: A systematic review. PLoS Med 10(1):e1001362, 2013. 2. Chih MY, Dubenske LL, Cleary J, et al: Communicating advanced cancer patients’ symptoms via the Internet: A pooled analysis of two randomized trials examining caregiver preparedness, physical burden, and negative mood. Palliat Med. September 17, 2012 (early release online). 3. Gustafson DH, Hawkins RP, Boberg EW, et al: The use and impact of a computerbased support system for people living with AIDS and HIV infection. Proc Annu Symp Comput Appl Med Care, pp 604-608, 1994. 4. Gustafson DH: A systems engineer meets the system. JAMA 309:247-248, 2013.

ASCOPost.com | MAY 15, 2013

PAGE 103

Journal Spotlight

patient death. The primary study outcome was caregiver-reported patient symptom distress, measured using a modified Edmonton Symptom Assessment Scale that assessed pain, nausea, appetite, shortness of breath, fatigue, constipation, and diarrhea. For total score, the values ranged from 0 (absence of all symptoms) to 70 (worst possible on all symptoms). Although the CHESS and Internet interventions were designed to support informal caregivers, patients could also use them. Among patients in the CHESS and Internet groups, mean ages were 62 and 61 years, 50% and 48% were women, 65% and 67.5% had stage IV disease, mean time from diagnosis to study intervention was 343 and 370.5 days, 66% and 75% had ECOG performance status of 0 or 1. In addition, 47% and 38% were currently receiving first-line treatment and 43% and 51% had failed first-line treatment and were receiving or had received additional treatment, 30.5% and 37.5% had an education level of high school diploma or less, and 55.5% and 62% had another major illness or health condition. Among caregivers in the CHESS and Internet groups, mean ages were 57 and 55 years, 66% and 70.5% were women, 20% and 22.5% had an education level of high school diploma or less, and 43% and 47% had a major illness or health condition. The only significant between-group difference in baseline characteristics was in caregiver Internet comfort scores (0 to 4, with 4 indicating “extremely comfortable”), which were 2.4 in the CHESS group and 2.7 in the Internet group (P = .044).

Lower Symptom Distress Scores Symptom distress scores were adjusted for baseline scores, study site, caregiver-patient relationship, and caregiver race. Overall, the CHESS group reported a significantly lower mean score (17.04 vs 22.32, P = .005). Differences at month 2 (16.75 vs 21.21, P = .051), month 4 (16.89 vs 21.72, P = .031), month 6 (16.03 vs 22.95, P = .004), and month 8 (18.47 vs 23.39, P = .061) were consistent with the main effect difference. Analysis of individual symptoms showed significant between-group differences for all except nausea.

Potential Survival Differences During the study, the investigators

observed that caregivers from the Internet group were transitioning to bereavement status more frequently than caregivers from the CHESS group. The investigators therefore performed an exploratory survival analysis, finding some differences between study groups and when survival was assessed according to whether patients in the

CHESS group did or did not actually use CHESS. Overall, during the 2year intervention, 62% of patients in the CHESS group and 73% of patients in the InterB:8.25” net group died, with the CHESS group T:7.5” having a nonsignificant increase in S:6.75” median survival (14.8 vs 10.1 months, P = .172). After adjustment for age,

sex, cancer stage, treatment history, and interval between diagnosis and intervention, the reduced risk for death in the CHESS group approached significance (hazard ratio [HR] = 0.75, P = .083). CHESS was used at least once by 73% of caregivers and 50% of patients, continued on page 104

INVESTIGATIONAL PHASE 3 TRIALS CURRENTLY ACCRUING

Cabozantinib phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases 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

Randomized, double-blind, controlled trial

Mitoxantrone + Prednisone

The ASCO Post | MAY 15, 2013

PAGE 104

Journal Spotlight

Online Support System continued from page 103

with 52% and 38%, respectively, using the system at least five times. Median survival was 19.2 months among patients who used CHESS at least once, compared with 9.9 months among those who did not (P = .003), with the difference remaining significant after controlling for age, sex, cancer stage, treatment history, and interval between diagnosis and intervention (adjusted HR = 0.49, P = .009). Survival was also significantly better among CHESS group patients who used CHESS than among all patients in the Internet group (adjusted HR = 0.58, P = .012). There were significant differences at baseline between CHESS group patients who used CHESS and those who did not with regard to sex of the caregiver (women for 55% vs 77%, P = .008) and treatment history (no treatment in 12% vs 2%, currently receiving first-line treatment for 47% vs 47%, in remission after first-line treatment for 7% vs 0%, and additional

treatment after first-line failure for 35% vs 51%; overall P = .021). Caregiver sex also differed significantly between CHESS group patients who used CHESS and the Internet group,

and 8 months prior to death among patients dying during the study. No significant differences in scores were found, suggesting that patients who lived longer did not suffer more.

Impact of Online Support System on Patient Care ■ Caretakers and patients using the Comprehensive Health Enhancement

Support System (CHESS) reported lower patient symptom distress scores than those in a group provided with other Internet resources.

■ Exploratory analyses suggested longer survival among CHESS group

patients who used CHESS, compared with CHESS group patients who did not use the system and with Internet group patients.

with a difference in treatment history approaching significance.

Survival and Suffering To assess whether prolonged survival might have been accompanied by prolonged suffering, caregiver-reported symptom distress scores for CHESS group patients who used CHESS were compared with those who did not and with Internet group patients at 2, 4, 6,

In considering why a system designed mainly for caregivers might affect outcomes in patients, the investigators stated, “Information in CHESS may help caregivers provide better informal care, and the clinician report may have allowed both caregivers and clinicians to manage symptoms more effectively…. With better symptom management, patients may have been encouraged to adhere to treatment.

The CHESS clinician report also may have enabled clinicians to better address patient and caregiver concerns during clinic visits. In interviews, some clinicians reported that caregivers who were using CHESS were more engaged during clinic visits and better able to describe their concerns and the patient’s symptoms.” The investigators concluded, “Additional rigorous studies are needed to determine whether online emotional and instrumental support for both patients and caregivers can ease distress and lengthen survival. An effective online system of palliative care may offer a lowcost end-of-life intervention that would be relatively easy to distribute widely.” n

Disclosure: The study was supported by a National Cancer Institute grant. The authors reported no potential conflicts of interest.

Reference 1. Gustafson DH, Dubenske LL, Namkoong K, et al: An eHealth system supporting palliative care for patients with non-small cell lung cancer: A randomized trial. Cancer. January 25, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Sandra M. Swain, MD, FACP, on Women in Oncology see page 58

Monika L. Metzger, MD, MSc, on Female Reproductive Complications after Cancer Treatment in Children and Young Adults see page 80

Andrew D. Seidman, MD, Lori Pierce, MD, and Benjamin J. Smith, MD, on Cardiac Effects of Breast Radiotherapy see pages 49, 50, and 52

Pioneer in Oncology: Bernard Fisher, MD see page 145

Stephen M. Sagar, MD, FRCPC, on Symptom Management with Complementary Therapies see page 159

Visit The ASCO Post online at ASCOPost.com

Robert E. Bristow, MD, MBA, on Guideline-specified Treatment of Ovarian Cancer see page 163

A deeper look at the ALIMTA data See it now at ALIMTAhcp.com/data

PM84399

The ASCO Post | MAY 15, 2013

PAGE 106

National Comprehensive Cancer Network Annual Conference Supportive Care

Automated Telephone Monitoring Reduces Chemotherapy-related Symptoms By Caroline Helwick

he use of an automated computer-based telephone monitoring system to assess symptoms during outpatient chemotherapy—and provide intervention where appropriate by a nurse practitioner— substantially reduced the number of days with symptoms in a study reported at the 18th Annual Conference of the National Comprehensive Cancer Network (NCCN).1 “We asked whether this system would decrease symptom days, and we saw a dramatic effect in some areas,” said William A. Dunson, Jr, MD, of the Huntsman Cancer Institute at the University of Utah, Salt Lake City. “In research, a lot of things we show are statistically relevant but not practically relevant. This study is a beautiful example of both.” He cited two main concerns in the cancer clinic: controlling patients’ symptoms and freeing up nurses to care for patients—that is, not having their time consumed by telephone calls. “These are big challenges in every clinic,” Dr. Dunson said.

Study Design The study evaluated an automated system that all patients called every morning to report on common chemotherapy-related symptoms. Those who reported the presence of symptoms were questioned as to the frequency of vomiting, intake of liquids, and so forth. Symptoms that were moderate-

to-severe were referred to the nurse practitioner, in the intervention arm. The system was prospectively evaluated among 358 patients beginning a course of chemotherapy. The majority of patients were white, the average age was 55, and about one-third were currently employed. Diagnoses included mainly breast (43%), lung (17%), and ovarian (10%) cancers; fewer than 7% each had colorectal, pancreatic, head and neck, endometrial, and other tumor types.

In research, a lot of things we show are statistically relevant but not practically relevant. This study is a beautiful example of both. —William A. Dunson, Jr, MD

All participants called the automated system daily to report the presence and severity of symptoms on a 10-point scale. Additionally, those in the intervention group received automated self-care messages tailored to symptom severity during the daily call, and received a personal call from the nurse practitioner if the presence of moderate (4–7) or severe (> 7) 7) symptoms triggered an alert. The nurse practitioner then used NCCN Guidelines for Supportive Care in a case management system. “This was a proactive system. In-

Proactive Telephone Monitoring of Symptoms during Chemotherapy ■ Use of an automated telephone monitoring system to assess symptoms

during outpatient chemotherapy (with NCCN Guideline-based intervention by a nurse practitioner as necessary) reduced the number of days with symptoms by over one-half to nearly two-thirds, depending on the symptom.

■ The intervention group had significantly fewer days with moderate/severe fatigue, pain, nausea, depressed mood, and anxiety (P < .001 for each).

■ Participants were in the study an average of 83 days and completed 89% of the expected daily calls.

stead of waiting for patients to be in disaster mode, we had them call in daily with a status report,” he said. The majority of patients reported moderate or severe symptoms, including fatigue (83%), pain (79%), nausea (60%), depressed mood (52%), and nervousness/anxiety (49%). The participants were in the study an average of 83 days and completed 89% of the expected daily calls.

‘Dramatic’ Reduction in Days with Symptoms The intervention group had significantly fewer days with moderate/severe symptoms for all symptoms monitored (P < .001 .001 for each), Dr. Dunson reported. “This was pretty dramatic,” he said. Out of 83 days on the study, the estimated mean number of days (based on a binomial regression model) with moderate/severe fatigue was 25 in the usual-care group but just 11 in the intervention group—a 55% reduction. Days with moderate/severe pain averaged 19 in the usual-care group but 7 in the intervention group. Average days with nausea were 8 vs 3; with depressed mood, 5 vs 2; and with nervousness or anxiety, 4 vs 1, respectively. “Moderate to severe symptom days were reduced in the telephone-care group as compared to the usual-care group by over one-half for fatigue and by nearly two-thirds for the other symptoms,” he reported. Dr. Dunson maintained the study was well controlled in that both groups had to call the center. He believes the intervention by the nurse practitioner was likely the factor that

proved most effective in reducing symptom days. While the study had a dedicated nurse practitioner for this activity, the next step is to use an existing staff nurse. “We presume this will show the same benefit, and it might take even less time,” he said. “The obvious next question is whether it saves money or costs money. I think it will save money if we can use nurses instead of nurse practitioners, certainly if it decreases the amount of time the nurse spends on the phone. It also saves in terms of productivity from the patient’s point of view.” Dr. Dunson said depending on the outcomes in further testing, this system could become available in the marketplace. The study was funded by the National Cancer Institute. Larger overall investigations of the automated system, which demonstrated significant symptom reduction across 11 symptoms, were previously presented at last year’s ASCO Annual Meeting2 and the Quality Care Symposium.3 The poster presented at the NCCN Annual Conference represented an individual analysis of symptom outcomes for five symptoms, where the NCCN Guidelines were specifically used for the intervention arm. n Disclosure: Dr. Dunson reported no potential conflicts of interest.

References 1. Dunson WA, Mooney KH, Beck SL, et al: NCCN symptom guidelines coupled with nurse practitioner follow-up reduced moderate to severe symptom days by half or greater in cancer patients receiving chemotherapy. National Comprehensive Cancer Network Annual Conference. Abstract AB2013-7. Presented March 15, 2013. 2. Mooney K, Beck SL, Wong B, et al: Outpatient chemotherapy supportive care: Trial of an IT-integrated, NP-delivered system for unrelieved symptoms. ASCO Annual Meeting. Abstract 9137. Presented June 2, 2012. 3. Mooney K, Beck SL, Wong B, et al: An IT-integrated, computer-based telephone system for monitoring patientreported symptoms: Result of two trials. Quality Care Symposium. Abstract 2. Presented November 30, 2012.

ASCOPost.com | MAY 15, 2013

PAGE 107

National Comprehensive Cancer Network Annual Conference Breast Cancer

Novel Regimen Produces High Pathologic Complete Response Rates in Triple-negative Breast Cancer By Caroline Helwick

cluster with the basal subtype on molecular profiling, which overexpresses SPARC and CAV1; SPARC-albumin binding results in high intratumoral concentration of nabpaclitaxel. Due to defective BRCA-mediated DNA repair, basal-like cancers are sensitive Jasgit Sachdev, MD Mohammad Jahanzeb, MD to DNA-damaging drugs like platinums, and bevacizumab nterim results from a small neoadimproves the response rates for chemojuvant study of patients with tripletherapy in metastatic breast cancer. negative breast cancer has found high “Based on this rationale, we hyrates of pathologic complete response pothesized that nab-paclitaxel plus with the combination of nab-paclitaxel carboplatin would produce high rates (Abraxane), carboplatin, and bevaof pathologic com1 The study was cizumab (Avastin). plete response in tripresented at the 18th Annual Conferple-negative breast ence of the National Comprehensive cancer, further enCancer Network by Jasgit Sachdev, hanced by the antiMD, who led the investigation while angiogenic propera fellow under the mentorship of ties of bevacizumab,” she said. Mohammad Jahanzeb, MD, at the The phase II trial included a total University of Tennessee Cancer Instiof 42 patients, with data for the first tute, Memphis. She is now with Vir35 patients presented in this interim ginia G. Piper Cancer Center, at Scottreport. Median age was 52 years; 60% sdale Healthcare in Arizona. were postmenopausal, and 43% had positive nodes. Patients received four Study Rationale cycles of nab-paclitaxel at 100 mg/m2 Explaining the rationale for this and carboplatin at AUC 6, followed by triplet in triple-negative breast cancers, four cycles of doxorubicin at 60 mg/ Dr. Sachdev noted that these cancers m2 and cyclophosphamide at 600 mg/

Treating Triple-negative Breast Cancer ■ Interim results show high pathologic complete response rates for

neoadjuvant bevacizumab, nab-paclitaxel, and carboplatin followed by doxorubicin/cyclophosphamide, compared with those reported for anthracyclines plus taxanes in triple-negative breast cancer.

■ An ongoing randomized study is assessing the individual contributions of carboplatin and bevacizumab to response rates in this disease.

Table 1: Interim Efficacy Results for Neoadjuvant nab-Paclitaxel/Carboplatin/ Bevacizumab in Triple-negative Breast Cancer Endpoint

Efficacy Population (n = 31)a

Evaluable Population (n = 30)b

pCR breast

17 (55%)

17 (57%)

pCR breast plus nodes

16 (52%)

16 (53%)

pCR plus near-pCR in breast

30 (64%)

19 (63%)

Residual disease (> 0.5 cm in breast)

11 (35%)

11 (37%)

Among the first 35 patients, 4 withdrew prior to surgery. Patients in the evaluable population received at least 75% of planned neoadjuvant treatment and underwent surgery. pCR = pathologic complete response. Courtesy of Jasgit C. Sachdev, MD. a

m2. Bevacizumab at 10 mg/kg was given every 14 days with the first six cycles of preoperative chemotherapy and continued postoperatively to complete 1 year of treatment.

High Response Rates “Our interim results show high rates of [pathologic complete response] compared to standard anthracycline/ taxane regimens without bevacizumab” in triple-negative breast cancer, Dr. Sachdev reported (Table 1). “While the individual contribution of each of the experimental agents is difficult to determine, our results are in concordance with the GeparQuinto study, where a higher rate of [pathologic complete response] was observed in the bevacizumab-containing arm in patients with triple-negative breast cancer,” she said. 2 The most common grade 3 and 4 adverse events included, respectively, neutropenia (63%, 29%), thrombocytopenia (34%, 3%), and anemia (23%, 3%). No serious cardiac events were

observed. Seven patients had a serious adverse event; one grade 5 event occurred during the postoperative bevacizumab phase (acute liver injury and thrombocytopenia). An ongoing randomized study is evaluating the individual contributions of carboplatin and bevacizumab to pathologic complete response in the neoadjuvant treatment of triple-negative breast cancer, she said. n Disclosure: Dr. Sachdev receives research funding from Celgene, Genentech, and Pfizer.

References 1. Sachdev JC, Sinder J, Schwartzberg L, et al: Interim results of weekly nanoparticle albumin bound (nab)-paclitaxel plus carboplatin followed by doxorubicin plus cyclophosphamide with concurrent bevacizumab for triple-negative breast cancer. National Comprehensive Cancer Network Annual Conference. Abstract AB2013-2. Presented March 15, 2013. 2. Von Minckwitz G, Eidtmann H, Rezai M, et al: Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 366:299-309, 2012.

Contact The ASCO Post Editorial Office

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

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VOTRIENT® (pazopanib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).1

VOTRIENT – Move Forward in Advanced RCC VOTRIENT: Signiﬁcant PFS improvement in patients with advanced RCC1 Median PFS in patients with advanced RCC receiving VOTRIENT vs placebo1,2

11.1

12 10

MONTHS

9.2

MONTHS

7.4

8 Months

VOTRIENT Placebo

MONTHS

4.2

MONTHS

4.2

MONTHS

2.8

MONTHS

2 0 HR 0.46; 95% CI 0.34-0.62 (P<0.001)

HR 0.40; 95% CI 0.27-0.60 (P<0.001)

HR 0.54; 95% CI 0.35-0.84 (P<0.001)

All patients

Treatment-naïve patients

Cytokine-pretreated patients

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of VOTRIENT in patients (N=435) with advanced RCC. Patients with locally advanced or metastatic RCC of clear cell or predominantly clear cell histology were randomized (2:1) to receive either VOTRIENT 800 mg (n=290) once daily or placebo (n=145). The study included treatment-naïve patients receiving VOTRIENT (n=155) or placebo (n=78) as well as cytokine-pretreated patients receiving VOTRIENT (n=135) or placebo (n=67).1

• Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thrombotic Events: Arterial thrombotic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thrombotic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, venous thromboembolic

events were reported in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended.

Please see additional Important Safety Information and Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In advanced RCC, initial dose reduction should be 400 mg and additional dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced RCC trial, 42% of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose reduced • The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • Monitor serum liver tests before initiation of treatment and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modifications based on drug interactions, please see Section 2.2 in accompanying Brief Summary

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial thrombotic and venous thromboembolic events, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • Most common adverse reactions (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting Please see additional Important Safety Information and Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

NCCN Guidelines Category 1 recommendation as a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology. These Guidelines also include therapies other than pazopanib (VOTRIENT) as first-line treatment options.3

• Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. • Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT.

• Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. • Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax. • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

The most common adverse reactions (≥20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.1.2013. ©National Comprehensive Cancer Network, Inc. 2013. All rights reserved. Accessed February 1, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. • Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced.

VOTRIENT.com/HCP GSKSource.com

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had postbaseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/ intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thrombotic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. 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. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy

and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.10 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.14 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.15 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.16 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290) All All Gradesa Gradesa Grade 3 Grade 4 % % % % Adverse Reactions Diarrhea 5 23 <1 9 Hypertension 40 4 0 10 Hair color changes 3 < 81 0 3 Nausea 2 < 61 0 9 Anorexia 22 2 0 10 Vomiting 21 2 <1 8 Fatigue 1 92 0 8 Asthenia 1 43 0 8 Abdominal pain 1 12 0 1 Headache 1 00 0 5 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

(N=145) Grade 3 % <1 <1 0 0 <1 2 1 0 0 0

Grade 4 % 0 0 0 0 0 0 1 0 0 0

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=290) All Gradesa %

Grade 3 %

Placebo (N=145) Grade 4 %

All Gradesa %

Parameters Hematologic Leukopenia 3 70 0 6 Neutropenia 34 1 <1 6 Thrombocytopenia 32 <1 <1 5 Lymphocytopenia 31 4 <1 24 Chemistry ALT increased 53 10 2 22 AST increased 53 7 <1 19 Glucose increased 41 <1 0 33 Total bilirubin increased 36 3 <1 10 Phosphorus decreased 3 44 0 1 Sodium decreased 3 14 1 2 Magnesium decreased 26 <1 1 14 Glucose decreased 17 0 <1 3 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Grade 3 %

Grade 4 %

0 0 0 1

0 0 <1 0

1 <1 1 1 10 44 0 0

0 0 0 <1 0 0 0 0

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)]. 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drugdrug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.16)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.15)]. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility

in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

The ASCO Post | MAY 15, 2013

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Expert’s Corner

NCCN Patient Guidelines for Adolescents and Young Adults By Caroline Helwick

Guideline History

Peter F. Coccia, MD

he National Comprehensive Cancer Network (NCCN) has issued new NCCN Guidelines for Patients, titled “Caring for Adolescents and Young Adults [AYA].” These guidelines fill an unmet need in oncology, as Peter F. Coccia, MD, Chair of the NCCN Guidelines Panel for Young Adult Oncology and a member of the NCCN Board of Directors, explained to The ASCO Post. “I am very excited about this publication,” said Dr. Coccia, the Ittner Professor and Vice-Chairman of the Department of Pediatrics at the University of Nebraska Medical Center in Omaha. “I have been recommending for several years that NCCN develop guidelines for the AYA age group as they previously did for ‘Senior Adult Oncology.’ This age group has traditionally not participated in clinical trials, and their outcomes have not changed much.”

NCCN’s professional practice guidelines for adolescents and young adults were issued in 2012. These are now joined by the patient guidelines, which are available on the Web (www. nccn.com) and as hard copies. This was made possible through support from the NCCN Foundation and the LIVESTRONG Foundation as well as through collaboration with Critical Mass: The Young Adult Cancer Alliance. Recounting the history of the patient guidelines, Dr. Coccia recalled how the American Cancer Society once produced patient education booklets for common cancers. “The problem was that the NCCN would update its guidelines at least every

breast, colon, non–small cell lung, ovarian, pancreatic, and prostate cancers, chronic myelogenous leukemia, malignant pleural mesothelioma, melanoma, multiple myeloma, and lung cancer screening. “Ours is the most recent, and it is the first that is not tumor-specific. It’s mainly about supportive care,” he noted. Experts in adolescent and young adult oncology from all 21 NCCN member institutions developed both the NCCN Guidelines for AYA Oncology for medical professionals and had input into the AYA Guidelines for Patients. The Panel is a multidisciplinary group of oncologists specializing in malignancies common to adolescents and young

We were looking for a way to give these patients the right resources.… I have heard AYA patients say, ‘I wish the guidelines were available when I was first diagnosed. —Peter F. Coccia, MD

year, but the American Cancer Society couldn’t keep pace. About 5 years ago these little booklets were getting very out of date, so the NCCN decided to initiate the Guidelines for Patients series, which became possible through the NCCN Foundation,” he said. The AYA Guidelines for Patients join a list of 11 others, including

adults, as well as psychologists, social workers, and experts in survivorship. “It is their hope and expectation that both sets of guidelines will contribute to optimizing care and improving outcomes in AYA patients with cancer,” Dr. Coccia said.

Importance of Patient Guidelines for This Group Multiple host factors influence disease management and prognosis in adolescent and young adult patients, such as disease biology distinctions, genetic variants, developmental stage, pharmacologic considerations, and coexisting morbidities. “But the AYA population also has unique social, psychological, and economic issues that have major influences on morbidity and mortality,” Dr. Coccia emphasized. These include such factors as the transition from family to independent living, the generally poorer adherence to medications, fertility concerns, sexual issues, and others. These issues are discussed in detail in the NCCN’s Clinical Practice Guidelines for AYA oncology, and

they are presented in a lay format in the lavishly illustrated 118-page patient booklet. Dr. Coccia said he views the transition from family-focused to patient-focused care as a key element of adolescent and young adult cancer care, and this is reflected in the publication. “In my experience, this is one of the major issues leading to decreased compliance with treatment in this age group,” he said. “The absence of care partners argues strongly for the importance of multidisciplinary teams to assist in the management of AYA patients with cancer.”

What Are We Telling Younger Patients? The Patient Guidelines state the purpose this way:

Learning that you have cancer is a shock. Learning that you have cancer when you’re still in school, or just getting started in your career, or just starting a family makes the shock even greater. This booklet is designed to help you understand what’s happening and to get the support you need, including the best possible cancer treatment. It includes some basic information on the cancer tests and treatments you may go through, tips for coping with the physical, social, and emotional challenges of cancer treatment, and information on resources that can help make the process easier.

There are 11 chapters in all, including Dealing with the diagnosis, Navigating the treatment process, and Thinking about the unthinkable, as well as more than 100 resources and a cancer dictionary. Elaborating on a critical issue in this young age group, Dr. Coccia noted that up to 70% of young adult cancer patients who could benefit from fertility preservation never take advantage of such procedures. “We put fertility preservation right upfront,” he said. “Before you discuss treatment, if you have the time to delay it, fertility issues should be considered.”

How the Booklet Will Be Used Dr. Coccia said the booklets will be distributed to the 21 member institutions of the NCCN, the institutional members of the Children’s continued on page 114

Now Enrolling Nivolumab Clinical Research Studies Non-small Cell Lung Cancer (NSCLC)

You may have patients who are eligible to participate in a clinical research study to evaluate an investigational PD-1 receptor blocking antibody for previously treated advanced/metastatic squamous or non-squamous cell NSCLC Key eligibility criteria include:

• • • • •

≥18 years of age Stage IIIB/IV or recurrent squamous or non-squamous cell NSCLC Progression or recurrence during or after prior platinum-containing chemotherapy ECOG PS ≤1 No prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4, or other antibody-targeting T-cell co-stimulation or checkpoint pathways

For more information, including a list of study sites, please visit ClinicalTrials.gov and use the following study identifiers in the search fields:

• NCT01642004 (Squamous cell NSCLC/CA209-017) • NCT01673867 (Non-squamous cell NSCLC/CA209-057) • NCT01721759 (Squamous cell NSCLC/CA209-063) 136486 04/2013

The ASCO Post | MAY 15, 2013

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News Psychosocial Oncology

University of Denver and Exempla Healthcare Study Finds Patient Distress Screenings Practical, Helpful By Keegan Bales

esearchers at the University of Denver and Exempla Healthcare found that multiple distress screenings per patient over the course of cancer treatment informs health-care providers about emotional distress patterns and supportive needs over time. The information gathered allows providers to improve quality of life, satisfaction with medical care and support services,

the American Psychosocial Oncology Society (APOS), held recently in Huntington Beach, California.

Study Rationale The purpose of the study was “to increase understanding and awareness of patterns in distress, the stated needs, and patients’ willingness to complete multiple psychosocial screenings in

Nearly half of patients who identified distress indicated a level of 5 [out of 10] or greater. —Christine DeVore, MA

treatment compliance, and even survival rates. The study also found that distress screenings could be successfully administered at community cancer centers.1 Little research has been published in peer-reviewed journals about the trajectory of distress over the cancer continuum. The project tied for Best Program at the 10th Annual Conference of

an outpatient cancer center.” Despite recommendations by the Institute of Medicine, many patients with cancer are not screened for distress, including those patients being treated at comprehensive cancer centers. Cancer is a journey consisting of many ups and downs that cannot be measured by one distress screening. The researchers believe that patients

NCCN Patient Guidelines

Dr. Coccia said that oncologists and their support staff should let patients know these guidelines are available, and how to access them. An educated patient is a benefit not only to himself or herself, but to the busy oncologist as well, he added. “When patients are diagnosed, they Google their disease and end up with a pile of material, much of which is not relevant to their disease, or out of date, and scary. There is no way to discriminate on the Web, and they come in totally confused,” he said. “We were looking for a way to give these patients the right resources. It is also relationship-building. Within this book, there are patient stories. I have heard AYA patients say, ‘I wish the guidelines were available when I was first diagnosed.’” n

continued from page 112

Oncology Group, and the two dozen or so other AYA programs across the country. He hopes the booklets will also find their way into community cancer centers and private physician’s offices. While the hard copies are striking, the online version can be updated as needed and provide “live” links to more than 70 resources listed in the book (another two dozen or so are print resources). The resources, which constitute one of the most important components of the booklet, direct the reader to general information on cancer in adolescents and young adults, cancer diagnosis and treatment, fertility issues, managing side effects, dealing with life during and after treatment, and end-of-life issues.

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

need to be screened throughout the progression of their disease to receive the best possible care. Approximately 1,500 cancer patients were screened over a 6-month period. In total, over 3,000 screens were collected. Patients completed the questionnaire, which was offered in both Spanish and English, at multiple appointments over the course of their treatment. The purpose of the questionnaire was to identify patients who required greater support services. As a result of this project, 1,074 psychosocial oncology referrals were made.

Notable Findings “Nearly half of patients who identified distress indicated a level of 5 [out of 10] or greater,” said doctoral psychology intern and lead researcher Christine DeVore, MA. “To meet guidelines, it is essential that cancer centers have adequate psychosocial resources and staffing to provide the appropriate followup clinical interventions.” This particular screen offered respondents the option of consulting with a psychologist, social worker, dietitian, spiritual care provider, or pharmacist. An oncology dietitian was most frequently requested. Patients were also asked to rate four domains of symptoms and concerns: health, social,

practical, and emotional. The individuals polled were most concerned about their health, including fatigue, weight management, nausea, and sleep. “Physical and medical complaints are a major source of distress reported by the patients sampled,” Ms. DeVore said. “It is important that psychosocial oncology providers assess these concerns with patients and triage services when appropriate.” Moving forward, the researchers plan to conduct further research, particularly analyzing distress patterns over time. They plan to improve data collection and analysis processing so that monthly reporting of distress is more feasible. Ms. DeVore hopes that the study will serve as a model for program guidance and evaluation. n Disclosure: Ms DeVore reported no potential conflicts of interest.

Reference 1. DeVore C, Lomax JB, Aoyagi M, et al: Psychosocial distress screening in a community cancer center: A descriptive study of distress over the course of treatment. 2013 American Psychosocial Oncology Society Annual Conference. Abstract P214. Presented February 16, 2013.

NCCN Patient Guidelines for Adolescents and Young Adults

CCN Patient Guidelines for Adolescents and Young Adults with Cancer are now available. Visit www.nccn.com to view these and other NCCN guidelines for patients. Patient versions of the NCCN Guidelines are available in the following categories: • • • • • • • • • • • •

Adolescents and young adults Breast cancer Chronic myelogenous leukemia Colon cancer Lung cancer screening Malignant pleural mesothelioma Melanoma Multiple myeloma Non-small cell lung cancer Ovarian cancer Pancreatic cancer Prostate cancer

ASCOPost.com | MAY 15, 2013

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National Comprehensive Cancer Network Annual Conference

Guideline Adherence and Geriatric Assessment Studies among NCCN Scientific Posters of Interest By Caroline Helwick

or the first time at the National Comprehensive Cancer Network (NCCN) Annual Conference, scientific posters were included as part of the program. The ASCO Post captured some of the most interesting findings for our readers, including the following news briefs. The findings of these studies support the use of NCCN Guidelines in patient care.

Medical Oncologists, Surgeons, and NCCN Guidelines To learn more about physician’s attitudes toward and their use of NCCN Guidelines, investigators led by Reshma Jagsi, MD, DPhil, Associate Professor of Radiation Oncology at the University of Michigan Health System, Ann Arbor, surveyed 750 medical oncologists and 750 surgeons, analyzing responses from 766 respondents who reported seeing at least one new patient with breast cancer in the past year.1 They found attitudes to be generally favorable, with 96% reporting that they agreed with NCCN recommendations and a minority stating that NCCN Guidelines were outdated or overly restrictive. Medical oncologists were more likely than surgeons to be aware of the NCCN

Reshma Jagsi, MD, DPhil

“The NCCN Guidelines appear to have greater visibility to the medical oncology audience than to surgeons, and patient versions appear particularly infrequently recommended by providers,” Dr. Jagsi noted.

NCCN Guidelines and Diffuse Large B-cell Lymphoma There is little evidence that adherence to clinical practice guidelines enhances survival in real-world practice settings, but researchers in St. Louis have contributed to this discussion with their study of 1,826 patients in the Veterans Health Administration cancer registry diagnosed with diffuse large B-cell lymphoma after June 1, 2000, the release date for the NCCN Guidelines.2 Kenneth Carson, MD, Assistant Professor of Medicine at St. Louis Veterans Affairs Medical Center and Washington University School of Medicine, and colleagues reported that the ageadjusted 3-year survival rate was 62% for patients who received treatment consistent with the NCCN Guidelines, vs 41% (P < .001) for the nonadherent group. By Cox analysis, increased mortality was associated with age, stage, B symptoms, comorbidities, and lactate dehydroge-

Kenneth Carson, MD

Guidelines (100% vs 74%, P < .001) and to be influenced by them (96% vs 70%, P < .001). Although the vast majority (91%) of medical oncologists reported looking at the NCCN Guidelines more than once a year, fewer of the surgeons did so (59%, P < .001). The NCCN Guidelines for breast cancer had been read completely by almost half the medical oncologists and about one-quarter of the surgeons (P < .001). .001). Three-quarters Three-quarters of all respondents said their own practice conforms to the breast cancer guidelines. Still, 77% also reported that they refer, at most, one-quarter of their patients to the patient version.

William P. Tew, MD

nase level. Use of granulocyte colonystimulating factors was associated with a trend toward reduced mortality. After controlling for these factors, the study found that patients whose initial treatments were recommended by the NCCN Guidelines had a 39% reduction in mortality. “Of note,” Dr. Carson added, “only 56% completed the appropriate number of treatment cycles and/or radiation to finish in guideline-adherent fashion.” He said the findings suggest that adherence could be used as a quality measure that will correlate with survival. “Additional work is underway to fine-tune our results and understand the factors as-

New Research Presented at NCCN’s Annual Conference ■ A survey of physicians showed that cancer management guidelines are

generally viewed favorably, with attitudes slightly more positive among medical oncologists than surgeons, but patients are rarely referred to patient versions of guidelines.

■ A study of patients with diffuse large B-cell lymphoma found that those

whose initial treatments were recommended by the NCCN Guidelines had a 39% reduction in mortality at 3 years after diagnosis, compared with a non–guideline-adherent group.

■ A feasibility study of older women with ovarian cancer demonstrated

that a cancer-specific geriatric assessment and weekly nursing telephone intervention identified problems not captured in routine visits, including fall history, significant cognitive impairment, poor nutrition, and severe depression or anxiety.

sociated with beginning and completing treatment in adherent vs nonadherent fashion,” he said.

Geriatric Assessment and Ovarian Cancer A cancer-specific geriatric assessment and weekly nursing telephone intervention is able to detect problems experienced by elderly women with ovarian cancer, according to a feasibility study from Memorial SloanKettering Cancer Center, New York.3 William P. Tew, MD, a medical oncologist on Memorial’s Gynecologic Medical Oncology Service, and colleagues noted that more than half of patients with ovarian cancer are older than 65 years of age, and geriatric assessment, which can predict outcomes in other tumor types, is not commonly performed in this population. In this study, 23 ovarian cancer patients (median age, 72 years) were enrolled in a study that evaluated a serial cancer-specific geriatric assessment (largely self-administered) and geriatric nursing telephone interventions in a gynecologic oncology practice. Subjects completed four assessments over 6 months, months, including before initiation of chemotherapy, during chemotherapy, at completion of chemotherapy, and after surgery. They received a weekly telephone call from a geriatric nurse practitioner to reinforce medication compliance, to offer psychosocial support, and to facilitate appropriate referrals. Toxicity, quality of life, use of care, and satisfaction parameters were compared between the intervention group and patients receiving standard oncology care. The preliminary results showed that

patients can complete the brief geriatric assessment in a short period of time, 70% without assistance. The assessment identified problems not captured in routine visits, including fall history, which was reported by 14% of patients, significant cognitive impairment (9%), poor nutrition (33%), and severe depression or anxiety (45%). About two-thirds of patients appeared at medium-to-high risk for toxicity. The patients reported that the assessment was easy to understand (78%) and of appropriate length (65%). Toxicity and outcomes will be reported at a later date. n Disclosure: Drs. Jagsi, Carson, and Tew received Young Investigator Award grants from the NCCN Foundation.

References 1. Jagsi R, Huang G, Griffith K, et al: Attitudes toward and use of cancer management guidelines in a national sample of medical oncologists and surgeons. 18th Annual Conference of the National Comprehensive Cancer Network. Abstract 2013-20. Presented March 15-16, 2013. 2. Carson K, Luo S, O’Brian K, et al: Adherence to National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology improves survival in veterans with diffuse large B-cell lymphoma. 18th Annual Conference of the National Comprehensive Cancer Network. Abstract 2013-17. Presented March 15-16, 2013. 3. Tew WP, Yulico HM, Hurria A, et al: Geriatric assessment and telephone intervention in elderly women with ovarian cancer: Preliminary findings. 18th Annual Conference of the National Comprehensive Cancer Network. Abstract 2013-19. Presented March 15-16, 2013.

The ASCO Post | MAY 15, 2013

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News Genitourinary Oncology

AUA Releases New Clinical Guideline on Prostate Cancer Screening

en ages 55 to 69 who are considering prostate cancer screening should talk with their doctors about the benefits and harms of testing and proceed based on their personal values and preferences, ac-

cording to a new clinical practice guideline released by the American Urological Association (AUA). The new guideline, which updates the Association’s 2009 Best Practice Statement on prostate-specific antigen

(PSA) was announced during the 2013 AUA Annual Meeting in San Diego. The guideline does not address detection of prostate cancer in symptomatic men, where symptoms imply those that could be related to

locally advanced or metastatic prostate cancer. The new guideline is significantly different from previous guidance as it was developed using evidence from a systematic literature review rather than consensus opinion, provides rating and interpretation of the evidence based on randomized controlled trials with modeled and population data as supporting evidence, and develops statements that do not go beyond the available evidence. In developing the guideline, the panel acknowledged that ongoing research may lead to changes in the guidelines statements, and announced plans to update the guidelines regularly based on new evidence.

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The guideline makes the following specific statements: • PSA screening in men under age 40 years is not recommended. • Routine screening in men between ages 40 to 54 years at average risk is not recommended. • For men ages 55 to 69 years, the decision to undergo PSA screening involves weighing the benefits of preventing prostate cancer mortality in 1 man for every 1,000 men screened over a decade against the known potential harms associated with screening and treatment. For this reason, shared decision-making is recommended for men age 55 to 69 years who are considering PSA screening, and proceeding based on patients’ values and preferences. • To reduce the harms of screening, a routine screening interval of 2 years or more may be preferred over annual screening in those men who have participated in shared decision-making and decided on screening. As compared to annual screening, it is expected that screening intervals of 2 years preserve the majority of the benefits and reduce over diagnosis and false-positives. • Routine PSA screening is not recommended in men over age 70 or any man with less than a 10- to 15-year life expectancy. n

ASCOPost.com | MAY 15, 2013

PAGE 117

Journal Spotlight Gastrointestinal Oncology

12-Gene Recurrence Score Predicts Recurrence in Stage II Colon Cancer in CALGB 9851 Population By Matthew Stenger

s reported by Alan P. Venook, MD, Professor of Medicine (Hematology/Oncology) at the University of California, San Francisco, and colleagues in Journal of Clinical Oncol-

Alan P. Venook, MD

ogy, a 12-gene recurrence score (Oncotype DX Colon Cancer Assay) was shown to predict recurrence in stage II colon cancer in a validation study performed in the population of the Cancer and Leukemia Group B (CALGB)

9581 trial.1 These findings are consistent with those in a validation study of the assay performed in patients with stage II disease in the QUASAR study.2 The recurrence score appears to have greatest discerning power in patients with stage T3 mismatch repair gene–intact tumors. Given the lower recurrence risk observed in patients with mismatch repair–deficient vs mismatch repair–intact tumors, the ability to discriminate risk in patients with T3 mismatch repair–intact tumors may have implications for use of adjuvant therapy in such patients.

12-Gene Assay The 12-gene recurrence score is calculated from a validated and standardized quantitative reverse transcriptase polymerase chain reaction assay that measures the expression of seven “recurrence” genes and five reference

Predicting Colon Cancer Recurrence ■ On multivariate analysis, only the 12-gene recurrence score was a significant predictor of colon cancer recurrence.

■ In a model including recurrence score, T stage, and mismatch repair gene

(MMR) status, recurrence score and MMR status were significant predictors of recurrence.

genes in formalin-fixed paraffin-embedded primary colon tumor tissue. Six of the recurrence genes are in the key biologic pathways of cell cycle control (MKI67, MYC, MYBL2) and stromal response (FAP, BGN, INHBA); the seventh (GADD45B) is a marker of genotoxic stress and may regulate activity of stromal response genes. In CALGB 9581, 1,713 patients with stage II colon cancer were randomly assigned to treatment with the investigational monoclonal antibody edrecolomab or observation, with no

survival difference found between groups. The current analysis included all 162 patients in the trial with recurrence of disease and available tissue and 528 randomly selected patients (approximately 1:3) without recurrence.

Predictors of Recurrence Recurrence score values ranged from 2 to 78, with a median of 31.4 and a mean of 33. Continuous recurrence score was significantly associated with continued on page 118

Emerging Prognostic Markers in Colon Cancer By Richard L. Schilsky, MD, FASCO

atients with stage II colon cancer generally have a favorable prognosis, with about 80% of patients surviving 5 years after surgery and the majority of these long-term survivors presumed to be cured. Clearly though, some patients are destined to recur after surgery, and there is an urgent need to develop reliable prognostic markers to identify these high-risk patients. Until now, no prospective randomized clinical trials have clearly identified a role for adjuvant chemotherapy in patients with stage II colon cancer. The most recent ASCO guideline on this issue, published in 2004, recommended against the routine use of adjuvant chemotherapy and that patients be encouraged to participate in well-designed clinical trials.1 At the time this guideline was published, the most widely used prognostic factors in stage II colon cancer were T stage (ie, depth of tumor invasion), histologic grade, presence or absence of lymphovascular or perineural invasion, numDr. Schilsky is Chief Medical Officer, American Society of Clinical Oncology.

ber of lymph nodes sampled, evidence of colonic obstruction or perforation, and preoperative serum carcinoembryonic antigen level.

Mismatch Repair Genes In more recent years, a number of molecular prognostic markers have emerged that appear to be useful in refining the prognosis of patients with stage II colon cancer. Perhaps the most powerful of these are markers of DNA mismatch repair deficiency in the tumor cells, detected as either the absence of immunohistochemical staining for the proteins encoded by the DNA mismatch repair genes (MLH1, MSH2, MSH3, MSH6, etc) or the presence of small fragments of DNA known as microsatellites detected with molecular analysis. The commonly used nomenclature is cumbersome and confusing, but tumors characterized as mismatch repair–deficient or microsatellite instability high, representing about 15% of colon cancers, are now known to have a more favorable prognosis, with a 40% to 50% relative improvement in overall survival compared with stage II

tumors that are mismatch repair–proficient. Some data also suggest that these patients do not benefit from adjuvant chemotherapy with fluorouracil.2 Thus, many clinicians will now routinely obtain a test for microsatellite instability status in newly diagnosed patients with stage II colon cancer to help inform discussions regarding prognosis and the advisability of adjuvant treatment.

Recurrence Score Several gene expression profiles have also been introduced recently that offer prognostic information. The Oncotype DX colon cancer recurrence score test is now commercially available in the United States. This test is based on the relative expression of 12 genes (7 recurrence and 5 reference genes) and is reported as a recurrence score that is associated with the risk of tumor recurrence. The recurrence score is an independent risk factor in multivariable analyses that include microsatellite instability status, T stage, histologic grade, lymphovascular invasion, and number of nodes examined and thus ap-

Richard L. Schilsky, MD, FASCO

pears to offer incremental information on risk. The test has now been extensively tested and validated in several large clinical trials, some of which, including CALGB 9581, were performed exclusively in patients with stage II disease.3 The major limitation of the Oncotype DX assay is limited dynamic range. For example, in the CALGB 9581 study, low recurrence score patients had a risk of recurrence at 5 years of approximately 12% and high recurrence score patients had a 5-year risk of approximately 18%.4 The test may have its greatest utility in refining prognosis of patients with T3, mismatch repair–proficient tucontinued on page 118

The ASCO Post | MAY 15, 2013

PAGE 118

Journal Spotlight

12-Gene Recurrence Score continued from page 117

risk of recurrence on the primary Cox proportional hazards analysis, with a hazard ratio (HR) of 1.52 for each 25unit increase in score (P = .013). Estimates of 5-year recurrence risk according to predefined percentile thresholds for low risk (below 40th percentile, which corresponded to a recurrence score of 29), medium risk (40th to 75th percentile, which corresponded to a recurrence score of 39), and high risk (above 75th percentile) were 12%, 15%, and 18%, respectively. On univariate analysis, the only other factor significantly associated with risk was mismatch repair–deficiency (HR = 0.62, P = .044, vs mismatch repair–intact status). Presence of lymphovascular invasion was associated with borderline significantly increased risk (HR = 1.56, P = .062).

Multivariate Analysis On multivariate analysis including mismatch repair status (deficient vs intact), T stage (T4 vs T3), number of lymph nodes examined (< 12 vs ≥ 12),

Emerging Prognostic Markers continued from page 117

mors, in whom the risk of recurrence was 13% for low recurrence score patients and 21% in high recurrence score patients. Thus, before ordering the test, clinicians may wish to consider whether the test results will truly be useful in guiding discussion with patients regarding prognosis, keeping in mind that, even in high-risk patients, there is no conclusive evidence that adjuvant chemotherapy is beneficial.

Other Prognostic Biomarkers The Oncotype DX colon cancer test is one of only several gene expression signatures that have been developed to assess

tumor grade (high vs low), lymphovascular invasion (present vs absent), and continuous recurrence score, only recurrence score was a significant predictor of recurrence (HR = 1.62 per 25 units, P = .004). In a model examining the contribution of the recurrence score to prediction of recurrence in the context of mismatch repair status and T stage (which are consistent prognostic covariates in stage II II colon cancer), recurrence score (P = .007) and mismatch repair status (P = .02) were significant predictors. Among patients with T3 mismatch repair–intact tumors (75% of those with mismatch repair results, the largest subgroup in the study), 44% were in the low recurrence score group and 22% were in the high recurrence score group. Estimated 5-year recurrence risks for the prespecified low-, intermediate-, and high-risk subgroups among these patients were 13%, 16%, and 21%, respectively.

Potential Drug Targets? The authors noted that the results of the CALGB 9851 and QUASAR analyses are consistent with the involvement of cell-cycle control and stromal response as determinants of prognosis in patients with early-stage disease. All such tests are complicated to perform and interpret, and there are few overlapping genes among the signatures used in these tests, raising some question as to their biologic relevance. Other emerging prognostic biomarkers in colon cancer include presence of BRAF mutations in the tumor5 and the expression of microRNA 21.6 We can be encouraged that ongoing research will likely produce other biomarkers that will help guide clinical decision-making for patients with early-stage colon cancer. n

Disclosure: Dr. Schilsky had a consultant or advisory role with Foundation Medicine and stock ownership of Foundation Medicine and Universal Oncology; however, at the present time he has no relationships to disclose.

Mismatch Repair Genes

ismatch repair genes are involved in numerous cellular functions, including the recognition and correction of errors in DNA replication. Germline mutations of mismatch repair genes have been shown to be involved in various types of cancer. recurrence in colon cancer, and that it is plausible that directing inhibitors toward elements of the pathways identified in the recurrence score could lead to the development of new adjuvant therapies for colon cancer. The authors concluded: Following on the results of QUASAR, the results presented here confirm the accuracy of the standardized, validated recurrence score and its relevance for patients with T3 [mismatch repair– gene] intact tumors, in which further risk discrimination may be factored into the decision of whether or not to offer adjuvant chemotherapy. In addition, the genes comprising the recurrence score highlight biologic pathways

References 1. Benson AB III, Shrag D, Somerfield MR, et al: American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22:34083419, 2004. 2. Sargent D, Marsoni S, Monges G, et al: Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28:32193226, 2011. 3. Gray RG, Quirke P, Handley K, et al: Validation study of a quantitative multigene reverse transcriptase polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol

that may be most responsible for cancer recurrence and represent genes that should be interrogated further to identify promising [drug] targets…. Hopefully, the results presented here will lead to both immediate and future improvements in treatment for patients with colorectal cancer. n

Disclosure: Among the study authors, Margarita Lopatin, Mark Lee, Kim ClarkLangone, Carl Millward, and Steven Shak reported employment or leadership positions with and stock ownership of Genomic Health, Richard L. Schilsky reported a consultant or advisory role with Foundation Medicine and stock ownership of Foundation Medicine and Universal Oncology, and Alan P. Venook reported research funding from Genomic Health. All other authors reported no potential conflicts of interest.

References 1. Venook AP, Niedzwiecki D, Lopatin M, et al: Biologic determinants of tumor recurrence in stage II colon cancer: Validation study of the 12-gene recurrence score in Cancer and Leukemia Group B (CALGB) 9581. J Clin Oncol. March 25, 2013 (early release online). 2. Gray RG, Quirke P, Handley K, et al: Validation study of a quantitative multigene reverse transcriptase polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol 29:4611-4619, 2011.

29:4611-4619, 2011. 4. Venook AP, Niedzwiecki D, Lopatin M, et al: Biologic determinants of tumor recurrence in stage II colon cancer: Validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol March 25, 2013 (early release online). 5. Ogino S, Shima K, Meyerhardt JA, et al: Predictive and prognostic roles of BRAF mutation in stage III colon cancer: Results from intergroup trial CALGB 89803. Clin Caner Res 18:890-900, 2011. 6. Schetter AJ, Leung SY, Sohn JJ, et al: MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299:425-436, 2008.

Don’t Miss These Important Reports in This Issue of The ASCO Post Mario E. Lacouture, MD, on EGFR Inhibitors and Acneiform Rash see page 69

Edward E. Partridge, MD, on Disparities in Cancer Care see page 84

Visit The ASCO Post online at ASCOPost.com

Matthew Lunning, DO, on Debt and the Oncology Fellow see page 99

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. June 2012. 2. Verstovsek S, Mesa RA, Gotlib J, et al. N Engl J Med. 2012;366:799-807.

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

JAK targeted to make a difference

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

ASCOPost.com | MAY 15, 2013

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American Association for Cancer Research Annual Meeting Gynecologic Oncology

Combinatorial Immunologic Approach Yields Benefit in Preliminary Study of Recurrent Ovarian Cancer By Alice Goodman

two-step immunologic approach that includes a personalized dendritic cell vaccine for each patient followed by adoptive T-cell therapy holds promise for the treatment of recurrent ovarian cancer, according to results of two consecutive phase I studies presented at the American Association for Cancer Research (AACR) Annual Meeting in Washington, DC.1 These studies represent “the first time that such a combinatorial approach has been used for patients with ovarian cancer,” stated Lana E. Kandalaft, PharmD, PhD, MTR, Research Assistant Professor of Obstetrics and Gynecology and Director of Clinical Development, Ovarian Cancer Research Center in the Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Personalized Vaccine The strategy requires cryopreservation of the patient’s tumor at surgery so the tumor cells can be used to manufacture a personalized vaccine programmed to attack the cancer. Dendritic cells are isolated from the blood and exposed to tumor cells. Then they are administered in the body to “educate” the patient’s T cells. Dr. Kandalaft called the educated T cells “soldiers that go back into the body to fight the tumor.” The study included 31 patients with recurrent, progressive, stage III/IV ovarian cancer. Following surgery, the personalized vaccine was created and cryopreserved. Patients had the option to get standard-ofcare chemotherapy before enrolling in the trial. The vaccine is given intranodally in the groin five times over about 3 months of therapy. Some patients went

EXPERT POINT OF VIEW

ommenting on this study, Louis M. Weiner, MD, Director of the Georgetown University Lombardi Comprehensive Cancer Center in Washington, DC, commended this study of a combinatorial immunologic approach. “Immunology matters when it comes to cancer research. Drugs designed to harness the power of the immune system have meaningful anticancer activity. This recognition has led to the online inauguration of a new AACR journal called Cancer Immunology Research devoted to major advances in the field,” Dr. Weiner said.

Louis M. Weiner, MD

Complex Approach “Dr. Kandalaft’s study involved complex strategies that harness the immune system itself, where the vaccine points the immune system in the direction of the tumor, and then that response can be further expanded through adoptive transfer of T cells educated to attack tumor cells bearing those tumor antigens,” he continued. This work suggests that combination immunotherapies will be developed with more complex approaches to overcome the innate mechanisms of resistance within tumors, Dr. Weiner commented. “The difference between immunology and tumor immunology is the tumor. Combinatorial strategies are needed to attack cancer. The future of our field will include conventional drugs, and it is time to recognize the importance of immunology as part of anticancer therapies,” he stated. n Disclosure: Dr. Weiner reported no potential conflicts of interest.

Novel Therapies for Ovarian Cancer ■ New approaches are needed for recurrent progressive ovarian cancer. ■ A two-step combinatorial immunologic approach holds promise in this setting, according to preliminary study.

■ The approach entails a personalized vaccine made with dendritic cells and the patient’s own tumor tissue, followed by adoptive T-cell therapy with extracted and expanded primed T cells.

on to the next step, which was adoptive T-cell therapy with T cells collected from the blood after being primed during the vaccine process. These T cells are cryopreserved, then expanded and reinfused into the patient.

mor lesions were present at baseline. At the end of the study, most of the lesions had progressed, but 6 weeks later, some lesions stabilized or re-

Key Results Of the 31 patients who received a personalized vaccine, 20 (64%) had clinical benefit (3 partial responses and 17 with stable disease). Of those with stable disease, six had no evidence of disease at study entry and remained disease-free at the end of the study. The longest duration without evidence of disease has been 45 months, Dr. Kandalaft said. Eleven patients who were responders to the vaccine therapy but had residual disease moved on to the second phase of the study with adoptive T-cell therapy. Clinical benefit was observed in eight patients (about 75%), with one complete response and seven with stable disease. Side effects were minimal and limited to flu-like symptoms, she said. Both treatments were given with bevacizumab (Avastin) to control angiogenesis. According to Dr. Kandalaft, “this is a powerful duo.” She noted that in the current cohort aspirin is being included in the mix because it opens the tumor endothelial barrier to primed vaccine T cells, according to recent work by George Coukos, MD, PhD, Director of the Penn Ovarian Cancer Research Center. Other combination strategies will be tested with the vaccine, she said.

Delayed Immune Response “Immunotherapy is known to have a delayed response,” she explained. “In one patient, for example, multiple tu-

Lana E. Kandalaft, PharmD, PhD, MTR

gressed. The progression seen initially may be due to tumor T-cell infiltrate. Later on, these lesions do regress,” she elaborated. The vaccination approach will also be studied in the primary setting in patients in remission after surgery. (Janos L. Tanyi, MD, PhD, Assistant Professor of Obstetrics and Gynecology at Penn Medicine, will be the primary investigator on this study.) “The immune system is healthier at that time. We will try to boost the immune system after surgery and front-line chemotherapy to prevent recurrence. Theoretically this is the time when vaccine approaches would offer more benefit,” Dr. Kandalaft told listeners. n Disclosure: Dr. Kandalaft reported no potential conflicts of interest.

Reference 1. Kandalaft LE, Tanyi J, Chiang C, et al: Autologous whole-tumor antigen vaccination in combination with adoptive T cell therapy for patients with recurrent ovarian cancer. AACR Annual Meeting. Abstract LB-335. Presented April 10, 2013.

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Journal Spotlight Gynecologic Oncology

Women with Lynch Syndrome and Endometrial Cancer Are at Increased Risk of Other Cancers By Matthew Stenger

ynch syndrome is an autosomal dominantly inherited disorder due to germline mutations in DNA mismatch repair genes. Mismatch repair mutation carriers are at increased risk of several

Aung Ko Win, MBBS, MPH

cancers, with endometrial cancer being one of the most commonly diagnosed cancers in women with Lynch syndrome. In a recent study published in Journal of the National Cancer Institute, Aung Ko Win, MBBS, MPH, University of Melbourne, and colleagues found that women with Lynch syndrome and a diagnosis of endometrial cancer were at significantly increased risk of colorectal cancer, cancer of the kidney/renal pelvis/ ureter, urinary bladder cancer, and breast cancer compared with all women in the general population as well as women in the general population with a diagnosis of endometrial cancer.1

Study Details The investigators used data from the Colon Cancer Family Registry to identify a cohort of 127 women with a diagnosis of endometrial cancer preceding any diagnosis of other cancers who had a mutation in 1 of 4 mismatch repair genes: 30 had mutations in MLH1, 72 in MSH2, 22 in MSH6, and 3 in PMS2. Women had a mean age of 46 years at diagnosis of endometrial cancer. Among the 127 women, 70 (55%) developed at least one primary cancer after diagnosis of endometrial cancer, with 19 (15%) developing more than one. These cancers included colorectal cancer in 31% of women, followed by cancer of the breast in 9%, skin in 7%, urinary bladder in 6%, kidney/renal pelvis in 4%, ureter in 3%, small intestine and pancreas in 2% each, and stomach, thyroid, gall bladder, biliary tract,

vulva, and head and neck in 1% each. The cumulative risks for primary cancers at 10 and 20 years after endometrial cancer were 20% and 48% for colorectal cancer, 2% and 11% for kidney/renal pelvis/ureter cancer, 1% and 9% for urinary bladder cancer, and 5% and 11% for breast cancer. In general, the types of cancers observed in these women were not unexpected, given previously reported risks among women who are mismatch repair mutation

carriers; however, the risk for breast cancer was higher than expected.

Increased Risk of Colorectal and Other Cancers After endometrial cancer, the women were at significantly increased risk of several cancers compared with the general population; risks were increased 40-fold for colorectal cancer (standardized incidence ratio [SIR] = 39.9, 95% confidence interval [CI] = 27.2–58.3),

28-fold for kidney/renal pelvis/ureter cancer (SIR = 28.3, 95% CI = 11.9– 48.6), 24-fold for urinary bladder cancer (SIR = 24.3, 95% CI = 8.56–42.9), and 2.5-fold for breast cancer (SIR = 2.51, 95% CI = 1.17–4.14). The risks for other cancers in mismatch repair mutation carriers were also significantly greater than risks for other primary cancers in women in the general population with endomecontinued on page 126

Lynch Syndrome: A Multitude of Predispositions By Carrie L. Snyder, MSN, and Henry T. Lynch, MD

he current uncertainty regarding the relative frequencies of cancers of various anatomic sites in Lynch syndrome poses a difficulty in commenting on the syndrome’s overall cancer spectrum. It is even more vexing to address the order in which these cancers are prone to occur. What we do know is that there is an enormous lifetime risk of cancer at multiple anatomic sites in Lynch syndrome. For example, when the syndrome was described in the 1960s, there was only limited knowledge about its cancer propensity, and primary focus was given to colorectal and endometrial cancers. Since those early reports, Lynch syndrome has become known to be the most frequent hereditary colorectal cancer–prone disorder, but is also now known to predispose to cancers of an almost unlimited number of other sites. These include some of the more frequently occurring cancers in the general population among women (namely, carcinoma of the breast) and among men (namely, prostate cancer).

Role of Mismatch Repair Genes Approximately 5% of all endometrial cancers are the result of a hereditary predisposition. The majority of these hereditary cases are manifested Ms. Snyder is Cancer Genetics Nurse Specialist and Dr. Lynch is Professor and Chairman, Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Nebraska.

in carriers of mismatch repair germline mutations consonant with Lynch syndrome.1 Lynch syndrome is the most common form of hereditary colorectal cancer, and most of the cancer screening publicity regarding the disorder focuses on the proven effectiveness Carrie L. Snyder, MSN Henry T. Lynch, MD of colonoscopy. While it is crucial to appreciate the importance of dence interval [CI] = 35% to 62%); colonoscopy, most studies have found cancer of the kidney, renal pelvis, or women with Lynch syndrome to have a ureter (11%, 95% CI = 3% to 20%); higher risk for endometrial cancer than urinary bladder cancer (9%, 95% CI = 2% to 17%); and breast cancer (11%, for colorectal cancer. In fact, it has been estimated that 95% CI = 4% to 19%)....” These rates were statistically signifiboth males and females harboring mismatch repair genes have upwards of a cantly higher compared with women 69% lifetime risk for colorectal cancer, in the general population. The rate of while women face up to a 71% risk of ovarian cancer was not listed, suggestdeveloping endometrial cancer.2,3 The ing that a hysterectomy with bilateral risk of endometrial cancer subsequent salpingo-oophorectomy was conducted to colorectal cancer is also increased.4 at the time of each endometrial cancer In addition, compared with the gen- diagnosis; however, this is not explicitly eral population, women carrying a stated within the study. Given the excess mismatch repair gene mutation have a of gynecologic cancer (endometrium 19-fold greater risk of developing ovar- and ovary) in Lynch syndrome and the ian cancer and a 4-fold increased risk of respective limitations of their screening, developing breast cancer.5 which has virtually no benefit for ovarian cancer and is of only limited use in After Endometrial Cancer endometrial cancer, in our opinion a betWin et al6 set out to define the risk ter choice is the option for prophylactic of subsequent cancers in women who hysterectomy and bilateral salpingo-oohave developed endometrial cancer phorectomy, once family is completed and harbor a mismatch repair delete- and the patient is fully accepting. Workrious mutation. Their results showed ing with colleagues at MD Anderson that these women had the following 20- Cancer Center,7 we have demonstrated year risks of developing other cancers: the effectiveness of this approach. continued on page 126 “colorectal cancer (48%, 95% confi-

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The ASCO Post | MAY 15, 2013

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Journal Spotlight

Lynch Syndrome continued from page 124

trial cancer; risks were increased 36fold for colorectal cancer (SIR = 36.3, 95% CI = 25.8–49.6), 29-fold for kidney/renal pelvis/ureter cancer (SIR = 29.3, 95% CI = 13.2–56.9), 17-fold for urinary bladder cancer (SIR = 16.95, 95% CI = 6.8–35.2), 2.4-fold for breast cancer (SIR = 2.4, 95% CI = 1.2–4.2), 38-fold for cancer of the small intestine (SIR = 38.3, 95% CI = 7.65–119.0), and 9-fold for pancreas cancer (SIR = 8.9, 95% CI = 1.8–26.3). Although analysis was limited by the relatively small numbers of women with individual mismatch repair mutations, no significant differences were observed for 10- or 20-year cumulative risks for each cancer according to type of mismatch repair mutation present. There were no significant differences in SIRs for cancers according to mismatch repair mutation except for colorectal cancer. For colorectal cancer, SIRs were 38.7 for women with the MLH1 mutation and 58.5 for those with the MHS2 mutation, compared with 4.5 for women with the MSH6 mutation.

Study Limitations As noted by the investigators, limitations of the study included the absence of information on treatment history for endometrial cancer, which may have affected risk for subsequent cancers, and insufficient statistical power to fully distinguish risks associated with specific mismatch repair gene mutations. The findings also may not apply to women with poorerprognosis endometrial cancer; such patients were less likely to have been included in the current analysis, since they were less likely to be able to pro-

Multitude of Predispositions

lon cancer–specific tumor spectrum in most families with an EPCAM deletion.8

continued from page 124

Other Cancer Risks

Burden of Vigilance

In addition to endometrial cancer, cancers that occur in excess in germline mutation carriers for Lynch syndrome are the aforementioned colon and ovary cancers; cancers of the stomach, small bowel, pancreas, upper uroepithelial tract (ureter and renal pelvis),

The authors concluded that women with a mismatch repair gene mutation are at a significantly higher risk of developing subsequent Lynch syndrome–associated cancers. However, the site of the initial primary cancer does not appear to affect these risks.

The crucial message for the physician managing high-risk Lynch syndrome patients is to fully appreciate the fact that there is much more to Lynch syndrome than the endometrium and colon. —Carrie L. Snyder, MSN, and Henry T. Lynch, MD

breast, and prostate; sebaceous adenomas, sebaceous carcinomas, multiple keratoacanthomas, and possibly other skin cancers in the Muir-Torre syndrome variant; and glioblastoma multiforme in the Turcot syndrome variant. It was interesting to note that none of the 15 women who harbored a deletion in the EPCAM gene in the paper by Win and colleagues had a previous diagnosis of endometrial cancer and, therefore, all were excluded from this study. This is consistent with our finding of a more covide a blood sample for genetic testing or to complete study questionnaires. In addition, it is not known whether women in the study were informed of their mismatch repair mutation status prior to the mutation testing performed for the current study. Since mismatch repair mutation is known to carry increased

Lynch Syndrome, Endometrial Cancer, and Subsequent Risks ■ Women with Lynch syndrome and endometrial cancer are at dramatically increased risk of colorectal cancer and other primary cancers.

■ Estimated 10- and 20-year cumulative risks after endometrial cancer were 20% and 48% for colorectal cancer, 2% and 11% for kidney/renal pelvis/ ureter cancer, 1% and 9% for urinary bladder cancer, and 5% and 11% for breast cancer.

These issues are clearly significant and add to the burden of vigilance for the physician. The crucial message for the physician managing high-risk Lynch syndrome patients is to fully appreciate the fact that there is much more to Lynch syndrome than the endometrium and colon. n

Disclosure: Dr. Lynch and Ms. Snyder reported no potential conflicts of interest.

References 1. Tan YY, McGaughran J, Ferguson K,

risk of colorectal cancer, knowledge of mismatch repair status on the part of the women or their physicians might have affected the frequency of surveillance for colorectal polyps and cancer. Overall, 55% of women reported having at least one surveillance colonoscopy or sigmoidoscopy after diagnosis of endometrial cancer, with the average interval between evaluations being 2.1 years. The investigators concluded, “[W] omen carrying [mismatch repair] gene mutations with a previous diagnosis of endometrial cancer have increased risks of a range of cancers, including breast cancer. This study provides the most accurate representation of their ongoing cancer risks, providing a basis

et al: Improving identification of Lynchsyndrome patients: A comparison of research data with clinical records. Int J Cancer 132:2876-2883, 2013. 2. Hampel H, Stephens JA, Pukkala E, et al: Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: Later age of onset. Gastroenterology 129:415-421, 2005. 3. Koornstra JJ, Mourits MJ, Sijmons RH, et al: Management of extracolonic tumours in patients with Lynch syndrome. Lancet Oncol 10:400-408, 2013. 4. Obermair A, Youlden DR, Young JP, et al: Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma. Int J Cancer 127:2678-2684, 2010. 5. Win AK, Young JP, Lindor NM, et al: Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: A prospective cohort study. J Clin Oncol 30:958-964, 2012. 6. Win AK, Lindor NM, Winship I, et al: Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst 105:274-279, 2013. 7. Schmeler KM, Lynch HT, Chen L-M, et al: Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 354:261-269, 2006. 8. Lynch H, Riegert-Johnson D, Snyder C, et al: Lynch syndrome associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. Am J Gastroenterol 106:1829-1836, 2011.

for effective long-term surveillance and risk reduction strategies. Further larger studies are recommended for refining risk estimates separately for specific [mismatch repair] gene mutations to optimally inform practice and policy for clinical risk management.” n

Disclosure: The study was supported by the National Cancer Institute and through cooperative agreements with members of the Colon Cancer Family Registry and principal investigators. The authors had no conflicts of interest to report with regard to this article.

Reference 1. Win AK, Lindor NM, Winship I, et al: Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst 105:274-279, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Richard L. Schilsky, MD, FASCO, on Emerging Prognostic Markers in Colon Cancer see page 117

Stephen M. Sagar, MD, on Symptom Management with Complementary Therapies see page 159

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | MAY 15, 2013

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Journal Spotlight Gastrointestinal Oncology

Oral S-1 Noninferior to Gemcitabine in Advanced Pancreatic Cancer in Japan and Taiwan By Matthew Stenger

s reported by Hideki Ueno, MD, PhD, of National Cancer Center Hospital, Tokyo, and colleagues in Journal of Clinical Oncology, treatment with the oral fluoropyrimidine derivative S-1 was associated with noninferior overall survival and reduced hematologic toxicity compared with gemcitabine treatment in a phase III trial (the GEST study) in patients with advanced pancreatic cancer in Japan and Taiwan.1 Gemcitabine plus S-1 provided no survival advantage over gemcitabine alone, although benefit was observed in some patient subgroups with the combination.

Study Details In the trial, 832 chemotherapy-naive patients with locally advanced or meta-

Role of S-1 in Pancreatic Adenocarcinoma ■ In the GEST study of patients with advanced pancreas cancer, median

overall survival was 9.7 months in the S-1 group and 8.8 months in the gemcitabine group (P < .001 for noninferiority); a group receiving the two drugs combined did not have superior survival.

■ S-1 was associated with significantly lower rates of grade 3 or higher hematologic adverse events compared with gemcitabine.

Hideki Ueno, MD, PhD

static pancreatic cancer were randomized to receive gemcitabine (n = 277), S-1 (n = 280), or the combination (n = 275). Gemcitabine alone was given at 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle, and S-1 alone was given orally at 80, 100, or 120 mg/d based on body surface area on days 1 to 28 of a 42-

day cycle. In combination, gemcitabine was given at the same dose on days 1 and 8, and S-1 was given at 60, 80, or 100 mg/d on days 1 to 14 of a 21-day cycle. The primary outcome measure was overall survival, with the study testing the noninferiority of S-1 to gemcitabine alone and the superiority of the combination to gemcitabine alone.

The Intriguing Potential of S-1 in Pancreatic Cancer By Eileen M. O’Reilly

he results of the GEST study by Ueno and colleagues add to the intriguing potential role of the oral fluoropyrimidine S-1 in the treatment of pancreas adenocarcinoma. S-1 is a three-component drug consisting of tegafur (a prodrug of fluorouracil), gimeracil (5-chloro-2,4 dihydropyridine, or CDHP, a dihydropyrimidine dehydrogenase enzyme activity in-

have been inferred for Asian vs Western populations. The results of the GEST study demonstrate noninferiority of S-1 to gemcitabine in advanced pancreatic cancer. However, overall survival superiority of a gemcitabine and S-1 combination over gemcitabine alone was not demonstrated. These results will lead to the use of S-1 as a single-agent instead of

The collective results of the GEST and JASPAC-01 trials suggest that further study of S-1 in Western patients is warranted. —Eileen M. O’Reilly, MD

hibitor), and oteracil (potassium oxonate). The drug has been extensively studied in Asia in gastrointestinal and other malignancies, and notable differences regarding pharmacogenomic and pharmacodynamic considerations Dr. O’Reilly is a gastrointestinal medical oncologist at Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York.

gemcitabine for front-line therapy for advanced pancreas adenocarcinoma in Asia for patients in whom single-agent therapy is an appropriate consideration. An interim analysis of the results of the JASPAC-01 trial presented at the Gastrointestinal Cancers Symposium in early 2013 provided similar support for the notion that S-1 may have superior activity to gemcitabine.

Specifically, in this latter trial, which was conducted in an adjuvant therapy population and was also designed with a noninferiority endpoint, preliminary results indicate superiority of S-1 over gemcitabine with a significant hazard ratio for survival for S-1 vs gemcitabine of 0.56 (95% confidence interval 0.420.74, P < .0001 for noninferiority, and P < .001 for superiority). Two-year survival was 70% with S-1 and 53% with gemcitabine. Overall, S-1 adds to the therapeutic options available for front-line therapy for pancreas adenocarcinoma, and the results of the GEST study will likely lead to this drug’s further development in combination with other agents and provide an alternative nongemcitabine platform to build upon. The implications of the GEST results for treatment in the United States remain unclear, since there is no obvious pathway to regulatory approval and the benefits and risk/toxicity balance of S-1 in Western populations remain to be elucidated. Nevertheless, the collective results of the GEST and JASPAC-01 trials suggest that further study of S-1 in Western patients is warranted. n Disclosure: Dr. O'Reilly has received research funding from Clovis; honoraria from Celgene. She has served in a consultant or advisory role for Celgene and Clovis (uncompensated).

The patient groups were well balanced for baseline characteristics. For the gemcitabine, S-1, and combination groups, 61%, 61%, and 57.5% of patients were male; 52%, 48%, and 50% were aged 65 years or older; 65%, 64%, and 62.5% had ECOG performance status of 0; 76%, 76%, and 75% had metastatic disease; 98%, 99%, and 99% had adenocarcinoma; 92%, 94%, and 90% had not undergone pancreas excision; and 73%, 77.5%, and 76.0% did not have biliary drainage.

Overall Survival Outcomes The median durations of treatment were 2.6 months in the gemcitabine group, 2.6 months in the S-1 group, and 4.3 months in the combination group. The median duration of follow-up for surviving patients was 18.4 months. Median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group (hazard ratio [HR] = 0.96, P < .001 for noninferiority compared with gemcitabine), and 10.1 months in the combination group (HR = 0.88, P = .15 compared with gemcitabine). Subgroup analyses of overall survival according to sex, age, extent of disease, ECOG performance status (0 or 1), and biliary drainage (no or yes) showed no significant interactions between S-1 treatment and gemcitabine treatment. Although the P values for interaction were not significant, combination therapy showed favorable hazard ratios compared with gemcitabine alone for the subset of patients with locally advanced disease (HR = 0.67, 95% confidence interval [CI] = 0.46–0.99) and the subset of patients with ECOG performance status of 1 (HR = 0.69, 95% CI = 0.51– 0.92). Median progression-free survival in the S-1 group was noninferior to that in the gemcitabine group (3.8 vs 4.1 months, HR = 1.09, P = .02 for noncontinued on page 128

The ASCO Post | MAY 15, 2013

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Journal Spotlight

Oral S-1 continued from page 127

inferiority). Median progression-free survival in the combination group (5.7 months) was significantly longer than that in the gemcitabine group (HR = 0.66, P < .001). Objective response rates were 13.3% with gemcitabine, 21.0% with S-1 (P = .02 vs gemcitabine), and

29.3% with the combination (P < .001 vs gemcitabine). Second-line chemotherapy was given to 66% of patients in the gemcitabine group, 66% of S-1 patients, and 62.5% of combination patients. Treatments such as erlotinib (Tarceva), oxaliplatin, and irinotecan were not approved for use in pancreatic cancer in Japan or Taiwan at

the time of the study. Thus, second-line therapy consisted primarily of S-1 or S-1–based regimens in the gemcitabine group and gemcitabine or gemcitabinebased regimens in the S-1 group. Second-line therapy consisted primarily of gemcitabine alone, gemcitabine and S-1 in combination, or S-1 alone in the combination group.

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

Trials Now Enrolling

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

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

Primary Endpoint: • Progression-free survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

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

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

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

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + PLD 50 mg/m2 IV Q4W

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

Trebananib IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Trebananib IV QW Monotherapy

ENDPOINTS

Primary

PFS 2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Key Secondary

Placebo IV QW Monotherapy

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

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

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

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

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

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

S-1 Better Tolerated Of grade 3 or higher adverse events, patients in the S-1 group had significantly (all P ≤ .01) lower rates of leukopenia (3.7% vs 18.7%), neutropenia (8.8% vs 41.0%), thrombocytopenia (1.5% vs 11.0%), increased ALT (5.9% vs 15.0%), and increased AST (7.7% vs 15.0%), and a significantly higher rate of diarrhea (5.5% vs 1.1%) compared with patients in the gemcitabine group. Compared with the gemcitabine group, patients in the combination group had significantly (all P ≤ .02) higher rates of leukopenia (37.8%), neutropenia (62.2%), rash (4.1% vs 0.7%), diarrhea (4.5%), mucositis/ stomatitis (2.2% vs 0%), and vomiting (4.5% vs 0.7%). The authors note that it is uncertain whether the results of this study can be extrapolated to Western patients, since the pharmacokinetics and pharmacodynamics of S-1 may differ between Western and East Asian patients. The authors concluded, “[T]his study has verified the noninferiority of S-1 to gemcitabine, thereby suggesting that S-1 can be used as first-line therapy for locally advanced and metastatic pancreatic cancer. Because S-1 was confirmed to be a key treatment for pancreatic cancer, S-1–based regimens are expected to be developed in the future to improve the management of this formidable disease.” n Full disclosure information can be found online at ASCOPost.com. Reference 1. Ueno H, Ioka T, Ikeda M, et al: Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. April 1, 2013 (early release online).

The ASCO Post Wants to Hear from You

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

ASCOPost.com | MAY 15, 2013

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2013

2013 Oncology Meetings May Northern New England Clinical Oncology Society Spring Meeting May 17 • Manchester, New Hampshire For more information: www.nnecos.org Iowa Oncology Society Spring Membership Conference May 17-18 • West Des Moines, Iowa For more information: www.ios-iowa.com California Breast Cancer Research Symposium: From Research to Action: Two Decades of Change May 17-18 • Costa Mesa, California For more information: www.cabreastcancer.org/ symposium/ Oregon Society of Medical Oncology Spring 2013 Oncology Conference May 17-18 • Ashland, Oregon For more information: www.osmo.org/events/view/18 State of the Art Techniques Symposium May 17-19 • San Antonio, Texas For more information: www.astro.org/ stateofthearttechniques 3rd International Symposium on Lung-Sparing Therapies for Malignant Pleural Mesothelioma May 18, 2013 • Santa Monica, California For more information: www.cme.ucla.edu/courses/

Node Society Congress May 27-29, 2013 • San Francisco, California For more information: www.sn-cancermets.org

12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch

Targeting Cancer Drug Resistance May 28-30 • Chicago, Illinois For more information: www.cancer-drugresistance.com

British Gynaecological Cancer Society Annual Scientific Meeting June 20-21 • Belfast, Ireland For more information: bgcsconference.com

The Bone Marrow Niche, Stem Cells, and Leukemia: Impact of Drugs, Chemicals, and the Environment May 29-31 • New York, New York For more information: www.nyas.org/bonemarrow

6th International Nasopharyngeal Carcinoma Symposium June 20-22 • Istanbul, Turkey For more information: www.npc2013.org

Interventional Oncology Sans Frontières May 29-June 1 • Cernobbio, Italy For more information: www.iosfc2013.org 13th World Congress of the European Association for Palliative Care May 30-June 2 • Prague, Czech Republic For more information: www.eapc-2013.org Ohio Hematology Oncology Society/Kentucky Association of Medical Oncology Spring Meeting May 31 • Cincinnati, Ohio For more information: www.kentuckyoncology.org 2013 ASCO Annual Meeting May 31-June 4 • Chicago, Illinois For more information: www.asco.org

Michigan Society of Hematology and Oncology – Oncology Pharmacists’ Forum May 22 • Novi, Michigan For more information: www.msho.org Breast Cancer 2013: Seeing the Future May 24 • Cleveland, Ohio For more information: cancer.case.edu/training/cme/index. html 5th Symposium on Cancer Metastasis and the Lymphovascular System and the 8th International Sentinel

2nd International Breakthrough Breast Cancer Conference– Triple Negative Breast Cancer June 26-28 • London, United Kingdom For more information: www.breakthroughconference.org. uk

June Molecular and Translational Oncology Workshop June 14-18 • Fort Myers, Florida For more information: www.cancereducationconsortium. org/programs_mtow.html

Indiana Oncology Society Fall Membership Conference July 25 • Indianapolis, Indiana For more information: www.accc-cancer.org/ossn_network/ IN/INevents.asp 14th International Lung Cancer Congress July 25-27 • Huntington Beach, California For more information: www.gotoper.com/conferences Up Close and Personalized: The 2nd International Congress on Personalized Medicine July 25-28 • Paris, France For more information: www.upcp.org Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences

August Best of ASCO® Chicago August 9-10 • Chicago, Illinois For more information: boa.asco.org MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes.com

July 2nd International Michelangelo Conference on Promises and Challenges of Developing New Drugs in Oncology July 4-5 • Milan, Italy For more information: www.fondazionemichelangelo.org WIN 2013 Symposium: Personalized Cancer Therapy: From Innovation to Implementation July 10-12 • Paris, France For more information: www.winsymposium.org 12th International Congress on the Future of Breast Cancer July 18-20 • Huntington Beach, California For more information: www.gotoper.com/conferences

South Carolina Oncology Society Fall 2013 Membership Conference August 9-10 • Charleston, South Carolina For more information: www.scosonline.com Hematology and Medical Oncology Best Practices August 15-22 • Arlington, Virginia For more information: www.gwumc.edu/cehp/ hemoncbestpractices/ Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org

The ASCO Post | MAY 15, 2013

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2013

2013 Oncology Meetings North Carolina Oncology Association Fall Membership Conference August 24 • Greensboro, North Carolina For more information: www.ncoa-northcarolina.com 11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

September SGI Summit Turkey 2013: Innovations in Obstetrics and Gynecology September 6-8 • Istanbul, Turkey For more information: www.sgiturkey2013.org/ Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org

International Liver Cancer Association Seventh Annual Conference September 13-15 • Washington, DC For more information: www.ilca2013.org/ Inflammation, Microbiota, and Cancer September 19-20 • Bethesda, Maryland For more information: ncifrederick.cancer.gov/events/ microbiota/agenda.asp NCCN 8th Annual Congress: Hematologic Malignancies September 20-21, 2013 New York, New York For more information: www.nccn.org

Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences 2013 ASH State-of-the-Art Symposium September 27-28 • Chicago, Illinois For more information: www.hematology.org ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu 28th Annual Offering of Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: from Bench to Bedside to Biomarkers September 30-October 3 • Boston, Massachusetts For more information: steelelab.mgh.harvard.edu/ tumorcourse/

18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18

EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de 9th NCRI Cancer Conference November 3-6 • Liverpool, United

10th International Conference of the Society for Integrative Oncology: Translational Science in Integrative Oncology October 20-22, 2013 • Vancouver, British Columbia For more information: www.integrativeonc.org

Kingdom For more information: www.ncri.org.uk/ncriconference/ International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw 11th Annual School of Breast Oncology November 7-10 • Atlanta, Georgia For more information: www.gotoper.com/conferences

October

Society for Hematopathology/ European Association for Haematopathology 2013 Workshop October 24-26 • Houston, Texas For more information: www.mdanderson.org/conferences

The 2nd International Multidisciplinary Forum on Palliative Care (IMFPC 2013) October 3-6 • Sofia, Bulgaria For more information: www.imfpc.org

51st Annual Meeting of the Japan Society of Clinical Oncology October 24-26 • Kyoto, Japan For more information: www2.convention.co.jp/jsco2013/

www.astro.org/bestofastro

Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences

15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

9th International Symposium on Hodgkin Lymphoma October 12-15, 2013 • Cologne, Germany For more information: www.hodgkinsymposium.org/

Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13

International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/About+ASCO/ International+Affairs/International+Clini cal+Trials+Workshops

Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences

4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in

November Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org Multidisciplinary Symposium on Head and Neck Cancer November 2 • Chicago, Illinois For more information: www.gotoper.com/conferences

Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information:

New York Lung Cancer Symposium November 9 • New York, New York For more information: www.gotoper.com/conferences African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information: www.aortic2013.org

December 55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.org 36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org

NOW APPROVED

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

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

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

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

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

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

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

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

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

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

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

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

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

30.9 months

Proportion surviving (%)

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

70 60 50

25.1 months

40 30 20

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

10 0 0

164 133

136 110

111 86

86 63

62 45

38 27

28 17

13 7

5 4

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

485 471

474 453

457 435

439 403

418 368

349 297

293 240

242 204

197 159

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

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

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

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

The ASCO Post | MAY 15, 2013

PAGE 134

Appointments

Memorial Sloan-Kettering Cancer Center Announces New Appointments

emorial Sloan-Kettering Cancer Center in New York recently announced the following appointments:

Chief of Lymphoma Anas Younes, MD, has been named Chief of the Lymphoma Service in the

Division of Hematologic Oncology, Department of Medicine. An internationally recognized medical oncologist with more than 2 decades of experience treating and managing people with lym-

Anas Younes, MD

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

phoma, Dr. Younes’s research efforts were instrumental in the development of brentuximab vedotin (Adcetris), the S:6.875” first targeted drug approved by the U.S. Food and Drug Administration for the treat-

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

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

ment of patients with Hodgkin lymphoma in more than 3 decades. As Chief of Memorial Sloan-Kettering’s Lymphoma Service, Dr. Younes is responsible for continuing to accelerate the translation of scientific discoveries into novel treatment strategies to

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

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

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

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

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

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

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Appointments

improve the cure rate and survival of patients with Hodgkin and non-Hodgkin lymphoma. Before joining Memorial SloanKettering this year, Dr. Younes served as Director of Clinical Investigation and Translational Research in the Department of Lymphoma/Melanoma at The University of Texas M. D. Ander-

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

Adverse Drug Reactions (MedDRA) System Organ Class

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

Grade 3 – 4 (%)

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

Grade 3 – 4 (%)

Blood and Lymphatic System Disorders Neutropenia

6.7

2.0

9.0

4.3

Anemia

14.3

4.1

10.5

2.5

Thrombocytopenia

31.2

14.5

3.3

0.4

1.8

0.2

3.3

0.4

Lacrimation increased

3.3

2.5

Dry eye

3.9

3.1

Vision blurred

4.5

0.8

Conjunctivitis

3.9

2.3

0 0.4

Cardiac Disorders Left ventricular dysfunction Eye Disorders

Gastrointestinal Disorders Dyspepsia

9.2

11.5

Stomatitis

14.1

0.2

32.6

2.5

Dry Mouth

16.7

4.9

0.2

Abdominal pain

18.6

0.8

17.6

1.6

Vomiting

19.2

0.8

29.9

4.5

Diarrhea

24.1

1.6

79.7

20.7

Constipation

26.5

0.4

11.1

Nausea

39.8

0.8

45.1

2.5 0.2

General Disorders and Administration 8.2

3.1

Pyrexia

18.6

0.2

8.4

0.4

Asthenia

17.8

0.4

17.6

1.6

Fatigue

36.3

2.5

28.3

3.5

Nodular regenerative hyperplasia*

0.4

Portal hypertension*

0.4

0.2

0.8

0.2

9.4

0.6

3.9

Blood alkaline phosphatase increased

4.7

0.4

3.7

0.4

Increased transaminases

28.8

8.0

14.3

2.5

2.7

9.4

4.7 0

Hepatobiliary Disorders

Immune System Disorders Drug hypersensitivity

2.2

Injury, Poisoning, and Procedural Infusion-related reaction

1.4

Infections and Infestations Urinary tract infection Investigations

Metabolism and Nutrition Disorders Hypokalemia

10.2

Musculoskeletal and Connective Tissue Disorders Myalgia

14.1

0.6

3.7

Arthralgia

19.2

0.6

8.4

Musculoskeletal pain

36.1

1.8

30.5

1.4

Nervous System Disorders Dysgeusia

8.0

4.1

0.2

Dizziness

10.2

0.4

10.7

0.2

Peripheral neuropathy

21.2

2.2

13.5

0.2

Headache

28.2

0.8

14.5

0.8

12.0

0.4

8.6

0.2

Psychiatric Disorders Insomnia

Respiratory, Thoracic, and Mediastinal Disorders Pneumonitis

1.2

Dyspnea

12.0

0.8

8.0

0.4

Cough

18.2

0.2

13.1

0.2

Epistaxis

22.5

0.2

8.4

Skin and Subcutaneous Tissue Disorders Pruritus

5.5

0.2

9.2

Rash

11.6

27.5

1.8

5.1

1.2

2.3

0.4

Vascular Disorders Hypertension

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

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

KADCYLA (3.6 mg/kg)

Parameter

All Grade %

Grade 3 %

Grade 4 %

All Grade %

Grade 3 %

Grade 4 %

Increased bilirubin

Increased AST

Increased ALT

David S. Klimstra, MD

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

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

KADCYLA™ (ado-trastuzumab emtansine)

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

Chief of Colorectal Service Julio Garcia-Aguilar, MD, PhD, has been named Chief of the Colorectal Service in the Department of Sur-

Julio Garcia-Aguilar, MD, PhD

gery and incumbent of the Stuart H. Q. Quan Chair. Dr. Garcia-Aguilar has dedicated his career to the surgical care of people with colon and rectal cancer and is an expert in minimally invasive laparoscopic and robotic techniques. His research focuses on improving the quality of life of patients with rectal cancer.

Chief of Molecular Imaging and Therapy Wolfgang Weber, MD, has joined Memorial Sloan-Kettering as Chief of the Molecular Imaging and Therapy Service in the Department of Radiology and Director of the Laurent and B:11.5”

7.6

David S. Klimstra, MD, has been appointed Chair of the Department of Pathology and incumbent of the James S:6.875” Ewing Alumni Chair of Pathology. Dr. Klimstra is a surgical pathologist who is highly regarded for his expertise in

T:10.5”

7.1

Chills

Chief of Pathology

S:9.875”

Peripheral edema

the surgical pathology of tumors of the pancreas, gastrointestinal tract, liver, lung, salivary glands, and neuroendocrine organs. He has more than 20 years of diagnostic experience in tumor pathology at Memorial SloanKettering.

son Cancer Center, in Houston.

Wolfgang Weber, MD

Alberta Gerschel Positron Emission Tomography Center. Dr. Weber received his medical education, training, and advanced degrees at the Technical University of Munich, in Germany. In 2003 he joined the Department of Molecular and Medical Pharmacology at the University of California. In 2007, he returned to Germany as Chairman of Nuclear Medicine at the University of Freiburg. n

The ASCO Post | MAY 15, 2013

PAGE 136

ASCO State Affiliates Focus on Alaska’s Denali Oncology Group By Jo Cavallo

ocated in Anchorage, Alaska, the Denali Oncology Group faces the dual challenge of serving a diverse and large population of more than 731,000 spread across a vast state of 586,000 square miles, with just 20 medical oncologists and 5 radiation oncologists

was passed. I don’t think we could have gotten that bill passed without ASCO’s help and reputation. Being an ASCO affiliate has helped us stay in touch with what is going on nationally in terms of medical advances and in finding ways to raise public aware-

People have the preconceived notion that people in Alaska are still living in igloos. The truth is we practice excellent oncology care here. —Latha Subramanian, MD

located mainly in Alaska’s two biggest cities, Anchorage and Fairbanks. An ASCO affiliate since 2008, the group was founded 30 years ago by James M. Sprott, MD, and Dale I. Webb, MD, whose goal was to sponsor a yearly scientific meeting. For the past 2 years, Latha Subramanian, MD, has served as President of the Denali Oncology Group. The ASCO Post talked with Dr. Subramanian about the issues unique to her state society, including the difficulties of increasing patient participation in clinical trials and improving communication among physicians in remote locations.

ASCO Affiliation Why did the Denali Oncology Group decide to become an ASCO affiliate? What prompted us to become affiliated with ASCO was the problem we were having getting health insurers to pay for routine costs of care for patients enrolled in clinical trials, and that is where we focused our efforts at first. During its inaugural year as an ASCO affiliate, the Denali Oncology Group sought to get legislation passed mandating coverage by insurers for patients with cancer entering clinical trials. In February 2009, the group was supported in its effort by then ASCO President Douglas W. Blayney, MD, who testified by conference call at two Alaska Senate committee hearings on the importance of passing the bill. The following year, Senate Bill 10, requiring health insurers and Medicaid to provide coverage for cancer clinical trials,

ness regarding clinical trials and the importance of cancer screenings. ASCO has also helped bring the problem of drug shortages in Alaska to the forefront. I don’t think the Denali Oncology Group alone could have done that.

Clinical Trial Enrollment Is it difficult to get patients to enroll in clinical trials? Several issues make it difficult to increase participation in clinical trials in Alaska. One is that most of the native population is treated at the Alaska Native Tribal Health Consortium, which is based in Anchorage, but it doesn’t conduct clinical trials or have a clini-

cal trial referral system in place, so we don’t see most of those patients. In addition, people are located in such distant and isolated areas that the only way to get to a clinical trial facility is by plane or ferry. Another challenge is overcoming people’s skepticism about the value of clinical trials and educating them about the concept of randomization. Some people don’t want to be randomly assigned to therapy—they want to be able to choose their treatment—so that’s another barrier.

munication, but it is a big challenge.

Other Unique Challenges

Technologic Issues

How are you able to serve such a large and diverse population spread over such a great distance with so few oncologists? Our oncologists are concentrated in Anchorage and Fairbanks, so patients in the southeast go there. An oncologist from Seattle flies into Juneau once a month and takes care of patients there. There are no oncologists in Valdez, which is about a 6-hour drive east of Anchorage, so patients are seen by internists who administer chemotherapy under our supervision. We have a similar arrangement with family practitioners in Kodiak, which can only be reached by plane. We have very good phone com-

Can you use video conferencing technology to communicate with physicians in other cities? We are looking into how to overcome the obstacles of instituting video conferencing capabilities among the various institutions. We also need to contend with issues related to complying with HIPAA privacy rules, and we’re trying to resolve those obstacles. Another issue for us is that electronic health records are not commonly in use throughout the state. Even in hospitals and private practices that have electronic health records, they often can’t “speak” to each other because of the different software and hardware platforms. The Alaska Native Tribal Health Consortium does have a sophisticated telemedicine system, but it serves only the Consortium’s patient population.

Fast Facts ■ The Denali Oncology Group was founded in 1983 by James M. Sprott, MD, and Dale I. Webb, MD. The group was recognized as an ASCO affiliate in 2008. The current President is Latha Subramanian, MD.

■ There are approximately 30 members in the Denali Oncology Group. ■ The guiding principles of the group are to encourage continuing medical

education among its members and to promote cancer awareness among the population it serves, strengthen relationships and collegiality among its members, and advocate public health-care policy for cancer survivors.

■ The Denali Oncology Group holds an annual scientific meeting each

summer or fall, which usually focuses on recent advances in a specific cancer.

■ In addition to its annual scientific meeting, the group holds weekly

conferences on general cancer topics, biweekly conferences on breast cancer, and monthly conferences on malignant brain tumors for local oncologists in Anchorage.

■ Most of Alaska’s 25 medical and radiation oncologists are located in Alaska’s two biggest cities, Anchorage and Fairbanks.

■ The main types of cancer found in Alaska are lung, breast, and colon. Among the native population, gastric cancer is the most common.

Closing Thoughts What else would you like ASCO members to know about the Denali Oncology Group? In addition to our emphasis on technologic improvements, we are focused on how to use more evidence-based medicine and practice more cost-effective care. Despite our logistical challenges, we are able to provide our cancer patients with excellent care. We hold general cancer conferences in Anchorage every week, every other week we have a breast cancer conference, continued on page 137

HemOnc_Ad2_2.1875x13_BW:Layout 1

ASCOPost.com | MAY 15, 2013

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Perspective

Drug Approvals in Acute Myeloid Leukemia: Can We Do Better? By Hagop Kantarjian, MD, and Elihu Estey, MD

AML. We question those decisions and suggest that the policies they exemplify are, to at least some extent, responsible for the standstill.

Decitabine Decision

principles they espouse. First, they note the response rate in the low-dose cytarabine group (treatment choice for 88% of control arm) was lower than historical rates. Comparing response rates between trials is highly problematic and can introduce bias due to differences in patient populations and treatment that cannot be accounted for by multivariate analyses; hence, the need for randomized trials.2 Second, they cite improved survival of the treatment choice arm in Western Europe compared to other geographic regions. However, they fail to mention that the hazard ratio (HR) favored decitabine (HR range = 0.75–0.93) in all other geographic regions and that the P value for the Western European comparison was greater than the 0.10 that led to rejection

In a recent Comments and Controversies article in the Hagop Kantarjian, MD Elihu Estey, MD Journal of Clinical Oncology, Sekeres and Steensma comorty years ago, President Richard ment on the FDA Oncologic Drug AdNixon announced a “war on cancer.” visory Committee (ODAC)’s negative Some of that war’s first battles were won decision regarding decitabine. They dein the field of acute myeloid leukemia scribe the decision as rooted in “rigorous (AML) with two agents, cytarabine and statistical principles” and cite decitabine daunorubicin, receiving U.S. Food and as another example of the “boulevard of Drug Administration (FDA) approval broken dreams” characteristic of drug based on their ability to produce typically development in AML.1 They cite failure of the difference in survival (the primary only transient remissions. Since then, little has happened except for FDA approval of all-trans retinoic acid (aka tretinoin, The ODAC recommendation for rejection and ATRA) and arsenic trioxide (Trisenox) for acute promyelocytic leukemia (APL), subsequent FDA actions should have taken into a rare subset of AML. The war on AML account the totality of evidence that we believe argues appears to be at a standstill. Emblematic of this standstill are the that decitabine is likely to produce clinical benefit in recent FDA decisions to not grant apolder patients with AML. proval for decitabine (Dacogen) for the —Hagop Kantarjian, MD, and Elihu Estey, MD treatment of older patients with AML, and to withdraw its approval for gemtuzumab ozogamicin (Mylotarg) for the endpoint) between decitabine recipiof decitabine in the primary analysis. Furtreatment of older patients with relapsed ents (median survival, 7.7 months) and thermore, patients from Western Europe Dr. Kantarjian is Professor of Medicine and the control group, wherein physicianonly comprised 17.5% of patients; their Chair of the Department of Leukemia, The advised patients received their treatment randomized distribution was not 1:1, University of Texas MD Anderson Cancer choice (median survival, 5.0 months) to due to lack of geographic stratification; Center, Houston, and Dr. Estey is Professor reach statistical significance as a rigorpatients on the decitabine arm had worse of Medicine, Department of Hematology, ous justification for nonapproval.2 The baseline characteristics compared to the University of Washington School of Mediauthors, however, raise two additional treatment choice arm; and patients on cine, and Member of Fred Hutchinson Canissues that influenced the vote and that the treatment choice arm more often recer Research Center, Seattle. continued on page 138 both diverge from the rigorous scientific

Alaska’s Denali Oncology Group continued from page 136

and once a month we have a brain tumor conference. We get together to learn and present cases, and we also use e-mail and the telephone to confer with colleagues, so patients often do not have to travel long distances for specialized care. We are a growing group, and our oncologists practice state-of-the-art medicine. People have the preconceived notion that people in Alaska are still living in igloos. The truth is we practice excellent oncology care here. n

GWU MEETING AD 1 COLUMN

AUGUST

15 – 22, 2013 HEMATOLOGY ONLY: August 15 – 19 MEDICAL ONCOLOGY ONLY: August 18 – 22 d Reduce n atio Registr Rates NEW LOCATION: Crystal Gateway Marriott Arlington, VA

• COURSE DIRECTOR: Robert S. Siegel, M.D.

Accomplishments and Goals ■ During its first 2 years as an ASCO affiliate, the Denali Oncology Group

sought to get legislation passed mandating coverage by insurers for patients with cancer entering clinical trials. In 2010, that legislation (Alaska Senate Bill 10) was passed.

■ The group hopes to find ways to increase patient accrual in clinical trials. ■ The group is focused on establishing video conferencing capabilities with hospitals and oncology practices throughout the state, to consult with physicians on clinical decisions and ensure follow-up care for patients in isolated locations.

■ The group is working with ASCO to improve the use of electronic health

records in Anchorage oncology office practices and hospitals so that they are computer-compatible across Mac and PC platforms.

HemOncBestPractices.com

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The ASCO Post | MAY 15, 2013

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Perspective

Drug Approvals in AML continued from page 137

ceived azacitidine (Vidaza) or decitabine poststudy.2,3 In the overall study population, forest plots of subset analyses of response and survival also favored the decitabine arm in virtually all subgroups.

Conflicting Analyses Unfortunately, ODAC appears to have regarded a more mature but unplanned survival analysis (95% of patients dead), which continued to show an advantage for decitabine (median survivals of 7.7 vs 5.0 months—exactly the same as in the primary analysis but now with HR = 0.82, 95% confidence interval = 0.68– 0.99, P = .037), as less satisfactory than the primary less mature analysis because it was “unplanned.” This begs the question of how ODAC might have reacted had the less mature but planned analysis shown P = .037 and the more mature but unplanned analysis P = .10, and prompts us to question the consequences of our seeming infatuation with P = .05.5,6 ODAC also did not adequately consider the effect of subsequent therapy that could have reduced the benefit from decitabine. Sensitivity analyses—in which patients who received subsequent disease-modifying therapy (eg, intensive chemotherapy, hypomethylating agents) were censored at the date of such therapy or excluded from analyses—showed improved survival with decitabine (HR = 0.8, P = .044 for censoring: HR = 0.74, P = .006 for exclusion). Based on the totality of data, including the significant prospectively defined secondary study endpoints, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) came to a different conclusion and granted approval of decitabine in the European Union. That committee concluded that “the benefits with Dacogen are its ability to show an increase in overall survival.”4 The committee obviously took into account the later unplanned but more mature survival data and other sensitivity analyses.

Statistical and Clinical Contexts The ODAC recommendation for

rejection and subsequent FDA actions should have taken into account the totality of evidence that we believe argues that decitabine is likely to produce clinical benefit in older patients with AML. Large randomized clinical trials represent significant investments by patients, clinicians, and sponsors. Results should be interpreted in both statistical and clinical contexts. We are concerned that, in this case, rigorous statistical principles were applied inconsistently and, more importantly, that balance between clinical medicine and statistical analysis was not achieved. Fundamental to the former is the concept of benefit-to-risk ratio. Decitabine is relatively well tolerated and offers lowintensity therapy that improved survival by 2.7 months, a 50% benefit. Although the benefits of decitabine are perhaps modest, they are real and the drug’s risks are small.

least 60 years old and are not considered candidates for cytotoxic chemotherapy. However, on June 21, 2010, the FDA and Pfizer announced that gemtuzumab would be voluntarily withdrawn, after considering the results of a confirmatory trial mandated by the FDA and conducted by the Southwest Oncology Group (SWOG) in adults under age 60 with de novo newly diagnosed AML. The trial failed to show that patients randomly assigned to standard therapy (“3+7” induction regimen of cytarabine and an anthracycline) plus gemtuzumab had superior survival to those randomly assigned to standard therapy alone, and that the 30day death rate was higher in the former.9 The decision to withdraw did not account for several facts. First, four randomized trials (two by the Medical Research Council/National Cancer Research Institute [MRC/NCRI] in the United Kingdom, one in older and the other

In contrast to the market share of billions of dollars for drugs approved in lung, breast, and other common cancers, the market share of gemtuzumab was about $20 million. Could this have played a role in the lukewarm advocacy or the manufacturer’s decisions? —Hagop Kantarjian, MD, and Elihu Estey, MD

Moreover the application before ODAC was not for initial drug approval but for a second indication. With the loss of orphan drug exclusivity in 2013, generic formulations of decitabine will be inexpensive. Hence we believe that the AML community would have been better served with a positive ODAC vote. The negative vote impedes clinical care and research and leads to the perception of a “boulevard of broken dreams.”

Gemtuzumab Reconsidered Gemtuzumab raises different drug development and regulatory issues.7,8 Based on three open-label studies, gemtuzumab was approved by the FDA in May 2000 under accelerated approval authority for the treatment of patients with CD33positive AML in first relapse who are at

in younger patients; and two in France including patients up to age 70 years) found that certain patients consistently lived longer if given gemtuzumab.10,11 These were patients with core binding factor AML, who also had superior survival with gemtuzumab in the SWOG study, and many patients with a normal karyotype. Indeed, the MRC developed a prospectively validated index that can identify patients who will have superior survival with gemtuzumab. Second, the requirement for an aggregate benefit ignores the salient clinical and biologic feature of AML: that it is several, and probably many, diseases, each of which will almost certainly require distinctive treatments. Certainly a randomized trial comparing 3+7 with or without all-trans retinoic acid in AML would have

missed the important activity of all-trans retinoic acid in APL. Finally, none of the other randomized trials found a difference in 30-day mortality. Gemtuzumab appears to have been a casualty of a drug approval process that has unrealistic expectations of uniform benefit in an era of “personalized medicine” and that—as in the case of decitabine—did not consider the totality of the evidence.

Lack of Advocacy We are struck by the sense of resignation, if not apathy, with which the AML community has greeted the decitabine and gemtuzumab decisions. This is in sharp contrast with the solid tumor community’s strong advocacy of several drugs that have received FDA approval, although in most cases those agents failed to produce better survival (relative to standard therapy) than decitabine or gemtuzumab.12-15 Since 2005, the FDA approved seven agents for renal cell cancer, based on progression-free survival improvements of 2 to 6 months, with only one study (temsirolimus [Torisel]) showing a survival benefit. In lung and colorectal cancer, cetuximab (Erbitux) showed survival improvements of 1.2 to 1.7 months.12-14 In pancreatic cancer, erlotinib (Tarceva) was approved for improving survival by 10 days.15 AML is a relatively uncommon disease, and appears to have no strong advocacy groups. In contrast to the market share of billions of dollars for drugs approved in lung, breast, and other common cancers, the market share of gemtuzumab was about $20 million. Could this have played a role in the lukewarm advocacy or the manufacturer’s decisions? After all, a multitude of articles were written and strong protests were voiced when questions about the efficacy of bevacizumab (Avastin) were raised in particular tumors. Perhaps, in AML, the “boulevard of broken dreams” has become a self-fulfilling prophecy. n Disclosure: Dr. Kantarjian has received research grants from ChemGenex. Dr. Estey reported no potential conflicts of interest. References on page 142-143

Visit The ASCO Post at the ASCO Annual Meeting May 31 - June 4, 2013 The ASCO Post BOOTH 12096 • Harborside Press BOOTH 13096

STIVARGA® for Metastatic Colorectal Cancer (mCRC):

Expanding Treatment. Extending Survival. • Median overall survival: 6.4 months with STIVARGA vs 5.0 months with placebo; HR, 0.77; 95% CI, 0.64-0.94; P =0.01021

Indication STIVARGA® is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, an anti-EGFR therapy. Important Safety Information WARNING: HEPATOTOXICITY • Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. • Monitor hepatic function prior to and during treatment. • Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence. Please see brief summary of full Prescribing Information, including the Boxed Warning, on last pages.

Important Safety Information (Continued) Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in 0.3% of 1200 STIVARGA®treated patients across all clinical trials. In metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis. Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% with STIVARGA compared to 8% with placebo in mCRC. Fatal hemorrhage occurred in 4 of 632 (0.6%) STIVARGA-treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or lifethreatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin. Dermatological Toxicity: STIVARGA caused an increased incidence of hand-foot skin reaction (HFSR) (also known as palmar-plantar erythrodysesthesia [PPE]) and severe rash, frequently requiring dose modification. The overall incidence of HFSR was increased with STIVARGA compared to placebo in mCRC (45% vs 7%). The incidence of Grade 3 HFSR (17% vs 0%), Grade 3 rash (6% vs <1%), serious adverse reactions of erythema multiforme (0.2% vs 0%) and Stevens-Johnson syndrome (0.2% vs 0%) was higher in STIVARGA-treated patients. Toxic epidermal necrolysis occurred in 0.17% of 1200 STIVARGA-treated patients across all clinical trials. Withhold STIVARGA, reduce the dose, or permanently discontinue depending on the severity and persistence of dermatologic toxicity. Hypertension: STIVARGA caused an increased incidence of hypertension (30% with STIVARGA vs 8% with placebo in mCRC). Hypertensive crisis occurred in 0.25% of 1200 STIVARGA-treated patients across all clinical trials. Do not initiate STIVARGA until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle,

or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension. Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (1.2% with STIVARGA vs 0.4% with placebo). Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 of 1200 STIVARGA-treated patients across all clinical trials. Confirm the diagnosis of RPLS with MRI and discontinue STIVARGA in patients who develop RPLS. Gastrointestinal Perforation or Fistula: Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with STIVARGA across all clinical trials; this included 4 fatal events. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula. Wound Healing Complications: Treatment with STIVARGA should be stopped at least 2 weeks prior to scheduled surgery. Resuming treatment after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence. Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. Use effective contraception during treatment and up to 2 months after completion of therapy. 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. Nursing Mothers: Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from STIVARGA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Most Frequently Observed Adverse Drug Reactions in mCRC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).

Please see brief summary of full Prescribing Information, including the Boxed Warning, on last pages. Reference: 1. STIVARGA Prescribing Information. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2013.

23% reduction in the risk of death* Overall survival (OS)1 100

STIVARGA (n=505) Placebo (n=255)

Survival Probability (%)

Hazard ratio, 0.77 (95% CI, 0.64-0.94; P =0.0102)

Median: 6.4 months (95% CI, 5.8-7.3) with STIVARGA vs 5.0 months (95% CI, 4.4-5.8) with placebo

0 0 Patients at Risk STIVARGA + BSC Placebo + BSC

33 9

7 3

Months From Randomization 452 221

352 150

187 75

93 32

The CORRECT trial was an international, multicenter, randomized (2:1), doubleblind, placebo-controlled phase 3 trial in 760 patients with previously treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival.1

*Based on hazard ratio.

• There were 275 deaths out of 505 patients with STIVARGA (55%) vs 157 deaths out of 255 patients with placebo (62%)1 • STIVARGA improved OS in the CORRECT study, which included patients with historically collected KRAS status (n=729)1 — Mutated KRAS = 59%; wild-type KRAS = 41%

Indication STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, an anti-EGFR therapy. Important Safety Information WARNING: HEPATOTOXICITY • Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. • Monitor hepatic function prior to and during treatment. • Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

www.STIVARGA-US.com

6 West Belt, Wayne, NJ 07470 USA © 2013 Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ STIVARGA is co-promoted in the USA by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. Bayer® and the Bayer Cross® are registered trademarks of Bayer. 900-10-0004-13B 03/13

The ASCO Post | MAY 15, 2013

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Perspective

Drug Approvals in AML continued from page 138

References 1. Sekeres MA, Steensma DP: Boulevard of broken dreams: drug approval for older adults with acute myeloid leukemia. J Clin Oncol 33:4061-4063, 2012. 2. Kantarjian HM, Thomas XG, Dmo-

szynska A, et al: Multicenter randomized open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low dose cytarabine for treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 30:2670-2677, 2012. 3. Eisai Inc: FDA ODAC Briefing Document NDA 021790/S-010: Dacogen (decitabine). Indication: Acute Myeloid Leu-

kemia, February 9, 2012. Available at http:// www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ OncologicDrugsAdvisoryCommittee/ UCM290512.pdf. Accessed May 1, 2013. 4. European Medicines Agency: Dacogen (decitabine) Summary of opinion (initial authorization), July 19, 2012. Available at http://www.ema.europa.eu/ema/index.jsp?curl=pages/

STIVARGA (regorafenib) tablets, oral Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION WARNING: HEPATOTOXICITY • Severe and sometimes fatal hepatotoxicity has been observed in clinical trials [see Warnings and Precautions (5.1)]. • Monitor hepatic function prior to and during treatment [see Warnings and Precautions (5.1)]. • Interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence [see Dosage and Administration (2.2)]. 1 INDICATIONS AND USAGE 1.1 Colorectal Cancer Stivarga® is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. 1.2 Gastrointestinal Stromal Tumors Stivarga is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1200 Stivarga-treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. In Study 2, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm [see Adverse Reactions (6.1)]. Obtain liver function tests (ALT, AST and bilirubin) before initiation of Stivarga and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline. Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration (2.2)]. 5.2 Hemorrhage Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% in Stivarga-treated patients compared to 8% and 3% in placebo-treated patients in Studies 1 and 2. Fatal hemorrhage occurred in 4 of 632 (0.6%) of Stivarga-treated patients in Studies 1 and 2 and involved the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)]. 5.3 Dermatological Toxicity Stivarga caused increased incidences of adverse reactions involving the skin and subcutaneous tissues (72% versus 24% in Study 1 and 78% versus 24% in Study 2), including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE), and severe rash requiring dose modification. The overall incidence of HFSR was higher in Stivarga-treated patients, (45% versus 7% in Study 1 and 67% versus 12% in Study 2), than in the placebotreated patients. Most cases of HFSR in Stivarga-treated patients appeared during the first cycle of treatment (69% and 71% of patients who developed HFSR in Study 1 and Study 2, respectively). The incidence of Grade 3 HFSR (17% versus 0% in Study 1 and 22% versus 0% in Study 2), Grade 3 rash (6% versus <1% in Study 1 and 7% versus 0% in Study 2), serious adverse reactions of erythema multiforme (0.2% vs. 0% in Study 1) and Stevens Johnson Syndrome (0.2% vs. 0% in Study 1) was higher in Stivarga-treated patients [see Adverse Reactions (6.1)]. Toxic epidermal necrolysis occurred in 0.17% of 1200 Stivarga-treated patients across all clinical trials. Withhold Stivarga, reduce the dose, or permanently discontinue Stivarga depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for symptomatic relief. 5.4 Hypertension Stivarga caused an increased incidence of hypertension (30% versus 8% in Study 1 and 59% versus 27% in Study 2) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in 0.25% of 1200 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (72% in Study 1 and Study 2). Do not initiate Stivarga unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every

medicines/human/medicines/002221/ smops/Positive/human_smop_000404. jsp&mid=WC0b01ac058001d127. Accessed May 1, 2013. 5. Berger JO, Berry DA: Statistical analysis and the illusion of objectivity. Am Sci 76:159165,1988. 6. Goodman SN: Toward evidence-based medical statistics. 1: The p value fallacy. Ann Intern Med 130:995-1004, 1999.

cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold Stivarga for severe or uncontrolled hypertension [see Dosage and Administration (2.2)]. 5.5 Cardiac Ischemia and Infarction Stivarga increased the incidence of myocardial ischemia and infarction in Study 1 (1.2% versus 0.4%) [see Adverse Reactions (6.1)]. Withhold Stivarga in patients who develop new or acute onset cardiac ischemia or infarction. Resume Stivarga only after resolution of acute cardiac ischemic events, if the potential benefits outweigh the risks of further cardiac ischemia. 5.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 1200 Stivarga-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Stivarga in patients who develop RPLS. 5.7 Gastrointestinal Perforation or Fistula Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with Stivarga across all clinical trials; this included four fatal events. In Study 2, 2.1 % (4/188) of Stivarga-treated patients who were treated during the blinded or open-label portion of the study developed gastrointestinal fistula or perforation; of these, two cases of gastrointestinal perforation were fatal. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula. 5.8 Wound Healing Complications No formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as regorafenib can impair wound healing, treatment with regorafenib should be stopped at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on clinical judgment of adequate wound healing. Regorafenib should be discontinued in patients with wound dehiscence. 5.9 Embryo-Fetal Toxicity Stivarga can cause fetal harm when administered to a pregnant woman. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. 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)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hepatotoxicity [See Warnings and Precautions (5.1)] • Hemorrhage [See Warnings and Precautions (5.2)] • Dermatological Toxicity [See Warnings and Precautions (5.3)] • Hypertension [See Warnings and Precautions (5.4)] • Cardiac Ischemia and Infarction [See Warnings and Precautions (5.5)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [See Warnings and Precautions (5.6)] • Gastrointestinal Perforation or Fistula [See Warnings and Precautions (5.7)] 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 rate observed in practice. The most frequently observed adverse drug reactions (≥20%) in patients receiving Stivarga are asthenia/fatigue, HFSR, diarrhea, decreased appetite/ food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea. The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal perforation. 6.1 Clinical Trials Experience Colorectal Cancer The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously treated metastatic colorectal cancer received Stivarga as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 7.3 (range 0.3, 47.0) weeks for patients receiving Stivarga. Due to adverse reactions, 61% of the patients receiving Stivarga required a dose interruption and 38% of the patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 8.2% of Stivargatreated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of Stivarga. Table 1 compares the incidence of adverse reactions (≥10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 1).

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7. Ravandi F, Estey EH, Appelbaum FR, et al: Gemtuzumab ozogamicin. J Clin Oncol 30:3921-3923, 2012. 8. Estey E: Treatment of AML: Resurrection for gemtuzumab ozogamicin? Lancet 379:1468-1469, 2012. 9. Petersdorf S, Kopecky K, Stuart RK, et al: Preliminary results of Southwest Oncology Group Study S0106. Blood (ASH Annual Meeting Abstracts), 114:Abstract 790, 2009.

10. Burnett AK, Hills RK, Milligan D, et al: Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: Results of the MRC AML15 trial. J Clin Oncol 29:369377, 2010. 11. Castaigne S, Pautas C, Terre C, et al: Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): A ran-

Table 1 Adverse drug reactions (≥10%) reported in patients treated with Stivarga in Study 1 and reported more commonly than in patients receiving placebo Stivarga Placebo (N=500) (N=253) Adverse Reactions Grade Grade All ≥ 3 All ≥ 3 % % % % General disorders and administration site conditions Asthenia/fatigue 64 15 46 9 Pain 29 3 21 2 Fever 28 2 15 0 Metabolism and nutrition disorders Decreased appetite and food intake 47 5 28 4 Skin and subcutaneous tissue disorders HFSR/PPE 45 17 7 0 Rash a 26 6 4 <1 Gastrointestinal disorders Diarrhea 43 8 17 2 Mucositis 33 4 5 0 Investigations Weight loss 32 <1 10 0 Infections and infestations Infection 31 9 17 6 Vascular disorders Hypertension 30 8 8 <1 Hemorrhage b 21 2 8 <1 Respiratory, thoracic and mediastinal disorders Dysphonia 30 0 6 0 Nervous system disorders Headache 10 <1 7 0 a The term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash. b Fatal outcomes observed. Laboratory Abnormalities Laboratory abnormalities observed in Study 1 are shown in Table 2. Table 2 Laboratory test abnormalities reported in Study 1 Stivarga Placebo (N=500 a) (N=253 a) Laboratory Parameter Grade b Grade b All 3 4 All 3 4 % % % % % % Blood and lymphatic system disorders Anemia 79 5 1 66 3 0 Thrombocytopenia 41 2 <1 17 <1 0 Neutropenia 3 1 0 0 0 0 Lymphopenia 54 9 0 34 3 0 Metabolism and nutrition disorders Hypocalcemia 59 1 <1 18 1 0 Hypokalemia 26 4 0 8 <1 0 Hyponatremia 30 7 1 22 4 0 Hypophosphatemia 57 31 1 11 4 0 Hepatobiliary disorders Hyperbilirubinemia 45 10 3 17 5 3 Increased AST 65 5 1 46 4 1 Increased ALT 45 5 1 30 3 <1 Renal and urinary disorders Proteinuria 60 <1 0 34 <1 0 Investigations Increased INR c 24 4 N/A 17 2 N/A Increased Lipase 46 9 2 19 3 2 Increased Amylase 26 2 <1 17 2 <1 a % based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo). b Common Terminology Criteria for Adverse Events (CTCAE), v3.0. c International normalized ratio: No Grade 4 denoted in CTCAE, v3.0. Gastrointestinal Stromal Tumors The safety data described below are derived from a randomized (2:1), doubleblind, placebo-controlled trial (Study 2) in which 132 patients (median age 60 years; 64% men) with previously treated GIST received Stivarga as a single agent at a dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 66 patients (median age 61 years; 64% men) received placebo. The median duration of therapy was 22.9 (range 0.1, 50.9) weeks for patients receiving Stivarga. Dose interruptions for adverse events were required in 58% of patients receiving Stivarga and 50% of patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 2.3% of Stivarga-treated patients compared to 1.5% of patients who received placebo. Table 3 compares the incidence of adverse reactions (≥10%) in GIST patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 2).

domised, open-label, phase 3 study. Lancet 379:1508-1516, 2012. 12. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004. 13. Pirker R, Pereira JR, Szczesna A, et al: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer

Table 3 Adverse reactions (≥10%) reported in patients treated with Stivarga in Study 2 and reported more commonly than in patients receiving placebo Adverse Reactions

Stivarga (N=132) Grade All ≥3 % %

Placebo (N=66) Grade All ≥ 3 % %

Skin and subcutaneous tissue disorders HFSR/PPE 67 22 15 2 Rash a 30 7 3 0 Alopecia 24 2 2 0 General disorders and administration site conditions Asthenia/Fatigue 52 4 39 2 Fever 21 0 11 2 Vascular disorders Hypertension 59 28 27 5 Hemorrhage 11 4 3 0 Gastrointestinal disorders Diarrhea 47 8 9 0 Mucositis 40 2 8 2 Nausea 20 2 12 2 Vomiting 17 <1 8 0 Respiratory, thoracic and mediastinal disorders Dysphonia 39 0 9 0 Infections and infestations Infection 32 5 5 0 Metabolism and nutrition disorders Decreased appetite and food intake 31 <1 21 3 Hypothyroidism b 18 0 6 0 Nervous system disorders Headache 16 0 9 0 Investigations Weight loss 14 0 8 0 Musculoskeletal and connective tissue disorders Musculoskeletal stiffness 14 0 3 0 a The term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rash and pruritic rash. b Hypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline. Laboratory Abnormalities Laboratory abnormalities observed in Study 2 are shown in Table 4. Table 4 Laboratory test abnormalities reported in Study 2 Laboratory Parameter Stivarga Placebo (N=132 a) (N=66 a) Grade b Grade b All 3 4 All 3 4 % % % % % % Blood and lymphatic system disorders Thrombocytopenia 13 1 0 2 0 2 Neutropenia 16 2 0 12 3 0 Lymphopenia 30 8 0 24 3 0 Metabolism and nutrition disorders Hypocalcemia 17 2 0 5 0 0 Hypokalemia 21 3 0 3 0 0 Hypophosphatemia 55 20 2 3 2 0 Hepatobiliary disorders Hyperbilirubinemia 33 3 1 12 2 0 Increased AST 58 3 1 47 3 0 Increased ALT 39 4 1 39 2 0 Renal and urinary disorders Proteinuria 33 3 - c 30 3 -c Investigations Increased Lipase 14 0 1 5 0 0 a % based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or 66 (placebo). b CTCAE, v4.0. c No Grade 4 denoted in CTCAE, v4.0. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inducers on Regorafenib Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) [see Clinical Pharmacology (12.3)]. 7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean exposure of regorafenib and decreased

(FLEX). Lancet 373:1525-1531, 2009. 14. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004. 15. Moore MJ, Goldstein D, Hamm J, et al: National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960-1966, 2007.

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Appointments

Robert S. Miller, MD, FACP, Appointed Editor-in-Chief of ASCO’s Patient Information Website, Cancer.Net

obert S. Miller, MD, FACP, has been appointed Editor-inChief of ASCO’s patient information website, Cancer.Net. Dr. Miller will assume this role at the 2013 ASCO

Annual Meeting in Chicago on June 1, and succeeds Diane Blum, MSW, Chief Executive Officer for the Lymphoma Research Foundation, who served as Editor-in-Chief for 10 years.

the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)] Risk Summary Based on its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Stivarga in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal Data In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC). In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. In a repeat dose study with daily administration of regorafenib to pregnant rats during organogenesis, findings included delayed ossification in fetuses at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) with dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis. In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies. 8.3 Nursing Mothers It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of Stivarga in pediatric patients less than 18 years of age have not been established. In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings were observed at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate. 8.5 Geriatric Use Of the 632 Stivarga-treated patients enrolled in Studies 1 and 2, 37% were 65 years of age and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients. 8.6 Hepatic Impairment No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions (5.1)]. Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C), as it has not been studied in this population. 8.7 Renal Impairment No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended for patients with mild renal impairment. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease.

Dr. Miller is a medical oncologist and recognized authority in breast cancer, survivorship care, and consumer health informatics. “I have been fortunate to serve as

8.8 Females and Males of Reproductive Potential Contraception Use effective contraception during treatment and up to 2 months after completion of therapy. Infertility There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility [see Nonclinical Toxicology (13.1)]. 10 OVERDOSAGE The highest dose of Stivarga studied clinically is 220 mg per day. In the event of suspected overdose, interrupt Stivarga, institute supportive care, and observe until clinical stabilization. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity in in vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells. Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans. 13.2 Animal Toxicology and/or Pharmacology In a chronic 26 week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the recommended dose, this finding was present in half of the examined animals. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information). Inform your patients of the following: • Stivarga may cause severe or life-threatening liver damage. Inform patients that they will need to undergo monitoring for liver damage and to immediately report any signs or symptoms of severe liver damage to their health care provider. • Stivarga can cause severe bleeding. Advise patients to contact their health care provider for any episode of bleeding. • Stivarga can cause hand-foot skin reactions or rash elsewhere. Advise patients to contact their health care provider if they experience skin changes associated with redness, pain, blisters, bleeding, or swelling. • Stivarga can cause or exacerbate existing hypertension. Advise patients they will need to undergo blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • Stivarga increased the risk for myocardial ischemia and infarction. Advise patients to seek immediate emergency help if they experience chest pain, shortness of breath, or feel dizzy or like passing out. • Contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting, severe diarrhea (frequent or loose bowel movements), or dehydration. • Stivarga may complicate wound healing. Advise patients to inform their health care provider if they plan to undergo a surgical procedure or had recent surgery. • Inform patients that regorafenib can cause fetal harm. Advise women of reproductive potential and men of the need for effective contraception during Stivarga treatment and for up to 2 months after completion of treatment. Instruct women of reproductive potential to immediately contact her health care provider if pregnancy is suspected or confirmed during or within 2 months of completing treatment with Stivarga. • Advise nursing mothers that it is not known whether regorafenib is present in0 breast milk and discuss whether to discontinue nursing or to discontinue regorafenib. • Inform patients to take any missed dose on the same day, as soon as they remember, and that they must not take two doses on the same day to make up for a dose missed on the previous day. • Inform patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes. Any remaining tablets should be discarded 28 days after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle.

Robert S. Miller, MD, FACP

an Associate Editor of Cancer.Net for the past several years, and am deeply honored to be taking on this new role,” said Dr. Miller. “Cancer.Net is a cornerstone of ASCO’s patient advocacy and communication strategies, and I certainly want to see all of the resources the site offers flourish and reach an even wider audience.” “Dr. Miller has been a long-term advocate of measures that enhance cancer care, and as Editor-in-Chief of Cancer.Net, he will further that commitment by lending his vision to a resource that people with cancer and their loved ones trust to provide timely, oncologist-approved information,” said ASCO President Sandra M. Swain, MD, FACP. A key component of Dr. Miller’s vision for Cancer.Net includes enhancing the site’s interactivity. Through expanding Cancer.Net’s social media capabilities—including hosting tweetchats and incorporating more guest blog posts by those with cancer—he aims to create more opportunities for dialogue between wellknown, prominent cancer researchers and people with the disease. Currently, Dr. Miller is an Assistant Professor of Oncology at the Johns Hopkins University School of Medicine, and Clinical Associate of the Breast Cancer Program and Oncology Medical Information Officer at the Sidney Kimmel Comprehensive Cancer Center. Dr. Miller has been an active ASCO member and volunteer since 1992. He is Chair of the ASCO Integrated Media and Technology Committee and an active ASCOConnection.org blogger. Previously, he was a member of the ASCO Board of Directors. For his dedication to the Society, ASCO awarded Dr. Miller a Fellow of the American Society of Clinical Oncology (FASCO) Award in 2011. n

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Pioneers in Oncology Dr. Bernard Fisher’s Breast Cancer Research Left a Lasting Legacy of Improved Therapeutic Efficacy and Survival By Jo Cavallo

Bernard Fisher, MD

ernard Fisher, MD, is recognized today for his groundbreaking research in breast cancer, which ultimately ended the standard practice of performing the Halsted radical mastectomy, a treatment that had been in place for more than 75 years. His laboratory and clinical investigations led to more effective therapy, increased survival rates, and improved quality of life for women with breast cancer. His early medical career, however, was focused primarily on liver regeneration and transplantation. After graduating from the University of Pittsburgh School of Medicine in 1943 and completing a 2-year fellowship in experimental surgery at the University of Pennsylvania, Dr. Fisher returned to the University of Pittsburgh to create a surgical research laboratory, where he began experiments on rats to determine whether their livers would regenerate after large portions were removed. Finding that they did, he began transplanting various organs in rats. In 1955, to increase his knowledge about transplantation, Dr. Fisher served as a research fellow at the London Postgraduate Medical School, Hammersmith Hospital, London.

Novel Approaches to Treatment When he returned to Pittsburgh the following year, Dr. Fisher received a call from I.S. Ravdin, MD, his mentor at the University of Pennsylvania. That call would permanently alter the course of his scientific and clinical career. Dr. Ravdin, then Chairman of the Clinical

Studies Panel of the Cancer Chemotherapy National Service Center at the National Institutes of Health (NIH), asked Dr. Fisher to attend a meeting with 22 other surgeons to discuss the creation of the Surgical Adjuvant Chemotherapy Breast Project, which later became known as the National Surgical Adjuvant Breast and Bowel Project (NSABP), chaired by Dr. Fisher for 30 years. “I wasn’t the least bit interested in breast cancer,” said Dr. Fisher. “But since Dr. Ravdin was an army general who had operated on President Eisenhower, when he commanded me to attend the meeting, I did so. At the time of that first meeting in 1956, the idea of using clinical trials to obtain information, and certainly the idea of giving therapy following surgery, were novel approaches to treatment.” Although Dr. Fisher was initially hesitant to change the focus of his research from liver regeneration and

adjuvant therapy. “Subsequent to that first meeting at the NIH, I discovered how little information there was related to the biology of breast cancer and what a lack of interest there was in understanding the disease. At the meeting, I learned about the need for randomized clinical trials and the use of biostatistics to obtain credible information from those trials,” said Dr. Fisher.

Biology of Tumor Metastasis After that meeting, Dr. Fisher abandoned his research in liver regeneration and transplantation and devoted the next 4 decades to pursuing the biology of breast cancer tumor metastasis and more effective treatments for the disease. His research led him away from the anatomic hypothesis presented by Halsted—that cancer cells, originating from the breast, always passed through the lymph nodes prior to

At the time of that first [NIH] meeting in 1956, the idea of using clinical trials to obtain information, and certainly the idea of giving therapy following surgery, were novel approaches to treatment. —Bernard Fisher, MD

transplantation to breast cancer and the study of malignant disease, he was intrigued by the question of how tumors metastasize. The meeting at the NIH resulted in the 1958 launch of the first randomized clinical trial to evaluate the use of systemic therapy following radical mastectomy in the treatment of breast cancer.1,2 More than 800 women treated with the surgery were enrolled in the study and randomly assigned to receive either the alkylating agent thiotepa or a placebo. The study found that while the drug provided a significant benefit in recurrence-free survival in premenopausal women, altering the course of their breast cancer, the fact that the chemotherapy did not benefit all patients and caused some side effects made physicians reluctant to embrace the use of systemic

metastatic spread and, therefore, required radical surgery to remove the entire breast, underlying chest muscle, and axillary lymph nodes to halt metastasis. Instead, Dr. Fisher proposed, breast cancer is a systemic disease in which malignant cells are likely disseminated throughout the body before diagnosis, and radical mastectomies are unlikely to improve overall survival. Breast-sparing surgery such as lumpectomy, in which only the cancerous tumor and a small portion of the surrounding tissue are removed, would probably result in similar outcomes but without the disfigurement caused by total mastectomy, reasoned Dr. Fisher. Throughout the 1960s and 1970s, Dr. Fisher conducted laboratory investigations of cancer biology and randomized clinical stud-

ies evaluating the effectiveness of lumpectomy vs total mastectomy, as well as lumpectomy followed by systemic chemotherapy or radiation therapy in the prevention of disease recurrence. The use of less aggressive, breast-conserving surgical treatment was initially met with resistance from both the medical establishment and the general public—resistance that he looked back on as “extensive and often unpleasant.” Dr. Fisher’s findings, however, indicated that breast cancer metastasis is not solely determined by anatomic considerations, but is also influenced by biologic activity of both the tumor and the host. The results from those early studies changed the way breast cancer is treated and are credited with improving breast cancer survival rates. In 1991, Dr. Fisher and his NSABP colleagues began the first breast cancer prevention trial, which tested the efficacy of tamoxifen in preventing breast cancer in high-risk women. The study found that tamoxifen did decrease the incidence of both invasive and noninvasive breast cancer by nearly 50%.3

Six-decade Legacy Dr. Fisher served as ASCO President from 1992 to 1993 and has received numerous awards for his contributions to breast cancer research and treatment, including the American Association for Cancer Research Award for Lifetime Achievement in Cancer Research, the American Cancer Society Medal of Honor, and the Albert Lasker Clinical Medical Research Award. When asked what he considers his greatest contributions to medicine and science, Dr. Fisher replied, “That question might be best answered by others who are familiar with my efforts over the past 60 years. However, I do believe that my greatest contribution was carrying out laboratory investigations, beginning in 1950, which have altered our understanding and treatment of breast cancer. The results obtained from those studies led me to form a biologic hypothesis that replaced the Halstedian princicontinued on page 146

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PAGE 146

Patient’s Corner Breast Cancer

Living with the Fear of Cancer

After battling cancer once, I never thought I’d have to do it again. By Annette Soto, as told to Jo Cavallo

fter a friend was diagnosed with breast cancer, I became so worried it would happen to me, I decided to perform regular breast self-exams so I could familiarize myself with the normal feel of my breasts, and quickly spot any changes. My friend’s diagnosis scared me, and that fear probably saved my life. In 2000, 6 months after giving birth, I felt a lump in my right breast. I was just 36 years old. Wasting no time, I immediately called my gynecologist who then ordered a mammogram. I found the lump on a Sunday, and the following Tuesday I was staring at my test results as the radiologist showed me the tumor sitting right above my right nipple and surrounded by calcifications.

Within a week, I had gone from being a healthy, young mother to a person battling cancer, and all I could think about was getting well. My oncologist prescribed eight rounds of the chemotherapy regimen CMF (cyclophosphamide, methotrexate, and fluorouracil) plus 37 radiation treatments. At the end of my treatment, I

that the implant used to rebuild my breast was painful and had to be removed. Next, a deep inferior epigastric perforator (DIEP) flap breast reconstruction was performed, but this also resulted in complications, including tissue necrosis and a hole in the middle of the breast that never really closed. In 2010, some of the top tissue of

As a patient, it is so hard to really focus on what’s being said by an oncologist [when you get a cancer diagnosis], because all you hear is, ‘You have cancer.’ —Annette Soto

Next Steps The radiologist recommended an oncology surgeon, who scheduled a biopsy for the next day. The surgeon removed a 1.6-cm tumor, but the tissue removed did not have clear margins, and I had to have another excision 3 days later. At that time, more breast tissue and my nipple were removed, along with three lymph nodes, which were clear. The diagnosis was stage I, grade 3, triple-negative invasive ductal carcinoma.

Dr. Bernard Fisher continued from page 145

ples, which governed the treatment of breast cancer for almost a century.” Currently, Dr. Fisher is a Distinguished Service Professor in the Department of Surgery at the University of Pittsburgh, where he is engaged in preserving the accuracy of his life’s work. “It is necessary to do so because to be sure where you are, you must know where you have been, and thus be able to better predict what the future is likely to be,” said Dr. Fisher. n

was declared cancer-free. While I was relieved to hear the news and anxious to get my body—and my life—back to normal, I was so emotionally and physically drained that I put off having reconstructive surgery for 5 years.

Personal Reflections In hindsight, I believe I never should have had the reconstructive surgery. My chest tissue and muscle were so damaged from the radiation References 1. NSABP timeline. Available at nsabp.pitt.edu/NSABP_Timeline.pdf. Accessed April 2, 2013. 2. Fisher B, Ravdin RG, Ausman RK, et al: Surgical adjuvant chemotherapy in cancer of the breast: Results of a decade of cooperative investigation. Ann Surg 168:337-356, 1968. 3. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:13711388, 1998.

my breast was removed to relieve the continued pain. But the following summer, the pain was back and my breast was swollen. I had more surgery to remove the DIEP flap, and it was during this procedure a cancerous tumor was found below the tissue. To have a cancer recurrence after 12 years was shocking, and I’m still coming to terms with the news. I have completed six rounds of chemotherapy, surgery to remove my remaining

healthy breast, and radiation. Once again, I’ve been declared cancer-free, but the thought of another recurrence is paralyzing. Any slight ache or pain convinces me the cancer is back, and I find myself breaking into tears at the thought.

Looking Forward I’ve had some wonderful oncologists taking care of me throughout my cancer diagnosis and treatment. They couldn’t have known that all I was thinking about during our many conversations about treatment was, ‘I’m going to die and leave my three children behind.’ As a patient, it is so hard to really focus on what’s being said by an oncologist because all you hear is, ‘You have cancer.’ I’ve had such a hard time coping with my cancer recurrence that my doctor recommended I see a counselor, and I’m getting some relief for my anxiety. However, I know that my life will never be the same. I can no longer work, due to effects from the chemotherapy. Still, I know I’m lucky to be alive, and I’m working on resuming a healthy life that is filled with joy and optimism instead of constant fear. n Annette Soto lives in Clermont, Florida.

Visit the

Patient Advocacy Pavilion

at the ASCO Annual Meeting May 31 - June 4, 2013, Chicago

In metastatic melanoma

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

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

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

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

dEcodE metastatic melanoma.

ExtEnd

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

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

Percentage surviving

80 60

Not reached

7.9

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

20 0

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

‡

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

OS (months) ZELBORAF (n=337)

†

Dacarbazine (n=338)

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

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

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

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

Percentage surviving

80 60

13.6 9.7

ASCO=American Society of Clinical Oncology

20 0

Patients crossing over to ZELBORAF were censored.3

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

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

OS (months) Updated analysis of ZELBORAF

Updated analysis of dacarbazine

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

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

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

zelboraf.com

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Announcements

George Salti, MD, Appointed as Co–Medical Director of Edward Cancer Center, Naperville, Illinois

eorge Salti, MD, FACS, Surgical Oncologist and Associate Professor of Surgery at the University of Illinois at Chicago, has joined the Edward

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

Cancer Center in Naperville, Illinois. Dr. Salti will serve as the Co-Medical Director of the Edward Cancer Center and Medical Director of the Edward

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.

Hospital Surgical Oncology Program.

HIPEC an Area of Interest Dr. Salti has a special interest in

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

George Salti, MD, FACS

treating late-stage abdominal cancers with hyperthermic intraperitoneal chemotherapy, also known as HIPEC. According to Dr. Salti, HIPEC is most commonly applied to cancers of the appendix and colon, but also is used in some cases of ovarian, stomach and peritoneal cancers. “HIPEC may provide relief of symptoms, and it has improved the survival rate for some cancers,” says Dr. Salti. Dr. Salti was previously a surgical oncologist with University Surgical Consultants in Illinois. He earned his medical degree from the University of Chicago Pritzker School of Medicine, and completed his residency in General Surgery and fellowship training in Surgical Oncology at the University of Illinois at Chicago. Dr. Salti is certified by the American Board of Surgery. He is a fellow of the American College of Surgeons and a member of a number of professional societies, including the American Hepatobiliary Pancreatic Association, American Society of Breast Surgeons, American Society of Clinical Oncology, and the Society of Surgical Oncology. Edward’s Cancer Care has earned Accreditation with Commendation from the Commission on Cancer of the American College of Surgeons and full accreditation from the National Accreditation Program for Breast Centers; Edward’s Cancer Care is recognized by the Quality Oncology Practice Initiative Certification. n

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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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About the Contributors

The ASCO Post Up Close: Our Reporters and Contributors About the Writers Charlotte Bath has been writing about cancer and related fields of medicine since serving as Public Information Director of the American Cancer Society, Long Island Division, from 1975 to 1979. She subsequently

lications and organizations including The ASCO Post, Cure, Breastcancer.org, CancerandCareers.org, Living Beyond Breast Cancer, the Lymphoma Research Foundation, and the Leukemia and Lymphoma Society. When Jo isn’t writing, she’s staring at movie screens or reading biographies. Margot J. Fromer has been a freelance medical writer for more than 30 years, half of them specializing in oncology. She has 16 books to her credit

Charlotte Bath

worked as a writer for Memorial SloanKettering Cancer Center and several other hospitals in New York and Ohio. As assistant director of the Medical Society of the State of New York, she edited its monthly publication. Freelance clients have included national health organizations, such as the American Lung Association and the American Red Cross, as well as medical publishers. Charlotte and her husband, Alan, relocated last year to Chicago, where they can enjoy at least eight great operas a year and a torrent of symphonic and dance works. Jo Cavallo has been a journalist for over 35 years and has edited and written for consumer publications, including Newsweek, Sports Illustrated, Connoisseur, Self, Shape, Audubon, Family Circle, Ladies’ Home Journal,

Margot J. Fromer

(including two murder mysteries) and hundreds of articles. She has received a number of writing awards: the Excellence in Women’s Health Research in Journalism Award, a National Endowment for the Humanities grant in biomedical ethics, the APEX Award for Publications Excellence, two invitations to the National Press Club Book Fair, and twice Book of the Year from the American Journal of Nursing. Margot is an avid reader, a good cook, and a slapdash gardener. She and her cat Harry (S Truman) live in Maryland.

ized publications. She lives in the hamlet of Bearsville, New York, just west of the famous Woodstock. No longer is Woodstock home of the hippies; rather it is a bedroom community for many New Yorkers that features upscale shops, galleries, and restaurants. Alice has succeeded in adjusting to this new reality. When not on the trail of a hot medical news story, Alice can be found on the tennis courts or on the walking trails in the nearby hills and woods. During winters, she goes to San Miguel de Allende in Mexico, sort of the “Woodstock of Mexico,” where she can make silver jewelry and continue to write, albeit at a more relaxed pace than during the rest of the year. Caroline Helwick has covered the field of oncology as a freelance journalist for more than 25 years, annually producing more than 200 articles and special projects for The ASCO Post and other medical publications and websites. She is proud to have reported on cancer topics spanning the early years of the taxanes and trastuzumab, to the present era of targeted therapies and genomics, and to have traveled the globe doing so. Although a Georgia native,

Susan London

enjoys digging the dirt in a community garden and volunteering with a support organization for cancer patients. Caroline McNeil is a freelance science writer who focuses on clinical cancer research. At the National Institutes of Health for more than a decade, she wrote for the news section of the Journal of the National Cancer Institute ( JNCI) and served as Chief of the NCI Press Office, among other duties. From 2009 to 2011, she was News Editor of JNCI (by then owned by Oxford

Caroline McNeil

University Press). She lives in Reston, Virginia, where she is a tennis player, gardener, and proud author of several published poems. Caroline Helwick

Alice Goodman has been a freelance medical journalist for 36 years. Over that time, she has produced different types of materials for many clients. Most recently, she has focused on oncology and rheumatology, writing for The ASCO Post and other special-

she became a New Orleanian when she moved to the city for her first medical writing job. Some 35 years later, she fiercely promotes the Big Easy and confesses an addiction to local brass bands, shrimp, and oyster po-boys, masking for Mardi Gras, and advocating for the Saints and everything else NOLA.

Ronald Piana is an independent writer and reporter with more than 15 years of experience in oncology communica-

Jo Cavallo

and American Heritage. For the past 17 years, Jo has concentrated on writing about medicine and science with a special emphasis on cancer research and patient care for a number of pubTo contact a writer or contributor to The ASCO Post, write to editor@ASCOPost.com.

Alice Goodman

Susan London is an award-winning independent medical writer and editor based in Seattle, Washington. She has been covering developments in the field of oncology for 15 years, penning hundreds of articles on topics ranging from molecular pathways to global health. When she is not working, Susan

Ronald Piana

tions and publishing. In addition to his work for The ASCO Post, Ron has written more than 100 articles, interviews, continued on page 152

The ASCO Post | MAY 15, 2013

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About the Contributors

continued from page 151

and profiles for leading medical publications. A native New Yorker, Ron lived in Paris in his earlier years before traveling worldwide as a merchant seaman. He later worked as a laborer, truck driver, and chef. His lifelong boxing aspirations were halted after going a round in Gleason’s Gym with the legendary Roberto Duran on “one thrilling but boxing career–ending day.” Ron is currently working on a cancer-related book set for publication in March of 2014. He lives in Huntington, New York, with his wife Kristine. Matthew Stenger is an independent science writer with more than 20 years of experience in oncology, immunology, infectious diseases, and other areas. In addition to his work at The ASCO Post, Matt has written or contributed

About the Artist

Matthew Stenger

to more than 1,500 articles appearing in leading medical publications. He is an extremely avid parent, which he considers to be the most important job one can have. He is also an avid amateur animal tracker and naturalist, with particular interest in observing and documenting river otter activity in lower New York State. Matt devotes time every week to writing to his public servants in the federal government to let them

eith Witmer received his Bachelor’s degree in Fine Arts from Otis/Parsons School of Design. He subsequently launched his career in advertising and publication with a commanding presence, initially using pen and ink and scratchboard mediums. Working with clients such as FedEx, Apple Computer, Hewlett-Packard, and National Geographic, Keith refined his skills and developed new illustration techniques which combined both traditional and digital mediums. Today, Keith works exclusively with his trusty Stylus and Wacom Tablet to Keith Witmer execute every illustration. Keith addresses every portrait with absolute professionalism and uncompromising attention to detail. When Keith is not at the drawing board, he can be found on his mountain bike or in a sushi bar somewhere in the beautiful city of Portland, Oregon. n know how he feels about issues facing our great nation. Matt believes that The ASCO Post is the single best publication of its kind on the basis of its depth of coverage and its frequent highlight-

ing of debate over important findings in oncology and hematology. n Disclosures: The above writers and reporters contributing to The ASCO Post reported no potential conflicts of interest.

Literary Corner

Seasons: A Series of Haiku

I forget to take my pain medication … first robin long summer hikes my vitamin D level still low

Haiku and illustration by Jyothirmai Gubili

About the Author

FDA Warns about Potential Medication Errors

Confusion Regarding Nonproprietary Name for Kadcyla (ado-trastuzumab emtasine)

sunrise the winter tree not so bare

ignoring my no another leaf falls …

FDA Update

yothirmai Gubili is an editor with the Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center in New York City. Her work involves writing for and maintaining the “About Herbs” database. She also contributes book chapters and articles about complementary medicine for oncology journals and health magazines. She holds a master of science degree in microbiJyothirmai Gubili ology from the University of Hawaii and has coauthored molecular biology articles. In her spare time she enjoys writing poetry, knitting, and watercolor painting. Her poems have appeared in the Science Editor, The Oncologist, The Heron’s Nest, Simply Haiku, Magnapoets, and in Frogpond, the journal of the Haiku Society of America.

he FDA recently alerted healthcare professionals that the use of the incorrect nonproprietary name for the breast cancer drug Kadcyla (adotrastuzumab emtansine, also known as T-DM1 during preapproval clinical trials) in some medication-related electronic systems poses a risk of mixup with Herceptin (trastuzumab) and may result in medication errors. The dosing and treatment schedules for Kadcyla and Herceptin are quite different, and confusion between these products could lead to dosing errors and potential harm to patients. The FDA-approved nonproprietary name for Kadcyla, ado-trastuzumab emtansine, should be used. However, some third-party publications, compendia references, health information systems (eg, electronic health record systems and systems used for pharmacy prescription processing, wholesaler ordering, pharmacy ordering, etc), and sites on the Internet have been incorrectly using the U.S. Adopted Name, which is “trastuzumab emtansine,” and omitting the “ado” prefix and hyphen. Use of this truncated version of Kadcyla’s nonproprietary name may cause confusion with Herceptin (trastuzumab).

FDA Recommendations FDA recommends that healthcare professionals should use both the FDA-approved proprietary (brand) name Kadcyla and its nonproprietary name (ado-trastuzumab emtansine) when communicating medication orders, on preprinted order sets, and in computerized order entry systems. Such redundancy may help to reduce the potential for medication errors. Additionally, strategies should be employed to warn against confusion between Kadcyla (ado-trastuzumab emtansine) and Herceptin (trastuzumab) in medication-related computer systems. No medication errors related to confusion between Kadcyla and Herceptin have been reported to FDA since approval of Kadcyla on February 22, 2013. However, medication errors did occur during the clinical trials that evaluated its safety and efficacy prior to approval. n

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Letter to the Editor

Mammography Screening and DCIS

would like to suggest that ASCO take a proactive approach to the treatment of ductal carcinoma in situ (DCIS) and the problem it presents to the oncology community. There has been and continues to be heated debate around the value of mammography screening because of “overdiagnosis,” which in my opinion only applies to DCIS, a mammography-detected disease that does pose some threat to a woman’s health. I wonder whether the ASCO community could put together a task force to review approaches to treatment once a woman receives a diagnosis of DCIS. We had a great presentation

on the topic by Dr. Laura Esserman at last year’s ASCO Annual Meeting, but there are other opinions and approaches. The future of mammography screening relies on the medical community coming up with good expla-

nations and options for women who may get this diagnosis if they participate in screening programs. Perhaps ASCO is not the best group to address this issue, as oncologists may not see many DCIS patients, but ASCO is a well organized and thoughtful group

(of which I am a member). n —Judith Malmgren, MS, PhD President, HealthStat Consulting, Inc. Affiliate Assistant Professor, Epidemiology University of Washington Seattle, Washington

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

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PAGE 154

Lab Notes

Ongoing Molecular Research in the Science of Oncology TARGETED THERAPY Control of Autophagic Cell Death by Caspase-10 in Multiple Myeloma Multiple myeloma subtypes are driven by a variety of genetic abnormalities. Given the genetic diversity of the disease, identification of oncogenic mechanisms common to all subtypes is highly desirable. In a study reported in Cancer Cell, Lamy and colleagues found that that all multiple myeloma lines require caspase-10 for survival irrespective of their genetic abnormalities. This effect of caspase-10, which was unexpectedly discovered during loss-offunction RNA interference screening to identify therapeutic targets in multiple myeloma, occurs through inhibition of autophagic cell death. The investigators found that the transcription factor IRF4, a master regulator of the plasma cell phenotype found at higher levels in multiple myeloma than in normal plasma cells, induces both caspase-10 and its associated protein cFLIPL in multiple myeloma. This results in a caspase-10/cFLIPL protease that blocks an autophagy-dependent cell death pathway. In particular, caspase-10 was found to promote survival by cleaving BCLAF1 (BCL2-interacting protein), an inducer of autophagic death that acts by displacing beclin-1 from

BCL2. As a result of an as-yet undefined mechanism, multiple myeloma cells preferentially express cFLIPL, which promotes caspase-10 activity, and not the inhibitory cFLIPS isoform. In the context of this finding, the investigators stated, “Caspase-10 modulates this autophagic response, preventing it from inducing cell death. Therapies targeting caspase-10 would exploit this regulatory pathway and could have broad efficacy across myeloma subtypes.” Lamy L, et al: Cancer Cell 23:435449, 2013.

BIOMARKERS C-Reactive Protein Downregulates TRAIL, a Cytokine with Key Role in Cancer Immune Surveillance C-reactive protein is a biomarker of acute and chronic inflammation that is frequently elevated in patients with cancer. In a study reported in Clinical Cancer Research, Secchiero and colleagues found that increased levels of C-reactive protein were associated with downregulation of TRAIL, a cytokine that plays a key role in immune surveillance against tumors. The investigators showed that exposure in vitro to increasing C-reactive protein concentrations resulted in downregulation of TRAIL expres-

sion, at both the mRNA and protein level, in primary peripheral blood mononuclear cells and CD14-positive monocytes. TRAIL downregulation was not due to a specific toxicity or to contaminating lipopolysaccharide. C-reactive protein also downregulated TRAIL expression and release in CD14-positive monocytes after exposure to interferon-α, a potent inducer of TRAIL. TRAIL downregulation by C-reactive protein was accompanied by a significant increase in early response growth protein-1 (Egr-1) level. Egr-1 overexpression consistently reduced TRAIL mRNA and knockdown of Egr-1 offset the ability of C-reactive protein to downregulate TRAIL, indicating that the effect of CRP on TRAIL occurs via an Egr-1-dependent pathway. The investigators concluded, “Our findings suggest that a chronic elevation of [C-reactive protein], which occurs during systemic inflammation and often in patients with cancer, might contribute to promote cancer development and/ or progression by downregulating TRAIL in immune cells.” Secchiero P, et al: Clin Cancer Res 19:1949-1959, 2013.

IMMUNOTHERAPY

CD44-positive/A LDH-positive stem cell populations present exhibiting a greater degree of epithelial-tomesenchymal transition compared with parental cells. Acquisition of the phenotype was also associated with inhibition of cytotoxic T lymphocyte–mediated tumor cell lysis. The resistant cells exhibited formation of an immunologic synapse with cytotoxic T lymphocytes, accompanied by induction of autophagy in the target cells. This response was found to be critical to modulating susceptibility to cytotoxic T lymphocyte–mediated lysis, with siRNA-mediated silencing of beclin1 to inhibit autophagy in the target cells restoring target cell susceptibility to lysis. The investigators concluded, “Our results argue that in addition to promoting invasion and metastasis, epithelial-to-mesenchymal transition also profoundly alters the susceptibility of cancer cells to Tcell-mediated immune surveillance. Furthermore, they reveal epithelialto-mesenchymal transition and autophagy as conceptual realms for immunotherapeutic strategies to block immune escape.” Akalay I, et al: Cancer Res 73:24182427, 2013.

DRUG RESISTANCE

Epithelial-to-mesenchymal Transition and Autophagy Induction in Breast Carcinoma Promote Escape from T-cell–mediated Lysis

HDAC Inhibition Circumvents EGFR Tyrosine Kinase Inhibitor Resistance Due to BIM Polymorphism

Epithelial-to-mesenchymal transition is known to mediate cancer cell invasion, metastasis, and drug resistance, but its impact on cancer immune surveillance is less well defined. In a study reported in Cancer Research, Akalay and colleagues found that epithelial-to-mesenchymal transition and autophagy induction in breast cancer cells was associated with inhibition of cytotoxic T lymphocyte–mediated tumor cell lysis. In the study, acquisition of the epithelial-to-mesenchymal transition phenotype in derivatives of MCF-7 human breast cancer cells was associated with marked morphologic changes and actin cytoskeleton remodeling, with the CD24-negative/

Upregulation of BIM (BCL2L11), a proapoptotic member of the BCL2 protein family, is required for induction of apoptosis by EGFR tyrosine kinase inhibitors in EGFR-mutant forms of non–small cell lung cancer (NSCLC). A BIM deletion polymorphism occurs naturally in approximately 13% of East Asian individuals, impairing the production of the proapoptotic isoform and conferring a drug-resistant phenotype. In a study reported in Cancer Research, Nakagawa and colleagues showed that the histone deacetylase (HDAC) inhibitor vorinostat (Zolinza) could circumvent EGFR tyrosine kinase inhibitor resistance in EGFR-mutant NSCLC cell lines with this BIM polymorphism.

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Lab Notes

Cells with the BIM polymorphism were much less sensitive to gefitinib-induced apoptosis than EGFR-mutant cells not harboring the polymorphism. Vorinostat increased expression of the proapoptotic isoform of BIM in a dosedependent manner and restored sensitivity to gefitinib in the EGFRmutant, EGFR tyrosine kinase inhibitor–resistant cells. In xenograft models, the combination of vorinostat and gefitinib was necessary to induce regression of tumors with the BIM polymorphism similar to that seen with gefitinib alone in tumors without the polymorphism. The investigators concluded, “Together, our results show how HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR [tyrosine kinase inhibitors] in cases of EGFR-mutant NSCLC

where resistance to EGFR [tyrosine kinase inhibitors] is associated with a common BIM polymorphism.” Nakagawa T, et al: Cancer Res 73:2428-2434, 2013.

GENE PROFILING Common Deletion in APOBEC3 Genes Associated with Increased Risk of Breast Cancer Genome-wide association studies have identified numerous genetic susceptibility loci for breast cancer, although these loci explain only a small proportion of heritability. Relatively few studies have assessed associations of breast cancer risk with copy number variation, another important source of genetic variation. As reported in Journal of the Nation-

al Cancer Institute, a copy number variation genome-wide association study performed by Long and colleagues showed a strong association between a common deletion in APOBEC3 genes and increased breast cancer risk among Chinese women in Shanghai. In stage 1 of the study, conducted in 2,623 patients breast with cancer and 1,946 controls, a common deletion in the APOBEC3 genes (P = 1.1 × 10−4) showed the strongest association with breast cancer risk among the 268 common copy number variations investigated (minor allele frequency ≥ 5%). In stage 2 of the study, in which the most promising copy number variation was replicated using real-time quantitative polymerase chain reaction (PCR) in another set of 4,254 patients and 4,387 controls, the deletion in APO-

BEC3 genes was associated with a 1.35 odds ratio for breast cancer (P = 9.6 × 10−22). Analyses of all samples from both stages using quantitative PCR showed odds ratios of 1.31 (95% confidence interval = 1.21–1.42) for a one-copy deletion and 1.76 (95% confidence interval = 1.57– 1.97) for a two-copy deletion (P = 2.0 × 10−24). The authors concluded, “We provide convincing evidence for a novel breast cancer locus at the APOBEC3 genes. This [copy number variation] is one of the strongest common genetic risk variants identified so far for breast cancer.” Long J, et al: J Natl Cancer Inst 105:573-579, 2013. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

Society of Interventional Radiology 2013–2014 Officers and Executive Council Members Assume New Roles

cott C. Goodwin, MD, FSIR, an interventional radiologist and Hasso Brothers Professor and Chair of the Department of Radiological Sciences at the University of California, Irvine, assumed office as the 2013–2014 President of the Society of Interventional Radiology (SIR) during the Society’s 38th Annual Scientific Meeting in New Orleans. The Society also introduced a new slate of officers.

Interventional Radiology “Interventional radiologists offer patients the least invasive and most advanced treatment options—advances that generally replace open surgery and offer less risk, less pain, and less recovery time compared to surgery. We are known for innovation, and it’s something that is clearly a key component of the success

Scott C. Goodwin, MD, FSIR

of interventional radiology, present at the beginning of our field and still much in evidence as we celebrate SIR’s 40th an-

niversary,” said Dr. Goodwin.

New Officers SIR’s 2013– 2014 officers include: ■ President-elect James B. Spies, MD, MPH, James B. Spies, MD, MPH, FSIR Alan H. Matsumoto, MD, FSIR Charles E. Ray Jr, MD, PhD, FSIR Marshall E. Hicks, MD, FSIR FSIR, GeorgeInstitute of Radiology, Saint Louis; town UniversiShands Jacksonville, Jacksonville, Laura Findeiss, MD, FSIR, Univerty Medical Center, Washington, DC Florida, graduate medical education; sity of California at Irvine; and Sanjay ■ Secretary Alan H. Matsumoto, MD, Brian Funaki, MD, FSIR, University Misra, MD, FSIR, Mayo Clinic and FSIR, University of Virginia Health of San Francisco, postgraduate medical Foundation, Rochester, Minnesota. System, Charlottesville education; Matthew S. Johnson, MD, Ex-officio members include ■ Treasurer Charles E. Ray Jr, MD, FSIR, Indiana University School of Terence A.S. Matalon, MD, FSIR, PhD, FSIR, University of Colorado, Medicine, Indianapolis, member serAlbert Einstein Medical Center, PhilaDenver vices; and Boris Nikolic, MD, MBA, delphia, AMA delegate; and Ziv J. ■ Immediate Past President Marshall FSIR, Albert Einstein Medical Center, Haskal, MD, FSIR, University of E. Hicks, MD, FSIR, University of Philadelphia, standards. Maryland School of Medicine and UniTexas MD Anderson Cancer Center Councilors-at-Large versity of Maryland Medical Center, Executive Council Councilors-at-large include Suresh Baltimore, editor, Journal of Vascular Executive Council councilors inVedantham, MD, FSIR, Mallinckrodt and Interventional Radiology. n clude George A. Fueredi, MD, FSIR, Great Lakes Radiologists, Lake Geneva, Wisconsin, health policy and economics; John A. Kaufman, MD, MS, FSIR, Dotter Interventional Institute, Portland, Oregon, SIR Foundation Chair; Daniel B. Brown, MD, FSIR, Thomas Jefferson University Hospital, Philadelphia, Annual Scientific Meeting; Daniel Siragusa, MD,

To prevent SREs in patients with BREAST CANCER and bone metastases

vs zoledronic acid

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

27 26.4 At

Months (study end)

median time not yet reached

Months

XGEVA® 120 mg Q4W (n = 1,026)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

S:9.5”

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

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

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

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

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

RESPIRATORY Dyspnea Cough

21 15

18 15

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

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

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

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

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Integrative Oncology Symptom Management with Complementary Therapies for Patients Receiving Radiation Therapy By Stephen M. Sagar, MD, FRCPC

he supportive care of patients with cancer receiving radiotherapy is an important responsibility for the radiation oncologist, and complementary therapies are an integral component of many patients’ treatment strategy. A recent prospective study suggests that 54% of patients with breast cancer receiving radiotherapy are also self-initiating complementary therapies. Many interventions (71%) are activity-based (including Reiki and meditation), 45% of patients ingest oral natural health products, and 26% use topical products. Some of these interventions have a potential to interact with radiotherapy, yet only 16% of patients received advice prior to initiating these therapies.1 It is therefore important that radiation oncologists ask their patients about complementary therapies during the initial consultation, have some basic knowledge of these therapies, and know about sources of further information and advice.

Indications Because symptoms often are multifactorial, supportive care often requires multiple integrated interventions. Adverse effects remain a problem. Some pharmaceuticals may Dr. Stephen M. Sagar is a Professor in the Departments of Oncology and Medicine at McMaster University, and a Radiation Oncologist at the Juravinski Cancer Centre in Hamilton, Ontario, Canada.

produce undesired side effects, such as constipation caused by opiates and some 5-HT3 antagonists. Substitution or supplementation with complementary therapies results in the reduction of drug-induced adverse effects. In addition to supportive care, patients benefit from the sense of em-

radioactive sources. Many patients require interventional procedures such as a biopsy, feeding tube insertion, and insertion of gold seeds. Although anxiolytic drugs are quite helpful, they may cause inappropriate sedation, prevent driving, and take away the patient’s sense of empowerment.

It is therefore important that radiation oncologists ask their patients about complementary therapies during the initial consultation, have some basic knowledge of these therapies, and know about sources of further information and advice. —Stephen M. Sagar, MD, FRCPC

powerment associated with self-selected, nonpharmaceutical interventions in addition to appropriate drugs. Empowerment and a sense of control can help reduce symptoms. The following symptoms represent patients’ common complaints.

Anxiety Anxiety may be associated with radiation therapy procedures per se, or it may be generalized. Procedures during radiotherapy include MRI scanning, restriction in immobilization devices, application of tattoos, and insertion of

Mind/body techniques are especially useful in avoiding such effects. These include hypnosis,2 relaxation exercises, guided imagery,3 control of breathing, and meditation.4,5 In addition, the practitioner can facilitate relaxation through massage6 and aromatherapy. Over the longer term, generalized anxiety can be reduced by exercise programs, yoga,7 and tai chi. Mixed massage and so-called energy techniques, such as polarity therapy,8 also are safe and useful for anxiety reduction. These techniques also help reduce insomnia. Chronic overactivation of the sympa-

thetic nervous system exacerbates multiple symptoms, such as pain, emesis, and fatigue. Treating anxiety restores the sympathetic-parasympathetic balance and results in the reduction of multiple symptoms. Recent studies also suggest that a reduction in distress at the time of surgery can reduce metastases and improve wound healing. This is not surprising in view of the profound effect of chronic anxiety on both the immune and endocrine systems.9-12

Fatigue In addition to moderate exercise and reduction of anxiety, acupuncture13 and North American ginseng (Panax quinquefolius)14 can alleviate nonanemic fatigue.

Mucositis and Dermatitis Oral (topical or systemic) glutamine reduces mucositis,15 but there is no evidence that acetyl-L-carnitine helps with this symptom. Transmucosal N-acetylcysteine (RK-0202) reduces oral mucositis, without any evidence for tumor protection, through mopping up free radicals.16 Low-level laser therapy may be of benefit in preventing mucositis during chemoradiation therapy.17 Despite the popularity of aloe vera, clinical trials do not show an advantage for its topical application in reducing radiation dermatitis.18,19

Learn More About

Herbs, Botanicals, & Other Products Visit the About Herbs website at

www.mskcc.org/aboutherbs www.mskcc.

continued on page 160

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Integrative Oncology Symptom Management continued from page 159

No intervention seems better than any other for skin care.20

Pain Acupuncture is useful for pain control, especially muscle spasm. It may allow lower doses of opiates to be used for cancer pain, thereby reducing opioids’ adverse effects, such as constipation. In patients with head and neck cancer, acupuncture can improve postsurgical pain.21 Although a Cochrane systematic review is inconclusive,22 the higher-quality trials show efficacy.23 It can be helpful for chemotherapy-induced neuropathy, although definitive controlled trials are lacking.24,25 In general, acupuncture is an effective procedure for chronic pain, and its effect is greater than that of a placebo.26

Nausea, Vomiting, and Reduced Appetite Nausea and vomiting during chemoradiation remains common, adversely affecting quality of life, reducing nutrition, and increasing other complications.27 A planned program for the prevention of nausea and vomiting is essential. Once vomiting commences, it is more difficult to control because of the conditioned reflex. Appropriate nutritional counseling is mandatory. There is excellent evidence that acupuncture can contribute to the reduction of emesis.28 Oral ginger (Zingiber officinale) is effective for nausea and vomiting.29,30

Hot Flashes Hot flashes occur in association with both treatment-induced menopause and andropause (menopause-like condition in older men causing various symptoms, including hot flashes). Mind/body techniques including relaxation exercises and meditation are helpful in attenuating this distressing symptom and have no adverse effects. Appropriate nutritional modification includes the avoidance of coffee, alcohol, and spicy foods. Results from randomized controlled trials of acupuncture are mixed,31 but acupuncture can be as effective as venlaxafine.32 Soy and other phytoestrogens are not effective.33 Despite their popular use for this purpose, there is no good evidence that either black cohosh or red clover is helpful against hot flashes, and both herbs may be associated with serious adverse effects.34

Xerostomia Dry mouth syndrome, or xerostomia,

is common following head and neck radiation therapy, although it can be improved by using intensity-modulated radiotherapy. Long-term consequences are severe, resulting in major tooth decay. Prevention is important. If pilocarpine is not effective, acupuncture is a reasonable option with good supportive evidence from randomized controlled trials.21,35

Antioxidants The administration of high-dose antioxidants during radiotherapy is controversial. Their use is based on the pretext of reducing toxicity to normal tissues. On the other hand, it is not clear whether the effectiveness of radiotherapy also is reduced.36 While good nutrition, preferably with whole foods (vegetables, fruits, and whole grains) should be encouraged during radiotherapy, high-dose antioxidant treatment is best left until the course of radiation is complete. Some antioxidant vitamins, such as beta-carotene and vitamin E, can increase the risk of second cancers in exsmokers. The controversy is further discussed in published reviews.37,38

Recommendations The goal of integrative oncology is to provide the best possible care for patients, drawing on all reasonable, evidence-based sources.39 It includes prevention, treatment, and rehabilitation in the continuum of care.40 In addition, it explores systems of care, recognizing the importance of synergy between the components.41 It is important for oncologists to obtain knowledge in this field and to ensure that a program of radiotherapy includes the best supportive care. Patients struggle with information that may include bogus “alternative” therapies.42 A knowledgeable and empathetic practitioner can gain patients’ trust to ensure that they receive appropriate management. n Disclosure: Dr. Sagar reported no potential conflicts of interest.

References 1. Moran MS, Ma S, Jagsi R, et al: A prospective, multicenter study of complementary/alternative medicine (CAM) utilization during definitive radiation for breast cancer. Int J Radiat Oncol Biol Phys 85:40-46, 2013. 2. Lang EV, Berbaum KS, Faintuch S, et al: Adjunctive self-hypnotic relaxation for outpatient medical procedures: A prospective randomized trial with women undergoing large core breast biopsy. Pain 126:155164, 2006. 3. Kwekkeboom KL, Hau H, Wanta B, et al: Patients’ perceptions of the effectiveness

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, 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 Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, Barrie R. Cassileth, MS, PhD minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan-Kettering Cancer Center’s very first mobile application, was launched last fall. In the week following its release on September 21, the app was downloaded more than 6,300 times, making it #4 on the top new medical apps chart. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http:// itunes.apple.com/us/app/about-herbs/id554267162?mt=8. of guided imagery and progressive muscle relaxation interventions used for cancer pain. Complement Ther Clin Pract 14:185-194, 2008. 4. Garland SN, Carlson LE, Antle M, et al: I-CAN SLEEP: Rationale and design of non-inferiority RCT of mindfulness-based stress reduction (MBSR) and cognitive behavioral therapy (CBT) for the treatment of insomnia in cancer survivors. Contemp Clin Trials 32:747-754, 2011. 5. Campbell TS, Labelle LE, Bacon SL, et al: Impact of mindfulness-based stress reduction (MBSR) on attention, rumination and resting blood pressure in women with cancer: A waitlist-controlled study. J Behav Med 35:262-271, 2012. 6. Sagar S, Dryden T, Wong R: Massage therapy for cancer patients. Curr Oncol 14:45-56, 2007. 7. Shannahoff-Khalsa DS: Patient perspectives: Kundalini yoga meditation techniques for psycho-oncology and as potential therapies for cancer. Integr Cancer Ther 4:87-100, 2005. 8. Mustian KM, Roscoe JA, Palesh OG, et al: Polarity therapy for cancer-related fatigue in patients with breast cancer receiving radiation therapy: A randomized controlled pilot study. Integr Cancer Ther 10:27-37, 2011. 9. Lutgendorf SK, Lamkin DM, DeGeest K., et al: Depressed and anxious mood and T-cell cytokine expressing populations in ovarian cancer patients. Brain Behav Immun 22:890-900, 2008. 10. Sood AK, Bhatty R, Kamat AA, et al: Stress hormone-mediated invasion of ovarian cancer cells. Clin Cancer Res 12:369-375, 2006. 11. Su F, Ouyang N, Zhu, P, et al: Psychological stress induces chemoresistance in breast cancer by upregulating mdr1. Biochem Biophys Res Commun 329:888-897, 2005. 12. Neeman E, Zmora O, Ben-Eliyahu S: A new approach to reducing postsurgical

cancer recurrence: Perioperative targeting of catecholamines and prostaglandins. Clin Cancer Res 18:4895-4902, 2012. 13. Molassiotis A, Bardy J, FinneganJohn J, et al: Acupuncture for cancer-related fatigue in patients with breast cancer: A pragmatic randomized controlled trial. J Clin Oncol 30:4470-4476, 2012. 14. Barton DL, Soori GS, Bauer BA, et al: Pilot study of Panax quinquefolius (American ginseng) to improve cancer-related fatigue: A randomized, double-blind, dosefinding evaluation: NCCTG trial N03CA. Support Care Cancer 18:179-187, 2009. 15. Aquino VM, Harvey AR, Garvin JH, et al: A double-blind randomized placebocontrolled study of oral glutamine in the prevention of mucositis in children undergoing hematopoietic stem cell transplantation: A pediatric blood and marrow transplant consortium study. Bone Marrow Transplant 36:611-616, 2005. 16. Chambers MS, Welsh DV, Scrimger RA, et al: RK-0202 for radiation-induced oral mucositis. J Clin Oncol 24(18S):Abstract 5523, 2006. 17. Castro G, de Lima AG, Lopes DR, et al: Oral mucositis prevention by low-level laser therapy in head and neck cancer patients submitted to concurrent chemoradiation: A prospective randomized study. J Clin Oncol 27(15S):Abstract 6019, 2009. 18. Heggie S, Bryant GP, Tripcony L, et al: A phase II study on the efficacy of topical aloe vera gel on irradiated breast tissue. Cancer Nurs 25:442-451, 2002. 19. Richardson J, Smith JE, McIntyre M, et al: Aloe vera for preventing radiation-induced skin reactions: A systematic literature review. Clin Oncol (R Coll Radiol) 17:478484, 2005. 20. Salvo N, Barnes E, van Draanen J, et al: Prophylaxis and management of acute radiation-induced skin reactions: A systematic review of the literature. Curr Oncol 17:94112, 2010.

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Integrative Oncology 21. Pfister DG, Cassileth BR, Deng GE, et al: Acupuncture for pain and dysfunction after neck dissection: Results of a randomized controlled trial. J Clin Oncol 28:25652570, 2010. 22. Paley CA, Johnson MI, Tashani OA, et al: Acupuncture for cancer pain in adults. Cochrane Database Syst Rev 19(1):CD007753, 2011. 23. Alimi D, Rubino C, Pichard-Léandri E, et al: Analgesic effect of auricular acupuncture for cancer pain: A randomized, blinded, controlled trial. J Clin Oncol 21:4120-4126, 2003. 24. Wong R, Sagar S: Acupuncture treatment for chemotherapy-induced peripheral neuropathy: A case series. Acupunct Med 24:87-91, 2006. 25. Schroeder S, Meyer-Hamme G, Epplée S: Acupuncture for chemotherapy-induced peripheral neuropathy (CIPN): A pilot study using neurography. Acupunct Med 30:4-7, 2012. 26. Vickers AJ, Cronin AM, Maschino AC, et al: Acupuncture for chronic pain: Individual patient data meta-analysis. Arch Intern Med 172:1444-1453, 2012. 27. Ezzo J, Vickers A, Richardson MA, et al: Acupuncture point stimulation for chemotherapy-induced nausea and vomiting. J Clin Oncol 23:7188-7198, 2005. 28. Ernst E, Pittler MH: Efficacy of ginger for nausea and vomiting: A systematic review of randomized clinical trials. Br J Anaesth 84:367-371, 2000. 29. Ryan JL, Heckler CE, Roscoe JA, et al: Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: A URCC CCOP study of 576 patients. Support Care Cancer 20:1479-1489, 2012. 30. Doranne LN. Hilarius DL, Kloeg PH, et al: Chemotherapy-induced nausea and vomiting in daily clinical practice: A community hospital-based study, Support Care Cancer 20:107-117, 2012. 31. Deng G, Vickers A, Yeung S, et al: Randomized controlled trial of acupuncture for the treatment of hot flashes in breast cancer patients. J Clin Oncol 25:5584-5590, 2007. 32. Walker EM, Rodriguez AI, Kohn B, et al: Acupuncture versus venlafaxine for the management of vasomotor symptoms in patients with hormone receptor-positive breast cancer: A randomized controlled trial. J Clin Oncol 28:634-640, 2010. 33. Gold EB, Leung K, Crawford SL, et al: Phytoestrogen and fiber intakes in relation to incident vasomotor symptoms: Results from the Study of Women’s Health Across the Nation. Menopause. October 29, 2012 (early release online). 34. Geller SE, Shulman LP, van Breemen RB, et al: Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: A randomized controlled trial. Menopause 16:1156-1166, 2009. 35. Meng Z, Garcia M K, Hu C, et al: Randomized controlled trial of acupuncture for prevention of radiation-induced xerostomia among patients with nasopharyngeal

carcinoma. Cancer 118:3337-3344, 2012. 36. Watson J: Oxidants, antioxidants and the current incurability of metastatic cancers. Open Biol 3:120144, 2013. 37. Sagar S: Should patients take or avoid antioxidant supplements during anticancer therapy? An evidence-based review. Curr Oncol 12:44-54, 2005. 38. Lawenda BD, Kelly KM, Ladas EJ, et al: Should supplemental antioxidant admin-

istration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst 100:773-783, 2008. 39. Deng GE, Frenkel M, Cohen L, et al: Evidence-based clinical practice guidelines for integrative oncology: Complementary therapies and botanicals. J Soc Integr Oncol 7:85-120, 2009. 40. Sagar S, Lawenda B: The role of integrative oncology in a tertiary prevention

survivorship program. Prev Med 49:93-98, 2009. 41. Lawenda BD, Friedenthal SA, Sagar SM, et al: Systems modeling in integrative oncology. Integr Cancer Ther 11:5-17, 2012. 42. Sagar SM: Alternative therapies as primary treatments for cancer, in Abrams D, Weil A (eds): Integrative Oncology, chapter 26, pp 502-529. New York, Oxford University Press, 2009.

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News Genitourinary Oncology

Obese Men with Benign Biopsy at High Risk for Prostate Cancer

bese men were more likely to have precancerous lesions detected in their benign prostate biopsies compared with nonobese men and were at a greater risk for subsequently developing prostate cancer, according to data pub-

lished recently in Cancer Epidemiology, Biomarkers & Prevention.1 “Our study is focused on a large group of men who have had a prostate biopsy that is benign but are still at a very high risk for prostate cancer,” said

Andrew Rundle, DrPH, Associate Professor of Epidemiology at Columbia University Mailman School of Public Health in New York. “Studies conducted in the past have attempted to determine if there are subpopulations of men diag-

nosed with benign conditions that may be at a greater risk for developing prostate cancer. This is one of the first studies to assess the association between obesity and precancerous abnormalities.”

Study Details Dr. Rundle and his colleagues investigated the association between obesity and future prostate cancer incidence within a cohort of 6,692 men at the Henry Ford Health System who were followed for 14 years after a biopsy or transurethral resection of the prostate with benign findings. The investigation was part of a larger study of environmentally-induced tissue biomarkers for prostate cancer funded through a research grant awarded by the National Institutes of Health to Benjamin Rybicki, PhD, a research scientist at the Henry Ford Health System and the senior coauthor of the study. The researchers conducted a casecontrol study among 494 of these patients and 494 matched controls; they found precancerous abnormalities in 11% of the patients’ benign specimens. These abnormalities were significantly associated with obesity at the time of the procedure, according to Dr. Rundle. After accounting for several variables, including family history of prostate cancer, prostate-specific antigen (PSA) levels during the initial procedure, and the number of PSA tests and digital rectal exams during follow-up, the researchers found that obesity at the time of the initial procedure was associated with a 57% increased incidence of prostate cancer during follow-up.

True Biology Unclear Dr. Rundle noted, however, that this association was only apparent for tumors occurring earlier in the followup period. “We don’t absolutely know what the true biology is,” he said. “In some ways, this reflects the association between the body size and larger prostate size, which is thought to reduce the sensitivity of the needle biopsy. It is possible that the tumors missed by initial biopsy grew and were detected in a follow-up biopsy.” n Reference 1. Rundle A, et al: Obesity and future prostate cancer risk among men after an initial benign biopsy of the prostate. Cancer Epidemiol Biomark Prevention. April 23, 2013(early release online).

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In the News Gynecologic Oncology

Most Women with Ovarian Cancer Do Not Get Guideline-specified Treatment Linked to Survival Benefits By Charlotte Bath

ost women with ovarian cancer are not receiving adequate treatment, as specified in National Comprehensive Cancer Network (NCCN) Guidelines,1 and as a re-

Robert E. Bristow, MD, MBA

sult are being deprived of the survival benefits correlated with guidelinerecommended treatment, according to a study presented at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer in Los Angeles (see The ASCO Post, April 15, page 117).2 Adherence to the NCCN Guidelines “was one of the strongest independent predictors of improved ovarian-specific survival,” the study’s

lead author, Robert E. Bristow, MD, MBA, said in an interview with The ASCO Post. Dr. Bristow is the Director of the Division of Gynecologic Oncology, University of California, Irvine. The retrospective population-based study reviewed the medical records of 13,321 patients extracted from the California Cancer Registry. All patients were diagnosed with epithelial ovarian cancer between the beginning of 1999 and the end of 2006. Overall, 37.2% received NCCN guideline-adherent care, defined by stage-appropriate surgical procedures and recommended chemotherapy. High-volume surgeons, defined as those who treated 10 or more cases of ovarian cancer per year, were significantly more likely to deliver guidelineadherent care—47.6% compared to 34.5% of those treating fewer cases (P < .001). High-volume hospitals, defined as those with a case volume of 20 or more per year, were significantly more likely to deliver guidelineadherent care—50.8% compared to 34.1% of hospitals with fewer cases

(P < .001). Hospitals with an American College of Surgeons—approved cancer program were also more likely to administer NCCN guideline–adherent care.

Disease-specific Survival The 5-year ovarian cancer–specific survival for all patients was 45.3%, and univariate survival analysis revealed a statistically significant difference in disease-specific survival between patients receiving NCCN guideline–adherent vs nonadherent care. For patients with stage I/II disease, the 5-year diseasespecific survival rates were 86% for patients receiving guideline–adherent care vs 81% for those receiving nonadherent care (P = .0003). For patients with stage III/IV disease, the 5-year disease-specific survival rates were 35% for patients receiving guideline-adherent care vs 25% for those receiving nonadherent care (P < .0001). Multivariate survival analysis controlling for patient, disease-related, and health-care system factors found that non–guideline adherent care was

Expect Questions about Experience and Outcomes

“P

atients are becoming more sophisticated in their ability and willingness to interrogate the health-care system about their care,” according to Robert E. Bristow, MD, MBA, lead author of the study finding

surgical procedures for ovarian cancer they do each year. Other questions to expect include: What are your outcomes? What is your patient survival rate? What percentage of your patients get intraperitoneal chemotherapy,

We now understand that the main driver of improved outcomes of surgery is being able to debulk those patients to no visible disease. That is the gold standard outcome for patients with advanced ovary cancer. —Robert E. Bristow, MD, MBA

that many women with ovarian cancer are not receiving care consistent with National Comprehensive Cancer Network (NCCN) Guidelines. Dr. Bristow is the Director of the Division of Gynecologic Oncology, University of California, Irvine. It is becoming more and more common, he said, for patients with ovarian cancer to ask physicians how many

and how do they do afterward? What percentage of patients with advanced disease are able to have an optimal or complete debulking? “We now understand that the main driver of improved outcomes of surgery is being able to debulk those patients to no visible disease. That is the gold standard outcome for patients with advanced ovary cancer—com-

plete debulking down to no gross residual disease,” Dr. Bristow said. He cited an abstract presented at the Society of Gynecologic Oncology meeting last year1: A subanalysis of data from Gynecologic Oncology Group (GOG) 172 looked at whether patients with stage III ovarian cancer that received intraperitoneal therapy had complete debulking to no visible disease, or whether they had debulking to 1 to 10 mm of residual disease. “For those patients taken down to no visible disease who got intraperitoneal chemotherapy, the median survival was 127 months—10½ years—which is like a Star Trek number for advanced ovary cancer survival,” Dr. Bristow said. n Reference 1. Landrum L, Java J, Matthews C, et al: Prognostic factors for stage III epithelial ovarian cancer treated with intraperitoneal chemotherapy: A Gynecologic Oncology Group study. Abstract 56. Gynecol Oncol 125:S24, 2012.

independently associated with inferior overall survival (hazard ratio [HR] = 1.34, 95% confidence interval [CI] = 1.26 – 1.42]. “Compared to patients treated according to NCCN Guidelines, patients receiving substandard care experienced more than a 30% increase in the risk of ovarian cancer–related death. Among provider characteristics, both low-volume hospitals and low-volume physicians were also significantly negatively associated with survival, independent of overall treatment adherence to NCCN Guidelines,” Dr. Bristow reported. “The type of research I do is looking at trying to get people to the right settings for care,” Dr. Bristow said. “If we were able to do that in a more effective fashion, we could probably have a much greater impact on ovarian cancer survival than developing any new drug or biologic agent.” Dr. Bristow said that it is still too early to tell if the study and the attention directed to the study by national media coverage will serve to improve adherence to guidelines or direct women to high-volume physicians and facilities. While the research has “some nuances to it that are new, the underlying principle that patients do better when they are treated by people specifically trained and in hospitals that have the capability to take the best care of them is not a new observation,” Dr. Bristow noted. “It is gratifying that it took this paper to start piquing people’s interest about it and it is getting the attention it deserves,” he continued. “One of the sidelights of this is that patients will see these findings and then become empowered to help direct their care and make sure they are getting taken care of in an environment that is optimized to try to give them the best outcome.”

Other Factors Affecting Guideline Adherence Age ≥ 70 and early-stage disease were associated with a decreased likelihood that treatment would follow the NCCN Guidelines. The median age of the patients was 61, but ages ranged from 18 to 104. “A number of studies have shown continued on page 164

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In the News

Guideline-Specified Treatment continued from page 163

that age in and of itself is not necessarily a contraindication to standard therapy. It really depends more on performance status and what the medical comorbidities are,” Dr. Bristow said. The California Cancer Registry doesn’t contain specific information on medical comorbidities, he noted, “So in our study, age was probably more of a proxy for a compilation of medical morbidities than just chronologic age.” Adherence to guidelines was less likely when the patients had stage III or IV disease, primarily due to the staging procedures required and complexity of treatment. “Patients with advanced-stage ovarian cancer are also more likely to be medically compro-

mised because of their disease status,” Dr. Bristow explained. “So that is an additional challenge that comes with more advanced-stage disease in terms of being able to adhere to the recommended guidelines.” Even for the high-volume hospitals, which accounted for 2.8% of all hospitals in the study and18.8% of the total cases, adherence to NCCN Guidelines was just over 50%. For high-volume surgeons, who were just 0.3% of all physicians in the study and treated 20.9% of all cases, adherence to NCCN Guidelines was not even 50%, but 47.6%. “If you look specifically at the surgery or the chemotherapy, most of the high-volume groups were in the neighborhood of 70% guideline adherence for the individual components,” Dr. Bristow commented. “It is only when

Going Public with Ovarian Cancer Outcomes

ommenting on the study finding that most women with ovarian cancer are not being treated with the recommended standard of care, a New York Times editorial noted, “One of the surest ways to improve performance would be to analyze and make public how well individual doctors and hospitals do in treating various diseases.”1

It may be that to get care at a high-volume center by a high-volume surgeon ends up costing more upfront, but if your payoff is an additional 4 or 5 or 6 years of survival time, with a good quality of life, then that may very well be interpreted as a good health-care investment. —Robert E. Bristow, MD, MBA

Robert E. Bristow, MD, MBA, lead author of the study and Director, Division of Gynecologic Oncology, University of California, Irvine, considered that a fair approach. “I think we are going to see a time when we have to not only publish our data, but publish our cost of care so that consumers will be able to search for the best value. It may be that to get care at a high-volume center by a high-volume surgeon ends up costing more upfront, but if your payoff is an additional 4 or 5 or 6 years of survival time, with a good quality of life, then that may very well be interpreted as a good health-care investment,” he said. “So I think we will see a time when these risk-adjusted outcomes are going to be publicly available, and that is going to drive the market,” he continued. “That is what will reduce utilization of low-volume centers and increase utilization of high-volume centers, and then we get into a self-sustaining cycle, where hopefully the community at large is able to learn from the top performers and raise practice standards across the board, so that the innovators, the places and people doing things that generate improved outcomes at reduced cost, are leading the curve and bringing everyone else along with them.” n Reference 1. Editorial board: Inadequate treatment of ovarian cancer. New York Times. Available at nytimes.com. Posted March 13, 2013.

you mesh the two together that that number drops down to around 50%, suggesting that a sick patient may have been able to tolerate the proper surgery, but they were too sick to tolerate proper chemotherapy or vice versa.” While the numbers used to determine high-volume physicians were not very high—just 10 or more cases per year—Dr. Bristow said those numbers “have been studied previously in the literature and are pretty well accepted as defining high-volume providers.” For this study, “the high-volume providers are going to be a surrogate for gynecologic oncologists,” he noted, since the California Cancer Registry doesn’t contain data on physician specialty.

Barriers to ‘Ideal Triage Algorithm’ “The reasons that patients aren’t making it to the appropriate specialists or hospitals are multifactorial,” Dr. Bristow explained. “There are a lot of potential barriers to that ideal triage algorithm. One is just not making the correct diagnosis.” Another reason relates to the patient’s comfort with and loyalty to her general gynecologist, who may have treated her for years and delivered all of her children. When the general gynecologist tells her that she has an ovarian mass and needs a hysterectomy, the patient may opt to have the procedure done by that general gynecologist. “Specifically with ovary cancer, a gynecologic oncologist really needs to make that initial assessment and determine whether the patient is an appropriate candidate for surgery. If she is, then it should be the gynecologic oncologist that does that surgery, not only because we are trained in the surgical techniques, but also because we have a deeper understanding of the underlying disease process and are able to tailor the surgery to the individual patient’s risk factors,” Dr. Bristow said. “Most general surgeons don’t routinely take care of a comparable disease process like ovarian cancer, which is largely a chemotherapysensitive malignancy in which the surgical debulking status has been shown to be such a good prognostic factor for long-term survival,” he said. “They can do the technical aspect of the surgery, but are often lacking in that broad understanding of the disease process and how the individual procedures work together

to optimize patient outcome.”

Role of Third-party Payers Another barrier is related to third-party payers, particularly those that are profit-driven. “The individual contracts that some third-party payers have with hospitals do not make the referral process easy for patients,” Dr. Bristow said. Those contracts may specify that certain procedures be done at community hospitals with which particular payers have contracts, he said, rather than at large tertiary referral centers, which tend to also be the high-volume centers. “The control that the payers have over determining where the patient actually undergoes a procedure is definitely one of the factors that determines patient access to what we would call a high-volume ovarian cancer center,” Dr. Bristow remarked. “We are entering into a time where clinical practice patterns are going to need to be driven by data, and with current concerns about health-care expenditures, reimbursement is going to be tightly linked to following guidelines, with built-in exceptions,” Dr. Bristow stated. An example of an exception to the ovarian cancer guidelines might be an 87-year-old woman in a nursing home who has had hypertension and congestive heart failure and is not in good medical condition. “She is probably not going to be a great candidate for guideline therapy because it will end up being too toxic and hasten her demise. So there need to be built-in exceptions or deviations from guidelines care, and that is probably our next challenge—to figure out how to risk-adjust adherence to guidelines.” n

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

References 1. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 1.2013. Available at www.nccn.org. Accessed April 19, 2013. 2. Bristow R, Chang J, Ziogas A, et al: NCCN treatment guidelines for ovarian cancer: A population-based validation study of structural and process quality measures. Society of Gynecologic Oncology Annual Meeting on Women’s Cancer. Abstract 45. Presented March 11, 2013.

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In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Exemestane an Adjuvant Option for Postmenopausal Hormone Receptor–positive Breast Cancer A phase III open-label trial of exemestane vs anastrozole in postmenopausal women with hormone-dependent early breast cancer found that both agents produced similar median rates of event-free survival—91% for exemestane and 91.2% for anastrozole—as well as similar distant disease-free and disease-specific survival. “This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by twoway test,” the investigators from the NCIC Clinical Trials Group (NCIC CTG) MA.27 reported in the Journal of Clinical Oncology. “Exemestane should now be considered another safe and effective option in addition to anastrozole or letrozole as initial adjuvant therapy for patients with hormone receptor–positive postmenopausal breast cancer,” the researchers concluded. The multicenter, multinational study enrolled 7,576 women with a median age of 64.1 years. All had histologically confirmed, adequately excised, primary invasive breast cancer. “Compliance was poor, with a 31.6% discontinuation rate (33.8% and 29.4% in exemestane and anastrozole groups, respectively) for adverse effects, concomitant diseases, or study refusal,” the authors noted. The investigators found no evidence of differences in menopausal-like symptoms between the two treatment groups, although adverse effects differed. “Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms,” the investigators stated. The effects of exemestane on bone health will be investigated more fully in the group’s bone substudy. Goss PE, et al: J Clin Oncol 31:13981404, 2013.

ENDOMETRIAL CANCER Higher Prediagnosis Body Mass Index Raises Mortality Risk in Endometrial Cancer Higher prediagnosis body mass index (BMI) increases risk of overall and disease-specific mortality among women diagnosed with endometrial cancer, suggested a study published in the Journal of the National Cancer Institute. Physical activity was associated with reduced risk of all-cause, but not disease-specific mortality. The study examined associations of overall and endometrial cancerspecific 5- and 10-year mortality with prediagnosis BMI in 1,400 women and with physical activity in 875 women in the National Institutes of Health– AARP Diet and Health Study. “Compared with women with a BMI in the range of 18.5 to less than 25 kg/m2, the hazard ratios for 5-year all-cause mortality were 1.74 (95% confidence interval [CI] = 1.13–2.66) for BMI in the range of 25 to less than 30 kg/m2, 1.84 (95% CI = 1.17–2.88) for BMI in the range of 30 to less than 35 kg/ m2, and 2.35 (95% CI = 1.48–3.73) for BMI greater than or equal to 35 kg/ m2 (Ptrend < .001),” the investigators reported. Higher BMI was also statistically significantly associated with poorer endometrial cancer–specific mortality. The 5- and 10-year hazard ratio estimates for all-cause and endometrial cancer–specific mortality were similar at 10 years. A baseline questionnaire was used to assess moderate-to-vigorous-intensity physical activities performed by study participants in the last 10 years. “Example activities included tennis, golf, biking, swimming, heavy gardening, fast walking or dancing, aerobics, and jogging,” the researchers reported. “In adjusted models, prediagnosis [moderate-to-vigorous-intensity physical activities] was associated with a 43% lower risk of 5-year all-cause mortality in a comparison of never/ rare exercisers to women who reported more than 7 hours of [moderate-tovigorous-intensity physical activities] per week (hazard ratio [HR] = 0.57, 95% CI = 0.33–0.98),” the authors wrote. “After further adjustment for BMI, the association was attenuated (HR = 0.64, 95% CI = 0.37–1.12).” The authors also noted that a joint

effect analysis found that even among women who were not obese, those who were not physically active had an increased risk of 5-year mortality compared to their active counterparts. The authors called for “intervention studies of the effect of these modifiable lifestyle factors.” Arem H, et al: J Natl Cancer Inst 105:342-349, 2013.

LEUKEMIA High-dose Liposomal Vincristine Produces Durable Responses in Advanced ALL High-dose monotherapy with vincristine sulfate liposome injection (Marqibo) resulted in meaningful clinical outcomes, including durable responses and bridging to hematopoietic cell transplantation, in adult patients with advanced, relapsed, and refractory Philadelphia chromosome (Ph)negative acute lymphoblastic leukemia (ALL), according to a study reported in the Journal of Clinical Oncology. This “near end-stage adult ALL population” is “desperately in need of new therapies,” the authors noted. Liposomal vincristine is a nanoparticle formulation of vincristine “designed to overcome the dosing and pharmacokinetic limitations of standard, nonliposomal vincristine,” the authors explained. “This study,” they noted, “served as the basis for accelerated approval” of liposomal vincristine in the United States.

The phase II multinational study involved 65 patients with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies. “Intravenous [liposomal vincristine] 2.25 mg/m2, without dose capping, was administered once per week until response, progression, toxicity, or pursuit of [hematopoietic cell transplantation],” the researchers stated. The overall response rate was 35%, and the rate of complete response or complete response with incomplete hematologic recovery was 20%, with a median complete response duration of 23 weeks (range, 5–66 weeks). “Younger age and higher baseline platelet count were independently associated with a favorable response,” the investigators noted. “[Liposomal vincristine] monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies,” the researchers wrote. Twelve patients (19%) bridged to hematopoietic cell transplantation. Median overall survival was 4.6 months and 7.7 months in those achieving complete response or complete response with incomplete hematologic recovery. Five patients survived for more than 1 year. “The toxicity profile of [liposomal vincristine] was predictable, manageable, and comparable to standard [vincristine] despite the delivery of large, normally unachievable, individual and

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In the Literature

cumulative doses of [vincristine],” the investigators stated. [Liposomal vincristine] was “associated with a low 30day mortality rate (12%).” Based on this study and other phase II studies successfully combining [liposomal vincristine] with other chemotherapies and rituximab (Rituxan), patients with front-line adult ALL and front-line aggressive non-Hodgkin lymphoma are being enrolled in phase III studies. O’Brien S, et al: J Clin Oncol 31:676683, 2013.

RENAL CELL CARCINOMA Cisplatin and Radiotherapy Linked to Increased Renal Cancer Risk in Childhood Cancer Survivors Survivors of childhood cancer have an increased risk of subsequent renal cancers compared to the general population, researchers reported in the Journal of the National Cancer Institute. The risk is particularly high among survivors of neuroblastoma and those who have had irradiation involving the kidneys. The researchers estimated standardized incidence ratios for subsequent renal carcinoma among the 14,358 survivors enrolled in the Childhood Cancer Survivor Study, which includes survivors who were treated at 26 institutions in the United States and Canada between 1970 and 1986. Among the 26 survivors diagnosed with a subsequent renal carcinoma, the median time to diagnosis was 22.6 years (range, 6.3–35.7 years). “Survivors were more likely to develop renal carcinoma than the general population” (standardized incidence ratio = 8.0, 95% CI = 5.2–11.7), the authors reported, as were survivors of neuroblastoma (8 cases among 954 survivors, standardized incidence ratio = 85.8, 95% CI = 38.4–175.2). “The overall absolute excess risk was 8.4 per 105 person-years,” they wrote. Multivariate analysis showed that “increased risk was associated with renal-directed radiotherapy of 5 Gy or greater (relative risk [RR] = 3.8, 95%

CI = 1.6–9.3) and cisplatin exposure (RR = 3.5, 95% CI = 1.0–11.2),” the researchers reported. “To our knowledge,” they stated, “this is the first report of an association between cisplatin and subsequent renal carcinoma among survivors of childhood cancer.” Wilson CL, et al: J Natl Cancer Inst 105;504-508, 2013.

MYELOFIBROSIS Ruxolitinib Results in Clinically Meaningful Symptom Improvement Patients with myelofibrosis who received ruxolitinib ( Jakafi) therapy experienced “meaningful reductions in symptom burden” and improvements in quality of life in a double-blind, placebo-controlled phase III trial published in the Journal of Clinical Oncology. The COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment–I) study enrolled 309 patients who were diagnosed with primary myelofibrosis, postpolycythemia vera myelofibrosis, or postessential thrombocythemia myelofibrosis, had palpable splenomegaly, and “were resistant or refractory to, intolerant of, or not candidates for available therapy (in the investigator’s opinion).” Patients randomly assigned to ruxolitinib had improvements in individual myelofibrosis-related symptoms, whereas those receiving placebo had worsening (P < .001). The study also found that the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 correlated well with established patient-reported outcome assessments and “was sensitive to differentiating responses in the placebo and ruxolitinib arms over time,” according to investigators. Every night from baseline through week 24, patients used the modified MFSAFv2.0 to rate the following myelofibrosis symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs (left side), early satiety, bone/muscle pain, and inactivity. The degree of spleen volume reduction with ruxolitinib correlated

with improvements in several patientreported outcomes—Total Symptom Score (TSS), Patient Global Impression of Change (PGIC), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life. “Ruxolitinibtreated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these [patient-reported outcomes],” the authors stated. “Although there was a trend for greater improvements in [patient-reported outcomes] with greater spleen volume reductions with ruxolitinib, even patients with modest changes in spleen size or symptom scores demonstrated improvements in symptom burden and [quality of life], whereas patients receiving placebo continued to worsen by these same measures,” the authors concluded. Mesa RA, et al: J Clin Oncol 31:12851292, 2013.

PSYCHOLOGICAL DISTRESS High Levels of Psychological Distress Are Common among Parents of Children with Advanced Cancer High to severe levels of psychological distress are common among parents of children with advanced cancer, according to a study conducted at three children’s hospitals—Boston Children’s Hospital, Children’s Hospital of Philadelphia, and Seattle Children’s Hospital. The cohort study was embedded in a randomized clinical trial (Pediatric Quality of Life and Evaluation of Symptoms Technology [PediQUEST] study) and included 81 parents of children with advanced cancer. More than 50% of parents reported high psychological distress and 16% met criteria for serious psychological distress, compared with 2% to 3% in the U.S. population. Parent perceptions of prognosis,

goals of therapy, child symptoms/suffering, and financial hardship were associated with psychological distress. “In multivariate analyses, average parent Kessler-6 Psychological Distress Scale scores were higher among parents who believed their child was suffering highly and who reported great economic hardship. Conversely, [psychological distress] was significantly lower among parents whose prognostic understanding was aligned with concrete goals of care,” the researchers reported. This is true even if parents understand that their child’s illness is incurable. “Because a cancer diagnosis represents the potential death of a child and challenges a parent’s basic assumptions, the level of cognitive dissonance, and consequent [psychological distress], may be greater in this population. These results support the notion that early integration of palliative care strategies as a means of facilitating the alignment of parents’ prognostic understanding with concrete goals of care may ease their distress,” the authors wrote. “Parent perception of child suffering was also related to their experience of [psychological distress],” the authors continued. “Parents may have greater emotional struggles when they feel that their child is unhappy or afraid. They may feel less knowledgeable or more helpless in the face of their child’s emotional symptoms than they would with other cancer-related somatic complaints and may feel more responsible for addressing psychological concerns. Likewise, a child’s emotional suffering may more strongly impair parental coping.” Parental psychological distress “can ultimately affect patient and sibling psychological outcomes,” and alleviating the distress “may lead to more optimal patient and family health,” the authors noted. “Importantly, our findings suggest ways in which providers may ease parental [psychological distress] by exploring their views on prognosis and treatment goals, perceived child suffering, and economic hardship.” n Rosenberg A, et al: JAMA Pediatrics. April 1, 2013 (early release online).

Coming in Future Issues of The ASCO Post Comprehensive coverage of the 2013 Annual Meeting of the American Society of Clinical Oncology May 31 - June 4, 2013, Chicago, Illinois Visit ASCOPost.com for more information

The ASCO Post | MAY 15, 2013

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Announcements

Saul N. Weingart, MD, PhD, Named New Chief Medical Officer of Tufts Medical Center

ufts Medical Center has appointed Saul N. Weingart, MD, PhD, of Newton, Massachusetts as its next Chief Medical Officer. Dr. Weingart

is currently serving as Vice President for Quality Improvement and Patient Safety at Dana-Farber Cancer Institute in Boston. He is a nationally re-

nowned leader in the movement to improve hospital quality. Dr. Weingart succeeds Michael Wagner, MD, who was named Chief

Executive Officer of the Tufts Medical Center Physicians Organization last year, and has continued to fill the role of Chief Medical Officer during the search for his successor

Quality, Innovation, Patient Safety “I know Dr. Weingart will do an incredible job continuing initiatives already launched at Tufts Medical Center and establishing new projects and goals for our future,” Dr. Wagner said. He added “Saul Weingart is a name that is synonymous with quality, innovation, and patient safety. I am extremely pleased that his name now will also be associated with Tufts Medical Center.”

Saul N. Weingart, MD, PhD

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“I look forward to working with Tufts’ extraordinary staff to continue the organization’s rich tradition of superb patient care, research, and education,” said Dr. Weingart. While at Dana Farber, Dr. Weingart led a series of quality and safety initiatives that had significant impact on the organization. He implemented infection control enhancements, including universal influenza vaccinations for staff - improving compliance from 58% to 100% in 4 years. Dr. Weingart earned his his PhD degree from Harvard, and his MD degree from the University of Rochester. At Dana-Farber, he has continued an active clinical practice in internal medicine and the care of adult survivors of pediatric cancers. He will also see patients with Tufts Medical Center’s General Medical Associates. Dr. Weingart is nationally recognized for his efforts in patient safety. He recently received the John Eisenberg Award for Patient Safety and Quality, one of the highest quality awards in the country, from the National Quality Forum and The Joint Commission. n

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In Memoriam

Emil ‘Tom’ Frei III, MD, Trailblazer in the Development of Combination Chemotherapy, Dies at 89

Source: NCI; Dana Farber Cancer Institute

By Ronald Piana

Emil Frei III, MD

he pages of medical history are dog-eared with breakthroughs that have transformed medicine and saved lives. One of those dog-eared pages belongs to Emil Frei III, MD, known to his colleagues and friends as Tom. In the dawn of oncology, Dr. Frei, along with his associate, Emil Freireich, MD, did something new in the treatment of cancer—they combined chemotherapies, a transcendent therapeutic approach that accelerated the field and, in turn, saved millions of lives. Dr. Frei died on April 30 at the age of 89. Emil Frei III was born in St. Louis in 1924 into a free-spirited artistic family. He seemed destined for a life in the arts, but in his early teens, his interests turned toward science, which later seeded his passion to find a cure for cancer. In 1942, he entered St. Louis University as a premed student. A year later, at the onset of World War II, he was drafted into the Navy V-12 college training program. He would attend Colgate University and later, in 1948,

graduate from Yale with an MD. After that, he began his internship at the St. Louis University Hospital. Having been in the V-12 program, Dr. Frei was obligated for active duty, if it became necessary at a later date. “So when Truman sent the troops into Korea, I got a telegram fairly shortly after that. I was in the service for 2 years, 15 months of which were in the Far East and the Korean theater,” said Dr. Frei, during a National Cancer Institute (NCI) Oral History Interview. After the Korean War, Dr. Frei returned to the St. Louis to finish his residency. One of the professors he conducted research under, Gordon

Adventurous Researchers Backed by a robust Federal government, the NCI was the right place to be for adventurous researchers. Drs. Frei and Freireich had everything they needed: a new clinic, lots of empty beds, a vast laboratory, and the enthusiastic support of the Institute’s Director, Dr. Zubrod. The two researchers decided to focus their clinical activities on acute lymphocytic leukemia (ALL) in children. Asked why they chose leukemia, Dr. Frei said, “There were several reasons. One is that Dr. Jim Holland, who had been there before us, started the program in leukemia, so we inherited his patients, if you will.”

His work helped bring about the first complete cures for pediatric leukemia patients and led to more effective treatments for adult malignancies ranging from breast cancer to bone cancer. Zubrod, MD, would have a careerchanging influence on him. “Dr. Zubrod took a position as the Clinical Director of the NCI and he asked me to join him, which I did in April 1955,” said Dr. Frei. Soon after arriving at NCI, Dr. Frei met Emil Freireich, MD. Although polar opposites in countenance—Dr. Frei was reserved, cool, contemplative, to Freireich’s intellectual flamboyance—the “two Emils” would become the closest of associates.

Working on limited scientific “leads” in ALL, Drs. Frei and Freireich attempted to sort out the “chaos in the field” at the time, which was largely a compilation of anecdotes; prospective experimental designs were lacking. At the time, there were two agents—6-mercaptopurine and methotrexate—that showed activity in ALL. At the insistence of Dr. Zubrod, the two young researchers wrote protocols and defined what complete response was in advance, thus defining how to proceed tactically. It was a watershed event in experi-

 In Memoriam

Emil ‘Tom’ Frei III, MD 1924 – 2013 

mental trial design; however, not without controversy. Dr. Frei explained, “It was controversial because it was felt that we were making patients fit a protocol, whereas you should instead fit the protocol to the patient. It sounds like a compelling argument, but if you don’t really know what you’re doing, you need to have a prospective protocol that asks a question and gets an answer.”

Paradigm Shift in Therapeutics Within a year, Dr. Frei was named Chief of NCI’s Leukemia Section and later, Chief of Medicine. Frustrated by the short-term remissions achieved in ALL that they were seeing with singledrug therapies, Drs. Frei, Freireich, and Holland began testing combinations of two or more agents to attack the various aspects of leukemia cells’ growth. Testing ideas through controlled experimentation requires a thirst for innovation and change, often in the face of a stubborn status quo. Dr. Frei and his colleagues persevered, marshaling in a paradigm shift in oncology therapeutics: combination chemotherapy. The team also worked on the difficult problem of chemotherapy-related bleeding by demonstrating that the infusion of platelets would allow larger, more effective doses of chemotherapy to be delivered safely. In 1965, Dr. Frei moved to The University of Texas MD Anderson Cancer Center in Houston, where he served as Associate Director of Clinical Research and Chair of the Department of continued on page 170

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The ASCO Post | MAY 15, 2013

In Memoriam

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Emil ‘Tom’ Frei III, MD continued from page 169

Experimental Therapeutics. He joined Dana-Farber Cancer Institute in 1972, serving as Physician-in-Chief, succeeding the Institute’s founder, Sidney Farber, MD, who died later that same year. Just 1 year later, Dr. Frei was named Dana-Farber’s Director and Professor of Medicine at Harvard Medical School.

Other Pioneering Work With Dana-Farber colleagues, Arthur Skarin, MD, and George Canellos, MD, Dr. Frei developed a treatment for adults with non-Hodgkin lymphoma, which was one of the first regimens to produce substantial cure rates in the disease. In the 1970s, Dr. Frei’s work helped develop combination therapies that increased survival in breast cancer. During that time, he also participated in pioneering work in the use of bone marrow transplants for a variety of cancers. It is worth noting that under his confident and meticulous stewardship, Dana-Farber became one of the world’s top-rated cancer centers. In tribute, Dana-Farber President Edward J. Benz, Jr, MD, said, “This approach has led to cures in many patients with cancer. The majority of patients with certain forms of childhood leukemia, Hodgkin disease, testicular cancer, and some other cancers can now expect to live long, high-quality lives because of his contributions.” Dr. Frei published more than 500

papers in scientific and professional journals and was the recipient of numerous awards and honors. In 1972, he was awarded the Albert Lasker Medical Research Award in recognition of his scientific contributions.

Patients Mattered Most Even still, in a career as lush with accomplishments, awards, positions, and publications as Dr. Frei’s, it was his patients that mattered most. His work helped bring about the first complete cures for pediatric leukemia patients and led to more effective treatments for adult malignancies ranging from breast cancer to bone cancer. In his early days working in childhood leukemia, when the outcomes were still grim, he remarked, “Children are a challenge, and also a joy to work with.” That he found joy in caring for desperately ill children is what his colleagues, friends, and patients will best remember him for. On Monday, February 12, 2007 Senator Dean Heller from Nevada stood on the floor of the U.S. Senate and said, “Madam Speaker, I rise today to pay tribute to Dr. Emil Frei III, a pioneer in cancer treatment, one of the world’s foremost oncologists, and a leader in medical education … His exceptional career deserves the highest commendation and praise.” The oncology community also rises in tribute. Hear, hear, Dr. Frei. n

Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. Avastin in combination with fluoropyrimidine‑irinotecan or fluoropyrimidine‑ oxaliplatin based chemotherapy is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

Chicago–The 2013 ASCO Annual Meeting is being held May 31 to June 4 at McCormick Place. Watch future issues of The ASCO Post for comprehensive coverage of the meeting.

5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.

T:10.25" S:9.5" AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

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

(approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

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

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

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

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

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

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

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

20%

26%

39% 10% 15% 2%

47% 35% 26% 9%

26% 1%

32% 6%

19% 40% 32% 25% 6% 6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

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

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥65 years (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab

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

S:12.5"

Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). [See Warnings and Precautions (5.8).]

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

T:13" S:12.5"

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

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

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

To confront a common threat across approved indications...

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

Because anti-angiogenesis matters Avastin is designed to directly inhibit the VEGF ligand to specifically inhibit angiogenesis1*

VEGF=vascular endothelial growth factor. *The mechanism of action of Avastin has been elucidated primarily in preclinical models. Its clinical significance is unknown.

Indications

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. 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. Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events 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 were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection In GBM patients receiving Avastin alone or Avastin plus irinotecan,† the incidences of Avastinrelated adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

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

AVA0000488402

Printed in USA.

(01/13)

Avastin is not approved for use in combination with irinotecan.

†

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. Reference: 1. Avastin Prescribing Information. Genentech, Inc. November 2012.