TAP Vol 5 Issue 19

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

CancerLinQ: Building a Data Infrastructure to Improve Quality and Reduce CostBy Ronald Piana

In November 2013, ASCO initiated the develop-ment of CancerLinQ, a learning health system

designed to transform cancer care and improve out-comes. At this year’s Quality Care Symposium in Boston, ASCO President Peter Paul Yu, MD, FACP, FASCO, Director of Cancer Research at the Palo Alto Medical Foundation, highlighted the work that has been done on the project and outlined future plans.

“So far at the meeting, we’ve heard a lot about

different data repositories on the national, state, fed-eral, and hospital levels. They all represent different collection sources in our data ecosystem. However, CancerLinQ represents the data collected from elec-tronic health records in practitioners’ offices,” said Dr. Yu. He added that the CancerLinQ data “are vitally important because we practitioners are the main in-terface between patients and the health-care system, and the information in our health records constitutes

the foundational data that other data sources are de-rived from.”

He explained that al-though CancerLinQ endeavors to provide a mechanism to aggregate massive amounts of data from electronic health records across the coun-

Chemotherapy Foundation Symposium

This year’s European Society for Medical Oncology (ESMO) meeting held in Ma-

drid was attended by 19,000 delegates, and it was encouraging to see among that number so many young oncologists being given time off for education and discussion. There has never before been a time when so much new informa-tion has become available so rapidly, showing positive results in many common cancers, and where science is driving the agenda. Keeping abreast of all this information is hard enough for all of us, but there are special challenges for less experienced oncologists or those in train-ing. One example of this is the issue of knowing when to stop active anticancer treatment—that

When Should We Stop Prescribing?

By John F. Smyth, MD

Oncology Meetings CoverageChemotherapy Foundation ��3–9Thoracic Oncology Symposium ��11–12Quality Care Symposium ��15, 19–25AACR Conference ��30Palliative Care in Oncology ��85Best of ASCO �� 90

Maha Hussain, MD, FACP, FASCO, on Metastatic Prostate Cancer ��49Direct From ASCO �� 57–60Robert S. Miller, MD, FACP, FASCO, on Quality of Care ��61Tracy Batchelor, MD, on Treating Brain Cancer in 2014 ��70

MORE IN THIS ISSUE

continued on page 15

Quality Care Symposium

Optimizing HER2 Therapy in Early and Advanced Breast Cancers By Alice Goodman

T rastuzumab (Herceptin) has been the corner-stone of therapy for HER2-positive tumors,

which comprise about 20% of all breast tumors. Ad-ditional therapies targeted to other HER2 pathways or other targets to be used in combination with trastu-zumab are being explored in both the adjuvant and metastatic settings. At the 2014 Chemotherapy Foun-dation Symposium, experts reviewed new approaches to HER2-positive breast cancer in these settings.

Adjuvant TherapySeveral drugs are now approved or under in-

tensive study for adjuvant therapy of HER2-positive breast cancer: trastuzumab, pertuzumab (Perjeta), ado-trastuzumab emtansine (formerly known as T-DM1 [Kadcyla]), lapatinib (Tykerb), and the investigational tyrosine kinase inhibitor neratinib. These treatments act differently, explained José Baselga, MD, Physician-in-Chief at Memorial Sloan Kettering Cancer Center

and President-Elect of the American Association for Cancer Research.1

“Trastuzumab has aged extremely well,” Dr. Baselga told the audience. Overall survival and disease-free survival benefits of trastu-zumab are well established in the adjuvant setting. It has also been established that 2 years of trastuzumab is not better than 1 year, and 1 year should be the stan-dard of care at present. “But we are not sure that 12 months is a magic number,” Dr. Baselga noted.

The CLEOPATRA trial showed that dual blockade of HER2 with docetaxel and pertuzumab plus trastu-zumab achieved an overall survival improvement of 16 months compared with docetaxel and trastuzumab in

José Baselga, MD

CAR T-Cell Therapy 32 | Focused Ultrasound 53 | Hazards of Overscreening 128 | Letters to the Editor 139 VOLUME 5, ISSUE 19DECEMBER 1, 2014

continued on page 5


Our pilot program shows that such a learning health system will work. Based on our platform development work this year, we plan to debut a functioning CancerLinQ system in 2015.

—Peter Paul Yu, MD, FACP, FASCO

Dr. Smyth is Emeritus Professor of Medical Oncol-ogy, University of Edinburgh, United Kingdom.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

A Harborside Press® PublicationVisit The ASCO Post at ASH booth 741 and SABCS T1

The ASCO Post | DECEMBER 1, 2014

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 appropri-ate 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 (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 [email protected]. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email [email protected] or fax (631) 692-0805.

Copyright ©2014 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

hibited. For permission inquiries, contact [email protected].

Editorial Mission: The ASCO Post communicates timely in-formation to a broad audience of oncology specialists, help-ing 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 ap-proximately 27,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and he-matologist/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: $271;

Canada: $397; Individual International: $523; Institutional Domestic: $335; Canada: $461; Institutional International: $587. Single Copy Domestic: $52; Canada: $59; Interna-tional: $65. Contact [email protected].

Correspondence: Address general inquiries to Harbor-side 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, Edi-tor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: [email protected].

Advertising: For information on advertising rates, re-prints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: [email protected].

Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language ap-pears 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 li-ability for all content (including text, representations, il-lustrations, opinions, and facts) of advertisements print-ed, 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, in-surrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation inter-ruption of any kind, work slow-down, or any condition be-yond the control of the publisher affecting production or delivery in any manner.

James O. Armitage, MD Editor-in-Chief

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Associate EditorsJame Abraham, MD Cleveland Clinic

Manmeet Ahluwalia, MD, FACP Cleveland Clinic

Joseph S. Bailes, MD Texas Oncology

Laurence H. Baker, DO University of Michigan Health System

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

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

E. David Crawford, MD University of Colorado

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

George D. Demetri, MD Dana-Farber Cancer Institute

Paul F. Engstrom, MD Fox Chase Cancer Center

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

Bishoy Morris Faltas, MD Weill Cornell Medical College

John A. Fracchia, MD New York Urological Associates

Alison Freifeld, MD University of Nebraska Medical Center

Louis B. Harrison, MD Moffitt Cancer Center

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Clifford A. Hudis, MD, FACP Memorial Sloan Kettering Cancer Center

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Hagop M. Kantarjian, MD MD Anderson Cancer Center

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

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

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

Michael P. Link, MD Stanford University Medical Center

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

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

William T. McGivney, PhD Philadelphia, Pennsylvania

James L. Mulshine, MD Rush University Medical Center

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

Steven T. Rosen, MD City of Hope National Medical Center

Lee S. Schwartzberg, MD University of Tennessee Health Science Center

Andrew D. Seidman, MD Memorial Sloan Kettering Cancer Center

Samuel Silver, MD, PhD University of Michigan Health System

George W. Sledge, MD Indiana University

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

Jamie Von Roenn, MD American Society of Clinical Oncology

Lynn D. Wilson, MD Yale University School of Medicine

Stanley H. Winokur, MD Singer Island, Florida

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

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

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

Nagi El-Saghir, MD American University of Beirut, Lebanon

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Jacek Jassem, MD Medical University of Gdansk, Poland

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

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

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

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

John F. Smyth, MD University of Edinburgh Edinburgh, Scotland

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

Harborside Press® Publishing Staff

Conor Lynch, Executive Editor [email protected]

Cara H. Glynn, Director of Editorial [email protected]

Andrew Nash, Associate Director of Editorial [email protected]

Jo Cavallo, Senior Editor and Correspondent [email protected]

Susan Reckling, Senior Editor [email protected]

Sarah McGullam, Web Editor [email protected]

Michael Buckley, Art Director [email protected]

Terri Caivano, Layout Artist [email protected]

Gail Van Koot, Editorial Coordinator [email protected]

Norman Virtue, Production Manager [email protected]

Shannon Meserve, Circulation Manager [email protected]

Frank Buchner, Chief Technology Officer [email protected]

Leslie Dubin, Vice-President, Director of Sales [email protected]

Anthony Cutrone, President [email protected]

John A. Gentile, Jr, Chairman [email protected]

Contributing Writers:Charlotte Bath, Margot Fromer, 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.

Editorial Board

ASCOPost.com | DECEMBER 1, 2014 PAGE 3


New Agents and Novel Targets for Multiple Myeloma By Alice Goodman

New therapies for multiple my-eloma have dramatically im-

proved life expectancy, but despite these advances, 5-year overall survival still remains below 50%. Investigators are in hot pursuit of new therapies that will extend remissions and im-prove survival. Thus far, monoclonal antibodies, immunotherapy, histone deacetylase inhibitors, and the new proteasome inhibitor ixazomib show promise.

“There is still room for improve-ment. Multiple myeloma is treatable but not necessarily considered curable. Monoclonal antibodies are likely to play a key role in progress in treating the disease, and immunotherapy may be a key for refractory myeloma with high-risk genetics. There are a number of new targets and agents in the pipe-

line, and this is where personalized medicine may play a role,” said Sundar Jagannath, MD, Icahn School of Medi-cine at Mt. Sinai, New York. At the re-cent 2014 Chemotherapy Foundation Symposium, Dr. Jagannath updated listeners about promising new drugs for multiple myeloma.1

Ultimately, all patients become re-fractory to current treatments, he con-tinued, attributing this mainly to the genetic complexity of the disease.

“At diagnosis, five different clones have been identified. With treatment, different clones emerge over time. There is selection of mutations, and this tells us that combination therapy is better than single-agent therapy,” Dr. Jagannath said.

“Right now in multiple myeloma, there is no molecularly targeted thera-py. This is an area where progress has to be made,” he stated.

For a treatment to be considered an advance, it would have to boost com-plete and partial remission and achieve molecularly defined remission. Ide-ally, new agents should be well tolerated without causing cytopenias and dem-

onstrate value across multiple lines of therapy.

“Multiple myeloma has many dif-ferent treatment options and the path patients follow is different depending on response. A new therapy would need to show efficacy across different lines of therapy,” he told listeners.

About 15% to 29% of patients with multiple myeloma die within 3 years, even with novel agents. “For these high-risk groups, we want drugs that are ge-nome neutral. This leads us to mono-clonal antibodies,” he said.

Promising ApproachesThree monoclonal antibodies show

promise in multiple myeloma: daratu-mumab, SAR650984, and an older drug called elotuzumab. All three drugs im-prove response rates as single agents in

multiple myeloma and show encourag-ing activity when combined with stan-dard drugs used in multiple myeloma, such as lenalidomide (Revlimid) and dexamethasone.

Based on the success of rituximab (Rituxan) in lymphoma and the fact that CD38 is highly expressed in mul-tiple myeloma cells, developing an anti-CD38 monoclonal antibody is an active area of study in multiple myeloma. Da-ratumumab and SAR650984 are both anti-CD38 monoclonal antibodies in phase III testing, he continued.

Daratumumab as a single agent achieved excellent response rates in re-lapsed multiple myeloma.2 Responses were more robust when daratumumab is combined with lenalidomide/dexa-

methasone, Dr. Jagannath explained. In one phase II study, the combination of daratumumab plus lenalidomide/dexa-methasone achieved responses in 15 of 20 patients.3

SAR650984 as a single agent achieved a 33% response rate in patients with relapsed/refractory multiple my-eloma, similar to that seen with daratu-mumab. In a small study of 31 patients with relapsed/refractory multiple my-eloma, overall benefit for the combina-tion of SAR650984 plus lenalidomide/dexamethasone was 65%, overall re-sponse rate was 58%, very good partial response was 23%, and partial response was 35%.4

“Anti-CD38 monoclonal antibodies are very exciting. They currently have breakthrough designation from the U.S. Food and Drug Administration [FDA]. We hope to have these drugs available sooner rather than later,” Dr. Jagannath stated.

“Elotuzumab is another monoclo-nal antibody that has been around for a while, but the newer drugs stole its thunder,” he continued.

This drug targets SLAMF7, which is highly expressed in multiple myeloma cells and natural killer cells. This en-ables targeting multiple myeloma cells via natural killer cell–mediated mecha-nisms, Dr. Jagannath explained.

In phase II studies, elotuzumab did not have impressive single-agent activ-ity, but dramatic responses were seen in the phase II ELOQUENT-2 trial, when elotuzumab was combined with lenalidomide/dexamethasone. The me-dian duration of response was 11 to 15 months.5

“Immunotherapy is an area of in-tense interest in all of oncology, and this may be where future progress lies,” he continued. Checkpoint inhibitors, chimeric antigen receptor T cells, and approaches to stimulating innate im-munity may hold promise in multiple myeloma.

Panobinostat, a pan histone deacety-lase inhibitor, has showed promising

results with a 4-month improvement in progression-free survival when combined with bortezomib (Velcade)/dexametha-sone vs bortezomib/dexamethasone alone: median of 12 months progression-free survival vs 8.1 months, respectively.6 Subgroup analysis of progression-free sur-vival revealed a strong benefit in poor-risk patients. [Editor’s note: During the 2014 Chemotherapy Foundation Symposium meeting, the FDA’s Oncology Drug Ad-visory Committee recommended against the approval of panobinostat based on results of the PANORAMA-1 trial. FDA is not obligated to follow the committee’s vote, but it generally does.]

The histone deacetylase inhibitor 6 inhibitor ACY-1215 showed encour-aging activity alone and in combina-tion with bortezomib in patients with relapsed/refractory multiple myeloa, he said. In these heavily pretreated pa-tients, the response rate was 25%, and the clinical benefit rate was 60%. Re-sponses were seen in bortezomib-re-fractory patients.7

Other TargetsOther targets in the pipeline include

kinesin spindle protein inhibitors (ie, filanesib); AKT inhibitors (ie, afure-sertib); CDK inhibitors (ie, dinaciclib); nuclear transport inhibitors; PI3K in-hibitors; Bruton’s tyrosine kinase in-hibitors; and BCL2 inhibitors.

“Dr. Jagannath has given us an ex-cellent educational session about what to expect in the future for treatment of multiple myeloma,” said Kanti Rai, MD, session moderator. n

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

References1. Jagannath S: New drugs in multiple

myeloma. 2014 Chemotherapy Founda-tion Symposium. Presented November 5, 2014.

2. Lokhorst HM, Laubach J, Nahi H, et al: Dose-dependent efficacy of daratumum-ab as monotherapy in patients with relapsed or refractory multiple myeloma. 2014 ASCO Annual Meeting. Abstract 8513.

3. Plesner T, Arkenau H-T, Lokhorst HM, et al: Safety and efficacy of daratu-mumab with lenalidomide and dexameth-asone in relapsed or relapsed, refractory multiple myeloma. 2014 ASCO Annual Meeting. Abstract 8533.

4. Martin TG, Hsu K, Charpentier E, et al: A phase 1b dose escalation trial of

Hematology

Right now in multiple myeloma, there is no molecularly targeted therapy. This is an area where progress has to be made.

—Sundar Jagannath, MD

New Therapies for Multiple Myeloma

■ Almost all patients with multiple myeloma ultimately become refractory to treatment, and new approaches are needed.

■ Newer therapies will need to be used in combination, due to the genetic heterogeneity of multiple myeloma.

■ Monoclonal antibodies, immunotherapy, and histone deacetylase inhibitors (HDAC1) are among the most promising strategies.

continued on page 4



SAR650984 (Anti-CD38 mAb) in com-bination with lenalidomide and dexa-methasone in relapsed/refractory multiple myeloma. 2014 ASCO Annual Meeting. Abstract 8512.

5. Richardson PG, Jagannath S, Moreau P, et al: A phase 2 study of elotu-zumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myelo-ma: Updated results. 2012 ASH Annual Meeting. Abstract 202.

6. Richardson PG, Hungria VTM, Yoon S-S, et al: Panorama 1: A random-ized, double-blind phase 3 study of pano-binostat or placebo plus bortezomib and dexamethasone in relapsed or relapsed and refractory multiple myeloma. 2014 ASCO Annual Meeting. Abstract 8510.

7. Raje N, Vogl DT, Parameswaran NH, et al: ACY-1215, a selective his-tone deacetylase (HDAC) 6 inhibitor: Interim results of combination therapy with bortezomib in patients with multiple myeloma. 2013 ASH Annual Meeting. Abstract 759.

Multiple Myelomacontinued from page 3

Hormonal Therapy for Early Breast Cancer: Do We Learn From Past Mistakes? By Alice Goodman

Guidelines can be incorrect if they are not based on incontrovertible

evidence. Such was the case with the National Cancer Institute (NCI) 1995 guidelines recommending 5 years of tamoxifen adjuvant therapy for stage I to III hormone receptor–positive breast cancer. With more definitive evidence, ASCO issued 2014 guidelines recom-mending 10 years of tamoxifen as the new standard.

In 2015, new guidelines on aro-matase inhibitors and gonadotropin-releasing hormone agonists are ex-pected, and these guidelines could fall into a similar trap as the NCI 1995 guidelines for tamoxifen, according to Norman Wolmark, MD, Chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP) and Profes-sor and Chairman of Human Oncology at the Drexel University School of Medi-cine, Philadelphia.

He stated that the new guidelines should incorporate genomic profiling; otherwise they will miss the mark.

“Hormonal management of adju-vant therapy of breast cancer justifies a reprise. Are we destined to learn from the mistakes of the past, or are we going to repeat them?” was the challenge Dr.

Wolmark issued in his Keynote Address at the 2014 Chemotherapy Foundation Symposium.1

Mistakes of the PastThe 1995 NCI guidelines for adju-

vant tamoxifen, distributed to every on-cologist at every U.S. hospital, were based on results of a 7-year interim analysis of

the NSABP 14 protocol, which evalu-ated the use of adjuvant tamoxifen for 5 years vs 10 years for breast cancer. At 7 years, 5 years looked like it was superior, but this analysis failed to account for the rebound effect that continues after stop-ping tamoxifen. The study was stopped because it crossed futility limits.

“What a mistake!” he exclaimed. “This set us back a decade.”

More recently, data from the AT-

LAS and aTTOM trials showed a 4% incremental benefit for 10 years of tamoxifen compared with 5 years (hazard ratio = 0.80).2,3

“The ATLAS and aTTOM trials were unencumbered by interim analy-ses—they plotted on and went forward. This refuted the NSABP 5-year gold

standard,” he stated. The new ASCO guidelines recommend 10 years of total tamoxifen therapy.

Dr. Wolmark suggested that the new guidelines may be “authoritarian,” and there may be cohorts for whom 10 years of hormonal therapy is not desirable. Per-haps these cohorts could be identified by genomic signatures such as Oncotype DX

that determine which patients are at risk for early or late tumor recurrence.

Resurgence of Luteinizing Hormone-Releasing Hormone Agonists

“New data that have emerged in the past 2 years exacerbate the dilemma of how to address the enigma of the ovary. Some of these therapeutic strategies are competing and mutually exclusive,” Dr.

Wolmark told listeners. “We may be de-luding ourselves if we have conflicting data and think that we will find a Rosetta stone,” he said.

Several trials suggest that gonado-tropin-releasing hormone agonist ana-logs and luteinizing hormone-releasing hormone analogs can reduce the risk of tumor recurrence in premenopausal women with hormone receptor–positive breast cancer.

“These agents are making a come-back in premenopausal women. They have been tried before. It’s like being on a roller coaster,” Dr. Wolmark said. “2014 is the year of resurgence of luteinizing hormone-releasing hormone agonists.”

Data are conflicting about whether tamoxifen plus ovarian function suppres-sion (ie, with gonadotropin-releasing hormone agonist or luteinizing hormone-releasing hormone agonists) or aromatase inhibitor plus ovarian function suppres-sion has a greater effect on reducing tumor recurrence in premenopausal women.

Updated results of a joint analysis of the TEXT and SOFT salvage trials should provide further evidence of this question. These results will be presented at the 2014 San Antonio Breast Cancer

Symposium. A previous joint analysis fa-vored ovarian function suppression plus exemestane over tamoxifen plus ovarian function suppression, with a 5% absolute difference in disease-free survival at 5.7 years of follow-up.4

“Are we going to think this is a home run? I’m not holding my breath,” he said.

Hypothetically, the 2015 guidelines could state that premenopausal women should be offered an aromatase inhibitor with gonadotropin-releasing hormone agonist for 5 years. He questions this, as well as the duration of therapy beyond 5 years whether they remain premeno-pausal or become postmenopausal.

He suggested there may be premeno-pausal cohorts who can benefit from 5 vs 10 years of this type of therapy. Addition-al trials will show the optimal duration of aromatase inhibitors (NSABP-42) and disease-free survival with ovarian func-tion suppression (MA17R).

“Strap yourselves into that roller coaster,” he said.

Take-Home Message“The take-home message is that if

the data are definitive and incontrovert-ible, go ahead and formulate guidelines. On the other hand, we are in the era of genomic profiling. Do the guidelines apply to every patient, in this age of mo-lecular genomics? If the guidelines don’t take into account genomic profiling, you may miss the mark. You can run the risk of paying an enormous price and setting back the field by at least a decade,” Dr. Wolmark stated. n

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

References1. Wolmark N: 2014 Chemotherapy

Foundation Symposium. Presented Novem-ber 5, 2014.

2. Davies C, et al: Lancet 381:805-816, 2013.

3. Gray RG, et al: 2013 ASCO Annual Meeting. Abstract 5.

4. Pagani O, et al: 2014 ASCO Annual Meeting. Abstract LBA1.

Breast Cancer

If the guidelines don’t take into account genomic profiling, you may miss the mark. You can run the risk of paying an enormous price and setting back the field by at least a decade.

— Norman Wolmark, MD

Update on Hormonal Therapy for Early Breast Cancer

■ The 1995 guidelines recommending 5 years of tamoxifen adjuvant therapy for hormone receptor–positive early breast cancer were based on flawed evidence from an interim analysis.

■ Based on results of the ATLAS and aTTOM trials, the new standard of care is 10 years of tamoxifen in that setting.

■ The upcoming 2015 guidelines for hormonal therapy could fall into the same trap as the 1995 guidelines. To avoid this, they should be based on incontrovertible evidence and incorporate genomic profiling.

©AS

CO/Z

ach

Boyd

en-H

olm

es



metastatic HER2-positive breast cancer.2

“This represents great progress, and now there are studies of trastuzumab/pertuzumab in the adjuvant setting,” he said. They included the phase II NEO-SPHERE trial, which showed a dou-bling of pathologic complete response

rate with the combination of pertu-zumab/trastuzumab plus docetaxel compared with trastuzumab/docetaxel (39.3% vs 21.5%).3

The randomized, double-blind, pla-cebo-controlled, two-arm APHINITY trial is evaluating adjuvant pertuzumab plus chemotherapy plus trastuzumab vs chemotherapy with trastuzumab plus placebo for 1 year after surgery.4

Neoadjuvant trastuzumab/lapatinib has been studied in four trials, and all of them have shown an advantage for the combination, he continued. However, in the large ALTTO trial, the combina-tion failed to improve disease-free sur-vival in the adjuvant setting, which was disappointing, he added.5

Another approach—sequential ther-apy with 1 year of trastuzumab followed by 1 year of neratinib—appears to be effective in the extended adjuvant set-ting, according to preliminary data from the ExteNET study showing improved disease-free survival.6 “We look forward to hearing more about this sequential therapy,” Dr. Baselga said.

Moving on, he noted, “There is tremen-dous excitement about [ado-trastuzumab emtansine] in the adjuvant setting.”

The phase II KATHERINE study is comparing 14 cycles of adjuvant ado-

trastuzumab emtansine vs 14 cycles of trastuzumab, and 50% of planned enrollment is completed. The primary endpoint is disease-free survival.7

KAITLIN, the phase III registration trial for ado-trastuzumab emtansine, will randomize patients (after surgery and anthracycline-based chemotherapy) to ado-trastuzumab emtansine vs taxane/

trastuzumab.8 The study is designed to determine how much chemotherapy is needed, Dr. Baselga said.

Advanced HER2-Positive Breast Cancer

Kimberly Blackwell, MD, Duke Cancer Institute, Durham, North Caro-lina, brought attendees up to date on targeting HER2-positive advanced breast cancer for first-line treatment (de novo or metastatic tumor recurrence) and beyond the first-line setting.9

“The introduction of trastuzumab is one of the most important breakthroughs in the treatment of breast cancer with its improvement in overall survival. This survival bar has now been raised to over 15 months with the combination of per-tuzumab plus trastuzu mab,” she said.

“One important study showed us what not to do for first-line metastatic breast cancer,” she continued. The MA-31 trial compared lapatinib/taxane followed by lapatinib vs trastuzumab/taxane followed by trastuzumab in 600 patients and found a progression-free survival detriment for lapatinib/taxane at the interim analysis.10 Moreover, the combination was associ-ated with increased febrile neutropenia and grade 3 or higher diarrhea.

“We need to remember these data [ie,

negative findings for lapatinib/taxane] in clinical decision-making when lining up our therapeutic options for women facing this disease,” she emphasized.

Another very important study, CLEOPATRA,2 showed the power of adding a second antibody to trastuzu mab as first-line treatment in the metastatic setting [see above]. Final results showed improved progression-free and overall survival with pertuzumab/ trastuzumab.

“CLEOPATRA showed that it is important to first give six cycles of docetaxel [with antibody],” she said. “Getting the chemotherapy out of the way allows the targeted agents to work in this scenario without the chemother-apy toxicity.”

“With limited toxicity, pertuzumab/trastuzumab has become the preferred treatment regimen in patients diag-nosed with de novo advanced or recur-

rent HER2-positive breast cancer,” Dr. Blackwell stated.

Second- and Third-Line OptionsOnce patients progress on this regi-

men, therapeutic options include ado-trastuzumab emtansine and lapatinib.

In the EMILIA trial, ado-trastuzum-ab emtansine offered significantly supe-rior survival compared with lapatinib/capecitabine in the second- and third-line settings (P < .001), with a favor-able toxicity profile.11 When EMILIA was designed, the standard of care was lapatinib/capecitabine, Dr. Blackwell explained. Ado-trastuzumab emtansine achieved a median overall survival of 30.9 months vs 25.1 months with lapa-tinib/capecitabine (P = .0007).

“This survival benefit is similar to what we saw initially with trastuzumab. This study, plus CLEOPATRA, show how far we have come,” she stated.

Ado-trastuzumab emtansine has dif-ferent toxicities than chemotherapy, she said, mainly elevated liver enzymes and grade 3 and 4 cytopenias.

Based on the TH3RESA trial, ado-trastuzumab emtansine is a reasonable choice for third-line therapy and be-

yond.12 In this study, patients with at least two prior lines of HER2-directed therapy were randomized to receive ado-trastu-zumab emtansine or physician’s choice of chemotherapy. Ado-trastuzumab emtan-sine produced a 2.7-month advantage in progression-free survival, and overall sur-vival has not yet been reached.

A phase III study provided additional support for dual HER2 blockade, this time with lapatinib/trastuzumab vs lapa-tinib alone, showing that patients with HER2-driven metastatic breast cancer derived a survival benefit from HER2 combination therapy.13 The median over-all survival was 51 weeks for the combina-tion vs 39 months for lapatinib alone.

“Choice of third-line therapy should be based on patient characteristics and toxicity,” Dr. Blackwell said.

“Several ongoing trials will tell us about new options once trastuzumab,

pertuzumab, [ado-trastuzumab emtan-sine], and lapatinib have been optimally utilized. Promising approaches include mTOR inhibitors [everolimus (Afini-tor), the MARIANNE, BOLERO 1, and BOLERO 3 trials], and PI3 kinase inhibitors,” she said. n

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

References1. Baselga J: Adjuvant therapy for

HER2-positive breast cancer. 2014 Chemo-therapy Foundation Symposium. Presented November 6, 2014.

2. Swain SM, Kim SB, Cortés J, et al: Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast can-cer (CLEOPATRA study): Overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 14:461-471, 2013.

3. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant per-tuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (neoSphere): A randomised, open-label, phase 2 trial. Lancet Oncol 13:25-32, 2012.

Breast Cancer

HER2 Therapycontinued from page 1

Trastuzumab has aged extremely well. But we are not sure that 12 months is a magic

number [for duration of therapy]. —José Baselga, MD

The introduction of trastuzumab is one of the most important breakthroughs in the treatment of breast cancer with its improvement in overall survival. This survival bar has now been raised to over 15 months with the combination of pertuzumab plus trastuzumab.

—Kimberly Blackwell, MD

Therapeutic Update on HER2-Positive Breast Cancer

■ Trastuzumab continues to be the cornerstone of treatment for HER2-positive breast cancer.

■ Dual HER2 blockade with pertuzumab and trastuzumab achieves improved survival in HER2-positive metastatic breast cancer.

■ In the adjuvant setting, new trastuzumab-based approaches are being explored.

■ Lapatinib/taxane should not be used in the first-line setting for metastatic breast cancer.

■ Ado-trastuzumab emtansine and lapatinib are second- and third-line options for metastatic breast cancer.

■ mTOR inhibitors and PI3K inhibitors are being explored in combination with HER2-directed therapy in the metastatic setting.

continued on page 8

Pro

bab

ility

of

Pro

gre

ssio

n-fr

ee S

urvi

val

Time of Progression-free Survival (Months)

ARZERRA plus Chlorambucil

Chlorambucil

Number at risk

ARZERRA + chlorambucil (n=221)Chlorambucil (n=226)

(HR 0.57 [95% CI: 0.45, 0.72] P<0.001)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

221 192 169 148 125 104 70 46 28 15 9 3 1

226 173 130 92 67 52 33 17 6 1 1

22.4Months

13.1Months

An Effective Combinationto Extend PFS*1

First-line Treatment for CLLARZERRA® (ofatumumab) is indicated, in combination with chlorambucil, for previously untreated patients with CLL for whom fl udarabine-based therapy is considered inappropriate

Please see Brief Summary of Prescribing Information, including Boxed Warning, for ARZERRA on the following pages.

* Assessed by a blinded Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute–sponsored Working Group (NCI-WG) guidelines (2008).

CLL=chronic lymphocytic leukemia; PFS=progression-free survival; AR=adverse reaction; IR=infusion reaction.

www.GSKSource.com

ARZERRA J-Code: J9302To learn more, please visit www.ARZERRAhcp.com.

IndicationsARZERRA® (ofatumumab) is indicated:• In combination with chlorambucil, for the treatment of previously

untreated patients with chronic lymphocytic leukemia (CLL) for whom fl udarabine-based therapy is considered inappropriate

• For the treatment of patients with CLL refractory to fl udarabine and alemtuzumab

Important Safety Information for ARZERRAWARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY• Hepatitis B Virus (HBV) reactivation can occur in

patients receiving CD20-directed cytolytic antibodies, including ARZERRA, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)].

• Progressive Multifocal Leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA [see Warnings and Precautions (5.4)].

Infusion ReactionsARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, fl ushing, hypertension, hypotension, syncope, cardiac events (eg, myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the fi rst 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment. Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication.Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment.

Hepatitis B Virus ReactivationHepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).HBV reactivation is defi ned as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, ie, increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insuffi cient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation. Hepatitis B Virus InfectionFatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis.

Important Safety Information for ARZERRA (cont’d)Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation.Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function.Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

ImmunizationsThe safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.Most Common Adverse ReactionsIn the previously untreated CLL clinical trial, the most common adverse reactions (≥10%, all grades) were infusion reactions (67% for ARZERRA plus chlorambucil vs 0% for chlorambucil) and neutropenia (27% vs 18%). In the single-arm refractory CLL clinical trial, the most common adverse reactions (≥10%, all grades) were neutropenia, pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation.Laboratory AbnormalitiesIn the previously untreated CLL clinical trial, post-baseline hematologic laboratory abnormalities (all grades) occurring with ≥5% incidence in patients receiving ARZERRA plus chlorambucil and also ≥2% more than patients receiving chlorambucil were leukopenia (67% for ARZERRA plus chlorambucil vs 28% for chlorambucil), neutropenia (66% vs 56%), and lymphopenia (52% vs 20%).

Reference: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GSK; 2014.

ARZERRA in combination with chlorambucil vs chlorambucil alone was studied in a randomized, open-label, parallel-arm, multicenter trial of 447 patients with previously untreated CLL for whom fl udarabine-based therapy was considered inappropriate. The population for safety analysis comprised 444 patients.1

HR=hazard ratio; CI=confi dence interval.

ARZERRA Plus Chlorambucil Demonstrated a Median PFS of 22.4 Months vs 13.1 Months With Chlorambucil Alone1

The Most Common ARs (≥10%) Were IRs and Neutropenia1

• 10% incidence of Grade ≥3 IRs; occurred most frequently during Cycle 1

— 6% on Day 1— 3% on Day 8

• 67% incidence of IRs (all grades), including Grade ≥3, serious, or those that led to interruption or discontinuation; majority were Grade 1-2 and decreased after Cycle 1

— 56% on Day 1— 23% on Day 8

• No patients in the chlorambucil-alone arm experienced IRs

• 3% of IRs led to discontinuation of ARZERRA

• 27% incidence of neutropenia with ARZERRA plus chlorambucil vs 18% with chlorambucil alone

©2014 GSK group of companies. All rights reserved. Printed in USA. AZA522R0 October 2014

Y25930ALT_127_King_v1.indd 1 10/17/14 10:58 AM

Pro

bab

ility

of

Pro

gre

ssio

n-fr

ee S

urvi

val

Time of Progression-free Survival (Months)

ARZERRA plus Chlorambucil

Chlorambucil

Number at risk

ARZERRA + chlorambucil (n=221)Chlorambucil (n=226)

(HR 0.57 [95% CI: 0.45, 0.72] P<0.001)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

221 192 169 148 125 104 70 46 28 15 9 3 1

226 173 130 92 67 52 33 17 6 1 1

22.4Months

13.1Months

An Effective Combinationto Extend PFS*1

First-line Treatment for CLLARZERRA® (ofatumumab) is indicated, in combination with chlorambucil, for previously untreated patients with CLL for whom fl udarabine-based therapy is considered inappropriate

Please see Brief Summary of Prescribing Information, including Boxed Warning, for ARZERRA on the following pages.

* Assessed by a blinded Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute–sponsored Working Group (NCI-WG) guidelines (2008).

CLL=chronic lymphocytic leukemia; PFS=progression-free survival; AR=adverse reaction; IR=infusion reaction.

www.GSKSource.com

ARZERRA J-Code: J9302To learn more, please visit www.ARZERRAhcp.com.

IndicationsARZERRA® (ofatumumab) is indicated:• In combination with chlorambucil, for the treatment of previously

untreated patients with chronic lymphocytic leukemia (CLL) for whom fl udarabine-based therapy is considered inappropriate

• For the treatment of patients with CLL refractory to fl udarabine and alemtuzumab

Important Safety Information for ARZERRAWARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY• Hepatitis B Virus (HBV) reactivation can occur in

patients receiving CD20-directed cytolytic antibodies, including ARZERRA, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)].


Infusion ReactionsARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, fl ushing, hypertension, hypotension, syncope, cardiac events (eg, myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the fi rst 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment. Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication.Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment.

Hepatitis B Virus ReactivationHepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).HBV reactivation is defi ned as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, ie, increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insuffi cient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation. Hepatitis B Virus InfectionFatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis.

Important Safety Information for ARZERRA (cont’d)Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation.Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function.Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

ImmunizationsThe safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.Most Common Adverse ReactionsIn the previously untreated CLL clinical trial, the most common adverse reactions (≥10%, all grades) were infusion reactions (67% for ARZERRA plus chlorambucil vs 0% for chlorambucil) and neutropenia (27% vs 18%). In the single-arm refractory CLL clinical trial, the most common adverse reactions (≥10%, all grades) were neutropenia, pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation.Laboratory AbnormalitiesIn the previously untreated CLL clinical trial, post-baseline hematologic laboratory abnormalities (all grades) occurring with ≥5% incidence in patients receiving ARZERRA plus chlorambucil and also ≥2% more than patients receiving chlorambucil were leukopenia (67% for ARZERRA plus chlorambucil vs 28% for chlorambucil), neutropenia (66% vs 56%), and lymphopenia (52% vs 20%).

Reference: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GSK; 2014.

ARZERRA in combination with chlorambucil vs chlorambucil alone was studied in a randomized, open-label, parallel-arm, multicenter trial of 447 patients with previously untreated CLL for whom fl udarabine-based therapy was considered inappropriate. The population for safety analysis comprised 444 patients.1

HR=hazard ratio; CI=confi dence interval.

ARZERRA Plus Chlorambucil Demonstrated a Median PFS of 22.4 Months vs 13.1 Months With Chlorambucil Alone1

The Most Common ARs (≥10%) Were IRs and Neutropenia1

• 10% incidence of Grade ≥3 IRs; occurred most frequently during Cycle 1

— 6% on Day 1— 3% on Day 8

• 67% incidence of IRs (all grades), including Grade ≥3, serious, or those that led to interruption or discontinuation; majority were Grade 1-2 and decreased after Cycle 1

— 56% on Day 1— 23% on Day 8

• No patients in the chlorambucil-alone arm experienced IRs

• 3% of IRs led to discontinuation of ARZERRA

• 27% incidence of neutropenia with ARZERRA plus chlorambucil vs 18% with chlorambucil alone

©2014 GSK group of companies. All rights reserved. Printed in USA. AZA522R0 October 2014


https://www.gsksource.com/gskprm/en/US/adirect/gskprm?cmd=ProductDetailPage&product_id=1271174787485&featureKey=601782



4. U.S. National Institutes of Health: A study of pertuzumab in addition to chemo-therapy and Herceptin (trastuzumab) as adjuvant therapy in patients with HER2-positive primary breast cancer. Available at ClinicalTrials.gov/show/NCT01358877. Accessed November 17, 2014.

5. Piccart-Gebhart MJ, Holmes MP, Baselga J, et al: First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone, trastuzumab alone, their sequence, or their combination in the adjuvant treatment of HER2-positive ear-ly breast cancer. 2014 ASCO Annual Meeting. Abstract LBA4. Presented June 1, 2014.

6. U.S. National Institutes of Health: Study evaluating the effects of neratinib after adjuvant trastuzumab in women with early stage breast cancer (ExteNET). Available at ClinicalTrials.gov/show/ NCT00878709. Accessed November 17, 2014.

7. U.S. National Institutes of Health: A study of trastuzumab emtansine versus trastuzumab as adjuvant therapy in pa-

tients with HER2-positive breast cancer who have residual tumor in the breast or axillary lymph nodes following preopera-tive therapy (KATHERINE). Available at ClinicalTrials.gov/show/ NCT01772472. Accessed November 17, 2014.

8. U.S. National Institutes of Health: A study of Kadcyla (trastuzumab emtansine) plus Perjeta (pertuzumab) following an-

HER2 Therapycontinued from page 5

BRIEF SUMMARY

ARZERRA® (ofatumumab) Injection, for intravenous infusion

The following is a brief summary only; see full prescribing information, including Boxed Warning, for complete product information.

WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY• Hepatitis B Virus (HBV) reactivation can occur in patients

receiving CD20-directed cytolytic antibodies, including ARZERRA®, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)].


1 INDICATIONS AND USAGE1.1 Previously Untreated Chronic Lymphocytic Leukemia ARZERRA (ofatumumab) is indicated, in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate [see Clinical Studies (14.1) of full prescribing information]. 1.2 Refractory CLL ARZERRA is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab [see Clinical Studies (14.2) of full prescribing information].

4 CONTRAINDICATIONSNone.

5 WARNINGS AND PRECAUTIONS5.1 Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (e.g., myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment [see Adverse Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing information]. Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3) of full prescribing information]. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment. 5.2 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receiving ARZERRA, immediately

discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation. 5.3 Hepatitis B Virus Infection Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis. 5.4 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function. 5.6 Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA [see Adverse Reactions (6.1)]. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. 5.7 Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the labeling:• Infusion Reactions [see Warnings and Precautions (5.1)]• Hepatitis B Virus Reactivation [see Warnings and Precautions (5.2)]• Hepatitis B Virus Infection [see Warnings and Precautions (5.3)]• Progressive Multifocal Leukoencephalopathy [see Warnings and

Precautions (5.4)]• Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]• Cytopenias [see Warnings and Precautions (5.6)]Previously Untreated CLL: The most common adverse reactions (≥10%) were infusion reactions and neutropenia (Table 1). Refractory CLL: The most common adverse reactions (≥10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections (Table 3). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation. 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Previously Untreated CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 1) in 444 patients with previously untreated CLL. Patients were randomized to receive either ARZERRA as an intravenous infusion every 28 days in combination with chlorambucil (n = 217) or chlorambucil as a single agent (n = 227). In both arms, patients received chlorambucil 10 mg/m2 orally on Days 1 to 7 every 28 days. The infusion schedule for ARZERRA was 300 mg administered on Cycle 1 Day 1, 1,000 mg administered on Cycle 1 Day 8, and 1,000 mg administered on Day 1 of subsequent 28-day cycles. The median number of cycles of ARZERRA completed was 6. The data described in Table 1 include relevant adverse reactions occurring up to 60 days after the last dose of study medication; Table 2 includes relevant hematologic laboratory abnormalities.

(cont’d)

Table 1. Adverse Reactions With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil and Also ≥2% More Than Patients Receiving Chlorambucil

Adverse Reactions

ARZERRA Plus Chlorambucil

(N = 217)Chlorambucil

(N = 227)

All Grades

%Grade ≥3

%

All Grades

%Grade ≥3

%

Infusion reactionsa 67 10 0 0

Neutropenia 27 26 18 14

Asthenia 8 <1 5 0

Headache 7 <1 3 0

Leukopenia 6 3 2 <1

Herpes simplexb 6 0 4 <1

Lower respiratory tract infection

5 1 3 <1

Arthralgia 5 <1 3 0

Upper abdominal pain 5 0 3 0

a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria.

b Includes oral herpes, herpes, herpes virus infection, genital herpes, and herpes simplex.

Table 2. Post-baseline Hematologic Laboratory Abnormalities Occurring With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil and Also ≥2% More Than Patients Receiving Chlorambucil



(N = 227)

All Grades%

Grade ≥3%

All Grades%

Grade ≥3%

Leukopenia 67 23 28 4


Lymphopenia 52 29 20 7

Infusion Reactions: Overall, 67% of patients who received ARZERRA in combination with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal). Infusion reactions that were either Grade 3 or greater, serious, or led to treatment interruption or discontinuation occurred most frequently during Cycle 1 (56% on Day 1 [6% were Grade 3 or greater] and 23% on Day 8 [3% were Grade 3 or greater]) and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients. Serious adverse events of infusion reactions occurred in 2% of patients. Neutropenia: Overall, 3% of patients had neutropenia as a serious adverse event, reported up to 60 days after the last dose. One patient died with neutropenic sepsis and agranulocytosis. Prolonged neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 4% of patients receiving chlorambucil. Late-onset neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 1% of patients receiving chlorambucil alone. Refractory CLL: The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 2 [n = 154]) or 3 doses (Study 3 [n = 27]). The data described in Table 3 and other sections below are derived from 154 patients in Study 2. All patients received 2,000 mg weekly from the second dose onward. Ninety percent of patients received at least 8 infusions of ARZERRA

and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were white.

Table 3. Incidence of All Adverse Reactions Occurring in ≥5% of Patients and in the Fludarabine- and Alemtuzumab-refractory Subset

Adverse Reaction

Total Population(N = 154)

Fludarabine- and Alemtuzumab-

refractory(N = 59)

All Grades

%

Grade ≥3%

All Grades

%

Grade ≥3%

Pneumoniaa 23 14 25 15

Pyrexia 20 3 25 5

Cough 19 0 19 0

Diarrhea 18 0 19 0

Anemia 16 5 17 8

Fatigue 15 0 15 0

Dyspnea 14 2 19 5

Rashb 14 <1 17 2

Bronchitis 11 <1 19 2

Nausea 11 0 12 0

Upper respiratory tract infection

11 0 3 0

Edema peripheral 9 <1 8 2

Back pain 8 1 12 2

Chills 8 0 10 0

Nasopharyngitis 8 0 8 0

Sepsisc 8 8 10 10

Urticaria 8 0 5 0

Insomnia 7 0 10 0

Headache 6 0 7 0

Herpes zoster 6 1 7 2

Hyperhidrosis 5 0 5 0

Hypertension 5 0 8 0

Hypotension 5 0 3 0

Muscle spasms 5 0 3 0

Sinusitis 5 2 3 2

Tachycardia 5 <1 7 2

a Includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia.

b Includes rash, rash macular, and rash vesicular.c Includes sepsis, neutropenic sepsis, bacteremia, and septic shock.

Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 or greater infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed Grade 3 or greater neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 300 patients with CLL were tested during and after treatment for antibodies to ARZERRA.

(cont’d)




thracyclines in comparison with Herceptin (trastuzumab) plus Perjeta and a taxane fol-lowing anthracyclines as adjuvant therapy in patients with operable HER2-positive primary breast cancer. Available at Clini-calTrials.gov/show/ NCT01966471. Ac-cessed November 17, 2014.

9. Blackwell K: New agents for advanced HER2-positive breast cancer. Chemotherapy

Foundation Symposium. Presented Novem-ber 6, 2014.

10. Gelmon KA, Boyle F, Kaufman B, et al: Open-label phase III randomized con-trolled trial comparing taxane-based chemo-therapy with lapatinib or trastuzumab as first-line therapy for women with HER2-positive metastatic breast cancer: Interim analysis of NCIC CTG MA.31/GSK EGF 108919. 2012

ASCO Annual Meeting. Abstract LBA671. 11. Verma S, Miles D, Gianni L, et al:

Trastuzumab emtansine for HER2-posi-tive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.

12. Krop IE, Kim SB, González-Martin A, et al: Trastuzumab emtansine versus treat-ment of physician’s choice for pretreated HER2-positive advanced breast cancer

(TH3RESA): A randomised, open-label, phase 3 trial. Lancet Oncol 15:689-699, 2014.

13. Blackwell KL, Burstein HJ, Stornio-lo AM, et al: Overall survival benefit with lapatinib in combination with trastuzumab for human epidermal growth factor recep-tor 2-positive metastatic breast cancer: Final results from the EGF104900 study. J Clin Oncol 30:2585-2592, 2012.

BRIEF SUMMARY

ARZERRA® (ofatumumab) Injection, for intravenous infusion

The following is a brief summary only; see full prescribing information, including Boxed Warning, for complete product information.

WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY• Hepatitis B Virus (HBV) reactivation can occur in patients

receiving CD20-directed cytolytic antibodies, including ARZERRA®, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)].


1 INDICATIONS AND USAGE1.1 Previously Untreated Chronic Lymphocytic Leukemia ARZERRA (ofatumumab) is indicated, in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate [see Clinical Studies (14.1) of full prescribing information]. 1.2 Refractory CLL ARZERRA is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab [see Clinical Studies (14.2) of full prescribing information].


5 WARNINGS AND PRECAUTIONS5.1 Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (e.g., myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment [see Adverse Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing information]. Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3) of full prescribing information]. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment. 5.2 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receiving ARZERRA, immediately

discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation. 5.3 Hepatitis B Virus Infection Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis. 5.4 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function. 5.6 Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA [see Adverse Reactions (6.1)]. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. 5.7 Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the labeling:• Infusion Reactions [see Warnings and Precautions (5.1)]• Hepatitis B Virus Reactivation [see Warnings and Precautions (5.2)]• Hepatitis B Virus Infection [see Warnings and Precautions (5.3)]• Progressive Multifocal Leukoencephalopathy [see Warnings and

Precautions (5.4)]• Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]• Cytopenias [see Warnings and Precautions (5.6)]Previously Untreated CLL: The most common adverse reactions (≥10%) were infusion reactions and neutropenia (Table 1). Refractory CLL: The most common adverse reactions (≥10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections (Table 3). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation. 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Previously Untreated CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 1) in 444 patients with previously untreated CLL. Patients were randomized to receive either ARZERRA as an intravenous infusion every 28 days in combination with chlorambucil (n = 217) or chlorambucil as a single agent (n = 227). In both arms, patients received chlorambucil 10 mg/m2 orally on Days 1 to 7 every 28 days. The infusion schedule for ARZERRA was 300 mg administered on Cycle 1 Day 1, 1,000 mg administered on Cycle 1 Day 8, and 1,000 mg administered on Day 1 of subsequent 28-day cycles. The median number of cycles of ARZERRA completed was 6. The data described in Table 1 include relevant adverse reactions occurring up to 60 days after the last dose of study medication; Table 2 includes relevant hematologic laboratory abnormalities.

(cont’d)

Table 1. Adverse Reactions With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil and Also ≥2% More Than Patients Receiving Chlorambucil

Adverse Reactions



(N = 227)

All Grades

%Grade ≥3

%

All Grades

%Grade ≥3

%

Infusion reactionsa 67 10 0 0


Asthenia 8 <1 5 0

Headache 7 <1 3 0

Leukopenia 6 3 2 <1

Herpes simplexb 6 0 4 <1

Lower respiratory tract infection

5 1 3 <1

Arthralgia 5 <1 3 0

Upper abdominal pain 5 0 3 0

a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria.

b Includes oral herpes, herpes, herpes virus infection, genital herpes, and herpes simplex.

Table 2. Post-baseline Hematologic Laboratory Abnormalities Occurring With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil and Also ≥2% More Than Patients Receiving Chlorambucil



(N = 227)

All Grades%

Grade ≥3%

All Grades%

Grade ≥3%

Leukopenia 67 23 28 4


Lymphopenia 52 29 20 7

Infusion Reactions: Overall, 67% of patients who received ARZERRA in combination with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal). Infusion reactions that were either Grade 3 or greater, serious, or led to treatment interruption or discontinuation occurred most frequently during Cycle 1 (56% on Day 1 [6% were Grade 3 or greater] and 23% on Day 8 [3% were Grade 3 or greater]) and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients. Serious adverse events of infusion reactions occurred in 2% of patients. Neutropenia: Overall, 3% of patients had neutropenia as a serious adverse event, reported up to 60 days after the last dose. One patient died with neutropenic sepsis and agranulocytosis. Prolonged neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 4% of patients receiving chlorambucil. Late-onset neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 1% of patients receiving chlorambucil alone. Refractory CLL: The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 2 [n = 154]) or 3 doses (Study 3 [n = 27]). The data described in Table 3 and other sections below are derived from 154 patients in Study 2. All patients received 2,000 mg weekly from the second dose onward. Ninety percent of patients received at least 8 infusions of ARZERRA

and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were white.

Table 3. Incidence of All Adverse Reactions Occurring in ≥5% of Patients and in the Fludarabine- and Alemtuzumab-refractory Subset

Adverse Reaction

Total Population(N = 154)

Fludarabine- and Alemtuzumab-

refractory(N = 59)

All Grades

%

Grade ≥3%

All Grades

%

Grade ≥3%

Pneumoniaa 23 14 25 15

Pyrexia 20 3 25 5

Cough 19 0 19 0

Diarrhea 18 0 19 0

Anemia 16 5 17 8

Fatigue 15 0 15 0

Dyspnea 14 2 19 5

Rashb 14 <1 17 2

Bronchitis 11 <1 19 2

Nausea 11 0 12 0

Upper respiratory tract infection

11 0 3 0

Edema peripheral 9 <1 8 2

Back pain 8 1 12 2

Chills 8 0 10 0

Nasopharyngitis 8 0 8 0

Sepsisc 8 8 10 10

Urticaria 8 0 5 0

Insomnia 7 0 10 0

Headache 6 0 7 0

Herpes zoster 6 1 7 2

Hyperhidrosis 5 0 5 0

Hypertension 5 0 8 0

Hypotension 5 0 3 0

Muscle spasms 5 0 3 0

Sinusitis 5 2 3 2

Tachycardia 5 <1 7 2

a Includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia.

b Includes rash, rash macular, and rash vesicular.c Includes sepsis, neutropenic sepsis, bacteremia, and septic shock.

Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 or greater infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed Grade 3 or greater neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 300 patients with CLL were tested during and after treatment for antibodies to ARZERRA.

(cont’d)



FDA Update

FDA Approves Bevacizumab Plus Chemotherapy for Platinum-Resistant, Recurrent Ovarian Cancer

The U.S. Food and Drug Administra-tion (FDA) approved bevacizumab

(Avastin) in combination with paclitaxel, pegylated liposomal doxorubicin, or topote-can for the treatment of patients with plati-

num-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The approval is based on the results of an international, randomized, two-arm trial (AURELIA) with the primary

comparison of investigator-assessed progression-free survival. This trial compared bevacizumab plus chemo-therapy vs chemotherapy alone. The trial enrolled 361 patients: 179 patients

were assigned to receive bevacizumab plus chemotherapy, and 182 patients were assigned to receive chemotherapy alone. The chemotherapy included pa-clitaxel, pegylated liposomal doxorubi-cin, or topotecan.

Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. All enrolled pa-tients had received no more than two prior chemotherapy regimens, had an ECOG performance status of 0 to 2, and had recurred within less than 6 months from the most recent platinum-based therapy.

The progression-free survival assess-ment demonstrated a statistically sig-nificant improvement in patients who re-ceived bevacizumab plus chemotherapy compared to those who received chemo-therapy alone (hazard ratio [HR] = 0.38, 95% confidence interval [CI] = 0.30–0.49, P < .0001, stratified log-rank test). The median progression-free survival of patients who received bevacizumab plus chemotherapy was 6.8 months (95% CI = 5.6–7.8) compared to 3.4 months (95% CI = 2.1–3.8) for those receiving chemo-therapy alone. There was no significant difference in overall survival (16.6 vs 13.3 months; HR = 0.89, 95% CI = 0.69–1.14).

Exploratory AnalysesThe trial was stratified by chemo-

therapy regimen. Exploratory analyses were performed by comparing the ad-dition of bevacizumab to each chemo-therapy regimen.

The addition of bevacizumab to pa-clitaxel provided the largest improve-ment, resulting in a 5.7-month im-provement in median progression-free survival (9.6 vs 3.9 months; HR = 0.47, 95% CI = 0.31–0.72), an improvement in the overall response rate of 23% (53% vs 30%), and a 9.2-month im-provement in median overall survival (22.4 vs 13.2 months; HR = 0.64, 95% CI = 0.41–1.01).

Ninety-seven per cent of patients in the paclitaxel regimen had received paclitaxel with previous chemotherapy regimens. These exploratory analyses suggest that patients who have received prior treatment with paclitaxel may benefit from bevacizumab plus weekly paclitaxel. n

Gynecologic Oncology

There was no formation of anti-ofatumumab antibodies in patients with CLL after treatment with ofatumumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ARZERRA. 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. Infusion-related Cardiac Events: Cardiac arrest. Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda.

7 DRUG INTERACTIONSCoadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the maximum recommended human dose (2,000 mg) of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use In Study 1, 68% of patients (148/217) receiving ARZERRA plus chlorambucil were 65 years and older. Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%) [see Adverse Reactions (6.1)]. In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients [see Clinical Studies (14.1) of full prescribing information]. In refractory CLL, clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted.

10 OVERDOSAGENo data are available regarding overdosage with ARZERRA.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.

13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the maximum human dose (2,000 mg) of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15% to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared with control values). Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared with the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared with control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared with the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals.

17 PATIENT COUNSELING INFORMATIONAdvise patients to contact a healthcare professional for any of the following:• Signs and symptoms of infusion reactions including fever, chills, rash,

or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]

• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.2, 5.3)]

• New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.4)]

• Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.6)]

• Signs of infections including fever and cough [see Warnings and Precautions (5.6), Adverse Reactions (6.1)]

• Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)]

Advise patients of the need for:• Monitoring and possible need for treatment if they have a history

of hepatitis B infection (based on the blood test) [see Warnings and Precautions (5.2)]

• Periodic monitoring for blood counts [see Warnings and Precautions (5.6)]• Avoiding vaccination with live viral vaccines [see Warnings and

Precautions (5.7)]

ARZERRA is a registered trademark of the GSK group of companies.

Manufactured by:GLAXO GROUP LIMITEDBrentford, Middlesex, TW8 9GS, United KingdomU.S. License 1809

Distributed by:

GlaxoSmithKlineResearch Triangle Park, NC 27709

©2014, the GSK group of companies. All rights reserved.

Revised: 04/2014ARZ:8BRS

©2014 GSK group of companies.All rights reserved. Printed in USA. AZA522R0 October 2014



Top 5 Breakthroughs in the Treatment of Advanced Lung Cancer By Charlotte Bath

A countdown of the top 5 break-through therapies in the treatment

of advanced lung cancer was presented by D. Ross Camidge, MD, PhD, at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology.1 Dr. Camidge is Director, Thoracic On-cology Clinical and Clinical Research Programs, and Associate Director for Clinical Research, University of Colo-rado Comprehensive Cancer Center, Aurora. He singled out the following molecular therapies:

#5. Crizotinib Dr. Camidge chose crizotinib

(Xalkori) as a breakthrough therapy “because of how it has exemplified the philosophy of one size does not fit all,” he said.

“Before the phase I study, preclinical work had already clarified that crizo-tinib had particular activity only in some cell lines, which could be charac-terized by their evidence of either MET or ALK activation,” Dr. Camidge stated. Clinical trial results showing overall re-sponse rates exceeding 60% among pa-tients with ALK-positive non–small cell lung cancer (NSCLC) “led to the initial licensing of crizotinib and the defining of ALK-positive lung cancer as a clini-cally relevant subtype of disease,” he added.

This was followed by publication a few months ago of the ROS1-positive lung cancer cohort data “showing equal-ly impressive efficacy,” Dr. Camidge noted. “And at this year’s ASCO An-nual Meeting, we saw data for the first time on crizotinib’s activity in the MET-amplified lung cancer cohorts showing a 67% response rate and a median du-ration of response of over a year in the highest amplified cohort.”

#4. Second-Generation ALK Inhibitors

The second-generation ALK inhibi-tors were chosen “not because of their activity postcrizotinib, but because of their progress in accurately defining how we capture data on benefit in cen-tral nervous system (CNS) disease,” Dr. Camidge explained.

The benefit of crizotinib in the central nervous system is limited, Dr. Camidge noted. “Patients with ALK-positive disease who receive or never receive crizotinib have very similar life-time incidences of brain metastases; nearly 50% of patients on crizotinib

have a first progression within the brain, with it being the sole site of progression in most cases,” he said.

Second-generation ALK inhibitors shown to be clinically active following an initial tyrosine kinase inhibitor in-clude ceritinib (Zykadia), which has been approved by the U.S. Food and Drug Administration (FDA) for use in patients with metastatic NSCLC, and alectinib and AP26113, which have both received Breakthrough Therapy designations from the FDA for use in patients with metastatic NSCLC who have had disease progression on crizotinib. Magnetic resonance imag-ing (MRI) has shown responses of CNS lesions occurring with second-generation ALK inhibitors, but Dr. Camidge cautioned that hard data are still lacking on the proportion of patients with CNS responses to these

newer agents and the duration of the responses.

“The good news is that the brain is now achieving appropriate recogni-tion as a relevant battleground, and robust CNS data are now being gen-erated prospectively,” Dr. Camidge said. The ongoing ALEX study is “comparing alectinib head-to-head with crizotinib in the [tyrosine kinase inhibitor]–naive setting, with time to CNS progression as a prominent secondary endpoint in the study,” he reported.

#3. Third-Generation EGFR Inhibitors

Dr. Camidge chose the third-genera-tion EGFR inhibitors “because of what they are teaching us about understand-ing acquired resistance in order to effec-tively treat it,” he said.

“From multiple elegant rebiopsy series we know that the T790M exon 20 mutation drives acquired resistance in 50% to 60% of cases. But inhibiting T790M has been a problem,” accord-ing to Dr. Camidge. Second-generation

drugs “could not achieve tolerable enough levels to inhibit T790M due to their lower IC50 [half maximal inhibi-tory concentration] for the wild-type form of the EGFR. The third-genera-tion drugs were not screened against the wild-type form of the enzyme, but rather, against the mutant forms present in the cancer,” he said.

“The two most notable third-gener-ation drugs, AZD9291 and CO-1686 (now called rociletinib), both have significant activity against the stan-dard activating EGFR mutations and T790M while relatively sparing the wild-type EGFR.” Both rociletinib and AZD9291 “are now showing robust response rates in known T790M-posi-tive disease,” Dr. Camidge added, with skin and gut toxicity appearing to be significantly less than with earlier gen-eration drugs.

#2. PD-1/PD-L1 AntagonistsDr. Camidge singled out the inhibi-

tors of programmed death protein 1 (PD-1) and its ligand (PD-L1) with the open question of whether they will be a panacea or whether they have the potential to become a truly personal-ized medicine.

“From the earliest nivolumab data it was clear that responses could be very long lasting in lung cancer, but benefit doesn’t occur in everyone,” Dr. Camidge said. Objective response rates have been relatively modest and progression-free survival short. Low median progression-free survival has also been seen with pembroli-zumab (Keytruda) in the pretreated population, although treatment-naive patients may do well. The rate of re-sponse to MPDL3280A has been higher among those with a smoking history and among those with spe-cific mutations. “Who exactly is de-riving benefit from these agents and why remain a work in progress,” Dr. Camidge stated.

“Perhaps the biggest challenge to

the idea of PD-1/PD-L1 inhibitors as a panacea is the recognition that the PD-1/PD-L1 axis is only one of multi-ple immune stimulatory and inhibitory pathways that will be exploited as drug targets in the next few years,” he added. The excitement about PD-1 and PD-L1 inhibitors needs to be tempered “with the reality that they don’t work in every-one, and many new immune modulato-ry agents are on the horizon, suggesting the one-size-does-not-fit-all philosophy will also extend into the realm of immu-notherapies.”

#1. Three Possible Future Breakthroughs

Dr. Camidge’s number 1 spot was shared by three “mini-fantasies” about what future breakthroughs might be, based on the concepts of mining the past, intraoncogene heterogeneity, and affordable incremental benefit.

Explaining his interest in mining the past, Dr. Camidge said, “We have walked away from a large number of tar-geted agents because they didn’t work when given to otherwise unselected lung cancer populations. However, in almost all of these cases, no attempt at robustly exploring predictive biomark-ers was conducted,” he noted.

“Consequently, the classes of drugs may not truly be ineffective, and there may have been evidence of hypersensi-tive subpopulations ripe for re-explo-ration,” he continued. “We might need to look at our back catalogues for treat-ments we could retrospectively explore for effective predictive biomarkers with our more modern approaches.”

As an example, he cited the class of drugs known as death receptor agonists. These drugs “which directly stimulate apoptosis and worked ex-ceptionally well in various preclinical models, were all dropped when a series of randomized phase II studies adding these agents to first-line chemotherapy failed to show an advantage.” But the nonprogressors in the experimental arms approached 15% of the popula-tion in several of the studies, he said. “Unfortunately little or no tissue was collected in these studies so no pre-dictive biomarkers could really be ex-plored at the time.”

Dr. Camidge used KRAS as an exam-ple of intraoncogene heterogeneity. The most common mutation among adeno-carcinomas of the lung, KRAS has been

We might need to look at our back catalogues for treatments we could retrospectively explore for effective predictive biomarkers with our more modern approaches.

—D. Ross Camidge, MD, PhD


Chicago Multidisciplinary Symposium in Thoracic OncologyThoracic Oncology

There was no formation of anti-ofatumumab antibodies in patients with CLL after treatment with ofatumumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ARZERRA. 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. Infusion-related Cardiac Events: Cardiac arrest. Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda.

7 DRUG INTERACTIONSCoadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the maximum recommended human dose (2,000 mg) of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use In Study 1, 68% of patients (148/217) receiving ARZERRA plus chlorambucil were 65 years and older. Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%) [see Adverse Reactions (6.1)]. In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients [see Clinical Studies (14.1) of full prescribing information]. In refractory CLL, clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted.

10 OVERDOSAGENo data are available regarding overdosage with ARZERRA.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.

13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the maximum human dose (2,000 mg) of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15% to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared with control values). Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared with the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared with control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared with the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals.

17 PATIENT COUNSELING INFORMATIONAdvise patients to contact a healthcare professional for any of the following:• Signs and symptoms of infusion reactions including fever, chills, rash,

or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]

• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.2, 5.3)]

• New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.4)]

• Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.6)]

• Signs of infections including fever and cough [see Warnings and Precautions (5.6), Adverse Reactions (6.1)]

• Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)]

Advise patients of the need for:• Monitoring and possible need for treatment if they have a history

of hepatitis B infection (based on the blood test) [see Warnings and Precautions (5.2)]

• Periodic monitoring for blood counts [see Warnings and Precautions (5.6)]• Avoiding vaccination with live viral vaccines [see Warnings and

Precautions (5.7)]

ARZERRA is a registered trademark of the GSK group of companies.

Manufactured by:GLAXO GROUP LIMITEDBrentford, Middlesex, TW8 9GS, United KingdomU.S. License 1809

Distributed by:


©2014, the GSK group of companies. All rights reserved.

Revised: 04/2014ARZ:8BRS

©2014 GSK group of companies.All rights reserved. Printed in USA. AZA522R0 October 2014



Health-Care Policy

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

Aline Charabaty, MD, on colorectal cancer screening see page 47

Camilla Zimmermann, MD, PhD, FRCPC, on earlier introduction of palliative care see page 78

Jesus F. San-Miguel, MD, on panobinostat for relapsed/refractory myeloma see page 65

Maha Hussain, MD, FACP, FASCO, on metastatic castration-resistant prostate cancer see page 49

Sagar Lonial, MD, on HDAC inhibitors in myeloma see page 66

Arif H. Kamal, MD, on survivorship care see page 90

Neal F. Kassell, MD, on focused ultrasound see page 53

Tracy Batchelor, MD, on treating brain cancer in 2014 see page 70

Visit The ASCO Post online at ASCOPost.com

shown in preclinical and clinical studies to have tremendous heterogeneity. The trial design for the FAK inhibitor VS-6063 in KRAS-mutant lung cancer is “at least starting to address this hetero-geneity by exploring its benefit in four KRAS-mutant cohorts that have also been characterized with regard to their INK4a and p53 status to see if these contexts alter the response to the drug,

based on relevant preclinical data,” Dr. Camidge said.

To explain affordable incremental benefit, Dr. Camidge cited the REVEL study, which looked at the addition of ramucirumab (Cyramza), an antibody against VEGFR2, to standard second-line docetaxel. “The addition of ramu-cirumab increased the response rate from 14% to 30% and the disease con-trol rate from 53% to 64%, increased the progression free survival from 3.0

to 4.5 months, and increased the overall survival from 9.1 to 10.5 months,” Dr. Camidge reported.

“So with an unequivocally positive phase III study, adding a little to all ma-jor endpoints, we might want to be us-ing this drug. But only if it, and drugs like it, are affordable, as one recurring problem has been in pricing a break-through as if it’s a game-changer and not just a way of offering a little incre-mental benefit to everyone.” If not af-

fordable, “these minor breakthroughs will never be practical to use in the real world,” he said. n

Disclosure: Dr. Camidge has received honoraria from Pfizer, Genentech/Roche, Clovis, Aria, and Eli Lilly.

Reference1. Camidge DR: The top five most

promising molecular therapies on the hori-zon. Chicago Multidisciplinary Symposium in Thoracic Oncology. Presented October 31, 2014.

Top 5 Breakthroughscontinued from page 11

H. Gilbert Welch, MD, MPH, on the hazards of overscreening see page 128

ASCO Calls for Major Medicaid Reform to Improve Quality Cancer Care for Low-Income AmericansBy Jo Cavallo

ASCO issued its new Policy State-ment on Medicaid Reform on

November 17, which calls for major

changes to the program to ensure ac-cess to high-quality cancer care for all low-income individuals. The Society’s

recommendations call for Medicaid ex-pansion in all 50 states to close coverage gaps, improve cancer screening and pre-vention services, and end coverage re-strictions that prevent Medicaid enroll-ees from receiving high-quality cancer care, among others. The Policy State-ment on Medicaid Reform is published in the Journal of Clinical Oncology.1

“People with cancer, for whom the costs of evaluation and treatment can be extraordinarily high, are particularly in need of insurance coverage to allow for timely diagnosis and high-quality treat-ment,” wrote statement authors Blase N. Polite, MD, MPP, of the University of Chicago, and colleagues. Currently,

67.9 million Americans are enrolled in Medicaid. Of them, an estimated 2.1 million beneficiaries, including those

added under the Affordable Care Act, have had a cancer diagnosis, and many more depend on Medicaid for routine

Blase N. Polite, MD, MPP

ASCO Policy Statement on Medicaid Reform

■ ASCO calls for Medicaid reform to close major gaps in coverage to ensure access to life-saving screening, treatment, and prevention services for low-income Americans with cancer.

■ ASCO’s policy recommendations include expanding Medicaid eligibility to all 50 states, parity for oral cancer drugs, adequate physician reimbursement, reform of the 340B Drug Pricing Program, full coverage for cancer screening and genetic testing, guaranteed coverage for clinical trials, adherence to quality metrics, and oncology medical home designations.

■ Low-income patients with cancer are in particular need of insurance coverage to allow for timely diagnosis and high-quality treatment.


Health-Care Policy


cancer screenings and prevention ser-vices. Twenty-seven states and the Dis-trict of Columbia have already expanded their Medicaid programs under the Af-fordable Care Act, 21 have not, and the remaining 2 states are in “open debate.”

In releasing its policy statement, ASCO noted that the November mid-term elections are unlikely to significantly change the outlook for state expansion under the Affordable Care Act. But other opportunities exist for improving access to cancer-related care among Medicaid beneficiaries, and unexpanded states, ac-cording to the ASCO policy statement, “should come up with an alternative strategy that provides comprehensive

subsidized health coverage that ensures, among other benefits, access to high-quality cancer care, measured by cancer-specific quality metrics, delivered by a cancer specialist.”

Critical Health-Care DisparitiesDuring a news conference announc-

ing the policy statement, Peter Paul Yu, MD, FACP, FASCO, ASCO Presi-dent and Director of Cancer Research at Palo Alto Medical Foundation, ex-plained why ASCO has decided to issue recommendations for Medicaid reform.

“The evidence shows that uninsured patients are significantly more likely to be diagnosed with advanced cancer than are insured patients. Further, Medicaid’s low reimbursement rates are a disincen-tive for physician participation, mak-ing it increasingly difficult for patients to access care from specialists,” said Dr. Yu. “As oncologists, we believe it is our responsibility to advocate for policies that expand and improve the care of all people with cancer regardless of finan-cial means. We also believe that no indi-vidual diagnosed with cancer should be

without insurance that guarantees access to high-quality cancer care delivered by a cancer specialist. Therefore, patients with cancer who have Medicaid should receive the same timely and high-quality cancer care as patients with private insur-ance. Lastly, Medicaid payments should be sufficient to ensure that Medicaid pa-tients have access to quality cancer care.

“For these and other reasons, ASCO strongly believes that the Society should, first, draw attention to the critical issues facing cancer patients under Medicaid and, second, make concrete, construc-tive recommendations for strengthen-ing this program to assure that our most vulnerable citizens receive needed health care. The ASCO Policy Statement on

Medicaid Reform is designed to achieve both of those objectives,” said Dr. Yu.

The recommendations ASCO pre-sented in its policy statement offer sev-eral ways Medicaid could be reformed to expand access to cancer care and remove barriers to key elements of quality cancer care for enrollees. They include:

ASCO strongly believes the Society should, first,

draw attention to the critical issues facing

cancer patients under Medicaid and, second,

make recommendations for strengthening this

program to assure that our most vulnerable

citizens receive needed health care.


http://www.neulastahcp.com


Health-Care Policy

Medicaid Reformcontinued from page 13• Expanding insurance coverage for in-

dividuals below the federal poverty level in all 50 states

• Ensuring oral parity for patients with Medicaid coverage and including oral and intravenous cancer therapies, as

well as supportive care medications, as exempt services for cost-sharing pur-poses

• Extending clinical trial participation included in the Affordable Care Act to patients with Medicaid coverage, and allowing patients to cross state lines to participate in those trials

• Eliminating artificial barriers between current Medicaid beneficiaries and newly eligible ones, and applying Af-fordable Care Act final-rule mandates for cancer screening and diagnostic fol-low-up without copay for all Medicaid beneficiaries

• Requiring coverage for genetic testing,

without deductibles or copays, in any patient deemed at high risk for an in-heritable cancer-risk syndrome

• Improving the 340B Drug Pricing Pro-gram to incentivize care for uninsured and underinsured patients regardless of care setting

• Eliminating variation between Medi-care and Medicaid physician pay-ment rates for cancer diagnosis and treatment by raising Medicaid pay-ment to Medicare rates

• Tying state flexibility in running Med-icaid programs to the requirement to meet predefined cancer quality met-rics

• Allowing oncology practices to be designated as medical homes, and de-veloping expanded reimbursement for care coordination and patient educa-tion for oncology practices nDisclosure: Coauthor Nefertiti C. duPont

reported a consultant or advisory role with Genentech, honoraria from DySIS Medical, and research funding from Genentech.

Reference1. Polite BN, Griggs JJ, Moy B, et al: J

Clin Oncol. November 17, 2014 (early re-lease online).

The ASCO Post Wants to Hear

From YouWe encourage readers to share

their opinions and thoughts on issues of interest to the

oncology community.

Write to The ASCO Post at [email protected]

Harborside Press 37 Main Street

Cold Spring Harbor, NY 11724

Phone: 631.692.0800 Fax: 631.692.0805

www.ASCOPost.com



try into one repository, that goal alone would not be enough justification for ASCO to take on such an ambitious and difficult project. “CancerLinQ is re-ally a rapid-learning health system. The concept is to upload data from the point of care into CancerLinQ and allow the data to be aggregated and studied by and on behalf of the provider. This generates insights and, ultimately, new learning that yields services to the pro-vider and patient in the form of reports and clinical decision support tools. This process helps to power quality improve-ment in real time,” said Dr. Yu.

Moreover, CancerLinQ allows data exploration of real-world clinical is-sues and may offer new understanding of treatment variations. “Clinical trials data are very important and granular but often don’t represent patient popu-lations in the real world. This process will accelerate our development of guidelines and other clinical decision support tools,” noted Dr. Yu.

Could Such a System Work?Dr. Yu explained that to test the con-

cept, ASCO built a prototype 2 years ago. “Frankly, we didn’t know if this system was actually doable. No one had approached this type of rapid-learning health system before. It was a challenge that came out of the Institute of Medi-

cine, and we took it up,” said Dr. Yu. He explained that while building the proto-type, the team decided to limit its work to one disease site—breast cancer.

He continued, “We populated the prototype with more than 170,000 de-identified cases of breast cancer from the electronic health records of five dif-ferent practices. This first step showed us that we could ingest data from mul-tiple electronic sources. After that, we began to conduct preliminary analyses of the data, which showed us that not only could we collect data, we could make observations from it as well.”

FDA Testing GroundsThe ASCO team next went to the

U.S. Food and Drug Administration (FDA) and presented its work. “The FDA felt our work was intriguing since they really don’t have a lot of data on drugs they approve once they’re re-leased into the real world. They asked us to tell them about the use of eryth-ropoietin-stimulating agents after the Agency changed its policy on their indi-cation,” said Dr. Yu.

“We analyzed the use of [erythropoi-etin-stimulating agents] in 8,300 breast cancer cases, and we could see that there was a trend developing even before the FDA changed its labeling and guidance on their use. Use of [erythropoietin-stimulating agents] declined markedly once the FDA’s labeling change went

public. We also looked at the hemoglo-bin level that doctors were targeting be-fore and after the FDA’s labeling change on these drugs, and that, too, dropped considerably after the FDA’s new la-beling change went public,” said Dr. Yu. “So using CancerLinQ analysis, we were indeed able to tell the FDA about [erythropoietin-stimulating agent] us-age in the real world.”

The Next StepOn the merit of this early success, the

ASCO Board was encouraged enough to move to a production model. “The first step was an extensive requirement-gathering process to find out exactly what information would be useful to clinicians. To that end, more than 1,000 ‘user stories’ were submitted by ASCO members, who told us what they want-ed from CancerLinQ. We then distilled these data into 13 detailed user scenar-ios, from which we crafted a request for proposal that we issued to the technolo-gy industry, asking if they could build a platform with this information and how much it would cost,” said Dr. Yu.

The ASCO team received 10 consor-tia responses involving 50 technology companies. “We also needed to talk to oncologists and see if they’d be will-ing to work with us. At this point, we have a memorandum of understanding signed by 15 vanguard practices across the country that will share their data in

CancerLinQ,” said Dr. Yu.The CancerLinQ team was advised

by volunteers on several committees including data governance, technology, physician practice, patient advocate, and business development. “The con-cept is to collect the [electronic medical record] and practice management data from the 15 vanguard practices, which will comprise both structured fields and unstructured fields (such as physician notes). We can then analyze this wealth of clinical information,” said Dr. Yu.

Clinical Decision SupportDr. Yu stressed that one ultimate

goal of CancerLinQ is to provide real-time clinical decision support. By hav-ing the capability to process specific pa-tient characteristics and compare them to outcomes from comparable patients, CancerLinQ will allow the practitioner to offer a personalized diagnosis and treatment plan based on real-world evi-dence in addition to published clinical trial data. CancerLinQ can also offer prompts to improve quality, such as on-cology drug-related interactions.

“Our pilot program shows that such a learning health system will work. Based on our platform development work this year, we plan to debut a func-tioning CancerLinQ system in 2015,” concluded Dr. Yu. n

Disclosure: Dr. Yu is the President of ASCO for 2014–2015.

CancerLinQcontinued from page 1

Technology

Download The ASCO Post iPad App

FREE from iTunes today!


Announcements

ASH Pairs Hematologists From Developing and Developed Nations for Global Training Program

The American Society of Hematol-ogy (ASH) recently announced

the 20 hematologists and other medi-cal professionals selected to partici-pate in the 2014 ASH Visitor Train-ing Program. This program provides talented hematologists, scientists, and laboratory staff from developing countries the opportunity to receive training on a specific area of hema-tology from an ASH member located anywhere in the world for up to 12 weeks. The goal of this program is to build hematology capacity in develop-ing countries and ultimately improve the care of patients with blood diseas-es worldwide.

The ASH Visitor Training Program is offered to hematologists and scien-tists from developing countries at any level of their careers. The availability of program mentors from any insti-tution and country around the world allows participants to select an expert in the specific area of hematology in which they are interested. Hema-tologists selected for the ASH Visitor Training Program are also paired with a member of the ASH International Members Committee, who is charged with helping participants prepare for and evaluate their training program experience.

“The exchange of knowledge and best practices among hematologists around the world is critical to con-tinue to move the field of hematology forward,” said ASH President Linda J. Burns, MD, of the University of

Minnesota. “The ASH Visitor Train-ing Program aims to facilitate that exchange, helping participants bring their new knowledge back to their home institutions to ultimately ex-pand research opportunities and im-prove the care of patients with blood disorders.”

2014 ParticipantsThe 2014 Visitor Training Program

participants are:

• Renate Asare, BSc (Ghana) and mentor Alok Srivastava, MD (Chris-tian Medical College, Vellore, India)

• Adriana Bello, MD (Venezuela) and mentor Sergio Giralt, MD (Memo-

rial Sloan Kettering Cancer Center, New York)

• Jorge Luis Contreras Saavedra, MD (Peru) and mentor Monica Thakar, MD (Children’s Hospital of

Wisconsin, Milwaukee)• Reynaldo Angelo De Castro, BSc

(Philippines) and mentor Caro-lyn C. Hoppe, MD (Children’s Hospital and Research Center,

Linda J. Burns, MD

JOB#

: 483

34

CLIE

NT: E

xelix

is DE

SC: J

ourn

al Ad

A si

ze

FILE

NAM

E: E

XL_X

LX_Q

4833

4_JA

_D01

.indd

DA

TE: 5

-12-

2014

6:1

1 PM

RO

UND:

1

1 PG: P

ared

esA/

Cruz

, Feli

x AD

: L B

udre

au

PM: N

one

AE: K

Ruf

f CW

: S G

uest

La

st S

aved

: 5-1

2-20

14 6

:11

PMTR

IM: 1

5” x

10.

25”

BLEE

D: 1

7.5”

x 1

1.25

” SA

FETY

: 6.7

5” x

9.7

5”

PROD

: M H

aight

IN

K Sp

ec: 4

c PR

INT

SCAL

E: 7

5%FO

NTS:

Neo

San

s Pr

o (B

old),

DIN

Pro

(Bold

, Med

ium, R

egula

r, Bl

ack,

Italic

), He

lvet

ica

Neue

LT

Std

(65

Mediu

m)

IMAG

ES: 4

8334

_JA_W

hale

s_fn

.tif (

CMYK

; 300

ppi;

100

%),

4833

4_KM

Cha

rt_O

L3_v

2a_A

LT S

IZE_

2415

.eps

(100

%),

4833

4_JA

_Sol

o_W

hale

s_fn

.psd

(CMY

K; 3

00 p

pi; 1

00%

), Ex

elix

is_b

lk.e

ps (2

0.6%

, 19.

01%

), Co

met

riq_

gene

ric_®

_80m

g_4C

.eps

(24.

69%

)IN

KS:

Cya

n,

Mag

enta

, Y

ellow

, B

lack

DOC

PATH

: Mac

intos

h HD

:Use

rs:p

ared

esa:

Desk

top:

EXL_

XLX_

Q483

34_JA

_D01

.indd

NOTE

S: N

one

EXL_

XLX_

Q483

34_JA

_D01

.indd

Ga

lley:

1

S&H

Phar

maG

raph

ics

Disk

DATE

SIGN

OFF

PGQC

TCAD

CDCW

AE/A

SED

PROD

4.0 11.2months months

1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21

No. of patients at risk:COMETRIQ® 219 121 78 55 31 12 2 1 Placebo 111 35 11 6 3 2 0 0

Months

Prob

abili

ty o

f pat

ient

s w

ho a

re p

rogr

essi

on fr

ee

4.0 11.2months

median

months

median

COMETRIQ® (n=219) Placebo (n=111)

HR=0.2895% CI: 0.19, 0.40P<0.0001

PFS1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21

No. of patientsat risk:COMETRIQ® 219 121 78 55 31 12 2 1Placebo 111 35 11 6 3 2 0 0

Months

Prob

abili

ty o

f pat

ient

s w

ho a

re p

rogr

essi

on fr

ee

4.0 11.2months

median

months

median

COMETRIQ® (n=219)Placebo (n=111)

HR=0.2895% CI: 0.19, 0.40P<0.0001

PFS

Attack from multiple anglesCOMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro• These tyrosine kinases are involved in both normal cellular function and pathologic

processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment

MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

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

Statistically significant efficacy in patients with progressive, metastatic MTC• COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients

with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within

14 months prior to study entry• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001)• Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the

planned interim analysis

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo

© 2014 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 05/14 [COM-0086]COORDINATED ATTACK

Important Safety InformationWARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE• 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.

• 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.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

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.Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). 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.Osteonecrosis of the Jaw (ONJ): 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.Palmar- Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe 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: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 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.Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. 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.Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).In clinical trials, 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.Please see accompanying brief summary of Prescribing Information, including Boxed Warnings.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

C M Y KCosmos Communications 1

1ej

27902a 05.12.14 133

Q1 Q2

S:6.75” S:6.75”

S:9.75”

T:15”

T:10.25”

B:17.5”

B:11.25”


Announcements

Oakland, California)• Ahmet Emre Eskazan, MD (Tur-

key) and mentor Jorge Cortes, MD (The University of Texas MD Ander-son Cancer Center, Houston)

• Pamela Fajardo, MD (Philippines) and mentor David Williams, MD (Boston Children’s Hospital, Har-vard Medical School, Boston)

• Toman Tua Julian, MD (Indone-sia) and mentor Wee Joo Chng, MD (National University Cancer Insti-tute, Singapore)

• Sehar Khaliq, MBBS, FCPS (Paki-stan) and mentor Suthat Fucharoen, MD (Mahidol University, Bangkok)

• Pedro Lovato, MD (Peru) and men-tor Rizwan Romee, MD (Washing-

ton University School of Medicine, St. Louis)

• Aime Mbaya, MD (Democratic Re-public of the Congo) and mentor Le-kidelu Taddesse-Heath, MD (How-ard University Hospital, Washington, DC)

• Magdalene Namuwonge, Nurs-ing Officer Diplomat (Uganda) and

mentor Jeannie Callum, MD, FRCP (Sunnybrook Health and Sciences Centre and University Health Net-work, Toronto)

• Onsongo Simon Nyangena, MMed (Kenya) and mentor Nigel Key, MB, ChB (University of North Carolina, Chapel Hill)


JOB#

: 483

34

CLIE

NT: E

xelix

is DE

SC: J

ourn

al Ad

A si

ze

FILE

NAM

E: E

XL_X

LX_Q

4833

4_JA

_D01

.indd

DA

TE: 5

-12-

2014

6:1

1 PM

RO

UND:

1

1 PG: P

ared

esA/

Cruz

, Feli

x AD

: L B

udre

au

PM: N

one

AE: K

Ruf

f CW

: S G

uest

La

st S

aved

: 5-1

2-20

14 6

:11

PMTR

IM: 1

5” x

10.

25”

BLEE

D: 1

7.5”

x 1

1.25

” SA

FETY

: 6.7

5” x

9.7

5”

PROD

: M H

aight

IN

K Sp

ec: 4

c PR

INT

SCAL

E: 7

5%FO

NTS:

Neo

San

s Pr

o (B

old),

DIN

Pro

(Bold

, Med

ium, R

egula

r, Bl

ack,

Italic

), He

lvet

ica

Neue

LT

Std

(65

Mediu

m)

IMAG

ES: 4

8334

_JA_W

hale

s_fn

.tif (

CMYK

; 300

ppi;

100

%),

4833

4_KM

Cha

rt_O

L3_v

2a_A

LT S

IZE_

2415

.eps

(100

%),

4833

4_JA

_Sol

o_W

hale

s_fn

.psd

(CMY

K; 3

00 p

pi; 1

00%

), Ex

elix

is_b

lk.e

ps (2

0.6%

, 19.

01%

), Co

met

riq_

gene

ric_®

_80m

g_4C

.eps

(24.

69%

)IN

KS:

Cya

n,

Mag

enta

, Y

ellow

, B

lack

DOC

PATH

: Mac

intos

h HD

:Use

rs:p

ared

esa:

Desk

top:

EXL_

XLX_

Q483

34_JA

_D01

.indd

NOTE

S: N

one

EXL_

XLX_

Q483

34_JA

_D01

.indd

Ga

lley:

1

S&H

Phar

maG

raph

ics

Disk

DATE

SIGN

OFF

PGQC

TCAD

CDCW

AE/A

SED

PROD

4.0 11.2months months

1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21

No. of patients at risk:COMETRIQ® 219 121 78 55 31 12 2 1 Placebo 111 35 11 6 3 2 0 0

Months

Prob

abili

ty o

f pat

ient

s w

ho a

re p

rogr

essi

on fr

ee

4.0 11.2months

median

months

median

COMETRIQ® (n=219) Placebo (n=111)

HR=0.2895% CI: 0.19, 0.40P<0.0001

PFS1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21

No. of patientsat risk:COMETRIQ® 219 121 78 55 31 12 2 1Placebo 111 35 11 6 3 2 0 0

Months

Prob

abili

ty o

f pat

ient

s w

ho a

re p

rogr

essi

on fr

ee

4.0 11.2months

median

months

median

COMETRIQ® (n=219)Placebo (n=111)

HR=0.2895% CI: 0.19, 0.40P<0.0001

PFS

Attack from multiple anglesCOMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro• These tyrosine kinases are involved in both normal cellular function and pathologic

processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment

MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

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

Statistically significant efficacy in patients with progressive, metastatic MTC• COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients

with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within

14 months prior to study entry• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001)• Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the

planned interim analysis

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo

© 2014 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 05/14 [COM-0086]COORDINATED ATTACK

Important Safety InformationWARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE• 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.

• 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.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

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.Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). 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.Osteonecrosis of the Jaw (ONJ): 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.Palmar- Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe 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: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 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.Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. 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.Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).In clinical trials, 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.Please see accompanying brief summary of Prescribing Information, including Boxed Warnings.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1


1ej

27902a 05.12.14 133

Q1 Q2

S:6.75” S:6.75”

S:9.75”

T:15”

T:10.25”

B:17.5”

B:11.25”

http://www.cometriq.com/hcp/


Announcements

• Sunday Ocheni, MBBS, FMCPath (Nigeria) and mentor Ayman Saad, MD (Evelina London Children’s Hospital, London)

• Emmanuel Okakpu, MBBS (Nige-ria) and mentor Jean-Jacques Kilad-jan, MD, PhD (Saint-Louis Centre

D’Investigations Clinique, Paris)• Ekarat Rattarittamrong, MD (Thai-

land) and mentor Jean-Jacques Kil-adjan, MD, PhD (Saint-Louis Cen-tre D’Investigations Clinique, Paris)

• Eloísa Riva, MD (Uruguay) and mentor Giampaolo Merlini, MD (Amyloidosis Research and Treat-ment Center at the University

of Pavia, Italy)• Ninoska Rojas Soto, MD (Peru)

and mentor Heather Symons, MD (The Johns Hopkins University, Bal-timore)

• Yuliya Shestovska, MD (Ukraine) and mentors Sergio Giralt, MD, and Miguel-Angel Perales, MD (Memorial Sloan Kettering Cancer

Center, New York)• Zsofia Varady, MD, PhD (Roma-

nia) and mentor Richard Jones, MD ( Johns Hopkins Kimmel Cancer Center, Baltimore)

• Tamunomieibi Wakama, MBBS, FMCPath (Nigeria) and mentor Vishalla Neppalli, MD (Roswell Park Cancer Center, Buffalo) n

Global Training Programcontinued from page 17

JOB#

: 483

34

CLIE

NT: E

xelix

is DE

SC: J

ourn

al Ad

A si

ze

FILE

NAM

E: E

XL_X

LX_Q

4833

4_JA

_D01

.indd

DA

TE: 5

-12-

2014

6:1

1 PM

RO

UND:

1

1 PG: P

ared

esA/

Cruz

, Feli

x AD

: L B

udre

au

PM: N

one

AE: K

Ruf

f CW

: S G

uest

La

st S

aved

: 5-1

2-20

14 6

:11

PMTR

IM: 1

5” x

10.

25”

BLEE

D: 1

7.5”

x 1

1.25

” SA

FETY

: 6.7

5” x

9.7

5”

PROD

: M H

aight

IN

K Sp

ec: 4

c PR

INT

SCAL

E: 7

5%FO

NTS:

Non

e

IMAG

ES: C

omet

riq_7

x10_

Jan1

4_BS

_p1.

pdf (

100%

), Co

met

riq_7

x10_

Jan1

4_BS

_p2.

pdf (

100%

)IN

KS:

Blac

kDO

C PA

TH: M

acint

osh

HD:U

sers

:par

edes

a:De

skto

p:EX

L_XL

X_Q4

8334

_JA_D

01.in

ddNO

TES:

Non

e

EXL_

XLX_

Q483

34_JA

_D01

.indd

Ga

lley:

2

S&H

Phar

maG

raph

ics

Disk

DATE

SIGN

OFF

PGQC

TCAD

CDCW

AE/A

SED

PROD

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012

1. INDICATIONS AND USAGECOMETRIQ 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 COMETRIQPermanently 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; or 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 PRECAUTIONS5.1 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 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% of 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%) 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 REACTIONS6.1 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, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred 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 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)]

MedDRA System Organ Class/ Preferred Terms

Cabozantinib (n=214)

Placebo (n=109)

All Grades

Grades 3-4

All Grades

Grades 3-4

GASTROINTESTINAL DISORDERSDIARRHEA 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 CONDITIONSFATIGUE 41 9 28 3

ASTHENIA 21 6 15 1

INVESTIGATIONSDECREASED WEIGHT 48 5 10 0

METABOLISM AND NUTRITION DISORDERSDECREASED APPETITE 46 5 16 1

DEHYDRATION 7 2 2 1

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERSARTHRALGIA 14 1 7 0

MUSCLE SPASMS 12 0 5 0

MUSCULOSKELETAL CHEST PAIN 9 1 4 0

NERVOUS SYSTEM DISORDERSDYSGEUSIA 34 0 6 0

HEADACHE 18 0 8 0

DIZZINESS 14 0 7 0

PARESTHESIA 7 0 2 0

PERIPHERAL SENSORY NEUROPATHY

7 0 0 0

PERIPHERAL NEUROPATHY 5 0 0 0

PSYCHIATRIC DISORDERSANXIETY 9 0 2 0

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERSDYSPHONIA 20 0 9 0

SKIN AND SUBCUTANEOUS TISSUE DISORDERSPPES5 50 13 2 0

HAIR COLOR CHANGES/ DEPIGMENTATION, GRAYING

34 0 1 0

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 DISORDERSHYPERTENSION 33 8 4 0

HYPOTENSION 7 1 0 01 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. 2 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.

5Palmar-plantar erythrodysesthesia syndrome.

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGESee 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)

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.17. PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients

of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ.

• COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.

• COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.

• COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.

• To contact their healthcare provider before any planned surgeries, including dental procedures.

• COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.

• Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ.

• Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least

2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.

• Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.

Reference ID: 3223542

Distributed by Exelixis, Inc.11/2012

© 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 11/12 [24523]

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)]

ADVERSE EVENT COMETRIQ (n=214) Placebo (n=109)

All Grades

Grade 3-4 All Grades Grade 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.

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301

HYPERTENSION, JNC1 STAGE COMETRIQ N=2113 (%)

Placebo N=1073 (%)

Normal: Grade 0: Systolic <120 mmHg and Diastolic <80 mmHg

4

15

Pre-hypertension: Systolic ≥120 mmHg or Diastolic ≥80 mmHg

34

54

Stage 1: Systolic ≥140 mmHg or Diastolic ≥90 mmHg

46

25


15 5

Malignant: Diastolic ≥120 mmHg

0

0

1 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.

3Subjects with at least two blood pressure measurements after the first dose.

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 single-dose 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 single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, 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 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

KCosmos Communications 1

1ej

27902a 05.12.14 133

Q1 Q2

S:6.75” S:6.75”

S:9.75”

T:15”

T:10.25”

B:17.5”

B:11.25”



Medicare Part D Low-Income Subsidy Program Improves Adherence to Hormone Therapy After Breast Cancer Surgery

Findings from a study of more than 23,000 women suggest that the

Medicare Part D Extra Help program, which provides low-income subsidies for medications, improves adherence

to hormone therapy after breast can-cer surgery in all racial/ethnic groups and reduces racial/ethnic disparities. The study, reported at the 2014 ASCO Quality Care Symposium,1 suggests

that overcoming economic barriers to medication access may ultimately help reduce breast cancer outcome dispari-ties, especially among racial minorities.

“Patients are more likely to take their

medications if they are able to afford them,” said lead study author Alana Biggers, MD, MPH, Assistant Profes-sor of Clinical Medicine at the Uni-versity of Illinois, Chicago. “Our study shows that federal policy interventions that help cover out-of-pocket costs have the potential to reduce the breast can-cer outcome gap by race and ethnicity.”

While breast cancer predominantly affects white women, breast cancer out-comes are worse among black women. In fact, black women are more likely to die of breast cancer than any other group. Breast cancer death rates are also higher among women with low socioeconomic status, regardless of race/ethnicity.

Study DetailsHormone therapy can reduce risk of

breast cancer recurrence and improve chances for long-term survival. In this study, data were collected from a national sample of 23,299 Medicare Part D enroll-ees with early-stage breast cancer who re-ceived hormone therapy within 1 year of surgery. Overall, 27% of the women were enrolled in the Extra Help low-income subsidy program, which eliminated or reduced out-of-pocket costs for the hor-mone therapy. The out-of-pocket costs ranged from $155 to $428 per year, on av-erage. Racial minorities were more likely to be enrolled in the program.

In the first year of hormone therapy, overall adherence rates were similar across all races (64% for white women, 63% for black women, and 67%for Hispanic women). However, racial/ethnic dispari-ties in adherence were evident among the subgroup of women who were not enrolled in the Extra Help program, with white women having significantly higher adherence rates (62%) compared to black and Hispanic women (55%).

In all racial/ethnic groups, adherence rates were higher among women who re-ceived the low-income subsidy, compared to those who did not. In addition, although hormone therapy adherence rates declined in years 2 and 3, adherence rate reductions were smaller among those who used the Extra Help program, and this trend was ob-served in all racial/ethnic groups. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference1. Biggers A, et al: Medicare Part D low-

income subsidy and disparities in breast cancer treatment. Quality Care Symposium. Abstract 2. Presented October 17, 2014.

JOB#

: 483

34

CLIE

NT: E

xelix

is DE

SC: J

ourn

al Ad

A si

ze

FILE

NAM

E: E

XL_X

LX_Q

4833

4_JA

_D01

.indd

DA

TE: 5

-12-

2014

6:1

1 PM

RO

UND:

1

1 PG: P

ared

esA/

Cruz

, Feli

x AD

: L B

udre

au

PM: N

one

AE: K

Ruf

f CW

: S G

uest

La

st S

aved

: 5-1

2-20

14 6

:11

PMTR

IM: 1

5” x

10.

25”

BLEE

D: 1

7.5”

x 1

1.25

” SA

FETY

: 6.7

5” x

9.7

5”

PROD

: M H

aight

IN

K Sp

ec: 4

c PR

INT

SCAL

E: 7

5%FO

NTS:

Non

e

IMAG

ES: C

omet

riq_7

x10_

Jan1

4_BS

_p1.

pdf (

100%

), Co

met

riq_7

x10_

Jan1

4_BS

_p2.

pdf (

100%

)IN

KS:

Blac

kDO

C PA

TH: M

acint

osh

HD:U

sers

:par

edes

a:De

skto

p:EX

L_XL

X_Q4

8334

_JA_D

01.in

ddNO

TES:

Non

e

EXL_

XLX_

Q483

34_JA

_D01

.indd

Ga

lley:

2

S&H

Phar

maG

raph

ics

Disk

DATE

SIGN

OFF

PGQC

TCAD

CDCW

AE/A

SED

PROD

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012

1. INDICATIONS AND USAGECOMETRIQ 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 COMETRIQPermanently 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; or 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 PRECAUTIONS5.1 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 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% of 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%) 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 REACTIONS6.1 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, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred 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 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)]

MedDRA System Organ Class/ Preferred Terms

Cabozantinib (n=214)

Placebo (n=109)

All Grades

Grades 3-4

All Grades

Grades 3-4

GASTROINTESTINAL DISORDERSDIARRHEA 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 CONDITIONSFATIGUE 41 9 28 3

ASTHENIA 21 6 15 1

INVESTIGATIONSDECREASED WEIGHT 48 5 10 0

METABOLISM AND NUTRITION DISORDERSDECREASED APPETITE 46 5 16 1

DEHYDRATION 7 2 2 1

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERSARTHRALGIA 14 1 7 0

MUSCLE SPASMS 12 0 5 0

MUSCULOSKELETAL CHEST PAIN 9 1 4 0

NERVOUS SYSTEM DISORDERSDYSGEUSIA 34 0 6 0

HEADACHE 18 0 8 0

DIZZINESS 14 0 7 0

PARESTHESIA 7 0 2 0

PERIPHERAL SENSORY NEUROPATHY

7 0 0 0

PERIPHERAL NEUROPATHY 5 0 0 0

PSYCHIATRIC DISORDERSANXIETY 9 0 2 0

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERSDYSPHONIA 20 0 9 0

SKIN AND SUBCUTANEOUS TISSUE DISORDERSPPES5 50 13 2 0

HAIR COLOR CHANGES/ DEPIGMENTATION, GRAYING

34 0 1 0

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 DISORDERSHYPERTENSION 33 8 4 0

HYPOTENSION 7 1 0 01 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. 2 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.

5Palmar-plantar erythrodysesthesia syndrome.

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGESee 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)

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.17. PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients

of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ.

• COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.

• COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.

• COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.

• To contact their healthcare provider before any planned surgeries, including dental procedures.

• COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.

• Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ.

• Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least

2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.

• Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.

Reference ID: 3223542

Distributed by Exelixis, Inc.11/2012

© 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 11/12 [24523]

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)]

ADVERSE EVENT COMETRIQ (n=214) Placebo (n=109)

All Grades

Grade 3-4 All Grades Grade 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.

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301

HYPERTENSION, JNC1 STAGE COMETRIQ N=2113 (%)

Placebo N=1073 (%)

Normal: Grade 0: Systolic <120 mmHg and Diastolic <80 mmHg

4

15

Pre-hypertension: Systolic ≥120 mmHg or Diastolic ≥80 mmHg

34

54


46

25


15 5

Malignant: Diastolic ≥120 mmHg

0

0

1 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.

3Subjects with at least two blood pressure measurements after the first dose.

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 single-dose 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 single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, 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 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


1ej

27902a 05.12.14 133

Q1 Q2

S:6.75” S:6.75”

S:9.75”

T:15”

T:10.25”

B:17.5”

B:11.25”



Checklists: Simple Tools That Enhance QualityBy Ronald Piana

Evidence indicates that the use of surgical safety checklists results

in marked improvements in patient outcomes. Unfortunately, their adop-tion in the field of medicine has largely been limited to equipment operations or parts of specific treatment algo-rithms. Yet they have tremendous po-tential to improve patient outcomes by democratizing knowledge and helping ensure that all patients receive evidence-based best practices and safe high-quality care.

That said, not all checklists are cre-ated equal, and the development and use of this simple tool are more com-plicated than it would appear. The value and proper use of checklists were fully examined at this year’s Quality Care Symposium by William Berry, MD, MPA, MPH, FACS, Principal Research Scientist, Department of Health Policy and Management, Harvard School of Public Health, Boston.1

“I want to spend time talking about a decades-long journey I’ve been on with several colleagues, which has led to a better understanding about how to use checklists for quality improve-ment. And I believe there is a place for a checklist or a standardized protocol when delivering chemotherapy, espe-cially in the oral administration setting,” said Dr. Berry.

Learning From DisasterTo illustrate the potential conse-

quences of missing a protocol step, Dr. Berry took the audience back to the early 1930s. At that time, the U.S. Army Air Corps was looking for a multiengine bomber that had greater capacity and range to replace the old Martin B-10. Boeing won the contract and designed and built the B-17 bomber, known as the Flying Fortress. On October 30, 1935, with Boeing’s two best test pilots at the controls, the B-17 rolled down the runway on its second test flight be-fore a crowd of reporters.

When the huge plane lifted off the runway, it stalled, nosed over, and crashed in a ball of fire, killing the

two pilots. It was discovered that the crew had forgotten to disengage the “gust locks,” a system of devices that are locked in place while the aircraft is parked on the ground but must be un-locked before takeoff to avoid the kind of disaster that befell the B-17. Subse-quently, the use of preflight checklists became standard procedure by military pilots and was later adopted by all com-mercial pilots.

Enhanced Patient OutcomesThe checklist didn’t stop with the

airline industry. Dr. Berry pointed to the famous intensive care checklist de-veloped by Peter J. Pronovost, MD, PhD, of Johns Hopkins Hospital, Balti-

more, that experts say has saved count-less thousands of lives and hundreds of millions of health-care dollars. “Check-lists are now spreading more broadly throughout medicine, particularly for certain settings where they are very use-ful and enhance patient outcomes,” said Dr. Berry.

He continued, “I think you can use checklists to change workplace policies, improve your patient care process, en-hance teamwork and communication, and help guide a conversation among your colleagues.” He added that check-lists standardize and improve the reli-able translation of information so that the same knowledge is available to doc-tors, nurses, and patients.

Know When and Where to Use Checklists

Dr. Berry then drilled down to the specific strongpoints of the checklist.

“If a task has a lot of important steps, which increases the possibility of ac-cidently omitting one, a checklist be-comes an important tool. Moreover, tasks that are performed under stress can benefit from a checklist because people working under stress are more likely to forget an important item, which can prove fatal in certain patient care settings. Checklists are also useful for reminding people to do new things that have recently been integrated into the patient care path,” said Dr. Berry.

Dr. Berry explained that there are places where checklists should not be used. “Checklists aren’t particularly valuable as a learning tool since we don’t absorb complex information in

that kind of linear fashion. Also, check-lists by their very nature are designed for simplicity; they don’t take the place of algorithms or procedure guides that are needed in highly complex scenari-os,” said Dr. Berry.

He explained that there are two basic kinds of checklists. “There is a read-do checklist, which means that you read through the checklist while you’re do-ing the task. And there is the read-con-firm checklist, in which one party of the medical team reads a point off the list, and it is verbally confirmed by another team member,” said Dr. Berry.

“I look at checklist development in several major phases and virtually ev-ery quality improvement measure ad-dresses these phases. In the first phase, you need to be focused on the steps you want integrated into your tool. Then comes the tool-making part, when you actually draft the document. The most

important step here is to keep it as sim-ple as possible. No one should have to work off a six-page checklist. And prob-ably the most important aspect of mak-ing a checklist is to test it in the clinical setting it’s designed for before finalizing it as a document,” stressed Dr. Berry.

Practice Is NeededDr. Berry noted that a checklist by

itself is just a piece of paper, and proper training is essential to making it a valu-able tool in the clinic. “Actual practice using the checklist away from the pa-tient setting is the best way for people to learn. Repetitive workshops during which the checklist is used also creates a good communication base for the care team,” said Dr. Berry, adding, “Collect-ing feedback and learning about what works well is essential for long-term use.”

Dr. Berry’s presentation concluded with a simple takeaway message. “The one idea I want to leave you with, which might seem patently obvious, is that if you want someone to use this tool, have a one-on-one conversation with him. Don’t send out e-mails or tweet about it. That works for some ideas but not this kind of hands-on tool. If you want people to change their behavior in the clinic, it is important to have a personal conversation with them.” n

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

Reference1. Berry W: Patient safety across disci-

plines: Checklists (surgery). Quality Care Symposium. Presented October 18, 2014.

Using Checklists in the Clinic

■ Respect the workflow.

■ Keep them simple.

■ Create a multidisciplinary team.

■ Test before you use them with patients.

■ Train people how to use them.

■ Engage everyone individually.

If you want people to change their behavior in the clinic, it is important to have a personal conversation with them.

—William Berry, MD, MPA, MPH, FACS

Visit The ASCO Post website at ASCOPost.com

Our Roots Go DeepTake a deeper look at our reliability and qualityvisit biotechnologybyamgen.comDownload the LAYAR app on your smartphone and scan this page.

At Amgen, we pour commitment, passion, and a drivefor perfection into every biologic medicine we make.

From innovative biotechnology to extensive experience in biologic manufacturing, see how Amgen strives to deliver on its commitment to your patients.

©2014 Amgen Inc. All rights reserved. 80012-R2-V1

our roots go deepFor reliability and quality,

http://www.amgenbiotech.com/index.html



A National Cancer Database and Cancer Care Quality ImprovementBy Ronald Piana

At this year’s Quality Care Sym-posium, Lawrence N. Shulman,

MD, Chief of Staff and Director of the Center for Global Cancer Medicine at Dana-Farber Cancer Institute, Bos-ton, looked at the issue of quality in-frastructure development through the prism of several tools developed by the American College of Surgeons’ Com-mission on Cancer. Dr. Shulman is one of two ASCO representatives to that consortium and Chair of the Commis-sion on Cancer’s Quality Committee.

“The Commission on Cancer was established by the American College of Surgeons in 1922, at a time when surgery was the only available cancer treatment. It is a now a broad-based consortium of professional organiza-tions dedicated to improving survival and quality of life for cancer patients in hospitals. There are currently about 1,500 U.S. hospitals that are ac-credited by the Commission,” said Dr. Shulman.

Dr. Shulman explained that the Na-tional Cancer Data Base was formed in 1988 as a joint venture of the American College of Surgeons and the American Cancer Society. “Approximately 70% of newly diagnosed cancer patients have their records in the [National Cancer Data Base]. We currently have about 30 million records from hospital cancer registries across the country,” said Dr. Shulman.

Web-Based ToolsHe then described the Rapid Qual-

ity Reporting System (RQRS), a fairly new Web-based data collection tool from the National Cancer Data Base. “All case information reported to the system is collected by cancer registries at participating programs and entered into their registry database. The sys-tem makes it easier for us to deliver evidence-based care in real clinical time. We do case tracking and ongoing reporting of quality metrics,” said Dr. Shulman.

“Another important component of the reporting system is that we can give feedback to clinicians if their

patients have not had their recom-mended treatment in the appropriate time frame,” he continued. “So, if you have a patient who has had breast-conserving surgery, and after a certain period of time—I believe it should be about 180 days—she hasn’t received breast radiation therapy, the system pings the cancer program about the need for the treatment,” said Dr. Shul-man. He added, “This is a voluntary program, and about 900 of the 1,500 hospital programs are participating in the RQRS. We feel that within a year or two, all hospital programs will be enrolled.”

Another Web-based tool is the Can-cer Program Practice Profile Report,

which hospitals can use to measure their compliance rates in a number of different quality metrics in the treat-ment of breast, colon, and rectal can-cers. “This tool helps cancer programs gauge their intrafacility trends over time and compare the results to other facilities. It empowers clinicians, ad-ministrators, and other hospital staff to work cooperatively and diminish care disparities,” noted Dr. Shulman.

Other InitiativesDr. Shulman discussed another

benefit of being a College of Surgeons’ accredited institution. “The Partici-pant User File Research Program al-lows external researchers from any of the 1,500 member hospitals to con-duct outcomes research utilizing the 30 million cancer patient records in the [National Cancer Data Base]. It’s

a relatively easy three-page application for research data. In 2014, we received 227 applications and approved 194. The main reason for not approving a submission is that the data they were requesting didn’t exist.”

Dr. Shulman then discussed the very important initiative, the Cancer Quality Improvement Program, which was launched in 2013, and the first re-ports were delivered in February 2014. “We’re currently preparing the 2014 report and we hope to deliver them to the [Commission on Cancer] institu-tions by the end of the calendar year. This program is a data-driven, process and outcomes-based quality improve-ment program that generates individ-

ual facility level quality reports with a side-by-side comparison to other [Commission on Cancer] hospitals,” said Dr. Shulman.

He explained that the annual re-ports are in PowerPoint format that analyzes patient demographics, quality measures, survival data, and patients’ migration into and out of the system. “We think the target audience for these reports includes the hospital’s cancer committee, the individual oncolo-gists, and the hospital’s executives and administration. So this data tool has value across the full spectrum of the hospital,” said Dr. Shulman.

Report FeaturesIn the 2014 report, there will be

data on 12 quality metrics. “Before we develop quality measures, we look into the [National Cancer Data Base]

to identify the most important ini-tiatives we should approach. For in-stance, one of the new measures is to have at least 10 regional lymph nodes removed and pathologically exam-ined for staging IA, IB, IIA, and IIB resected non–small cell lung cancer. In 2012, the baseline adherence to this measure was only 39%, so there’s a lot of room for quality improvement there,” commented Dr. Shulman.

The report shows the individual hospital’s performance rate in each disease and also against the state, the region, and all Commission on Can-cer programs, giving hospital leaders and doctors a good overall picture of their performance rate. “We’re also looking at survival data, both risk-adjusted and unadjusted. Beginning with breast, colon, and lung disease sites, these stage-specific data will be adjusted for age, race, gender, insur-ance status, and comorbidities,” ex-plained Dr. Shulman.

Dr. Shulman noted that the pro-gram automatically produces reports on a yearly basis, so no chart abstrac-tions are required, and it includes all cases from the participating institu-tion. Moreover, there are a growing number of quality metrics being developed.

“There are a couple of disadvan-tages to the system. For example, specific systemic drugs are not in-cluded in the report and the informa-tion on tumor biomarkers is not yet complete,” said Dr. Shulman, adding, “The [Commission on Cancer] is dedicated to improving quality of life for patients through evidence-based care, and these tools that I’ve been discussing are an integral part of that effort.” n

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

Reference1. Shulman LN: National Cancer Data-

base and the Cancer Quality Improvement Program for the Commission On Cancer. Quality Care Symposium. Presented Octo-ber 18, 2014.

Technology

Approximately 70% of newly diagnosed cancer patients have their records in the [National Cancer Data Base]. We currently have about 30 million records from hospital cancer registries across the country.

—Lawrence N. Shulman, MD



Having Dependent Children Motivates Parents With Advanced Cancer to Pursue More Aggressive, Life-Extending Treatments

Findings from a pilot study of 42 par-ents with advanced cancer indicate

that parental status is an important fac-tor in treatment decision-making. When asked how having children influences their treatment decisions, the majority of par-ents (64%) responded that being a parent motivates them to pursue life-extending treatments, largely out of a desire to have more time with their children. A smaller proportion of parents (15%) identified preserving parental functioning as a treat-ment priority, and 12% mentioned the importance of receiving treatment close to their families, vs traveling for a second opinion, or pursuing treatment that may require long hospital stays.

Parenting concerns identified in this study will inform further research in this understudied patient population. The study findings were reported at the 2014 ASCO Quality Care Symposium.1

“Numerous psychosocial factors in-fluence patients’ decisions about can-cer treatment. It’s important for patients with dependent children to discuss their treatment priorities with their oncolo-gist, who may not know, for example, how important it is for a patient with children to preserve their function-ing at home,” said lead author Devon Check, a PhD student at the University of North Carolina, Chapel Hill. “We hope that our study can help oncologists engage patients with children in shared decision-making and promote alignment of the treatment plan with the patients’ priorities.”

Study DetailsPrior studies suggested that patients

with advanced cancer who are parents prefer aggressive treatments for their ill-ness more often than patients who are not parents. The present study, which focused solely on patients with dependent children, is the first to directly ask parents if and how having children affects their treatment pref-erences, beyond serving as a motivator for aggressive treatment. It is also the first to include qualitative methods, which helped elucidate more nuanced factors influenc-ing decision-making.

Researchers interviewed 42 patients with metastatic cancer who have children younger than 18 years. Parents had an aver-age age of 44, and the average age of their children was 12. When queried about preferences for palliative care and hospice, 52% of parents indicated an interest in using hospice services. Of these parents, many recognized hospice as a supportive resource for their family. Others were spe-

cifically interested in institutional vs home hospice care, due to a desire to protect their children from the dying experience. Twen-ty-four percent of parents reported an in-terest in receiving palliative care concurrent

with their cancer treatment, although sev-eral parents seemed to conflate palliative care with end-of-life care. n


Reference1. Check D, et al: How does parental sta-

tus influence preferences for cancer treatment and palliative care? Quality Care Symposium. Abstract 65. Presented October 18, 2014.

Primary Endpoint: • Objective survival

Secondary Endpoints: • Safety: incidence of adverse events

• Overall response rate

• Progression-free survival

• Duration of response

Key Inclusion Criteria2: • Locally advanced or metastatic NSCLC

(stage IIIB, stage IV, or recurrent)

• Representative FFPE tumor specimens

• Disease progression during or following platinum-containing treatment regimen

• Measurable disease, defined by RECIST v1.1

• ECOG performance status of 0-1

Key Exclusion Criteria2: • History of autoimmune disease

• Active hepatitis B or hepatitis C

• Prior treatment with docetaxel, CD137 agonists, anti-CTLA4, anti-PD1, anti-PDL1 antibodies, or pathway-targeting agents

Patients with locally advanced ormetastatic NSCLC who have failed platinum-containing chemotherapy

Now Enrolling

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp.

© 2014 Genentech USA, Inc. All rights reserved. BIO0002588200 Printed in USA.

A Randomized Phase III Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) Compared to Docetaxel in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Failed Platinum Therapy (NCT02008227, Study ID GO28915)OAK

MPDL3280A1

(an engineered anti-PDL1 antibody)

Docetaxel

N=850Randomized 1:1

Visit: clinicaltrials.gov or

antiPDL1ClinicalTrials.com/hcp

For more information

Visit: clinicaltrials.gov or

antiPDL1ClinicalTrials.com/hcp

Call: Genentech Trial Information

Support Line: 1-888-662-6728 (US only)

E-mail: [email protected]

77659ha_h.indd 1 7/29/14 11:19 PM

http://www.biooncology.com



Tumor Board Participation Associated With Improved Survival in Stage IV Lung and Colorectal CancersBy Alice Goodman

A large, population-based, obser-vational study suggests that par-

ticipation in weekly tumor boards can improve outcomes in oncologic care. Specifically, oncologist participation in weekly tumor board meetings was asso-ciated with improved survival in patients with stage IV small cell lung cancer and stage IV colorectal cancers. Weekly tu-mor board participation was also asso-ciated with an increased likelihood of patient enrollment in clinical trials and increased the likelihood of guideline-based curative surgery for patients with early-stage non–small cell lung cancer (NSCLC).

“Prior single-center studies suggest that tumor boards often change treat-ment recommendations. These findings from a larger study are exploratory and will be the basis of future research. Pa-tients with lung cancer and colorectal cancer may want to ask their doctors if

their cases will be discussed by a tumor board that includes multidisciplinary experts,” said lead author Kenneth L. Kehl, MD, a fellow in cancer medicine at The University of Texas MD Ander-son Cancer Center, Houston.

Study DetailsThe study utilized data from the

Cancer Care Outcomes Research and Surveillance Consortium (CanCORS), with a total of 9,732 patients diagnosed

with lung or colorectal cancer from 2003 to 2005. Of them, a cohort of 4,620 pa-tients were included in this study, as well as 1,601 physicians who reported on their tumor board participation; of them, 1,198 were linked directly to the patients in the cohort. Physicians were asked how often they participated in tu-mor board meetings, whether the meet-ings were educational or helped in treat-ment-planning, whether they reviewed challenging cases only, and whether tumor board meetings focused on more than one cancer site.

Patients had a mean age of 68 years, 51% were male, 62% were married, and stage at diagnosis was evenly distributed between both types of cancers. Among physicians, 33% were medical oncolo-gists, 15% were radiation oncologists, 37% were general surgeons, and 15% were subspecialty surgeons. Physicians treated a mean of eight lung cancer pa-tients and eight colorectal cancer pa-tients per month. Twenty-seven percent of physicians worked at a National Can-cer Institute–designated cancer center.

Patterns of ParticipationThe study revealed different patterns

of oncologist participation in multidis-ciplinary tumor boards. About 54% par-ticipated weekly, 26% monthly, 8% quar-terly, 8% less than quarterly, and 4% said they never participated in tumor boards.

Among those who ever participated in a tumor board, 83% said their tumor board primarily served a pretreatment planning function, 92% said it includ-ed evaluation of treatment decisions, 59% reviewed only challenging cases, 87% reviewed multiple tumor sites, and 12% were for educational purpos-es only.

Among physicians, radiation oncol-ogists were more likely to participate in tumor boards, while surgeons and surgery subspecialists were less likely to participate. Those who worked at a Veteran’s Administration/government facility were more likely to participate, whereas those in solo or group prac-tices were less likely.

Tumor board participation in chal-lenging cases only was associated with lower mortality rates, and participa-tion in educational tumor boards was associated with higher mortality.

Note of CautionDr. Kehl cautioned that this was

not a randomized trial, so one should not leap to the conclusion that tumor board participation directly improves survival. The study identifies associa-tions rather than direct effects.

“This study supports our belief that multidisciplinary communication im-proves outcomes and enrollment in clinical trials. Tumor boards represent one tool that can improve care for can-cer patients, and the effect is difficult to measure,” Dr. Kehl noted. n

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

Reference1. Kehl KL: Tumor boards among

physicians caring for lung and colorectal cancer patients. Quality Care Symposium. Abstract 179. Presented October 17, 2014.

EXPERT POINT OF VIEW

Formal discussant of the Quality Care Symposium presentation on the impact of tumor boards, Deborah Schrag, MD, MPH, Dana-Farber

Cancer Institute, Boston, commended the authors for the collaborative use of data to improve quality of care. “For this study, Dr. Kehl and coauthors leveraged the considerable strengths of the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) and linked unique physicians car-ing for particular patients. This is as powerful an observational study as we

are likely to see on this topic. The upshot is that tumor board participation does seem to be associated with higher quality clinical care,” she said.

“The study shows an association but no causal link, but physicians who practice at sites that have the wherewithal to hold tumor boards have the training, colleagues, and expertise to deliver high-quality care. In other words, the tumor boards could be an ancillary effect, not a cause, of the bet-ter outcomes seen in this study,” she continued.

This issue needs to be further studied to identify what works and what doesn’t, Dr. Schrag said. She cautioned that patients and entrepreneurs are in the wings inviting doctors to spend a half-hour on the phone participating in tumor boards. “If we don’t get our act together, companies are going to get ahead of us,” she stated. n

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

Impact of Tumor Boards on Cancer Care

A large observational study suggested that weekly tumor board participa-tion by oncologists improves survival in advanced lung and colorectal

cancers, increases participation in clinical trials, and leads to greater use of guideline-based curative care for early non–small cell lung cancer.

This is an observational study only, and it is difficult to quantify the direct effect of tumor board participation.

It is likely that facilities that sponsor tumor boards have improved exper-tise to deliver high-quality care, so participation may not be directly related to improved outcomes. n

The upshot is that tumor board participation does seem to be associated with higher quality clinical care.

—Deborah Schrag, MD, MPH

This study supports our belief that multidisciplinary communication improves outcomes and enrollment

in clinical trials. Tumor boards represent one tool that can improve care for cancer patients,

and the effect is difficult to measure. —Kenneth L. Kehl, MD



Assessing the Nature of Unplanned Emergency Cancer Care SituationsBy Ronald Piana

Unplanned cancer care—emer-gency department presentations

and other unanticipated events—can result in poor outcomes that are po-tentially preventable. Suzanne Ta-mang, PhD, Stanford University, Stanford, California, addressed this important issue in her presentation at this year’s Quality Care Symposium in Boston.1 “Avoiding unplanned care is in the interest of many health-care stakeholders. Not only is it unpleasant for patients and their caregivers, it can compromise the ability to achieve ex-pected outcomes and can also disrupt carefully planned cancer treatments. And as we move toward value-based payment systems, unplanned cancer care is of increasing interest to payers and providers,” said Dr. Tamang.

Goals and MethodsDr. Tamang and her colleagues

conducted a study to identify and reduce unplanned episodes of un-planned care. She explained that al-though cancer care teams document each patient’s care trajectory in free-text notes, care outcomes are typical-ly measured from structured patient record data and do not contain key information necessary for quality im-provement efforts, such as the etiol-ogy of emergent events, or events that occur outside the facility.

“We conducted our study with the Clinical Effectiveness Council at Stanford’s Cancer Institute, look-ing at emergency department visits and unplanned hospitalizations. Our data-driven approach used electronic health records and captured emer-gent events coded in the Stanford Cancer Institute electronic health record and non-Stanford episodes, which were documented in clinician notes,” said Dr. Tamang. She contin-ued, “After the data were captured, we combined the information from both data sources and used the emer-gency department presentations to

characterize their symptomatology.” Dr. Tamang explained that the

team’s quality improvement goal was to achieve a reduction in unplanned episodes of cancer care among the co-horts. “Quality measurement supports high-value care. And in order to assess the quality, we needed a benchmark to establish a better baseline, which helped inform the design of new inter-ventions and provide continued learn-ing for established protocols,” noted Dr. Tamang.”

Reducing Unplanned Care “The best models we have now are

built from administrative data and oth-

er structured sources for quality mea-sures, which are fairly limited in their ability to report quality measures and patient characteristics. For instance, at Stanford we see only a partial trajecto-ry of care. There may be other episodes of unplanned care occurring at other inpatient facilities or urgent care cen-ters. In terms of chief-complaint analy-ses, one chief symptom may be unable to describe a more complex symptom-atology of cancer patients who are pre-senting to the emergency room,” said Dr. Tamang.

Dr. Tamang explained that their inno-vation goal is to leverage both the struc-tured and unstructured data that are in the electronic health record. “It’s clear that care teams document so much more data in the [electronic health record], especially in terms of quality indicators, process measures, and outcomes. So

there’s a bulk of data in the [electronic health record], of which only a small per-centage is structured-based. And for the most part, a lot of this very rich clinically oriented information, much of which contains quality measures, is being left to gather dust,” stressed Dr. Tamang.

Text-Mining PipelineThe research team conducted a ret-

rospective study of unplanned care among 3,318 patients with a new diag-nosis of breast, gastrointestinal, or tho-racic cancer during the years 2010 to 2013. Dr. Tamang gave a brief overview of the team’s text-mining pipeline and how they integrated structured and un-

structured data for information extrac-tion purposes.

“The first two steps involve con-cept recognition during which we need to establish a terminology to an-notate the note. For that we used Cal-ifornia’s OSHPD [Office of Statewide Health Planning and Development] as our resource to find a list of the ur-gent care centers and other facilities with emergency departments. From the National Library of Medicine’s UMLS [Unified Medical Language System], we can extract clinical ter-minologies for the text-mining algo-rithm,” said Dr. Tamang.

The OSHPD and UMLS resourc-es, in effect, served the team as a large dictionary of clinical terms and locations used for annotating clini-cian notes. “There were more than 300,000 clinician notes on patient

care for two tasks and we tagged them, which is part of the concept-recognition process. The third step is the event detection, where we con-struct a patient event matrix in order to further filter and process candidate events,” said Dr. Tamang.

For all cancer patients, text mining detected more than 400 unplanned events at outside facilities with high positive predictive value. “Among breast cancer patients, pain, nausea and vomiting are documented in combination in 34% of documented emergency department presenta-tions, and pain and infection in 29%. Pain is consistently the most preva-lent symptom up to 1 year after di-agnosis, and the most common type documented is abdominal pain,” said Dr. Tamang.

Potential BenefitsShe noted that the application

of text-mining methods could im-prove the quantification of morbid-ity outcomes by improving the esti-mation of unplanned care rates and by providing continued learning for symptom-driven interventions to mitigate preventable emergent care. “Structured and unstructured [elec-tronic health record] data sources are technically feasible to implement and beneficial for profiling symptoms and disorders associated with emer-gency department presentations,” said Dr. Tamang.

She concluded, “These information extraction applications have broad im-plications for improved cancer qual-ity care measures and quality improve-ment efforts.” n

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

Reference1. Tamang S, Patel MI, Finlayson S, et al:

Assessing the true nature of unplanned can-cer care. Quality Care Symposium. Abstract 183. Presented October 18, 2014.

These information extraction applications have broad implications for improved cancer quality care measures and quality improvement efforts.

—Suzanne Tamang, PhD

JOB#: 40831B CLIENT: Chemistry DESC: CLL Resonate Journal Ad - King Size FILE NAME: CHE_IBR_Q40831B_JA_D01.indd DATE: 11-12-2014 6:01 PM ROUND: 1PG: CordobaR/VazZ AD: R Chu x3890 PM: G Ariza-Greve x3825 / V Yenolevage x4743 AE: L Rubin x4284 CW: L Strandell x3824 / D Hanrahan x3812 Last Saved: 11-12-2014 6:01 PMTRIM: 21” x 14” BLEED: 22.25” x 14.25” SAFETY: None PROD: M Haight x4245 INK Spec: 4C PRINT SCALE: 55%FONTS: Trebuchet (Bold, Regular, Italic), Verdana (Regular), Helvetica Neue LT Std (77 Bold Condensed, 57 Condensed), TT Slug OTF (Regular)

IMAGES: 40831_B_JA_fn.tif (CMYK; 300 ppi; 100%), imbruvica_US_4C.eps (59.9%, 21.31%), Janssen_Horiz_gray_rule_4C.eps (80.3%), pharmacyclics_4C.ai (89.8%), 40831B_Resonate_PFS_v1.eps (100%)INKS: Cyan, Magenta, Yellow, BlackDOC PATH: Macintosh HD:Users:cordobar:De...k_prep:CHE_IBR_Q40831B_JA_D01.inddNOTES: None

CHE_IBR_Q40831B_JA_D01.indd Galley: 1

S&H PharmaGraphics

Disk

DATE

SIGNOFF

PG QC TC AD CD CW AE/AS ED PROD

IMBRUVICA® demonstrated single-agent survival inpreviously treated CLL

Superior overall survival (OS) with IMBRUVICA® vs ofatumumab—secondary endpoint(HR=0.43; 95% CI: 0.24, 0.79); P<0.05

• 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA® arm • Median OS not yet reached in either treatment arm

Superior progression-free survival (PFS) with IMBRUVICA® vs ofatumumab—primary endpoint

• Median PFS not yet reached with IMBRUVICA® vs 8.1 months with ofatumumab

IMPORTANT SAFETY INFORMATION

© Pharmacyclics, Inc. 2014© Janssen Biotech, Inc. 201411/14 PRC-00659

In patients with previously treated del 17p CLL, IMBRUVICA® demonstrated a 75% reduced risk of progression or death (HR=0.25; 95% CI: 0.14, 0.45)

• Median PFS not reached with IMBRUVICA® (n=63) vs 5.8 months with ofatumumab (n=64)

Oral, once-daily dosing

In CLL studies, approximately 5% of patients discontinued due to adverse events

Please review the Important Safety Information on adjacent page.

To learn more, visit us atwww.IMBRUVICA.com

INDICATIONS: IMBRUVICA® is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with:

• Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy• CLL with 17p deletion

(HR for progression or death: 0.22; 95% CI: 0.15, 0.32); P<0.0001 Results from the randomized, multicenter, open-label, Phase 3 RESONATE™ trial of IMBRUVICA® vs ofatumumab in patients with previously treated CLL. Patients (N=391) were randomized 1:1 to receive either IMBRUVICA® 420 mg orally daily until disease progression or unacceptable toxicityor IV ofatumumab at an initial dose of 300 mg,followed 1 week later by a dose of 2000 mgweekly for 7 doses, and then every 4 weeks for 4 additional doses. Fifty-seven patients randomized to ofatumumab crossed over following Independent Review Committee (IRC)-confirmed progression to receive IMBRUVICA®. Primary endpoint: PFS as assessed by an IRC according to modified International Workshop on CLL Criteria.

HR=hazard ratio.

WARNINGS AND PRECAUTIONS

Hemorrhage - Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®.

The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving anti-platelet or anti-coagulant therapies. Consider the bene� t-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA®. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial � brillation and atrial � utter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial � brillation. Periodically monitor patients clinically for atrial � brillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial � brillation persists, consider the risks and bene� ts of IMBRUVICA® treatment and dose modi� cation.

Second Primary Malignancies - Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in

patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).

Embryo-Fetal Toxicity - Based on � ndings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. 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.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICA® discontinued treatment due to adverse events. These included infections, subdural hematomas, and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients.

DRUG INTERACTIONS

CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.

CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment - Avoid use in patients with baseline hepatic impairment.

Please review the Brief Summary of full Prescribing Information on the following page.

78% statistically significant reduction in the risk of death or progression (independent review)

PFS

(%)

100

80

60

40

20

00 3 6 9 12 15

Months

P<0.0001 by log-rank test

Number at riskIMBRUVICA®

Ofatumumab195196

183161

11683

3815

71 0

0

Ofatumumab


1ej

29361a 11.12.14 133

Q1 Q2

G: .5" G: .5"L:9.5" L:9.5"

L: 13.375"

T: 14"

B: 14.25"

T: 21"

B: 22.25"

https://www.imbruvica.com/hcp/

JOB#: 40831B CLIENT: Chemistry DESC: CLL Resonate Journal Ad - King Size FILE NAME: CHE_IBR_Q40831B_JA_D01.indd DATE: 11-12-2014 6:01 PM ROUND: 1PG: CordobaR/VazZ AD: R Chu x3890 PM: G Ariza-Greve x3825 / V Yenolevage x4743 AE: L Rubin x4284 CW: L Strandell x3824 / D Hanrahan x3812 Last Saved: 11-12-2014 6:01 PMTRIM: 21” x 14” BLEED: 22.25” x 14.25” SAFETY: None PROD: M Haight x4245 INK Spec: 4C PRINT SCALE: 55%FONTS: Trebuchet (Bold, Regular, Italic), Verdana (Regular), Helvetica Neue LT Std (77 Bold Condensed, 57 Condensed), TT Slug OTF (Regular)

IMAGES: 40831_B_JA_fn.tif (CMYK; 300 ppi; 100%), imbruvica_US_4C.eps (59.9%, 21.31%), Janssen_Horiz_gray_rule_4C.eps (80.3%), pharmacyclics_4C.ai (89.8%), 40831B_Resonate_PFS_v1.eps (100%)INKS: Cyan, Magenta, Yellow, BlackDOC PATH: Macintosh HD:Users:cordobar:De...k_prep:CHE_IBR_Q40831B_JA_D01.inddNOTES: None


S&H PharmaGraphics

Disk

DATE

SIGNOFF


IMBRUVICA® demonstrated single-agent survival inpreviously treated CLL

Superior overall survival (OS) with IMBRUVICA® vs ofatumumab—secondary endpoint(HR=0.43; 95% CI: 0.24, 0.79); P<0.05

• 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA® arm • Median OS not yet reached in either treatment arm

Superior progression-free survival (PFS) with IMBRUVICA® vs ofatumumab—primary endpoint

• Median PFS not yet reached with IMBRUVICA® vs 8.1 months with ofatumumab

IMPORTANT SAFETY INFORMATION

© Pharmacyclics, Inc. 2014© Janssen Biotech, Inc. 201411/14 PRC-00659

In patients with previously treated del 17p CLL, IMBRUVICA® demonstrated a 75% reduced risk of progression or death (HR=0.25; 95% CI: 0.14, 0.45)

• Median PFS not reached with IMBRUVICA® (n=63) vs 5.8 months with ofatumumab (n=64)

Oral, once-daily dosing

In CLL studies, approximately 5% of patients discontinued due to adverse events

Please review the Important Safety Information on adjacent page.

To learn more, visit us atwww.IMBRUVICA.com

INDICATIONS: IMBRUVICA® is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with:

• Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy• CLL with 17p deletion

(HR for progression or death: 0.22; 95% CI: 0.15, 0.32); P<0.0001 Results from the randomized, multicenter, open-label, Phase 3 RESONATE™ trial of IMBRUVICA® vs ofatumumab in patients with previously treated CLL. Patients (N=391) were randomized 1:1 to receive either IMBRUVICA® 420 mg orally daily until disease progression or unacceptable toxicityor IV ofatumumab at an initial dose of 300 mg,followed 1 week later by a dose of 2000 mgweekly for 7 doses, and then every 4 weeks for 4 additional doses. Fifty-seven patients randomized to ofatumumab crossed over following Independent Review Committee (IRC)-confirmed progression to receive IMBRUVICA®. Primary endpoint: PFS as assessed by an IRC according to modified International Workshop on CLL Criteria.

HR=hazard ratio.


Hemorrhage - Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®.

The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving anti-platelet or anti-coagulant therapies. Consider the bene� t-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA®. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial � brillation and atrial � utter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial � brillation. Periodically monitor patients clinically for atrial � brillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial � brillation persists, consider the risks and bene� ts of IMBRUVICA® treatment and dose modi� cation.

Second Primary Malignancies - Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in

patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).

Embryo-Fetal Toxicity - Based on � ndings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. 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.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICA® discontinued treatment due to adverse events. These included infections, subdural hematomas, and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients.

DRUG INTERACTIONS

CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.

CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment - Avoid use in patients with baseline hepatic impairment.

Please review the Brief Summary of full Prescribing Information on the following page.

78% statistically significant reduction in the risk of death or progression (independent review)

PFS

(%)

100

80

60

40

20

00 3 6 9 12 15

Months

P<0.0001 by log-rank test

Number at riskIMBRUVICA®

Ofatumumab195196

183161

11683

3815

71 0

0

Ofatumumab


1ej

29361a 11.12.14 133

Q1 Q2

G: .5" G: .5"L:9.5" L:9.5"

L: 13.375"

T: 14"

B: 14.25"

T: 21"

B: 22.25"

JOB#: 40831B CLIENT: Chemistry DESC: CLL Resonate Journal Ad - King Size FILE NAME: CHE_IBR_Q40831B_JA_D01.indd DATE: 11-12-2014 6:01 PM ROUND: 1PG: CordobaR/VazZ AD: R Chu x3890 PM: G Ariza-Greve x3825 / V Yenolevage x4743 AE: L Rubin x4284 CW: L Strandell x3824 / D Hanrahan x3812 Last Saved: 11-12-2014 6:01 PMTRIM: 21” x 14” BLEED: 22.25” x 14.25” SAFETY: None PROD: M Haight x4245 INK Spec: 4C PRINT SCALE: 55%FONTS: TT Slug OTF (Regular)

IMAGES: 40831B_IBR_9X13_Jul14_BS_p1.pdf (100%), 40831B_IBR_9X13_Jul14_BS_p2.pdf (100%)INKS: BlackDOC PATH: Macintosh HD:Users:cordobar:De...k_prep:CHE_IBR_Q40831B_JA_D01.inddNOTES: None


S&H PharmaGraphics

Disk

DATE

SIGNOFF


Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib)IMBRUVICA® (ibrutinib) capsules, for oral useSee package insert for Full Prescribing Information

INDICATIONS AND USAGEMantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Improvements in survival or disease-related symptoms have not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in full Prescribing Information].Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in full Prescribing Information].Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in full Prescribing Information].CONTRAINDICATIONSNone

WARNINGS AND PRECAUTIONSHemorrhage: Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full Prescribing Information].Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Twenty-five percent of patients with MCL and 26% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly.Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA.Monitor complete blood counts monthly. Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in full Prescribing Information]. Second Primary Malignancies: Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. 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 REACTIONSThe following adverse reactions are discussed in more detail in other sections of the labeling:• Hemorrhage[see Warnings and Precautions]• Infections[see Warnings and Precautions]• Cytopenias[see Warnings and Precautions]• AtrialFibrillation[see Warnings and Precautions]• SecondPrimaryMalignancies[see Warnings and Precautions]Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.The most commonly occurring adverse reactions (≥ 20%) were thrombo cytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2).The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111)

System Organ Class Preferred Term All Grades (%)

Grade 3 or 4 (%)

Gastrointestinal disorders DiarrheaNauseaConstipationAbdominal painVomitingStomatitisDyspepsia

51312524231711

5005010

Infections and infestations Upper respiratory tract infectionUrinary tract infectionPneumoniaSkin infectionsSinusitis

3414141413

03751

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) (continued)


Grade 3 or 4 (%)

General disorders and administrative site conditions

FatiguePeripheral edemaPyrexiaAsthenia

41351814

5313

Skin and subcutaneous tissue disorders

Bruising Rash Petechiae

302511

030

Musculoskeletal and connective tissue disorders

Musculoskeletal painMuscle spasmsArthralgia

371411

100

Respiratory, thoracic and mediastinal disorders

DyspneaCoughEpistaxis

271911

400

Metabolism and nutrition disorders

Decreased appetiteDehydration

2112

24

Nervous system disorders DizzinessHeadache

1413

00

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111)

Percent of Patients (N=111)All Grades

(%)Grade 3 or 4

(%)Platelets Decreased 57 17Neutrophils Decreased 47 29HemoglobinDecreased 41 9

* Based on laboratory measurements and adverse reactions

Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients.Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranialhemorrhage, lethargy,gait instability,andheadache.However,someof thesecaseswere in the setting of disease progression.Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL.The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia.Approximately five percent of patients receiving IMBRUVICA in Study 1 and 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients.Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1


Grade 3 or 4 (%)

Gastrointestinal disorders DiarrheaConstipationNauseaStomatitisVomitingAbdominal painDyspepsia

63232121191513

4220200

Infections and infestations Upper respiratory tract infectionSinusitisSkin infectionPneumoniaUrinary tract infection

4821171010

26680

General disorders and administrative site conditions

FatiguePyrexia Peripheral edemaAstheniaChills

3125231313

42040


Bruising Rash Petechiae

542717

200


CoughOropharyngeal painDyspnea

191510

000


Musculoskeletal painArthralgiaMuscle spasms

272319

602

Nervous system disorders DizzinessHeadachePeripheral neuropathy

211910

020

Metabolism and nutrition disorders

Decreased appetite 17 2

Neoplasms benign, malignant, unspecified

Second malignancies* 10* 0

Injury, poisoning and procedural complications

Laceration 10 2

Psychiatric disorders AnxietyInsomnia

1010

00

Vascular disorders Hypertension 17 8

*One patient death due to histiocytic sarcoma.

IMBRUVICA® (ibrutinib) capsules

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1

Percent of Patients (N=48)All Grades

(%)Grade 3 or 4

(%)Platelets Decreased 71 10Neutrophils Decreased 54 27HemoglobinDecreased 44 0

* Based on laboratory measurements per IWCLL criteria and adverse reactions

Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2.

Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

System Organ Class ADR Term

IMBRUVICA(N=195)

Ofatumumab(N=191)

All Grades(%)

Grade 3 or 4(%)

All Grades(%)

Grade 3 or 4(%)

Gastrointestinal disordersDiarrhea 48 4 18 2Nausea 26 2 18 0Stomatitis* 17 1 6 1Constipation 15 0 9 0Vomiting 14 0 6 1

General disorders and administration site conditions

Fatigue 28 2 30 2Pyrexia 24 2 15 1

Infections and infestationsUpper respiratory tract infection 16 1 11 2Pneumonia* 15 10 13 9Sinusitis* 11 1 6 0Urinary tract infection 10 4 5 1


Rash* 24 3 13 0Petechiae 14 0 1 0Bruising* 12 0 1 0


Musculoskeletal Pain* 28 2 18 1Arthralgia 17 1 7 0

Nervous system disordersHeadache 14 1 6 0Dizziness 11 0 5 0

Injury, poisoning and procedural complications

Contusion 11 0 3 0Eye disorders

Vision blurred 10 0 3 0

Subjects with multiple events for a given ADR term are counted once only for each ADR term. The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.* Includes multiple ADR terms

Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

IMBRUVICA(N=195)

Ofatumumab(N=191)

All Grades(%)

Grade 3 or 4(%)

All Grades(%)

Grade 3 or 4(%)

Neutrophils Decreased 51 23 57 26Platelets Decreased 52 5 45 10HemoglobinDecreased 36 0 21 0

* Based on laboratory measurements per IWCLL criteria

DRUG INTERACTIONSIbrutinib is primarily metabolized by cytochrome P450 enzyme 3A.CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information].CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively.

Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONSPregnancy: Pregnancy Category D [see Warnings and Precautions].Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus.Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.Nursing Mothers: It is not known whether ibrutinib 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 IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established.Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in full Prescribing Information]. Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations].

PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Patient Information)• Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in

stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions].

• Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever,

chills) suggestive of infection [see Warnings and Precautions].• Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting,

shortness of breath, and chest discomfort [see Warnings and Precautions].• Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with

IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions].• Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings

and Precautions].• InformpatientstotakeIMBRUVICAorallyoncedailyaccordingtotheirphysician’sinstructions

and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information].

• AdvisepatientsthatintheeventofamisseddailydoseofIMBRUVICA,itshouldbetakenassoonas possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information].

• AdvisepatientsofthecommonsideeffectsassociatedwithIMBRUVICA[see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.

• Advisepatientstoinformtheirhealthcareprovidersofallconcomitantmedications,includingprescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions].

• Advisepatients that theymayexperience loose stoolsordiarrhea, and shouldcontact theirdoctor if their diarrhea persists. Advise patients to maintain adequate hydration.

Active ingredient made in China.

Distributed and Marketed by:Pharmacyclics, Inc.Sunnyvale, CA USA 94085andMarketed by:Janssen Biotech, Inc.Horsham,PAUSA19044

Patent http://www.imbruvica.comIMBRUVICA® is a registered trademark owned by Pharmacyclics, Inc.

© Pharmacyclics, Inc. 2014© Janssen Biotech, Inc. 2014PRC-00526 07/14

IMBRUVICA® (ibrutinib) capsules IMBRUVICA® (ibrutinib) capsules


1ej

29361a 11.12.14 133

Q1 Q2

G: .5" G: .5"L:9.5" L:9.5"

L: 13.375"

T: 14"

B: 14.25"

T: 21"

B: 22.25"


AACR Conference on Cancer Prevention

Childhood Obesity and Leukemia: Is It Time to Intervene? By Meg Barbor

“Obesity is associated with can-cer mortality,” said Steven D.

Mittelman, MD, PhD, at the recent American Association for Cancer Re-search (AACR) International Confer-ence on Frontiers in Cancer Prevention Research.1 Dr. Mittelman presented a wealth of data to explain the link be-tween obesity and cancer, focusing on leukemia, and suggested there may be a variety of opportunities for interven-tion to improve survival.

A landmark study by Calle et al2 found that obesity is responsible for more than 90,000 cancer deaths per year in the United States, and according to the American Institute for Cancer Research (AICR), more than 100,000

cancers each year are linked to excess body fat, said Dr. Mittelman, who is Director of the Diabetes and Obesity Program at Children’s Hospital Los Angeles and Associate Professor of Pe-diatrics and Physiology & Biophysics at Keck School of Medicine, University of Southern California, Los Angeles.

Obesity has been shown to increase cancer incidence, and obese cancer patients experience worse outcomes than lean patients. Retrospective stud-ies have confirmed that children who were obese at the time of diagnosis of high-risk acute lymphoblastic leukemia

(ALL) have a significantly higher risk of relapse than their leaner counterparts.

“Leukemia is the most common type of cancer in children, and relapsed leukemia is about the number 6 or 7 cancer in children, so there is a lot of work to be done,” he explained.

Underlying Mechanisms“Obesity is not a simple phenotype,”

said Dr. Mittelman. Hence, the sheer number of associations and internal and external factors associated with obe-sity make it difficult to elucidate mecha-nisms in humans, stressing the need for animal models.

Using mouse models, Dr. Mittel-man and colleagues found that obesity

accelerates the onset of spontaneous leukemia. Additionally, obese mice im-planted with leukemia cells experienced poorer survival after being treated with either vincristine or asparaginase (El-spar), and adipocytes appeared to be at the root of this worse outcome.

Adipocytes attract ALL cells to mi-grate closer to fat cells. The fat cells absorb the chemotherapy, making the treatment unable to reach the ALL cells and less available in the leukemia microenvironment. Adipocytes also secrete asparagine, glutamine, fatty ac-ids, and other fuels that help leukemia

cells survive, allowing them to prolif-erate and avoid apoptosis. “We think fat cells might be protecting nearby leukemia cells from oxidative stress, which may be part of how they’re pro-tecting them from chemotherapies,” he explained.

Ultimately, Dr. Mittelman and col-leagues concluded that adipocytes may contribute to a poorer prognosis in obese patients with ALL and impair their leukemia-related survival. This is cause for particular concern, consider-ing the high prevalence of overweight and obese pediatric cancer patients, particularly among those with leuke-mia, suggested Dr. Mittelman.

Childhood Obesity and Leukemia

About one-third of children in the United States are overweight or obese. “We’re in Los Angeles, and almost half of our children were overweight or obese at the time of cancer diagnosis,” Dr. Mittelman said.

To further compound this problem, cancer treatment typically leads to weight gain. “In the first month of treatment, these kids’ body fat goes up by 25%,” he observed. This is due to steroid treatment intended to kill the leukemia, which also increases appetite and causes fat accumu-lation. As a result, high-risk ALL patients experience a sizable and cumulative bur-den of adipose tissue, which will likely hinder their leukemia treatment and less-en their chances of survival.

Opportunities for InterventionEvidence suggests that the conse-

quences of obesity may be reversible. A recently published retrospective analysis3 cited by Etan Orgel, MD, also from Children’s Hospital Los Angeles, found that those who were obese at diagnosis but lost weight and became nonobese for more than half the duration of their treatment expe-rienced better outcomes, comparable

to their counterparts who were never overweight or obese.

“This implies that the effect of obe-sity to impair survival is not fixed at diagnosis,” suggested Dr. Mittelman. “The data seem to suggest that inter-vening might actually help survival. If we were to intervene to try to im-prove leukemia outcome, at the same time, we would likely (or hopefully) be improving some of these long-term complications.”

In additional laboratory experi-ments, Dr. Mittelman and his col-leagues also found that switching obese mice to a low-fat diet at the on-set of ALL treatment greatly improved their survival, giving them better out-comes than the control mice who had been raised on that same low-fat diet. “Considering these data, looking at the clinical outcomes, looking at the mouse data, and knowing what we know about adipose tissue-protecting leukemia cells, I think that some in-terventions in kids would certainly be justified to see if we can reduce their obesity, slow their gain in body fat, and maybe even improve their survival,” he suggested.” n

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

References1. Mittelman SD: Childhood obesity

and leukemia: Opportunities for interven-tion. AACR International Conference on Frontiers in Cancer Prevention Research. Presented September 30, 2014.

2. Calle EE, Rodriguez C, Walker-Thur-mond K, et al: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625-1638, 2003.

3. Orgel E, Sposto R, Malvar J, et al: Im-pact on survival and toxicity by duration of weight extremes during treatment for pedi-atric acute lymphoblastic leukemia: A re-port from the Children’s Oncology Group. J Clin Oncol 32:1331-1337, 2014.

Hematology

Looking at the clinical outcomes, looking at the mouse data, and knowing what we know about adipose tissue-protecting leukemia cells, I think that some interventions in kids would certainly be justified to see if we can reduce their obesity, slow their gain in body fat, and maybe even improve their survival.

—Steven D. Mittelman, MD, PhD

twitter.com/ascopost

Follow us on


EORTC-NCI-AACR Symposium

Patients With Advanced Papillary Kidney Cancer Respond Well to Bevacizumab/Erlotinib Combination Therapy

R esearchers have found that patients with an advanced form of kidney

cancer, for which there is no standard treatment and a very poor prognosis, respond well to a combination of two existing anticancer drugs. The combi-nation of bevacizumab (Avastin) and erlotinib (Tarceva) produced excellent response rates with tolerable side effects in patients with advanced papillary re-nal cell carcinoma and in those with he-reditary leiomyomatosis and renal cell cancer, a highly aggressive form of the disease. The findings were presented at the 26th EORTC-NCI-AACR Sympo-sium on Molecular Targets and Cancer Therapeutics in Barcelona.1

“The genetic and biochemical events that lead to papillary renal cell carci-

noma are different to those that lead to the more common form of kidney cancer, clear cell renal carcinoma,” said Ramaprasad Srinivasan, MD, PhD, Head of the Molecular Cancer Thera-peutics Section, Urologic Oncology Branch, of the National Cancer Insti-tute in Bethesda, Maryland.

“Treatments that are effective in clear cell renal cell carcinoma are not particularly effective in papillary renal

cell carcinoma. Some forms of papillary renal cell carcinoma, particularly those associated with hereditary leiomyoma-tosis and renal cell cancer, are character-ized by altered cellular metabolism; the tumor cells obtain energy from a pro-cess called aerobic glycolysis, and they require high levels of glucose to survive. We believe the combination of erlotinib and bevacizumab may target this partic-ular weakness, at least partly, by impair-ing glucose delivery to the tumor cells,” Dr. Srinivasan said.

Study DetailsThis phase II clinical trial included 41

patients with advanced papillary renal cell carcinoma (20 with advanced hered-itary leiomyomatosis and renal cell can-

cer and 21 with advanced sporadic pap-illary renal cell carcinoma). Nineteen of the patients had received at least one pre-vious systemic therapy, such as sunitinib (Sutent), that had not been successful in preventing their disease progressing. Pa-tients received bevacizumab 10 mg/kg given intravenously once every 2 weeks, combined with erlotinib 150 mg taken orally every day. Treatment was contin-ued until disease progression or unac-

ceptable toxic side effects.“Almost all the patients with

hereditary leiomyomatosis and renal cell cancer responded with their tumours either shrinking or remaining stable and not progressin,” Dr. Srinivasan said. The overall response rate was 65%, with 13 patients showing tumor shrinkage of more than 30% and 7 patients with stable disease. “Many of the responses were long-lasting; some of patients have remained on the study for 3 years or more, which is a significant since metastatic hereditary leiomyomatosis and renal cell cancer is uniformly fatal and patients usually die within a year or so,” he added.

Among the patients with sporadic papillary renal cell carcinoma, approxi-mately one-third demonstrated very good, often durable, partial responses. The overall response rate as 29%, 6 pa-tients showed tumor shrinkage, and 12 patients had stable disease.

The median progression-free sur-vival in the hereditary leiomyomatosis and renal cell cancer cohort was 24.2 months, while for sporadic papillary renal cell carcinoma cohort it was 7.4 months. This compares well with ex-isting survival times for patients on other treatments. “The median pro-gression-free survival for metastatic papillary renal cell carcinoma appears to be less than 6 months with most regimens commonly used today,” Dr. Srinivasan said. “This is also true for patients with metastatic hereditary leiomyomatosis and renal cell cancer, who generally demonstrate rapidly progressive fatal disease.

Manageable Side EffectsTreatment was well tolerated, and

most patients reported a good quality of life. Side effects were mostly mild or moderate and included high blood pressure, acne, proteinuria, and fatigue, which could be managed effectively with drugs or other supportive mea-sures. One patient died from a gastro-intestinal hemorrhage, which may have been related to the bevacizumab.

“The combination of erlotinib and bevacizumab for treating patients with advanced papillary renal cell carcinoma shows excellent response rates with toler-able side effects. This is particularly true of patients with hereditary leiomyomatosis and renal cell cancer,” Dr. Srinivasan con-cluded. “The current data are sufficiently encouraging for this combination to be explored further in larger trials as a pos-sible standard-of-care treatment for papil-lary renal cell carcinoma patients. We are in the process of designing these studies. It is also important to try and identify spe-cific subgroups of patients most likely to benefit from this regimen and our group is working on this issue.” n


Reference1. Srinivasan R, et al: Mechanism based

targeted therapy for hereditary leiomyoma-tosis and renal cell cancer (HLRCC) and sporadic papillary renal cell carcinoma: in-terim results from a phase 2 study of bevaci-zumab and erlotinib. EORTC-NCI-AACR Symposium on Molecular Targets and Can-cer Therapeutics. Abstract 5. Presented No-vember 19, 2014.

Genitourinary Oncology

The combination of erlotinib and bevacizumab for treating patients with advanced papillary renal cell

carcinoma shows excellent response rates with tolerable side effects. This is particularly true of patients with hereditary leiomyomatosis and renal cell cancer.

—Ramaprasad Srinivasan, MD, PhD

Like us on Facebook

facebook.com/TheASCOPost

The ASCO Post


Journal Spotlight

CD19-Directed CAR T Cells Produce Sustained Remission in Relapsed/Refractory Acute Lymphoblastic LeukemiaBy Matthew Stenger

In a study reported in The New Eng-land Journal of Medicine, Shannon L.

Maude, MD, PhD, of Children’s Hos-pital of Philadelphia, and Noelle Frey, MD, of the Perelman School of Medi-cine, University of Pennsylvania, and colleagues reported achieving sustained remissions in children and adults with

relapsed/refractory acute lymphoblas-tic leukemia (ALL) using autologous CD19-targeted chimeric antigen recep-tor (CAR)–modified T cells.1

Study DetailsIn the study, 25 patients aged 5 to 22

years at Children’s Hospital of Philadel-phia and 5 patients aged 26 to 60 years at Hospital of the University of Pennsyl-vania with relapsed or refractory ALL received infusions of autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector at doses of 0.76×106 to 20.6×106 CTL019 cells/kg. Of the 30 patients, 26 had B-cell ALL in first to fourth relapse, 3 had primary re-fractory B-cell ALL, and 1 had relapsed T-cell ALL expressing CD19; 18 had re-lapsed disease after allogeneic stem cell transplantation and 3 had disease previ-ously shown to be refractory to blinatu-momab, a bispecific antibody that binds to both CD3 on T cells and CD19.

RemissionsComplete remission was achieved in

27 patients (90%), including 2 of the 3 patients with blinatumomab-refractory disease and 15 of 18 patients who had un-dergone stem cell transplantation.

With a follow-up period of 2 to 24 months, sustained remissions were ob-served in 19 patients, with 15 receiv-ing no further treatment; these remis-sions were associated with persistence of CTL019 and B-cell aplasia, which continued for up to 2 years. Six-month event-free survival was 67% (95% con-

fidence interval [CI] = 51%–88%), and overall survival was 78% (95% CI = 65%–95%).

RelapsesSeven patients with complete remis-

sion had relapse between 6 weeks and 8.5 months after infusion, with 3 develop-ing relapses after early loss of CTL019-modified T cells at 2 weeks to 3 months and the relapsed ALL remaining CD19-positive in each case. After recovery of normal B cells at 2 to 3 months, one re-lapse occurred rapidly at 3 months, and two were delayed, occurring at 6 and 8.5 months. One patient, who had minimal residual disease (0.22%) at 1 month, had relapse with CD19-positive ALL at 6 weeks, which progressed rapidly and resulted in death; this patient had highly refractory disease in fourth relapse at baseline and was not eligible for stem cell transplantation. Loss of expression of CD19 in leukemia cells resulted in

relapse in three patients, including one who had received blinatumomab ther-apy; CTL019 cells were not lost at the time of relapse in these patients.

Expansion and Persistence of CTL019

Detection of CTL019 cells by flow cytometry showed in vivo proliferation. The median peak proportion in blood was 39.8% of CTL019-positive cells in CD3-positive cells (range 4.4%–69.3%) in responders compared with 0.2%, 0.6%, and 8.2% of CD3-positive cells at peak levels in the three nonresponders. CTL019 cells were detectable in blood for up to 11 months, with a probability of persistence at 6 months of 68% (95% CI = 50%–92%).

Further, CTL019 sequences remained detectable by quantitative polymerase chain reaction (PCR) assay until 2 years in patients with sustained remissions. PCR showed high levels of proliferation, with all patients having peak levels > 5,000 copies/µg of genomic DNA and 26 having peak levels > 15,000 copies/µg.

Persistence of CTL019 was observed in one patient after reinfusion at 3 months and 6 months due to early loss of CTL019 cells with B-cell recovery. The patient with the longest remission (2 years) exhibited B-cell aplasia (absence of CD19-positive cells) for 1 year after CTL019 cells were no longer detectable on flow cytometry; this finding suggests functional persistence of CTL019 cells below flow cytometry lim-its of detection but at levels detectable by means of quantitative PCR. Overall, the probability of relapse-free B-cell aplasia at 6 months was 73% (95% CI = 57%–94%).

Cytokine-Release SyndromeNo deaths appeared to be related to

the study treatment. Seven patients died after disease progression or relapse, in-cluding one who died of myelodysplastic syndrome that developed during ALL re-mission and withdrew from the study to receive other treatment.

All patients exhibited cytokine-re-lease syndrome. Severe cytokine-release syndrome, requiring intensive care with

varying degrees of respiratory support, developed in eight patients (27%), with all requiring vasopressor support for hy-potension. These patients also exhibited coagulopathy, with clinical bleeding ob-served in three (10%).

Severe cytokine-release syndrome started a median of 1 day after infusion, compared with a median of 4 days in patients with nonsevere syndrome (P = .005). Inflammatory markers, including C-reactive protein and ferritin, were el-evated in all patients; patients with severe reactions had higher peak levels of inter-leukin-6 (P < .001), C-reactive protein (P = .02), ferritin (P = .005), interferon-γ (P < .001), and soluble interleukin-2 re-ceptor (P < .001). Higher disease burden at baseline (percentage of blast cells in marrow before infusion) was significantly associated with an increased risk of severe cytokine-release syndrome (P = .002), and severity was also associated with higher levels of CTL019-positive CD8 cells (P = .012) and CTL019-positive CD3 cells (P = .026).

Nine patients with severe reactions received the anti–interleukin-6 receptor antibody tocilizumab, which produced rapid reduction of fever and stabilization of blood pressure over 1 to 3 days. Six patients also received short glucocorticoid course and four received a second dose of tocili-zumab (Actemra) for recurrence of the cy-tokine-release syndrome after transient im-provement with the first dose. All patients recovered fully, with complete reversal of symptoms and normalization of lab results. Relapses were observed in two of the nine patients who received immunosuppressive therapy for cytokine-release syndrome.

The investigators concluded: “Chime-ric antigen receptor–modified T-cell ther-apy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem cell trans-plantation had failed, and durable remis-sions up to 24 months were observed.” n

Disclosure: The study was funded by Novartis and others. For full disclosures of the study authors, visit www.nejm.org.

Reference1. Maude SL, Frey N, Shaw PA, et al:

Chimeric antigen receptor T cells for sus-tained remissions in leukemia. N Engl J Med 371:1507-1517, 2014.

See commentary by Andrew Evens, DO, MSc, on page 33.

Hematology

Update on CTL019 Therapy

■ CTL019 treatment resulted in complete remission in 90% of 30 patients.

■ Sustained remissions of up to 2 years were observed in 19 patients, with 15 receiving no further treatment.

CTL019 was associated with a high remission rate, even among patients for whom stem cell transplantation had failed, and durable remissions up to 24 months were observed.

—Shannon L. Maude, MD, PhD, and Noelle Frey, MD


Perspective

CAR T-Cell Therapy in Cancer: Driving Toward the ClinicBy Andrew Evens, DO, MSc

Chimeric antigen receptor (CAR) T-cell therapy represents a novel

and promising therapeutic advance in cancer.1,2 It constitutes a form of personalized therapy that harnesses adoptive cell transfer through genetic engineering of autologous T cells. The initial step in this therapeutic para-digm involves leukapheresis of the patient’s peripheral T cells; this is fol-lowed by ex vivo transduction (by ret-rovirus or lentivirus), which encodes components of a chimeric T-cell re-ceptor. These components include a fragment of a monoclonal antibody that targets the desired tumor antigen as well as signaling domains, the latter being responsible for activation, pro-liferation, survival, and cytokine pro-duction of T cells; cells are then rein-fused into the patient. An important advance that has helped make this therapeutic platform more convenient is the relatively straightforward manu-facturing process of the peripheral blood-derived re-engineered T cells.

Collectively, these gene-modified immune cells combine the specificity of B cells (via antibody binding) with the proliferative and cytotoxic capabilities of T cells. Binding via a chimeric anti-body confers several advantages over classic T-cell–receptor activation, name-ly the ability to bind to the specific target of interest independent of major histo-compatibility complex (MHC) restric-tion and immune tolerance of the T-cell repertoire. An MHC-independent pro-cess may be leveraged to target a multi-tude of cell-surface markers.

To date, CAR T-cells recognizing the B-cell–associated molecule CD19 have emerged as the most prominent treatment strategy.3 CD19 is a cell-surface protein that is expressed in the majority of B-cell lymphoid ma-lignancies, thus representing an at-tractive therapeutic approach in these cancers. CTL019 (formerly known as CART19) is one of the most de-velopmentally advanced constructs in this class of personalized immu-notherapies. CTL019 is a second-generation CAR T cell that combines an extracellular anti-CD19 antibody

fragment with costimulatory intracel-lular signaling domains, CD3-zeta and CD137 (4-1BB).

‘Unparalleled’ Results in the Refractory Setting

As reviewed in this issue of The ASCO Post, Maude and colleagues con-ducted pilot clinical trials at the Uni-versity of Pennsylvania to assess the safety and feasibility of CTL019 CAR T-cell therapy in patients with relapsed and refractory CD19-positive cancers.4 Over an approximate 2-year period, 30 patients were treated (25 children and

5 adults); all patients had relapsed/re-fractory acute lymphoblastic leukemia (ALL), with all but the one having B-cell disease (one patient had T-cell ALL that expressed CD19). Furthermore, 18 of 30 patients (60%) had relapsed disease after prior allogeneic stem cell trans-plantation and 3 additional patients had primary refractory disease.

Impressively, 27 (90%) of 30 pa-tients experienced morphologic com-plete remission 1 month after CTL019 infusion. Further, 22 of 30 ALL patients (73%) had no evidence of minimal re-sidual disease, as measured by multipa-rametric flow cytometry. These rapid responses and overall highly efficacious results are unparalleled in this refractory and difficult-to-treat patient population.

Of the 27 patients who entered complete remission, 19 (70%) re-mained in remission, although follow-up is relatively short (ie, median fol-low-up of 7 months). The probability of persistence of CTL019 at 6 months was 68%, and CTL019 sequences remained detectable by quantitative polymerase chain reaction through 2 years in patients with sustained remis-sions. Moreover, all remissions were as-sociated with persistence of CTL019. Among patients who achieved remis-

sion and subsequently experienced progressive disease, relapse was associ-ated with early loss of CTL019-modi-fied T cells in three patients, and there was absence of CD19 expression in the leukemic cells of three other patients.

This remarkable clinical efficacy was tempered by the development of cytokine-release syndrome, a serious and potentially life-threatening toxicity. Although there were no deaths attribut-ed to CTL019 therapy, 8 of 30 patients (27%) required intensive care support, including vasopressors for hypotension. Nine patients were treated with the

anti–interleukin-6 receptor antibody to-cilizumab (Actemra), which produced prompt reduction of fever and stabili-zation of blood pressure; four patients required a second dose of tocilizumab. All patients in this study ultimately re-covered from this cytokine storm, with complete reversal of symptoms and nor-malization of laboratory data.

Despite the universal occurrence of the aforementioned cytokine re-lease syndrome toxicity, the clini-cal efficacy of CTL019 CAR T-cell therapy is unprecedented in this pa-tient population. On July 7, 2014, the U.S. Food and Drug Administration granted breakthrough therapy status to CTL019 CAR T-cell therapy for the treatment of adult and pediatric relapsed/refractory ALL.

Challenges Still AheadDespite the early success of CAR

T-cell therapy, there are a number of roadblocks that must be navigated.5 They include optimization of dosing and mitigation of toxicity along with ongoing legal proceedings regarding intellectual property. In addition, it will be important to manage scalability and cost to ensure accessibility and afford-ability. These issues and others must be

addressed to expand the utility of this innovative therapy to other hematolog-ic malignancies as well as solid tumors.

Solid tumor studies are ongo-ing with CAR T-cell therapy (eg, via CA19-9 and carcinoembryonic anti-gen constructs), although tumor bulk, tumor heterogeneity, and off-target effects are challenges that need to be overcome.6,7 A strategy being exam-ined to potentially enhance efficacy is a treatment platform using T cells re-directed for universal cytokine killing (TRUCK).8 TRUCKs are CAR T cells that are engineered with the additional capacity to induce IL-12 production in the tumor. Release of IL-12 attracts an innate immune response, including macrophages and natural killer cells, which may subsequently augment the antitumor response. Other potential rational treatment approaches that may augment the efficacy of CAR T-cell therapy, include use in combination with other immunology-based thera-peutics such as programmed cell death protein 1 (PD-1) blockade.9

Altogether, CAR T-cell therapy represents a significant and exciting advance in the treatment of cancer. Furthermore, CTL019 represents a likely first-in-class personalized T-cell immunotherapeutic that may soon be available to patients in the clinic. Con-tinued study of these agents in clinical trials will be critical in helping to define the most optimal role for this highly novel and personalized therapy. n

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

References1. Corrigan-Curay J, Kiem HP, Balti-

more D, et al: T-cell immunotherapy: Look-ing forward. Mol Ther 22:1564-1574, 2014.

2. Maus MV, Grupp SA, Porter DL, June CH: Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123:2625-2635, 2014.

3. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al: T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in chil-dren and young adults: A phase 1 dose-escalation trial. Lancet. October 10, 2014 (early release online).

4. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sus-tained remissions in leukemia. N Engl J

Hematology

Dr. Evens is Director of Tufts Cancer Cen-ter and Chief of the Division of Hematolo-gy/Oncology at Tufts Medical Center and Tufts University School of Medicine

These rapid responses and overall highly efficacious results [with CTL019 CAR T-cell therapy] are unparalleled in this refractory and difficult-to-treat patient population.

—Andrew Evens, DO, MSc


For patients with advanced nonsquamous† NSCLC

Continue treatment.* Extend survival.1-4

Select Important Safety InformationContraindicationALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and PrecautionsPremedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

* Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent.

Median Overall Survival: 13.9 months with ALIMTA single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02

† Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA continuation maintenance showed extended overall survival with a safety pro� le consistent with previously reported ALIMTA single-agent trials

After initial treatment with ALIMTA/cisplatin, patients who achieve stable disease or better may be eligible for continued therapy with single-agent ALIMTA

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based � rst-line chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.

019517_elalns_PM92674_OT_fa.indd 1 9/26/14 1:28 PM

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

After completion of � rst-line therapy, several studies have shown that 50% of patients with advanced NSCLC off active treatment will experience rapid disease progression (within 3 months)‡2,5-8

You may have patients* with advanced nonsquamous† NSCLC who are eligible for continuation maintenance with single-agent ALIMTA

Why consider maintenance therapy*?

57% (n=539) of patients in the PARAMOUNT trial were eligible for continuation maintenance therapy (ALIMTA or placebo) from the 939 patients who received ALIMTA/cisplatin induction therapy1,4

2.9 months’ median overall survival advantage was demonstrated with single-agent ALIMTA following induction with ALIMTA/cisplatin compared with placebo in patients* with advanced nonsquamous NSCLC1,4

Median overall survival (months) (95% CI): ALIMTA + BSC (n=359): 13.9 (12.8-16.0); Placebo + BSC (n=180): 11.0 (10.0-12.5); Unadjusted HRa,b: 0.78 (95% CI: 0.64-0.96); P=0.02

The safety profile of ALIMTA continuation maintenance in patients with advanced nonsquamous NSCLC was consistent with the safety profile of single-agent ALIMTA in previously reported phase III trials1-4

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC

Category 1§: NCCN Guidelines® recommend continuation of pemetrexed for injection (ALIMTA) after 4-6 cycles of cisplatin and pemetrexed chemotherapy in the absence of disease progression for patients with advanced or metastatic nonsquamous NSCLC9

‡ The median PFS for the referenced studies was less than 3 months.§ Based upon high-level evidence, there is uniform National Comprehensive Cancer Network® (NCCN®) consensus that the intervention is appropriate.a OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy.b An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Select Important Safety InformationCommon Terminology Criteria for Adverse Events Drug-related Toxicities (Version 3.0)

Adverse Reactions: Grades 3-4In the PARAMOUNT trial, grades 3-4 adverse reactions occurring more frequently (≥2%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (4.8% vs 0.6%), neutropenia (3.9% vs 0%), and fatigue (4.5% vs 0.6%).

Adverse Reactions: All GradesIn the PARAMOUNT trial, adverse reactions of any severity (all grades) occurring more frequently (≥5%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (15% vs 4.8%), neutropenia (9% vs 0.6%), fatigue (18% vs 11%), nausea (12% vs 2.4%), vomiting (6% vs 1.8%), mucositis/stomatitis (5% vs 2.4%), and edema (5% vs 3.6%).

See the complete data at ALIMTAhcp.com/data

See the Important Safety Information and Brief Summary for ALIMTA on the following pages.

References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432‐1440. 3. Hanna N, et al. J Clin Oncol. 2004;22(9):1589‐1597. 4. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902. 5. Fidias PM, et al. J Clin Oncol. 2009;27(4):591-598. 6. Paz-Ares L, et al. Lancet Oncol. 2012;13(3):247-255. 7. Cappuzzo F, et al. Lancet Oncol. 2010;11(6):521-529. 8. Zhang L, et al. Lancet Oncol. 2012;13(5):466-475. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed August 18, 2014. To view the most recent and complete version of the guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.


For patients with advanced nonsquamous† NSCLC

Continue treatment.* Extend survival.1-4

Select Important Safety InformationContraindicationALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and PrecautionsPremedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

* Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent.

Median Overall Survival: 13.9 months with ALIMTA single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02

† Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA continuation maintenance showed extended overall survival with a safety pro� le consistent with previously reported ALIMTA single-agent trials

After initial treatment with ALIMTA/cisplatin, patients who achieve stable disease or better may be eligible for continued therapy with single-agent ALIMTA

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.



Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.


NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

After completion of � rst-line therapy, several studies have shown that 50% of patients with advanced NSCLC off active treatment will experience rapid disease progression (within 3 months)‡2,5-8

You may have patients* with advanced nonsquamous† NSCLC who are eligible for continuation maintenance with single-agent ALIMTA

Why consider maintenance therapy*?

57% (n=539) of patients in the PARAMOUNT trial were eligible for continuation maintenance therapy (ALIMTA or placebo) from the 939 patients who received ALIMTA/cisplatin induction therapy1,4

2.9 months’ median overall survival advantage was demonstrated with single-agent ALIMTA following induction with ALIMTA/cisplatin compared with placebo in patients* with advanced nonsquamous NSCLC1,4

Median overall survival (months) (95% CI): ALIMTA + BSC (n=359): 13.9 (12.8-16.0); Placebo + BSC (n=180): 11.0 (10.0-12.5); Unadjusted HRa,b: 0.78 (95% CI: 0.64-0.96); P=0.02

The safety profile of ALIMTA continuation maintenance in patients with advanced nonsquamous NSCLC was consistent with the safety profile of single-agent ALIMTA in previously reported phase III trials1-4

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC

Category 1§: NCCN Guidelines® recommend continuation of pemetrexed for injection (ALIMTA) after 4-6 cycles of cisplatin and pemetrexed chemotherapy in the absence of disease progression for patients with advanced or metastatic nonsquamous NSCLC9

‡ The median PFS for the referenced studies was less than 3 months.§ Based upon high-level evidence, there is uniform National Comprehensive Cancer Network® (NCCN®) consensus that the intervention is appropriate.a OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy.b An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Select Important Safety InformationCommon Terminology Criteria for Adverse Events Drug-related Toxicities (Version 3.0)

Adverse Reactions: Grades 3-4In the PARAMOUNT trial, grades 3-4 adverse reactions occurring more frequently (≥2%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (4.8% vs 0.6%), neutropenia (3.9% vs 0%), and fatigue (4.5% vs 0.6%).

Adverse Reactions: All GradesIn the PARAMOUNT trial, adverse reactions of any severity (all grades) occurring more frequently (≥5%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (15% vs 4.8%), neutropenia (9% vs 0.6%), fatigue (18% vs 11%), nausea (12% vs 2.4%), vomiting (6% vs 1.8%), mucositis/stomatitis (5% vs 2.4%), and edema (5% vs 3.6%).

See the complete data at ALIMTAhcp.com/data

See the Important Safety Information and Brief Summary for ALIMTA on the following pages.

References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432‐1440. 3. Hanna N, et al. J Clin Oncol. 2004;22(9):1589‐1597. 4. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902. 5. Fidias PM, et al. J Clin Oncol. 2009;27(4):591-598. 6. Paz-Ares L, et al. Lancet Oncol. 2012;13(3):247-255. 7. Cappuzzo F, et al. Lancet Oncol. 2010;11(6):521-529. 8. Zhang L, et al. Lancet Oncol. 2012;13(5):466-475. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed August 18, 2014. To view the most recent and complete version of the guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.


http://www.alimtahcp.com/Pages/index.aspx

Indications for ALIMTAALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small celllung cancer.



Important Safety Information for ALIMTAMyelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

ContraindicationALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and PrecautionsPrior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities.

Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insuf� ciency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insuf� ciency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function.

Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

Drug InteractionsSee Warnings and Precautions for speci� c information regarding NSAID administration in patients with renal insuf� ciency.

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA.

Use in Speci� c Patient Populations

It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Ef� cacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dosage and Administration GuidelinesComplete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA.

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC)The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/desquamation (10% vs 3%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapyThe most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the Brief Summary of Prescribing Information on the adjacent page.

PM_HCP_ISI_NSCLC1M_17OCT2012

PM92674 09/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED.ALIMTA® is a registered trademark of Eli Lilly and Company.


ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed for injection) PV 8927 AMP

ALIMTA PM HCP BS NSCLC1M 18Nov2013 PV8927 BRF SUM 6.5 x 9.5 PRINTER VERSION 1 OF 4

ALIMTA® (pemetrexed for injection)

BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 INDICATIONS AND USAGE

1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with CisplatinALIMTA® is indicated in combination with cisplatin therapy for the initial treatment

of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.2 Nonsquamous Non-Small Cell Lung Cancer — MaintenanceALIMTA is indicated for the maintenance treatment of patients with locally advanced

or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.5 Limitations of UseALIMTA is not indicated for the treatment of patients with squamous cell non-small

cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION

2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural MesotheliomaThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information.

2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line TherapyThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3 Premedication Regimen and Concurrent MedicationsVitamin SupplementationInstruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily

beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)].

Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)].

CorticosteroidsAdminister dexamethasone 4 mg by mouth twice daily the day before, the day of, and

the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation RecommendationsMonitoringComplete blood cell counts, including platelet counts, should be performed on all

patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction RecommendationsDose adjustments at the start of a subsequent cycle should be based on nadir

hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities

Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. 75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC.

75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC.


a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3,

treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b

Dose of ALIMTA (mg/m2)

Dose of Cisplatin (mg/m2)

Any Grade 3 or 4 toxicities except mucositis 75% of previous dose

75% of previous dose

Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea



Grade 3 or 4 mucositis 50% of previous dose


a NCI Common Toxicity Criteria (CTC).b Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity

CTC GradeDose of ALIMTA

(mg/m2)Dose of Cisplatin

(mg/m2)

0-1 100% of previous dose 100% of previous dose

2 100% of previous dose 50% of previous dose

Discontinuation RecommendationALIMTA therapy should be discontinued if a patient experiences any hematologic or

nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired PatientsIn clinical studies, patients with creatinine clearance ≥45 mL/min required no

dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHSALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow

lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONSALIMTA is contraindicated in patients who have a history of severe hypersensitivity

reaction to pemetrexed.

5 WARNINGS AND PRECAUTIONS

5.1 Requirement for Premedication and Concomitant Medication to Reduce ToxicityVitamin SupplementationPrior to treatment with ALIMTA, initiate supplementation with oral folic acid and

intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0].

CorticosteroidsAdminister dexamethasone the day before, the day of, and the day after ALIMTA

administration [see Dosage and Administration (2.3)].

5.2 Bone Marrow SuppressionALIMTA can suppress bone marrow function, as manifested by neutropenia,

thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal FunctionALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment

is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal InsufficiencyCaution should be used when administering NSAIDs concurrently with ALIMTA to

patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)].

5.5 Required Laboratory MonitoringObtain a complete blood count and renal function tests at the beginning of each cycle

and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.)



Perspective

Med 371:1507-1517, 2014.5. Amos SM, Duong CP, Westwood

JA, et al: Autoimmunity associated with immunotherapy of cancer. Blood 118:499-509, 2011.

6. Junghans RP: Strategy escalation: An emerging paradigm for safe clinical development of T cell gene therapies. J Transl Med 8:55, 2010.

7. Moon EK, Wang LC, Dolfi DV, et al: Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chime-

ric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res 20:4262-4273, 2014.

8. Chmielewski M, Hombach AA, Abken H: Of CARs and TRUCKs: Chi-meric antigen receptor (CAR) T cells engineered with an inducible cytokine

to modulate the tumor stroma. Immunol Rev 257:83-90, 2014.

9. John LB, Devaud C, Duong CP, et al: Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res 19:5636-5646, 2013.

Andrew Evens, DO, MSccontinued from page 33



ALIMTA® (pemetrexed for injection)

BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 INDICATIONS AND USAGE

1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with CisplatinALIMTA® is indicated in combination with cisplatin therapy for the initial treatment

of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.2 Nonsquamous Non-Small Cell Lung Cancer — MaintenanceALIMTA is indicated for the maintenance treatment of patients with locally advanced

or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.5 Limitations of UseALIMTA is not indicated for the treatment of patients with squamous cell non-small

cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION

2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural MesotheliomaThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information.

2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line TherapyThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3 Premedication Regimen and Concurrent MedicationsVitamin SupplementationInstruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily

beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)].

Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)].

CorticosteroidsAdminister dexamethasone 4 mg by mouth twice daily the day before, the day of, and

the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation RecommendationsMonitoringComplete blood cell counts, including platelet counts, should be performed on all

patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction RecommendationsDose adjustments at the start of a subsequent cycle should be based on nadir

hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities

Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. 75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC.


Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC.


a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3,

treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b

Dose of ALIMTA (mg/m2)

Dose of Cisplatin (mg/m2)

Any Grade 3 or 4 toxicities except mucositis 75% of previous dose


Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea



Grade 3 or 4 mucositis 50% of previous dose


a NCI Common Toxicity Criteria (CTC).b Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity

CTC GradeDose of ALIMTA

(mg/m2)Dose of Cisplatin

(mg/m2)

0-1 100% of previous dose 100% of previous dose

2 100% of previous dose 50% of previous dose

Discontinuation RecommendationALIMTA therapy should be discontinued if a patient experiences any hematologic or

nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired PatientsIn clinical studies, patients with creatinine clearance ≥45 mL/min required no

dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHSALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow

lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONSALIMTA is contraindicated in patients who have a history of severe hypersensitivity

reaction to pemetrexed.

5 WARNINGS AND PRECAUTIONS

5.1 Requirement for Premedication and Concomitant Medication to Reduce ToxicityVitamin SupplementationPrior to treatment with ALIMTA, initiate supplementation with oral folic acid and

intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0].

CorticosteroidsAdminister dexamethasone the day before, the day of, and the day after ALIMTA

administration [see Dosage and Administration (2.3)].

5.2 Bone Marrow SuppressionALIMTA can suppress bone marrow function, as manifested by neutropenia,

thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal FunctionALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment

is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal InsufficiencyCaution should be used when administering NSAIDs concurrently with ALIMTA to

patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)].

5.5 Required Laboratory MonitoringObtain a complete blood count and renal function tests at the beginning of each cycle

and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.)



Journal Spotlight

Power Behind ‘Master’ Gene for Cancer Discovered

A study at The University of Texas MD Anderson Cancer Center, Houston,

led by Mong-Hong Lee, PhD, Profes-sor of Molecular and Cellular Oncol-ogy, has demonstrated the significance of CSN6 in regulating Myc which may well open up a new pathway for treat-

ing and killing tumors. The study results are published in a recent issue of Nature Communications.1

“We have discovered that CSN6 is a strong oncogene that is frequently overex-pressed and significantly speeds up tumor growth in many types of cancer,” said Dr.

Lee. “Furthermore, CSN6 also affects the expression of Myc in tumors.”

Myc is a proto-oncogene or master cancer gene that spurs tumor growth in a variety of cancers including breast, lung, colon, brain, skin, leukemia, prostate, pan-creas, stomach, and bladder.

Dr. Lee said that the study findings are important because targeting Myc is a challenging task due to its unique protein structure. Even though it has been stud-ied for decades, no effective inhibitor for Myc has been successfully developed. His team’s study found that inhibiting CSN6

Molecular Oncology



platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].

5.6 Pregnancy Category DBased on its mechanism of action, ALIMTA can cause fetal harm when administered

to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA 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. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse

reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC) – ALIMTA in Combination with CisplatinTable 4 provides the frequency and severity of adverse reactions that have been

reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa

ReactionbALIMTA/cisplatin

(N=839)Gemcitabine/cisplatin

(N=830)

All Grades Toxicity (%)

Grade 3-4 Toxicity (%)



All Adverse Reactions 90 37 91 53

Laboratory Hematologic Anemia Neutropenia Leukopenia Thrombocytopenia

33291810

61554

46382127

1027813

Renal Creatinine elevation 10 1 7 1

Clinical Constitutional Symptoms Fatigue 43 7 45 5

Gastrointestinal Nausea Vomiting Anorexia Constipation Stomatitis/Pharyngitis Diarrhea Dyspepsia/Heartburn

5640272114125

7621110

5336242012136

4610020

Neurology Neuropathy-sensory Taste disturbance

98

00c

129

10c

Dermatology/Skin Alopecia Rash/Desquamation

127

0c

0218

1c

1

a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.

b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity.c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported

as Grade 1 or 2.No clinically relevant differences in adverse reactions were seen in patients based

on histology.In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin

arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5%Body as a Whole — febrile neutropenia, infection, pyrexiaGeneral Disorders — dehydrationMetabolism and Nutrition — increased AST, increased ALTRenal — creatinine clearance decrease, renal failureSpecial Senses — conjunctivitis

Incidence Less than 1%Cardiovascular — arrhythmiaGeneral Disorders — chest painMetabolism and Nutrition — increased GGTNeurology — motor neuropathy

Non-Small Cell Lung Cancer (NSCLC) – Maintenance ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction TherapyTable 5 provides the frequency and severity of adverse reactions reported in >5% of

the 438 patients with NSCLC who received ALIMTA maintenance and the 218 patients with NSCLC who received placebo following a platinum-based induction therapy.

All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12.

Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa Following Platinum-Based Induction Therapy

ReactionbALIMTA (N=438)

Placebo (N=218)






Laboratory Hematologic Anemia Neutropenia Leukopenia

1566

332

601

101

Hepatic Increased ALT Increased AST

108

00

44

00


Gastrointestinal Nausea Anorexia Vomiting Mucositis/stomatitis Diarrhea

1919975

12011

65123

10000

Infection 5 2 2 0

Neurology Neuropathy-sensory 9 1 4 0

Dermatology/Skin Rash/Desquamation 10 0 3 0


b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients

based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).

Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.

Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).

The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA.

Incidence 1% to 5%Dermatology/Skin — alopecia, pruritus/itchingGastrointestinal — constipationGeneral Disorders — edema, fever (in the absence of neutropenia)Hematologic — thrombocytopeniaRenal — decreased creatinine clearance, increased creatinine, decreased

glomerular filtration rate



Special Senses — ocular surface disease (including conjunctivitis), increased lacrimation

Incidence Less than 1%Cardiovascular — supraventricular arrhythmiaDermatology/Skin — erythema multiformeGeneral Disorders — febrile neutropenia, allergic reaction/hypersensitivityNeurology — motor neuropathyRenal — renal failure

Continuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum Induction TherapyTable 6 provides the frequency and severity of adverse reactions reported in >5%

of the 500 patients with non-squamous NSCLC who received at least one cycle of ALIMTA maintenance (n=333) or placebo (n=167) on the continuation maintenance trial.

The median of maintenance cycles administered to patients receiving one or more doses of maintenance therapy was 4 on both the pemetrexed and placebo arms. Dose reductions for adverse events occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm. Dose delays for adverse events occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm. Patients in both study arms were supplemented with folic acid and vitamin B12.

Table 6: Selecteda Adverse Reactionsb Occurring in ≥5% of Patients Receiving ALIMTA in Nonsquamous NSCLC Following ALIMTA Plus Cisplatin Induction Therapy

Adverse Reaction Organ System and Term

ALIMTA(N=333)

Placebo(N=167)

All Gradesa

Toxicity (%)Grade 3-4a

Toxicity (%)All Gradesa

Toxicity (%)Grades 3-4a

Toxicity (%)

All Adverse Reactions 53 17 34 4.8

Laboratory Hematologic Anemia Neutropenia

159

4.83.9

4.80.6

0.60

Clinical Constitutional Symptoms Fatigue 18 4.5 11 0.6

Gastrointestinal Nausea Vomiting Mucositis/stomatitis

1265

0.30

0.3

2.41.82.4

000

General Disorders Edema 5 0 3.6 0

a Adverse reactions of any severity (all grades) occurring more frequently (≥5%) or Grade 3-4 adverse reactions occurring more frequently (≥2%) in ALIMTA-treated patients compared to those receiving placebo

b NCI CTCAE Criteria version 3.0

Administration of RBC (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0) were higher in the ALIMTA arm compared to the placebo arm.

The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA arm.

Incidence 1% to 5%Blood/Bone Marrow — thrombocytopeniaGeneral Disorders — febrile neutropenia

Incidence Less than 1%Cardiovascular — ventricular tachycardia, syncopeGeneral Disorders — painGastrointestinal — gastrointestinal obstructionNeurologic — depressionRenal — renal failureVascular — pulmonary embolism

No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).

Additional Experience Across Clinical TrialsSepsis, which in some cases was fatal, occurred in approximately 1% of patients. Esophagitis occurred in less than 1% of patients.

6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of

ALIMTA. 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.

These reactions occurred with ALIMTA when used as a single-agent and in combination therapies.

Blood and Lymphatic System – Immune-mediated hemolytic anemiaGastrointestinal — colitis, pancreatitisGeneral Disorders and Administration Site Conditions — edema

Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy.

Respiratory — interstitial pneumonitisSkin — Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal

necrolysis. Some cases were fatal.

7 DRUG INTERACTIONS

7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)Although ibuprofen (400 mg four times a day) can decrease the clearance of

pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function [see Clinical Pharmacology (12.3)].

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min).

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of ALIMTA.

In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

7.2 Nephrotoxic DrugsALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration

and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA.

8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyTeratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)].Based on its mechanism of action, ALIMTA can cause fetal harm when administered

to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA 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 use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA.

8.3 Nursing MothersIt is not known whether ALIMTA 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 ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4 Pediatric UseEfficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was

administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults.

8.5 Geriatric UseALIMTA is known to be substantially excreted by the kidney, and the risk of adverse

reactions to this drug may be greater in patients with impaired renal function. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].

Of 3,946 patients (34.0% ≥65) studied across the five clinical trials [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in patients







6 ADVERSE REACTIONS









(N=830)







33291810

61554

46382127

10278

13




5640272114125

7621110

5336242012136

4610020


98

00c

129

10c


127

0c

0218

1c

1














Placebo (N=218)







1566

332

601

101


108

00

44

00



1919975

12011

65123

10000

Infection 5 2 2 0




















ALIMTA(N=333)

Placebo(N=167)

All Gradesa




Toxicity (%)



159

4.83.9

4.80.6

0.60



1265

0.30

0.3

2.41.82.4

000

















7 DRUG INTERACTIONS





















Journal Spotlight

quickly destabilizes Myc, greatly impair-ing metastasis and tumor growth.

“This has the potential to unlock a promising and completely new door to effectively eliminating tumors and sup-pressing cancers that overexpress Myc,” said Dr. Lee. n

Disclosure: The study was funded by the National Institutes of Health, the Fidelity

Foundation, and the Susan G. Komen Breast Cancer Foundation. The authors reported no potential conflicts of interest.

Reference1. Chen J, et al: CSN6 drives carcinogene-

sis by positively regulating Myc stability. Nat Commun. November 14, 2014 (early release online).


From You

We encourage readers to share their opinions and thoughts on issues of

interest to the oncology community.







6 ADVERSE REACTIONS









(N=830)







33291810

61554

46382127

1027813




5640272114125

7621110

5336242012136

4610020


98

00c

129

10c


127

0c

0218

1c

1














Placebo (N=218)







1566

332

601

101


108

00

44

00



1919975

12011

65123

10000

Infection 5 2 2 0




















ALIMTA(N=333)

Placebo(N=167)

All Gradesa




Toxicity (%)



159

4.83.9

4.80.6

0.60



1265

0.30

0.3

2.41.82.4

000

















7 DRUG INTERACTIONS

























6 ADVERSE REACTIONS









(N=830)







33291810

61554

46382127

10278

13




5640272114125

7621110

5336242012136

4610020


98

00c

129

10c


127

0c

0218

1c

1














Placebo (N=218)







1566

332

601

101


108

00

44

00



1919975

12011

65123

10000

Infection 5 2 2 0




















ALIMTA(N=333)

Placebo(N=167)

All Gradesa




Toxicity (%)



159

4.83.9

4.80.6

0.60



1265

0.30

0.3

2.41.82.4

000

















7 DRUG INTERACTIONS





















FDA Update

FDA Grants Orphan Drug Designation to BGB324 for Acute Myeloid Leukemia

The U.S. Food and Drug Admin-istration (FDA) has granted or-

phan drug designation to BGB324 for the treatment of acute myeloid leuke-mia (AML). BGB324 is a first-in-class, highly selective small-molecule inhibi-tor of the Axl receptor tyrosine kinase.

It blocks the epithelial-mesenchymal transition (EMT), which is a key driver in drug-resistance and metastasis.

Earlier this month BerGenBio an-nounced that the first patient has been dosed in its multicenter phase Ib trial of BGB324 in patients with AML. The

two-part trial will primarily investigate the safety and tolerability of BGB324 when administered as a single agent and in combination with a standard-of-care drug (cytarabine). Secondary endpoints will also explore evidence of clinical re-sponse and assess novel biomarkers.

The FDA grants Orphan Drug des-ignation to development-stage novel therapeutics that are intended for use in treating rare diseases and medical con-ditions that affect fewer than 200,000 patients in the United States. n

Editorial CorrespondenceJames O. Armitage, MD

Editor-in-Chief e-mail: [email protected]

Cara H. Glynn Director of Editorial

e-mail: [email protected]: 631.935.7654

Andrew Nash Assoc. Director of Editorial

e-mail: [email protected] Phone: 631.935.7657

Editorial OfficeHarborside Press

37 Main Street Cold Spring Harbor, NY 11724

Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com

HarborsidePress.com

Rights & Permissionse-mail:

[email protected]

Advertising Rates, reprints, or supplements

Leslie Dubine-mail: [email protected]

Phone: 631.935.7660

Contact The ASCO Post


ALIMTA® (pemetrexed for injection) PV 8927 AMP

<65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia , fatigue, thrombocytopenia, hypertension, and neutropenia.

8.6 Patients with Hepatic ImpairmentThere was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics

of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Patients with Renal ImpairmentALIMTA is known to be primarily excreted by the kidneys. Decreased renal function

will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8 GenderOf 3,946 patients (Male 70.5% ) studied across the five registration studies for

ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in female and male patients.

8.9 RaceOf 3,946 patients (Caucasian 78.6%) studied across the five registration studies for

ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients.

10 OVERDOSAGEThere have been few cases of ALIMTA overdose. Reported toxicities included

neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was

clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATIONSee FDA- Approved Patient Labeling (PPI)Instruct patients to read the patient package insert before initiating ALIMTA.• Instructpatientsontheneedforfolicacidandvitamin B12 supplementation to

reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

• Inform patients of the risk of low blood cell counts and instruct them toimmediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia.

• Instructpatients tocontact theirphysician if persistent vomiting,diarrhea,orsigns of dehydration appear.

• Instruct patients to inform their physician of all concomitant prescriptionor over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch.

Additional information can be found at www.AlimtaHCP.com

Marketed by: Lilly USA, LLC

Indianapolis, IN 46285, USA

Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved.

PM HCP BS NSCLC1M 18Nov2013



Expert’s Corner

The Harvard Global Equity Initiative: From Research to Policy A Conversation With Felicia Knaul, PhDBy Ronald Piana

The Harvard Global Equity Initiative is a research program at Harvard

University that is dedicated to promot-ing equitable global development, with a strong emphasis on health-care issues. This initiative brings together scholars, policymakers, advocates, and practitio-ners from around the world to address global-equity challenges by contributing evidence and research.

The ASCO Post recently spoke with the Harvard Global Equity Initiative Director, Felicia Knaul, PhD, about her research in breast cancer in low- and middle-in-come countries and her work in enhanc-ing access to pain control in resource-challenged areas of the world. Dr. Knaul is a breast cancer survivor.

Cancer Survivor’s PerspectiveDoes being a breast cancer survivor affect

the way you approach the work you’re cur-rently engaged in?

Yes, profoundly. In 2007, I was diag-nosed with breast cancer in a small clinic in Cuernavaca, the capital and largest city of the state of Morelos in Mexico, which is my home. At the time, I was 41-years-old, with no history of the disease; the diagno-sis gave me a deeper understanding of the shock and sense of helplessness one has af-ter a cancer diagnosis. But in my case, I was fortunate enough to have great medical, personal, and financial support during my treatment and survivorship, which is not the case in much of Mexico, where large portions of the population live in poverty.

After my diagnosis, I dedicated my personal and professional life to con-fronting the inequity and cancer divide of preventable and treatable cancers that exists between rich and poor countries. In 2008, I founded the Mexican non-profit organization, Cáncer de Mama: Tómatelo a Pecho, which promotes re-search, advocacy, awareness, and early-detection initiatives.

Goals of the Global Task ForceAnother collaborative enterprise that

the Harvard Global Equity Initiative is part of is the Global Task Force on Ex-panded Access to Cancer Care and Con-trol in Developing Countries. There are some shocking figures that put the inequi-ty problem into perspective. For instance, of the 7 million cancer deaths per year worldwide, more than 70% occur in the developing world. And despite this enor-mous burden, only 5% of global cancer re-sources are spent in the developing world.

In October 2011, the Harvard Global Equity Initiative released the report Clos-ing the Cancer Divide: A Blueprint to Ex-pand Access in Low and Middle Income Countries. The report has been dissemi-nated worldwide, describing innovative models for achieving expanded access and supplying a well-drawn plan for fu-ture action in resource-constrained areas.

Moreover, the Global Task Force will focus on areas that have largely been ne-glected. Working from the standpoint of health-system strengthening, we will spe-cifically target ways to implement cancer care pathways and expand medical cover-age of existing vaccines; detect and treat cancers early, where cure and significant life expectant are likely; and increase ser-vices for palliation of cancer symptoms to reduce unnecessary human suffering.

Enhancing Cancer ServicesCan you discuss a specific strategy that

you feel will make a meaningful impact on cancer care services in a poor region?

To promote and increase the level of cancer care in the poorer areas of the world, you first must assess the primary needs of the population to develop a strat-egy. For example, my colleagues and I re-cently completed a report in Mexico look-ing at breast cancer knowledge among health-care promoters before and after focused training.

It’s important to note that breast can-cer is the leading cause of death in adult women, and the mortality rates are ris-ing, now exceeding the mortality rates of cervical cancer. Like in most poor countries, in Mexico, breast cancers are typically diagnosed at an advanced stage, making the outlook for positive out-comes dismal. On the positive side, as part of Mexico’s health reform, in 2003 the Popular Health Insurance program was established, covering about 50 mil-lion Mexicans who were otherwise unin-sured. And since 2007, breast cancer care

is included in Popular Health Insurance coverage. However, access to screening services for early detection remains lim-ited in the poor sections of the country.

In our report, we assessed the effective-ness of a train-the-trainer program in two states in Mexico, where community health workers are a vital part of the health-care force. Realizing the opportunity to expand care, Mexico is committed to increasing the number of these workers to promote early detection of breast cancer and im-prove outcomes. We worked with local organizations to develop and implement the train-the-trainer program to improve breast cancer knowledge among commu-nity health-care workers. We then surveyed the workers before and after the 3-month training period, which included one-on-one classes and online classes.

We found that the trained workers had significantly increased their knowledge of breast cancer in areas including early de-

tection screening, risk factors, treatments, and insurance coverage. So in low-income areas of the world, easy-to-implement training programs can enhance cancer services markedly and cost-effectively.

Closing the Pain DivideCan you discuss your role as Director of

the Harvard Global Equity Initiative in ad-dressing untreated cancer pain in low- and middle-income countries.

Similar to my approach to breast cancer, I approach the issue of cancer pain through the lens of personal experience. In 1984, my father Sigmund Knaul, who was a Ho-locaust survivor, died of stomach cancer at the age of 60. My father’s cancer was swift and deadly; he died within 4 months of his diagnosis. I was 18 at the time, and his suffering from inadequately treated cancer pain left a lasting impression on me.

During his final days in the hospital, when he desperately needed better pain control, I had to struggle with the medical staff, who were reluctant to prescribe more morphine. In the end, I was the one who gave him the extra medication. When I administered the final dose of morphine, I did it with peace of mind, because he was in such severe, uncontrolled pain.

It was largely the memory of my fa-ther’s struggle with horrible cancer pain that later fueled my passion to help close the pain divide that exists between the rich and poor sections of the world. To that end, as Director of the Harvard Glob-al Equity Initiative, I’m pleased that we’ve created the Harvard Global Equity Initia-tive–Lancet Commission on Global Ac-cess to Pain Control and Palliative Care.

The raw data on this issue are nothing short of startling. The difference in opioid consumption per cancer death is close to 600-fold between the poorest 20% and the richest 20% of countries. For example, the United States and Canada consume about 300,000 mg per pain-related cancer death, compared with 450 mg in Uganda and 47 mg in Haiti. The World Health Or-ganization estimates that about 5.5 mil-lion terminal cancer patients are suffering in severe pain because they do not have access to opioid medications.

Ironically, global and national health systems have the ability to close this di-vide of needless suffering. A huge part of the problem is caused by archaic drug regulations, which need to be addressed through lobbying and education.

For instance, in Mexico not only does a doctor have to have a special prescrip-tion pad for pain meds, but also those pre-scription pads are only available in major cities. Making matters worse, they only produce a limited amount of these special pads. This makes it almost impossible for young physicians working in rural areas to prescribe adequate pain medications for their cancer patients. And Mexico is a middle-income country with a solvent economy. Lack of access to opioids in oth-er parts of the world, such as sub-Saharan Africa, is catastrophic.

Frankly, denial of pain medication is a form of torture. Unfortunately, far too few are willing to acknowledge this human crisis. Living pain free is a human right that can be met, even in our poorest areas. This terrible pain divide can be closed, and it’s a cause that the health-care com-munity needs to rally around. n

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

Health-Care Disparities

Felicia Knaul, PhD

Frankly, denial of pain medication is a form of torture. Living pain free is a human right that

can be met, even in our poorest areas. —Felicia Knaul, PhD

LAUNCH JOURNAL KING SIZE4C

THIS ADVERTISEMENT PREPARED BY FCB

Job#: 10263819 ONYX_KYPROLIS_10263819Client: KeryxDate: October 27, 2014 4:29 PMProof: 2

Name: PrePress:Onyx:Kyprolis:10263819:_Packaged_Jobs_:10263819_King_Size_Ad:10263819_King_Size_Ad_FR1

Prod.: B. Iannizzotto x2419Colors: 4/cBleed: 22.25” x 14.25”Trim: 10.5” x 13.875”Live: 9.5” x 13” each pageFonts: Helvetica Neue,

Interstate, Minion, September

AD: L. Ryan x2848AE: M. McCormick x2395Traffic: E. Naylor x2414QC: L. Powell x 8674Artist: tp, ms Spellcheck:M1 by Jennifer Ryan

Important Safety Information

CONTRAINDICATIONSNone.


The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma.

Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications.

Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients.

Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.

Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline.

Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur.

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved.

Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver enzyme abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently.

Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONSSerious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each).

The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONSSince dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of the full Prescribing Information on adjacent pages.

For the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION TAKES FLIGHT

KYPROLIS is engineered for selective inhibition1

• Single-agent KYPROLIS phase 2 study results2,* - Overall response rate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest,

dyspnea, increased blood creatinine, and acute renal failure (1% each)

ADVERSE REACTIONSThe safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma.• Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%),

acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%),

thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%)

* Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391. 2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Kyprolis® (carfilzomib) for Injection Now Has a Permanent J Code: J9047

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc.

©2014 Onyx Pharmaceuticals, Inc., South San Francisco, CA TROPIC-KYPR-100603 October 2014

S:19.75”

S:13”

T:21”

T:13.875”

B:22.25”

B:14.25”

F:10.5”

FS:9.5”

F:10.5”

FS:9.5”

10263819_King_Size_Ad_FR1.indd 1 10/27/14 4:42 PM

LAUNCH JOURNAL KING SIZE4C


Job#: 10263819 ONYX_KYPROLIS_10263819Client: KeryxDate: October 27, 2014 4:29 PMProof: 2

Name: PrePress:Onyx:Kyprolis:10263819:_Packaged_Jobs_:10263819_King_Size_Ad:10263819_King_Size_Ad_FR1

Prod.: B. Iannizzotto x2419Colors: 4/cBleed: 22.25” x 14.25”Trim: 10.5” x 13.875”Live: 9.5” x 13” each pageFonts: Helvetica Neue,


AD: L. Ryan x2848AE: M. McCormick x2395Traffic: E. Naylor x2414QC: L. Powell x 8674Artist: tp, ms Spellcheck:M1 by Jennifer Ryan


CONTRAINDICATIONSNone.


The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma.

Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications.

Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients.

Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.

Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline.

Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur.

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved.

Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver enzyme abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently.

Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONSSerious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each).

The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONSSince dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of the full Prescribing Information on adjacent pages.

For the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION TAKES FLIGHT

KYPROLIS is engineered for selective inhibition1

• Single-agent KYPROLIS phase 2 study results2,* - Overall response rate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest,

dyspnea, increased blood creatinine, and acute renal failure (1% each)

ADVERSE REACTIONSThe safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma.• Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%),

acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%),

thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%)

* Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391. 2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Kyprolis® (carfilzomib) for Injection Now Has a Permanent J Code: J9047

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc.

©2014 Onyx Pharmaceuticals, Inc., South San Francisco, CA TROPIC-KYPR-100603 October 2014

S:19.75”

S:13”

T:21”

T:13.875”

B:22.25”

B:14.25”

F:10.5”

FS:9.5”

F:10.5”

FS:9.5”

10263819_King_Size_Ad_FR1.indd 1 10/27/14 4:42 PM

http://www.kyprolis.com/hcp#


Journal Spotlight

New Imaging Technique Identifies Receptors for Targeted Cancer Therapy

D artmouth researchers have devel-oped a fluorescence imaging tech-

nique that can more accurately identify receptors for targeted cancer therapies without a tissue biopsy. They report on their findings in a recently published ar-ticle in Cancer Research.1

“Protein overexpression is a hall-mark of certain cancers and is used in clinical oncology to personalize treatment through tumor detection, molecular therapies, and therapeutic monitoring,” said lead author Kim-berley S. Samkoe, PhD, Assistant

Professor of Surgery at the Geisel School of Medicine and Adjunct As-sistant Professor at Thayer School of Engineering. “Protein expression is currently measured through a total protein analysis of tumor tissue. This new technique allows us to accurately

determine the amount of protein re-ceptors available for binding a drug without invasive biopsy.”

Study DetailsThe researchers developed a dual-

tracer in vivo receptor concentra-

Technology

LAUNCH JOURNAL SPREAD4C


Job#: 10263819 KERYX_10263819Client: KeryxDate: October 27, 2014 2:20 PMProof: 2

Name: PrePress:Onyx:Kyprolis:10263819:Holding:Outlined To Fix Crashing Text:10263819_Launch_Jrnl_Ad_FR_OL

Prod.: B. Iannizzotto x2419Colors: 4/cBleed: 16.75” x 11.25”Trim: 8.125” x 10.875”Live: 7” x 10” each pageFonts: Helvetica Neue,


AD: L. Ryan x2848AE: M. McCormick x2395Traffic: E. Naylor x2414QC: L. Powell x 8674Artist: gh, NJSpell Checked at FR by Katrina

KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma

KYPROLIS(20 mg/m2):

KYPROLIS(27 mg/m2):

Cycle 1Week 1 Week 2 Week 3 Week 4

Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28

20 20 20 20 NoDosing

20 20 NoDosing

NoDosing

Cycles 2 and Beyonda

Week 1 Week 2 Week 3 Week 4

Day15

Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28

Day15


NoDosing

NoDosing

27 27 NoDosing

NoDosing

aIf previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2.Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment

Hematologic Toxicity Recommended Action• Grade 3a or 4 Neutropenia • Grade 4 Thrombocytopenia [see Warnings and Precautions]

• Withhold dose.• If fully recovered before next scheduled dose, continue

at same dose level.• If recovered to Grade 2 neutropenia or Grade 3

thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

Non-Hematologic Toxicity Recommended ActionCardiac ToxicityGrade 3 or 4, new onset or worsening of:• congestive heart failure; • decreased left ventricular

function; • or myocardial ischemia [see Warnings and Precautions]

• Withhold until resolved or returned to baseline. • After resolution, consider if restarting KYPROLIS at

a reduced dose is appropriate (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).


Pulmonary Hypertension[see Warnings and Precautions]

• Withhold until resolved or returned to baseline.• Restart at the dose used prior to the event or reduced

dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2

to 15 mg/m2), at the discretion of the physician.• If tolerated, the reduced dose may be escalated to the

previous dose at the discretion of the physician.Pulmonary Complications• Grade 3 or 4 [see Warnings and Precautions]

• Withhold until resolved or returned to baseline.• Consider restarting at the next scheduled treatment

with one dose level reduction (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).


Hepatic Toxicity• Grade 3 or 4 elevation of

transaminases, bilirubin or other liver abnormalities

[see Warnings and Precautions)]

• Withhold until resolved or returned to baseline.• After resolution, consider if restarting KYPROLIS is

appropriate; may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function.


Renal Toxicity• Serum creatinine equal to or

greater than 2 × baseline[see Adverse Reactions]

• Withhold until renal function has recovered to Grade 1 or to baseline and monitor renal function.

• If attributable to KYPROLIS, restart at the next scheduled treatment at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If not attributable to KYPROLIS, restart at the dose used prior to the event.


Peripheral Neuropathy• Grade 3 or 4 [see Adverse Reactions]




previous dose at the discretion of the physician.Other • Grade 3 or 4 non‑hematological

toxicities




aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag. 6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3. Table 3: Stability of Reconstituted KYPROLIS

Storage Conditions of Reconstituted KYPROLIS

Stabilitya per Container

Vial SyringeIV Bag (D5Wb)

Refrigerated (2°C to 8°C; 36°F to 46°F) 24 hours 24 hours 24 hours

Room Temperature (15°C to 30°C; 59°F to 86°F) 4 hours 4 hours 4 hoursaTotal time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and recovery to baseline by the start of the next 28‑day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration]. Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued)

(continued)

Patients (N = 526) [n (%)]

EventAll

GradesaGrade 3 Events

Grade 4 Events

S:14.625”

S:10”

T:16.25”

T:10.875”

B:16.75”

B:11.25”

F:8.125”

FS:7”

F:8.125”

FS:7”

10263819_Launch_Jrnl_Ad_FR_OL.indd 2 10/27/14 2:28 PM


Journal Spotlight

tion imaging technique that involves the simultaneous injection of both a targeted and a nontargeted imaging agent. They then studied the protein expression of five tumors, comparing the receptor concentration imaging data to that determined by clinical immunohistochemistry, either scored by a pathologist (as performed in the

clinic) or analyzed independently by a computer.

They found that the protein expres-sion determined by receptor concen-tration imaging strongly correlated to that determined by tissue analysis. They also found that commonly used techniques of measuring protein ex-pression, such as Western blots or flow

cytometry, did not correlate to the re-ceptor concentration imaging values, and in fact overpredicted the number of receptors available for therapeutic or diagnostic targeting.

Potential Impact on Outcomes“Accurately determining the popu-

lation of protein receptors in a tumor

available for targeting by molecular therapies or diagnostic imaging agents can greatly impact oncology patient outcomes,” said Dr. Samkoe.

“Our in vivo receptor concentration imaging technique is a novel approach for fluorescence imaging that can po-tentially impact clinical assessment of tumor status and malignant tissue clas-sification,” she added.

Dr. Samkoe noted that this study looks at the average receptor expres-sion within the tumor. The next step will be to look at tumors on a micro-scopic level in order to correlate recep-tor expression to distinct physiological features such as cellular viability, cellu-lar type, vascularity, and overall tumor architecture.

The study was a collaboration between Geisel School of Medicine at Dartmouth College, the Thayer School of Engineering, members of the Norris Cotton Cancer Center, and the Wellman Center for Photo-medicine at Massachusetts General Hospital. n

Disclosure: The study was supported by NIH grants R01CA156177, U54CA151662 and P01CA84203. For full disclosures of the study authors, visit cancerres.aacrjournals.org.

Reference1. Samkoe KS, Tichauer KM, Gunn JR,

et al: Quantitative in vivo immunohisto-chemistry of epidermal growth factor re-ceptor using a receptor concentration im-aging approach. Cancer Res. October 24, 2014 (early release online).

Our in vivo receptor concentration imaging

technique is a novel approach for fluorescence

imaging that can potentially impact clinical assessment of tumor status and malignant

tissue classification. —Kimberley S. Samkoe, PhD

LAUNCH JOURNAL SPREAD4C


Job#: 10263819 KERYX_10263819Client: KeryxDate: October 27, 2014 2:20 PMProof: 2

Name: PrePress:Onyx:Kyprolis:10263819:Holding:Outlined To Fix Crashing Text:10263819_Launch_Jrnl_Ad_FR_OL

Prod.: B. Iannizzotto x2419Colors: 4/cBleed: 16.75” x 11.25”Trim: 8.125” x 10.875”Live: 7” x 10” each pageFonts: Helvetica Neue,


AD: L. Ryan x2848AE: M. McCormick x2395Traffic: E. Naylor x2414QC: L. Powell x 8674Artist: gh, NJSpell Checked at FR by Katrina

KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma

KYPROLIS(20 mg/m2):

KYPROLIS(27 mg/m2):

Cycle 1Week 1 Week 2 Week 3 Week 4

Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28


20 20 NoDosing

NoDosing

Cycles 2 and Beyonda

Week 1 Week 2 Week 3 Week 4

Day15

Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28

Day15


NoDosing

NoDosing

27 27 NoDosing

NoDosing

aIf previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2.Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment

Hematologic Toxicity Recommended Action• Grade 3a or 4 Neutropenia • Grade 4 Thrombocytopenia [see Warnings and Precautions]

• Withhold dose.• If fully recovered before next scheduled dose, continue

at same dose level.• If recovered to Grade 2 neutropenia or Grade 3

thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).


Non-Hematologic Toxicity Recommended ActionCardiac ToxicityGrade 3 or 4, new onset or worsening of:• congestive heart failure; • decreased left ventricular

function; • or myocardial ischemia [see Warnings and Precautions]

• Withhold until resolved or returned to baseline. • After resolution, consider if restarting KYPROLIS at

a reduced dose is appropriate (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).


Pulmonary Hypertension[see Warnings and Precautions]




previous dose at the discretion of the physician.Pulmonary Complications• Grade 3 or 4 [see Warnings and Precautions]




Hepatic Toxicity• Grade 3 or 4 elevation of

transaminases, bilirubin or other liver abnormalities

[see Warnings and Precautions)]

• Withhold until resolved or returned to baseline.• After resolution, consider if restarting KYPROLIS is

appropriate; may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function.


Renal Toxicity• Serum creatinine equal to or

greater than 2 × baseline[see Adverse Reactions]

• Withhold until renal function has recovered to Grade 1 or to baseline and monitor renal function.

• If attributable to KYPROLIS, restart at the next scheduled treatment at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If not attributable to KYPROLIS, restart at the dose used prior to the event.


Peripheral Neuropathy• Grade 3 or 4 [see Adverse Reactions]




previous dose at the discretion of the physician.Other • Grade 3 or 4 non‑hematological

toxicities




aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag. 6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3. Table 3: Stability of Reconstituted KYPROLIS

Storage Conditions of Reconstituted KYPROLIS

Stabilitya per Container

Vial SyringeIV Bag (D5Wb)

Refrigerated (2°C to 8°C; 36°F to 46°F) 24 hours 24 hours 24 hours

Room Temperature (15°C to 30°C; 59°F to 86°F) 4 hours 4 hours 4 hoursaTotal time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and recovery to baseline by the start of the next 28‑day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration]. Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued)

(continued)

Patients (N = 526) [n (%)]

EventAll

GradesaGrade 3 Events

Grade 4 Events

S:14.625”

S:10”

T:16.25”

T:10.875”

B:16.75”

B:11.25”

F:8.125”

FS:7”

F:8.125”

FS:7”

10263819_Launch_Jrnl_Ad_FR_OL.indd 2 10/27/14 2:28 PM


Journal Spotlight

NORCCAP Trial Shows Reduced Colorectal Cancer Incidence and Mortality With Flexible Sigmoidoscopy Screening at 11 YearsBy Matthew Stenger

The Norwegian Colorectal Cancer Prevention (NORCCAP) trial

comparing colorectal cancer screen-ing with flexible sigmoidoscopy vs no screening showed no reduction in colorectal cancer incidence or mortali-ty after 7 years of follow-up. As reported by Øyvind Holme, MD, of Sorlandet Hospital Kristiansand, and colleagues in JAMA, the 11-year follow-up shows significant reductions in both incidence and mortality with screening.1

Study DetailsIn the trial, individuals aged 50 to

64 years were randomly assigned to no screening (usual care) or once-only flexible sigmoidoscopy screening with or without fecal occult blood testing. Those randomized to screening were invited to undergo screening, per-formed in 1999 to 2000 in the 55- to 64-year age group and in 2001 in the

50- to 54-year age group. Participants with positive screening tests, consisting of cancer, adenoma, polyp ≥ 10 mm, or positive fecal occult blood test, were of-fered colonoscopy.

A total of 98,792 participants were included in the intention-to-screen analyses, consisting of 78,220 in the no-screening control group and 20,572 in the screening group. Of those in the screening group, 10,283 were randomly assigned to receive flexible sigmoidosco-py and 10,289 to receive flexible sigmoid-oscopy and fecal occult blood testing.

Mean age was 57 years in the screen-

ing group and 56 years in the control group, with 34% and 47% aged 50 to 54 years and 66% and 53% aged 55 to 64 years. Half the participants in each group were women. The screening ad-herence rate was 63%.

Colorectal Cancer IncidenceColorectal cancer was diagnosed in

253 participants in the screening group vs 1,086 in the control group, yielding age-standardized rates of 112.6 vs 141.0 cases per 100,000 person-years (abso-lute rate difference = 28.4, 95% confi-dence interval [CI] = 12.1–44.7, hazard ratio [HR] = 0.80, 95% CI = 0.70–0.92). The number needed to invite for screening to prevent 1 colorectal cancer case over 10 years was 498.

Hazard ratios were 0.68 (95% CI = 0.49–0.94) in the 50- to 54-year age group and 0.83 (95% CI = 0.71–0.96) in the 55- to 64-year age group (P = .27 for

heterogeneity), 0.73 (95% CI = 0.60–0.89) in men and 0.87 (95% CI = 0.72–1.06) in women (P = .26 for heterogene-ity), and 0.76 (95% CI = 0.63–0.92) for distal colorectal cancer and 0.90 (95% CI = 0.73–1.10) for proximal colorectal cancer. Hazard ratios were 0.72 (95% CI = 0.59–0.87) for sigmoidoscopy alone and 0.88 (95% CI = 0.74-1.05) for sig-moidoscopy plus fecal occult blood test-ing (P = .11 for heterogeneity). Screen-detected colorectal cancer was more frequently diagnosed at an earlier stage.

Overall, 19.5% of participants un-dergoing screening sigmoidoscopy

and 21.3% of those who also had fecal occult blood testing were referred for colonoscopy, with 18.7% and 20.3% undergoing the procedure. Perforation or hospital admission for postpolypec-tomy bleeding occurred in none of the participants after sigmoidoscopy and in 10 after colonoscopy.

Colorectal Cancer MortalityAfter a median of 10.9 years of fol-

low-up, death due to colorectal cancer had occurred in 71 screening group par-ticipants and 330 control group partici-pants, yielding age-standardized rates of 31.4 vs 43.1 deaths per 100,000 person-years (absolute rate difference = 11.7, 95% CI = 3.0–20.4, HR = 0.73, 95% CI = 0.56–0.94). The number needed to in-vite for screening to prevent 1 colorectal cancer death over 10 years was 1,547.

Hazard ratios for colorectal cancer mortality were 0.74 (95% CI = 0.40–1.35) in the 50- to 54-year age group and 0.73 (95% CI = 0.55–0.97) in the 55- to 64-year age group, 0.58 (95% CI = 0.40–0.85) in men and 0.91 (95% CI, 0.64–1.30) in women (P = .10 for heterogene-ity), and 0.79 (95% CI = 0.55–1.11) for distal colorectal cancer and 0.73 (95% CI = 0.49–1.09) for proximal colorectal cancer. Hazard ratios were 0.84 (95% CI = 0.61–1.17) for flexible sigmoidoscopy and 0.62 (95% CI = 0.42–0.90) with sig-moidoscopy plus fecal occult blood test-ing (P = .20 for heterogeneity).

There was no difference between groups in all-cause mortality (HR = 0.97, 95% CI = 0.93–1.02).

Adjustment for NonadherenceThe intention-to-screen 10-year risk

absolute difference was −0.22% (95% CI = −0.38% to −0.06%) for colorec-tal cancer incidence and −0.06% (95% CI = −0.14% to 0.03%) for colorectal cancer death in the entire population. After adjustment for nonadherence, the 10-year risk differences were −0.42% (95% CI = −0.69% to −0.15%) for in-cidence and −0.10% (95% CI = −0.25% to 0.05%) for death.

The investigators concluded: “In Norway, once-only flexible sigmoid-oscopy screening or flexible sig-moidoscopy and [fecal occult blood testing] reduced colorectal cancer in-cidence and mortality on a population level compared with no screening. Screening was effective both in the 50- to 54-year and the 55- to 64-year age groups.” n

Disclosure: NORCCAP was funded by grants from the Norwegian government and Norwegian Cancer Society. Work on the JAMA article was funded by grants from the Norwegian Cancer Society, Research Council of Norway, South-East Regional Health Authority of Norway, Fulbright Foundation, Sorlandet Hospital Kristiansand, and National Institutes of Health. For full disclosures of the study authors, visit jama.jamanetwork.com.

Reference1. Holme Ø, Løberg M, Kalager M, et al:

Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mor-tality: A randomized clinical trial. JAMA 312:606-615, 2014.

See commentary by Aline Charabaty, MD, on page 47.

Gastrointestinal Oncology

In Norway, once-only flexible sigmoidoscopy screening or flexible sigmoidoscopy and [fecal occult blood testing] reduced colorectal cancer incidence and mortality on a

population level compared with no screening. —Øyvind Holme, MD, and colleagues

Colorectal Cancer Screening

■ Invitation to screening with flexible sigmoidoscopy with or without fecal occult blood testing was associated with a significant 20% reduction in colorectal cancer incidence.

■ Invitation to screening was associated with a 27% reduction in colorectal cancer mortality.

www.ASCOPost.com Phone: 631.692.0800 Fax: 631.692.0805

Harborside Press 37 Main Street

Cold Spring Harbor, NY 11724

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.



Perspective

Sigmoidoscopy or Colonoscopy for Colorectal Cancer Screening: Is It Still the Question?By Aline Charabaty, MD

Mortality from colorectal cancer remains a public-health concern,

being the second leading cause of cancer-related death for men and women com-bined. The major preventive measure for colorectal cancer is to screen for and re-move adenomatous polyps. Average-risk individuals (ie, those who do not have a hereditary colorectal syndrome) are of-fered several screening options starting at age 50 at regular intervals: colonos-copy every 10 years, flexible sigmoid-oscopy every 5 years, fecal occult blood test yearly, and computed tomographic colonography every 5 years.

Sigmoidoscopy StudyAs reviewed in this issue of The

ASCO Post, Holme and colleagues re-cently reported the results of a large randomized trial of colorectal cancer screening in Norway, comparing the effect of a one-time flexible sigmoidos-copy (with or without fecal occult blood test) with no screening on the incidence and mortality of colorectal cancer af-ter 11 years of follow-up.1 Participants with an abnormal screening result were offered a colonoscopy. In an intention-to-treat analysis (ie, including the one-third of patients who were invited to be screened but did not participate), flex-ible sigmoidoscopy screening reduced this incidence and mortality by 20% and 27%, respectively. It is estimated that the absolute reduction of colorectal cancer risk at 10 years would double if all pa-tients adhered to the screening recom-mendations. Fecal occult blood test did not improve outcomes beyond flexible sigmoidoscopy alone.

Practice Implications and Limitations

The results of this study are in ac-cordance with those reported in three prior large randomized trials of flexible sigmoidoscopy screening (UK Flexi-Scope Trial, Italian SCORE Trial, and U.S. PLCO trial),2-4 highlighting the effectiveness and safety of this rela-tively inexpensive method to prevent colorectal cancer and decrease cancer-associated mortality. However, despite these results, flexible sigmoidoscopy screening is underutilized in the Unit-

ed States, and colonoscopy has be-come the most recommended and per-formed procedure for colorectal cancer screening. Other screening methods are usually offered to patients who de-cline colonoscopy, who have severe co-morbidities, who do not have access to colonoscopy, or who are underinsured or uninsured. Several factors have con-tributed to colonoscopy becoming the preferred screening method.

In 2001, Medicare began paying for colonoscopy to screen average-risk in-dividuals, and private insurers followed. Gastroenterologists now had an eco-nomic incentive to recommend colo-noscopy over other screening tests, and training in flexible sigmoidoscopy by nongastroenterologists (primary-care physicians and internists) has sharply de-clined. Even though the American Col-lege of Physicians and the U.S. Preventive Task Force do not favor one screening

method over another, several specialty societies such as the American Col-lege of Gastroenterology recommend colonoscopy as the preferred colorectal cancer screening test.5-8 Although the National Polyp Study group showed that colonoscopic polypectomy provided a 53% reduction in cancer mortality compared with the general population (Surveillance, Epidemiology, and End Results database),9 there is no random-ized trial level evidence that screening colonoscopy of the general population reduces cancer-related mortality.

The perception of the superiority of colonoscopy as a screening test by the public and health-care providers is largely based on the fact that it is a pro-cedure that allows the visualization of the entire colon (with experts compar-ing the performance of a screening sig-moidoscopy as opposed to a full colo-

noscopy with that of mammography on one breast) and is both diagnostic and therapeutic. However, one of the most important arguments for colonoscopy are data from large cohort average-risk patients (mainly males, in the Veterans Affairs Cooperative Study), suggesting that approximately 50% of advanced neoplasia (adenomas larger than 1 cm, villous adenomas, adenomas with high-grade dysplasia, or colorectal cancer) proximal to the splenic flexure would be missed if the initial screening strategy relied on sigmoidoscopy (with colonos-copy only performed if a distal adenoma is detected on sigmoidoscopy).

The issue seems to be even more rel-evant in women. A large cohort study of screening colonoscopy for average-risk women showing that up to 65% of proximal advanced neoplasia would have been missed if the initial screening test was limited to sigmoidoscopy.10,11

Further ConsiderationsWhat we are certain of is that any

screening is better than no screening at all and that there might not be a gold standard test that applies to all patients. Beyond defining which screening tool is optimal in decreasing the incidence and related mortality of colorectal cancer, a more important issue to be addressed is the fact that colorectal cancer screening rates remain low (less than 50% of average-risk individuals undergo screened) despite the many test options available to patients.12

A screening test that examines the en-tire colon, that is not invasive like an en-doscopy, that is easy to perform and not time-consuming, and that is cost-effec-tive would be an ideal screening tool for patients and physicians alike. The mul-titarget stool DNA test (which also in-cludes a hemoglobin immunoassay) has

the potential to become such a screening tool. Compared with colonoscopy, stool DNA testing has a sensitivity of 92% and 42% for detecting colorectal cancer and advanced adenomas, respectively.13

Hence, the debate between screen-ing sigmoidoscopy followed by colo-noscopy only if a distal adenoma is found vs initial screening colonoscopy might soon become a thing of the past, with the recent U.S. Food and Drug Administration approval of stool DNA testing for colorectal cancer screening. Physicians and professional societies will need to define the role of this new technology and include it in our strategy to improve colorectal cancer screening compliance and reduce the incidence and mortality of colorectal cancer. n

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

References1. Holme Ø, et al: Effect of flexible sig-

moidoscopy screening on colorectal cancer incidence and mortality. JAMA 312:606-615, 2014.

2. Atkin WS, et al: Lancet 375:1624-1633, 2010.

3. Segnan N, et al: Once-only sigmoid-oscopy in colorectal cancer screening. J Natl Cancer Inst 103:1310-1322, 2011.

4. Schoen RE, et al: Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy. N Engl J Med 366:2345-2357, 2012.

5. Qaseem A, et al: Screening for colorectal cancer. Ann Intern Med 156:378-386, 2012.

6. U.S. Preventive Services Task Force: Screening for colorectal cancer. Ann Intern Med 149:627-637, 2008.

7. Rex DK, et al: American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol 104:739-750, 2009.

8. Levin B, et al: Screening and surveil-lance for the early detection of colorectal cancer and adenomatous polyps, 2008. Gas-troenterology 134:1570-1595, 2008.

9. Zauber AG, et al: Colonoscopic polypectomy and long-term prevention of colorectal-cancer death. N Engl J Med 366:687-696, 2012.

10. Lieberman DA, et al: Use of colo-noscopy to screen asymptomatic adults for colorectal cancer. N Engl J Med 343:162-168, 2000.

11. Schoenfeld P, et al: Colonoscopic screening of average-risk women for colorec-tal neoplasia. N Engl J Med 352:2061-2068, 2005.

12. Swan J, et al: Progress in cancer screening practices in the United States. Cancer 97:1528-1540, 2003.

13. Imperiale TF, et al: Multitarget stool DNA testing for colorectal-cancer screen-ing. N Engl J Med 370:1287-1297, 2014.

Colorectal Cancer

Dr. Charabaty is Director of the Center for Inflammatory Bowel Diseases at George-town University Hospital, Washington, DC.

The debate between screening sigmoidoscopy followed by colonoscopy only if a distal adenoma is found vs initial screening colonoscopy might soon become a thing of the past, with the recent FDA approval of stool DNA testing for colorectal cancer screening.

—Aline Charabaty, MD


Journal Spotlight

Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: ASCO/CCO Clinical Practice GuidelineBy Matthew Stenger

The ASCO Clinical Practice Guide-lines Committee and the Can-

cer Care Ontario (CCO) program in evidence-based care have released a clinical practice guideline on systemic therapy in men with metastatic cas-tration-resistant prostate cancer. The guideline was published in the Journal of Clinical Oncology.1

The guideline is the result of efforts of a multidisciplinary ASCO/CCO expert

panel, which developed evidence-based recommendations through a systematic review of the literature guided by the question: “Which systemic therapies im-prove outcomes in men with metastatic [castration-resistant prostate cancer]?” The evidentiary basis of the guideline consists of 26 randomized controlled trials identified through a 2012 CCO systematic review2 and an updated litera-ture search through June 2014.

The panel was chaired by Ethan Basch, MD, MSc, Director of the Can-cer Outcomes Research Program and Associate Professor of Medicine and Public Health at the Lineberger Com-prehensive Cancer Center, The Univer-sity of North Carolina at Chapel Hill.

In BriefIn brief, the guideline recommends

that androgen deprivation be contin-ued indefinitely. Systemic therapy that should be offered includes abiraterone acetate (Zytiga)/prednisone, enzalu-tamide (Xtandi), and radium-223 (Xo-figo) for men with predominantly bone metastases, with docetaxel/prednisone also being offered accompanied by dis-cussion of toxicity risk. Sipuleucel-T (Provenge) may be offered to asymp-tomatic/minimally symptomatic men, with an understanding that quality-of-life outcomes data are not available. Cabazitaxel ( Jevtana) may be offered to patients experiencing disease progres-sion on docetaxel, with an understand-

ing that quality-of-life benefits are not shown and high levels of toxicities have been reported.

Mitoxantrone can be offered accom-panied by discussion of limited clinical benefit and toxicity risk, and ketocon-azole or antiandrogens (eg, bicalutamide, flutamide, and nilutamide [Nilandron]) may be offered, accompanied by discus-sion of unknown clinical benefit amidst known toxicities. Bevacizumab (Avas-

tin), estramustine (Emcyt), and suni-tinib (Sutent) should not be used.

There is insufficient evidence to identify optimal sequences or combina-tions of therapies. Palliative care should be offered to all patients.

Individual recommendations are summarized below.

Androgen-Deprivation Therapy• Continuous androgen deprivation

(pharmaceutical or surgical) should be continued indefinitely regard-less of additional therapies (benefit = moderate; harm = moderate; evi-dence strength = weak; recommen-dation strength = moderate).

Therapies in Addition to Androgen-Deprivation Therapy

Therapy with survival and quality-of-life benefits• Abiraterone acetate and prednisone

(benefit = moderate; harm = low; evidence strength = strong; recom-mendation strength = strong).

• Enzalutamide (benefit = moderate; harm = low; evidence strength = strong; recommendation strength = strong).

• Radium-223 should be offered to men with bone metastases (benefit = moderate; harm = low; evidence quality = strong; recommendation strength = strong).

• Docetaxel and prednisone (benefit = moderate; harm = moderate; evi-dence strength = strong; recommen-dation strength = moderate). Recent data suggest a substantial survival benefit with addition of a limited course of docetaxel to androgen-de-privation therapy in newly diagnosed metastatic androgen-sensitive pros-tate cancer, primarily in patients with high burden of metastatic disease (ie, visceral disease or more than four bone metastatic lesions). The addi-tive benefits or toxicities associated with subsequent docetaxel retreat-ment of such patients in the castra-tion-resistant setting are unknown. Therapy with survival benefit and un-

clear quality-of-life benefit• Sipuleucel-T may be offered to asymp-

tomatic or minimally symptomatic men (benefit = moderate; harm = low; evidence strength = moderate; recom-mendation strength = weak).

• Cabazitaxel and prednisone may be offered to patients with disease progression on docetaxel (benefit = moderate; harm = moderate to high; evidence strength = strong; recom-mendation strength = moderate).Therapy with quality-of-life benefit

without demonstrated survival benefit• Mitoxantrone plus prednisone (ben-

efit = low; harm = high; evidence strength = weak; recommendation strength = weak).Therapy with biologic activity and un-

known survival or quality-of-life benefit• Antiandrogens—eg, bicalutamide, flu-

tamide, and nilutamide (benefit = low; harm = low; evidence strength = weak; recommendation strength = weak).

• Ketoconazole (benefit = low; harm = moderate; evidence strength = weak; recommendation strength = weak).

• Low-dose corticosteroid monother-apy (benefit = low; harm = low; evi-dence strength = weak; recommen-dation strength = weak).Therapy with no demonstrated surviv-

al or quality-of-life benefit• Bevacizumab, estramustine, and

sunitinib should not be offered (for each: benefit = none; harm = high; evidence strength = moderate; rec-ommendation strength = strong).

Palliative Care Services• Palliative care should be offered to all

patients, particularly to those exhibit-

ing symptoms or quality-of-life de-creases, regardless of treatment type (benefit = moderate; harm = none; evidence strength = moderate; rec-ommendation strength = strong).

Qualifying Statements• Clinicians should review the published

regimens discussed in the guideline for use in appropriate patient populations and for dose selections/modifications.

• There is insufficient published evi-dence to recommend specific se-quencing or combinations of rec-ommended therapies (except as otherwise noted in full guideline).

• A distinction made in some clinical trials between pre- and post-docetaxel treatment contexts should not play a role in selecting therapies for individ-ual patients (unless otherwise noted).

• Patients may place a higher impor-tance on quality of life than length of life. Treatment decisions require understanding of individual pa-tient values and preferences. Many patients with incurable metastatic disease believe the goals of care to be curative; clear communication about goals and potential benefits and harms of care is necessary.

• Cost and availability may influence treatment decisions, and these fac-tors must be discussed with patients.

• Most phase III clinical trials have included patients with good base-line performance status. Choices of treatment for patients with dimin-ished performance status are not clearly established by existing evi-dence in most cases. nDisclosure: For full disclosures of the

guideline authors, visit jco.ascopubs.org.

References1. Basch E, Loblaw DA, Oliver, TK, et

al: Systemic therapy in men with metastatic castration-resistant prostate cancer: Ameri-can Society of Clinical Oncology and Can-cer Care Ontario Clinical Practice Guide-line. J Clin Oncol. September 8, 2014 (early release online).

2. Loblaw DA, Walker-Dilks C, Win-quist E, et al: Systemic therapy in men with metastatic castration-resistant prostate cancer: A systematic review. Clin Oncol (R Coll Radiol) 25:406-430, 2013.

See commentary by Maha Hussain, MD, FACP, on page 49.

Genitourinary Oncology

Patients may place a higher importance on quality of life than length of life. Treatment decisions require understanding of individual patient values and preferences.

—Ethan Basch, MD, MSc, and colleagues


Perspective

From ‘Clinical Judgment’ to Evidence-Based Medicine: Thoughts on the ASCO/CCO Guideline in Metastatic Castration-Resistant Prostate CancerBy Maha Hussain, MD, FACP, FASCO

We are witnessing unprecedent-ed progress in the develop-

ment of therapy for patients with metastatic castration-resistant pros-tate cancer. The U.S. Food and Drug Administration (FDA) has issued 13 approvals since 1996 for agents that have demonstrated an impact on over-all survival, pain, or skeletal-related events—all very clearly clinical ben-efit outcomes relevant for managing this group of patients. In a similar time period, more phase III trials proved negative despite some very promising biologic, preclinical, and randomized phase II trials data. In the previous era, when there were no established effective therapies to manage meta-static castration-resistant prostate cancer, oncologists based their deci-sion on judgment, prior experience, and phase II clinical trials data.

The need to reduce the morbid-ity of bone metastasis resulted in the early FDA approvals for agents that re-duce pain or minimize skeletal-related events, beginning with the approval of mitoxantrone/prednisone in 1996, followed by strontium, samarium-153 (Quadramet), and zoledronic acid. However, the major landmark occurred in 2004 with the approval of docetaxel, which is the first agent to demonstrate a survival impact in this disease setting. With the limited number of agents available then, clinical decisions as to what to use first were relatively simple. Now, the great news is that we have several agents with impact on sur-vival in both docetaxel-naive patients (sipuleucel-T [Provenge], abiraterone [Zytiga]/prednisone, radium-223 [Xofigo], enzalutamide [Xtandi]) and docetaxel-treated patients (cabazitaxel [ Jevtana]/prednisone, abiraterone, enzalutamide, radium-223).

Need for Guidelines?Now that we have level 1 evidence

for these approaches, one may ask: Why do we need clinical practice guidelines?

The fact that oncologists now have

many treatment options to offer their patients is a wonderful development. However, the contexts in which these agents were tested creates clinical deci-sion dilemmas as to what to pick first, how to sequence therapies, and how best to counsel patients on what to expect from individual treatments—since, in practice, patients’ prior ther-apy profiles are increasingly different from those of the patients included in the phase III trials.

It is within this context that the ASCO Clinical Practice Guidelines Committee and the Cancer Care On-

tario (CCO) program in evidence-based care have released a clinical practice guideline on systemic therapy in men with metastatic castration-resistant prostate cancer,1 published in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post. The evidentiary foundation of the guideline consists of 26 randomized controlled trials identified through a 2012 CCO systematic review and an updated literature search through June 2014.

With regard to the specific recom-mendations of the guideline, the data regarding the continued importance of androgen receptor signaling in prostate cancer progression are the foundation for the guidance to continue primary gonadal suppression in patients with metastatic castration-resistant prostate cancer. While luteinizing hormone-releasing hormone–based therapy has pretty much replaced bilateral orchiec-tomy, patients should be informed of the option for orchiectomy, which, in addition to convenience, will minimize the cost of care.

Important Decision FactorsThe guidelines recommend offer-

ing abiraterone/prednisone, enzalu-tamide, and radium-223, with docetax-el/prednisone also being offered with accompanying discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomat-ic men, whereas cabazitaxel can be of-fered to patients experiencing disease progression on docetaxel. The recom-mendations do not provide guidance on sequencing of therapy for obvious reasons—lack of data—yet, this is one of the key clinical needs in recom-

mending therapy to patients.In the absence of definitive data on

proper sequencing, clinical decisions should take into account patient perfor-mance status, comorbidities, presence or absence of symptoms, disease extent and location, nature of prior response to therapy, and cost. When all is equal and feasible, treating physician recom-mendation/judgment, patient prefer-ences, and cost/logistics of therapy are very important decision factors. While tempting, it is important not to assume that combining treatments, because it’s possible, will have a better outcome than sequencing therapy.

The guideline does include mito-xantrone/prednisone, and this com-bination is certainly an option when all life-prolonging therapies have been exhausted and when the patient has no experimental options, is in need of pain palliation, and is fit enough to undergo chemotherapy. However, it is not clear that the recommendations for ketoconazole or antiandrogens (eg, bi-calutamide, flutamide, and nilutamide [Nilandron]) are justified by today’s

standards, considering the lack of meaningful clinical benefits with these agents in this disease context.

The recent data from the CHAART-ED intergroup trial comparing andro-gen-deprivation therapy vs androgen-deprivation therapy plus docetaxel in patients with hormone-sensitive meta-static prostate cancer demonstrated an unprecedented survival advantage with the addition of docetaxel in this setting. Although the bulk of the ben-efit seems to be in patients with high-volume disease (visceral disease or at least four bone metastatic lesions with at least one involving the appendicular skeleton), the data are practice-chang-ing and will likely have an impact on the role of docetaxel in the setting of metastatic castration-resistant prostate cancer—that is, it is unclear whether patients receiving docetaxel for hor-mone-sensitive disease will respond to it when their disease is castration resis-tant.

At this time, there are no data on subsequent sensitivity or resistance to docetaxel and other therapies. Hence, there is a need for at least broad out-comes-based data to help inform treat-ment decisions, since it is unlikely that a prospective trial will address this question in the United States.

Practical Implications The authors should be congratulat-

ed on their effort and a very balanced discussion. As a practicing oncologist, however, I am not clear that the con-tent and the guidance change what we are currently doing in practice. It is also important that we streamline the dif-ferent practice and consensus guide-lines through collaboration between representative societies and groups (eg, ASCO, American Urological As-sociation, National Comprehensive Cancer Network) to create one unified guideline in this disease setting that is practical to use.

Short of cure, patients wish to know in the short term if their cancer is responding (a potential surrogate for clinical benefit), and in the long term whether they are likely to live longer and (as much as possible) “live better.” Despite the tremendous prog-

Dr. Hussain is Associate Director for Clini-cal Research and Co-Leader of the Prostate Cancer Program at University of Michigan Comprehensive Cancer Center, Ann Arbor.

We must raise the bar for future trials by requiring greater therapeutic efficacy, minimizing use of placebo, avoiding artificial disease contexts, developing multitargeted treatment strategies, and evaluating and maximizing cost-effectiveness.

—Maha Hussain, MD, FACP, FASCO


Cancer can evade immune destruction by upregulating the inhibitory ligand PD-L1 on

tumor cells and tumor-in� ltrating immune cells, such as macrophages and dendritic

cells.1,2 PD-L1 binds to B7.1 and PD-1 on cytotoxic T cells, disabling the anticancer

immune response.1-3

Emerging research is directing focus on programmed death-ligand 1 (PD-L1) expressed on and around tumors

Tumor cellMacrophage

Dendritic cell

PD-L1 expression

PD-L1

PD-L1

PD-1

B7.1

Exploring the PD-L1 pathway as a new direction in cancer immunotherapy research

References: 1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. 2. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy––inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587. 3. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212.

© 2014 Genentech USA, Inc. All rights reserved. BIO/092214/0028 Printed in USA.

Discover the PD-L1 pathway, a focus of investigation and cancer immunotherapy research by visiting

www.ResearchPDL1.com

Inactive T cell

78123ha_g.indd All Pages 10/29/14 11:04 PM

http://www.gene.com

Cancer can evade immune destruction by upregulating the inhibitory ligand PD-L1 on

tumor cells and tumor-in� ltrating immune cells, such as macrophages and dendritic

cells.1,2 PD-L1 binds to B7.1 and PD-1 on cytotoxic T cells, disabling the anticancer

immune response.1-3

Emerging research is directing focus on programmed death-ligand 1 (PD-L1) expressed on and around tumors

Tumor cellMacrophage

Dendritic cell

PD-L1 expression

PD-L1

PD-L1

PD-1

B7.1

Exploring the PD-L1 pathway as a new direction in cancer immunotherapy research

References: 1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. 2. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy––inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587. 3. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212.


Discover the PD-L1 pathway, a focus of investigation and cancer immunotherapy research by visiting

www.ResearchPDL1.com

Inactive T cell

78123ha_g.indd All Pages 10/29/14 11:04 PM



News

ress in metastatic castration-resistant prostate cancer, there are several glar-ing limitations to the current portfo-lio of agents. The impact on survival continues to be modest, we use a “one size fits all” approach despite the fact that a significant percentage of pa-tients will not respond to or will have

a suboptimal response to therapy, and the cost of therapy is escalating.

That said, the past decade has dem-onstrated that investment in research will produce significant returns and progress in treating this deadly disease is possible. The need for greater thera-peutic impact necessitates significantly more investment and commitment to high-quality research. Patients should be offered opportunities for clinical

trials. Finally, we must raise the bar for future trials by requiring greater therapeutic efficacy, minimizing use of placebo, avoiding artificial disease con-texts, developing multitargeted treat-ment strategies aiming at a maximum cytotoxic impact, and evaluating and maximizing cost-effectiveness. n

Disclosure: Dr. Hussain has received funding from the National Cancer Institute and the Prostate Cancer Foundation, research

support from Astellas/Medivation, Pfizer, Genentech, and Bayer, and is a consultant for Synthon and Johnson & Johnson.

Reference1. Basch E, Loblaw DA, Oliver, TK, et

al: Systemic therapy in men with metastatic castration-resistant prostate cancer: Ameri-can Society of Clinical Oncology and Can-cer Care Ontario Clinical Practice Guide-line. J Clin Oncol 32:3436-3448, 2014.

Maha Hussain, MD, FACP, FASCOcontinued from page 49

With New Innovator Award, Biomedical Engineer to Study How Ovarian Cancer Spreads

With approximately 22,000 diag-noses annually in the United

States, ovarian cancer isn’t among the most commonly occurring cancers. Yet, the mortality rate for women who have ovarian cancer hovers above 60%.

For Pamela Kreeger, PhD, a Uni-versity of Wisconsin–Madison As-sistant Professor of Biomedical En-gineering, that number is needlessly high. Dr. Kreeger is among a group of forward-thinking researchers to receive a 2014 New Innovator Award from the National Institutes of Health. And with funding of nearly $2.3 million, she is studying what factors cause ovarian cancer cells to progress from their ori-gin in a woman’s fallopian tube through the ovaries and on to metastatic sites—where they become resistant to chemo-therapy drugs.

“When we look at most cancers, we focus on gene mutations and how they impact the cells’ behavior, and then that’s the drug target,” she said. “Cancer is somewhat clonal, so early mutations tend to replicate throughout the tumor. But some cancers don’t show this clear pattern of mutated genes for clinicians to target.”

Role of TP53That’s the case with ovarian cancer,

according to a 2011 study of the disease by The Cancer Genome Atlas (TCGA)

Research Network. Nearly all ovarian cancers have a mutation in the gene TP53—a gene that encodes a tumor-suppressor protein that normally pre-vents cancer development, and is very difficult to target therapeutically.

However, ovarian cancer cells also tend to have increased or decreased copies of genes—rather than muta-

tions in the genes themselves. “So, the proteins are all potentially there and may function in the normal way, but their relative levels are skewed,” said Dr. Kreeger. “Ovarian cancer patients have a common mutation and then a proteomic mess.”

As a result of this pattern, Dr. Kreeger’s hypothesis is that the ge-netic mutation is less of a factor in the cancer’s spread than is protein expres-sion, which is the way that proteins are made, regulated and modified in cells. “What the TP53 mutation sets up is

the genomic instability where we see changes in the levels of proteins,” she said. “I’m trying to figure out what we can target as a result of this variation.”

Three Areas of ExpertiseDr. Kreeger’s research will draw on

her background in three seemingly dif-ferent areas: ovarian cancer biology,

biomimetic culture development, and using systems biology models to ana-lyze quantitative data. For this project, she is developing in vitro culture sys-tems to mimic the spread of ovarian cancer cells through a woman’s body, and how they develop resistance to chemotherapy.

Using these models, she and her students will examine how cells with different protein expression patterns will behave, and then, drawing on Dr. Kreeger’s expertise in developing com-puter models, they will simulate how

multiple variables impact cell deci-sions and influence tumor progression.

“Progress in treating ovarian can-cer over the past 30 years has been flat,” she says. “One reason is that the disease is nearly universally diagnosed too late—so understanding ovarian cancer’s early stages might lead to new screens for the disease, as well as po-tential treatments.”

Dr. Kreeger hopes researchers can use her tools and approach in their efforts to understand progression in other cancer types, because many tu-mors have both genetic mutations and quantitative protein variations in their cell networks.

Two Other KeysDr. Kreeger says there are two other

keys to her research: an engineering background, which helps her address a multifaceted biologic challenge, and UW-Madison’s culture of transdisci-plinary collaboration. “Wisconsin is the kind of environment in which peo-ple can take on this high-risk, high-re-ward research because of the intellec-tual openness here,” she said. “People talk to each other, and they naturally want to collaborate. They want to see if there’s a way to do it better by working together. It’s just a part of our culture and what makes Wisconsin a fantastic place to do research.” n


The disease is nearly universally diagnosed too late — so understanding ovarian cancer’s early stages might lead to new screens for the disease, as well as potential treatments.

—Pamela Kreeger, PhD



News

Focused Ultrasound, a Young Technology, Begins to GrowBy Caroline McNeil

In the United States, it’s been a good 2 years for focused ultrasound. The

technology, which uses multiple, inter-secting ultrasound beams to treat cancer and other diseases, completed its first suc-cessful U.S. phase III oncology trial—to alleviate the pain of bone metastases—and received approval from the U.S. Food and Drug Administration (FDA) in 2012. Medicare began covering it in 2013, and in 2014, Health Care Service Corpora-tion, a large Blue Cross/Blue Shield in-surer, began providing coverage.

An FDA panel did not recommend approval of two other focused ultra-sound devices for treating prostate can-cer in 2014 but left the door open for future consideration.

Not surprisingly, next steps and fu-ture directions were a major theme at a recent meeting of the Focused Ultra-sound Foundation in Washington, DC. Speakers described studies not only in

pain palliation, but also for tumor abla-tion in several cancers. Recent success-es with essential tremor and other neu-rologic diseases were also discussed.

Still, speakers were careful to point out that the field was young. “We are enthusiasts but are careful to use the word ‘potential,’ said Neal F. Kassell, MD, Professor of Neurosurgery at the University of Virginia, who chairs the Foundation. “This technology is in an early stage.”

Studies of focused ultrasound to treat cancer go back several decades. In the 1990s, INSERM, the French na-tional research institute, and a commer-cial firm, EDAP-TMS, developed the Ablatherm® system, which uses ultra-sound imaging to guide high-intensity

beams. Ablatherm won approval in Eu-rope 1999 as an alternative to radiation therapy in early prostate cancer.

In the meantime, the Israeli firm InSightec began studying magnetic

resonance-guided focused ultrasound to treat painful bone metastases, the system that won FDA approval in the United States.

The focused ultrasound systems

combine beams that heat and destroy targeted tissue with a real-time im-aging component—either magnetic resonance or ultrasound—that enables

Technology

We are enthusiasts but are careful to use the word

‘potential.’ This technology is in an early stage.

—Neal F. Kassell, MD


Proceed with confidence

Reference: 1. Prosigna [Package Insert]. Seattle, WA: NanoString Technologies, Inc; 2013.

Prosigna is indicated for use in postmenopausal women with hormone receptor–positive, node-negative or node-positive early-stage (stages I and II) breast cancer to be treated with adjuvant endocrine therapy.

Special conditions for use: Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients.

© 2014 NanoString Technologies, Inc. All rights reserved. NanoString, the NanoString Technologies logo, Prosigna and the Prosigna logo are trademarks and/or registered trademarks of NanoString Technologies, Inc. in various jurisdictions. USPS_PM0006 04/14

To find a Prosigna provider and for a copy of the Package Insert, visit Prosigna.com today.

• Prosigna translates a patient’s underlying tumor biology into an individualized risk assessment

• Prosigna’s PAM50-based genomic assay quickly and accurately provides prognostic information you need

• Prosigna is the only genomic assay for breast cancer that is FDA 510(k) cleared for use in local qualified laboratories

• Obtain precise, reproducible results from formalin-fixed paraffin-embedded (FFPE) tissue in as few as 3 days

Introducing Prosigna™: Guide your decisions with the power of PAM50-based molecular profiles1

Confidence begins with a highly accurate risk assessment

For HR+, early-stage invasive breast cancer

18434_nanpro_fa2_ascopst_ad.indd 1 3/24/14 1:43 PM

http://prosigna.com


News

precise targeting and potentially a lower risk of collateral damage. In the ExAb-late trial, the magnetic resonance–guid-ed beam was used to destroy pain-caus-ing nerves in the outer membrane of the bone overlying a painful metastasis.

Focused ultrasound has the advan-tage of being noninvasive compared with other thermal treatments, such as cryotherapy, and can be performed on an outpatient basis. Its risks include damage to healthy tissue and skin burns, among others.

Painful Bone Metastases Clinical Trial

The trial that led to FDA approval en-rolled 147 patients who still had pain after radiation therapy or other standard inter-ventions for painful bone metastases or who were not eligible for or had refused radiation therapy. Participants were ran-

domly assigned to receive either focused ultrasound or placebo treatment. Nearly two-thirds of those on the focused ultra-sound arm had an improvement in self-reported pain score without an increase in pain medication, compared with about 20% on the placebo arm.

Pain scores improved by an average of 3.6 points on a 10-point scale (more than a 50% improvement in pain), in-dicating the treatment had a signifi-cant impact, said principal investigator Mark Hurwitz, MD, Director of Ther-mal Oncology at Jefferson University in Philadelphia. Patients on the focused ultrasound arm also reported less pain-related interference with functioning, often within a day of treatment. Adverse

events included two pathologic frac-tures (one outside the treatment field), one skin burn, and one neuropathy. The study was published in the Journal of the National Cancer Institute in April 2014.1

New randomized trials of focused ultrasound for bone metastases are now on the horizon. In October 2013, the Focused Ultrasound Foundation con-vened a workshop in Rome, bringing together researchers and industry rep-resentatives to talk about future trials. Many believe that the ideal study would be a three-arm trial comparing radia-tion therapy alone, focused ultrasound alone, and the combination of radiation therapy and focused ultrasound, Dr. Hurwitz said. Another, possibly more feasible, option would compare radia-tion alone with radiation therapy plus focused ultrasound. A consensus state-ment with recommendations from the workshop is in press.

Another approach to painful bone metastases is to ablate the entire tumor as well as the nerve endings. This might lead to even better results, said Dr. Hur-witz, since some of the pain may be due to mechanical factors, such as the tumor pressing on expansion within bones.

Beyond PalliationIn other cancers, tumor ablation is

the goal. Localized prostate cancer re-mains a prime candidate for focused ultrasound treatment, with five actively recruiting phase I and II trials listed in ClinicalTrials.gov. Two companies have completed trials of ultrasound-guided focused ultrasound and submitted pre-market approval applications to the FDA.

One of these trials, a phase II/III study looking at EDAP-TMS’s Ablatherm system in localized prostate cancer, was designed to determine its “substantial equivalence” to cryotherapy. An FDA advisory panel recommended against its approval in July 2014, indicating that ben-efits did not appear to outweigh risks, but kept open the possibility of future consid-eration. In a statement, EDAP-TMS said that the FDA recommended it provide

more data on patients at higher risk, such as those with Gleason scores > 6.

Also this year, SonaCare Medical asked an FDA panel to approve its Son-ablate system. The panel responded, as it did with Ablatherm, that it would be useful to have data in patients with Glea-son scores > 6. According to a company statement by SonaCare Medical, “several panel members suggested that for this more specific indication for use, the effi-cacy, safety profile, and benefit-risk ratio for the device may provide the basis for a

more favorable recommendation.”Both firms said they were moving

ahead on the recommendations. Focused ultrasound is in early clini-

cal studies in other cancers, including pancreatic and breast cancers, sarcoma, brain metastases, and glioblastomas, with 51 open trials listed in ClinicalTri-als.gov. For example, a sarcoma study at Stanford University is evaluating safety in patients who receive focused ultra-sound followed by surgery. It is also looking at efficacy, comparing the mag-netic resonance imaging results with pathology findings. Pejman Ghanouni, MD, PhD, the principal investigator, along with Raffi Avedian, MD, said that results so far have been encouraging.

Researchers are also thinking in terms of applications beyond ablation, said Jessica Foley, PhD, the Focused Ultrasound Foundation’s Scientific Di-rector. For instance, the concentrated ultrasound beams can loosen the net-work of endothelial cells joined by tight junctions within the blood-brain bar-rier, allowing drugs to get through.

Another potential use of this ap-proach is for the localized delivery of chemotherapy, she said. A liposomal drug, for instance, could be injected in conjunction with focused ultrasound. The liposome would be activated or disrupted to release its contents at the precise focus of the ultrasound.

In addition, focused ultrasound might be used to “jump start” an an-titumor immune response. Thermal therapies including focused ultrasound can stimulate anti-immune responses in

part through heat shock protein–medi-ated pathways, said Dr. Hurwitz. “We are actively exploring how best to both stimulate and effectively target this re-sponse to the tumor,” he said.

For the present, focused ultrasound enthusiasts are glad to have another tool to manage metastatic bone pain. Radiation therapy does not work in ev-eryone, and as Dr. Ghanouni pointed out, patients are now living longer with bone metastases. “I’m excited to see it work,” he said, “to see patients with no other options [for managing their pain] to be able to pursue normal ac-tivities again.” n

Disclosure: Dr. Hurwitz has provided consulting services to Insightec. Dr. Ghanouni has participated in multicenter clinical trials that were funded by InSightec. Dr. Foley reported no potential conflicts of interest.

Reference1. Hurwitz MD, Ghanouni P, Kanaev

SV, et al: Magnetic resonance-guided fo-cused ultrasound for patients with painful bone metastases: Phase III trial results. J Natl Cancer Inst 106(5):dju082, 2014.

Focused Ultrasoundcontinued from page 53

Mark Hurwitz, MD

I’m excited to see it work, to see patients [with bone metastases] with no other options [for managing their pain] to be able to pursue normal activities again.

—Pejman Ghanouni, MD, PhD

twitter.com/ascopost

Follow us on


Perspective

is, when to recognize that the best medi-cal care should focus on palliation of symptoms and quality of life rather than pursuing tumor destruction.

Confusing Array of ChoicesAfter an exciting afternoon listen-

ing to updates on the plethora of new molecules available for the treatment of malignant melanoma, I was involved in a discussion with a group of young on-cologists who were trying to digest the range of possibilities now open to those who manage this disease, which until only a few years ago was considered essentially refractory to all medicines.

The afternoon presentations detailed a range of new medicines prescribed sin-gly or in combination, sequential expo-sure, and so forth.

Leaving aside any consideration of cost, I realized that these young oncolo-gists were tempted to think that you could go on prescribing one medicine after another literally until the patient

dropped—this is not good medical practice! Our conversation then devel-oped into the challenges of explaining relapsed or resistant disease to patients and families and how to choose between recommending further treatment or a change of strategy to palliative care.

In earlier times, patients looked to

John F. Smyth, MDcontinued from page 1


WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

• Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)].

• Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGEGAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)].


5 WARNINGS AND PRECAUTIONS5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation.

5.2 Progressive Multifocal LeukoencephalopathyJC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to pre-existing neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two-thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

Premedicate patients with acetaminophen, anti-histamine, and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)].

For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy.

For patients with Grade 1, 2, or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)].

For patients with pre-existing cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their hypertensive medication as is suggested here.

5.4 Tumor Lysis SyndromeAcute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12 –24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function, and fluid balance, and administer supportive care, including dialysis as indicated.

5.5 InfectionsSerious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection.

5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 34% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).

Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

5.7 ThrombocytopeniaGAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 11% of patients in the trial. In 5% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA.

Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

5.8 ImmunizationThe safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.

6 ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in other sections of the label:• Hepatitis B reactivation [see Warnings and Precautions (5.1)]• Progressive multifocal leukoencephalopathy [see Warnings

and Precautions (5.2)]

• Infusion reactions [see Warnings and Precautions (5.3)]• Tumor lysis syndrome [see Warnings and Precautions (5.4)]• Infections [see Warnings and Precautions (5.5)]• Neutropenia [see Warnings and Precautions (5.6)]• Thrombocytopenia [see Warnings and Precautions (5.7)]

The most common adverse reactions (incidence ≥ 10%) were: infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders.

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 described in Tables 3 and 4 below are based on a total of 356 previously untreated patients with CLL during treatment with GAZYVA in combination with chlorambucil or with chlorambucil alone. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 45 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA based therapy.

Table 3 Summary of Adverse Reactions Reported with ≥ 5% Incidence and ≥ 2% Greater in the GAZYVA Treated Arm

Table 4 Post-Baseline Laboratory Abnormalities by CTCAE Grade with ≥ 5% Incidence and ≥ 2% Greater in the GAZYVA Treated Arm

a MedDRA coded adverse reactions as reported by investigators. b No Grade 5 adverse reactions have been observed with a

difference of ≥ 2% between the treatment arms.c Adverse events reported under ‘Blood and lymphatic

system disorders’ reflect those reported by investigator as clinically significant.

InvestigationsGAZYVA

+ Chlorambuciln = 240

Chlorambuciln = 116

AllGrades %

Hematology

Chemistry

77 46 53 2780 40 9 2

29 8 11 2

28 < 1 12 0

32 3 29 < 1

31 5 17 2

28 < 1 18 < 1

Hypocalcemia

Hyperkalemia

Hyponatremia

AST (SGOT increased)

Creatinineincreased

NeutropeniaLymphopeniaLeukopeniaThrombocytopenia

AllGrades %

Grades 3–4 %

Grades 3–4 %

84 36 12 < 147 14 50 11

GAZYVA® (obinutuzumab)

Injection, for intravenous infusionInitial U.S. Approval: 2013This is a brief summary of information about GAZYVA.Before prescribing, please see full Prescribing Information.

Injury, Poisoning and Procedural Complications

Infusion 69 21 0 0related reactions

Blood and lymphatic system disordersc


Thrombocytopenia 15 11 7 3

Anemia 12 4 10 5

Leukopenia 7 5 0 0

General disorders and administration site conditions

Pyrexia 10 < 1 7 0


Cough 10 0 7 < 1

Adverse Reactions(MedDRAa) System Organ Class

GAZYVA+ Chlorambucil

n = 240

Chlorambuciln = 116

AllGrades %

Grades 3–4b %

AllGrades %

Grades 3–4b %

ALT (SGPT 25 < 1 14 0increased)

Hypoalbuminemia 22 < 1 14 < 1

Alkaline 16 0 11 0 Phosphatase increased

Hypokalemia 13 1 4 < 1

02-12245C_R01_GAUS_BriefSummary.indd 1 10/7/14 3:23 PM


Perspective

their physicians for guidance, and some still do, but the modern tendency is to offer a menu of options and ask the pa-tient to decide which choice to accept. While patients and their families should always make such decisions, they must of course be informed by their doctor,

and good doctors guide their patients to the most appropriate choice.

The new challenge is that there are an ever-increasing number of third-, fourth-, and fifth-line treatments for malignancies such as breast cancer, lymphoma, and even melanoma, and the patient and physician sometimes seem to have a confusing array of choic-

es. The reason I’m reporting this discus-sion with the young oncologists is to emphasize from my own experience the importance of knowing when to stop.

Difficult DiscussionSometimes the patient makes this

choice for him/herself—“doctor, I have had enough”—but there may be inap-

propriate hope that the next treatment will work a miracle, or conflicting ambi-tions from close friends or family des-perately keen that no option should be left untried, although the patient clearly wants to stop. From the doctor’s per-spective (and, again, I am leaving aside the financial aspects of all of this), it is important to recognize when further active treatment is very unlikely to alter the course of the disease.

Death is not a medical failure—in-deed, it is the only certainty that awaits us all—but, as physicians, we can influence the timing (sometimes) and the qual-ity (always) of the weeks or months that precede a death from cancer. It is much easier to recommend that a further line of treatment be tried, however flimsy the ev-idence of likely benefit, than to begin the discussion that now is the time to change the emphasis and objectives of care to fo-cus solely on symptoms and emotional support of a preterminal patient.

Nevertheless, some of the best con-versations I have ever had have been with patients at this stage of their disease, and I have witnessed the gratitude that follows if you get this conversation right. However painful the emotional experience, helping patients to understand that death is not far off allows them to move beyond false hope, and to relate to family and friends in a different way from the situation at di-agnosis or during active treatment, when optimism is usually prevalent.

Enabling ExperienceHaving time to reflect, and allow-

ing family to plan for later, is a wonder-ful and enabling experience for many patients, whatever their age. It is sad if we as doctors deny patients that op-portunity by taking the easier route of prescribing more medicines, know-ing that the likelihood of side effects is certain and the extension of useful life unlikely. That said, the advent of ever more choices can only confound this situation. I am not sure if my conversa-tion in Madrid did anything to help the young oncologists involved, but at least we aired this important topic. n

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

John F. Smyth, MDcontinued from page 55

John F. Smyth, MD

Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, anti-histamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and < 2% thereafter [see Dosage and Administration (2)].

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). Cases of late onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the chlorambucil alone arm.

Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3–4 and none were fatal.

Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). The number of fatal hemorrhagic events was similar between the treatment arms, with 4 in the GAZYVA treated arm. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1.

Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm.

Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%).

6.2 ImmunogenicitySerum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period. Neutralizing activity of anti-GAZYVA antibodies has not been assessed.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known.

6.3 Additional Clinical Trial ExperienceProgressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)].

Worsening of pre-existing cardiac conditions: Fatal cardiac events have been reported in patients treated with GAZYVA.

Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)].

7 DRUG INTERACTIONSNo formal drug interaction studies have been conducted with GAZYVA.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CRisk SummaryThere are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal DataIn a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

8.3 Nursing MothersIt is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to 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 GAZYVA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the importance of the drug to the mother.

8.4 Pediatric UseThe safety and effectiveness of GAZYVA in pediatric patients has not been established.

8.5 Geriatric UseOf 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. Of the 109 patients ≥ 75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients < 75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) an adverse event leading to death. Similar rates were observed in the comparator arm. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)].

8.6 Renal ImpairmentBased on population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) > 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr < 30 mL/min [see Clinical Pharmacology (12.3)].

8.7 Hepatic ImpairmentGAZYVA has not been studied in patients with hepatic impairment.

10 OVERDOSAGEThere has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy.

17 PATIENT COUNSELING INFORMATIONAdvise patients to seek immediate medical attention for any of the following:• Signs and symptoms of infusion reactions including

dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

• Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

• Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)].

• New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)].

Advise patients of the need for:• Periodic monitoring of blood counts [see Warnings and

Precautions (5.6 and 5.7) and Adverse Reactions (6.1)]. • Avoid vaccinations with live viral vaccines [see Warnings

and Precautions (5.8)].• Patients with a history of hepatitis B infection

(based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

GAZYVA® [obinutuzumab]Manufactured by: Genentech, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 U.S. License No: 1048

GAZYVA is a trademark of Genentech, Inc. 8/14 GAZ0002214501© 2014 Genentech, Inc.



Direct From ASCO

ASCO Announces Top 5 Advances in Modern Oncology

To mark ASCO’s 50th anniversary, the Society called on the oncol-

ogy community to select the five most pivotal advances in cancer research and patient care over the past 50 years. Now, with more than 2,000 votes cast, ASCO has announced the results on CancerProgress.Net, its interac-tive website on the history of progress against cancer.

The results offer a range of clinical re-search advances, from cancer prevention to chemotherapy, molecularly targeted therapy to supportive care.

Spotlight on NIH-Funded Research

Voters selected these milestones from a “ballot” of 32 advances drawn from CancerProgress.Net’s “Major Mile-stones” timeline, which was developed under the guidance of leading oncolo-gists. The ballot also allowed voters to describe why they made their selection (see the sidebar, “Why They Voted”).

Importantly, federal research fund-ing played a role in many of these ad-vances, which were announced a day ahead of the second annual Rally for Medical Research Hill Day on Septem-ber 18, in Washington, DC. The goal of this event is to call attention to the real and meaningful progress that has been made because of the federal investment

in medical research through the National Institutes of Health (NIH). Patients and advocates will also join in a call to Con-gress for greater funding for the NIH, which actually lost almost a quarter of its purchasing power in the past decade, adjusting for inflation.

“Progress builds on progress. Over the past 5 decades, NIH-funded research has transformed the outlook for people with cancer. These Top 5 in 50 highlight transformational discoveries that rep-resent a shining sliver of what we have

learned from a sustained investment in federally funded research,” said ASCO President Peter Paul Yu, MD, FACP, FASCO. “However, without greater federal investment going forward, the pace of progress against cancer and other diseases will be far slower. We’re already seeing more high-quality research grants being turned down and a projected 40%

cut to patient enrollment in NIH-funded cancer clinical trials just since 2009.”

Here are the results of the vote on the “Top 5 Advances in Modern Oncology”:

1. MOPP chemotherapy cures advanced Hodgkin lymphoma

In 1965, Vincent T. DeVita, Jr, MD, FASCO (ASCO Past President, 1977-1978) and his colleagues at the National Institutes of Health discov-ered that combination chemotherapy—mechlorethamine, vincristine, procar-

bazine (Matulane), and prednisone (MOPP)—induced long-term remis-sions in over half of adults with Hodgkin lymphoma. The discovery sparked the first hope that advanced cancers could be cured with drug treatment and paved the way for 90% cure rates in patients with this disease today.

2. HPV vaccine approved to prevent cervical cancer

The first human papillomavirus (HPV) vaccine—approved in 2006—brought 100% protection against the two strains of HPV known to cause most cer-vical cancers. Widespread vaccination, if fully implemented, could drive dramatic reductions in cervical and other HPV-related cancers in the United States and worldwide.

3. Imatinib transforms treatment of chronic myelogenous leukemia

The rapid U.S. Food and Drug Admin-istration review and approval of imatinib (Gleevec) in 2001 transformed treatment for most patients with chronic myeloge-nous leukemia (CML). This easy-to-take pill turned a disease with no long-term survivors into one with 5-year survival rates of almost 90%. It also heralded a new era of research on molecularly targeted anticancer drugs. Today, over 60 of these medicines are available.

4. PVB chemotherapy cures testicular cancer

In 1977, Lawrence H. Einhorn,

MD, FASCO (ASCO Past President, 2000-2001) and colleagues showed that a new three-drug combination chemo-therapy regimen—cisplatin, vinblastine, and bleomycin (PVB)—produced com-plete remissions for 70% of men with ag-gressive testicular cancer. Prior chemo-therapy treatments worked in just 5% of men. This discovery, coupled with later multidisciplinary advances, made testic-ular cancer treatment one of oncology’s biggest success stories.

5. Powerful antinausea drugs dramatically improve many patients’ quality of life

The introduction of ondansetron in 1991, together with other supportive care advances, dramatically changed the expe-rience of cancer treatment for patients. These drugs not only brought relief from intense, treatment-induced nausea and vomiting, but also made it possible for pa-tients to avoid once-routine hospital stays, complete their full course of treatment, and live longer and better overall.

“All of these advances mark major turning points for cancer care and have improved and saved the lives of countless Americans,” said Dr. Yu. “Federally fund-ed research answers questions that are critically important to patients, questions that would otherwise go unanswered—like comparing the effectiveness of two regimens, exploring new uses for generic drugs, finding new ways to improve pa-tients’ quality of life, and testing truly novel approaches like many of those highlighted in the Top 5 in 50 announced today.”

These results not only demonstrate the remarkable progress achieved in cancer research since ASCO’s founding, but also the payoff of federal investment in clinical research: NIH research grants played a role in many of the discoveries that made the “Top 5.”

For more information on the “Top 5,” including historic photos and more comments from people who voted, go to www.CancerProgress.Net/Top5. n

© 2014. American Society of Clinical Oncology. All rights reserved.

Why They Voted: Comments From the Oncology Community 1965: MOPP chemotherapy cures Hodgkin lymphoma

“This was the clearest proof of concept that cancer was/is curable. It gave great impulse to therapeutic research that ultimately improved outcomes in breast, colon, kidney cancer, the leukemias, and most childhood malignancies.”

2006: HPV vaccine approved to prevent cervical cancer“This advance—if broadly adopted—could lead to the total eradication of cer-

vical cancer globally as well. …Millions could be saved.”

2001: Imatinib transforms treatment for CML“[Imatinib] not only revolutionized CML, but cancer therapy in general.

A targeted agent directed at a cancer-causing gene—it represents the dawn of targeted therapy for cancer.”

1977: PVB cures men with testicular cancer“Took the most lethal cancer for young men to the most curable.”

1991: Powerful antinausea drugs alleviate major side effect of cancer treatment

“[Antiemetics] permit millions of patients to receive full cancer regimens, de-livered in a timely fashion . . . many even continue to work and lead high-function-ing lives during treatment.”

These Top 5 in 50 highlight transformational discoveries that represent a shining sliver of what we have learned from a sustained investment in federally funded research.


Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, anti-histamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and < 2% thereafter [see Dosage and Administration (2)].

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). Cases of late onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the chlorambucil alone arm.

Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3–4 and none were fatal.

Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). The number of fatal hemorrhagic events was similar between the treatment arms, with 4 in the GAZYVA treated arm. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1.

Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm.

Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%).

6.2 ImmunogenicitySerum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period. Neutralizing activity of anti-GAZYVA antibodies has not been assessed.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known.

6.3 Additional Clinical Trial ExperienceProgressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)].

Worsening of pre-existing cardiac conditions: Fatal cardiac events have been reported in patients treated with GAZYVA.

Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)].

7 DRUG INTERACTIONSNo formal drug interaction studies have been conducted with GAZYVA.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CRisk SummaryThere are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal DataIn a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

8.3 Nursing MothersIt is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to 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 GAZYVA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the importance of the drug to the mother.

8.4 Pediatric UseThe safety and effectiveness of GAZYVA in pediatric patients has not been established.

8.5 Geriatric UseOf 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. Of the 109 patients ≥ 75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients < 75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) an adverse event leading to death. Similar rates were observed in the comparator arm. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)].

8.6 Renal ImpairmentBased on population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) > 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr < 30 mL/min [see Clinical Pharmacology (12.3)].

8.7 Hepatic ImpairmentGAZYVA has not been studied in patients with hepatic impairment.

10 OVERDOSAGEThere has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy.

17 PATIENT COUNSELING INFORMATIONAdvise patients to seek immediate medical attention for any of the following:• Signs and symptoms of infusion reactions including

dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

• Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

• Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)].

• New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)].

Advise patients of the need for:• Periodic monitoring of blood counts [see Warnings and

Precautions (5.6 and 5.7) and Adverse Reactions (6.1)]. • Avoid vaccinations with live viral vaccines [see Warnings

and Precautions (5.8)].• Patients with a history of hepatitis B infection

(based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

GAZYVA® [obinutuzumab]Manufactured by: Genentech, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 U.S. License No: 1048

GAZYVA is a trademark of Genentech, Inc. 8/14 GAZ0002214501© 2014 Genentech, Inc.


http://www.CancerProgress.Net/Top5


Direct From ASCO

Top 5 Features of ASCO’s Newly Redesigned Patient Education Website Highlighted

ASCO recently launched a new and redesigned version of Can-

cer.Net, its patient-facing website that includes timely, comprehensive, and oncologist-approved information. With support from the Conquer Can-cer Foundation, Cancer.Net is able to bring the expertise and resources of ASCO to your patients and their fami-lies and caregivers. The redesign was based on extensive consumer testing

and included several phases of imple-mentation over the past year, all aimed at providing patients and caregivers with the best educational experience.

“The redesign has solidified Can-cer.Net’s position as the premier website of oncologist-approved infor-mation for cancer patients and their families,” said Cancer.Net Editor-in-Chief Robert S. Miller, MD, FACP, FASCO. “We encourage all health-care professionals to recommend the site for all of the patients and families that they serve.”

We recently talked with Dr. Miller

about the top 5 new or updated features of Cancer.Net’s redesign.

1. Cancer.Net BlogOne of the first new features of the

redesign to be pushed live is the Cancer.Net Blog, which launched in December 2013. Unlike some of the more tradi-tional content on the website, which is peer-reviewed and has a more formal tone, the new blog provides a much

more flexible and conversational plat-form for communicating with patients and their caregivers.

“We are proud to have many differ-ent types of authors contributing con-tent to the blog,” Dr. Miller said. “To date, blog posts have been authored by physician members of the website’s editorial board and ASCO staff, and a growing number of guest authors in-cluding health-care professionals, advo-cates, patients, and families.”

In addition, the blog posts frequent-ly cover breaking scientific news from ASCO’s conferences and journals that

may be of interest to patients and fam-ily members, but it also includes topical posts about cancer treatment, preven-tion, supportive care, or, in some cases, the personal stories and experiences of survivors.

2. Ease of Navigation, Redesigned Homepage

The relaunched Cancer.Net has been thoroughly designed to be more streamlined and easy to navigate. One of the most prominent new features of the homepage includes the six navi-

gational tiles in its center, introducing the major navigational sections of the website: Types of Cancer, Navigating Cancer Care, Coping & Emotions, Re-search & Advocacy, Survivorship, and Support Our Work.

According to Dr. Miller, usability testing and focus groups helped to fo-cus the content of the website, group-ing the vast majority of Cancer.Net’s extensive content into these six cat-egories. Website users can also find the main categories listed across the top of

The redesign has solidified Cancer.Net’s position as the premier website of oncologist-approved information for cancer patients and their families.

—Robert S. Miller, MD, FACP, FASCO


New ASCO Survivorship Care Plan Template Is Simpler, Faster for Health-Care Providers

ASCO has issued a new template for health-care professionals to use

when providing a survivorship care plan to patients who have completed curative cancer therapy. The survivorship care plan contains important information about treatment the patient received, the patient’s need for future checkups and cancer tests, the potential long-term late effects of treatment, and ideas for ways survivors can improve their health.

The new template, updating a previous version ASCO developed nearly a decade ago, was published in the Journal of Oncology Practice as part of an ASCO statement on the impor-tance of—and minimum components for—survivorship care plans.

“This cleaner, simpler form will help health-care professionals get survivor-ship care plans into the hands of pa-tients,” said Deborah K. Mayer, PhD, RN, Chair of the ASCO Survivorship Care Plan Working Group and Profes-sor in the School of Nursing and Direc-tor of Cancer Survivorship at University of North Carolina Lineberger Compre-hensive Cancer Center. “At the end of their treatment, patients should expect to receive a survivorship care plan, but if they don’t get one, they should ask their doctor or nurse for one.”

Streamlined Care PlanASCO believes that all cancer sur-

vivors benefit from a survivorship

care plan to assist survivors and their primary care provider in coordina-tion of care. Based on feedback from ASCO members, the survivorship care plan template has been revised and streamlined. The new version focuses more on critical informa-tion, is easier for physicians and pa-tients to use, and requires less time to complete.

The Commission on Cancer of the American College of Surgeons has en-dorsed ASCO’s recommendations for the minimum elements included in the

new template. These elements were de-fined through a consensus process in-volving multidisciplinary stakeholders including oncology providers, social workers, survivors, and primary care providers. The template was proven through an IRB-approved pilot test in 11 practices to be a time-saving and useful instrument.

View the template at www.asco .org/survivorship. n



Direct From ASCO

each page, so they are easily available as visitors navigate throughout the site.

If these categories do not point a user to what they are looking for quickly, they can turn to an enhanced and much more prominent search function.

“We always had a search function, but it was harder to find, and the be-hind-the-scenes functionality of the search system is much more robust now,” Dr. Miller said.

For example, if a user misspells what they are searching for, the search func-tion will now offer suggestions based on corrected spellings, using the “did you mean?” functionality that is available on most major search engine websites.

3. ‘Find a Cancer Doctor’ Database Enhancements

Find a Cancer Doctor is one of the most widely used features of Cancer.Net. This database of oncology profes-sionals is populated using self-identified information from ASCO members who opt to be included when filling out de-mographic information for his or her societal membership.

The enhanced database now allows users to filter their search results by spe-cialty, and by tumor type as well. Users can also filter their results by distance, choosing to search all of the United States, internationally, or within a cer-tain number of miles from their home.

Once their search results appear, us-ers can sort the results using the same options, distance, city name, oncologist name, or view their results on a map.

4. Multimedia IntegrationCancer.Net visitors may also notice

that video content is now integrated into the content available throughout the website. Years ago, when the site first be-gan to produce audio and video content for its patient audience it was all grouped together under a “multimedia” heading.

“The old method was not particular-ly logical,” Dr. Miller said. “When most people are looking for information they are interested in seeing all different channels. When searching for a specific cancer topic, they want to see articles, podcasts, and videos that are appropri-ate all in the same spot.”

Now, for example, if a user is trying to research information about teens with cancer, they will navigate to an article about the topic, with a video embedded on the page. And, different collaborations between ASCO and the LIVESTRONG Foundation have also

yielded a greater amount of video con-tent for patients, which has been inte-grated within the website.

5. Spanish Language ContentSpanish language users of Cancer.

Net are now able to enjoy a mirror of the site in their native language. The homepage features an “Español” button

in the top right hand corner that will toggle to a Spanish homepage, intro-ducing the site and its sections in Span-ish, just like the English version. This toggle appears on all pages that have a Spanish translation available.

“With the relaunch, it was impor-tant that the website looked the same but include Spanish content,” Dr. Miller

said. “People who require Spanish con-tent are no longer sent to a subsection of the English site, but to a specialized, Spanish-language Cancer.Net.”

To check out these new features and more, visit Cancer.Net. n


Cancer.Net Redesigncontinued from page 58

• The blood-brain barrier, composed of numerous effl ux transporters, forms a sanctuary for metastatic disease by actively preventing some therapeutic molecules from entering the CNS2

• Therapies with minimal exposure in the CNS may be unable to inhibit progression in the CNS1,2

• Patients with CNS metastases often experience poor outcomes and signifi cant morbidity3

In up to 46% of ALK+ NSCLC patients, the CNS is the fi rst site of progression while receiving an ALK-directed therapy1

WHAT DOES THE BLOOD-BRAIN BARRIER HAVE TO DO WITH ALK+ NSCLC?

Discover more at ResearchALK.com

ALK=anaplastic lymphoma kinase; CNS=central nervous system; NSCLC=non-small cell lung cancer.

References: 1. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non–small-cell lung cancer. J Thorac Oncol. 2012;7:1807-1814. 2. Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13:1663-1674. 3. Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010;2:2100-2137.


THIS ADVERTISEMENT PREPARED BY AREA23 Sig Date Time Time Spent Spell Check

Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC

Client: RocheProduct: GenentechJob#: 10255890Colors: 4C Sizes: Bleed: 8.625”w x 11.5”h

Sm Trim: 7.875”w x 10.5”hLive: 7”w x 10”hgutter: N/A

Publications:Journal of Thoracic OncologyOncology TimeThe ASCO Post Journal of Clinical OncologyHEM/ONC TodayThe New England Journal of MedicineThe Lancet

Journal Ad Size

10255890_PreLaunch_Journal_Ad_FR.indd 1 10/24/14 4:21 PM



Direct From ASCO

Now in Spanish on Cancer.Net: Managing Your Weight After a Cancer Diagnosis, and More!

ASCO’s booklet to help patients learn how to manage weight gain

after a cancer diagnosis is now available in Spanish. In addition, new information in Spanish has been added to Cancer.Net on obesity, weight, and cancer risk, as well as articles on nutrition and physi-cal activity. Your patients can download a PDF of this booklet and find these ar-ticles at www.cancer.net/obesidad. n


Charting the Successes: CancerProgress.Net Chronicles More Than 50 Years of ASCO and Progress Against Cancer

On this historic year, as ASCO proud-ly commemorates its 50th anniver-

sary and decades of evolutionary change and growth, it also celebrates the signifi-cant progress that has been made against cancer throughout history. ASCO’s an-niversary website, CancerProgress.Net,

chronicles these achievements and more.In honor of the Society’s anniversary,

the site features stories about ASCO’s evolution, a timeline of advances in

cancer, aggregated news and views on ASCO’s anniversary and progress, and social media features.

The interactive Cancer Progress Timeline, a key feature of the site devel-oped under the guidance of an editorial board of 21 of the nation’s leading on-

cologists, explores advances in nearly 20 types of cancers. The story of progress is shared by the timeline editors in their video interviews.

Decades of Improvements in Quality of Life

In her video interview, Quality of Life Specialty Editor Lidia Schapira, MD, FASCO, said, “We’ve come a long way in making our cancer treatments better, more precise, and also easier to bear. Years ago, getting cancer treatment—which usually just meant chemotherapy—was a pretty awful experience for many patients. We had very few drugs to help them deal with side effects, and we had a culture that was far less open than it is now.

“I think that just as important as our advances in understanding the differenc-es between cancers is our understanding that human beings are different. It’s the integration of all of the human aspects

into the personalized medical approach-es that is really helping us move toward a far better era of delivering care, where patients and their families will feel sup-ported throughout their cancer journey and hopefully also will have far better outcomes.”

Tour ASCO’s anniversary website, CancerProgress.Net, to navigate the timeline advances and to hear from oth-er editors about milestones in cancer research. Also, follow ASCO on ASCO Connection, Twitter, and Facebook to join in on the conversation about progress. n


It’s the integration of all of the human aspects into the personalized medical approaches that is really helping us move toward a far better era of delivering care.

—Lidia Schapira, MD, FASCO

Save the DateGastrointestinal Cancers Symposium

January 15-17, 2015

Moscone West Building

San Francisco, California

Genitourinary Cancers SymposiumFebruary 26-28, 2015

Rosen Shingle Creek

Orlando, Florida

Conquering Cancer.

The Conquer Cancer Foundation. Our name says a lot.

Our mission says even more: Conquering cancer

worldwide by funding breakthrough research and sharing

cutting-edge knowledge. We are the go-to organization

in supportingthe world’s preeminent cancer specialists,

so one day we can live in a world free from the fear of

cancer. To get to know us better now and be a part of our

ambitious future, visit ConquerCancerFoundation.org.

Together, anything is possible.

DonATe ToDAY!ConquerCancerFoundation.org


Expert’s Corner

Advancing ASCO’s Commitment to Quality to Ensure That Every Patient Receives the Highest Level of Cancer CareA Conversation With Robert S. Miller, MD, FACP, FASCOBy Jo Cavallo

On December 3, 2014, Robert S. Miller, MD, FACP, FASCO, will

start his new position as Medical Di-rector of ASCO’s Institute for Quality (iQ). Established in 2012 to oversee the development of clinical practice guide-lines, the Quality Oncology Practice Initiative (QOPI), the QOPI Certifica-tion Program, Performance Measures and Practice Improvement, and Can-cerLinQ, iQ provides ASCO members with the resources necessary to ensure that every patient receives the highest level of oncology care.

Currently Assistant Professor of On-cology and Oncology Medical Informa-tion Officer at the Sidney Kimmel Com-prehensive Cancer Center at the Johns Hopkins University School of Medicine in Baltimore, Dr. Miller is a pioneer in health-related information technology and an expert on social media for pro-fessional education and patient engage-ment. He has served on ASCO’s Board of Directors, the Quality of Care Com-mittee, the Clinical Practice Commit-tee, the Cancer Education Committee, the Integrated Media and Technology Committee, and the Health Informa-tion Technology Workgroup. He is also currently Editor-in-Chief of Cancer.Net and is on the editorial board of the Jour-nal of Oncology Practice.

An ASCO member since 1992, Dr. Miller said he decided to join ASCO as Medical Director of the Institute for Quality because, “ASCO’s vision for the future of oncology has always been something that has resonated with me personally.”

The ASCO Post talked with Dr. Mill-er about his immediate goals for iQ, the

biggest obstacles to quality improve-ment in cancer care, and his decision to make a career change.

New RolePlease talk about your new position

as Medical Director of ASCO’s Insti-tute for Quality. What are some of your priorities?

My job will be to provide medical oversight and bring a clinician’s per-spective to the Institute for Quality’s initiatives. One area of particular focus will be ASCO’s learning health system CancerLinQ, which is scheduled to launch next year.

Among the things I’ll bring to my position as Medical Director of iQ is an ability to provide more regular input as a physician into the Institute’s quality improvement efforts. I have practiced both in an academic medical center set-ting and in the community practice set-ting, so I’ve seen both sides in terms of some of the pressures oncologists face (and I think there are more similarities than differences in the two modes of practice).

Right now, ASCO’s quality initia-tives are under the purview of the Qual-

ity of Care Committee and a number of important CancerLinQ committees. The fact that ASCO is a volunteer, mis-sion-driven organization is not going to change, but I think the Society decided to create this new position because having someone on staff with my back-ground who can provide consistent in-put in these areas will help strengthen ASCO’s effort to improve the quality of cancer care.

To some extent, I’m going to be dis-covering exactly how my insights will be useful in the first year I’m here, but I think the idea for hiring me was that ASCO needed specific medical over-sight on the development and imple-mentation of some of these programs.

Measuring and Improving Quality

What role does quality measurement play in physician reimbursement, and how is quality improvement being incorporated into the American Board of Internal Medi-cine’s (ABIM’s) Maintenance of Certifica-tion program?

We are working to transition reim-bursement from a quantity-based sys-tem tied only to face-to-face patient encounters to one that reimburses phy-sicians for medical outcomes. This is a very complex area, and clearly we do not have one structure in place yet, but quality measurement will continue to rise in importance because oncologists will need feedback for practices to re-main viable. Oncologists have to know how they are doing in meeting the vari-ous quality metrics and how they com-pare with their peers.

No one quite yet has the vision about how the nuts and bolts are go-ing to work, but I think that there is no ambiguity about the importance of out-comes in patient care and the fact that this is the direction in which health-care reimbursement is moving.

A secondary aspect of quality im-

provement is adherence to the ABIM’s Maintenance of Certification (MOC) program. ABIM recently changed its MOC program, which now requires phy-sicians to have continuous engagement in MOC activities, and these changes will become integral to daily practice.

Major ObstacleWhat do you see as the biggest obstacle

to quality improvement?The biggest obstacle to quality im-

provement is probably access to qual-ity measurement data. Despite the fact that the majority of oncology practices now use electronic health records, we still struggle with extracting meaning-ful, specialty-specific quality measure-

ment data from our systems to know how we are doing even in our own practices.

One of the advantages of the QOPI program is that it forces oncology practices to look at very specific qual-ity measurement indicators. Although we’ve seen a marked increase in the adoption of electronic health records, as a specialty we are still struggling to identify what metrics we are meeting in our practices and what the outcomes and improvements might be. I think that will be key to the future of quality improvement efforts.

Career MoveWhat made you decide to make this

change in your oncology career?ASCO’s vision for the future of oncol-

ogy has always been something that has resonated with me personally. ASCO’s guiding principle is that all patients with cancer should have access to high-quality care and that information learned from every patient should accelerate the prog-ress against cancer. These are the things that I really believe in as an oncologist.

In my current position, I’m a clini-cian and I’m involved in informatics, and in those roles I can have some in-fluence over a single institution. But this position potentially allows me to benefit cancer patients everywhere. It is a great opportunity to become involved in a visionary organization like ASCO, where the staff is passionate about this mission. I’m hoping it allows me the opportunity to focus my energies and interests on more global areas and en-able me to have a broader impact than I could at my single institution.

One thing I have clearly learned is that when you work in an institution, you have a responsibility to your pa-tients, of course, and to the goals of the institution when it comes to adminis-trative responsibilities. I realized that I would not be able to focus on these im-portant, more global ASCO initiatives if I continued to be employed where I am now. It is a bit of a leap and a change for me professionally, but I am really ex-cited about starting my new position. n

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

Quality of Care

Robert S. Miller, MD, FACP, FASCO

I think that there is no ambiguity about the importance of outcomes in patient care and the fact that this is the

direction in which health-care reimbursement is moving. —Robert S. Miller, MD, FACP, FASCO

Take a bite out of G-CSF acquisition costs*

Indication» GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction

in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information» Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration

of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

* Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in

patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.Reference: 1. GRANIXTM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

GRANIXTM is another option in short-acting G-CSF therapy

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1

– GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1

– Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40175 January 2014. Printed in USA.

ASCO Post_March 15 2014_Teva_Granix_GRX-40175_Abelson Taylor.indd All Pages 2/13/14 10:49 AM

http://www.granixhcp.com/?utm_source=ASCOPost&utm_medium=DigitalEdition&utm_campaign=Journal


Journal Spotlight

Cancer-Killing Virus Plus Chemotherapy Studied in Recurrent Ovarian Cancer

In 6 out of 10 cases, ovarian cancer is diagnosed when the disease is ad-

vanced and 5-year survival is only 27%. A new study suggests that a cancer-killing virus combined with a chemotherapy drug might safely and effectively treat ad-vanced or recurrent forms of the disease.

Researchers at The Ohio State Uni-versity Comprehensive Cancer Cen-ter–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC–James), led the cell and animal study. Reporting in the journal Clinical Cancer Research,1 the researchers

showed that the oncolytic virus called 34.5ENVE has significant antitumor ac-tivity against ovarian cancer on its own, and that its activity is even greater when combined with the chemotherapy drug doxorubicin in an animal model of dis-seminated peritoneal ovarian cancer.

Potential Therapy“Our findings suggest that this could

be a promising therapy, and we believe it should be further developed for the treatment of recurrent or refractory ovarian cancer in humans,” said prin-cipal investigator Balveen Kaur, PhD, Professor of Neurological Surgery and an OSUCCC–James researcher.

Among women treated for ovar-ian cancer whose tumors regress, 70% experience recurrence. The recurrent tumors are thought to develop from reserves of cancer stem-like cells that are chemotherapy-resistant and survive therapy. Consequently, recurrent tu-mors also tend to be resistant to prima-ry chemotherapy regimens, and lethal.

The oncolytic herpes simplex vi-rus 34.5ENVE is engineered to target cancer cells that overexpress the pro-tein nestin and to inhibit the growth of blood vessels to tumors. The research-ers chose to combine the oncolytic vi-rus with doxorubicin because the drug is often administered to patients with recurrent ovarian cancer.

“This study underscores the signifi-cance of combining the oncolytic virus with doxorubicin for patients who have developed resistance to primary che-motherapy,” Dr. Kaur said.

Key FindingsThe investigators assessed the an-

ticancer activity of the oncolytic virus 34.5ENVE, which is a genetically engi-neered herpesvirus, using several ovar-ian cancer cell lines, human and mouse tumor cells, and an animal model. Key technical findings included:• The expression of nestin was 10 to 100

times greater in human ovarian tumor cells than in normal ovarian cells.

• In a model of disseminated peritoneal ovarian cancer, the combination of doxorubicin plus the oncolytic virus increased survival, with an average survival of 58 days for treated animals vs 32.5 days for controls.

• The combination of doxorubicin and the oncolytic virus showed a synergistic increase in apoptosis in ovarian cancer cells compared to each agent alone. n

Disclosure: Funding from the NIH/National Cancer Institute (grant CA150153) supported this research. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.

Reference1. Bolyard CM, Yoo JY, Wang PY, et al:

Doxorubicin synergizes with 34.5ENVE to enhance antitumor efficacy against meta-static ovarian cancer. Clin Cancer Res. Oc-tober 7, 2014 (early release online).


BRIEF SUMMARY OF PRESCRIBING INFORMATION FORGRANIX™ (tbo-filgrastim) Injection, for subcutaneous useSEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEGRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Splenic RuptureSplenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.5.2 Acute Respiratory Distress Syndrome (ARDS)Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.5.3 Allergic ReactionsSerious allergic reactions including anaphylaxis can occur in patients receiv-ing human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodi-lators‚ and/or epinephrine may reduce the severity of the reactions. Perma-nently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reac-tions to filgrastim or pegfilgrastim.5.4 Use in Patients with Sickle Cell DiseaseSevere and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Con-sider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.5.5 Potential for Tumor Growth Stimulatory Effects on Malignant CellsThe granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.6 ADVERSE REACTIONSThe following potential serious adverse reactions are discussed in greater detail in other sections of the labeling:• SplenicRupture[see Warnings and Precautions (5.1)]• AcuteRespiratoryDistressSyndrome[see Warnings and Precautions (5.2)]• SeriousAllergicReactions[see Warnings and Precautions (5.3)]• UseinPatientswithSickleCellDisease[see Warnings and Precautions (5.4)]• Potential forTumorGrowthStimulatoryEffectsonMalignantCells[see

Warnings and Precautions (5.5)]The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.6.1 Clinical Trials ExperienceBecause 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.GRANIX clinical trials safety data are based upon the results of three ran-domized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recom-mended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).LeukocytosisIn clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.8 USE IN SPECIFIC POPULATIONS 8.1 PregnancyPregnancy Category CThere are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rab-bits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effec-tiveness were observed between patients age 65 and older and younger patients.8.6 Renal ImpairmentThe safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.8.7 Hepatic ImpairmentThe safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.10 OVERDOSAGENo case of overdose has been reported.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.GRANIX is a trademark of Teva Pharmaceutical Industries Ltd.Manufactured by: Distributed by:Sicor Biotech UAB Teva Pharmaceuticals USA, Inc.Vilnius, Lithuania North Wales, PA 19454U.S. License No. 1803Product of IsraelGRX-40188 January 2014This brief summary is based on TBO-003 GRANIX full Prescribing Information.

ASCO Post_March 15 2014_Teva_Granix_GRX-40188_Abelson Taylor_briefsummary.indd 1 2/13/14 10:50 AM


Journal Spotlight

Adding Pan-Deacetylase Inhibitor Panobinostat to Bortezomib and Dexamethasone Improves Progression-Free Survival in Relapsed MyelomaBy Matthew Stenger

In the phase III PANORAMA 1 trial reported in The Lancet Oncology,

Jesus F. San-Miguel, MD, of Clinica Universidad de Navarra-CIMA, Pam-plona, Spain, and colleagues found that adding the pan-deacetylase inhibitor panobinostat to bortezomib (Velcade) and dexamethasone improved pro-gression-free survival in patients with relapsed or relapsed and refractory mul-tiple myeloma.1

Study DetailsIn this double-blind trial, 768 pa-

tients from 215 centers in 34 coun-tries who had relapsed or relapsed and refractory myeloma and who had re-ceived one to three previous treatments were randomly assigned between Janu-ary 2010 and February 2012 to receive panobinostat, bortezomib, and dexa-methasone (n = 387) or placebo, bort-ezomib, and dexamethasone (n = 381). Regimens consisted of 21-day cycles of panobinostat at 20 mg on days 1, 3, 5, 8, 10, and 12, bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11, and dexametha-sone at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12.

Randomization was stratified by the number of previous treatment lines and previous use of bortezomib. Patients with primary refractory or bortezomib-refractory myeloma were not eligible. Crossover was not permitted. The pri-mary endpoint was progression-free survival.

The panobinostat and placebo groups were well balanced for age (me-dian, 63 years in both, 58% in both < 65 years), sex (52% and 54% male), eth-nicity (64% and 66% white, 33% and 27% Asian, 1% and 4% black), Eastern Cooperative Oncology Group perfor-mance status (0 in 45% and 43%, 1 in 49% in both), creatinine clearance (60–89 mL/min in 68% and 65%, ≥ 90 mL/min in 31% and 34%).

Myeloma was relapsed in 64% and 62%, and relapsed/refractory in 35% and 37%. Patients had undergone pre-vious autologous stem cell transplanta-tion in 56% and 59%, and the number of previous treatment lines was one in 51% and 52%, two in 32% and 28%, and three in 17% and 20%.

Previous treatments included bort-ezomib in 44% and 42%, lenalidomide (Revlimid) in 19% and 22%, thalido-

mide (Thalomid) in 53% and 49%, oral melphalan (Alkeran) in 30% and 27%, cyclophosphamide in 47% and 44%, dexamethasone in 80% and 83%, bort-ezomib plus an immunomodulatory drug in 24% and 26%, and bortezomib plus dexamethasone in 38% of both groups.

Improved Progression-Free Survival

Median follow-up was 6.47 months (interquartile range = 1.81–13.47 months) in the panobinostat group and 5.59 months (interquartile range = 2.14–11.30 months) in the placebo group. Median progression-free sur-vival was 11.99 months (95% confi-dence interval [CI] = 10.33–12.94) in the panobinostat group vs 8.08 months (95% CI = 7.56–9.23) in the placebo group (hazard ratio [HR] = 0.63, P < .0001). The hazard ratio for progres-sion-free survival was similar on multi-variate analysis (HR = 0.58, P < .0001).

Two-year progression-free survival was 20.6% vs 8.4%.

The progression-free survival benefit of panobinostat was observed across most prespecified subgroups, including patients with relapsed and refractory disease (HR = 0.54), those with stage II and III disease (HR = 0.61), those aged ≥ 65 years (HR = 0.72), and those with prior use of bortezomib (HR = 0.58).

Survival and ResponseOverall survival data were not ma-

ture at the time of reporting. Median overall survival was 33.64 months (95% CI = 31.34 months–not esti-mable) vs 30.39 months (95% CI = 26.87 months–not estimable; HR = 0.87, P = .26). Objective response was observed in 60.7% vs 54.6% of patients (P = .09), including complete or near-

complete response rates of 27.6% vs 15.7% (P = .00006). Median time to response was 1.51 vs 2.00 months. Median duration of response (partial response or better) was 13.14 vs 10.87 months. Among patients with at least a near-complete response, median progression-free survival was 19.38 vs 15.21 months.

ToxicityThe most common nonhematologic

adverse events of any grade in the pano-binostat group were diarrhea (68% vs 42% in the placebo group), peripheral neuropathy (61% vs 67%), and asthe-nia/fatigue (57% vs 41%). The most

common grade 3/4 events were diar-rhea (25% vs 8%), asthenia/fatigue (24% vs 12%), peripheral neuropathy (18% vs 15%), and pneumonia (13% vs 11%). Grade 3/4 hematologic adverse events included thrombocytopenia in 67% vs 31%, lymphopenia in 53% vs 40%, neutropenia in 35% vs 11%, and anemia in 18% vs 19%.

Serious adverse events occurred in 60% vs 42% of patients in the pla-cebo group. Dose modifications were required for panobinostat in 51% of patients, bortezomib in 61%, and dexa-methasone in 24% of the panobinostat group and for placebo in 23%, bortezo-mib in 42%, and dexamethasone in 17% of the placebo group.

Discontinuation of treatment due to adverse events occurred in 36% vs 20%. Grade 3/4 adverse events led to discon-

tinuation in 25% vs 13%, with the most common events being diarrhea (4%), peripheral neuropathy (4%), asthenia/fatigue (6%), thrombocytopenia (2%), and pneumonia (1%) in the panobino-stat group and fatigue (3%), pneumo-nia (2%), peripheral neuropathy (2%), and diarrhea (2%) in the placebo group.

There were few cases of QT prolon-gation in either group; 0 vs 2 patients had QTc > 500 ms and 3 vs 4 had a QTc increase > 60 ms from baseline. T-wave changes (40% vs 18%) and ST-T seg-ment changes (22% vs 3%) were more common in the panobinostat group but appeared to be asymptomatic.

A total of 11 deaths were considered possibly related to study treatment in the panobinostat group, consisting of 7 due to infection, 2 to hemorrhage, 1 to myocardial infarction, and 1 to cerebro-vascular accident. A total of 7 deaths in the placebo group were considered pos-sibly related to treatment, consisting of 4 due to infection, 1 to hemorrhage, 1 to pulmonary embolism, and 1 to cardiac arrest.

The investigators concluded: “Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with re-lapsed or relapsed and refractory multi-ple myeloma. Longer follow-up will be necessary to determine whether there is any effect on overall survival.” n

Disclosure: The study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit www.thelancet.com/oncology.

Reference1. San-Miguel JF, Hungria VTM, Yoon

S-S, et al: Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in pa-tients with relapsed or relapsed and refrac-tory multiple myeloma: A multicentre, ran-domised, double-blind phase 3 trial. Lancet Oncol 15:1195-1206, 2014.

See commentary by Sagar Lonial, MD, on page 66.

Hematology

Impact of Panobinostat on Relapsed/Refractory Myeloma

■ Adding panobinostat to bortezomib/dexamethasone significantly increased progression-free survival in patients with relapsed or relapsed and refractory disease.

■ Follow-up for overall survival is ongoing.

Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma.

—Jesus F. San-Miguel, MD, and colleagues

BRIEF SUMMARY OF PRESCRIBING INFORMATION FORGRANIX™ (tbo-filgrastim) Injection, for subcutaneous useSEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEGRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Splenic RuptureSplenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.5.2 Acute Respiratory Distress Syndrome (ARDS)Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.5.3 Allergic ReactionsSerious allergic reactions including anaphylaxis can occur in patients receiv-ing human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodi-lators‚ and/or epinephrine may reduce the severity of the reactions. Perma-nently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reac-tions to filgrastim or pegfilgrastim.5.4 Use in Patients with Sickle Cell DiseaseSevere and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Con-sider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.5.5 Potential for Tumor Growth Stimulatory Effects on Malignant CellsThe granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.6 ADVERSE REACTIONSThe following potential serious adverse reactions are discussed in greater detail in other sections of the labeling:• SplenicRupture[see Warnings and Precautions (5.1)]• AcuteRespiratoryDistressSyndrome[see Warnings and Precautions (5.2)]• SeriousAllergicReactions[see Warnings and Precautions (5.3)]• UseinPatientswithSickleCellDisease[see Warnings and Precautions (5.4)]• Potential forTumorGrowthStimulatoryEffectsonMalignantCells[see

Warnings and Precautions (5.5)]The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.6.1 Clinical Trials ExperienceBecause 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.GRANIX clinical trials safety data are based upon the results of three ran-domized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recom-mended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).LeukocytosisIn clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.8 USE IN SPECIFIC POPULATIONS 8.1 PregnancyPregnancy Category CThere are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rab-bits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effec-tiveness were observed between patients age 65 and older and younger patients.8.6 Renal ImpairmentThe safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.8.7 Hepatic ImpairmentThe safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.10 OVERDOSAGENo case of overdose has been reported.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.GRANIX is a trademark of Teva Pharmaceutical Industries Ltd.Manufactured by: Distributed by:Sicor Biotech UAB Teva Pharmaceuticals USA, Inc.Vilnius, Lithuania North Wales, PA 19454U.S. License No. 1803Product of IsraelGRX-40188 January 2014This brief summary is based on TBO-003 GRANIX full Prescribing Information.

ASCO Post_March 15 2014_Teva_Granix_GRX-40188_Abelson Taylor_briefsummary.indd 1 2/13/14 10:50 AM


Perspective

HDAC Inhibitors and Triple Therapy in Relapsed MyelomaBy Sagar Lonial, MD

The use of histone deacetylase (HDAC) inhibitors as human can-

cer therapy has focused on the impact of these agents on epigenetic regula-tion and gene transcription. However, the use of HDAC inhibitors in myelo-ma may be working through a differ-ent mechanism. Specifically, HDAC6 is known to regulate the aggresome/autophagy pathway, a secondary path-way for protein catabolism. When the proteasome is inhibited, the aggresome pathway becomes an accessory pathway through which protein homeostasis is maintained intracellularly.1,2

Early TrialsThis concept of HDAC/protea-

some inhibitor was first tested in ear-nest with the combination of vori-nostat (Zolinza) and bortezomib (Velcade); the combination demon-strated efficacy,3 but at the doses and schedule used in the larger phase II and phase III clinical trials, the regi-men was simply not tolerated well enough to support long-term use among a majority of patients. The studies did, however, provide proof of principle that the combination was able to overcome bortezomib resis-tance, and at certain doses, could be tolerated.

The use of panobinostat in a simi-lar set of trials4,5 was based on early data again suggesting the potential to overcome bortezomib resistance.6 In the PANORAMA 2 trial,7 patients with known bortezomib-resistant my-eloma were treated with the combina-tion of panobinostat and bortezomib. Overall, the trial demonstrated that 30% of patients responded to the nov-el combination.

This encouraging early data gave rise to the phase III PANORAMA 1 trial, reported by San-Miguel and col-leagues and reviewed in this issue of The ASCO Post.8 This trial is evaluat-ing the benefit of adding panobinostat to bortezomib/dexamethasone vs bortezomib/dexamethasone alone. The primary endpoint of the study was met, with an improvement in pro-gression-free survival from 8 months

with bortezomib/dexamethasone to 12 months with panobinostat plus bortezomib/dexamethasone.

Overall survival data were not ma-ture at the time of reporting. The dif-ference in progression-free survival was, interestingly, not associated with an improvement in overall response rate, though the quality of response was better among those who received panobinostat. While the combination clearly demonstrated benefit, a signifi-cant fraction of patients were not able to continue on study due to the devel-opment of adverse events.

Interpreting PANORAMA Findings

So what are the challenges with in-terpretation of this study, and how do we as clinicians use the information to provide better care for our patients? The clinical benefit of the treatment is clear, with a significant improvement

in progression-free survival. But what about the adverse events that were en-countered by patients that limited the duration of therapy?

First, it should be recalled that at the time of study initiation, the routine use of subcutaneous admin-istration of bortezomib had not yet become the standard. Thus, toxicity of the regimen overall may in part be related to the use of intravenous rather than subcutaneous bortezomib.

Second, the most common adverse events that occurred on study were gastrointestinal events (nausea and di-arrhea) as well as fatigue. Gastrointes-tinal toxicity is likely in part due to the overlap with intravenous bortezomib but also directly related to panobino-stat itself. Management requires some experience with the drug and may in-clude modification of dose and sched-ule and use of antiemetics. Fatigue can often be reversed through the use

of concomitant steroids or stimulants. In terms of hematologic toxicity,

there was a higher incidence of grade 4 thrombocytopenia seen with the combination, but given that thrombo-cytopenia is a common adverse event for both agents, this is not a surprise. In an in vivo murine model of throm-bocytopenia, it was demonstrated that while the nadir of platelets was lower when panobinostat was com-bined with bortezomib, the time to platelet recovery (back to baseline) was the same as when either agent was given alone.9 Thus, patients may need support for hematologic toxic-ity during the initial therapy, but such toxicity should not be a reason to limit delivery of therapy.

Patient SelectionThe question remains: Which

patients are best suited for this treat-ment approach? From the outset, it is

clear from the data that patients with high-risk myeloma and those who ap-pear to be less sensitive to bortezomib should likely receive the combination. From the subset analyses, it was ap-parent that patients from these groups gained benefit vs those who received bortezomib/dexamethasone alone.

The larger question revolves around the patients with early relapse in general. Do we know that triplets are better than doublets in this set-ting? This has been nicely demonstrat-ed among newly diagnosed myeloma patients, where there is near global consensus that a three-drug induction is superior to two-drug induction, and there are now hints that the same may apply to patients with early relapse (af-ter one to three prior lines of therapy, the same population that was studied in the current study).

This concept began to take hold several years ago, when the MMVAR/

IFM 2005-04 trial showed a signifi-cant improvement in progression-free survival and a trend toward improved overall survival with bortezomib/thalidomide (Thalomid)/dexametha-sone vs thalidomide/dexametha-sone.10 The ASPIRE trial comparing carfilzomib (Kyprolis)/lenalidomide (Revlimid)/dexamethasone vs le-nalidomide/dexamethasone also sug-gests a similar benefit of triple-drug salvage, and now we have the PAN-ORAMA 1 findings continuing the trend of three drugs being superior to two in the early relapse setting.

I suspect that in order to make the leap to three drugs being better than two in the relapsed disease setting, we will likely need to see an impact on overall survival. Nevertheless, the question is an interesting one, espe-cially as we begin to delve into the im-portance of minimal residual disease and its impact on duration and du-rability of response.11-13 While atten-tion to this issue has been focused on newly diagnosed myeloma, the issue is also likely to be relevant in the early relapse setting.

HDAC inhibitors would be a wel-come addition to our treatment ar-mamentarium—one that may be very helpful for those challenging patients with more aggressive myeloma. Care-ful attention to symptom manage-ment and supportive care will help to increase the duration of HDAC inhib-itor–containing therapy, which will ultimately allow more patients to gain benefit from the new treatment. n

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

References1. McConkey DJ, White M, Yan W:

HDAC inhibitor modulation of proteo-toxicity as a therapeutic approach in can-cer. Adv Cancer Res 116:131-163, 2012.

2. Simms-Waldrip T, Rodriguez-Gon-zalez A, Lin T, et al: The aggresome path-way as a target for therapy in hematologic malignancies. Mol Genet Metab 94:283-286, 2008.

3. Dimopoulos M, Siegel DS, Lonial S, et al: Vorinostat or placebo in combi-nation with bortezomib in patients with multiple myeloma (VANTAGE 088): A multicentre, randomised, double-blind study. Lancet Oncol 14:1129-1140, 2013.

Dr. Lonial is Vice Chair of Clinical Affairs, Department of Hematology and Medical Oncology, Winship Cancer Institute, Em-ory University, Atlanta.

HDAC inhibitors would be a welcome addition to our treatment armamentarium—one that may be very helpful for those challenging patients with more aggressive myeloma.

—Sagar Lonial, MD



Journal Spotlight

4. Wolf JL, Siegel D, Goldschmidt H, et al: Phase II trial of the pan-deacetylase in-hibitor panobinostat as a single agent in ad-vanced relapsed/refractory multiple myelo-ma. Leuk Lymphoma 53:1820-1823, 2012.

5. Hideshima T, Richardson PG, An-derson KC: Mechanism of action of pro-teasome inhibitors and deacetylase inhib-itors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther 10:2034-2042, 2011.

6. Neri P, Bahlis NJ, Lonial S: Pano-binostat for the treatment of multiple myeloma. Expert Opin Investig Drugs 21:733-747, 2012.

7. Richardson PG, Schlossman RL, Al-sina M, et al: PANORAMA 2: Panobino-stat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 122:2331-2337, 2013.

8. San-Miguel JF, Hungria VT, Yoon SS, et al: Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in pa-tients with relapsed or relapsed and re-fractory multiple myeloma: A multicen-tre, randomised, double-blind phase 3 trial. Lancet Oncol 15:1195-1206, 2014.

9. Giver CR, Jaye DL, Waller EK, et al: Rapid recovery from panobinostat (LBH589)-induced thrombocytope-

nia in mice involves a rebound effect of bone marrow megakaryocytes. Leukemia 25:362-365, 2011.

10. Garderet L, Iacobelli S, Moreau P, et al: Superiority of the triple combina-tion of bortezomib-thalidomide-dexa-methasone over the dual combination of thalidomide-dexamethasone in pa-tients with multiple myeloma progress-ing or relapsing after autologous trans-plantation: The MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 30:2475-2482, 2012.

11. Galimberti S, Benedetti E, Morabito

F, et al: Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplanta-tion. Leuk Res 29:961-966, 2005.

12. Martinez-Sanchez P, Montejano L, Sarasquete ME, et al: Evaluation of minimal residual disease in multiple my-eloma patients by fluorescent-polymerase chain reaction: The prognostic impact of achieving molecular response. Br J Hae-matol 142:766-774, 2008.

13. Paiva B, Vidriales MB, Cervero J, et al: Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplanta-tion. Blood 112:4017-4023, 2008.

Study Finds Wide Variation in Quality, Content of Clinical Cancer Guidelines

What’s the best way to treat rectal cancer? Consult any of five top

clinical guidelines for rectal cancer and you will get a different answer, accord-ing to a new study by researchers at the University of Michigan Comprehen-

sive Cancer Center. Their findings were published online in the journal Cancer.1

They looked at clinical practice guidelines for rectal cancer from five highly regarded organizations in the United States, Europe, and Canada. The guidelines, which were all pub-lished within the last 6 years, were assessed for overall quality based on

how they were developed. The tool used gives a percentage score based on six quality domains. Average scores for the rectal cancer guidelines ranged from 27% to 90%, suggesting wide variation in quality.

21 Points of Care ComparedA good amount of published data

and randomized clinical trials exist to help guide best practices for rectal cancer treatment. The researchers took a deep dive into the guideline content itself, looking at 21 common points of care. They found that the five guide-lines all agreed on only eight processes

of care and that six recommendations were in direct conflict.

“In this day and age of practicing medicine, particularly with cancer, phy-sicians rely on these guidelines heavily. Our study suggests we need to be careful about that. The guidelines are of varying quality and they have varying recom-mendations. It’s not as easy as just view-ing a guideline and following it,” said se-nior study author Sandra L. Wong, MD, MS, Associate Professor of Surgery at the University of Michigan Medical School.

Dr. Wong, a cancer surgeon, also serves on several guideline panels. She and her colleagues have previously published a study that found cancer guidelines do not fully meet Institute of Medicine standards for how they are developed.

Same Data, Different Recommendations

In the current study, the researchers found instances where guidelines cited the same published research but offered different recommendations.

“Guideline panels should be review-ing and assimilating data to help physi-cians understand what to do. Random-ized clinical trials are supposed to be the gold standard, but even then, we’re interpreting results differently. It sug-gests the data can actually be controver-sial,” Dr. Wong said.

She urges physicians as well as pa-tients to be aware of this variation in guidelines and not follow them blindly. In addition, organizations that produce guidelines should make it clear when expert consensus or opinion enters into the recommendations. n

Disclosure: The study was supported by Agency for Healthcare Research and Quality grants T32 HS000053-22 and 1K08 HS20937-01, and National Cancer Institute grant 1K07 CA163665-22. The authors reported no potential conflicts of interest.

Reference1. Abdelsattar ZM, Reames BN, Regen-

bogen SE, et al: Critical evaluation of the scientific content in clinical practice guide-lines. Cancer. November 6, 2014 (early re-lease online).

Sagar Lonial, MDcontinued from page 66

Guidelines

Randomized clinical trials are supposed to be the gold standard, but even then, we’re interpreting results differently. It suggests the data can actually be controversial.

—Sandra L. Wong, MD, MS

Like us on Facebook

facebook.com/TheASCOPost

The ASCO Post

Does your ovarian cancer patient have a BRCA mutation?Only testing will tell.

Testing ALL of your ovarian cancer patients for their BRCA status provides powerful information for you, your patient, and her family.

REFERENCES:1. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2014. 3. Lu KH, Wood ME, Daniels M, et al; American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 4. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. October 2014. http://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/. Accessed October 23, 2014. 5. Norquist BM, Pennington KP, Agnew KW, et al. Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identifi ed by clinical testing. Gynecol Oncol. 2013;128(3):483-487. 6. Myriad Genetics. http://www.myriadpro.com. Accessed November 4, 2014. 7. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945-952. 8. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 9. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. 10. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of diff erent ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 11. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 12. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 13. Bouwman P, Jonkers J. The eff ects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 14. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237.

©2014 AstraZeneca. All Rights Reserved. 3061900 Last Updated 11/14

Screening based on family history or age misses a substantial number of ovarian cancer patients with a BRCA mutation.

positive ovarian cancer patients are aged 50 or older, and about one-third are aged 60 or older.8,9

Moreover, the prevalence of a BRCA mutation has been shown to be remarkably similar regardless of ethnicity,yet BRCA testing is not as common in women of non-European descent.10

Even sophisticated predictive models, which attempt to use a number of factors (including family history and age) to determine who should be tested for a BRCA mutation, fail to identify a signifi cant proportion of patients who carry a BRCA mutation.11,12

Ovarian cancer cells with a BRCA mutation have DNA repair defi ciencies and therefore are particularly sensitive to DNA-damaging agents.13

Germline BRCA mutations are associated with improved survival and generally favorable response to platinum-based chemotherapy in ovarian cancer.9,13

Additionally, there is evidence to suggest that BRCA expression is predictive of a clinical benefi t for the use of IP-administered chemotherapy compared with IV-administered chemotherapy.14

71%of patients withovarian cancer and a BRCA mutation areaged 50 or olderat diagnosis.8

39%

32%

29%

<5050-59>60

BRCAm Ovarian Cancer Patients by Age at Diagnosis8

Approximately 15% of women with ovarian cancer have a deleterious BRCA mutation.1 Testing for a BRCA mutation provides powerful information for patients with ovarian cancer, their families, and their physicians. Yet most patients with ovarian cancer are not tested, leaving their BRCA status unknown.

National guidelines recommend that allpatients with epithelial ovarian cancer beconsidered for BRCA testing, regardless offamily history, age, or ethnicity.2,3

In clinical practice, however, the decision to recommend genetic testing is too often based on certain patient and disease characteristics.5 Despite guidelines, every year less than a quarter of patients with ovarian cancer are tested for a BRCA1/2 mutation.6,7

Family history and age at diagnosis are poor predictors of BRCA status in ovarian cancer patients.8,9

Nearly half of patients with ovarian cancer and a BRCA1/2 mutation have no signifi cant family history of ovarian or breast cancer. In addition, more than two-thirds of BRCA-

[A]ll women diagnosed with ovarian, fallopian tube or peritoneal carcinoma, regardless of age or family history, should receive genetic counseling and be offered genetic testing.”- SGO Clinical Practice Statement, October 20144

47%53%

Relevant family history

No relevant family history

BRCAm Ovarian Cancer Patients by Family History Status8

B:21.5”

B:14.25”

OLAP14AGRX1444_HCP_Unbranded_BRCA_Advertorial_r28.indd All Pages 11/5/14 5:40 PM

Does your ovarian cancer patient have a BRCA mutation?Only testing will tell.

Testing ALL of your ovarian cancer patients for their BRCA status provides powerful information for you, your patient, and her family.

REFERENCES:1. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2014. 3. Lu KH, Wood ME, Daniels M, et al; American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 4. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. October 2014. http://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/. Accessed October 23, 2014. 5. Norquist BM, Pennington KP, Agnew KW, et al. Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identifi ed by clinical testing. Gynecol Oncol. 2013;128(3):483-487. 6. Myriad Genetics. http://www.myriadpro.com. Accessed November 4, 2014. 7. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945-952. 8. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 9. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. 10. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of diff erent ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 11. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 12. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 13. Bouwman P, Jonkers J. The eff ects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 14. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237.

©2014 AstraZeneca. All Rights Reserved. 3061900 Last Updated 11/14

Screening based on family history or age misses a substantial number of ovarian cancer patients with a BRCA mutation.

positive ovarian cancer patients are aged 50 or older, and about one-third are aged 60 or older.8,9

Moreover, the prevalence of a BRCA mutation has been shown to be remarkably similar regardless of ethnicity,yet BRCA testing is not as common in women of non-European descent.10

Even sophisticated predictive models, which attempt to use a number of factors (including family history and age) to determine who should be tested for a BRCA mutation, fail to identify a signifi cant proportion of patients who carry a BRCA mutation.11,12

Ovarian cancer cells with a BRCA mutation have DNA repair defi ciencies and therefore are particularly sensitive to DNA-damaging agents.13

Germline BRCA mutations are associated with improved survival and generally favorable response to platinum-based chemotherapy in ovarian cancer.9,13

Additionally, there is evidence to suggest that BRCA expression is predictive of a clinical benefi t for the use of IP-administered chemotherapy compared with IV-administered chemotherapy.14

71%of patients withovarian cancer and a BRCA mutation areaged 50 or olderat diagnosis.8

39%

32%

29%

<5050-59>60

BRCAm Ovarian Cancer Patients by Age at Diagnosis8

Approximately 15% of women with ovarian cancer have a deleterious BRCA mutation.1 Testing for a BRCA mutation provides powerful information for patients with ovarian cancer, their families, and their physicians. Yet most patients with ovarian cancer are not tested, leaving their BRCA status unknown.

National guidelines recommend that allpatients with epithelial ovarian cancer beconsidered for BRCA testing, regardless offamily history, age, or ethnicity.2,3

In clinical practice, however, the decision to recommend genetic testing is too often based on certain patient and disease characteristics.5 Despite guidelines, every year less than a quarter of patients with ovarian cancer are tested for a BRCA1/2 mutation.6,7

Family history and age at diagnosis are poor predictors of BRCA status in ovarian cancer patients.8,9

Nearly half of patients with ovarian cancer and a BRCA1/2 mutation have no signifi cant family history of ovarian or breast cancer. In addition, more than two-thirds of BRCA-

[A]ll women diagnosed with ovarian, fallopian tube or peritoneal carcinoma, regardless of age or family history, should receive genetic counseling and be offered genetic testing.”- SGO Clinical Practice Statement, October 20144

47%53%

Relevant family history

No relevant family history

BRCAm Ovarian Cancer Patients by Family History Status8

B:21.5”B:14.25”

OLAP14AGRX1444_HCP_Unbranded_BRCA_Advertorial_r28.indd All Pages 11/5/14 5:40 PM

http://www.astrazeneca.com/Home


State of the Art

While primary malignant brain tu-mors account for only 2% of all

adult cancers, these deadly neoplasms cause severe cancer-related disability; the 5-year survival rates for brain tumors rank third lowest among all cancers, with those for pancreas and lung cancers being first and second lowest, respectively. However, new developments in molecular biology have led to a better understanding and classification of central nervous system (CNS) tumors, offering the potential for the development of promising new treat-ments. Internationally regarded brain tu-mor expert Tracy Batchelor, MD, spoke with The ASCO Post about recent advanc-es and future directions in the treatment of CNS tumors.

Major AdvancesWhat have been the biggest advances

in brain tumor treatment over the course of your career?

I would arrange the advances accord-ing to surgical, radiation, and medical therapies. Certainly in the surgical setting, the advent of intraoperative magnetic resonance imaging (MRI) has markedly increased our ability to perform complete and much safer resection of various types of CNS tumors.

In radiation, we’ve seen the develop-ment of far more precise and controlled conformal techniques, which limits the amount of neurotoxicity that was associ-ated with older radiation delivery tech-niques. The newer conformal techniques also offer the possibility of limiting the long-term side cognitive and endocrine effects of brain irradiation.

By far, the two biggest advances in

medical therapy have been the U.S. Food and Drug Administration approval of te-mozolomide in 2005 and bevacizumab (Avastin) in 2009, both indicated for glioblastoma—the deadliest of CNS tumors. It’s important to highlight diag-nostic and pathologic advances as well. Over the past several years, we’ve seen the expanded use of tumor profiling, which, for instance, has allowed us to divide glioblastoma into more relevant biologic categories. The next WHO clas-sification of CNS tumors will incorpo-rate molecular markers for the first time. Most importantly, this new information will ultimately be the basis for the devel-opment of more personalized therapies and better-designed clinical trials.

Clinical ChallengesPlease discuss the different clinical chal-

lenges involved in managing brain metasta-ses and primary tumors.

Brain metastases are more difficult to treat than most primary brain tumors, be-cause by the time they develop in the brain

they are usually the result of advanced, re-fractory cancer that hasn’t responded to standard treatments. Another challenge is that it is very difficult to deliver some of the newer targeted drugs effective in lung cancer, melanoma and other malig-nancies to the brain, as these agents have difficulty crossing the blood-brain barrier.

This area is in desperate need of new therapies, but before we get there, we need to have a better scientific understanding of the metastatic process as a whole. Conse-

quently, the treatment options in surgery and radiation for brain metastases haven’t really changed much over the past decade.

Naturally, we still have a lot of work to do in primary brain tumors, but since we’re usually not dealing with the burden of widespread disease in those cases, it be-comes a more focused challenge. Recently completed randomized trials have iden-tified new drug combinations (bevaci-zumab plus lomustine), immunotherapies (rindopepimut) and novel techniques (al-ternating electrical fields) that may prove to be useful for glioblastoma patients.

CNS LymphomaCNS lymphoma has historically been as-

sociated with poor survival. Over the past de-cade, however, we’ve seen some improvement in survival. Please give the readers an update on this issue.

Outcomes for primary CNS diffuse large B-cell lymphoma (PCNSL), > 90% of all cases of primary CNS lymphoma, remain inferior to other extranodual forms of non-Hodgkin lymphoma. This may be

due to the fact that > 90% of PCNSL cases consist of the more aggressive activated B-cell–like form. The improvement we’ve seen in PCNSL is due largely to the de-velopment of customized chemotherapy regimens that can cross the blood brain barrier and effectively treat the lymphoma. The drug combinations used to treat a non-Hodgkin lymphoma of the body are very different from those used to treat PCNSL. As we’ve gotten better at devising ways that allow our patients to tolerate high-dose

therapy, we’re now seeing early evidence suggesting that combining high-dose che-motherapy and bone marrow transplant could be quite effective for this group of patients. Also, investigators are develop-ing treatment regimens for PCNSL that include targeted agents with demonstrated activity against the activated B-cell subtype of diffuse large B-cell lymphoma.

Moreover, we’ve finally reached a point in this rare brain cancer where we are able to conduct cooperative group randomized clinical trials. It’s important to note that when I began in this field, there had only been one published randomized trial that was terminated early because it failed to get proper accrual numbers. Now we have three completed and five ongoing random-ized trials. So, for the first time we are truly beginning to develop some evidence-based medical practice data around PCNSL.

Treatment ToleranceYou mentioned that a major step for-

ward in treatment and research came with patients’ ability to tolerate regimens such as high-dose chemotherapy with bone marrow transplantation. Please elaborate on that.

First of all, not every patient is a candi-date for transplantation, because many of the older patients are not. But in those pa-tients with adequate organ function who are candidates for bone marrow trans-plant, we now have much better support-ive treatments that allow them to tolerate the toxicities associated with these rather aggressive therapies.

Detection and DiagnosisPlease talk a bit about the challenges

involved in detection and diagnosis of brain tumors.

A big challenge in detection is that neurologic symptoms due to a brain tumor have many similarities to other neurologic disorders such as stroke or multiple sclerosis. Given the dearth of symptoms unique to brain tumors, there is no way for early detection un-

A Conversation With Tracy Batchelor, MD By Ronald Pi ana

Treating Brain Cancer in 2014

Glioblastoma is where we have the most work to do…. The most promising area is in molecular diagnostics that

enable us to subdivide glioblastomas into specific subtypes, which at least gives us an opportunity to develop more

personalized therapeutic approaches and clinical trials. —Tracy Batchelor, MD

Neuro-oncology

Dr. Batchelor is Executive Director, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Director, Division of Neuro-On-cology, Department of Neurology, Massachu-setts General Hospital, and Director, Division of Neuro-Oncology, Department of Neurol-ogy, Harvard Medical School, Boston.


State of the Art

less you use imaging. Since these are rel-atively rare tumors, there is no rationale to use imaging as a screening tool. Plus, we currently have no curative therapies for the most common primary brain cancers like glioblastoma.

On the other hand, if certain symp-toms could possibly be caused by a brain tumor, then we advise a contrast-en-hanced brain MRI, which in most cases gives us enough information either to rule a tumor out or make an accurate diagno-sis. Because surgical techniques and peri-operative care have improved so much, re-section or biopsy of a brain is much safer with far less chance of side effects.

Closing ThoughtsDo you have any closing thoughts on

this very difficult oncologic setting that you’ve devoted much of your career to?

In this varied group of CNS malig-nancies, glioblastoma is where we have the most work to do and the biggest clinical and scientific questions to an-swer. A promising area is in molecular diagnostics, which enable us to subdi-vide glioblastomas into specific sub-types, giving us an opportunity to de-velop more personalized therapeutic approaches and clinical trials. At the same time, by reclassifying an uncom-mon tumor like glioblastoma into mul-

tiple molecular groups, we are creating rare biological tumor subtypes, which makes it more difficult to execute clini-cal trials.

This highlights the need for those of us in the clinical and research com-munities to develop and standardize molecular profiling platforms so that we’re all on the same page with regard to the markers we are using to classify tumors. Once we cross that bridge, we need to initiate large cooperative group and intergroup studies so that we have the numbers to adequately investigate these targeted drugs in sub-types of glioblastoma.

Another area of promise in glioblas-toma is immunotherapy. We’re antici-pating the results of a randomized trial that should be wrapping up fairly soon. There are also some interesting glio-blastoma studies underway examining the role of vaccines and checkpoint in-hibitors. And, as mentioned, we are still hopeful that combinations of certain antiangiogenic treatments will prove active in glioblastoma. We have a long way to go, but there is also great prom-ise in several areas that didn’t exist a de-cade ago. n

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

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

Peter Paul Yu, MD, on building a data infrastructure see page 1

Deborah Schrag, MD, MPH, on tumor board participation see page 24

D. Ross Camidge, MD, PhD, on treatment of advanced lung cancer see page 11

John F. Smyth, MD, on when to stop prescribing see page 1

William Berry, MD, MPA, MPH, FACS, on tools that enhance quality see page 20

Suzanne Tamang, PhD, on the nature of unplanned cancer care see page 25

Norman Wolmark, MD, on hormonal therapy for early breast cancer see page 4

Lawrence N. Shulman, MD, on a national cancer database see page 22

Visit The ASCO Post online at ASCOPost.com

Steven D. Mittelman, MD, PhD, on childhood obesity and leukemia see page 30

Download The ASCO Post iPad App

FREE from iTunes today!


EORTC-NCI-AACR Symposium

Scientists Develop New Approach to Treating HPV-Related Cervical Cancer

Cidofovir, an antiviral drug that is well established as a treatment

for infection of the retina in people with AIDS, has been shown to be ef-fective in combination with chemora-diation in a phase I study of women with human papillomavirus (HPV)-

related cervical cancer. The study results were presented at the recent EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Thera-peutics in Barcelona.1

Fifteen women were enrolled in the study and received injections of

cidofovir at doses ranging from 1 to 6.5 mg per kilogram of body weight weekly for 2 weeks, and then every 2 weeks from the start of chemoradia-tion (45 Gy radiotherapy delivered to the pelvis and weekly intravenous carboplatin until the start of brachy-

therapy in the uterus and vagina). The women received a total of six in-jections of cidofovir, and the median duration of therapy was 10 weeks. The combination of cidofovir and chemoradiation resulted in tumor shrinkage in all patients and did not increase toxicity or the tumor’s resis-tance to radiation.

“The major finding from the trial is that cidofovir did not increase the toxicity or worsen the tolerability of chemoradiation,” said Eric Deutsch, MD, PhD, Professor of Radiation Oncology at the Institut Gustave Roussy, in Villejuif, France, and a co-author of the study, in a press state-ment. “We also found that the com-bination resulted in tumor shrinkage in all the patients who could be eval-uated in the trial, with a complete response, in which the tumors dis-appeared for a time, in 80% of these patients.”

A Safe ApproachAlthough one of the major side ef-

fects from cidofovir can be kidney damage, none was seen in this trial, suggesting the dosage was safe.

“The results from this phase I trial show that the combination of cido-fovir with chemoradiation is a new, targeted anticancer approach, which enables us to target cancer cells spe-cifically with a limited impact on healthy tissues, thereby avoiding un-acceptable adverse side effects,” said Dr. Deutsch.

The researchers hope to launch a phase II/III trial soon to investigate how the combination therapy impacts overall survival. n


Reference1. Deutsch E, et al: Phase I trial

evaluating the antiviral agent cidofovir in combination with chemoradiation in cervical cancer patients: A novel ap-proach to treat HPV related malignan-cies? EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Thera-peutics. Abstract 219. Presented No-vember 20, 2014.


Send Us Your NEWSWrite to [email protected].

All submissions will be considered for publication

ADDRESSING THE TOUGHEST CHALLENGESIN ONCOLOGY TAKES ALL OF US.

That’s why we collaborate each day with peers, academics, clinical experts and others.

Together, we aim to create solutions that work against the ability of cancer cells to survive.

At AbbVie, our solutions start withscience and end with a vision of a better future for patients around the world.

Learn more at oncology.abbvie.com

CM-0006-0814

http://www.abbvie.com/oncology/home.html


Expert’s Corner

Helping Adolescents and Young Adults Cope With CancerA Conversation With Susan K. Parsons, MD, MRP, and Tully Saunders, BSBy Jo Cavallo

Each year, about 70,000 adoles-cents and young adults (AYAs)

are diagnosed with cancer in the Unit-ed States, almost six times the number of cases diagnosed in children up to 14 years of age. While overall cancer sur-vival rates continue to rise—according to the American Cancer Society, there are currently 14.5 million cancer sur-vivors in the United States—most of that improvement is among pediatric and older adult patients.

For adolescent and young adult pa-tients with cancer, defined by the Na-tional Cancer Institute as those between the ages of 15 and 39, survival rates have remained stagnant since 1975. In certain cancer types, such as acute lym-phoblastic leukemia, the 5-year survival rate has actually decreased—91% for children younger than 15 years com-pared with 78% for adolescents aged 15 to 19 years.

The possible reasons for this dis-crepancy in survival rates are many, including lack of health insurance or underinsurance, delayed diagnosis, lack of participation in clinical trials, inad-equate treatment practices, the unique social needs of this age group, and a ma-jor emerging potential factor: underly-ing biologic differences.

To generate attention to the physi-cal, cognitive, and emotional challenges that AYAs face, spur clinical trial de-velopment for this age group, and pro-vide ongoing psychological and social support services to AYA survivors, in 2013, Tufts Medical Center in Boston opened the Reid R. Sacco Adolescent and Young Adult Program for Cancer and Hereditary Blood Diseases. So far, the clinic has accepted 60 AYAs who are either on active treatment or have com-pleted treatment for cancer.

The ASCO Post talked with Susan K. Parsons, MD, MRP, Founding Di-

rector of the Reid R. Sacco Adolescent and Young Adult Program for Cancer and Hereditary Blood Diseases at Tufts Medical Center, and Tully Saunders, BS, the Program Coordinator, about the issues confronting AYAs during or after a cancer diagnosis and treatment and how programs like Reid R. Sacco’s are meeting the long-term needs of these survivors.

At age 27, Mr. Saunders brought his personal perspective of coping with

cancer to our conversation. Diagnosed with a rare form of lung cancer when he was just 3 years old, Mr. Saunders was treated by Dr. Parsons when she was a pediatric oncologist at Dana-Farber Cancer Institute.

Variety of ServicesPlease talk about the services provid-

ed by the Reid R. Sacco Adolescent and Young Adult Program for Cancer and He-reditary Blood Diseases.

Dr. Parsons: Like other AYA pro-grams, we provide holistic patient care. We help our patients with disease and survivorship management, initial and late effects of therapy, and primary and secondary cancer prevention. We help them learn more about their health his-tory and how to self-advocate within the health-care environment. We pre-pare survivorship care plans for survi-vors and construct active care plans for

all patients, updating them with each subsequent visit.

We also help AYA survivors in ways that are a little bit nontraditional. For example, we focus on many of the life-related issues they are dealing with as a function of their age and developmen-tal stage. To help with this, we have in-corporated trained peer navigators into the clinic. The peer navigators have all completed a 12-week course in patient navigation and receive in-depth clinical and administrative supervision. Each patient is assigned a peer navigator who works with the patient on a range of top-ics, including education, employment, personal and professional relationships, financial concerns, and housing.

The peer navigators and clinicians help the patients explore their cancer history within the context of their life stage and address their psychological, social, and financial needs. One issue that we have grappled with repeatedly is their health insurance status. Some AYAs are transitioning from their par-

ents’ health-care plans. Others don’t have stable employment or income. But regardless of the situation, we help patients navigate through the maze of health insurance options to find an appropriate plan and ensure that they understand their plan’s costs and copays.

Another big area we touch on is educational and vocational counsel-ing. Some patients are dealing with neurocognitive late effects from their treatment. When appropriate, we refer patients to formal neuropsychological testing and provide coaching and dis-cussions about educational and profes-sional goals.

We also help AYAs as they create and maintain social relationships. One of the advantages of this type of life-stage–based program is that our patients feel like they are now part of a group—a feeling they lost as a result of their can-

cer and treatment.The program also offers services to

help patients maintain health-care fol-low-up appointments.

Role of Social MediaWhat role can social media play in

helping AYA survivors stay healthy, and how can oncologists be better prepared in using social media to stay current with their patients’ needs?

Dr. Parsons: We recognize that our patients are much more connected to social media than we might be!

Mr. Saunders: True. Many AYAs are engaged in social media. It is heavily incorporated into their daily lives and is their main source of communicating with peers and receiving news.

At our clinic, we are very proactive in reaching out to AYAs through Face-book, our website, e-mail, and blog. We were fortunate to receive a grant to build a secure website so we could have a dedicated patient forum where pa-tients can interact and “meet” each oth-er virtually. Patients receive a user name and can log into a secure portal to con-nect with other AYAs, privately contact our clinic team, and ask questions about their care. Having this virtual tool has helped us improve the level of care we provide AYAs.

Helpful TechnologyDo you use mobile device apps to keep

these survivors engaged in their medical care?

Mr. Saunders: We leverage smart phone technology to e-mail patients if we have a question, want to schedule appointments, and as a reminder to take a daily medication. We ask patients early on about their preferred mode of communication: text, e-mail, or phone call, and we try to accommodate their communication style.

Dr. Parsons: We have found tech-nology to be very powerful in helping patients remember their appointments, medications, and medication sched-ules. We worked with one patient, who could not remember his medications, to enter his medication list into his smart phone. Now, when he comes into the clinic he just pulls up the list on his phone. Another patient had a difficult time remembering to take her medica-tion, so we helped her set alarms on her smart phone to remind her.

AYA Oncology

Susan K. Parsons, MD, MRP Tully Saunders, BS


Adolescents and young adults are a fascinating group to work with, and now that more attention is being paid to them and the potential barriers to their care

and survivorship, I believe we are making progress in understanding the multiple factors contributing to their

cancers and in improving their care and survival. —Susan K. Parsons, MD, MRP

Reference: 1. Melcher A, Parato, K, Rooney CM, Bell JC. Mol Ther. 2011;19:1008-1016.

©2014 Amgen Inc. All rights reserved. 10/14 USA-678-100791

Cancer cell

LyseOncolytic Immunotherapy is an innovative area of research that uses a modified virus designed to induce tumor cell lysis and expose tumor-derived antigens.

Amgen is researching ways to help T cells target cancer.

Activated dendritic cells can teach T cells to help find and fight cancer cells with a matching antigen profile.1

LearnDendritic cell

Explore what’s new at:OncolyticImmunotherapy.com

TVUS14CDNY6107_D_OI_JA_CompD_Spread_King_r8.indd All Pages 10/15/14 9:37 AM

Reference: 1. Melcher A, Parato, K, Rooney CM, Bell JC. Mol Ther. 2011;19:1008-1016.

©2014 Amgen Inc. All rights reserved. 10/14 USA-678-100791

Cancer cell

LyseOncolytic Immunotherapy is an innovative area of research that uses a modified virus designed to induce tumor cell lysis and expose tumor-derived antigens.

Amgen is researching ways to help T cells target cancer.

Activated dendritic cells can teach T cells to help find and fight cancer cells with a matching antigen profile.1

LearnDendritic cell

Explore what’s new at:OncolyticImmunotherapy.com

TVUS14CDNY6107_D_OI_JA_CompD_Spread_King_r8.indd All Pages 10/15/14 9:37 AM

http://www.oncolyticimmunotherapy.com


Expert’s Corner

Mr. Saunders: We’ve been pleased with the results of our peer navigator program. A peer navigator is present dur-ing every patient visit and represents our “boots on the ground” to help patients access resources, find clinical trial infor-mation, or program their smart phone or other mobile device to set appointment or medication reminders.

Survival IssuesWhy haven’t survival rates improved

for AYAs as they have for younger and older patients with cancer?

Dr. Parsons: There are many, many factors contributing to the lack of sur-vival progress among AYAs. This gap is a huge motivator for those of us in-volved in AYA care to determine how to improve those survival rates. Several reasons for this lack of progress have been proposed.

Prior to the Affordable Care Act, un-derinsurance or lack of insurance was a huge problem for this age group, but with provisions in the Affordable Care Act that allow some children to stay on their parent’s insurance plans until age 26 and with the elimination of preexist-ing conditions, more people in this age group have insurance, so that is one less health barrier to deal with.

The other issue is a function of age and a sense of invincibility. Some AYAs believe that cancer only happens to old people. Health-care providers, too, don’t have cancer in the front of their minds when they are examining peo-ple in this age group, so we often see delayed diagnosis as a result. Many of our survivors believe that cancer only strikes once, which is why it is challeng-ing to sell some AYAs on secondary-cancer prevention.

Some AYA experts have also argued that there may be underlying biologic differences in this age group. Further-more, we may not be treating some of the diseases aggressively enough. Emerging research suggests that treat-ment of some diseases may benefit from a pediatric approach, while oth-ers may best be treated with an adult approach.

The biologic differences are intrigu-ing to us. Several interesting studies are underway, looking at whether there is something about when these cancers occur, how they present, and how they respond to treatment that may be dif-ferent in this age group.

Several years ago, Wendy Stock, MD [Professor of Medicine, Section of Hematology/Oncology and Director of the Leukemia Program at the Univer-sity of Chicago Comprehensive Cancer Center], did a study1 that examined the

survival differences of AYAs with acute lymphoblastic leukemia being treated on adult chemotherapy regimens vs pe-diatric chemotherapy regimens. While the individual chemotherapy drugs were similar, the doses and schedules were different. The study showed a 63% disease-free survival for individu-als on pediatric trials vs 34% for those on adult trials.

Similar studies have been under-taken for patients with sarcoma and lymphoma to see which treatment ap-proach would yield better outcomes for patients in this age group. There may not be a one-size-fits-all approach.

The good news is that there is now heightened awareness that much more research is needed in this area.

Improving AdherenceHow can oncologists encourage their pa-

tients to adhere to care recommendations?Dr. Parsons: A lot of discussion

is needed to convince AYAs to follow care guidelines. Some patients want to see the evidence behind the guidelines, while others don’t want to hear any of the details. Some are worried about co-pays or about missing time from work or school.

We provide each patient with a con-crete care plan, including the specific follow-up tests, indication(s) for these tests, the date of the last test, and the

person responsible for getting the test done. That responsible party might be the AYA team, the primary care provid-er, or the patient him/herself.

We review the updated care plan at each visit and share a copy with the pri-mary care provider. By clearly outlining and communicating care recommenda-tions, we hope to empower patients to effectively manage their care.

Closing ThoughtsDo you have any closing thoughts about

working with AYAs?Adolescents and young adults are a

fascinating group to work with. Now that more attention is being paid to them and the potential barriers to their care and survivorship, I believe we will make progress in understanding the multiple factors contributing to their cancers and in improving their care and survival.

Disclosure: Dr. Parsons and Mr. Saunders reported no potential conflicts of interest.

Reference1. Stock W, La M, Sanford B, et al:

What determines the outcomes for ado-lescents and young adults with acute lymphoblastic leukemia treated on coop-erative group protocols? A comparison of Children’s Cancer Group and Cancer Leu-kemia Group B studies. Blood 112:1646-1654, 2008.

Adolescents and Young Adults With Cancercontinued from page 73










HarborsidePress.com


[email protected]



Phone: 631.935.7660



Journal Spotlight

Proteome-Scale Map of the Human Interactome Network Created

Researchers have produced a new largest-scale map of human protein

interactions that will better enable scien-tists to trace how genetic changes lead to diseases ranging from cancer to Hun-tington’s disease. The expanded map, published in the journal Cell,1 is about 30% larger than the combination of all small-scale studies published in scien-tific literature and suggests that scientists may have been too narrowly focused in tracking the mechanisms responsible for disease.

“The search for genetic connections to disease has been compared to an individual looking for his car keys beneath a streetlight at night,” said Thomas Rolland, PhD, a re-searcher at Dana-Farber Cancer Institute in Boston, and a co–lead author of the study. “When a police officer asks why he’s look-ing there, he explains that that’s where the light is. By analogy, the new map casts a wider beam over the area to be searched, where the car keys would lie.”

New Protein-Protein MapIn the study, scientists first searched

the scientific literature to identify all the protein pairs that have been tested so far. Of that group, they found 11,000 high-quality interactions, representing less than 10% of all the protein-protein interactions thought to be in the human interactome.

The studies made it appear that less than half of human proteins are densely interconnected while the rest did not participate in any interaction, the re-searchers found. The pattern suggested to the researchers one of two possibili-ties: either those proteins interact only rarely with other proteins, or, because previous studies have focused on pro-teins known to be involved in disease, interactions involving other, less noto-rious proteins have been overlooked.

To determine which conclusion was correct, the researchers generated a new map by systematically looking for inter-actions among 13,000 proteins, cover-ing almost half the space to be searched. Unlike smaller-scale studies, which were built around known disease proteins, the new study tested proteins “across the board,” regardless of whether they had previously been implicated in disease.

The result was a high-quality map of almost 14,000 interactions among 4,300 distinct proteins. It is the largest experi-mentally determined binary protein-protein interaction map yet produced, more than doubling the number of high-quality interactions identified in the past 2 decades by small-scale studies.

Based on the new map, the research-

ers found that instead of well-known proteins being densely interconnected, their interactions were evenly distribut-ed across the proteome, suggesting that the human interactome is broader than previously thought.

“The map will be especially useful

in cancer research,” said Dr. Rolland. “It revealed numerous connections between known and suspected cancer proteins, broadening the landscape for understanding the mechanics behind the disease. Combining our map with the results of small-scale studies, we

now know of about 30,000 interacting pairs of proteins in human cells.” n

Disclosure: For full disclosures of the study authors, visit www.cell.com.

Reference1. Rolland T, et al: Cell. November 20,

2014 (early release online).

Proteomics

Why setle for fuzzy results?

Insist on a clearer picture.

MammaPrint® provides more informaton about your patent’s breast cancer recurrence risk with defnitve, High Risk/Low Risk

results. BluePrint® classifes Luminal-type, Basal-type and HER2-type functonal molecular subtypes. Together, they reveal more

clinically actonable biology:

• MammaPrint + BluePrint can reclassify up to 25% of breast cancers with potental therapeutc and prognostc implicatons,

according to a study published in Cancer Research.1

• Most recently, NBRST, a prospectve neoadjuvant study, concluded that BluePrint may be a beter guide than IHC-FISH tests in

making decisions about how to treat early-stage breast cancer before surgery.2

For more clinically actonable informaton, order MammaPrint + BluePrint to uncover your patent’s functonal molecular

subtype. The diference is clear.

MammaPrint + BluePrint: Beter together. Convenient online ordering available at www.agendia.com.

Agendia, Inc. 22 Morgan, Irvine, CA 92618 (888) 321-2732

www.agendia.com © 2014

1 Cristofanilli M, et al. Cancer Res. 2012;72(24 Suppl):Abstract nr P3-05-01.

2 Whitworth P, et al. Ann Surg Oncol. 2014 Aug 7.

[Epub ahead of print];doi: 10.1245/s10434-014-3908-y.

M-USA-044-V1

Visit us at S

ABCS Booth #518!

KHJ20573_AGD-016_MPBP_TV_ASCO_7.575x10.575_mech.indd 1 11/6/14 2:14 PM

http://www.agendia.com


Palliative Care in Oncology

How the Earlier Introduction of Palliative Care Improves Quality of Life for Patients With Advanced CancerA Conversation With Camilla Zimmermann, MD, PhD, FRCPCBy Jo Cavallo

A 4-year study1 involving 461 pa-tients with advanced stages of

lung, gastrointestinal, genitourinary, breast, and gynecologic cancers has found that providing early outpatient palliative care vs standard oncology care alone improved quality of life and patient satisfaction. The study par-ticipants received care at 24 medical oncology clinics at Princess Marga-ret Cancer Center, University Health Network in Toronto, Canada, and had a clinical prognosis of between 6 and 24 months. The clinics were clus-ter randomized in a 1:1 ratio using a computer-generated sequence and stratified by clinic size and tumor site to consultation and follow-up by a pal-liative care team or to standard cancer care.

The aim of the study, said lead in-vestigator Camilla Zimmermann, MD, PhD, FRCPC, was to deter-mine whether the early involvement of a team of palliative care specialists made a difference in the quality of life of patients and their caregivers and improved patient satisfaction with the care they received. Despite recom-mendations by ASCO2 that palliative care services be integrated into stan-dard oncology practice at the time a person is diagnosed with metastatic or advanced cancer to relieve pain and other physical, psychosocial, and spiritual issues, palliative care is most often introduced at the end of life, if at all, according to Dr. Zimmermann.

“Right now there is a difference be-tween what we say we should be do-ing and what we actually do regarding palliative care in the advanced cancer setting. We wanted to see if there is any proof that doing what we say we should do has any positive impact on

patients’ quality of life—and we found that it does,” she said.

The ASCO Post talked with Dr. Zimmermann, Head of the Palliative Care Program and Rose Family Chair in Supportive Care at the Princess Margaret Cancer Center and Univer-sity Health Network, about the results of her study and how improving the quality of life of patients also improves the quality of life of their caregivers.

Study DetailsWhat were the major results of your

study?Patients were assessed monthly for

4 months for quality of life using the Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being (FACIT-Sp) scale and Quality of Life at the End of Life (QUAL-E) scale, symptom severity using the Edmon-ton Symptom Assessment System (ESAS), satisfaction with care us-ing FAMCARE-P16, and problems with medical interactions using the Cancer Rehabilitation Evaluation

System Medical Interaction Subscale (CARES-MIS).

We defined the primary outcome in advance as the change in score on the FACIT-Sp measure from baseline to 3 months. Secondary endpoints in-cluded the change in FACIT-Sp score at 4 months and change for the other scales at 3 and 4 months.

We found that at 3 months, there was a trend toward a significant change in our primary outcome mea-sure, a significant change in the other quality-of-life measure, and a highly significant change in satisfaction with care, all favoring the intervention group. At 4 months, almost all the out-comes were significantly positive. The only score that wasn’t positive was the one measuring problems with medical interactions.

Relevance to Early DiseaseCan the results of your study also be

used to show the benefit of palliative care for patients with early-stage disease, espe-cially to remedy physical symptoms such as fatigue, pain, and sexual dysfunction, and mental health issues such as depres-sion and anxiety?

I would be careful about extrapolat-ing too much from this study, because it was focused on patients with advanced-stage disease and their overall quality of life. There would have to be a specific study for patients with earlier-stage dis-ease to see what benefits might be de-rived from early palliative care in that setting. However, I think that interven-ing in these sorts of symptoms in earlier disease makes a lot of sense and would improve patients’ quality of life.

Today, more and more, the whole focus of palliative care is from initial di-agnosis and throughout survivorship. During cancer treatment of any kind, patients and their families need sup-port, both physical and psychological, throughout the illness and not just at

the end of life. It doesn’t make sense to suddenly become very interested in pa-tients’ symptoms only at the end of life. Palliative care is relevant throughout the course of the illness and survivorship.

Acute Myeloid LeukemiaYou are currently investigating the pal-

liative care needs of patients with acute myeloid leukemia. Do these patients have different needs than patients with other types of cancer?

They certainly do. Despite the fact that patients with acute myeloid leuke-mia have a very poor prognosis, espe-cially those over age 65, traditionally the palliative care needs of these patients have not been adequately addressed.

Overall, the 5-year survival rate is be-tween 20% and 30%, and in patients over age 65, the survival rate is about 15%, so

there is a high death rate from this dis-ease right from diagnosis. That said, in some cases the disease can be cured, so the focus is very much on cure and less on quality of life. But from initial diagno-sis and throughout the disease trajectory, because the outcome is so variable, acute myeloid leukemia patients have high de-grees of stress and anxiety, so they have significant psychosocial issues. They also have physical symptoms from both the leukemia and its treatment side effects.

For that reason, we are investigat-ing whether the early integration of palliative care services at diagnosis can improve traumatic stress symptoms, which are prevalent in this population, as well as achieve physical symptom control. We have just launched a ran-domized phase II pilot study and will plan a phase III study based on the re-sults of the pilot study.

Early palliative care is relevant in all sorts of cancers, but there probably needs to be slightly different treatment models, with a tailored approach for each disease.

Team ApproachPlease talk about what you have found

in your research focusing on the effective delivery of palliative care.

The effective delivery of palliative care will vary depending on the health-care system in which it is given and the collaboration among the existing pro-fessional caregivers in that field.

At 3 months, there was a trend toward a significant change in our primary outcome measure [FACIT-Sp], a significant change in the other quality-of-life measure,

and a highly significant change in satisfaction with care, all favoring the intervention group.

—Camilla Zimmermann, MD, PhD, FRCPC

Camilla Zimmermann, MD, PhD, FRCPC

GUEST EDITOR

Addressing the evolving needs of cancer survivors at various stag-

es of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science and Professional Development Department.

Jamie H. Von Roenn, MD


Palliative Care in Oncology

In our cancer center setting, which in-cludes a large outpatient population with many physical and psychosocial concerns and care planning issues, we have a pallia-tive care team comprising palliative care physicians and nurses, physical and occu-pational therapists, spiritual care profes-sionals, and mental health and social work experts to provide support for the patient and family members. The core team in the outpatient palliative care clinic was a palliative care physician and nurse who brought in the other team members when required and also collaborated with the home-care team. We found that this type of multidisciplinary effort was very effec-tive in improving patients’ quality of life and satisfaction with care.

Cost ConsiderationsDoes introducing palliative care ear-

lier in a patient’s cancer diagnosis also

have a cost-saving benefit?We are investigating cost, and that as-

pect of the study is ongoing. I don’t have the exact findings yet. But it makes sense that if palliative care specialists are in-volved in a patient’s care from the begin-ning, there will probably be more discus-sions about questions such as: Is this last line of chemotherapy really necessary? Will it improve the patient’s quality of life, or is it being done to avoid confront-ing the reality of the situation (ie, that the patient is dying)?

Sometimes when we give palliative chemotherapy very late in the course of illness, it can result in a worse sur-vival outcome. When that is the case, there is no cost-effectiveness benefit. Providing palliation that allows the patient to remain at home and avoids admission to the hospital (and even travel to and from the cancer center

to treat symptoms) will also reduce medical costs.

Caregiver BenefitWhat did your study show regarding

how palliative care support for the patient can also benefit the caregiver?

Although we didn’t recruit enough caregivers in our study to give it suffi-cient power to determine conclusive re-sults, one thing we have seen is that the quality of life of caregivers is very closely associated with the quality of life of pa-tients. So if you improve patient quality of life, you can likely also improve care-giver quality of life.

One reason for this might be that the caregivers’ ability to engage in ac-tivities outside of their caregiving du-ties—for example, continuing to work, going to exercise class, or meeting with friends—is directly affected by the pa-

tient’s quality of life. Also, there will be increased caregiver distress if the pa-tient being cared for has uncontrolled pain or other symptoms. Therefore, it makes sense that if we improve the pa-tient’s quality of life, we improve the caregiver’s quality of life as well. n

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

References1. Zimmermann C, Swami N, Krzy-

zanowska M, et al: Early palliative care for patients with advanced cancer: A clus-ter-randomized controlled trial. Lancet 383:1721-1730, 2014.

2. Smith TJ, Temin S, Alesi ER, et al: American Society of Clinical Oncology Provisional Clinical Opinion: The Inte-gration of Palliative Care Into Standard Oncology Care. J Clin Oncol 30:880-887, 2012.

Use of Hospice Care by Medicare Patients Associated With Lower Rate of Hospitalization, ICU Admission, Invasive Procedures, and Costs

Medicare patients with poor-prognosis cancers who received

hospice care had significantly lower rates of hospitalization, intensive care unit (ICU) admissions and invasive proce-dures at the end of life, along with sig-nificantly lower health care expenditures during the last year of life, according to a study in a recent issue of JAMA.1

Multiple studies have documented the high intensity of medical care at

the end of life, and there is increasing consensus that such care can produce poor outcomes and conflict with patient preferences. The Institute of Medicine report Dying in America has drawn at-tention to the difficulties of promoting palliative care, including Medicare’s hos-pice program, the largest palliative care intervention in the United States.

More patients with cancer use hos-pice currently than ever before, but there are indications that care intensity out-

side of hospice is increasing, and length of hospice stay decreasing. Uncertainties regarding how hospice affects health-care utilization and costs have hampered efforts to promote it, according to back-ground information in the article.

Study DetailsUsing data from Medicare beneficiaries

with poor-prognosis cancers (eg, brain, pancreatic, metastatic malignancies), Ziad Obermeyer, MD, MPhil, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues matched those enrolled in hospice before death to those who died without hospice care and compared utilization and costs at the end of life. The study included a nationally rep-resentative 20% sample of Medicare fee-for-service beneficiaries who died in 2011.

Among 86,851 patients with poor-prognosis cancers, 51,924 (60%) en-tered hospice before death. Matching pa-

tients based on various criteria produced a hospice and nonhospice group, each with 18,165 patients. Median hospice duration was 11 days.

The researchers found that non-hospice beneficiaries had significantly greater health-care utilization, largely for acute conditions not directly related to cancer and higher overall costs. Rates of hospitalizations (65% vs 42%), ICU admissions (36% vs 15%), invasive pro-cedures (51% vs 27%), and death in a hospital or nursing facility (74% vs 14%) were higher for nonhospice beneficiaries compared to hospice patients. Overall, costs during the last year of life were $62,819 for hospice beneficiaries and $71,517 for nonhospice beneficiaries.

“Our findings highlight the poten-tial importance of frank discussions be-tween physicians and patients about the realities of care at the end of life, an issue of particular importance as the Medicare administration weighs decisions around reimbursing physicians for advance care planning,” the authors wrote. n

Disclosure: This work was supported by grants from the National Institutes of Health, National Cancer Institute, and Agency for Healthcare Research and Quality. For full disclosures of the study authors, visit jama.jamanetwork.com.

Reference1. Obermeyer Z, et al: JAMA 312:1888-

1896, 2014.

Palliative Care

Journal Spotlight

EXPERT POINT OF VIEW

Joan M. Teno, MD, MS, and Pedro L. Gozalo, PhD, of the Brown Universi-ty School of Public Health, Providence, Rhode Island, commented on end-

of-life care in an editorial accompanying the JAMA study by Obermeyer et al.“As financial incentives change in the U.S. health-care system, valid mea-

sures of care quality are increasingly important for ensuring transparency and accountability. Obermeyer and colleagues assessed hospitalization rates, intensive care admissions, and invasive procedures, but additional measures must have evidence of their ability to discriminate the quality of care and must be responsive to change, easy to understand, and actionable. This will involve investing public dollars in the ‘quality’ of quality measures and their dissemination. If quality of care is not front and center, the momentum to improve end-of-life care in the United States could face a serious setback.” n

Disclosure: Dr. Teno is the recipient of a Robert Wood Johnson Foundation Health Policy Investigators Award grant. She and Dr. Gozalo reported no potential conflicts of interest.

Reference1. Teno JM, Gozalo PL: Quality and costs of end-of-life care: The need for trans-

parency and accountability. JAMA 312:1868-1869, 2014.

Ziad Obermeyer, MD, MPhil

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING

Vascular Occlusion: Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can also cause recurrent or multi-site vascular occlusion. Overall, 20% of Iclusig-treated patients experienced an arterial occlusion and thrombosis event of any grade. Fatal and life-threatening vascular occlusion has occurred within 2 weeks of starting Iclusig treatment and in patients treated with average daily dose intensities as low as 15 mg per day. The median time to onset of the first vascular occlusion event was 5 months. Patients with and without cardiovascular risk factors have experienced vascular occlusion although these events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia. Interrupt or stop Iclusig immediately in patients who develop vascular occlusion events.

Heart Failure: Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig-treated patients (22/449). Eight percent of patients (35/449)

experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure.Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death. 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 blast phase CML (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe hepatotoxicity occurred in all disease cohorts. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.Hypertension: 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). Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled.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.Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common

peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1%, grade 3/4). Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate.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 1% (3/449) of Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of 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). Interrupt Iclusig and evaluate.

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.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 full Prescribing Information on the following pages, including the Boxed Warning, for additional Important Safety Information.Note: Unless otherwise indicated, data presented are from Iclusig [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; September 2014.

Most patients who achieved MCyR also achieved CCyR.*†

More than half of CP-CML patients who experienced resistance or intolerance to prior TKI therapy achieved MCyR within a median of 12 weeks (range: 7-48 weeks).*

Efficacy results described should be interpreted within the context of updated safety information.

54% MCyR

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

44% CCyR

(118/267) 95% CI: 38-50

*10-month median duration of follow-up. † The primary efficacy endpoint of the PACE trial in CP-CML was MCyR.

Iclusig is a registered trademark of ARIAD Pharmaceuticals, Inc. © 2014 ARIAD Pharmaceuticals, Inc. All rights reserved.

PB/1014/0156/USf

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY See full Prescribing Information for complete boxed warning.

• Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig-treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit-risk consideration should guide a decision to restart Iclusig therapy.

• Heart Failure: Heart failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.

• Hepatotoxicity: Hepatotoxicity, liver failure, and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.

ASHBooth #1505

INDICATIONS AND USAGE Iclusig® (ponatinib) is a kinase inhibitor indicated for the:• Treatment of adult patients with T315I-positive chronic myeloid leukemia (CML) (chronic phase, accelerated phase,

or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).• Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or

Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.

These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Consider Iclusig® (ponatinib) as an option for appropriate third-line CML and Ph+ ALL patients.

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING

Vascular Occlusion: Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can also cause recurrent or multi-site vascular occlusion. Overall, 20% of Iclusig-treated patients experienced an arterial occlusion and thrombosis event of any grade. Fatal and life-threatening vascular occlusion has occurred within 2 weeks of starting Iclusig treatment and in patients treated with average daily dose intensities as low as 15 mg per day. The median time to onset of the first vascular occlusion event was 5 months. Patients with and without cardiovascular risk factors have experienced vascular occlusion although these events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia. Interrupt or stop Iclusig immediately in patients who develop vascular occlusion events.

Heart Failure: Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig-treated patients (22/449). Eight percent of patients (35/449)

experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure.Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death. 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 blast phase CML (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe hepatotoxicity occurred in all disease cohorts. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.Hypertension: 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). Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled.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.Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common

peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1%, grade 3/4). Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate.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 1% (3/449) of Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of 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). Interrupt Iclusig and evaluate.

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.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 full Prescribing Information on the following pages, including the Boxed Warning, for additional Important Safety Information.Note: Unless otherwise indicated, data presented are from Iclusig [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; September 2014.

Most patients who achieved MCyR also achieved CCyR.*†

More than half of CP-CML patients who experienced resistance or intolerance to prior TKI therapy achieved MCyR within a median of 12 weeks (range: 7-48 weeks).*

Efficacy results described should be interpreted within the context of updated safety information.

54% MCyR

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

44% CCyR

(118/267) 95% CI: 38-50

*10-month median duration of follow-up. † The primary efficacy endpoint of the PACE trial in CP-CML was MCyR.

Iclusig is a registered trademark of ARIAD Pharmaceuticals, Inc. © 2014 ARIAD Pharmaceuticals, Inc. All rights reserved.

PB/1014/0156/USf

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY See full Prescribing Information for complete boxed warning.

• Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig-treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit-risk consideration should guide a decision to restart Iclusig therapy.

• Heart Failure: Heart failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.

• Hepatotoxicity: Hepatotoxicity, liver failure, and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.

ASHBooth #1505

INDICATIONS AND USAGE Iclusig® (ponatinib) is a kinase inhibitor indicated for the:• Treatment of adult patients with T315I-positive chronic myeloid leukemia (CML) (chronic phase, accelerated phase,

or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).• Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or

Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.


Consider Iclusig® (ponatinib) as an option for appropriate third-line CML and Ph+ ALL patients.

http://iclusig.com/hcp/

1 INDICATIONS AND USAGE Iclusig is a kinase inhibitor indicated for the: • Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase,

accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

• Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated. (1)


4 CONTRAINDICATIONS None5 WARNINGS AND PRECAUTIONS5.1 Vascular Occlusion Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke,

stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can cause fatal and life-threatening vascular occlusion within 2 weeks of starting treatment. Iclusig can also cause recurrent or multi-site vascular occlusion.

In the dose-escalation (phase 1) clinical trial, 48% (31/65) of patients with CML or Ph+ ALL developed vascular occlusive events. The median time to onset of the first vascular occlusion event was 5 months. Iclusig can cause fatal and life-threatening vascular occlusion in patients treated at dose levels as low as 15 mg per day.

Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Vascular occlusion adverse events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia (see Table 4).

Arterial Occlusion and Thrombosis Arterial occlusion and thrombosis occurred in at least 20% (91/449) of Iclusig-treated

patients with some patients experiencing events of more than one type. Patients have required revascularization procedures (cerebrovascular, coronary, and peripheral arterial) due to vascular occlusion from Iclusig.

Cardiac vascular occlusion, including fatal and life-threatening myocardial infarction and coronary artery occlusion has occurred in 12% (55/449) of Iclusig-treated patients. Patients have developed heart failure concurrent or subsequent to the myocardial ischemic event.

Cerebrovascular occlusion, including fatal stroke, has occurred in 6% (27/449) of Iclusig-treated patients. Iclusig can cause stenosis over multiple segments in major arterial vessels that supply the brain (e.g., carotid, vertebral, middle cerebral artery).

Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and life-threatening peripheral arterial disease, have occurred in 8% (36/449) of Iclusig-treated patients. Patients have developed digital or distal extremity necrosis and have required amputations.

Clinicians should consider whether the benefits of Iclusig treatment are expected to exceed the risks of therapy. In patients suspected of developing arterial thrombotic events, interrupt or stop Iclusig. A benefit-risk consideration should guide a decision to restart Iclusig therapy. [see Dosage and Administration (2.3)].

Venous Thromboembolism Venous thromboembolic events occurred in 5% (23/449) of Iclusig-treated patients,

including deep venous thrombosis (8 patients), pulmonary embolism (6 patients), superficial thrombophlebitis (3 patients), and retinal vein thrombosis (2 patients). Consider

dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].

5.2 Heart Failure Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig-

treated patients (N=22). Eight percent of patients (N=35) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure [see Dosage and Administration (2.3)].

5.3 Hepatotoxicity Iclusig can cause hepatotoxicity, including liver failure and death. 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 blast phase (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.

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

5.4 Hypertension Treatment-emergent hypertension occurred in 67% of patients (300/449). Eight patients

(2%) treated with Iclusig in clinical trials experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90 mm 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 during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled.

5.5 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). 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.

5.6 Neuropathy Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13%

(59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1% grade 3/4).

Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

5.7 Ocular Toxicity Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-

treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment [see Adverse Reactions (6)].

5.8 Hemorrhage Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated

with Iclusig. Hemorrhage occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase (AP) CML, BP-CML, and Ph+ ALL. Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events. Most hemorrhagic events, but not all, occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.11)]. Interrupt Iclusig for serious or severe hemorrhage and evaluate [see Dosage and Administration (2.3)].

5.9 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%).

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 [see Dosage and Administration (2.3)].

5.10 Cardiac Arrhythmias Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation

occurred in 1% (3/449) of 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). Interrupt Iclusig and evaluate.

Supraventricular tachyarrhythmias occurred in 5% (25/449) of 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). Interrupt Iclusig and evaluate.

5.11 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 [see Dosage and Administration (2.2)].

5.12 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 CP-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.

5.13 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.

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.

5.14 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)].

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction

rates observed in the clinical trials of a drug cannot be directly compared 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:

• Vascular Occlusion [see Warnings and Precautions (5.1)] • Heart Failure [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)] • Hepatotoxicity [see Dosage and Administration (2.3) and 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)] • Neuropathy [see Warnings and Precautions (5.6)] • Ocular Toxicity [see Warnings and Precautions (5.7)] • Hemorrhage [see Warnings and Precautions (5.8)] • Fluid Retention [see Warnings and Precautions (5.9)] • Cardiac Arrhythmias [see Warnings and Precautions (5.10)] • Myelosuppression [see Dosage and Administration (2.2) and Warnings and Precautions

(5.11)] 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. The events of arterial ischemia, cardiac failure, and peripheral neuropathy reported in Tables 5 and 6 include data from an additional 13 months of follow-up (median duration of treatment CP-CML: 672 days, AP-CML: 590 days, BP-CML: 89 days, Ph+ ALL: 81 days).

Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 5. 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 CP-CML, 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 reductions) 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 vpain (11%), pancreatitis (6%), and ALT, AST, or GGT increased (6%).

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITYSee full prescribing information for complete boxed warning.

• Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. (5.1).

• Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure (5.2).

• Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected (2.3, 5.3).

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

Table 4: Vascular Occlusion Incidence in Iclusig-Treated Patients in Phase 2 Trial According to Risk Categories

Prior history of ischemia, hypertension, diabetes, or hyperlipidemia

No history of ischemia, hypertension, diabetes, or hyperlipidemia

Age: 49 or younger 18% (6/33) 12% (13/112)

Age: 50 to 74 years 33% (50/152) 18% (20/114)

Age: 75 and older 56% (14/25) 46% (6/13)

All age groups 33% (70/210) 16% (39/239)

Total 24% (109/449)

Table 5: Adverse Reactions Occurring in >10% of Patients, Any Group

CP-CML (N=270)

AP-CML (N=85)

BP-CML (N=62)

Ph+ ALL (N=32)

System Organ Class Any Grade

(%)

CTCAE Grade 3 / 4 (%)

Any Grade(%)


Any Grade(%)


Any Grade

(%)


Cardiac or Vascular disordersHypertension (a) 68 39 71 36 65 26 53 31Arterial ischemia (b)* 20 11 19 9 10 5 3 0Cardiac Failure (c)* 7 4 6 4 15 8 6 3

Gastrointestinal disordersAbdominal pain (d) 49 10 40 8 34 6 44 6Constipation 37 2 24 2 26 0 47 3Nausea 23 1 27 0 32 2 22 0Diarrhea 16 1 26 0 18 3 13 3Vomiting 13 2 24 0 23 2 22 0Oral mucositis (e) 10 1 15 1 23 0 9 3GI hemorrhage (f) 2 <1 8 1 11 5 9 6

Blood and lymphatic system disordersFebrile neutropenia 1 <1 4 4 11 11 25 25

Infections and infestationsSepsis 1 1 5 5 8 8 22 22Pneumonia 3 2 11 9 13 11 9 3Urinary tract infection 7 1 12 1 0 0 9 0Upper respiratory tract infection 11 1 8 0 11 2 0 0Nasopharyngitis 9 0 12 0 3 0 3 0Cellulitis 2 1 4 2 11 3 0 0

Nervous system disordersHeadache 39 3 28 0 31 3 25 0Peripheral neuropathy (g)* 16 2 11 1 8 0 6 0Dizziness 11 0 5 0 5 0 3 0

Respiratory, thoracic, and mediastinal disordersPleural effusion 3 1 11 2 13 0 19 3Cough 12 0 17 0 18 0 6 0Dyspnea 11 2 15 2 21 7 6 0

Skin and subcutaneous tissue disordersRash and related conditions 54 5 48 8 39 5 34 6Dry skin 39 2 27 1 24 2 25 0

Musculoskeletal and connective tissue disordersArthralgia 26 2 31 1 19 0 13 0Myalgia 22 1 20 0 16 0 6 0Pain in extremity 17 2 17 0 13 0 9 0Back pain 15 1 11 2 16 2 13 0Muscle spasms 12 0 5 0 5 0 13 0Bone pain 12 <1 12 1 11 3 9 3

General disorders and administration site conditionsFatigue or asthenia 39 3 36 6 35 5 31 3Pyrexia 23 1 31 5 32 3 25 0Edema, peripheral 13 <1 19 0 13 0 22 0Pain 8 <1 7 0 16 3 6 3Chills 7 0 11 0 13 2 9 0

Metabolism and nutrition disordersDecreased appetite 8 <1 12 1 8 0 31 0

InvestigationsWeight decreased 6 <1 7 0 5 0 13 0

Psychiatric disorders

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 cardiovascular, cerebrovascular, and peripheral vascular 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, skin burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, polyneuropathy

*represents an additional 13 months of follow-up

(a) includes pericardial effusion, pleural effusion, and ascites

* represents an additional 13 months of follow-up

Table 6: Serious Adverse Reactions (SAR)N (%)

Cardiovascular disordersArterial ischemic event* Cardiovascular Cerebrovascular Peripheral vascular

53 (11.8%)28 (6.2%)18 (4.0%)16 (3.6%)

Hemorrhage CNS hemorrhage

22 (4.9%)10 (2.2%)

Cardiac failure* 22 (4.9%)Effusions(a) 13 (2.9%)Atrial fibrillation 11 (2.4%)Venous thromboembolism 10 (2.2%)Hypertension 8 (1.8%)

Gastrointestinal disordersPancreatitis 23 (5.1%)Abdominal pain 17 (3.8%)

Blood and lymphatic system disordersFebrile neutropenia 13 (2.9%)Thrombocytopenia 13 (2.9%)Anemia 12 (2.7%)

Infections Pneumonia 24 (5.3%)Sepsis 11 (2.4%)

General

7 DRUG INTERACTIONS Based on in vitro studies, ponatinib is a substrate of CYP3A 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, coadministration 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 [see Dosage and Administration (2.4)]. Patients taking concomitant strong CYP3A 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 strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin,

and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the risk of decreased ponatinib exposure. Monitor patients for reduced efficacy. Selection of concomitant medication with no or minimal CYP3A induction potential is recommended. In a drug interaction study in healthy volunteers, co-administration of Iclusig following multiple doses of rifampin resulted in decreased ponatinib AUC0-inf and Cmax values by 62% and 42%, respectively [see Clinical Pharmacology (12.3)].

7.3 Drugs That Elevate Gastric pH Iclusig may be co-administered with gastric pH-elevating medications. In a drug interaction

study in healthy volunteers, co-administration of Iclusig following multiple doses of lansoprazole resulted in a minimal (6%) decrease in ponatinib exposure. [see Clinical Pharmacology (12.3)].

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 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 (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy

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%). Forty-six percent of patients ≥ 65 years had vascular occlusion events. Patients of age ≥ 65 years are more likely to experience adverse reactions including vascular occlusion, 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 Administer Iclusig at a dose of 30 mg once daily in patients with hepatic impairment (Child-

Pugh A, B, or C). [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. In a single-dose (30 mg) pharmacokinetic (PK) study; compared to subjects with normal

liver function, no major differences in ponatinib PK were observed in subjects with hepatic impairment (Child-Pugh A, B, or C). However, there was an increased overall incidence of adverse reactions (e.g., gastrointestinal disorders, including a case of severe pancreatitis) in the subjects with hepatic impairment following the single 30 mg dose compared to subjects with normal liver function. The safety of multiple ponatinib doses, or doses higher than 30 mg have not been studied in patients with hepatic impairment.

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)].

10 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 (1-855-552-7423) [email protected]

PB/0314/0074/US(1)

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 Grade 3/4* Hematologic AbnormalitiesLaboratory Test CP-CML

(N=270)(%)

AP-CML(N=85)

(%)

BP-CML(N=62)

(%)

Ph+ ALL(N=32)

(%)Hematology

Thrombocytopenia (platelet count decreased)

36 47 57 47

Neutropenia (ANC decreased) 24 51 55 63Leukopenia (WBC decreased) 14 35 53 63Anemia (Hgb decreased) 9 26 55 34

ALT=alanine aminotransferase, AST=aspartate aminotransferase.*Graded using NCI-CTC-AE v 4.0

Table 8: Incidence of Clinically Relevant Non-Hematologic Laboratory AbnormalitiesLaboratory Test Safety Population

N=449Any Grade*

(%)CTCAE Grade 3/4

(%)Liver function tests

ALT increased 53 8AST increased 41 4Alkaline phosphatase increased 37 2Albumin decreased 28 1Bilirubin increased 19 1

Pancreatic enzymesLipase increased 41 15Amylase increased 3 <1

ChemistryGlucose increased 58 6Phosphorus decreased 57 8Calcium decreased 52 1Sodium decreased 29 5Glucose decreased 24 0Potassium decreased 16 2Potassium increased 15 2Sodium increased 10 <1Bicarbonate decreased 11 <1Creatinine increased 7 <1Calcium increased 5 0

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 7).


Palliative Care in Oncology Symposium

Experts Stress the Need for Integrating Palliative Care Into Standard Oncology CareBy Jo Cavallo

The overriding consensus from the 2014 Palliative Care in On-

cology Symposium: Patient-Centered Care Across the Cancer Continuum held in Boston was that achieving op-timal high-quality cancer care requires both state-of-the-art cancer therapy and the integration of palliative care principles throughout the course of a patient’s care to monitor and reduce the physical and psychosocial effects of cancer or its treatment.

Part of the Puzzle“As we strive for optimal care for

our patients throughout the trajecto-ry of illness, we are actively exploring where palliative care in oncology fits as part of the puzzle,” said Michael J. Fisch, MD, MPH, Chair, Depart-ment of General Oncology, Division of Cancer Medicine at The Univer-sity of Texas MD Anderson Cancer Center and Chair of the Palliative Care in Oncology Symposium.

“ASCO leadership had a vision in 2009 that concurrent palliative care and oncology care would become

‘usual’ care by 2020. Thus, ASCO made plans to carve out a sympo-sium that would put palliative oncol-ogy care at center stage,” he added.

Dr. Fisch opened the 2-day sympo-sium with a review of ASCO’s 50-year history and the parallel advancement

of the concept of palliative care for the whole patient, first introduced by Dame Cicely Saunders (founder of the modern hospice movement) in 1964.1 “The first ASCO meeting was in April 1965, with 70 people pres-ent. We have nearly 10-fold that many here in Boston for this inaugural sym-

posium of palliative care in oncology,” said Dr. Fisch. “There is no question that the intersection of several disci-plines in this overlapping and cross-cutting realm that we call palliative oncology is one of great interest and opportunity.”

Diversity of Talent and IdeasThe symposium, which was co-

sponsored by ASCO, the American Academy of Hospice and Palliative Medicine, the American Society for Radiation Oncology, and the Multi-national Association of Supportive Care in Cancer, attracted 700 attend-ees, 119 from outside the United States, and presented 272 abstracts. The greatest number of abstracts dealt with the early integration of palliative care in cancer care (97), followed by end-of-life care (73); patient-reported outcomes, mecha-nisms of symptoms, and treatment toxicities (64); psycho-oncology (21); and survivorship (17).

The abstracts covered research in a range of areas, including the use of a “smart technology” telephone-based symptom management system to monitor and ease patient symp-toms during the final weeks of life2; the financial burden of cancer3,4; the partnership between medical on-cologists and palliative care special-ists to improve patient care; and the prevalence of burnout among pallia-tive care clinicians,5 among others.

The symposium’s program includ-ed sessions in five tracks: • Symptom Science: Mechanisms,

Measurement, Management• Survivorship• Skills for Addressing End-of-Life

Care• Early Integration of Palliative

Care in Cancer Care• Psycho-oncology

“This meeting attracted people who are interested in achieving op-timal ways to deliver cancer care that are individualized to the cir-cumstances and preferences of each patient and family and resonate with the six major aims of health care, as outlined by the Institute of Medi-cine,”6 said Dr. Fisch.

“It will take creativity, courage, and a lot of team science to find the best ways to integrate the prin-ciples and practices of palliative care throughout the trajectory of cancer care. The attendees seem energized by this meeting and, hopefully, in-spired with some new ideas as well as new contacts to enhance team-work and sharing of best practices,” he added.

The diversity and high number of attendees, abstracts presented, and level of enthusiasm generated at the symposium made this inaugural pal-liative care meeting a “tremendous success” said Dr. Fisch. “I especially enjoyed the diversity of attendees, ranging from physicians in cancer specialties, including medical on-cologists, surgeons, and radiation oncologists, to palliative care and hospice, to primary care physicians as well as physicians from other sub-specialties, including geriatrics, car-diology, and others.” n

[Editor’s note: For a complete listing of the study abstracts present-ed at the Palliative Care in Oncology Symposium and to view the presen-tations, visit pallonc.org.]

Disclosure: Drs. Fisch and Kamal reported no potential conflicts of interest.

References1. Saunders C: The symptomatic treat-

ment of incurable malignant disease. Pre-scribers J 4:68-73, 1964.

2. Mooney K, Berry P, Wong B, et al: Helping cancer-family caregivers with end-of-life home symptom management: Initial evaluation of an automated symp-tom monitoring and coaching system. 2014 Palliative Care in Oncology Sym-posium. Abstract 85. Presented October 24, 2014.

3. Whitney RL, Bell J, Reed S, et al: Work and financial disparities among adult cancer survivors in the United States. 2014 Palliative Care in Oncology Symposium.

Recipients of the 2014 Conquer Cancer Foundation of ASCO Merit Awards in Palliative Care HonoredThe following seven recipients of the 2014 Conquer Cancer Foundation of ASCO Merit Awards in Palliative Care were honored at the 2014 Palliative Care in Oncology Symposium for their work in improving the care of people living with cancer around the world.• Erin Alexi, MD, Virginia Commonwealth University: Palliating oncologists: A pilot

study on primary palliative care development in hematology-oncology trainee outpatient clinics (Abstract 21)

• Kenneth Bishop, MD, PhD, Brown University Oncology Group: Perspectives on palliative care in a multisite oncology practice (Abstract 52)

• David Einstein, MD, Tufts Medical Center: Dying for advice: Code-status discus-sions between resident physicians and patients with advanced cancer—A national sur-vey (Abstract 83)

• Neha Gupta, MD, State University of New York at Buffalo: Meta-analysis of trials comparing standard antiemetic treatment with aprepitant containing antiemetic regi-mens for prevention of chemotherapy-induced nausea and vomiting (Abstract 171)

• Carolyn Lefkowits, MD, MPH, Magee-Womens Hospital of UPMC: Change in symptom burden within one day of palliative care consultation in a cohort of gyneco-logic oncology inpatients (Abstract 28)

• Harminder Singh, MD, MBBS, Baba Farid University of Health Sciences, Uni-versity in Faridkot, Punjab, India: Quality of life and adverse drug reaction measured in patients undergoing cancer chemotherapy (Abstract 214)

• Alysson Wann, MBSS, Fellowship of the Royal Australian College of Physician, Syd-ney: Use of targeted therapy in cancer patients in the end-of-life period (Abstract 129)

It will take creativity, courage, and a lot of team science to find the best ways to integrate the principles and practices of palliative care throughout the trajectory of cancer care.

—Michael J. Fisch, MD, MPH

Supportive Care


7 DRUG INTERACTIONS Based on in vitro studies, ponatinib is a substrate of CYP3A 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, coadministration 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 [see Dosage and Administration (2.4)]. Patients taking concomitant strong CYP3A 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 strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin,

and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the risk of decreased ponatinib exposure. Monitor patients for reduced efficacy. Selection of concomitant medication with no or minimal CYP3A induction potential is recommended. In a drug interaction study in healthy volunteers, co-administration of Iclusig following multiple doses of rifampin resulted in decreased ponatinib AUC0-inf and Cmax values by 62% and 42%, respectively [see Clinical Pharmacology (12.3)].

7.3 Drugs That Elevate Gastric pH Iclusig may be co-administered with gastric pH-elevating medications. In a drug interaction

study in healthy volunteers, co-administration of Iclusig following multiple doses of lansoprazole resulted in a minimal (6%) decrease in ponatinib exposure. [see Clinical Pharmacology (12.3)].

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 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 (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy

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%). Forty-six percent of patients ≥ 65 years had vascular occlusion events. Patients of age ≥ 65 years are more likely to experience adverse reactions including vascular occlusion, 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 Administer Iclusig at a dose of 30 mg once daily in patients with hepatic impairment (Child-

Pugh A, B, or C). [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. In a single-dose (30 mg) pharmacokinetic (PK) study; compared to subjects with normal

liver function, no major differences in ponatinib PK were observed in subjects with hepatic impairment (Child-Pugh A, B, or C). However, there was an increased overall incidence of adverse reactions (e.g., gastrointestinal disorders, including a case of severe pancreatitis) in the subjects with hepatic impairment following the single 30 mg dose compared to subjects with normal liver function. The safety of multiple ponatinib doses, or doses higher than 30 mg have not been studied in patients with hepatic impairment.

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)].

10 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 (1-855-552-7423) [email protected]

PB/0314/0074/US(1)

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 Grade 3/4* Hematologic AbnormalitiesLaboratory Test CP-CML

(N=270)(%)

AP-CML(N=85)

(%)

BP-CML(N=62)

(%)

Ph+ ALL(N=32)

(%)Hematology

Thrombocytopenia (platelet count decreased)

36 47 57 47

Neutropenia (ANC decreased) 24 51 55 63Leukopenia (WBC decreased) 14 35 53 63Anemia (Hgb decreased) 9 26 55 34

ALT=alanine aminotransferase, AST=aspartate aminotransferase.*Graded using NCI-CTC-AE v 4.0

Table 8: Incidence of Clinically Relevant Non-Hematologic Laboratory AbnormalitiesLaboratory Test Safety Population

N=449Any Grade*

(%)CTCAE Grade 3/4

(%)Liver function tests

ALT increased 53 8AST increased 41 4Alkaline phosphatase increased 37 2Albumin decreased 28 1Bilirubin increased 19 1

Pancreatic enzymesLipase increased 41 15Amylase increased 3 <1

ChemistryGlucose increased 58 6Phosphorus decreased 57 8Calcium decreased 52 1Sodium decreased 29 5Glucose decreased 24 0Potassium decreased 16 2Potassium increased 15 2Sodium increased 10 <1Bicarbonate decreased 11 <1Creatinine increased 7 <1Calcium increased 5 0

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 7).


Palliative Care in Oncology Symposium

Abstract 238. Presented October 24, 2014.4. Nipp RD, Zullig LL, Samsa G, et al:

Coping with cancer treatment-related fi-nancial burden. 2014 Palliative Care in Oncology Symposium. Abstract 161. Pre-sented October 24, 2014.

5. Kamal A, Bull J, Wolf S, et al: Preva-

lence and predictors of burnout among spe-cialty palliative care clinicians in the United States: Results of a national survey. 2014 Palliative Care in Oncology Symposium. Abstract 87. Presented October 25, 2014.

6. Institute of Medicine: Crossing the Quality Chasm: A New Health System for the 21st Century. March 2001. www.iom.edu. Accessed November 18, 2014.

2015 Palliative Care in Oncology Symposium

October 9–10, Boston

Save the DateIntegrating Palliative Carecontinued from page 85

Don’t Miss These Important

Reports in This Issue of

The ASCO Post

Andrew Evens, DO, MSc, on CAR T-cell therapy see page 32

Felicia Knaul, PhD, on the Harvard Global Equity Initiative see page 41

Visit ASCOPost.com

Carolyn D. Runowicz, MD, on her personal perspective on being an oncologist see page 95


Announcements

The American Society of Hematology Elects New Leadership

The American Society of Hematol-ogy (ASH) recently announced

the election of four new members to its Executive Committee, the govern-ing body of the organization, for terms beginning after the 2014 ASH Annual Meeting, which will be held December 6–9 in San Francisco.

Kenneth C. Anderson, MD, will serve a 1-year term as Vice President, followed by successive terms as Pres-ident-Elect and President. Susan B. Shurin, MD, will serve a 4-year term as Treasurer. Mary C. Dinauer, MD, PhD, and Terry B. Gernsheimer, MD, will both serve 4-year terms as Councillors.

“The field of hematology is chang-ing rapidly around us—from the way we educate trainees to the way we de-liver care at the patient bedside. These changes present opportunities and chal-lenges that must be met by visionary leadership,” said ASH President Linda J. Burns, MD, of the University of Minne-sota. “Drs. Anderson, Shurin, Dinauer, and Gernsheimer bring vast knowledge and diverse experience to address these opportunities and challenges, and we look forward to working with them to help further the Society’s mission to con-quer blood diseases worldwide.”

Kenneth C. Anderson, MDDr. Anderson is Director of the Leb-

ow Institute for Myeloma Therapeutics and the Jerome Lipper Myeloma Cen-ter at Dana-Farber Cancer Institute

in Boston. He also serves as Kraft Fam-ily Professor of Medi-cine and Vice Chair of the Joint Program in Transfusion Medi-cine at Harvard Med-ical School.

Dr. Anderson’s ma-jor fields of interest in-clude the biology and treatment of plasma cell disorders and transfusion. Outside of the laboratory, he is interested in identifying new opportu-nities for mentorship and role models to attract the next generation into hematol-ogy as well as strengthening international leadership to improve the care of patients with blood disorders across the world.

During his more than 15 years of involvement in ASH, Dr. Anderson has served in a variety of Society vol-unteer roles. He currently serves as Executive Editor of Hematology (the ASH Education Program) and served a 4-year term as an ASH councillor from 2010 to 2013.

Susan B. Shurin, MDDr. Shurin is Senior Adviser to the

Center for Global Health of the Na-tional Cancer Institute at the National Institutes of Health (NIH) in Bethes-da, Maryland, working from San Di-ego. Her most recent NIH roles have included Deputy and Acting Direc-tor of the National Heart, Lung, and Blood Institute.

Her fields of interest include nonma-lignant hematologic diseases; pediatric oncology; noncommunicable diseases; and the biology and epidemiology of cardiovascular, pulmonary, and blood diseases. Dr. Shurin has previously served as a member of the ASH Com-mittee on Government Relations and as faculty for the ASH Clinical Research Training Institute.

Mary C. Dinauer, MD, PhDDr. Dinauer is the Fred M. Saigh

Distinguished Chair in Pediatric Re-search and Professor of Pediatrics and of Pathology and Immunology at Wash-ington University School of Medicine in St. Louis. She is also the Scientific Director at the Children’s Discovery In-stitute of Washington University and St. Louis Children’s Hospital.

Dr. Dinauer’s fields of interest in-clude molecular mechanisms of innate immunity, inflammatory responses, and the development and function of white blood cells. Dr. Dinauer currently serves as an Associate Editor of Blood,

the journal of the American Society of Hematology, and she served as a Sci-entific Program Co-Chair of the 2011 ASH Annual Meeting.

Terry B. Gernsheimer, MDDr. Gernsheimer is Medical Di-

rector of the Platelet Immunology Laboratory at Puget Sound Blood Center, Medical Director of Transfu-sion at the Seattle Cancer Care Alli-ance, and Assistant Medical Director of Clinical Transfusion Service at the University of Washington Medical Center. She also serves as Professor of Medicine in the Division of Hematol-ogy and Adjunct Professor of Labo-ratory Medicine at the University of Washington.

Dr. Gernsheimer’s major research interests include platelet immunology and immune platelet disorders, platelet transfusion and hemostasis in hemato-logic malignancies, and hemostasis and transfusion management of the periop-erative patient. She currently serves on the ASH Committee on Practice. n

Kenneth C. Anderson, MD Mary C. Dinauer, MD, PhDSusan B. Shurin, MD Terry B. Gernsheimer, MD

Visit The ASCO Post website at www.ASCOPost.com

News and Views from the World of Clinical Oncology and Hematology


Announcements

ASH Awards New Bridge Grants to Help Alleviate Pain of Federal Funding Cuts

In November, the American Society of Hematology (ASH) announced

the names of seven recipients of its Bridge Grant awards. These 1-year, $150,000 awards provide critical in-terim support for hematology research proposals that, despite earning high scores, could not be funded by the Na-tional Institutes of Health (NIH) amid severe funding reductions. The re-cently announced ASH Bridge Grant award recipients join 44 hematologists who have received funding since ASH committed $9 million in Society funds to create the program in July 2012.

Competititve Funding“Since 2003, congressional appro-

priations for NIH have stagnated and failed to keep pace with inflation. As a result, research dollars have become

much more competitive, and research-ers whose projects might have been funded 5 years ago might not be fund-ed today,” said ASH President Linda J. Burns, MD, of the University of Minnesota. “The ASH Bridge Grant program is designed to help bridge talented hematology investigators to their next NIH research grant by fund-ing their efforts to gather additional data to ultimately strengthen their next application.”

In addition to helping basic, clini-cal, and translational hematology investigators sustain their current re-search projects, another goal of the

ASH Bridge Grant program is to en-sure that recipients remain committed to hematology despite NIH budget austerity. While the program provides short-term relief, continued invest-ment in NIH is necessary to keep U.S. biomedical research moving forward.

“While ASH is fortunate to be able to provide researchers with the resources they desperately require, we hope that lawmakers understand the urgent need to directly invest in research so scientists will not have to worry about whether they can sustain

their projects and staff for another year,” said Dr. Burns.

Wide-Ranging ResearchResearch projects supported by

ASH’s fourth round of Bridge Grants span the breadth of hematology. Fund-

The ASH Bridge Grant program is designed to help bridge talented hematology

investigators to their next NIH research grant by

funding their efforts to gather additional data to

ultimately strengthen their next application.

—Linda J. Burns, MD

25695_clovco_fa2_rash_ASCOpst.indd 1 9/23/14 3:31 PM

We want to change the face of EGFR-targeted therapy

In the treatment of EGFR mutation–positive non–small cell lung cancer (NSCLC), rash and other skin toxicities are well-established side effects of EGFR tyrosine kinase inhibitors.3,4

90% of patients treated with approved EGFR inhibitors experience rash3,4 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.3,4

Rash and its symptoms can negatively affect both patient quality of life and patient compliance, while its psychosocial impact contributes to the assessment of severity.5,6 Beyond the clinical symptom burden, rash visibility can cause significant patient distress even when it is not severe.5

At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals LLC; 2014. 4. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 5. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurse. 2011;15(1):88-96. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed August 26, 2014.

Clovis Oncology is leading the fight

Rash is caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2

Copyright © 2014 Clovis Oncology. DARO-101 8/14



Announcements

ed projects range from exploring the biologic significance of recurrent mu-tations in disease to the impact of ex-ploring the role of natural killer cells in fighting myeloma to studying how stem cell dysfunction can affect chron-ic inflammation.

Lisa Borghesi, PhD, Associate Professor of Immunology at the Uni-

versity of Pittsburgh and one of seven Bridge Grant recipients announced in November, is studying the close rela-tionship between blood cell produc-tion and inflammation. The goal of her research is to better understand the mechanisms regulating blood cell pro-duction after infection. While Dr. Bor-ghesi received a major NIH grant sev-

eral years ago, her latest grant renewal application did not meet the NIH pay-line, despite earning high marks from reviewers.

“The ASH Bridge Grant enables my team to test new ideas and develop new concepts to the fullest potential,” said Dr. Borghesi. “This critical ASH sup-port will not only benefit my research

program, but it will also help advance the career trajectories of my trainees who represent the next generation of innovative scientists.”

Myeloma InvestigatorAmong this next generation of in-

vestigators is Fotis Asimakopoulos, MD, PhD, Assistant Professor of Med-icine at the University of Wisconsin and another recipient of the recently announced ASH Bridge Grants. Dr. Asimakopoulos’ current research fo-cuses on evaluating experimental ther-apies for multiple myeloma.

“My situation is typical among many new investigators: I’m enter-ing a zone of uncertainty between dwindling start-up funds and the need for additional investment,” said Dr. Asimakopoulos. “This is a critical time that will determine my ability to launch into a sustainable, productive, and independent career in science and I am grateful to ASH for helping to support me through this period.”

The awards announced in Novem-ber constitute the last of two rounds of ASH Bridge Grants awarded in 2014. Beyond the Society’s financial commitment that will provide grants to be awarded annually through at least 2015, additional awards will be supplemented by support from corpo-rate and individual contributors. Gen-erous support from individual donors as well as Millenium: The Takeda On-cology Company, Novartis Pharma-ceuticals, and Onyx Pharmaceuticals enabled the Society to award several additional Bridge Grants as part of this fourth round. n

Follow us on

@ASCOPost

The ASCO Post


We want to change the face of EGFR-targeted therapy

In the treatment of EGFR mutation–positive non–small cell lung cancer (NSCLC), rash and other skin toxicities are well-established side effects of EGFR tyrosine kinase inhibitors.3,4

90% of patients treated with approved EGFR inhibitors experience rash3,4 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.3,4

Rash and its symptoms can negatively affect both patient quality of life and patient compliance, while its psychosocial impact contributes to the assessment of severity.5,6 Beyond the clinical symptom burden, rash visibility can cause significant patient distress even when it is not severe.5

At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals LLC; 2014. 4. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 5. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurse. 2011;15(1):88-96. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed August 26, 2014.

Clovis Oncology is leading the fight

Rash is caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2

Copyright © 2014 Clovis Oncology. DARO-101 8/14


http://www.clovisoncology.com


Best of ASCO®

Major Strides Seen This Year in Survivorship CareBy Susan London

“This year was actually a boon for the patient and survivor

care section,” Arif H. Kamal, MD, said at the Best of ASCO meeting in Seattle, where he reviewed the leading abstracts and gave some of his own perspective. “What you see is a lot of the limitations of research in the palliative care and survivor care setting are now being met with [randomized] clinical trials…that are starting to match the evidence level that’s already apparent in all the other [oncology] disease groups. So the evi-dence base is building, and it’s building very quickly.”

Older, Less Costly Drug Controls Nausea and Vomiting

An Italian randomized noninferi-ority trial compared the neurokinin inhibitor aprepitant with the antido-paminergic agent metoclopramide, each combined with dexamethasone, for prevention of delayed nausea and vomiting in patients receiving cispla-tin-containing chemotherapy.1 Meto-clopramide, often used in the United States at lower doses to treat diabetic

gastroparesis, was given at 20 mg four times daily on days 2 to 4. “As long as your patient is not older and does not have a history of Parkinson-type symptoms, you can actually get away with doses like that,” commented Dr. Kamal, who is Director of Quality and Outcomes at the Duke Cancer Insti-tute in Durham, North Carolina.

Results showed no significant dif-ferences between the metoclopramide and aprepitant groups in the rate of complete response (lack of any vom-iting and rescue medication)—82.5% vs 80.3%—or in use of breakthrough

medication, quality of life, or adverse effects. Dr. Kamal estimated that a 30-day prescription of metoclopramide costs roughly $4, whereas two tablets of aprepitant cost $144 to $340.

“The major limitation to this study was that they did not use fosaprepi-tant [Emend] and eliminate aprepi-tant on days 2 and 3, although fosa-prepitant still has a higher cost than metoclopramide. Even if you use fosaprepitant, the antidopaminergic

medications—metoclopramide, olan-zapine, and [haloperidol]—are very, very good as antiemetics and should be used commonly,” he maintained. “Metoclopramide can be considered as a first-line antiemetic, and certainly, if a patient cannot afford a neurokinin inhibitor, should be considered.”

Less Frequent Zoledronic Acid Dosing Is Just as Efficacious

The OPTIMIZE-2 randomized non-inferiority trial compared the bisphos-phonate zoledronic acid given every 4 weeks vs every 12 weeks to patients with bone metastases of breast cancer.2 “These are patients who had been living a long time with advanced disease and who had already received quite a bit of bisphospho-nates up front,” Dr. Kamal commented.

The time to a first skeletal-related event was statistically indistinguishable between treatment groups, at a median of about 1 year. There was also no sig-nificant difference in the rate of skeletal morbidity.

As a result of the findings, “the is-sue of frequency of bisphosphonates or bone-modifying agents is certainly up for question,” Dr. Kamal commented. The trial had methodologic issues, such as the need to drop a placebo arm be-cause of the low accrual and the advent of RANKL inhibitors, he noted. In fact,

a similar denosumab (Xgeva)-based trial is now enrolling patients.3

DHEA With Moisturizer Relieves Vaginal Symptoms

A trial from the Alliance group tested a combination of vaginal dehy-droepiandrosterone (DHEA) and a bioadhesive moisturizer for relieving vaginal symptoms in postmenopausal women treated for breast or gynecolog-ic cancers.4 Patients were randomly as-signed to lower-dose DHEA (3.25 mg) plus moisturizer, higher-dose DHEA (6.5 mg) plus moisturizer, or moistur-izer alone—each applied nightly for 12 weeks. “So this was not [as-needed] use, which is very different from other trials in how they’ve been designed and certainly differently than how it may be clinically given,” Dr. Kamal pointed out.

Results showed significant improve-ments in some sexual function outcomes with lower-dose DHEA and in nearly all of them with the higher dose, relative to moisturizer alone. The products stud-ied are not yet on the market, but in the meantime, “bioadhesive moisturizers, which can be found over the counter—one example is Replens—should be used in patients with sexual dysfunction who are on antihormonal treatments for breast cancer specifically and should be

Discussing Cessation of Medications Near the End of Life

D iscussions with patients and families about stopping non–cancer-relat-ed medications near the end of life are thorny but necessary, according

to Arif H. Kamal, MD, of Duke Cancer Institute, at the Best of ASCO meet-ing in Seattle.

“What’s happening now is that a lot of hospices are having a conversa-tion with patients because of financial reasons. So there is a lot more scrutiny now because of accurately shifting medications to Medicare Part D, which is where a lot of these should be vs being covered by the hospices themselves. Now, hospices have to go through every single medication and either put it on the Part A side, which is the hospital benefit, or the Part D side [the drug benefit], and at the same time indicate whether it is for quality of life or not, and whether it needs to be continued or not, whether it is essential or not,” he explained. “It’s a delicate conversation.”

For example, in patients who have had a pulmonary embolism and are now on heparin or a similar agent, oncologists may need to have a discussion about CHADS2 risk scores (congestive heart failure, hypertension, age, diabetes, and prior stroke, transient ischemic attack, or thromboembolism) and how they apply over various time periods. “I think ultimately if you talk to patients about what their goals are and what’s important to them, and ask them if, by stopping [warfarin], what they’re afraid of, and they say I’m afraid of having a stroke or that kind of thing, then you can address that,” Dr. Kamal said. n

Tapping Palliative Care’s Survival Benefit

A trial reported in 2010 found that adding palliative care to standard care at the time of lung cancer diagnosis prolonged overall survival by an

average of about 2.6 months,1 Arif H. Kamal, MD, told attendees at the Best of ASCO meeting in Seattle. Dr. Kamal is Director of Quality and Outcomes at the Duke Cancer Institute in Durham, North Carolina.

In the reported study, the amount of chemotherapy given did not differ be-tween groups, but the timing did. “If patients got early palliative care, they got just as much, but they got less of it in the last 30 days of life. And that is thought to be why there may be a survival benefit,” he elaborated. Studies comparing palliative care alone with active therapy in lung cancer do show better survival with the latter, he acknowledged. “The models that are being studied are in addition to [standard care], and that’s a huge difference that needs to be under-stood: it’s in addition to, not instead of,” Dr. Kamal stressed. n

Reference1. Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with

metastatic non-small-cell lung cancer. N Engl J Med 363:733-742, 2010.continued on page 92

A lot of the limitations of research in the palliative care and survivor care setting are now being met with [randomized] clinical trials.… [T]he evidence base is building, and it’s building very quickly.

—Arif H. Kamal, MD

Survivorship

Months0 2 4 6 8 10 12

9.2 months(95% CI: 7.1, 10.8)

10.4 months1

(95% CI: 9.3, 13.6)

8.3 months1

(95% CI: 6.3, 10.8)

All responders(n=74)

Patients whoachieved a

CR/CRu

Patients whoachieved a PR

Median DRMedian DR

0 2 4 6 8 10 12

All responders(n=74)

Patients whoachieved a

CR/CRu

Patients whoachieved a PR

FastLess

preparation time

Preparing for IV administration is:

PreciseNo reconstitution

necessary

ConvenientFewer steps

prior to admixing

Indication TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Important Safety InformationContraindication: TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine.

Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. If myelosuppression occurs, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle.

Infections: Infection, including pneumonia, sepsis, septic shock, and death have occurred. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections.

Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly.

Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA.

Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with TREANDA therapy has not been determined.

Extravasation Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA.

Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA.

Most Common Adverse Reactions: The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia.

Please see accompanying brief summary of Full Prescribing Information on the following pages.Learn more at TREANDAHCP.comReference: 1. Data on � le. Teva Pharmaceuticals.

Single-agent TREANDA® (bendamustine HCl) Injection

provided durable responses that lasted a median of 9 months

The ef� cacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

In 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176), the most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%).

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40428 November 2014

NEW—

LIQUID

FORMULA

TION

KJob Number: 20987Revision No: 0Date: 11/06/14

YMC727-40821 Page 1 PRINT

http://treandahcp.com/cll/default.aspx?gclid=CM2ql4fImMICFXBp7AodPDgAtg


Best of ASCO®

used daily or nightly, and for a long pe-riod of time,” Dr. Kamal recommended.

Cardiomyopathy Screening in Childhood Cancer Survivors

A randomized trial among at-risk adult survivors of pediatric malignan-

cies from the Childhood Cancer Sur-vivor Study assessed whether adding counseling by an advanced practice nurse to a printed survivorship care plan improved cardiomyopathy screen-ing.5 The counseling consisted of two telephone motivational interviewing sessions plus two follow-up letters sum-marizing the content.

The patients studied had not had car-diomyopathy screening during the past 5 years. “So these are patients who are not getting very close follow-up support, for example, not participating in any other long-term follow-up program. So this was their major way of having contact with any-thing in survivorship,” Dr. Kamal noted.

At 12 months, 52% of intervention

patients had undergone echocardiog-raphy compared with 22% of control patients (adjusted relative risk = 2.31). “What’s not surprising is that the piece of paper on its own has limited value,” Dr. Kamal commented. “The highlight of this is that the value is still at 52%. So you essentially are putting a lot of resources into survivorship follow-up here for an

Survivorship Carecontinued from page 90

Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176)System organ classPreferred term

Number (%) of patients*All Grades Grade 3/4

Total number of patients with at least1 adverse reaction 176 (100) 94 (53)Cardiac disorders

TachycardiaGastrointestinal disorders

NauseaVomitingDiarrheaConstipationStomatitisAbdominal painDyspepsiaGastroesophageal reflux diseaseDry mouthAbdominal pain upperAbdominal distension

General disorders and administrationsite conditions

FatiguePyrexiaChillsEdema peripheralAstheniaChest painInfusion site painPainCatheter site pain

Infections and infestationsHerpes zosterUpper respiratory tract infectionUrinary tract infectionSinusitisPneumoniaFebrile neutropeniaOral candidiasisNasopharyngitis

InvestigationsWeight decreased

Metabolism and nutrition disordersAnorexiaDehydrationDecreased appetiteHypokalemia


Back painArthralgiaPain in extremityBone pain

Nervous system disordersHeadacheDizzinessDysgeusia

Psychiatric disordersInsomniaAnxietyDepression


CoughDyspneaPharyngolaryngeal painWheezingNasal congestion

Skin and subcutaneous tissue disordersRashPruritusDry skinNight sweatsHyperhidrosis

Vascular disordersHypotension

13 (7)

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

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

18 (10)18 (10)17 (10)15 (9)14 (8)11 (6)11 (6)11 (6)

31 (18)

40 (23)24 (14)22 (13)15 (9)

25 (14)11 (6)8 (5)8 (5)

36 (21)25 (14)13 (7)

23 (13)14 (8)10 (6)

38 (22)28 (16)14 (8)8 (5)8 (5)

28 (16)11 (6)9 (5)9 (5)8 (5)

10 (6)

0

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

00

1 (<1)00

19 (11)3 (2)

01 (<1)4 (2)1 (<1)

000

5 (3)0

4 (2)0

9 (5)11 (6)2 (1)

0

3 (2)

3 (2)8 (5)1 (<1)9 (5)

5 (3)0

2 (1)0

000

01 (<1)

0

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

00

1 (<1)0000

2 (1)*Patients may have reported more than 1 adverse reaction.NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), ele-vated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies

Hematology variablePercent of patients

All Grades Grades 3/4Lymphocytes Decreased 99 94Leukocytes Decreased 94 56Hemoglobin Decreased 88 11Neutrophils Decreased 86 60Platelets Decreased 86 25

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clin-ical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodys-plastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syn-drome and infusion reactions [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly related to TREANDA treat-ment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions (5.5)]10 OVERDOSAGE The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of over-dosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.15 REFERENCES1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]16 HOW SUPPLIED/STORAGE AND HANDLING16.1 Safe Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA con-tacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water.TREANDA is a cytotoxic drug. Follow special handling and disposal procedures1.16.2 How SuppliedTREANDA (bendamustine hydrochloride) Injection is supplied as a 90 mg/mL clear colorless to yellow solution as follows: NDC 63459-395-02: 45 mg/0.5 mL of solution in an amber single-use vialNDC 63459-396-02: 180 mg/2 mL of solution in an amber single-use vialVials are supplied in individual cartons.16.3 StorageTREANDA Injection must be stored refrigerated between 2°-8°C (36°-46°F). Retain in original package until time of use to protect from light.Distributed By:Teva Pharmaceuticals USA, Inc. North Wales, PA 19454TREANDA is a trademark of Cephalon, Inc. or its affiliates.©2008-2014 Cephalon, Inc., a wholly owned subsidiary of Teva Pharma- ceutical Industries Ltd. or its affiliates. All rights reserved. 9/2013(Label Code: 00016287.06)TRE-40361This brief summary is based on TRE-009 TREANDA full Prescribing Information.

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) Injection


727-40821 TRE-40361 Page 3 PRINT Island

Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin Lymphoma That Has Progressed1 INDICATIONS AND USAGE1.2 Non-Hodgkin Lymphoma (NHL)TREANDA® is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.2 DOSAGE AND ADMINISTRATION 2.2 Dosing Instructions for NHLRecommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hema-tologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.2.3 Preparation for Intravenous AdministrationEach vial of TREANDA Injection is intended for single use only. Aseptically with-draw the volume needed for the required dose from the 90 mg/mL solution.Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 - 0.7 mg/mL. The admixture should be a clear colorless to yellow solution.Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. 2.4 Admixture Stability TREANDA Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dex-trose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature 15°-30°C (59°-86°F) and room light. Administration of TREANDA must be completed within this period.3 DOSAGE FORMS AND STRENGTHS TREANDA for Injection is supplied in single-use vials containing either 45 mg/0.5 mL or 180 mg/2 mL of bendamustine HCl.4 CONTRAINDICATIONSTREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)]5 WARNINGS AND PRECAUTIONS 5.1 MyelosuppressionTREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sep-sis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneu-monia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next sched-uled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration (2.2)]5.2 InfectionsInfection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA

are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.5.3 Anaphylaxis and Infusion ReactionsInfusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and cortico-steroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clini-cally appropriate considering individual benefits, risks, and supportive care.5.4 Tumor Lysis SyndromeTumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].5.5 Skin ReactionsSkin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bul-lous exanthema. Some events occurred when TREANDA was given in combi-nation with other anticancer agents. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rit-uximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was admin-istered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in sever-ity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other MalignanciesThere are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. 5.7 Extravasation InjuryTREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intrave-nous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal ToxicityTREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and vis-ceral malformations, and decreased fetal body weights.6 ADVERSE REACTIONSThe following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression (5.1); Infec-tions (5.2); Anaphylaxis and Infusion Reactions (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasation injury (5.7). The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.6.2 Clinical Trials Experience in NHL The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥ 30%) were nausea (75%), fatigue (57%), vomiting (40%), diar-rhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥ 5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

™ TREANDA® (bendamustine hydrochloride) Injection




Best of ASCO®

echocardiogram and you’re still only get-ting to about 50%, which highlights the idea that probably the actual solution to this problem is going to be multimodality and potentially even multiprofessional.”

Palliative Care for Caregivers The randomized ENABLE III trial

compared immediate vs delayed pal-

liative care for family caregivers of patients with advanced cancer.6 In the immediate group, patients had an in-person consult with an advanced practice nurse that the caregiver was welcome to attend; thereafter, nurses conducted telephone-based sessions and follow-up with both. Patients in the delayed group were wait-listed.

“This is actually the first time in the world ever that I am aware of that a family caregiver study using palliative care was actually performed and with this rigor of methodology,” Dr. Kamal noted.

Results showed that relative to wait-listed peers, caregivers in the early palliative care group had better

quality of life, less depression, and lower subjective burden. However, among families in which the patient died, early palliative care did not re-duce depression or grief.

“This is the first trial that shows that [palliative care] does the same thing for families and caregivers as long as they are brought in at the same time as the patient,” Dr. Kamal noted. At his facility, “as a rule we don’t do a lot of palliative care consults—certainly first visits—without having some-body else in the room, such as other caregivers.” n

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

References1. Roila F, Ballatori E, Ruggeri B, et

al: Aprepitant versus metoclopramide, both combined with dexamethasone, for preventing cisplatin-induced delayed em-esis: A randomized, double-blind study. 2014 ASCO Annual Meeting. Abstract 9503.

2. Hortobagyi GN, Lipton A, Chew HK, et al: Efficacy and safety of contin-ued zoledronic acid every 4 weeks versus every 12 weeks in women with bone me-tastases from breast cancer: Results of the OPTIMIZE-2 trial. 2014 ASCO Annual Meeting. Abstract LBA9500.

3. U.S. National Institutes of Health: Prevention of symptomatic skeletal events with denosumab administered every 4 weeks versus every 12 weeks. Available at ClinicalTrials.gov/show/NCT02051218. Accessed November 17, 2014.

4. Barton DL, Sloan JA, Shuster LT, et al: Impact of vaginal dehydroepiand-osterone (DHEA) on vaginal symptoms in female cancer survivors: Trial N10C1 (Alliance). 2014 ASCO Annual Meeting. Abstract 9507.

5. Hudson MM, Leisenring WM, Stratton K, et al: Increasing cardiovas-cular screening in at-risk adult survivors of pediatric malignancies: A random-ized controlled trial. 2014 ASCO Annual Meeting. Abstract 9506.

6. Dionne-Odom JN, Azuero A, Ly-ons K, et al: Benefits of immediate versus delayed palliative care to informal fam-ily caregivers of persons with advanced cancer: Outcomes from the ENABLE III randomized clinical trial. 2014 ASCO Annual Meeting. Abstract LBA9513.

Send Us Your NEWSWrite to [email protected].

All submissions will be considered for publication

Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176)System organ classPreferred term

Number (%) of patients*All Grades Grade 3/4

Total number of patients with at least1 adverse reaction 176 (100) 94 (53)Cardiac disorders

TachycardiaGastrointestinal disorders

NauseaVomitingDiarrheaConstipationStomatitisAbdominal painDyspepsiaGastroesophageal reflux diseaseDry mouthAbdominal pain upperAbdominal distension

General disorders and administrationsite conditions

FatiguePyrexiaChillsEdema peripheralAstheniaChest painInfusion site painPainCatheter site pain

Infections and infestationsHerpes zosterUpper respiratory tract infectionUrinary tract infectionSinusitisPneumoniaFebrile neutropeniaOral candidiasisNasopharyngitis

InvestigationsWeight decreased

Metabolism and nutrition disordersAnorexiaDehydrationDecreased appetiteHypokalemia


Back painArthralgiaPain in extremityBone pain

Nervous system disordersHeadacheDizzinessDysgeusia

Psychiatric disordersInsomniaAnxietyDepression


CoughDyspneaPharyngolaryngeal painWheezingNasal congestion

Skin and subcutaneous tissue disordersRashPruritusDry skinNight sweatsHyperhidrosis

Vascular disordersHypotension

13 (7)

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

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

18 (10)18 (10)17 (10)15 (9)14 (8)11 (6)11 (6)11 (6)

31 (18)

40 (23)24 (14)22 (13)15 (9)

25 (14)11 (6)8 (5)8 (5)

36 (21)25 (14)13 (7)

23 (13)14 (8)10 (6)

38 (22)28 (16)14 (8)8 (5)8 (5)

28 (16)11 (6)9 (5)9 (5)8 (5)

10 (6)

0

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

00

1 (<1)00

19 (11)3 (2)

01 (<1)4 (2)1 (<1)

000

5 (3)0

4 (2)0

9 (5)11 (6)2 (1)

0

3 (2)

3 (2)8 (5)1 (<1)9 (5)

5 (3)0

2 (1)0

000

01 (<1)

0

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

00

1 (<1)0000

2 (1)*Patients may have reported more than 1 adverse reaction.NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), ele-vated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies

Hematology variablePercent of patients

All Grades Grades 3/4Lymphocytes Decreased 99 94Leukocytes Decreased 94 56Hemoglobin Decreased 88 11Neutrophils Decreased 86 60Platelets Decreased 86 25

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clin-ical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodys-plastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syn-drome and infusion reactions [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly related to TREANDA treat-ment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions (5.5)]10 OVERDOSAGE The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of over-dosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.15 REFERENCES1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]16 HOW SUPPLIED/STORAGE AND HANDLING16.1 Safe Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA con-tacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water.TREANDA is a cytotoxic drug. Follow special handling and disposal procedures1.16.2 How SuppliedTREANDA (bendamustine hydrochloride) Injection is supplied as a 90 mg/mL clear colorless to yellow solution as follows: NDC 63459-395-02: 45 mg/0.5 mL of solution in an amber single-use vialNDC 63459-396-02: 180 mg/2 mL of solution in an amber single-use vialVials are supplied in individual cartons.16.3 StorageTREANDA Injection must be stored refrigerated between 2°-8°C (36°-46°F). Retain in original package until time of use to protect from light.Distributed By:Teva Pharmaceuticals USA, Inc. North Wales, PA 19454TREANDA is a trademark of Cephalon, Inc. or its affiliates.©2008-2014 Cephalon, Inc., a wholly owned subsidiary of Teva Pharma- ceutical Industries Ltd. or its affiliates. All rights reserved. 9/2013(Label Code: 00016287.06)TRE-40361This brief summary is based on TRE-009 TREANDA full Prescribing Information.

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) Injection



Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin Lymphoma That Has Progressed1 INDICATIONS AND USAGE1.2 Non-Hodgkin Lymphoma (NHL)TREANDA® is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.2 DOSAGE AND ADMINISTRATION 2.2 Dosing Instructions for NHLRecommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hema-tologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.2.3 Preparation for Intravenous AdministrationEach vial of TREANDA Injection is intended for single use only. Aseptically with-draw the volume needed for the required dose from the 90 mg/mL solution.Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 - 0.7 mg/mL. The admixture should be a clear colorless to yellow solution.Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. 2.4 Admixture Stability TREANDA Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dex-trose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature 15°-30°C (59°-86°F) and room light. Administration of TREANDA must be completed within this period.3 DOSAGE FORMS AND STRENGTHS TREANDA for Injection is supplied in single-use vials containing either 45 mg/0.5 mL or 180 mg/2 mL of bendamustine HCl.4 CONTRAINDICATIONSTREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)]5 WARNINGS AND PRECAUTIONS 5.1 MyelosuppressionTREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sep-sis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneu-monia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next sched-uled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration (2.2)]5.2 InfectionsInfection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA

are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.5.3 Anaphylaxis and Infusion ReactionsInfusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and cortico-steroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clini-cally appropriate considering individual benefits, risks, and supportive care.5.4 Tumor Lysis SyndromeTumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].5.5 Skin ReactionsSkin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bul-lous exanthema. Some events occurred when TREANDA was given in combi-nation with other anticancer agents. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rit-uximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was admin-istered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in sever-ity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other MalignanciesThere are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. 5.7 Extravasation InjuryTREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intrave-nous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal ToxicityTREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and vis-ceral malformations, and decreased fetal body weights.6 ADVERSE REACTIONSThe following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression (5.1); Infec-tions (5.2); Anaphylaxis and Infusion Reactions (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasation injury (5.7). The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.6.2 Clinical Trials Experience in NHL The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥ 30%) were nausea (75%), fatigue (57%), vomiting (40%), diar-rhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥ 5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

™ TREANDA® (bendamustine hydrochloride) Injection




Journal Spotlight

Memorial Sloan Kettering Team Discovery Advances Understanding of Immunotherapy’s Successes—and Its Failures

A collaborative team of leaders in the field of cancer immunology

from Memorial Sloan Kettering Can-cer Center has made a key discovery that advances the understanding of why some patients respond to the CTLA-4 blocking antibody ipilimum-ab (Yervoy), an immunotherapy drug, while others do not.

A report published online first in The New England Journal of Medicine1 shows that in patients who respond to ipilimumab, their cancer cells carry a high num-ber of gene mutations—some of which make tumors more visible to the immune system, and therefore easier to fight. The research was led by Vice Chair of Ra-

diation Oncology and cancer genomics researcher Timothy Chan, MD, PhD, oncology fellow Alexandra Snyder Cha-ren, MD, and Chief of the Melanoma and Immunotherapeutics Service and the Lloyd J. Old Chair for Clinical Investiga-tion Jedd Wolchok, MD, PhD.

“We are learning that there are few treatments that don’t have some foot-print in the cancer genome,” said Dr. Chan. “For the first time, it might be feasible to develop a reliable diagnostic test to help guide treatment decisions by predicting who will respond.”

Practice-Changing DataClinical trials of ipilimumab have

produced practice-changing results for many types of cancer. The drug works by blocking a protein called CTLA-4, boosting the body’s natural immune de-fense against tumors. Normally, CTLA-4 keeps the tumor-fighting activity of the immune system’s T cells in check. In the presence of the drug, T cells are unleashed and their inherent ability to recognize and destroy cancer cells is enhanced.

For some patients, the drug shrinks tumors and significantly prolongs lives. Over the past decade, immunotherapy has signaled a scientific game changer. “We’ve spent much time and effort studying how to target the tumor. And

we’ve only recently understood how to have the patient’s immune defenses mo-bilized to treat the tumor. Immunother-apy is by definition how that happens,” said Dr. Wolchok.

But the approach doesn’t help ev-eryone. In fact, about 80% of people with melanoma get little or no benefit from ipilimumab. And thus far, doctors have had no way of predicting which patients are more likely to respond to the drug.

This new study brings the team one step closer to finding an answer. “There was a correlation between having an el-evated number of mutations, or more DNA changes in a tumor, and benefit-

ting from the treatment with ipilimumab, with benefit being long-term sta-bility or resolution of metastatic dis-ease,” explained Dr. Snyder Charen.

Study MethodologyThe team collected tumor samples

from 64 melanoma patients who had been treated with ipilimumab or treme-limumab, an experimental drug that works in a similar way. The tumors were analyzed by whole-exome sequencing, a method that deciphers DNA changes across all parts of the genome that code for protein. About half of the tumors analyzed came from patients for whom the treatment had been successful and the other half from people who derived little or no benefit from it.

“We found that tumors that had responded to the drug had a higher mutational burden, or overall number of DNA changes,” said Dr. Snyder Cha-ren. “But the correlation isn’t perfect. Not all patients with a high mutational burden in their tumors responded to the drug.”

“This made us ask, ‘What is the im-mune system seeing?’” said Dr. Wolchok. “What is it about the mutational land-scape of a tumor that helps the immune system recognize and attack it?”

Using sophisticated computational tools, the researchers were able to ex-plore their data through the lens of immunology. They found that drug-responsive tumors share a certain type

of mutation that makes cancer cells ex-press new antigens. The collaborative team responsible for these key findings also includes patients.

“These advances would not have been made without the generosity of patients who consented to having their tumor tissue collected and analyzed,” Dr. Snyder Charen concluded. “Dr. Wolchok and his lab members have spent many years banking samples, and it’s an invaluable resource for research.”

Practical ImplicationsEventually, these findings could trans-

late into a diagnostic test to detect the mutations in melanoma patients. Results could help doctors and patients make more-informed treatment choices. In addition, the Memorial Sloan Kettering team plans to investigate whether specific tumor mutations influence the effective-ness of other immunotherapy drugs. Dr. Chan says, “If we know a patient won’t respond to ipilimumab, we may be able to identify other drugs that are more likely to be effective against this person’s tumor.” n

Disclosure: For full disclosures of the study authors, visit www.nejm.org.

Reference1. Snyder A, Makarov V, Merghoub T,

et al: Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. November 19, 2014 (early release online).

Alexandra Snyder Charen, MD

Jedd Wolchok, MD, PhD

Melanoma

Like us on Facebookfacebook.com/TheASCOPost

The ASCO Post

We are learning that there are few treatments that don’t have some footprint in the cancer genome.

—Timothy Chan, MD, PhD


When Life Couldn’t Be BetterBy Carolyn D. Runowicz, MD

J ust imagine a world without cancer!I encountered my first patient

with advanced ovarian cancer during the summer before my second year of medical school. It was the early 1970s. I remember her sitting in a chair, her legs swollen and her abdomen distended with fluid; she was unable to eat. She died a few days later. I was astounded that a disease could be so virulent. This woman never knew the profound impact her disease had on me. She in-fluenced my career choice and commit-ment to care for women with gyneco-logic cancers.

As a first-year medical student, I’d been awarded an American Cancer So-ciety student fellowship to shadow an oncologist. That’s how I met Dr. George C. Lewis, Jr, and Dr. Jim Lee, my first mentors. They radiated an excitement and enthusiasm for their specialty—gynecologic oncology—that was in-fectious and inspirational. They loved being physicians and were never too busy to teach and have me tag along on hospital rounds, the operating room, or

the office. I wanted to be just like them.Later, as a resident at Mount Sinai

Hospital in New York, I joined the De-partment of Obstetrics and Gynecol-ogy led by Dr. Saul Gusberg, a found-ing father of gynecologic oncology. Larger than life, Saul was President of the American Cancer Society, a na-tionally and internationally renowned oncologist. Yet he was always available and never too busy [to talk with me]. We became lifelong colleagues. When he died, at the memorial service, his son stated that I was the daughter that Dr. Gusberg never had. I was so proud.

Progress in Cancer TreatmentAs a resident, I worked under re-

searchers designing and participating in clinical trials using a new drug, cispla-tin. It would prove incredibly effective

in the treatment of ovarian cancer, but it was also terribly toxic. One of my re-sponsibilities was to persuade (at times, cajole) patients to be admitted for treat-ment. At the time, we did not have the arsenal of antinausea agents and other supportive therapies that we have to-day. I recall some patients stating they would rather die than be treated with these toxic drugs.

Vividly remembering that patient from my first summer in medical school, I was sure that cisplatin toxicity was bet-ter than the torment she suffered before she died. Eventually, all the patients agreed to be admitted. I had a growing appreciation and admiration for these strong women. I still shudder when I think of what they went through. The chemotherapy now available for ovar-ian cancer patients and the antinausea and supportive therapies have eradicat-ed this horrible experience.

After my fellowship, I continued on at Mount Sinai for a couple of years as a faculty member, and then I was recruit-ed to Albert Einstein College of Medi-cine and Montefiore Medical Center to develop a division of gynecologic on-

cology and a fellowship program. Train-ing fellows and watching them become leaders in the field are enormously re-warding experiences.

Underserved PopulationIn the Bronx, where Einstein is lo-

cated, patients are very different from those in Manhattan. Generally speak-ing, they are underserved and conse-quently present with much more ad-vanced disease. I recall a 35-year-old patient with advanced cervical cancer that had spread to her lungs. I’d never encountered such advanced gynecolog-ic cancer in a newly diagnosed patient. Such extensive disease is uncommon in the United States. Working in the Bronx was like being in a Third World country.

I reviewed her medical records and realized that she had been told of an “ab-

normal” Pap smear at the birth of her youngest child 7 years earlier. I asked her why she had not accessed the Ein-stein/Montefiore health-care system, which was right in her backyard. She said her priority was taking care of her seven children—providing food, cloth-ing, and shelter. How many times had she visited the pediatrician and emer-gency room for her children? Yet, she didn’t have time for herself.

At her deathbed, she was surround-ed by her children. The oldest was 17 years old and pregnant. I realized that these children would not likely escape the same vicious cycle of poverty. I en-visioned this teenager in 10 years with seven children, neglecting her own health care, just as her mother had done. Ironically, she told me she was having a girl and would name the baby after her mother.

Surviving Breast CancerAt Einstein/Montefiore, we were

able to establish a successful clinical program and fellowship. Just when I thought my life couldn’t be better, I was diagnosed with breast cancer. I was 41.

I was not only an oncologist but also a cancer patient. Because the disease had spread to my lymph nodes, I was treat-ed with chemotherapy, radiation, and tamoxifen. My treatments went from July until the following Memorial Day, a grueling 11 months.

Antinausea therapy and supportive treatments were not yet available. I lost weight and truly looked like a concen-tration camp victim. (My family and friends consistently told me how good I looked.) I thought I was an empathetic and caring physician before I was diag-nosed with cancer, but now I had lived through it all. I developed even more respect for my patients and truly under-stood that those of us who survive feel like survivors. We have won a personal battle against cancer.

Cancer as a Chronic DiseaseWith my cancer behind me, my next

big career challenge was moving to the University of Connecticut School of Medicine to rebuild its cancer program into a multidisciplinary, comprehensive cancer center. During this time, there were many advances in ovarian cancer. Patients began living with the “chronic” disease of ovarian cancer—living for years on che-motherapy. I remember one patient who was diagnosed with ovarian cancer at the time of her cesarean section. This patient is still alive with the disease, intermittent-ly on chemotherapy—and her “baby” is now getting ready for college.

Over my career, I have seen progress in ovarian cancer but few long-term cures. The cure is elusive, but we work on understanding the disease and de-veloping more effective therapies. My first patient with ovarian cancer would most likely have lived a very different life if she had been diagnosed today.

My journey as a patient was not yet over. One weekend night, I found myself short of breath, wheezing, and coughing. I was sure I had very bad bronchitis and just needed antibiot-ics. I went to the emergency room and again entered the world of the patient. A nurse took my pulse and vital signs and immediately moved me to a monitored bed. Everyone around me looked much too serious—not at all what I had an-ticipated for bronchitis.

Finally, the radiologist, a friend of mine, came to my bed and said my chest x-ray looked bad. My first thoughts were that my cancer had recurred and that I had

Reflections

The following essay by Carolyn D. Runowicz, MD, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon.com and thebigcasino.org.

Dr. Runowicz is Professor, Obstetrics and Gynecology, and Executive Associate Dean for Academic Affairs at the Herbert Wert-heim College of Medicine at Florida Inter-national University in Miami.

My hope is that one day, we will think of cancer like we do polio—a historical footnote in medicine.

—Carolyn D. Runowicz, MD


0

10

20

30

40

50

60

70

80

90

100

21 24 27 30 33 36 390 3 6 9 12 15 18

Xofigo median OS:14.9 months(95% CI: 13.9-16.1)

Placebo median OS:11.3 months

(95% CI: 10.4-12.8)


(95% CI: 10.4-12.8)


Median Overall Survival (OS) Was Extended1b

Xofigoc (n=614)Placeboc (n=307)

Time (months)

HR=0.695(95% CI: 0.581-0.832)

Prob

abili

ty o

f sur

viva

l (%

)

60 41 18 7 1 0 0614 578 504 369 277 178 10524 14 7 4 2 1 0307 288 228 157 104 67 39

XofigoPlacebo

EARLIEST ONSETOF SYMPTOMSa

BEST STANDARD OF CARE 30%REDUCED RISK OF DEATH vs PLACEBO PLUS BEST

STANDARD OF CARE1

Give your patient’s standard

EBRT=external beam radiation therapy; OTC=over-the-counter. Not an actual doctor. Model used for illustrative purposes only.a In the ALSYMPCA trial, symptomatic was defined as regular analgesic use, including OTC, or use of EBRT to treat bone pain.

START NOWWITH 6 INJECTIONS OF

• In ALSYMPCA, best standard of care was defined as local EBRT, treatment with glucocorticoids, ketoconazole, or antihormonal agents2

• Xofigo is not recommended in combination with chemotherapy1

XOFIGO® IS INDICATED for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

of care a survival boost1

b An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.1

cPlus best standard of care.1

© 2014 Bayer HealthCare Pharmaceuticals Inc.BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer. PP-600-US-0474 09/14 Printed in USA

• Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman

• Bone Marrow Suppression: In the randomized trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression—notably thrombocytopenia,

neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure

• Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC)should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeksafter the last administration despite receiving supportive care

• Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use


• In a prespecified interim analysis, median overall survival was 14.0 monthsfor Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1

— P=0.00185; 95% CI: 0.552-0.875; HR=0.6951

of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

• Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations

• Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% ofXofigo-treated patients and 63% of placebo-treated

patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)

References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see following pages for brief summary of full Prescribing Information.

To learn more, visit www.xofigo-us.com

THE XOFIGO BOOST 3.6 month increase in median overall survival1

0

10

20

30

40

50

60

70

80

90

100

21 24 27 30 33 36 390 3 6 9 12 15 18



(95% CI: 10.4-12.8)


(95% CI: 10.4-12.8)


Median Overall Survival (OS) Was Extended1b

Xofigoc (n=614)Placeboc (n=307)

Time (months)

HR=0.695(95% CI: 0.581-0.832)

Prob

abili

ty o

f sur

viva

l (%

)

60 41 18 7 1 0 0614 578 504 369 277 178 10524 14 7 4 2 1 0307 288 228 157 104 67 39

XofigoPlacebo

EARLIEST ONSETOF SYMPTOMSa

BEST STANDARD OF CARE 30%REDUCED RISK OF DEATH vs PLACEBO PLUS BEST

STANDARD OF CARE1

Give your patient’s standard

EBRT=external beam radiation therapy; OTC=over-the-counter. Not an actual doctor. Model used for illustrative purposes only.a In the ALSYMPCA trial, symptomatic was defined as regular analgesic use, including OTC, or use of EBRT to treat bone pain.

START NOWWITH 6 INJECTIONS OF

• In ALSYMPCA, best standard of care was defined as local EBRT, treatment with glucocorticoids, ketoconazole, or antihormonal agents2

• Xofigo is not recommended in combination with chemotherapy1

XOFIGO® IS INDICATED for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

of care a survival boost1

b An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.1

cPlus best standard of care.1

© 2014 Bayer HealthCare Pharmaceuticals Inc.BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer. PP-600-US-0474 09/14 Printed in USA

• Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman

• Bone Marrow Suppression: In the randomized trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression—notably thrombocytopenia,

neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure

• Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC)should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeksafter the last administration despite receiving supportive care

• Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use


• In a prespecified interim analysis, median overall survival was 14.0 monthsfor Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1

— P=0.00185; 95% CI: 0.552-0.875; HR=0.6951

of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

• Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations

• Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% ofXofigo-treated patients and 63% of placebo-treated

patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)

References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see following pages for brief summary of full Prescribing Information.

To learn more, visit www.xofigo-us.com

THE XOFIGO BOOST 3.6 month increase in median overall survival1

http://www.xofigo-us.com/index.php

Xofigo (radium Ra 223 dichloride) Injection, for intravenous useInitial U.S. Approval: 2013

BRIEF SUMMARY OF PRESCRIBING INFORMATIONCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGEXofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

2 DOSAGE AND ADMINISTRATION2.3 Instructions for Use/Handling General warningXofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official organization.Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.Radiation protectionThe administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations. For drug handlingFollow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution is recommended to remove contamination.

For patient careWhenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly and separately from other clothing. Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations.The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments.

4 CONTRAINDICATIONSXofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo 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 [see Use in Specific Populations (8.1)].

5 WARNINGS AND PRECAUTIONS5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure.The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in another section of the label:

[see Warnings and Precautions (5.1)]

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) of Xofigo and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4).Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%).Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Xofigo exceeds the incidence for placebo.Table 3: Adverse Reactions in the Randomized Trial System/Organ Class Xofigo (n=600) Placebo (n=301)Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % %Blood and lymphatic system disordersPancytopenia 2 1 0 0Gastrointestinal disordersNausea 36 2 35 2Diarrhea 25 2 15 2Vomiting 19 2 14 2General disorders and administration site conditionsPeripheral edema 13 2 10 1Renal and urinary disordersRenal failure and impairment 3 1 1 1

Laboratory AbnormalitiesTable 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for Xofigo exceeds the incidence for placebo.Table 4: Hematologic Laboratory Abnormalities

Hematologic Xofigo (n=600) Placebo (n=301)Laboratory Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4Abnormalities % % % %Anemia 93 6 88 6Lymphocytopenia 72 20 53 7Leukopenia 35 3 10 <1Thrombocytopenia 31 3 22 <1Neutropenia 18 2 5 <1

Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.Fluid StatusDehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia.

Injection Site ReactionsErythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo.

Secondary Malignant NeoplasmsXofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial.

Subsequent Treatment with Cytotoxic ChemotherapyIn the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONSNo formal clinical drug interaction studies have been performed.

blockers did not affect the safety and efficacy of Xofigo in the randomized clinical trial.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Category X [see Contraindications (4)]Xofigo 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 Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo 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 Xofigo.

8.3 Nursing MothersXofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from Xofigo, 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 UseThe safety and efficacy of Xofigo in pediatric patients have not been established.In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 – 80 kBq (0.541 - 2.16 microcurie) per kg body weight.

8.5 Geriatric UseOf the 600 patients treated with Xofigo in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment

neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data.

8.7 Patients with Renal ImpairmentNo dedicated renal impairment trial for Xofigo has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)].

8.8 Males of Reproductive PotentialContraceptionBecause of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with Xofigo.

InfertilityThere are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGEThere have been no reports of inadvertent overdosing of Xofigo during clinical studies.There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1

1 clinical trial and no dose-limiting toxicities were observed.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityAnimal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action.

17 PATIENT COUNSELING INFORMATIONAdvise patients:

the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections.

treated with Xofigo. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufficiency.

good hygiene practices while receiving Xofigo and for at least 1 week after the last injection in order to minimize radiation exposure from bodily fluids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily fluids to avoid contamination. When handling bodily fluids, wearing gloves and hand washing will protect caregivers.

to use a highly effective method of birth control during treatment and for 6 months following completion of Xofigo treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway

Xofigo is a trademark of Bayer Aktiengesellschaft.© 2013, Bayer HealthCare Pharmaceuticals Inc.All rights reserved.Revised: 05/2013


Book Review

lung metastases. He said, “No, it’s worse.”What is worse than recurrent breast

cancer? Then I learned that I had a car-diomyopathy and was in congestive heart failure. The medical team admit-ted me to the cardiac unit and began treatment that night. I spent the next 2 weeks in that unit.

I went home; it was the middle of a cold and snowy winter. I was not able to

return to work for nearly 4 months while the medications worked on restoring my cardiac function. I was lucky: it came back to almost normal. I take my eight pills a day. I’m back to working and tak-ing care of patients. Taking care of my pa-tients was very important for me to feel that I was truly recovered.

Looking Toward a Bright FutureAbout this same time, I was offered

a new and challenging position as an as-

sociate dean in a new medical school. My doctors gave me the medical clear-ance, and I was off to warmer climes and new challenges.

Although my new position is mostly administrative, it is important for me to see patients at least part-time. I enjoy taking care of them as they embark on their cancer journey. I hope to lighten their burdens.

Training the next generation of physicians is exciting and rewarding.

They are excited about the future that awaits them. Once again, I think back to my summer in medical school and the ovarian cancer patient I met. What lies ahead for these students is likely to be far more exciting, with technologic advances beyond our imagination. My hope is that one day, we will think of cancer like we do polio—a historical footnote in medicine.

Just imagine a world without cancer! n

Carolyn D. Runowicz, MDcontinued from page 95

A Good Life, All the Way to the Very EndBy Ronald Piana

Mortality is the invisible observer in the oncology exam room.

When people hear the three words, “You have cancer,” they see their world as they knew it swiftly passing as they enter the other world of the sick. This human experience was strikingly de-scribed in the opening lines of Susan Sontag’s modern classic, Illness as a Metaphor:

Illness is the night-side of life, a more onerous citizenship. Everyone who is born holds dual citizenship, in the king-dom of the sick. Although we all prefer to use only the good passport, sooner or later each of us is obliged, at least for a spell, to identify ourselves as citizens of that other place.

From Euripides to Sontag, authors have tried to come to understand and demystify illnesses, aging, and mortality. Now, in his deeply affecting new book, Being Mortal, internationally regarded author Atul Gawande, MD, MPH, ex-amines the limitations and missteps in our health-care culture within the ines-capable realities of aging and death. Dur-ing this intense medical literary journey, the reader is introduced to people who know how to have the hard conversa-tions about being mortal, which is one of many reasons this is a valuable book for readers of The ASCO Post.

Key Narrative ThreadThe first few lines of Being Mortal’s in-

troduction speak to one of the disappoint-ments in current medical school curricula, an issue that parallels ongoing discussions in the oncology community over best practices in end-of-life care. Dr. Gawande writes, “I learned a lot of things in medi-cal school, but mortality wasn’t one of them. Although I was given a dry, leathery corpse to dissect my first term, that was solely a way to learn about human anato-my. Our textbooks had almost nothing on

aging or frailty or dying. How the process unfolds, how people experience the end of their lives, and how it affects those around them seemed beside the point.”

Further on, Dr. Gawande makes an-other important observation, one that he will explore throughout the narrative. “Modern scientific capability has pro-foundly altered the course of human life … but scientific advances have turned the process of aging and dying into med-ical experiences, matters to be managed by health-care professionals. And in the medical world, we have proved alarm-ingly unprepared for it.”

That is a serious charge, one that he qualifies within a few pages. “This is a book about mortality—about what it’s like to be creatures who age and die.… I find that neither I nor my patients find our current medical state tolerable. But I have also found it unclear what the an-swers should be, or even whether any ad-equate ones are possible.”

Over the past couple of decades, the on-cology community has been addressing the

state of end-of-life care that Dr. Gawande finds intolerable. For one, the integration of palliative care into best practices along with state-of-the-art psychosocial services has greatly enhanced the quality of care for our patients with advanced cancer. Leaders in the oncology community acknowledge that there is much work ahead in this dif-ficult clinical setting, but the growing quali-ty-of-life data are proof of the advances that have been made.

Being Mortal is as much about the broader cultural issue regarding aging and death as it is about how our medical system deals with mortality. The book consists of eight chapters that use anecdotes from Dr. Gawande’s personal and professional life

to examine various scenarios surrounding mortality. Readers looking for health-care policy discussions about cost-effective end-of-life care won’t find them here. But they won’t be disappointed, either.

Cultural ObservationsDr. Gawande briefly delves into

the debate about “rationing” medical care and the costs of end-of-life care in today’s cost-constrained environ-

ment, but those details are lost within his larger musings on our society that he feels—and rightly so—is decidedly ageist and unwilling to confront the re-alities of mortality.

Dr. Gawande contrasts and com-pares the way we age and die in differ-ent societies, using the experiences of his grandfather, who emigrated from India, and his college girlfriend’s aged grandmother, Alice. He makes some interesting points about cultural differ-ences and how we look at the elderly. He writes, “My father’s father had the kind of traditional old age that, from a Western perspective, seems idyllic.… [W]hen we ate, we served him first. When young people came into his home, they bowed and touched his feet in supplication.… [I]n America, he would almost certainly have been placed in a nursing home.”

Dr. Gawande’s criticism of our rush to institutionalize our elderly has some merit, but his grandfather was a robust man until he died, falling off a bus at the age of 100, and he didn’t fit the stereotype Dr. Gawande was look-ing to make his point. He married his

BookmarkTitle: Being Mortal

Author: Atul Gawande, MD

Publisher: Metropolitan Books

Publication date: October 7, 2014

Price: $26.00; hardcover, 304 pages

This is a book about mortality—about what it’s like to be creatures who age and die.… I find that neither I nor

my patients find our current medical state tolerable. But I have also found it unclear what the answers should be, or

even whether any adequate ones are possible. —Atul Gawande, MD, MPH


Book Review

college girlfriend, and we follow her grandmother, Alice, who by her mid-80s had dementia and multiple co-morbidities, leaving her helplessly frail and vulnerable. She was indeed put into a less-than-optimum nursing home.

We live in an aging society, and many cash-strapped American work-ing families are simply not equipped to handle the difficult care issues of el-derly parents and grandparents who are very sick. Writing about Alice’s nursing home experience, Dr. Gawande com-ments, “All privacy was gone. She was put into hospital clothes most of the time. She woke when they told her. She lived with whomever they said she had to.… [S]he felt incarcerated, like she was in prison for being old.”

Dr. Gawande then cites the sociolo-gist Erving Goffman, who noted the likeness between prisons and nursing

homes a half a century ago in his book Asylums. Some of this is difficult read-ing because we know the vast dispari-ties of medical care that exist between the haves and have-nots in our society, and some nursing homes are indeed depressing and lonely “prisons.”

But placing a loved one in a nursing home is a heartbreaking experience, and Dr. Gawande is at times a bit hard in his judgments. That said, once he gets rolling into more inspiring terri-tory, the book sails along as he follows a hospice nurse on her rounds, a geria-trician in his clinic, and reformers who want to radically change the nursing home model.

Provocative VignettesThis book was never intended to be

a blueprint for policymakers who want to fix broken parts of our health-care system. The power of Being Mortal lies

in the writing and story-telling gifts of Dr. Gawande, as he offers provocative vignettes that drill to the marrow of the human mortality experience.

His candor is also refreshing, as he recounts some of his own mis-guided prejudices about the health-care system. “Like many people, I had believed that hospice care has-tens death, because patients forgo hospital treatments and are allowed high-dose narcotics to combat pain. But multiple studies show other-wise.” The oncology community has long known that earlier initiation of hospice creates better patient and family outcomes.

Being Mortal’s sections on the cancer death journey, exacting and well drawn, will be valuable for the readers of The ASCO Post. “My father was in his early seventies when I was forced to realize that he might not be immortal,” writes

Dr. Gawande, as he introduces some of the book’s most instructive and moving scenes.

His beloved father, a well-known urologist of uncanny vigor, is diagnosed with a spinal cord tumor. After several years of heroic struggling that included surgery and chemotherapy, father and son had the difficult conversation about his prognosis. In the end, after a shared decision-making discussion with his son, Dr. Gawande’s father chose not to have more treatments with their debili-tating side effects. He was ready to face his mortality.

“We went to his bedside. My moth-er took his hand. And we listened, each of us silent.… [N]o more breaths came.” So ends this powerful and en-dearing book about human mortality, something we all share. Being Mortal is a must-read, especially for medical students. n

O Physician, MY PhysicianBy Parvez Dara, MD FACP

Where Art thou O Physician

With comforting smiles Soft touching hands

Your words that soothe And eyes that sympathize

What happened O Physician

With transforming skills A frown is affixed

The hands barely touch Your words are hurried

And eyes barely size

Like a peach O Physician

Once with intricate fuzz And heavenly sweetness Now the texture all gone

The surface all bland You seem empty inside

The student O Physician

With wide opened eyes Filled with human tenderness

Now dons the cap Marketing his promotions

All emotions aside

Where once O Physician

Sleep turned to winks And concern filled the space

Now emptiness games The hardened shelled domain

And yawns the great divide

From thought O Physician

Where purpose once dwelt And concern crafted desire

Now time is the enemy And productivity reigns

With anemic emotions implied

It is time O Physician

To gather your love For all you hold dear

Before your vessel hardens The change gains permanence

And you lose all pride

You are remembered O Physician

For the Hands you hold For the touch to console

For the joy you share Think hard, the journey

And don’t let your pride slide

O Physician My Physician

Let me see within you The love you hold

To nurture and care The desire to heal

Before both our souls are buried in cries


Dr. Dara is an oncologist practicing in Toms River, New Jersey.


Announcements

ASTRO Commends Medicare’s Proposed Decision to Cover Annual Low-Dose CT Screening for High-Risk Lung Cancer Patients Aged 55–74

The American Society for Radia-tion Oncology (ASTRO) praised

the November 11, 2014, decision pro-posal by the Centers for Medicare and Medicaid Services (CMS) to provide coverage for annual lung cancer screen-ing via low-dose computed tomography (CT) screening for those at highest-risk for lung cancer.

According to ASTRO, the Pro-posed Decision Memo for Screen-ing for Lung Cancer with Low Dose Computed Tomography confirms that there is sufficient evidence to warrant annual lung cancer screening for pa-tients most at-risk for developing lung cancer. The Memo details the patient

criteria for eligibility as follows: aged 55 to 74, asymptomatic, a smoking history of at least 30 pack-years, a cur-rent smoker or someone who has quit smoking within the last 15 years. CMS is accepting comments on the rule un-til December 10, 2014, and an effective date is expected in the final coverage decision.

Could Save Thousands of Lives“ASTRO is pleased that CMS has

weighed the evidence and decided in favor of annual screening for patients at highest risk for lung cancer, potentially reducing their lung cancer mortality by nearly 20%,” said ASTRO Chair Bruce G. Haffty, MD, FASTRO. “Lung can-cer is the leading cause of cancer death

for both men and women in the United States, causing the death of more than 160,000 people each year, surpassing the number of deaths from breast, colon and prostate cancers combined. Data

also indicate that nearly 60% of all new lung cancer diagnoses are among those who have never smoked or who have already quit smoking. With this highly effective, annual screening in place, we

will be able to diagnose patients earlier when treatment can be most successful, which will save thousands of lives.”

CMS’s decision follows the United States Preventive Task Force’s Decem-

ASTRO is pleased that CMS has weighed the

evidence and decided in favor of annual screening for patients at highest risk for lung cancer, potentially reducing their lung cancer mortality by nearly 20%.

—Bruce G. Haffty, MD

COBI-54978_M2_UnbrJrnlAd_Isl.indd10-3-2014 10:54 AM Patricia Lopez / John Sysak

Client CodeClient

LiveOverall TrimBleed

# of Colors

COB/092414/0002Genentech/Cobimetinib

6.925” x 9.25”7.3” x 10”8.2” x 10.75”

4C

Colors Cyan, Magenta, Yellow, Black

FontsTrade Gothic LT Std (Bold No. 2, Regular, Oblique, Bold Condensed No. 20)

Job info Fonts & ColorsImages

Saved at

0.29%

from hsplopez5577 by

Printed At

53858_Thumb_Spring_HR.tif (CMYK; 333 ppi; 90%), BioOnc_WM_R_4C.ai (69%), Gene_Logo_KO_T.ai (73.68%)

Notes None

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2

Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

© 2014 Genentech USA, Inc. All rights reserved. COB/092414/0002 Printed in USA.


Announcements

ber 2013 recommendation that low-dose CT is a Grade B screening, and which reviewed the results of four ran-domized clinical trials, including the National Cancer Institute’s National Lung Screening Trial. That study in-cluded more than 50,000 asymptomat-ic adults aged 55 to 75 who had at least a 30 pack-year history and found a 16%

reduction in lung cancer mortality for those who received annual screening and thus, earlier treatment.

ASTRO’s membership includes nearly 11,000 physicians, nurses, bi-ologists, physicists, radiation therapists, dosimetrists and other health-care pro-fessionals who specialize in treating pa-tients with radiation therapies. n


From You

We encourage readers to share their opinions and thoughts on issues of

interest to the oncology community.











HarborsidePress.com


[email protected]



Phone: 631.935.7660


COBI-54978_M2_UnbrJrnlAd_Isl.indd10-3-2014 10:54 AM Patricia Lopez / John Sysak

Client CodeClient

LiveOverall TrimBleed

# of Colors

COB/092414/0002Genentech/Cobimetinib

6.925” x 9.25”7.3” x 10”8.2” x 10.75”

4C

Colors Cyan, Magenta, Yellow, Black

FontsTrade Gothic LT Std (Bold No. 2, Regular, Oblique, Bold Condensed No. 20)

Job info Fonts & ColorsImages

Saved at

0.29%

from hsplopez5577 by

Printed At

53858_Thumb_Spring_HR.tif (CMYK; 333 ppi; 90%), BioOnc_WM_R_4C.ai (69%), Gene_Logo_KO_T.ai (73.68%)

Notes None

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2

Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

© 2014 Genentech USA, Inc. All rights reserved. COB/092414/0002 Printed in USA.


https://www.mapkpathwayinfo.com/?cid=cob_PR_00005108_1


2014-2015 Oncology Meetings 2014-2015DecemberSociety of Urologic Oncology 15th Annual MeetingDecember 3-5 • Bethesda, Maryland For more information: http://suonet.org/meetings/2014/default.aspx

UICC World Cancer CongressDecember 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org

1st Rome International Meeting on Geriatric Oncology December 4-5 • Rome, Italy For more information: www.rimog.com

Advances in Cancer Immunotherapy™December 5 • Tampa, Florida For more information: www.sitcancer.org/sitc-meetings/aci2014/fl

24th World Congress of the International Association of Surgeons, Gastroenterologists and OncologistsDecember 5-7 • Vienna, Austria For more information: iasgo2014.org

ASH Annual Meeting and ExpositionDecember 6-9 • San Francisco, California For more information: hematology.org

37th Annual San Antonio Breast Cancer SymposiumDecember 9-13 • San Antonio, Texas For more information: www.sabcs.org

Inaugural Venous Thromboembolism Symposium: Advances in the Treatment of VTEDecember 13 • Miami, Florida For more information: http://cme.baptisthealth.net/vte/pages/index.aspx

January 2015Melanoma 2015: 25th Annual Cutaneous Malignancy UpdateJanuary 10-11 • San Diego, California For more information: www.scripps.org/events/melanoma-annual-cutaneous-malignancy-update-january-10-2015

7th Breast Gynecological International Cancer ConferenceJanuary 15-16 • Cairo, Egypt For more information: www.bgicc.eg.net/Home.aspx

Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org

13th Oncology Update: Advances and ControversiesJanuary 16-19 • Steamboat Springs, Colorado For more information: www.mdanderson.org

11th Annual Clinical Breakthroughs and Challenges in Hematologic MalignanciesJanuary 17 • Lake Buena Vista, Florida For more information: http://moffitt.org/for-physicians-healthcare-professionals/conferences/conferences

The Society of Thoracic Surgeons 51st Annual MeetingJanuary 24-28 • San Diego, California For more information: www.sts.org/education-meetings/educational-meetings-activities/future-meetings

7th Annual T-cell Lymphoma ForumJanuary 29-31 • San Francisco, California For more information: www.tcellforum.com

February26th International Congress on Anti-Cancer TreatmentFebruary 3-5 • Paris, France For more information: http://www.icact.fr

Translation of the Cancer GenomeFebruary 7-9 • San Francisco, California For more information: www.aacr.org

AACR-SNMMI Joint Conference: State-of-the-Art Molecular Imaging in Cancer Biology and TherapyFebruary 11-14 • San Diego, California For more information: www.aacr.org

2015 BMT Tandem Meeting American Society for Blood and Marrow TransplantationFebruary 11-15 • San Diego, California For more information: www.asbmt.org

5th International Conference on Innovative Approaches in Head & Neck OncologyFebruary 12-14 • Nice, France For more information: www.estro.org/congresses-meetings/items/5th-ichno

15th Annual Targeted Therapies of The Treatment of Lung CancerFebruary 18-21 • Santa Monica, California For more information: www.iaslc.org/events/15th-annual-targeted-therapies-treatment-lung-cancer

The 17th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer ResearchFebruary 19-21 • San Diego, California For more information: www.imedex.com/anti-angiogenesis-and-immune-therapies/

Genitourinary Cancers SymposiumFebruary 26-28 • Orlando, Florida For more information: www.gucasym.org

6th Current Concepts in the Management of Thyroid and Parathyroid NeoplasmsFebruary 26-28 • Houston, Texas For more information: www.mdanderson.org

32nd Annual Miami Breast Cancer Conference®February 26-March 1 • Miami Beach, Florida For more information: www.gotoper.com/conferences/mbcc/meetings/32nd-Annual-Miami-Breast-Cancer-Conference

Society of Interventional RadiologyFebruary 28-March 5 • Atlanta, Georgia For more information: www.sirmeeting.org

March

13th International Congress on Targeted Anticancer TherapiesMarch 2-4 • Paris, France For more information: www.tatcongress.org

Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to BiomarkersMarch 5-8 • Orlando, Florida For more information: www.aacr.org

16th European Congress: Perspectives in Lung CancerMarch 6-7 • Torino, Italy For more information: www.imedex.com

Advances in the Management of Multiple MyelomaMarch 6-7 • Saint Petersburg, Florida For more information: http://moffitt .org/for-physicians-healthcare-professionals/conferences/conferences


Fonts: Helvetica Neue LT StdImages: BIG3_Cross Indication.eps (CMYK; 600 ppi; Bloc_GS:Celgene:Abraxane:ABX:A...R2:Links:BIG3_Cross Indication.eps), Indications.ai (Bloc_GS:Celgene:Abraxane:ABX:A...d_Big3_KingAd:Links:Indications.ai), Abrax Logo_4C_NoBlue.eps (Bloc_Images:Celgene:Abraxane_Logos:Abrax Logo_4C_NoBlue.eps)

ABX13338_NSCLC_Ad_Big3_3pg_DR.indd Amy Kortman

app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________

Print Scale: 100%Ink Density: 300%

Bleed: 10.75" x 14.25"Trim: 10.5" x 14"Safety: 9.5" x 13"

Folded Size: NoneGutter: NoneScale: 1" = 1"

Colors: Cyan Magenta Yellow Black

GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE

Job Description: Launch Ad -

KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

indications

CONTRAINDICATIONS

Neutrophil Counts• ABRAXANE should not be used in patients who have baseline neutrophil

counts of <1500 cells/mm3

Hypersensitivity• Patients who experience a severe hypersensitivity reaction to ABRAXANE

should not be rechallenged with the drug


Hematologic Effects• Bone marrow suppression (primarily neutropenia) is dose-dependent and a

dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non–small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

WARNING - NEUTROPENIA

• Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

ABRAXANE is indicated for the � rst-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

ABRAXANE is indicated for the � rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.


ignited we stand with

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.


9js

28344a1 07.10.14 133

Q1 Q2

S:9.5”

S:13”

T:10.5”

T:14”

B:10.75”

B:14.25”

Fonts: Helvetica Neue LT StdImages: BIG3_Cross Indication.eps (CMYK; 600 ppi; Bloc_GS:Celgene:Abraxane:ABX:A...R2:Links:BIG3_Cross Indication.eps), Indications.ai (Bloc_GS:Celgene:Abraxane:ABX:A...d_Big3_KingAd:Links:Indications.ai), Abrax Logo_4C_NoBlue.eps (Bloc_Images:Celgene:Abraxane_Logos:Abrax Logo_4C_NoBlue.eps)


app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________





GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

indications

CONTRAINDICATIONS

Neutrophil Counts• ABRAXANE should not be used in patients who have baseline neutrophil

counts of <1500 cells/mm3

Hypersensitivity• Patients who experience a severe hypersensitivity reaction to ABRAXANE

should not be rechallenged with the drug


Hematologic Effects• Bone marrow suppression (primarily neutropenia) is dose-dependent and a

dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non–small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

WARNING - NEUTROPENIA

• Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

ABRAXANE is indicated for the � rst-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

ABRAXANE is indicated for the � rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.


ignited we stand with

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.


9js

28344a1 07.10.14 133

Q1 Q2

S:9.5”S:13”

T:10.5”T:14”

B:10.75”B

:14.25”

http://www.abraxane.com/hcp/

Fonts: Helvetica Neue LT StdImages: Cross Indication_paralax_colorshift_AD3.psd (CMYK; 236 ppi, 221 ppi; Bloc_GS:Celgene:Abraxane:ABX:A...ication_paralax_colorshift_AD3.psd), Celgene_logo_KO.eps (Bloc_GS:Celgene:Abraxane:ABX:A...3_KingAd:Links:Celgene_logo_KO.eps), Abrax Logo_KO_4C_YellowBall_noblue.eps (Bloc_Images:Celgene:Abraxane_L...x Logo_KO_4C_YellowBall_noblue.eps), NSCLC_Ad_Chart3_3pg_AD1.ai (Bloc_GS:Celgene:Abraxane:ABX:A...d:Links:NSCLC_Ad_Chart3_3pg_AD1.ai), NSCLC_Ad_Chart2_AD4.ai (Bloc_GS:Celgene:Abraxane:ABX:A...ingAd:Links:NSCLC_Ad_Chart2_AD4.ai)


app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________





GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

Other

7/29

24%

5/33

15%

0

5

10

15

20

25

30

35

40

45

50

Large cell carcinoma

2/13

15%

3/9

33%

OR

R (%

)

Carcinoma/adenocarcinoma

27%

71/264

26%

66/254

Squamous cell carcinoma

94/229

41%

24%

54/221

ABRAXANE + carboplatin Paclitaxel injection + carboplatin

ORR by histology in the phase 3 NSCLC trial

ORR (%) ITT=intent-to-treat; ORR=overall response rate.a P value based on chi-square test.

There was no statistically significant difference in overall survival between the 2 study arms.

Primary end point: First-line ABRAXANE + carboplatin significantly improved ORR in the phase 3 NSCLC trial (ITT population)

P=0.005a

n=521

n=531

ABRAXANE + carboplatin

33% (170/521) 95% CI: 28.6%-36.7%

Paclitaxel injection + carboplatin

25% (132/531) 95% CI: 21.2%-28.5%

0 5 10 15 20 25 30 35 40 45 50

Important Safety Information (cont’d)

WARNINGS AND PRECAUTIONS (cont’d)• Monitor for myelotoxicity by performing complete blood cell

counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer)

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3

• In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC

• In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3

• In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle

• In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended

Nervous System• Sensory neuropathy is dose- and schedule-dependent

• The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modi� cation

• If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE

Sepsis

• Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine

• Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis

• If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics

• For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels

Pneumonitis• Pneumonitis, including some cases that were fatal,

occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine

• Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis

• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis

Hypersensitivity• Severe and sometimes fatal hypersensitivity reactions,

including anaphylactic reactions, have been reported• Patients who experience a severe hypersensitivity reaction to

ABRAXANE should not be rechallenged with this drugHepatic Impairment• Because the exposure and toxicity of paclitaxel can be

increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution

• For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment

• For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment

Albumin (Human)• ABRAXANE contains albumin (human), a derivative of

human blood Use in Pregnancy: Pregnancy Category D• ABRAXANE can cause fetal harm when administered to a

pregnant woman • If this drug is used during pregnancy, or if the patient

becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE

Use in Men• Men should be advised not to father a child while

receiving ABRAXANE

ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study• The most common adverse reactions (≥20%) with single-

agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively

• Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients

• Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), � uid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported

• Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)

• In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)

• Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension

• Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported

Please see next page for adverse events in the NSCLC study.

Pancreatic Adenocarcinoma Study• Among the most common (≥20%) adverse reactions in

the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)

• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group

• The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)

• Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%),

arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)

• Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations• Severe and sometimes fatal hypersensitivity reactions have

been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied

• There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs

• There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible in� ltration during drug administration

DRUG INTERACTIONS• Caution should be exercised when administering ABRAXANE

concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

USE IN SPECIFIC POPULATIONSNursing Mothers• It is not known whether paclitaxel is excreted in human

milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Pediatric • The safety and effectiveness of ABRAXANE in pediatric

patients have not been evaluatedGeriatric• No toxicities occurred notably more frequently among

patients ≥65 years of age who received ABRAXANE for MBC• Myelosuppression, peripheral neuropathy, and arthralgia

were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC

• Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas

Renal Impairment• The use of ABRAXANE has not been studied in patients with

renal impairment

DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended

for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN

• For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN

• Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity

• Monitor patients closely

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium®): Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

• The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue

• The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)

• The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin–treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group

• Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively

• Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively

• Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

ABRAXANE® is indicated for the fi rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

signifi cantly superior ORR in fi rst-line ITT population with advanced NSCLC

STUDY DESIGN • Multicenter 1:1 randomized, phase 3

study comparing ABRAXANE (100 mg/m2 IV; Days 1, 8, and 15 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) with paclitaxel injection (200 mg/m2 IV, Day 1 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) in 1052 chemonaïve patients with advanced NSCLC

41% ORR in squamous patients

A National Comprehensive Cancer Network® (NCCN®) Category 1 recommendation1,2,b,c

b First-line albumin-bound paclitaxel (ABRAXANE) + carboplatin is recommended for PS 0-1 patients with advanced NSCLC of negative or unknown EGFR mutation and ALK status.

c Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PS=performance status.

CATEGORY 1

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.For more information, please visit www.abraxane.com.ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 06/14 US-ABR140034

Adverse events in the NSCLC study


9js

28344a1 07.10.14 133

Q1 Q2

S:20”

S:13”

T:21”

T:14”

B:21.25”

B:14.25”

Fonts: Helvetica Neue LT StdImages: Cross Indication_paralax_colorshift_AD3.psd (CMYK; 236 ppi, 221 ppi; Bloc_GS:Celgene:Abraxane:ABX:A...ication_paralax_colorshift_AD3.psd), Celgene_logo_KO.eps (Bloc_GS:Celgene:Abraxane:ABX:A...3_KingAd:Links:Celgene_logo_KO.eps), Abrax Logo_KO_4C_YellowBall_noblue.eps (Bloc_Images:Celgene:Abraxane_L...x Logo_KO_4C_YellowBall_noblue.eps), NSCLC_Ad_Chart3_3pg_AD1.ai (Bloc_GS:Celgene:Abraxane:ABX:A...d:Links:NSCLC_Ad_Chart3_3pg_AD1.ai), NSCLC_Ad_Chart2_AD4.ai (Bloc_GS:Celgene:Abraxane:ABX:A...ingAd:Links:NSCLC_Ad_Chart2_AD4.ai)


app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________





GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

Other

7/29

24%

5/33

15%

0

5

10

15

20

25

30

35

40

45

50

Large cell carcinoma

2/13

15%

3/9

33%

OR

R (%

)

Carcinoma/adenocarcinoma

27%

71/264

26%

66/254

Squamous cell carcinoma

94/229

41%

24%

54/221

ABRAXANE + carboplatin Paclitaxel injection + carboplatin

ORR by histology in the phase 3 NSCLC trial

ORR (%) ITT=intent-to-treat; ORR=overall response rate.a P value based on chi-square test.

There was no statistically significant difference in overall survival between the 2 study arms.

Primary end point: First-line ABRAXANE + carboplatin significantly improved ORR in the phase 3 NSCLC trial (ITT population)

P=0.005a

n=521

n=531

ABRAXANE + carboplatin

33% (170/521) 95% CI: 28.6%-36.7%

Paclitaxel injection + carboplatin

25% (132/531) 95% CI: 21.2%-28.5%

0 5 10 15 20 25 30 35 40 45 50

Important Safety Information (cont’d)

WARNINGS AND PRECAUTIONS (cont’d)• Monitor for myelotoxicity by performing complete blood cell

counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer)

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3

• In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC

• In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3

• In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle

• In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended

Nervous System• Sensory neuropathy is dose- and schedule-dependent

• The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modi� cation

• If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE

Sepsis

• Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine

• Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis

• If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics

• For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels

Pneumonitis• Pneumonitis, including some cases that were fatal,

occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine

• Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis

• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis

Hypersensitivity• Severe and sometimes fatal hypersensitivity reactions,

including anaphylactic reactions, have been reported• Patients who experience a severe hypersensitivity reaction to

ABRAXANE should not be rechallenged with this drugHepatic Impairment• Because the exposure and toxicity of paclitaxel can be

increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution

• For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment

• For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment

Albumin (Human)• ABRAXANE contains albumin (human), a derivative of

human blood Use in Pregnancy: Pregnancy Category D• ABRAXANE can cause fetal harm when administered to a

pregnant woman • If this drug is used during pregnancy, or if the patient

becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE

Use in Men• Men should be advised not to father a child while

receiving ABRAXANE

ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study• The most common adverse reactions (≥20%) with single-

agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively

• Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients

• Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), � uid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported

• Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)

• In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)

• Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension

• Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported

Please see next page for adverse events in the NSCLC study.

Pancreatic Adenocarcinoma Study• Among the most common (≥20%) adverse reactions in

the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)

• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group

• The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)

• Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%),

arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)

• Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations• Severe and sometimes fatal hypersensitivity reactions have

been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied

• There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs

• There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible in� ltration during drug administration

DRUG INTERACTIONS• Caution should be exercised when administering ABRAXANE

concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

USE IN SPECIFIC POPULATIONSNursing Mothers• It is not known whether paclitaxel is excreted in human

milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Pediatric • The safety and effectiveness of ABRAXANE in pediatric

patients have not been evaluatedGeriatric• No toxicities occurred notably more frequently among

patients ≥65 years of age who received ABRAXANE for MBC• Myelosuppression, peripheral neuropathy, and arthralgia

were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC

• Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas

Renal Impairment• The use of ABRAXANE has not been studied in patients with

renal impairment

DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended

for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN

• For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN

• Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity

• Monitor patients closely

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium®): Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

• The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue

• The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)

• The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin–treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group

• Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively

• Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively

• Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

ABRAXANE® is indicated for the fi rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

signifi cantly superior ORR in fi rst-line ITT population with advanced NSCLC

STUDY DESIGN • Multicenter 1:1 randomized, phase 3

study comparing ABRAXANE (100 mg/m2 IV; Days 1, 8, and 15 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) with paclitaxel injection (200 mg/m2 IV, Day 1 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) in 1052 chemonaïve patients with advanced NSCLC

41% ORR in squamous patients

A National Comprehensive Cancer Network® (NCCN®) Category 1 recommendation1,2,b,c

b First-line albumin-bound paclitaxel (ABRAXANE) + carboplatin is recommended for PS 0-1 patients with advanced NSCLC of negative or unknown EGFR mutation and ALK status.

c Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PS=performance status.

CATEGORY 1

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.For more information, please visit www.abraxane.com.ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 06/14 US-ABR140034

Adverse events in the NSCLC study


9js

28344a1 07.10.14 133

Q1 Q2

S:20”S:13”

T:21”T:14”

B:21.25”B

:14.25”

Fonts: NoneImages: ABRAXANE_3_King_Brief Summary_012714.pdf (Bloc_GS:Celgene:Abraxane:ABX:A...NE_3_King_Brief Summary_012714.pdf)

ABX13338_NSCLC_Ad_Big3_3pg_DR.indd Amy Kortmanap

pro

vals

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________




Colors: Black GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

The following is a Brief Summary; refer to full Prescribing Information for complete productinformation.

1 INDICATIONS AND USAGE1.1 Metastatic Breast CancerABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapyfor metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy shouldhave included an anthracycline unless clinically contraindicated.1.2 Non-Small Cell Lung CancerABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small celllung cancer, in combination with carboplatin, in patients who are not candidates for curative surgeryor radiation therapy.1.3 Adenocarcinoma of the PancreasABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of thepancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION2.1 Metastatic Breast CancerAfter failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months ofadjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administeredintravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung CancerThe recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 daycycle immediately after ABRAXANE [see Clinical Studies (14.2)].2.3 Adenocarcinoma of the PancreasThe recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately afterABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].2.4 Dosage in Patients with Hepatic ImpairmentNo dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderateand severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities knownto paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations fordosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2

in patients with severe hepatic impairment in subsequent cycles based on individual tolerance.For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severehepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 astolerated. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) andClinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic ImpairmentSGOT (AST) Bilirubin ABRAXANE Dosea

Levels LevelsMBC NSCLCc Pancreaticc

AdenocarcinomaMild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2

≤ 1.25 x ULNModerate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not

2 x ULN recommendedSevere < 10 x ULN AND 2.01 to 130 mg/m2 b 50 mg/m2 not

5 x ULN recommended> 10 x ULN OR > 5 x ULN not not not

recommended recommended recommendedMBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer.a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in

subsequent courses should be based on individual tolerance.b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual

tolerance.c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials forpancreatic or lung cancer.

2.5 Dose Reduction/Discontinuation RecommendationsMetastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severesensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequentcourses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additionaldose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment untilresolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least

1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

• In patients who develop severe neutropenia or thrombocytopenia withhold treatment until countsrecover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 andplatelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption ofdosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.

• Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin atreduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completelyresolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLCWeekly Every 3-Week

Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL)

Neutropenic Fever (ANC less than500/mm3 with fever >38°C) First 75 4.5

ORDelay of next cycle by more than7 days for ANC less than 1500/mm3 Second 50 3

ORANC less than 500/mm3 for morethan 7 days

Third Discontinue Treatment

Platelet count less than 50,000/mm3 First 75 4.5 Second Discontinue Treatment

Severe sensory Neuropathy – First 75 4.5Grade 3 or 4 Second 50 3


Adenocarcinoma of the PancreasDose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the PancreasDose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2)Full dose 125 10001st dose reduction 100 8002nd dose reduction 75 600If additional dose reductionrequired Discontinue Discontinue

Recommended dose modifications for neutropenia and thrombocytopenia for patients withadenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas

Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / GemcitabineDay 1 < 1500 OR < 100,000 Delay doses until recoveryDay 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level

< 500 OR < 50,000 Withhold dosesDay 15: IF Day 8 doses were reduced or given without modification:

500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8< 500 OR < 50,000 Withhold doses

Day 15: IF Day 8 doses were withheld:≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1< 500 OR < 50,000 Withhold doses

Abbreviations: ANC = Absolute Neutrophil Count.Recommended dose modifications for other adverse drug reactions in patients with adenocarcinomaof the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas

Adverse Drug Reaction ABRAXANE Gemcitabine Febrile Neutropenia: Withhold until fever resolves and ANC ≥ 1500; resume at

Grade 3 or 4 next lower dose levelPeripheral Neuropathy: Withhold until improves to

Grade 3 or 4 ≤ Grade 1; resume at next No dose reductionlower dose level

Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatmentGrade 2 or 3 if toxicity persists

Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume atGrade 3 mucositis or diarrhea next lower dose level

4 CONTRAINDICATIONS• ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged

with the drug.5 WARNINGS AND PRECAUTIONS

5.1 Hematologic EffectsBone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity ofABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastaticbreast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patientswith pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior todosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do notadminister ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patientswith either MBC or NSCLC.In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recoversto a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2)at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANCrecovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to anANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of thecycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC isless than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the nextcycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 ofthe cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage andAdministration (2.5)].

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than

1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarilyneutropenia, which may be severe and result in infection, it is recommended that frequentperipheral blood cell counts be performed on all patients receiving ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relativeto those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXELFORMULATIONS.

5.2 Nervous SystemSensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. Theoccurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage andAdministration (2.5)].5.3 SepsisSepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combinationwith gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatalsepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrumantibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].5.4 PneumonitisPneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANEin combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis andinterrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling outinfectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatmentwith ABRAXANE and gemcitabine.5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have beenreported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not bere-challenged with this drug.5. 6 Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased with hepatic impairment,administration of ABRAXANE in patients with hepatic impairment should be performed with caution.The starting dose should be reduced for patients with moderate or severe hepatic impairment [seeDosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].5.7 Albumin (Human)ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donorscreening and product manufacturing processes, it carries a remote risk for transmission of viraldiseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is consideredextremely remote. No cases of transmission of viral diseases or CJD have ever been identified foralbumin.5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxelprotein-bound particles to rats during pregnancy at doses lower than the maximum recommendedhuman dose, based on body surface area, caused embryofetal toxicities, including intrauterinemortality, increased resorptions, reduced numbers of live fetuses, and malformations.There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If thisdrug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, thepatient should be apprised of the potential hazard to the fetus. Women of childbearing potentialshould be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in SpecificPopulations (8.1)].5.9 Use in MenMen should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology(13.1)].

6 ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastaticbreast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia,myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, anddiarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin fornon-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy,nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions ofABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) andpneumonia (3%). The most common adverse reactions resulting in permanent discontinuation ofABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). Themost common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%),thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading towithholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), andanemia (16%).In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreaticadenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5%higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy,nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, anddehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higherincidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The mostcommon adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheralneuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactionsresulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%).The most common adverse reactions leading to withholding or delay in ABRAXANE dosing areneutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia(5%) and diarrhea (5%).6.1 Clinical Trials Experience in Metastatic Breast CancerTable 6 shows the frequency of important adverse events in the randomized comparative trial for thepatients who received either single-agent ABRAXANE or paclitaxel injection for the treatment ofmetastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized MetastaticBreast Cancer Study on an Every-3-Weeks Schedule

Percent of PatientsABRAXANE Paclitaxel Injection

260 mg/m2 over 30 min 175 mg/m2 over 3 hb

(n=229) (n=225)Bone Marrow

Neutropenia< 2.0 x 109/L 80 82< 0.5 x 109/L 9 22

Thrombocytopenia< 100 x 109/L 2 3< 50 x 109/L <1 <1

Anemia < 11 g/dL 33 25< 8 g/dL 1 <1

Infections 24 20Febrile Neutropenia 2 1Neutropenic Sepsis <1 <1Bleeding 2 2

Hypersensitivity Reactionc

All 4 12Severed 0 2

CardiovascularVital Sign Changes DuringAdministration

Bradycardia <1 <1Hypotension 5 5

Severe Cardiovascular Eventsd 3 4Abnormal ECG

All Patients 60 52Patients with Normal Baseline 35 30

RespiratoryCough 7 6Dyspnea 12 9

Sensory NeuropathyAny Symptoms 71 56Severe Symptomsd 10 2

Myalgia / ArthralgiaAny Symptoms 44 49Severe Symptomsd 8 4

AstheniaAny Symptoms 47 39Severe Symptomsd 8 3

Fluid Retention/EdemaAny Symptoms 10 8Severe Symptomsd 0 <1

GastrointestinalNausea

Any Symptoms 30 22Severe Symptomsd 3 <1

VomitingAny Symptoms 18 10Severe Symptomsd 4 1

DiarrheaAny Symptoms 27 15Severe Symptomsd <1 1

MucositisAny Symptoms 7 6Severe Symptomsd <1 0

Alopecia 90 94Hepatic (Patients with NormalBaseline)

Bilirubin Elevations 7 7Alkaline Phosphatase Elevations 36 31AST (SGOT) Elevations 39 32

Injection Site Reaction <1 1a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication.c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain,

hypotension) that began on a day of dosing.d Severe events are defined as at least grade 3 toxicity.

Adverse Event Experiences by Body SystemHematologic DisordersNeutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in therandomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patientstreated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a doseof 175 mg/m2. Pancytopenia has been observed in clinical trials.InfectionsInfectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis,respiratory tract infections and pneumonia were the most frequently reported infectiouscomplications.



9js

28344a1 07.10.14 133

Q1 Q2

S:20”

S:13”

T:21”

T:14”

B:21.25”

B:14.25”



app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________




Colors: Black GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1


The following is a Brief Summary; refer to full Prescribing Information for complete productinformation.

1 INDICATIONS AND USAGE1.1 Metastatic Breast CancerABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapyfor metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy shouldhave included an anthracycline unless clinically contraindicated.1.2 Non-Small Cell Lung CancerABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small celllung cancer, in combination with carboplatin, in patients who are not candidates for curative surgeryor radiation therapy.1.3 Adenocarcinoma of the PancreasABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of thepancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION2.1 Metastatic Breast CancerAfter failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months ofadjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administeredintravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung CancerThe recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 daycycle immediately after ABRAXANE [see Clinical Studies (14.2)].2.3 Adenocarcinoma of the PancreasThe recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately afterABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].2.4 Dosage in Patients with Hepatic ImpairmentNo dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderateand severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities knownto paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations fordosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2

in patients with severe hepatic impairment in subsequent cycles based on individual tolerance.For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severehepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 astolerated. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) andClinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic ImpairmentSGOT (AST) Bilirubin ABRAXANE Dosea

Levels LevelsMBC NSCLCc Pancreaticc

AdenocarcinomaMild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2

≤ 1.25 x ULNModerate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not

2 x ULN recommendedSevere < 10 x ULN AND 2.01 to 130 mg/m2 b 50 mg/m2 not

5 x ULN recommended> 10 x ULN OR > 5 x ULN not not not

recommended recommended recommendedMBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer.a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in

subsequent courses should be based on individual tolerance.b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual

tolerance.c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials forpancreatic or lung cancer.

2.5 Dose Reduction/Discontinuation RecommendationsMetastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severesensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequentcourses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additionaldose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment untilresolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least

1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

• In patients who develop severe neutropenia or thrombocytopenia withhold treatment until countsrecover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 andplatelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption ofdosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.

• Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin atreduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completelyresolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLCWeekly Every 3-Week

Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL)

Neutropenic Fever (ANC less than500/mm3 with fever >38°C) First 75 4.5

ORDelay of next cycle by more than7 days for ANC less than 1500/mm3 Second 50 3

ORANC less than 500/mm3 for morethan 7 days


Platelet count less than 50,000/mm3 First 75 4.5 Second Discontinue Treatment

Severe sensory Neuropathy – First 75 4.5Grade 3 or 4 Second 50 3


Adenocarcinoma of the PancreasDose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the PancreasDose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2)Full dose 125 10001st dose reduction 100 8002nd dose reduction 75 600If additional dose reductionrequired Discontinue Discontinue

Recommended dose modifications for neutropenia and thrombocytopenia for patients withadenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas

Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / GemcitabineDay 1 < 1500 OR < 100,000 Delay doses until recoveryDay 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level

< 500 OR < 50,000 Withhold dosesDay 15: IF Day 8 doses were reduced or given without modification:

500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8< 500 OR < 50,000 Withhold doses

Day 15: IF Day 8 doses were withheld:≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1< 500 OR < 50,000 Withhold doses

Abbreviations: ANC = Absolute Neutrophil Count.Recommended dose modifications for other adverse drug reactions in patients with adenocarcinomaof the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas

Adverse Drug Reaction ABRAXANE Gemcitabine Febrile Neutropenia: Withhold until fever resolves and ANC ≥ 1500; resume at

Grade 3 or 4 next lower dose levelPeripheral Neuropathy: Withhold until improves to

Grade 3 or 4 ≤ Grade 1; resume at next No dose reductionlower dose level

Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatmentGrade 2 or 3 if toxicity persists

Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume atGrade 3 mucositis or diarrhea next lower dose level

4 CONTRAINDICATIONS• ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged

with the drug.5 WARNINGS AND PRECAUTIONS

5.1 Hematologic EffectsBone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity ofABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastaticbreast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patientswith pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior todosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do notadminister ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patientswith either MBC or NSCLC.In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recoversto a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2)at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANCrecovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to anANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of thecycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC isless than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the nextcycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 ofthe cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage andAdministration (2.5)].

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than

1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarilyneutropenia, which may be severe and result in infection, it is recommended that frequentperipheral blood cell counts be performed on all patients receiving ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relativeto those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXELFORMULATIONS.

5.2 Nervous SystemSensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. Theoccurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage andAdministration (2.5)].5.3 SepsisSepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combinationwith gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatalsepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrumantibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].5.4 PneumonitisPneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANEin combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis andinterrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling outinfectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatmentwith ABRAXANE and gemcitabine.5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have beenreported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not bere-challenged with this drug.5. 6 Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased with hepatic impairment,administration of ABRAXANE in patients with hepatic impairment should be performed with caution.The starting dose should be reduced for patients with moderate or severe hepatic impairment [seeDosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].5.7 Albumin (Human)ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donorscreening and product manufacturing processes, it carries a remote risk for transmission of viraldiseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is consideredextremely remote. No cases of transmission of viral diseases or CJD have ever been identified foralbumin.5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxelprotein-bound particles to rats during pregnancy at doses lower than the maximum recommendedhuman dose, based on body surface area, caused embryofetal toxicities, including intrauterinemortality, increased resorptions, reduced numbers of live fetuses, and malformations.There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If thisdrug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, thepatient should be apprised of the potential hazard to the fetus. Women of childbearing potentialshould be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in SpecificPopulations (8.1)].5.9 Use in MenMen should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology(13.1)].

6 ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastaticbreast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia,myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, anddiarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin fornon-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy,nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions ofABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) andpneumonia (3%). The most common adverse reactions resulting in permanent discontinuation ofABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). Themost common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%),thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading towithholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), andanemia (16%).In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreaticadenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5%higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy,nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, anddehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higherincidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The mostcommon adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheralneuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactionsresulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%).The most common adverse reactions leading to withholding or delay in ABRAXANE dosing areneutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia(5%) and diarrhea (5%).6.1 Clinical Trials Experience in Metastatic Breast CancerTable 6 shows the frequency of important adverse events in the randomized comparative trial for thepatients who received either single-agent ABRAXANE or paclitaxel injection for the treatment ofmetastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized MetastaticBreast Cancer Study on an Every-3-Weeks Schedule

Percent of PatientsABRAXANE Paclitaxel Injection

260 mg/m2 over 30 min 175 mg/m2 over 3 hb

(n=229) (n=225)Bone Marrow

Neutropenia< 2.0 x 109/L 80 82< 0.5 x 109/L 9 22

Thrombocytopenia< 100 x 109/L 2 3< 50 x 109/L <1 <1

Anemia < 11 g/dL 33 25< 8 g/dL 1 <1

Infections 24 20Febrile Neutropenia 2 1Neutropenic Sepsis <1 <1Bleeding 2 2

Hypersensitivity Reactionc

All 4 12Severed 0 2

CardiovascularVital Sign Changes DuringAdministration

Bradycardia <1 <1Hypotension 5 5

Severe Cardiovascular Eventsd 3 4Abnormal ECG

All Patients 60 52Patients with Normal Baseline 35 30

RespiratoryCough 7 6Dyspnea 12 9

Sensory NeuropathyAny Symptoms 71 56Severe Symptomsd 10 2

Myalgia / ArthralgiaAny Symptoms 44 49Severe Symptomsd 8 4

AstheniaAny Symptoms 47 39Severe Symptomsd 8 3

Fluid Retention/EdemaAny Symptoms 10 8Severe Symptomsd 0 <1

GastrointestinalNausea

Any Symptoms 30 22Severe Symptomsd 3 <1

VomitingAny Symptoms 18 10Severe Symptomsd 4 1

DiarrheaAny Symptoms 27 15Severe Symptomsd <1 1

MucositisAny Symptoms 7 6Severe Symptomsd <1 0

Alopecia 90 94Hepatic (Patients with NormalBaseline)

Bilirubin Elevations 7 7Alkaline Phosphatase Elevations 36 31AST (SGOT) Elevations 39 32

Injection Site Reaction <1 1a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication.c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain,

hypotension) that began on a day of dosing.d Severe events are defined as at least grade 3 toxicity.

Adverse Event Experiences by Body SystemHematologic DisordersNeutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in therandomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patientstreated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a doseof 175 mg/m2. Pancytopenia has been observed in clinical trials.InfectionsInfectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis,respiratory tract infections and pneumonia were the most frequently reported infectiouscomplications.



9js

28344a1 07.10.14 133

Q1 Q2

S:20”S:13”

T:21”T:14”

B:21.25”B

:14.25”



app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________




Colors: Black GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

Hypersensitivity Reactions (HSRs)Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%)and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patientspreviously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.CardiovascularHypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused nosymptoms and required neither specific therapy nor treatment discontinuation.Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest,supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli,and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have beenreported.Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalitieson study did not usually result in symptoms, were not dose-limiting, and required no intervention.ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to studyentry, 35% of all patients developed an abnormal tracing while on study. The most frequently reportedECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinustachycardia.RespiratoryDyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment withABRAXANE.NeurologicThe frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathywas the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treatedwith ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documentedimprovement after a median of 22 days; 10 patients resumed treatment at a reduced dose ofABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documentedimprovement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) wasobserved in either arm of the controlled trial.Vision DisordersOcular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1%were severe. The severe cases (keratitis and blurred vision) were reported in patients who receivedhigher doses than those recommended (300 or 375 mg/m2). These effects generally have beenreversible. Arthralgia/MyalgiaThe symptoms were usually transient, occurred two or three days after ABRAXANE administration,and resolved within a few days.HepaticGrade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% ofpatients treated with paclitaxel injection in the randomized trial.RenalOverall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dosereductions, or dose delays were caused by renal toxicities.Other Clinical EventsNail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edemaoccurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were alsoreported.6.2 Clinical Trials Experience in Non-Small Cell Lung CancerAdverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxelinjection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized,open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as anintravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatmentarms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose-and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the medianage was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous celllung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles oftreatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence inABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE pluscarboplatin treatment group). Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with adifference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE pluscarboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups

ABRAXANE Paclitaxel Injection(100 mg/m2 weekly) (200 mg/m2 every 3 weeks)

plus carboplatin plus carboplatinGrades 1-4 Grade 3-4 Grades 1-4 Grade 3-4

(%) (%) (%) (%)Anemia1,2 98 28 91 7Neutropenia 1,3 85 47 83 58Thrombocytopenia1,3 68 18 55 9

1 508 patients assessed in ABRAXANE/carboplatin-treated group2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group

Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxelinjection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups


+ carboplatin (N=514) + carboplatin (N=524)Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4

MedDRA v 12.1 Toxicity Toxicity Toxicity ToxicitySystem Organ Class Preferred Term (%) (%) (%) (%)Nervous system Peripheral 48 3 64 12disorders neuropathya

General disorders Edema peripheral 10 0 4 <1and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0and mediastinaldisorders Musculoskeletal Arthralgia 13 <1 25 2and connective tissue disorders Myalgia 10 <1 19 2

a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathyimproved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation ofABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the PancreasAdverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinomaof the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patientsreceived a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8months in the gemcitabine group. For the treated population, the median relative dose intensity forgemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. Themedian relative dose intensity of ABRAXANE was 81%.Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plusgemcitabine-treated patients.

Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm

ABRAXANE(125 mg/m2)/ GemcitabineGemcitabined

Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4(%) (%) (%) (%)

Neutropeniaa,b 73 38 58 27Thrombocytopeniab,c 74 13 70 9

a 405 patients assessed in ABRAXANE/gemcitabine-treated groupb 388 patients assessed in gemcitabine-treated groupc 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated groupcompared to the gemcitabine group.

Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm

ABRAXANE Gemcitabine (N=402)(125 mg/m2)

and gemcitabine (N=421)

Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher

Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%)Peripheral edema 194 (46%) 13 (3%) 122 (30%) 12 (3%)Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%)Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%)Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%)Nausea 228 (54%) 27 (6%) 192 (48%) 14 (3%)Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%)Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%)Alopecia 212 (50%) 6 (1%) 21 (5%) 0Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%)Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%)Dysgeusia 68 (16%) 0 33 (8%) 0Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%)Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%)Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%)Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%)Cough 72 (17%) 0 30 (7%) 0Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%)Urinary tractinfectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%)Pain in extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%)Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%)Myalgia 44 (10%) 4 (1%) 15 (4%) 0

Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy(broad scope).b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis,urinary tract infection bacterial, and urinary tract infection enterococccal.


General disorders andadministration siteconditions

Gastrointestinal disorders

Skin and subcutaneoustissue disorders

Nervous system disorders

Metabolism and nutritiondisorders

Respiratory, thoracic andmediastinal disorders

Infections and infestations

Musculoskeletal andconnective tissuedisorders

Additional clinically relevant adverse reactions that were reported in < 10% of the patients withadenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:Infections & infestations: oral candidiasis, pneumoniaVascular disorders: hypertensionCardiac disorders: tachycardia, congestive cardiac failureEye disorders: cystoid macular edemaPeripheral NeuropathyGrade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibinecompared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheralneuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANEarm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement fromGrade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.SepsisSepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patientswho received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Riskfactors for sepsis included biliary obstruction or presence of biliary stent.PneumonitisPneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% ofpatients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitisdied.6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel FormulationsUnless otherwise noted, the following discussion refers to the adverse reactions that have beenidentified during post-approval use of ABRAXANE. Because these reactions are reported voluntarilyfrom a population of uncertain size, it is not always possible to reliably estimate their frequency orestablish a causal relationship to drug exposure. In some instances, severe events observed withpaclitaxel injection may be expected to occur with ABRAXANE.Hypersensitivity ReactionsSevere and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The useof ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or humanalbumin has not been studied. CardiovascularThere have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricularblock with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such asanthracyclines, or had underlying cardiac history.RespiratoryThere have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patientsreceiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injectionsafety and may also be observed with ABRAXANE.NeurologicCranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathyresulting in paralytic ileus.Vision DisordersReports in the literature of abnormal visual evoked potentials in patients treated with paclitaxelinjection suggest persistent optic nerve damage. These may also be observed with ABRAXANE.Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment withABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visualacuity may return to baseline.HepaticReports of hepatic necrosis and hepatic encephalopathy leading to death have been received as partof the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANEtreatment.Gastrointestinal (GI)There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemiccolitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis(typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injectionalone and in combination with other chemotherapeutic agents.Injection Site ReactionThere have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it isadvisable to monitor closely the ABRAXANE infusion site for possible infiltration during drugadministration.Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as partof the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injectionsite reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayedby a week to ten days. Recurrence of skin reactions at a site of previous extravasation followingadministration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical EventsSkin reactions including generalized or maculopapular rash, erythema, and pruritus have beenobserved with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recallphenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantarerythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.6.5 Accidental ExposureNo reports of accidental exposure to ABRAXANE have been received. However, upon inhalation ofpaclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Followingtopical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONSThe metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinicaldrug interaction studies, caution should be exercised when administering ABRAXANE concomitantlywith medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin,fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g.,rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category D [see Warnings and Precautions (5.9)].There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on itsmechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to apregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant whilereceiving this drug, the patient should be apprised of the potential hazard to the fetus. Women ofchildbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE.Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 atdoses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2

basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (upto 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase infetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue andskeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximumrecommended human dose on a mg/m2 basis).8.3 Nursing MothersIt is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites wereexcreted into the milk of lactating rats. Because many drugs are excreted in human milk and becauseof the potential for serious adverse reactions in nursing infants, a decision should be made todiscontinue nursing or to discontinue the drug, taking into account the importance of the drug to themother.8.4 Pediatric UseThe safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.8.5 Geriatric UseOf the 229 patients in the randomized study who received ABRAXANE for the treatment of metastaticbreast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicitiesoccurred notably more frequently among patients who received ABRAXANE.Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-linetreatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older.Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years orolder compared to patients younger than 65 years old. No overall difference in effectiveness, asmeasured by response rates, was observed between patients 65 years or older compared to patientsyounger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-linetreatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older.No overall differences in effectiveness were observed between patients who were 65 years of age orolder and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were morefrequent in patients 65 years or older compared with patients younger than 65 years old. Clinicalstudies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were75 years and older to determine whether they respond differently from younger patients.8.6 Patients with Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment,the administration of ABRAXANE should be performed with caution in patients with hepaticimpairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and ClinicalPharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for thetreatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.8.7 Patients with Renal ImpairmentThe use of ABRAXANE has not been studied in patients with renal impairment.

10 OVERDOSAGEThere is no known antidote for ABRAXANE overdosage. The primary anticipated complications ofoverdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How SuppliedProduct No.: 103450NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.16.2 StorageStore the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package toprotect from bright light.16.3 Handling and DisposalProcedures for proper handling and disposal of anticancer drugs should be considered. Severalguidelines on this subject have been published [see References (15)]. There is no general agreementthat all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling• ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while

receiving this drug. Women of childbearing potential should use effective contraceptives whilereceiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].• Patients must be informed of the risk of low blood cell counts and severe and life-threatening

infections and instructed to contact their physician immediately for fever or evidence of infection.[see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signsof dehydration.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patientsshould advise their physicians of numbness, tingling, pain or weakness involving the extremities[see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently withABRAXANE

• Instruct patients to contact their physician for signs of an allergic reaction, which could be severeand sometimes fatal [see Warnings and Precautions (5.5)].

• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough,or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for: Celgene CorporationSummit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC.©2005-2013 Abraxis BioScience, LLC.All Rights Reserved.Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

ABR_ALL_HCP_BSv007 10_2013



9js

28344a1 07.10.14 133

Q1 Q2

S:20”

S:13”

T:21”

T:14”

B:21.25”

B:14.25”



app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________




Colors: Black GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

Hypersensitivity Reactions (HSRs)Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%)and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patientspreviously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.CardiovascularHypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused nosymptoms and required neither specific therapy nor treatment discontinuation.Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest,supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli,and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have beenreported.Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalitieson study did not usually result in symptoms, were not dose-limiting, and required no intervention.ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to studyentry, 35% of all patients developed an abnormal tracing while on study. The most frequently reportedECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinustachycardia.RespiratoryDyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment withABRAXANE.NeurologicThe frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathywas the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treatedwith ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documentedimprovement after a median of 22 days; 10 patients resumed treatment at a reduced dose ofABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documentedimprovement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) wasobserved in either arm of the controlled trial.Vision DisordersOcular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1%were severe. The severe cases (keratitis and blurred vision) were reported in patients who receivedhigher doses than those recommended (300 or 375 mg/m2). These effects generally have beenreversible. Arthralgia/MyalgiaThe symptoms were usually transient, occurred two or three days after ABRAXANE administration,and resolved within a few days.HepaticGrade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% ofpatients treated with paclitaxel injection in the randomized trial.RenalOverall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dosereductions, or dose delays were caused by renal toxicities.Other Clinical EventsNail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edemaoccurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were alsoreported.6.2 Clinical Trials Experience in Non-Small Cell Lung CancerAdverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxelinjection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized,open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as anintravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatmentarms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose-and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the medianage was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous celllung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles oftreatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence inABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE pluscarboplatin treatment group). Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with adifference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE pluscarboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups


plus carboplatin plus carboplatinGrades 1-4 Grade 3-4 Grades 1-4 Grade 3-4

(%) (%) (%) (%)Anemia1,2 98 28 91 7Neutropenia 1,3 85 47 83 58Thrombocytopenia1,3 68 18 55 9

1 508 patients assessed in ABRAXANE/carboplatin-treated group2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group

Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxelinjection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups


+ carboplatin (N=514) + carboplatin (N=524)Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4

MedDRA v 12.1 Toxicity Toxicity Toxicity ToxicitySystem Organ Class Preferred Term (%) (%) (%) (%)Nervous system Peripheral 48 3 64 12disorders neuropathya

General disorders Edema peripheral 10 0 4 <1and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0and mediastinaldisorders Musculoskeletal Arthralgia 13 <1 25 2and connective tissue disorders Myalgia 10 <1 19 2

a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathyimproved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation ofABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the PancreasAdverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinomaof the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patientsreceived a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8months in the gemcitabine group. For the treated population, the median relative dose intensity forgemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. Themedian relative dose intensity of ABRAXANE was 81%.Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plusgemcitabine-treated patients.

Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm

ABRAXANE(125 mg/m2)/ GemcitabineGemcitabined

Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4(%) (%) (%) (%)

Neutropeniaa,b 73 38 58 27Thrombocytopeniab,c 74 13 70 9

a 405 patients assessed in ABRAXANE/gemcitabine-treated groupb 388 patients assessed in gemcitabine-treated groupc 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated groupcompared to the gemcitabine group.

Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm

ABRAXANE Gemcitabine (N=402)(125 mg/m2)

and gemcitabine (N=421)

Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher

Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%)Peripheral edema 194 (46%) 13 (3%) 122 (30%) 12 (3%)Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%)Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%)Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%)Nausea 228 (54%) 27 (6%) 192 (48%) 14 (3%)Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%)Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%)Alopecia 212 (50%) 6 (1%) 21 (5%) 0Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%)Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%)Dysgeusia 68 (16%) 0 33 (8%) 0Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%)Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%)Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%)Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%)Cough 72 (17%) 0 30 (7%) 0Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%)Urinary tractinfectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%)Pain in extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%)Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%)Myalgia 44 (10%) 4 (1%) 15 (4%) 0

Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy(broad scope).b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis,urinary tract infection bacterial, and urinary tract infection enterococccal.


General disorders andadministration siteconditions

Gastrointestinal disorders

Skin and subcutaneoustissue disorders

Nervous system disorders

Metabolism and nutritiondisorders

Respiratory, thoracic andmediastinal disorders

Infections and infestations

Musculoskeletal andconnective tissuedisorders

Additional clinically relevant adverse reactions that were reported in < 10% of the patients withadenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:Infections & infestations: oral candidiasis, pneumoniaVascular disorders: hypertensionCardiac disorders: tachycardia, congestive cardiac failureEye disorders: cystoid macular edemaPeripheral NeuropathyGrade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibinecompared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheralneuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANEarm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement fromGrade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.SepsisSepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patientswho received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Riskfactors for sepsis included biliary obstruction or presence of biliary stent.PneumonitisPneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% ofpatients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitisdied.6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel FormulationsUnless otherwise noted, the following discussion refers to the adverse reactions that have beenidentified during post-approval use of ABRAXANE. Because these reactions are reported voluntarilyfrom a population of uncertain size, it is not always possible to reliably estimate their frequency orestablish a causal relationship to drug exposure. In some instances, severe events observed withpaclitaxel injection may be expected to occur with ABRAXANE.Hypersensitivity ReactionsSevere and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The useof ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or humanalbumin has not been studied. CardiovascularThere have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricularblock with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such asanthracyclines, or had underlying cardiac history.RespiratoryThere have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patientsreceiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injectionsafety and may also be observed with ABRAXANE.NeurologicCranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathyresulting in paralytic ileus.Vision DisordersReports in the literature of abnormal visual evoked potentials in patients treated with paclitaxelinjection suggest persistent optic nerve damage. These may also be observed with ABRAXANE.Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment withABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visualacuity may return to baseline.HepaticReports of hepatic necrosis and hepatic encephalopathy leading to death have been received as partof the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANEtreatment.Gastrointestinal (GI)There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemiccolitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis(typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injectionalone and in combination with other chemotherapeutic agents.Injection Site ReactionThere have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it isadvisable to monitor closely the ABRAXANE infusion site for possible infiltration during drugadministration.Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as partof the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injectionsite reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayedby a week to ten days. Recurrence of skin reactions at a site of previous extravasation followingadministration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical EventsSkin reactions including generalized or maculopapular rash, erythema, and pruritus have beenobserved with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recallphenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantarerythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.6.5 Accidental ExposureNo reports of accidental exposure to ABRAXANE have been received. However, upon inhalation ofpaclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Followingtopical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONSThe metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinicaldrug interaction studies, caution should be exercised when administering ABRAXANE concomitantlywith medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin,fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g.,rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category D [see Warnings and Precautions (5.9)].There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on itsmechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to apregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant whilereceiving this drug, the patient should be apprised of the potential hazard to the fetus. Women ofchildbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE.Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 atdoses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2

basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (upto 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase infetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue andskeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximumrecommended human dose on a mg/m2 basis).8.3 Nursing MothersIt is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites wereexcreted into the milk of lactating rats. Because many drugs are excreted in human milk and becauseof the potential for serious adverse reactions in nursing infants, a decision should be made todiscontinue nursing or to discontinue the drug, taking into account the importance of the drug to themother.8.4 Pediatric UseThe safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.8.5 Geriatric UseOf the 229 patients in the randomized study who received ABRAXANE for the treatment of metastaticbreast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicitiesoccurred notably more frequently among patients who received ABRAXANE.Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-linetreatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older.Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years orolder compared to patients younger than 65 years old. No overall difference in effectiveness, asmeasured by response rates, was observed between patients 65 years or older compared to patientsyounger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-linetreatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older.No overall differences in effectiveness were observed between patients who were 65 years of age orolder and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were morefrequent in patients 65 years or older compared with patients younger than 65 years old. Clinicalstudies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were75 years and older to determine whether they respond differently from younger patients.8.6 Patients with Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment,the administration of ABRAXANE should be performed with caution in patients with hepaticimpairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and ClinicalPharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for thetreatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.8.7 Patients with Renal ImpairmentThe use of ABRAXANE has not been studied in patients with renal impairment.

10 OVERDOSAGEThere is no known antidote for ABRAXANE overdosage. The primary anticipated complications ofoverdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How SuppliedProduct No.: 103450NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.16.2 StorageStore the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package toprotect from bright light.16.3 Handling and DisposalProcedures for proper handling and disposal of anticancer drugs should be considered. Severalguidelines on this subject have been published [see References (15)]. There is no general agreementthat all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling• ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while

receiving this drug. Women of childbearing potential should use effective contraceptives whilereceiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].• Patients must be informed of the risk of low blood cell counts and severe and life-threatening

infections and instructed to contact their physician immediately for fever or evidence of infection.[see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signsof dehydration.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patientsshould advise their physicians of numbness, tingling, pain or weakness involving the extremities[see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently withABRAXANE

• Instruct patients to contact their physician for signs of an allergic reaction, which could be severeand sometimes fatal [see Warnings and Precautions (5.5)].

• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough,or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for: Celgene CorporationSummit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC.©2005-2013 Abraxis BioScience, LLC.All Rights Reserved.Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

ABR_ALL_HCP_BSv007 10_2013



9js

28344a1 07.10.14 133

Q1 Q2

S:20”S:13”

T:21”T:14”

B:21.25”B

:14.25”


2014-2015 Oncology Meetings 2014-2015Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial Sloan-Kettering Cancer CenterMarch 6-9 • New York, New York For more information: www.mskcc.org/hemoncreviewcourse

Advanced Prostate Cancer Consensus ConferenceMarch 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

NCCN Annual Conference: Advancing the Standard of Cancer CareMarch 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/meetings/annual_conference.asp

8th Annual Interdisciplinary Prostate Cancer Congress™March 14 • New York, New York For more information: http://www.gotoper.com/conferences/ipcc/meetings/8th-Annual-Interdisciplinary-Prostate-Cancer-Congress

25th Annual Interdisciplinary Breast Center ConferenceMarch 14-18 • Las Vegas, Nevada For more information: www2.breastcare.org

American Society of Preventive Oncology (ASPO) Annual MeetingMarch 15-17 • Birmingham, Alabama For more information: http://aspo.org/annual-meeting

ACCC 41st Annual National MeetingMarch 16-18 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/calendar.asp

14th St. Gallen International Breast Cancer ConferenceMarch 18-21 • Vienna, Austria For more information: www.oncoconferences.ch

State-of-the-Art Neuro-Oncology Conference: 3rd Annual MeetingMarch 19-20 • Clearwater Beach, Florida For more information: http://moffitt.org/for-physicians-healthcare-professionals/conferences/conferences

21st Annual Blood-Brain Barrier and Neuro-Oncology MeetingMarch 19-21 • Stevenson, Washington For more information: www.ohsu.edu/bbb

Society of Surgical Oncology Annual MeetingMarch 25-28 • Houston, Texas For more information: www.surgonc.org/

EORTC-EANO-ESMO 2015March 27-28 • Istanbul, Turkey For more information: www.ecco-org.eu/Events/EORTC_EANO_ESMO-2015

46th Annual Meeting on Women’s Cancer March 28-31 • Chicago, Illinois For more information: www.sgo.org

AprilAmerican Brachytherapy Society Annual MeetingApril 9-11 • Orlando, Florida For more information: http://www.americanbrachytherapy .org/meetings/annual2015/index.cfm

Hematologic Malignancies: New Therapies and the Evolving Role of TransplantApril 10-11 • Chicago, Illinois For more information: www.mayo.edu/cme/hematology-and-oncology-2015r919

7th Asian Oncology Summit and the 11th Annual Conference of the Organisation for Oncology and Translational Research April 10-12 • Shanghai, China For more information: www.asianoncologysummit.com

HPV-induced Head and Neck Cancer: Screening, Detection and Less Invasive TherapiesApril 11 • Miami, Florida For more information: http://cme.baptisthealth.net/headneckcancer/pages/index.aspx

ESMO European Lung Cancer ConferenceApril 15-18 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ELCC-2015-Lung-Cancer

Multidisciplinary Spine Oncology SymposiumApril 17-18 • New York, New York For more information: www.mskcc.org/events/cme/multidisciplinary-spine-oncology-symposium/form

American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org

ONS 40th Annual Congress April 23–26 • Orlando, Florida For more information: www.ons.org/conferences/congress-2015

3rd ESTRO Forum April 23-28 • Barcelona, Spain For more information: http://www.estro.org/congresses-meetings/items/3rd-estro-forum

MayThe 28th Annual Meeting of the American Society of Pediatric Hematology/OncologyMay 6-9 • Phoenix, Arizona For more information: www.aspho.org/education/content/annualmeeting.html

American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org

ASCO Annual MeetingMay 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

JuneInternational Cancer Screening Network (ICSN) Triennial MeetingJune 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/

2015 Clinical Update: 21st Century Prevention of HPV-Associated CancerJune 5-7 • Baltimore, Maryland For more information: www.asccp .org/Education/2015-21st-Century-Prevention-of-HPV-Associated-Cancer

Save the Date

13th International Conference on Malignant

Lymphoma (ICML)June 17–20, 2015

Lugano, Switzerland

The 13-ICML will bring 3,000 physicians to Lugano from all over the world: hematolo-gists, clinical oncologists, radia-tion oncologists, pediatricians, pathologists, and leading re-searchers involved in the study and treatment of lymphoid neo-plasms.

For more information, visit www.lymphcon.ch/imcl/index.php2

continued from page 104


2014-2015 Oncology Meetings 2014-2015Society of Nuclear Medicine and Molecular Imaging Annual MeetingJune 6-10 • Baltimore, Maryland For more information: www.snm.org

13th International Conference on Malignant Lymphoma (ICML)June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2

Anticancer Drug Action and Resistance: from Cancer Biology to the ClinicJune 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015

International Society on Thrombosis and Haemostasis Annual MeetingJune 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/

MASCC/ISOO Annual Meeting on Supportive Care in CancerJune 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

July7th World Congress on Gastrointestinal CancerJuly 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/WGIC2015/index.asp

NRG Oncology MeetingJuly 10-13 • Chicago. Illinois For more information: www.gog.org/meetinginformation .html

14th Annual International Congress on the Future of Breast Cancer®July 16-18 • Huntington Beach, California For more information: www.gotoper.com/conferences/ibc/meetings/14th-Annual-International-Congress-on-the-Future-of-Breast-Cancer

APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-OncologyJuly 28–August 1 • Washington, DC For more information: http://www.apos-society.org/professionals/meetings-ed/annualconference.aspx

16th Annual International Lung Cancer Congress®July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/meetings/16th-International-Lung-Cancer-Congress

Best of ASCO® BostonJuly 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

AugustBest of ASCO - San FranciscoAugust 7-8 • San Francisco, California For more information: http://boa.asco.org/

Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/

European Society for Medical Oncology Academy 2015August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

September9th Annual Conference of the International Liver Cancer AssociationSeptember 4-6 • Paris, France For more information: www.ilca2015.org

16th World Conference on Lung CancerSeptember 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org

25th World Congress of LymphologySeptember 7-11 • San Francisco, California For more information: www.lymphology2015.com/

American Society of Head & Neck Radiology Annual Meeting September 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ashnr-annual-meeting/

ASCO Breast Cancer Symposium September 25-27 • San Francisco, California For more information: breastcasym.org

The European Cancer CongressSeptember 25-29 • Vienna, Austria For more information: www.esmo.org/Conferences/European-Cancer-Congress-2015

OctoberAmerican College of Surgeons Clinical CongressOctober 4-8 • Chicago, Illinois For more information: www.facs.org/education/clinical-congress/future-clinical-congresses

6th InterAmerican Oncology Conference: Current Status and Future of Anti-Cancer Targeted TherapiesOctober 8-9 • Buenos Aires, Argentina For more information: www.oncologyconferences.com.ar

Palliative Care in Oncology SymposiumOctober 9-10 • Boston, Massachusetts For more information: www.pallonc.org

ASTRO’s 57th Annual MeetingOctober 18-21 • San Antonio, Texas For more information: www.astro.org

ACCC 32nd National Oncology ConferenceOctober 21-24 • Portland, Oregon For more information: www.accc-cancer.org/meetings/calendar.asp

November

Chemotherapy Foundation SymposiumNovember 3-7 • New York, New York For more information: www .chemotherapyfoundationsymposium .org

Advanced Breast Cancer Third International Consensus ConferenceNovember 5-7 • Lisbon, Portugal For more information: www.abc-lisbon.org

Fascia, Acupuncture and CancerNovember 14 • Boston, Massachusetts For more information: www.fasciacongress.org

12th International Conference of the Society for Integrative OncologyNovember 15-16 • Boston, Massachusetts For more information: www.integrativeonc.org/index.php/events

DecemberMarkers in Cancer 2015 December 1-2 • Brussels, Belgium For more information: http://markersincancer.org

38th Annual San Antonio Breast Cancer Symposium December 8-12 • San Antonio, Texas For more information: www.sabcs.org

ESMO Asia 2015 Congress December 18-21 • Singapore For more information: www.esmo.org/Conferences/ ESMO-Asia-2015-Congress


In the Clinic

Bevacizumab Plus Chemotherapy in Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

On November 14, 2014, bevacizum-ab (Avastin) in combination with

paclitaxel, pegylated liposomal doxorubi-cin, or topotecan was approved for treat-ment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received no more than two prior chemotherapy regimens.1,2

Supporting Trial Approval was based on the finding of

prolonged progression-free survival in the international open-label phase III AU-RELIA trial, in which 361 patients with platinum-resistant disease were randomly assigned to receive bevacizumab plus che-motherapy (n =179) or chemotherapy alone (n = 182).2,3 Chemotherapy consist-ed of paclitaxel (80 mg/m2 on days 1, 8, 15, and 22 every 4 weeks), pegylated liposomal doxorubicin (40 mg/m2 on day 1 every 4 weeks), or topotecan (4 mg/m2 on days 1, 8, and 15 every 4 weeks or 1.25 mg/m2 on days 1 to 5 every 3 weeks). Bevacizumab was given at 10 mg/kg every 2 weeks or at 15 mg/kg every 3 weeks in patients re-ceiving topotecan in the 3-week schedule. Investigator-assessed progression-free sur-vival was the primary endpoint.

Patients had received no more than two prior chemotherapy regimens and had experienced a recurrence at no more than 6 months from the most recent platinum-based therapy. Patients with evidence of rectosigmoid involvement by pelvic exami-nation, bowel involvement on computed tomography scan, or clinical symptoms of bowel obstruction were excluded.

Overall, patients had a median age of 61 years (range = 25–84 years; 37% ≥ 65 years), 79% had measurable disease; 87% had CA-125 level at least 2 × upper limit of normal; 31% had ascites; platinum-free interval was 3 to 6 months in 73% and < 3 months in 27%; and Eastern Cooperative Oncology Group performance status was 0 in 59%, 1 in 34%, and 2 in 7%.

Among all patients, median progres-sion-free survival was 6.8 months with bev-acizumab/chemotherapy vs 3.4 months with chemotherapy (hazard ratio [HR]

= 0.38, P < .0001, stratified log-rank test). Median overall survival did not signifi-cantly differ between groups (16.3 vs 13.3 months, HR = 0.89, 95% confidence inter-val [CI] = 0.69–1.14). Objective response rate was 28% vs 13%, and median duration of response was 9.4 vs 5.4 months.

Exploratory analyses by chemotherapy regimen showed that the best outcomes were for the bevacizumab/paclitaxel vs paclitaxel comparison (n = 60 vs 55), with median progression-free survival of 9.6 vs 3.9 months (HR = 0.47, 95% CI = 0.31–0.72), median overall survival of 22.4 vs 13.2 months (HR = 0.64, 95% CI = 0.41–1.01), and response rate of 53% vs 30%. This analysis suggests that patients with prior paclitaxel treatment may benefit from bevacizumab plus weekly paclitaxel.

For the bevacizumab/pegylated lipo-somal doxorubicin vs doxorubicin com-

parison (n = 62 vs 64), median progres-sion-free survival was 5.1 vs 3.5 months (HR = 0.47, 95% CI = 0.32–0.71), median overall survival was 13.7 vs 14.1 months (HR = 0.94, 95% CI = 0.63–1.42), and objective response rate was 16% vs 8%.

For the bevacizumab/topotecan vs topotecan comparison (n = 57 vs 63), me-dian progression-free survival was 6.2 vs 2.1 months (HR = 0.24, 95% CI = 0.15–0.38), median overall survival was 13.8 vs 13.3 months (HR = 1.12, 95% CI = 0.73–1.73), and response rate was 17% vs 2%.

How It WorksBevacizumab is recombinant human-

ized monoclonal IgG1 antibody that binds vascular endothelial growth fac-tor (VEGF) and prevents interaction of VEGF with its receptors on the surface of endothelial cells. Inhibition of this interac-tion results in inhibition of endothelial cell proliferation and new blood vessel forma-tion in in vitro models of angiogenesis.

How It Is GivenThe recommended bevacizumab dos-

age is 10 mg/kg every 2 weeks in com-

bination with paclitaxel, pegylated lipo-somal doxorubicin, or weekly topotecan regimens. Bevacizumab at 15 mg/kg ev-ery 3 weeks may be combined with topo-tecan regimen given every 3 weeks. The chemotherapy regimens are paclitaxel at 80 mg/m2 on days 1, 8, 15, and 22 every 4 weeks; pegylated liposomal doxorubicin at 40 mg/m2 on day 1 every 4 weeks; or topotecan at 4 mg/m2 on days 1, 8, and 15 every 4 weeks or at 1.25 m/m2 on days 1 to 5 every 3 weeks.

There are no recommended dose re-ductions for bevacizumab. Treatment should be permanently discontinued for gastrointestinal (GI) perforations (GI per-forations, fistula formation in the GI tract, intra-abdominal abscess) or fistula forma-tion involving an internal organ; wound dehiscence and wound healing complica-tions requiring medical intervention; seri-

ous hemorrhage; severe arterial thrombo-embolic events; life-threatening (grade 4) venous thromboembolic events, including pulmonary embolism; hypertensive crisis or hypertensive encephalopathy; posterior reversible encephalopathy syndrome; or nephrotic syndrome.

Bevacizumab should be temporarily suspended at least 4 weeks prior to elec-tive surgery and for severe hypertension not controlled with medical manage-ment, moderate to severe proteinuria, and severe infusion reactions. Bevacizumab should not be given to patients with seri-ous hemorrhage or recent hemoptysis.

Safety ProfileIn the phase III trial, grade 2 to 4 adverse

events occurring at an incidence ≥ 5% higher in the bevacizumab/chemotherapy group included neutropenia (30.7% vs 25.4%), hypertension (19.0% vs 5.5%), peripheral sensory neuropathy (17.9% vs 7.2%), mucosal inflammation (12.8% vs 5.5%), and proteinuria (12.3% vs 0.6%). Grade 3 or 4 adverse events occurring at an incidence ≥ 2% higher consisted of hyper-tension (6.7% vs 1.1%) and palmar-plantar

erythrodysesthesia syndrome (4.5% vs 1.7%). GI perforation occurred in 1.7% of bevacizumab-treated patients.

The exclusion of patients with evi-dence of rectosigmoid involvement, bowel involvement, or bowel obstruction from this trial may have contributed to the relatively low rate of perforation ob-served. Fistulae occurred in 2% of bevaci-zumab-treated patients and in no patients receiving chemotherapy alone.

Bevacizumab carries boxed warnings for GI perforation, surgery and wound healing complications, and hemorrhage (including severe or fatal hemorrhage, he-moptysis, gastrointestinal bleeding, cen-tral nervous system [CNS] hemorrhage, and vaginal bleeding). The appropriate interval between termination of bevaci-zumab and subsequent elective surgery to reduce the risk of impaired wound healing/wound dehiscence has not been determined; in addition to discontinuing bevacizumab ≥ 28 days prior to elective surgery, it should not be restarted for ≥ 28 days after surgery and until the surgical wound is fully healed.

Severe or fatal hemorrhage, including hemoptysis, GI bleeding, CNS hemor-rhage, epistaxis, and vaginal bleeding, occur up to fivefold more frequently in patients receiving bevacizumab.

Bevacizumab also carries warnings/precautions for perforation or fistula, ar-terial thromboembolic events, venous thromboembolic events, hypertension, posterior reversible encephalopathy syn-drome, proteinuria, infusion reactions, and ovarian failure. Patients must under-go routine monitoring of blood pressure and urine protein. Women of reproduc-tive potential must be informed of the risk of ovarian failure. n

References1. U.S. Food and Drug Administration:

Bevacizumab solution. Available at www.fda.gov.

2. AVASTIN® (bevacizumab) solution for intravenous infusion prescribing information, Genentech, Inc, November 2014. Available at www.accessdata.fda.gov.

3. Pujade-Lauraine E, Hilpert F, Weber B, et al: Bevacizumab combined with chemo-therapy for platinum-resistant recurrent ovar-ian cancer. J Clin Oncol 32:1302-1308, 2014.

OF NOTEBevacizumab carries boxed warn-ings for gastrointestinal perforation, surgery and wound healing compli-cations, and hemorrhage.

Combination Drug for Chemotherapy-Related Nausea/Vomiting

■ Bevacizumab (Avastin) combined with paclitaxel, pegylated liposomal doxorubicin, or topotecan was approved to treat patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received no more than two prior chemotherapy regimens.

■ The recommended bevacizumab dosage is 10 mg/kg every 2 weeks in combination with paclitaxel, pegylated liposomal doxorubicin, or weekly topotecan regimens.

In the Clinic provides overviews of novel oncology agents, addressing in-dications, mechanisms, administra-tion recommendations, safety pro-files, and other essential information needed for the appropriate clinical use of these drugs.

Take a Closer Look at ALL

Visit www.UnderstandingALL.com

Complete Remission May Not Ensure Survival in Adults with B-ALL (B-cell Acute Lymphoblastic Leukemia)

Of the adult patients with B-ALL who achieve a hematologic complete remission,1,2 44% will eventually relapse,1-3 with only 10% still alive 5 years after their first relapse.4

Several risk factors such as a patient’s age, cytogenetics, and the speed and depth at which a minimal residual disease (MRD) response is achieved can predict risk of relapse.1,3,5-9

Testing at the molecular level for MRD can allow a patient’s risk of relapse to be accurately gauged and treatment to be tailored accordingly.3

Is your treatment approach getting to the molecular level?

References: 1. Jain N, Gurbuxani S, Rhee C, Stock W. In: Hoffman R, Benz EJ Jr, Silberstein LE, Heslop H, Weitz J, Anastasi J, eds. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, PA: Saunders-Elsevier; 2013:960-980. 2. Hoelzer D. Am Soc Clin Oncol Educ Book. 2013:290-293. doi:10.1200/EdBook_AM.2013.33.290. 3. Hoelzer D, Gökbuget N, Ottmann O, et al. Hematology Am Soc Hematol Educ Program. 2002;162-192. 4. Forman SJ, Rowe JM. Blood. 2013;121:1077-1082. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia V.1.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed July 8, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 6. Leukemia and Lymphoma Society. Acute Lymphoblastic Leukemia. Published February 2014. http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/leukemia/pdf/all.pdf. Accessed July 8, 2014. 7. Rowe JM. Br J Haematol. 2009;144:468-483. 8. Moorman AV, Harrison CJ, Buck GA, et al. Blood. 2007;109:3189-3197. 9. Bassan R, Hoelzer D. J Clin Onc. 2011;29:532-543. © 2014 Amgen Inc. All rights reserved. USA-103-100324

How Well Can Risk of Relapse Be

Predicted in

Adult B-ALL?

08-04405_R01_AAUS_Tabl_1pg_JA_ASCO.indd 1 10/2/14 2:31 PM

http://www.amgenoncology.com


Through the Lens of Oncology History

Preoperative Rodent Cancer

Patient of Charles Moore, MD, Albumen Print, London, 1864

“A disease more repulsive and distress-ing can hardly be conceived than a

Rodent Cancer of the face. Commencing in some trifling manner in the skin, and then sometimes producing so little irritation as scarcely to attract notice, it spreads abroad in all directions with a slow but unswerving advance. It grows and ulcerates. It ulcerates but never heals. The skin suffers most widely from its ravages, but no structure arrests its progress. It removes whole organs, but restores nothing. In its front all is healthy: behind it is vacancy and frightful disfigure-ment. Whilst eroding integument, carti-lage, or bone, the disease is not, or is little, painful; but when eyelids disappear, when the eye or the inner ear is invaded, when branches of the fifth nerve are exposed, or are ulcerating, pain and sometimes severe pain, is added to the deformity.”

With these opening lines, cancer specialist Charles Hewitt Moore, MD (1821-1870), of London’s Middlesex Hospital, presented the first medical text devoted to the treatment of cancer and illustrated the text with a photograph. In his 1867 textbook Rodent Cancer: With Photographic and other Illustrations of Its Nature and Treatment, he presented the classic description of basal cell car-cinoma, or rodent cancer as it was then best known. Massive destructive lesions of the face were called lupus or rodent in emulation of the effect a wolf or rodent bite would have to the face.

In 1867, Dr. Moore also published in the Medico-Chirgical Transaction, Volume 50, “On the influence of in-adequate operations on the theory of cancer.” Because of these publications Dr. Moore has been credited with lay-ing down the modern principles for the surgical treatment of cancer. His surgi-cal accomplishments were already well known and respected. In 1864 he and

Charles Murchison, MD (1830-1879), had devised a fairly successful treat-ment for aneurysms. They introduced

the method whereby a wire was passed into an ‘incurable’ aneu-rysmal sac, resulting in the formation of a fibrin clot in the mass, which helped de-crease the growth rate and danger of rupture.

Since the Middle Ages, facial skin can-cer was known as ‘no-li-me-tangere’ (touch-me-not), as physicians assumed the lesions incurable. Neither surgery nor the use of caustics seemed to stop the disease. In 1755, Jacques Daviel, MD (1696-1762),

first claimed that certain types of these cancers could be cured by wide surgi-cal excision; he is best remembered for

his 1753 introduc-tion of the modern method of cataract lens extraction. Sev-eral noted physicians studied the facially destructive lesions and separated rodent cancer from syphi-litic and tubercular forms, as well as ‘epi-thelioma’ and other cancers, all of which were rapidly growing and metastasized. Dr. Moore’s exhaus-tive treatise reviewed the prior knowledge of the condition, fur-ther distinguished the disease, and de-

scribed effective treatment.Dr. Moore advised wide surgical ex-

cision to be followed by caustic agents and, when possible, transplanted skin flaps to cover as much of the defect as possible. In most cases of advanced dis-ease, a vulcanite mask was necessary to allow the patient to be seen in public. He concluded this cancer “is eminently a local disease: it is also eminently a cur-able disease.” Dr. Moore’s favorite caus-tic was chloride of zinc, which he noted if “applied to the cranium or the dura matter, an epileptiform fit” ensues, in one or more days after the application. Dr. Moore advised surgeons to attempt treating aggressively all but the most advanced cases. As a result of his suc-cesses, the most serious cases in Eng-land were referred to him.

The patient shown in this photo-graph arrived at the hospital on May 24, 1864, and was case number two in his text with four photographs to docu-ment the study. This 54-year-old man “was living as an incurable patient in the Infirmary of the Uxbridge Union. The disease in him being of 13 years du-ration… at the first sight of the fellow’s face it seemed hardly possible that any operation could afford him relief….” Some notion of the formidable char-acter of the disease may be obtained from an inspection of the photographic drawings, but these representations fall short of the reality, as they exhibit only the rugged orifice in the face, “the vast cavern amongst the bones behind it not being lighted up and visible….” n

Excerpted from Oncology: Tumors & Treatment: A Photographic History, The Anesthesia Era 1845-1875 by Stanley B. Burns, MD, FACS. Photograph cour-tesy of Stanley B. Burns, MD, and The Burns Archive.

The Anesthesia Era 1845-1875

A Century of ProgressThe text and photographs on these pages represent the establishment of oncology as a viable medical specialty during the mid-1800s to the mid-1900s and showcase the early medical advances and treatments in cancer.The images and captions are excerpted from a four-volume series of books titled Oncology Tumors & Treatment: A Photo-graphic History by Stanley B. Burns, MD, FACS. To view additional photos from this series of books, visit burnsarchive.com.


Through the Lens of Oncology History

Fluoroscopy for Lung Disease, Boston, 1903

When Thomas Alva Edison, the Wizard of Menlo Park, heard

of Roentgen’s discovery of the x-ray, he directed his research staff to create x-ray tubes and better screens on which to view the images. Edison owned Amer-ica’s first industrial research laboratory and could easily supply the know-how, money, and the most modern technolo-gy to devise new uses and improvements to almost any device. Edison’s scientists used a thinner glass bulb and aluminum disks as electrodes to create a more ef-ficient x-ray tube. They also tested over 8,000 chemicals in their search to im-prove the resolution on the fluorescent x-ray screen. They found calcium tung-state provided the best results. Edison named his devise the ‘fluoroscope.’ It was an easy-to-use, hand-held machine as seen here.

By the end of 1896, radiology’s

prime tools had been improved and their use spread worldwide. During its development, however, Edison had no-ticed that the skin around his eyes was reddening and he had developed rashes. By 1902, Edison had given up all x-ray work, but it was too late for his assistant Clarence Daly, the one who had tested the tubes. He had burns on his face and hands, which were soon followed by the extreme loss of head and facial hair. The burns turned into ulcers, then painful malignancies that started at his fingers and slowly ate their way up his arms. Trying to stop its advance, he gradually lost both his arms from multiple am-putations. Finally succumbing in 1904, “Daly had died by inches.” All over the world pioneer radiologists were losing their lives and limbs to the new ma-chine.

Edison’s fluoroscope was used to

tract internal disease, and derangements of internal organs could be seen in real time. In this image, a radiologist is drawing the disease areas directly onto the patient’s chest. This was a common method of analyzing a patient’s lung disease in this era. Modifications of Edison’s fluoroscope were used in shoe stores until the 1950s. n

Excerpted from On-cology: Tumors & Treat-ment: A Photographic History, The X-Ray Era 1901-1915 by Stanley B. Burns, MD, FACS. Pho-tograph courtesy of Stanley B. Burns, MD, and The Burns Archive.

Chevalier Jackson, MD, Performing Bronchoscopy, Philadelphia, Circa 1920

The bronchoscope was first used for extracting foreign bodies and

the evaluation of infectious processes, especially abscesses. By the end of the twentieth century, the bronchoscope had been determined the single most useful tool for accurate diagnosis of lung cancer. It allowed for the collec-tion of biopsy specimens or cells for histological and cytological analysis and, in some cases, direct observation of a lesion.

Chevalier Jackson, MD (1865-1958), is considered by many to be the father of modern broncho-esoph-agoscopy. In 1890, he constructed an oesophagoscope and continually re-fined his instruments over the next de-cade-and-a-half using them in a wide variety of clinical cases. Dr. Jackson’s improvements included the major step of removing the lighting system from the distal end, placing it at the proxi-mal end, and making the illuminating tube itself an auxiliary tube. This freed the main lumen for instrumentation. In 1905, he designed a bronchoscope with a suction tube, a light carrier, and a right-angled handle that made the instrument easy to manipulate. He created his own instrument shop for implementing the constant improve-ments. In 1907, he published the first book on endoscopy, Tracheo-bronchos-

copy, Esophagoscopy and Gastroscopy. By the second decade of the twentieth century, his improved instruments and expertise in laryngoscopy and other endoscopic procedures were drawing a worldwide audience of physicians to his postgraduate courses held in Philadelphia as well as Paris. Because of the constant demand, he continued these courses after his retirement until a few years before his death at age 93 in 1958.

Few physicians have exerted as great an influence or remained ‘the world authority’ for as long a period of time. In Surgical Diagnosis and Treatment by American Authors by Albert J. Ochsner, MD, published in 1920, Dr. Jackson describes his use of the bronchoscope and outlines its place in the treatment of disease and foreign bodies:

“Lung Abscesses can be entered di-rectly and drained… Abscesses caused by foreign bodies can be relieved by re-moval of the foreign body along with the abscess contents… Endobronchial lavage and instillation of local medication (is important)… Removal of secretions are difficult because they are too viscous and a special ‘sponge-pump’ system must be used… Foreign body removal is the bron-choscope’s biggest blessing… if no harm is done, the bronchoscopy can be repeat-ed any number of times. Therefore it is

absolutely unjustifiable to take the risk of pulling out a foreign body not free to move… Only too often in the early days of the work death promptly followed the ruthless tearing out of an entangled for-eign body.”

(He does not mention its use in identification, biopsy, or the testing of secretions for lung tumors. His only reference to “growths” accompanies this photograph.) The heavy laryngo-scope has been removed leaving the light bronchoscope in position. The operator (Dr. Jackson) is inserting for-ceps. Note how the operator holds the

tube lightly between the thumb and first two fingers of the left hand, while the last two fingers are hooked over the upper teeth of the patient, ‘anchoring’ the tube to prevent it from moving in or out or otherwise changing the rela-tion of the distal tube-mouth to a for-eign body or growth while the forceps are being used. n

Excerpted from Oncology: Tumors & Treatment: A Photographic History, The Radium Era 1916-1945 by Stan-ley B. Burns, MD, FACS. Photograph courtesy of Stanley B. Burns, MD, and The Burns Archive.

The Radium Era 1916-1945

The X-Ray Era 1901-1915


Patient’s Corner

Beating the OddsDiagnosed with non–small cell lung cancer 10 years ago, the disease altered the course of my life but not my sense of purpose.By Richard Heimler, as told to Jo Cavallo

I know it sounds odd, but the past 10 years spent living with non–small

cell lung cancer (NSCLC) have been very productive, wonderful years. It is not the life I had before my diagnosis, but it is the life I remember most clearly, and knowing how deadly this cancer is, I’m grateful for every day of those years.

I never expected a diagnosis of lung cancer. A nonsmoker, I’ve always lived a healthy lifestyle and was surprised when I began having chest pains after

returning from a business trip to Lon-don. Although just 44 at the time, I was worried that I was having a heart attack or stroke and saw a cardiologist imme-diately.

A battery of tests found my heart was healthy, but I had a 3-cm spot on my right lung. A biopsy confirmed that it was stage IA NSCLC. After surgery, my remaining lung was only at 30% breath-ing capacity, due to scoliosis that was di-agnosed when I was younger. Over the

years, I’ve managed to increase my lung capacity somewhat. Although I can no longer work full time, I am able to lead a fairly normal lifestyle.

Coping With Cancer Recurrence

After the surgery, I was bombarded with a series of standard chemothera-pies, including cisplatin, carboplatin, paclitaxel, and vinorelbine. Despite the extensive treatment, over the past de-

cade, I’ve had eight recurrences: three in my brain and several in my chest and remaining lung, with the latest lung tu-mor diagnosed in June 2014. Having a recurrence in my remaining lung was my worst fear, but my oncologist was able to keep me ahead of the disease with chemotherapy. Although the prior tumors never completely disappeared, they remained stable for several years.

Then in 2010, I got lucky when my oncologist sent a tissue sample of my

primary tumor for molecular diagnos-tic testing and found that my cancer was ALK-positive. I was enrolled in a clinical trial investigating crizotinib (Xalkori), and for 4 years, the drug worked wonders for me, either shrink-ing my tumors completely or keeping them from progressing.

When the cancer recurred in my lung this past June, the tissue was screened for new mutations, and I was prescribed ceritinib (Zykadia), a new-er ALK inhibitor, and it is working. What’s more, ceritinib appears to pro-hibit brain metastases, so I’m hoping it will prevent new tumors from develop-ing in my brain.

Living a Purposeful LifeI know that if these two drugs hadn’t

been discovered, I probably would not be alive today, and since my diagnosis, I don’t take any days for granted. I’ve al-ways been a person who tries to get the most out of every day and sees the glass half full, but there is no question that over the past decade, I’ve become even more conscious of living a more fully engaged life. I make it a point of seeing my children, parents, and friends more frequently and telling them how much I love them.

I have also dedicated my life to raising awareness of lung cancer and helping other survivors find informa-tion and support. When I was first diagnosed with the disease, I didn’t know where to turn for guidance, and I want to spare other people that sense of helplessness and fear. I also want to

give people hope that although lung cancer is not curable, it is treatable and manageable, and it is possible to live a full and meaningful life.

Cancer Is Imbedded in My Life’s Blueprint

Although I’ve been beating the odds for more than 10 years, I want more time. Like most parents, I’d like to see my children get married and have children, but, ultimately, I know that whatever the future holds is out of my control. For some reason, cancer is now imbedded in my life’s blueprint, and the rest of my life will unfold the way it is meant to. In the meantime, I’m going to enjoy every minute of it.

If my disease does become uncon-trollable at some point, I won’t have any regrets, because I know my oncologist has done everything possible to keep me alive. He has been with me every step of the way, and when I’m having a bad day, he encourages me to see him or calls me on the phone and reassures me. I’ve put my life in his hands. What a wonderful gift it is to find a doctor you can trust with your life.

Despite the challenges over the past 10 years, I have a wonderful life. Rather than a story filled with sadness and de-spair, my story is one of hope. That is the message I give to my family, friends, and other survivors. n

Richard Heimler lives in Stamford, Con-necticut. This past June, the LUNGevity Foundation honored Mr. Heimler with its Hero award for his advocacy in lung cancer.

I have dedicated my life to raising awareness of lung cancer and helping other survivors find information and support. When I was first diagnosed with the disease, I didn’t know where to turn for guidance, and I want to spare other people that sense of helplessness and fear.

—Richard Heimler

Patient Guides Available Through ASCO University Bookstore• ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including

health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare.

• ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to in-formation on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship.

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n


From YouWe encourage readers to share

their opinions and thoughts on issues of interest to the

oncology community.


JOB#: 40680 CLIENT: Genentech

DESC: Journal Ad 3-pg FILE NAM

E: GNH_HER_Q40680_JA_D01.indd DATE: 11-3-2014 11:13 AM

ROUND: 1PG: ParedesA/GolaG

AD: R Vetrano-Pyke PM

: B Fu x4416 AE: K McGinty

CW: L Gibbons

Last Saved: 11-3-2014 11:13 AMTRIM

: 15.5” x 10.5” BLEED: 17.5” x 11.5”

SAFETY: 14.75” x 9.875” PROD: M Haight

INK Spec: 4C PRINT SCALE: 82.94%

FONTS: Myriad Pro (Bold, Regular, Light), Helvetica Neue LT Std (45 Light)

IMAGES: 40680_JA_1_fn.tif (CMYK; 300 ppi; 100%

), 40680_glow_fn.psd (CMYK; 300 ppi; 100%

), Perjeta_US_MBC_NEO_4C.eps (69.5%

)INKS:

Cyan, Magenta,

Yellow, Black

DOC PATH: Macintosh HD:Users:paredesa:De..._JA_D01:GNH_HER_Q40680_JA_D01.inddNOTES: None

GNH_HER_Q40680_JA_D01.indd Galley: 1

S&H

PharmaGraphics

Mech

DATE

SIGNOFF

PGQC

TCAD

CDCW

AE/ASED

PROD

C M Y K

Cosmos Communications 1

1ja

29281a1 11.4.14 133

QC

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

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal ToxicityPERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confi rmed clinically signifi cant decrease in left ventricular function.

Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for eff ective contraception.

Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages.

STRENGTHEN HER DEFENSE

Treatment guidelines have been updated to recommend PERJETA-based therapy as the preferred first-line option

• NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend pertuzumab (PERJETA) + trastuzumab (Herceptin) + docetaxel as a (category 1) preferred option for the fi rst-line treatment of patients with HER2+ MBC1

NCCN®=National Comprehensive Cancer Network®; HER2=human epidermal growth factor receptor 2.

S:6.875”

S:9.875”

T:7.75”

T:10.5”

B:8.75”

B:11.5”


FDA Update

FDA Approves Extended-Release, Single-Entity Hydrocodone Product With Abuse-Deterrent Properties

The U.S. Food and Drug Admin-istration (FDA) today approved

hydrocodone bitartrate (Hysingla ER), an extended-release opioid an-algesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which

alternative treatment options are in-adequate. The product has approved labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2013 draft guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling.

Abuse-Deterrence PropertiesThe new product has properties that

are expected to reduce, but not totally prevent, abuse of the drug when chewed and then taken orally, or crushed and snorted or injected. The tablet is diffi-cult to crush, break or dissolve. It also forms a viscous hydrogel and cannot be easily prepared for injection. The FDA has determined that the physical and chemical properties of the new product are expected to make abuse by these routes difficult. However, abuse of the drug by these routes is still possible, and overdosing may result in death.

“While the science of abuse deter-rence is still evolving, the development of opioids that are harder to abuse is helpful in addressing the public health crisis of prescription drug abuse in the United States,” said Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research. “Pre-venting prescription opioid abuse is a top public health priority for the FDA, and encouraging the development of opioids with abuse-deterrent proper-ties is just one component of a broader approach to reducing abuse and misuse, and will better enable the agency to balance addressing this problem with ensuring that patients have access to ap-propriate treatments for pain.”

About Hydrocodone BitartrateExtended-release hydrocodone bi-

tartrate is not approved for, and should not be used for, as-needed pain relief. Given the drug’s risks for abuse, mis-use, and addiction, it should only be prescribed to people for whom alterna-

tive treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient pain management. As a single-entity opioid, The new drug does not carry the seri-

ous liver toxicity risks associated with hydrocodone combination products containing acetaminophen. The FDA encourages health-care professionals to review and consider all available infor-

mation as part of their decision-making when prescribing opioid analgesics.

Strengths of the new product contain 20, 30, 40, 60, 80, 100 and 120 mg of hy-








CW: L Gibbons


: 15.5” x 10.5” BLEED: 17.5” x 11.5”



FONTS: Myriad Pro (Bold, Regular, Light), Helvetica Neue LT Std (45 Light)


), 40680_glow_fn.psd (CMYK; 300 ppi; 100%

), Perjeta_US_MBC_NEO_4C.eps (69.5%

)INKS:

Cyan, Magenta,

Yellow, Black

DOC PATH: Macintosh HD:Users:paredesa:De..._JA_D01:GNH_HER_Q40680_JA_D01.inddNOTES: None


S&H

PharmaGraphics

Mech

DATE

SIGNOFF

PGQC

TCAD

CDCW

AE/ASED

PROD

C M Y K


1ja

29281a1 11.4.14 133

QC

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

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal ToxicityPERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confi rmed clinically signifi cant decrease in left ventricular function.

Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for eff ective contraception.

Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages.

STRENGTHEN HER DEFENSE

Treatment guidelines have been updated to recommend PERJETA-based therapy as the preferred first-line option

• NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend pertuzumab (PERJETA) + trastuzumab (Herceptin) + docetaxel as a (category 1) preferred option for the fi rst-line treatment of patients with HER2+ MBC1

NCCN®=National Comprehensive Cancer Network®; HER2=human epidermal growth factor receptor 2.

S:6.875”

S:9.875”

T:7.75”

T:10.5”

B:8.75”

B:11.5”

http://www.perjeta.com/hcp/


FDA Update

drocodone to be taken every 24 hours. Doses of 80 mg/d and higher should not be prescribed to people who have not previously taken an opioid medica-tion. While the product contains larger amounts of hydrocodone compared to immediate-release hydrocodone com-

bination products, the range of tablet strengths of the drug is comparable to ex-isting approved extended-release opioids.

The safety and effectiveness of the product were evaluated in a clinical trial of 905 people with chronic low back pain. Additional data from studies conducted in laboratories and in people demonstrated the abuse-deterrent fea-

tures of the drug for certain types of abuse (oral, snorting, and injection). The most common side effects are con-stipation, nausea, fatigue, upper respi-ratory tract infection, dizziness, head-ache, and drowsiness.

The FDA is requiring postmarketing studies to assess the effects of the abuse-deterrent features on the risk for abuse

and the consequences of that abuse in the community. In addition, the new drug is part of the ER/LA Opioid An-algesics Risk Evaluation and Mitigation Strategy (REMS), which requires com-panies to make available to health-care professionals educational programs on how to safely prescribe extended-re-lease/long-acting opioid analgesics. n

Hydrocodone Bitartratecontinued from page 119







CW: L Gibbons


: 15.5” x 10.5” BLEED: 17.5” x 11.5”



FONTS: Myriad Pro (Regular, Bold, Condensed, Condensed Italic, Bold Condensed)


), Genentech_AMOTRG_4C.eps (96.6%

), Perjeta_US_MBC_NEO_4C.eps (65%

), 40680_KMchart_v5.eps (100%

), 40680_40062_oschartREV_v3.eps (100%)

INKS: Cyan,

Magenta, Yellow,

BlackDOC PATH: Macintosh HD:Users:paredesa:De..._JA_D01:GNH_HER_Q40680_JA_D01.inddNOTES: None


S&H

PharmaGraphics

Mech

DATE

SIGNOFF

PGQC

TCAD

CDCW

AE/ASED

PROD

C M Y K


1js

29281a1 11.4.14 133

QC

PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly extend progression-free survival (PFS) in first-line HER2+ metastatic breast cancerCombining PERJETA with Herceptin + docetaxel added 6 months median PFS2

Overall survival (OS) dataPERJETA demonstrated an OS improvement when combined with Herceptin + docetaxel at the final analysis3

6.1-month improvement in median PFS by independent review (primary endpoint)2

15.7-month improvement in median OS in the final analysis (secondary endpoint)3

HR=hazard ratio; CI=confidence interval.Median PFS was reached at the first interim analysis.2 Results of the phase III, randomized, double-blind, placebo-controlled CLEOPATRA trial in patients (N=808) with HER2+ locally recurrent, unresectable, or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. Patients received PERJETA + Herceptin + docetaxel or placebo + Herceptin + docetaxel every 3 weeks until progression or unacceptable toxicity. Primary endpoint: PFS, assessed by independent review.2

At the second interim analysis (30 months median follow-up, 1 year after the first interim analysis), the HR and P value for OS crossed the predefined efficacy stopping boundary (HR ≤0.739, P≤0.0138). OS improvement with PERJETA + trastuzumab + docetaxel was statistically significant at the second interim analysis (HR=0.66, P=0.0008).2 The final analysis was performed when 221 patient deaths occurred in the placebo-treated group and 168 in the PERJETA-treated group. The statistically significant OS benefit in favor of the PERJETA-treated group was maintained (HR=0.68, P=0.0002).3

• At the first interim analysis, PFS events occurred in 191 (47.5%) patients treated with PERJETA + Herceptin + docetaxel and 242 (59.6%) patients treated with Herceptin + docetaxel2

Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

• At the final analysis, the OS benefit was maintained (HR=0.68, 95% CI: 0.56-0.84; P=0.0002) and the median was reached in the PERJETA + Herceptin + docetaxel arm (56.5 months vs 40.8 months in the Herceptin + docetaxel arm)3

• The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy2

• Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

Hypersensitivity Reactions/Anaphylaxis• In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was

10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI- CTCAE (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis

• Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

HER2 Testing• Detection of HER2 protein overexpression is necessary for selection of patients

appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown

• Patients were required to have evidence of HER2 overexpression, defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC

• Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

Most Common Adverse Reactions• In MBC, the most common adverse reactions (>30%) seen with PERJETA in combination

with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

For more information about PERJETA, contact your local representative or visit www.PERJETA.com/hcp.

Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages.References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.3.2014. © National Comprehensive Cancer Network, Inc. 2014. All rights reserved. Accessed May 12, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. PERJETA Prescribing Information. Genentech, Inc. September 2013. 3. Data on file. Genentech, Inc. 4. Swain SM, Kim S-B, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomized, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471. 5. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

Important Safety InformationBoxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity• PERJETA administration can result in subclinical and clinical cardiac

failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function

• Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception—Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the

risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant

—If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720

—Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

Additional Important Safety InformationPERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Left Ventricular Dysfunction (LVD)• In Study 1, for patients with MBC, PERJETA in combination with Herceptin and

docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel

• Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group

• Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and in 1.8% of patients in the placebo-treated group

• Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF

• Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting) during treatment to ensure that LVEF is within your institution’s normal limits

• If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions• PERJETA has been associated with infusion reactions• In Study 1, for patients with MBC, on the first day, when only PERJETA was

administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting

• During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

© 2014 Genentech USA, Inc. All rights reserved. PER/103014/0028 Printed in USA. 10/14

• In the second interim analysis, PERJETA improved both PFS and OS when combined with Herceptin + docetaxel in patients, including the visceral metastasis subgroup4,5 — There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases

(n=178; HR=1.42 [95% CI: 0.71-2.84])2

• In the second interim analysis, there was a statistically significant improvement in OS (secondary endpoint)2 — Median not yet reached in the PERJETA-containing arm vs 37.6 months with Herceptin + docetaxel

(HR=0.66; 95% CI: 0.52-0.84; P=0.0008)

100

90

80

70

60

50

40

30

20

10

0

0 5 10 15 20 25 30 35 40

HR=0.6295% CI: 0.51-0.75

P<0.0001

402406

P+H+DPl+H+D

345311

267209

13993

8342

3217

107

00

00

Placebo + Herceptin + docetaxel

12.4MONTHS

MONTHS

PERJETA + Herceptin + docetaxel

18.5MONTHS

Patients at risk

PFS (

%) median line

MONTHS

Patients at risk

402406

P + H + D PI + H + D

371350

318289

268230

0

226179

10491

2823

10

Placebo + Herceptin + docetaxelPERJETA + Herceptin + docetaxel

56.5MONTHS

HR=0.68 95% CI: 0.56-0.84

P=0.0002

40.8MONTHS

median line

30

20

10

020 30 40 50 60 70

100

90

80

70

60

50

40

10

OS (%

)

00

80

G:1.0”

S:9.875”

T:15.5”

T:10.5”

B:17.5”

B:11.5”

S:6.875” S:6.875”


Announcements

Rolf-Detlef Treede, MD, PhD, Elected IASP President

M embers of the International Association for the Study of

Pain (IASP) have elected Rolf-Detlef Treede, MD, PhD, as the organiza-tion’s new president. Dr. Treede is Chair of Neurophysiology and Managing Di-rector of the Center for Biomedicine

and Medical Te c h n o l o g y Mannheim at H e i d e l b e r g University in Germany.

Dr.Treede

assumed presidency in October at IASP’s 15th World Congress on Pain and will remain President until October 2016. He succeeds Fernando Cervero, MD, PhD, DSc, Director of the Alan Edwards Centre for Research on Pain and Professor of Anesthesiology at

McGill University in Montreal.Dr. Treede has been a member of

IASP for more than 30 years, and he is committed to expanding IASP’s scope to reach out to neighboring disciplines such as rheumatology, pediatrics, on-cology, and neurology. nRolf-Detlef Treede, MD, PhD







CW: L Gibbons


: 15.5” x 10.5” BLEED: 17.5” x 11.5”



FONTS: Myriad Pro (Regular, Bold, Condensed, Condensed Italic, Bold Condensed)


), Genentech_AMOTRG_4C.eps (96.6%

), Perjeta_US_MBC_NEO_4C.eps (65%

), 40680_KMchart_v5.eps (100%

), 40680_40062_oschartREV_v3.eps (100%)

INKS: Cyan,

Magenta, Yellow,

BlackDOC PATH: Macintosh HD:Users:paredesa:De..._JA_D01:GNH_HER_Q40680_JA_D01.inddNOTES: None


S&H

PharmaGraphics

Mech

DATE

SIGNOFF

PGQC

TCAD

CDCW

AE/ASED

PROD

C M Y K


1js

29281a1 11.4.14 133

QC

PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly extend progression-free survival (PFS) in first-line HER2+ metastatic breast cancerCombining PERJETA with Herceptin + docetaxel added 6 months median PFS2

Overall survival (OS) dataPERJETA demonstrated an OS improvement when combined with Herceptin + docetaxel at the final analysis3

6.1-month improvement in median PFS by independent review (primary endpoint)2

15.7-month improvement in median OS in the final analysis (secondary endpoint)3

HR=hazard ratio; CI=confidence interval.Median PFS was reached at the first interim analysis.2 Results of the phase III, randomized, double-blind, placebo-controlled CLEOPATRA trial in patients (N=808) with HER2+ locally recurrent, unresectable, or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. Patients received PERJETA + Herceptin + docetaxel or placebo + Herceptin + docetaxel every 3 weeks until progression or unacceptable toxicity. Primary endpoint: PFS, assessed by independent review.2

At the second interim analysis (30 months median follow-up, 1 year after the first interim analysis), the HR and P value for OS crossed the predefined efficacy stopping boundary (HR ≤0.739, P≤0.0138). OS improvement with PERJETA + trastuzumab + docetaxel was statistically significant at the second interim analysis (HR=0.66, P=0.0008).2 The final analysis was performed when 221 patient deaths occurred in the placebo-treated group and 168 in the PERJETA-treated group. The statistically significant OS benefit in favor of the PERJETA-treated group was maintained (HR=0.68, P=0.0002).3

• At the first interim analysis, PFS events occurred in 191 (47.5%) patients treated with PERJETA + Herceptin + docetaxel and 242 (59.6%) patients treated with Herceptin + docetaxel2

Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

• At the final analysis, the OS benefit was maintained (HR=0.68, 95% CI: 0.56-0.84; P=0.0002) and the median was reached in the PERJETA + Herceptin + docetaxel arm (56.5 months vs 40.8 months in the Herceptin + docetaxel arm)3

• The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy2

• Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

Hypersensitivity Reactions/Anaphylaxis• In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was

10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI- CTCAE (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis

• Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

HER2 Testing• Detection of HER2 protein overexpression is necessary for selection of patients

appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown

• Patients were required to have evidence of HER2 overexpression, defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC

• Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

Most Common Adverse Reactions• In MBC, the most common adverse reactions (>30%) seen with PERJETA in combination

with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

For more information about PERJETA, contact your local representative or visit www.PERJETA.com/hcp.

Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages.References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.3.2014. © National Comprehensive Cancer Network, Inc. 2014. All rights reserved. Accessed May 12, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. PERJETA Prescribing Information. Genentech, Inc. September 2013. 3. Data on file. Genentech, Inc. 4. Swain SM, Kim S-B, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomized, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471. 5. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

Important Safety InformationBoxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity• PERJETA administration can result in subclinical and clinical cardiac

failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function

• Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception—Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the

risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant

—If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720

—Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

Additional Important Safety InformationPERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Left Ventricular Dysfunction (LVD)• In Study 1, for patients with MBC, PERJETA in combination with Herceptin and

docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel

• Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group

• Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and in 1.8% of patients in the placebo-treated group

• Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF

• Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting) during treatment to ensure that LVEF is within your institution’s normal limits

• If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions• PERJETA has been associated with infusion reactions• In Study 1, for patients with MBC, on the first day, when only PERJETA was

administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting

• During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

© 2014 Genentech USA, Inc. All rights reserved. PER/103014/0028 Printed in USA. 10/14

• In the second interim analysis, PERJETA improved both PFS and OS when combined with Herceptin + docetaxel in patients, including the visceral metastasis subgroup4,5 — There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases

(n=178; HR=1.42 [95% CI: 0.71-2.84])2

• In the second interim analysis, there was a statistically significant improvement in OS (secondary endpoint)2 — Median not yet reached in the PERJETA-containing arm vs 37.6 months with Herceptin + docetaxel

(HR=0.66; 95% CI: 0.52-0.84; P=0.0008)

100

90

80

70

60

50

40

30

20

10

0

0 5 10 15 20 25 30 35 40

HR=0.6295% CI: 0.51-0.75

P<0.0001

402406

P+H+DPl+H+D

345311

267209

13993

8342

3217

107

00

00

Placebo + Herceptin + docetaxel

12.4MONTHS

MONTHS

PERJETA + Herceptin + docetaxel

18.5MONTHS

Patients at risk

PFS (

%) median line

MONTHS

Patients at risk

402406

P + H + D PI + H + D

371350

318289

268230

0

226179

10491

2823

10

Placebo + Herceptin + docetaxelPERJETA + Herceptin + docetaxel

56.5MONTHS

HR=0.68 95% CI: 0.56-0.84

P=0.0002

40.8MONTHS

median line

30

20

10

020 30 40 50 60 70

100

90

80

70

60

50

40

10

OS (%

)

00

80

G:1.0”

S:9.875”

T:15.5”

T:10.5”

B:17.5”

B:11.5”

S:6.875” S:6.875”


Announcements

ACCC Honors Nicholas J. Petrelli, MD, With 2014 Clinical Research Award

Nicholas J. Petrelli, MD, FACS, the Bank of America endowed Medi-

cal Director of Christiana Care’s Helen F. Graham Cancer Center & Research Institute, Newark, Delaware, received the 2014 Clinical Research Award from the Association of Community Cancer

Centers (ACCC) in recognition of his leadership initiatives promoting and ad-vocating for oncology clinical research. The ACCC presented Dr. Petrelli with the award at the 31st National Oncology Conference held recently in San Diego.

A recognized expert on colorectal

cancer, Dr. Petrelli has led the devel-opment of a state-of-the-art clinical oncology care program at the Graham Cancer Center. The center has served as a National Cancer Institute (NCI) Community Cancer Center Program site and has achieved an accrual rate of

24% in NCI-sponsored clinical trials, well above the national rate of 5%.

In August 2014 the Graham Can-cer Center earned a 5-year, $8.2 million grant from NCI’s Community Oncology Research Program to bring leading-edge cancer screenings, prevention, control,

PERJETA® (pertuzumab)INJECTION, FOR INTRAVENOUS USEINITIAL U.S. APPROVAL: 2012

WARNING: CARDIOMYOPATHY and EMBRYO-FETAL TOXICITY

Cardiomyopathy PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.2, 6.1)Embryo-Fetal Toxicity Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC)PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

1.2 Neoadjuvant Treatment of Breast CancerPERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)]. Limitations of Use: • The safety of PERJETA as part of a doxorubicin-containing

regimen has not been established. • The safety of PERJETA administered for greater than

6 cycles for early breast cancer has not been established.

4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

5 WARNINGS AND PRECAUTIONS5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known.

5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF.

In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxel-treated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients.In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient.PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent.Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)].

5.3 Infusion-Related ReactionsPERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting.During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting.In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v3.0) Grade 1 – 2.Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)].

5.4 Hypersensitivity Reactions/AnaphylaxisIn Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.

In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the PERJETA- and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCI-CTCAE (version 3) Grade 3 – 4.Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)]. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)].

5.5 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC.Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label:• Embryo-Fetal Toxicity [see Warnings and Precautions

(5.1)] • Left Ventricular Dysfunction [see Warnings and

Precautions (5.2)]• Infusion-Related Reactions [see Warnings and

Precautions (5.3)]• Hypersensitivity Reactions/Anaphylaxis [see Warnings


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.Metastatic Breast Cancer (MBC)The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional year of follow-up (median total follow-up of 30 months) in Study 1. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 3.3Asthenia 26.0 2.5 30.2 1.5Edema peripheral 23.1 0.5 30.0 0.8Mucosal inflammation 27.8 1.5 19.9 1.0Pyrexia 18.7 1.2 17.9 0.5Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 0.3Rash 33.7 0.7 24.2 0.8Nail disorder 22.9 1.2 22.9 0.3Pruritus 14.0 0.0 10.1 0.0Dry skin 10.6 0.0 4.3 0.0Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 5.0Nausea 42.3 1.2 41.6 0.5Vomiting 24.1 1.5 23.9 1.5Constipation 15.0 0.0 24.9 1.0Stomatitis 18.9 0.5 15.4 0.3Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 45.8Anemia 23.1 2.5 18.9 3.5Leukopenia 18.2 12.3 20.4 14.6Febrile neutropenia* 13.8 13.0 7.6 7.3Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 2.0Headache 20.9 1.2 16.9 0.5Dysgeusia 18.4 0.0 15.6 0.0Dizziness 12.5 0.5 12.1 0.0Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 0.8Arthralgia 15.5 0.2 16.1 0.8Infections and infestationsUpper respiratory tract infectionNasopharyngitis 11.8 0.0 12.8 0.3Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 2.0Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 1.5Eye disorders Lacrimation increased 14.0 0.0 13.9 0.0Psychiatric disorders Insomnia 13.3 0.0 13.4 0.0

The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in Study 1:Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebo-treated group)Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebo-treated group)Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebo-treated group)Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group)Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of DocetaxelIn Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).Neoadjuvant Treatment of Breast Cancer (Study 2)In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1. The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2.

Table 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel)Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm)Immune system disorders: Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm)Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm)Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm)Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm)Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm)Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm)Neoadjuvant Treatment of Breast Cancer (Study 3)In Study 3, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for

patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3.

Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumabThe following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab)Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 3.9% in the Ptz+TCH arm)Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm)

Body System/ Adverse Reactions

Trastuzumab + docetaxel

n=107

PERJETA+ trastuzumab + docetaxel

n=107

PERJETA + trastuzumab

n=108

PERJETA + docetaxel

n=108Frequency rate

%Frequency rate

%Frequency rate

%Frequency rate

%All

Grades %

Grades 3–4 %

All Grades

%

Grades 3–4 %

All Grades

%

Grades 3–4 %

All Grades

%

Grades 3–4 %

General disorders and administration site conditionsFatigue 27.1 0.0 26.2 0.9 12.0 0.0 25.5 1.1Asthenia 17.8 0.0 20.6 1.9 2.8 0.0 16.0 2.1Edema peripheral 10.3 0.0 2.8 0.0 0.9 0.0 5.3 0.0

Mucosal inflammation 21.5 0.0 26.2 1.9 2.8 0.0 25.5 0.0

Pyrexia 10.3 0.0 16.8 0.0 8.3 0.0 8.5 0.0Skin and subcutaneous tissue disordersAlopecia 66.4 0.0 65.4 0.0 2.8 0.0 67.0 0.0Rash 21.5 1.9 26.2 0.9 11.1 0.0 28.7 1.1Gastrointestinal disordersDiarrhea 33.6 3.7 45.8 5.6 27.8 0.0 54.3 4.3Nausea 36.4 0.0 39.3 0.0 13.9 0.0 36.2 1.1Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 16.0 2.1Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 9.6 0.0Blood and lymphatic system disordersNeutropenia 63.6 58.9 50.5 44.9 0.9 0.9 64.9 57.4Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 13.8 8.5Nervous system disordersHeadache 11.2 0.0 11.2 0.0 13.9 0.0 12.8 0.0Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 7.4 0.0Peripheral SensoryNeuropathy

12.1 0.9 8.4 0.9 1.9 0.0 10.6 0.0

Musculoskeletal and connective tissue disordersMyalgia 22.4 0.0 22.4 0.0 9.3 0.0 21.3 0.0Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 9.6 0.0Metabolism and nutrition disordersDecreased appetite 6.5 0.0 14.0 0.0 1.9 0.0 14.9 0.0

Psychiatric disordersInsomnia 11.2 0.0 8.4 0.0 3.7 0.0 8.5 0.0


PERJETA + trastuzumab + FEC followed

by PERJETA + trastuzumab + docetaxel

n=72

PERJETA + trastuzumab + docetaxel

following FECn=75

PERJETA + TCHn=76

Frequency rate, % Frequency rate, % Frequency rate, %

All Grades

%

Grades 3 – 4

%

All Grades

%

Grades 3 – 4

%

All Grades

%

Grades 3 – 4

%

General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 3.9Asthenia 9.7 0.0 14.7 1.3 13.2 1.3Edema peripheral 11.1 0.0 4.0 0.0 9.2 0.0Mucosal inflammation 23.6 0.0 20.0 0.0 17.1 1.3Pyrexia 16.7 0.0 9.3 0.0 15.8 0.0Skin and subcutaneous tissue disordersAlopecia 48.6 0.0 52.0 0.0 55.3 0.0Rash 19.4 0.0 10.7 0.0 21.1 1.3Dry skin 5.6 0.0 9.3 0.0 10.5 0.0Palmar-Plantar Erythrodysaesthesia Syndrome

6.9 0.0 10.7 0.0 7.9 0.0

Gastrointestinal disordersDiarrhea 61.1 4.2 61.3 5.3 72.4 11.8Dyspepsia 25.0 1.4 8 0.0 22.4 0.0Nausea 52.8 0.0 53.3 2.7 44.7 0.0Vomiting 40.3 0.0 36.0 2.7 39.5 5.3Constipation 18.1 0.0 22.7 0.0 15.8 0.0Stomatitis 13.9 0.0 17.3 0.0 11.8 0.0Blood and lymphatic system disordersNeutropenia 51.4 47.2 46.7 42.7 48.7 46.1Anemia 19.4 1.4 9.3 4.0 38.2 17.1Leukopenia 22.2 19.4 16.0 12.0 17.1 11.8Febrile neutropenia 18.1 18.1 9.3 9.3 17.1 17.1Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 11.8Immune system disordersHypersensitivity 9.7 2.8 1.3 0.0 11.8 2.6Nervous system disordersNeuropathy peripheral 5.6 0.0 1.3 0.0 10.5 0.0Headache 22.2 0.0 14.7 0.0 17.1 0.0Dysgeusia 11.1 0.0 13.3 0.0 21.1 0.0Dizziness 8.3 0.0 8.0 1.3 15.8 0.0Musculoskeletal and connective tissue disordersMyalgia 16.7 0.0 10.7 1.3 10.5 0.0Arthralgia 11.1 0.0 12.0 0.0 6.6 0.0Respiratory, thoracic, and mediastinal disordersCough 9.7 0.0 5.3 0.0 11.8 0.0Dyspnea 12.5 0.0 8.0 2.7 10.5 1.3Epistaxis 11.1 0.0 10.7 0.0 15.8 1.3Oropharyngeal pain 8.3 0.0 6.7 0.0 11.8 0.0Metabolism and nutrition disordersDecreased appetite 20.8 0.0 10.7 0.0 21.1 0.0Eye disordersLacrimation increased 12.5 0.0 5.3 0.0 7.9 0.0Psychiatric disordersInsomnia 11.1 0.0 13.3 0.0 21.1 0.0InvestigationsALT increased 6.9 0.0 2.7 0.0 10.5 3.9



Placebo + trastuzumab + docetaxel

n=407 n=397Frequency rate, % Frequency rate, %

All Grades, %

Grades 3–4, %

All Grades, %

Grades 3–4, %

* In this table this denotes an adverse reaction that has been reported in association with a fatal outcome

16.7 0.7 13.4 0.0


Announcements

Nicholas J. Petrelli, MD

treatment, and imaging research trials to more people in the places closest to where they live.

In addition, Dr. Petrelli spearheaded the development of a Tissue Procure-ment Center with more than 5,000 specimens, cataloged through the NCI’s Cancer Bioinformatics Grid (caBIG/caTissue), which led to $4.6 million

funding for participation in the Cancer Genome Atlas Project. Dr. Petrelli also developed the first Delaware statewide High Risk Family Cancer Registry, con-sisting of 5,640 families with more than 200,000 individuals.

Dr. Petrelli joined Helen F. Graham Cancer Center & Research Institute in August 2001. Previously, he was Chair

of the Department of Surgical Oncology and Director of the Surgical Oncology fel-lowship training program at Roswell Park Cancer Institute. He received his medical degree from Tulane Medical School in New Orleans, Louisiana. Following a gen-eral surgery residency in San Francisco, he completed a surgical oncology fellowship at Roswell Park Cancer Institute. n

©A

SCO

/Zac

h B

oyde

n-H

olm

es






















Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 3.3Asthenia 26.0 2.5 30.2 1.5Edema peripheral 23.1 0.5 30.0 0.8Mucosal inflammation 27.8 1.5 19.9 1.0Pyrexia 18.7 1.2 17.9 0.5Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 0.3Rash 33.7 0.7 24.2 0.8Nail disorder 22.9 1.2 22.9 0.3Pruritus 14.0 0.0 10.1 0.0Dry skin 10.6 0.0 4.3 0.0Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 5.0Nausea 42.3 1.2 41.6 0.5Vomiting 24.1 1.5 23.9 1.5Constipation 15.0 0.0 24.9 1.0Stomatitis 18.9 0.5 15.4 0.3Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 45.8Anemia 23.1 2.5 18.9 3.5Leukopenia 18.2 12.3 20.4 14.6Febrile neutropenia* 13.8 13.0 7.6 7.3Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 2.0Headache 20.9 1.2 16.9 0.5Dysgeusia 18.4 0.0 15.6 0.0Dizziness 12.5 0.5 12.1 0.0Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 0.8Arthralgia 15.5 0.2 16.1 0.8Infections and infestationsUpper respiratory tract infectionNasopharyngitis 11.8 0.0 12.8 0.3Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 2.0Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 1.5Eye disorders Lacrimation increased 14.0 0.0 13.9 0.0Psychiatric disorders Insomnia 13.3 0.0 13.4 0.0

The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in Study 1:Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebo-treated group)Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebo-treated group)Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebo-treated group)Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group)Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of DocetaxelIn Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).Neoadjuvant Treatment of Breast Cancer (Study 2)In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1. The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2.

Table 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel)Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm)Immune system disorders: Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm)Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm)Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm)Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm)Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm)Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm)Neoadjuvant Treatment of Breast Cancer (Study 3)In Study 3, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for

patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3.

Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumabThe following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab)Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 3.9% in the Ptz+TCH arm)Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm)


Trastuzumab + docetaxel

n=107

PERJETA+ trastuzumab + docetaxel

n=107

PERJETA + trastuzumab

n=108

PERJETA + docetaxel

n=108Frequency rate

%Frequency rate

%Frequency rate

%Frequency rate

%All

Grades %

Grades 3–4 %

All Grades

%

Grades 3–4 %

All Grades

%

Grades 3–4 %

All Grades

%

Grades 3–4 %

General disorders and administration site conditionsFatigue 27.1 0.0 26.2 0.9 12.0 0.0 25.5 1.1Asthenia 17.8 0.0 20.6 1.9 2.8 0.0 16.0 2.1Edema peripheral 10.3 0.0 2.8 0.0 0.9 0.0 5.3 0.0

Mucosal inflammation 21.5 0.0 26.2 1.9 2.8 0.0 25.5 0.0

Pyrexia 10.3 0.0 16.8 0.0 8.3 0.0 8.5 0.0Skin and subcutaneous tissue disordersAlopecia 66.4 0.0 65.4 0.0 2.8 0.0 67.0 0.0Rash 21.5 1.9 26.2 0.9 11.1 0.0 28.7 1.1Gastrointestinal disordersDiarrhea 33.6 3.7 45.8 5.6 27.8 0.0 54.3 4.3Nausea 36.4 0.0 39.3 0.0 13.9 0.0 36.2 1.1Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 16.0 2.1Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 9.6 0.0Blood and lymphatic system disordersNeutropenia 63.6 58.9 50.5 44.9 0.9 0.9 64.9 57.4Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 13.8 8.5Nervous system disordersHeadache 11.2 0.0 11.2 0.0 13.9 0.0 12.8 0.0Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 7.4 0.0Peripheral SensoryNeuropathy

12.1 0.9 8.4 0.9 1.9 0.0 10.6 0.0

Musculoskeletal and connective tissue disordersMyalgia 22.4 0.0 22.4 0.0 9.3 0.0 21.3 0.0Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 9.6 0.0Metabolism and nutrition disordersDecreased appetite 6.5 0.0 14.0 0.0 1.9 0.0 14.9 0.0

Psychiatric disordersInsomnia 11.2 0.0 8.4 0.0 3.7 0.0 8.5 0.0


PERJETA + trastuzumab + FEC followed

by PERJETA + trastuzumab + docetaxel

n=72


following FECn=75

PERJETA + TCHn=76

Frequency rate, % Frequency rate, % Frequency rate, %

All Grades

%

Grades 3 – 4

%

All Grades

%

Grades 3 – 4

%

All Grades

%

Grades 3 – 4

%

General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 3.9Asthenia 9.7 0.0 14.7 1.3 13.2 1.3Edema peripheral 11.1 0.0 4.0 0.0 9.2 0.0Mucosal inflammation 23.6 0.0 20.0 0.0 17.1 1.3Pyrexia 16.7 0.0 9.3 0.0 15.8 0.0Skin and subcutaneous tissue disordersAlopecia 48.6 0.0 52.0 0.0 55.3 0.0Rash 19.4 0.0 10.7 0.0 21.1 1.3Dry skin 5.6 0.0 9.3 0.0 10.5 0.0Palmar-Plantar Erythrodysaesthesia Syndrome

6.9 0.0 10.7 0.0 7.9 0.0

Gastrointestinal disordersDiarrhea 61.1 4.2 61.3 5.3 72.4 11.8Dyspepsia 25.0 1.4 8 0.0 22.4 0.0Nausea 52.8 0.0 53.3 2.7 44.7 0.0Vomiting 40.3 0.0 36.0 2.7 39.5 5.3Constipation 18.1 0.0 22.7 0.0 15.8 0.0Stomatitis 13.9 0.0 17.3 0.0 11.8 0.0Blood and lymphatic system disordersNeutropenia 51.4 47.2 46.7 42.7 48.7 46.1Anemia 19.4 1.4 9.3 4.0 38.2 17.1Leukopenia 22.2 19.4 16.0 12.0 17.1 11.8Febrile neutropenia 18.1 18.1 9.3 9.3 17.1 17.1Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 11.8Immune system disordersHypersensitivity 9.7 2.8 1.3 0.0 11.8 2.6Nervous system disordersNeuropathy peripheral 5.6 0.0 1.3 0.0 10.5 0.0Headache 22.2 0.0 14.7 0.0 17.1 0.0Dysgeusia 11.1 0.0 13.3 0.0 21.1 0.0Dizziness 8.3 0.0 8.0 1.3 15.8 0.0Musculoskeletal and connective tissue disordersMyalgia 16.7 0.0 10.7 1.3 10.5 0.0Arthralgia 11.1 0.0 12.0 0.0 6.6 0.0Respiratory, thoracic, and mediastinal disordersCough 9.7 0.0 5.3 0.0 11.8 0.0Dyspnea 12.5 0.0 8.0 2.7 10.5 1.3Epistaxis 11.1 0.0 10.7 0.0 15.8 1.3Oropharyngeal pain 8.3 0.0 6.7 0.0 11.8 0.0Metabolism and nutrition disordersDecreased appetite 20.8 0.0 10.7 0.0 21.1 0.0Eye disordersLacrimation increased 12.5 0.0 5.3 0.0 7.9 0.0Psychiatric disordersInsomnia 11.1 0.0 13.3 0.0 21.1 0.0InvestigationsALT increased 6.9 0.0 2.7 0.0 10.5 3.9



Placebo + trastuzumab + docetaxel

n=407 n=397Frequency rate, % Frequency rate, %

All Grades, %

Grades 3–4, %

All Grades, %

Grades 3–4, %

* In this table this denotes an adverse reaction that has been reported in association with a fatal outcome

16.7 0.7 13.4 0.0


Announcements

Yale Cancer Center’s Dr. Susan Mayne Appointed to FDA Position

Susan T. Mayne, PhD, C-EA, Win-slow Professor of Epidemiology; As-

sociate Director for Population Sciences at Yale Cancer Center; and Chair of the Department of Chronic Disease Epide-miology at Yale School of Public Health, has been appointed to the position of

Center Director of the Center for Food Safety and Applied Nutrition (CFSAN) at the U.S. Food and Drug Administra-tion (FDA).

Dr. Mayne joined Yale University in 1987 as a post-doctoral fellow, and di-rected Yale Cancer Center’s Cancer Pre-

vention and Control Research Program from 1993-2010. She also served as As-sociate Director for Population Sciences from 1995. Dr. Mayne played a key role in Cancer Center leadership and contrib-uted significantly to the Center’s ongo-ing status as a National Cancer Institute

(NCI) Comprehensive Cancer Center.“Dr. Mayne’s leadership has been

invaluable in the growth and evolution of Yale Cancer Center,” said Thomas J. Lynch, MD, Director of the Yale Cancer Center. “It is a testament to her research excellence and exceptional leadership that she has been given this new oppor-tunity to apply her expertise to significant public health issues at the national level.”

Supporting Public HealthDr. Mayne and her trainees have re-

ceived national recognition for their out-standing research, and Dr. Mayne is the recipient of several national awards in mentoring/training and for her service to many organizations, including the Na-tional Academy of Sciences. She is well known in the cancer community, having served on the Board of Scientific Coun-selors for the NCI. Dr. Mayne has also led a competitively funded cooperative train-ing program in cancer epidemiology and genetics with the NCI since 2003.

The FDA center she will lead is respon-sible for promoting the public’s health by ensuring that the nation’s food supply is safe, sanitary, wholesome, and honestly la-beled, and that cosmetic products are safe and properly labeled. The center regulates $417 billion worth of domestic food, $49 billion worth of imported foods, and over $60 billion worth of cosmetics sold across state lines, and is supported by a staff of over 800 employees, with a budget of nearly $300 million, over one-third of which supports research.

The CFSAN is the scientific, regu-latory, and educational cornerstone of the U.S. food and nutrition system, working to reduce chronic diseases like cancer and obesity. In today’s global marketplace, it has an important international role as well, routinely en-gaging foreign governments. Drawing on her scientific background in nutri-tion, toxicology, epidemiology, and public health, Dr. Mayne will provide strong leadership and continue to el-evate the Center’s work across many diverse areas ranging from the detec-tion of foodborne pathogens to food labeling/health claims on foods. n

Susan T. Mayne, PhD, C-EA























Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Hodgkin Lymphoma and Non-Hodgkin LymphomaCompiled by Jo Cavallo

PILOT

Study Type: Pilot/interventional/single-group assignment

Study Title: Safety and Feasibil-ity of Gene Transfer After Frontline Chemotherapy for Non-Hodgkin Lymphoma in AIDS Patients Using Pe-ripheral Blood Stem/Progenitor Cells Treated With a Lentivirus Vector-En-coding Multiple Anti-HIV RNAs

Study Sponsor and Collaborators: City of Hope Medical Center; National Cancer Institute

Purpose: To study gene therapy after front-line chemotherapy in treat-ing patients with AIDS-related non-Hodgkin lymphoma. Placing genes for anti–human immunodeficiency virus (HIV) RNA into stem/progenitor cells may make the body build an immune response to AIDS. Giving the chemo-therapy drug busulfan (Busulfex) be-fore gene therapy can help gene-modi-fied cells engraft and work better.

Ages Eligible for Study: 18 to 65 years

Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: Pro-

cedure related toxicity as determined by adverse events grading scale using the NCI Common Terminology Crite-ria for Adverse Events version 4.0 (time frame: up to 15 years)

Principal Investigator: Amrita Y.

Krishnan, MD, City of Hope; 626-256-4673, [email protected].

For More Information: Visit Clini-calTrials.gov and refer to this study by its identifier: NCT01961063

Study Type: Pilot/interventional/single-group assignment

Study Title: A Pilot Study of Single-Agent Ibrutinib in Relapsed or Refrac-tory Transformed Indolent B-Cell Non-Hodgkin Lymphoma

Study Sponsor and Collaborators: University of Washington; National Cancer Institute

Purpose: To study ibrutinib (Im-bruvica) in the treatment of patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma

Ages Eligible for Study: 18 years and older

Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures:

Overall response rate, combined com-plete response, plus partial response (time frame: up to 5 years)

Principal Investigator: Ajay K. Go-pal, MD, Fred Hutchinson Cancer Re-search Center/University of Washing-ton Cancer Consortium; 206-288-2037


PHASE I

Study Type: Phase I/intervention-al/single-group assignment

Study Title: Phase I Study of the Aurora Kinase Inhibitor MLN8237 in Combination With the Histone Deacet-ylase Inhibitor Vorinostat in Lymphoid Malignancies

Study Sponsor and Collaborators: National Cancer Institute

Purpose: To study the side ef-fects and the best dose of alisertib (MLN8237) when given together with vorinostat (Zolinza) in treating patients with relapsed or recurrent Hodgkin lymphoma, B-cell non-Hodgkin lym-phoma, or peripheral T-cell lymphoma



Maximum-tolerated dose of alisertib defined as the highest dose tested in

which less than 33% of patients expe-rienced dose-limiting toxicity graded according to the NCI Common Termi-nology Criteria for Adverse Events ver-sion 4.0 (time frame: 21 days)

Principal Investigator: Tanya Sid-diqi, MD, Beckman Research Institute; 626-256-4673, [email protected]



Study Title: A Phase I Study of MLN8237 in Combination With Bort-ezomib and Rituximab in Relapsed and Refractory Mantle Cell and Low Grade Non-Hodgkin Lymphoma


Purpose: To study the side effects and best dose of alisertib (MLN8237) and bortezomib (Velcade) when given together with rituximab (Rituxan) in treating patients with mantle cell lym-phoma or B-cell low-grade non-Hodg-kin lymphoma that has relapsed or is refractory


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: Rec-

ommended phase II dose of alisertib when combined with bortezomib and rituximab, defined as the highest dose level at which < 33% of the dose co-hort experience a dose-limiting toxicity (time frame: 21 days)

Principal Investigator: Catherine S. Diefenbach, MD, Montefiore Medi-cal Center; 212-731-5670, [email protected]



Study Title: Phase I Study of the Administration of EBV CTLs Express-ing CD30 Chimeric Receptors for Re-lapsed CD30+ Hodgkin’s Lymphoma and CD30+ Non-Hodgkin’s Lympho-ma (CAR CD 30)

Study Sponsor and Collaborators: Baylor College of Medicine; Center for Cell and Gene Therapy, Baylor College of Medicine; Texas Children’s Hospital;

The Methodist Hospital SystemPurpose: Researchers have found

that they can put a new gene into T cells that will make them recognize cancer cells and kill them. This study will inves-tigate whether researchers can attach a new gene to T cells that will help them do a better job at recognizing and killing lymphoma cells.


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: To

evaluate the safety of escalating doses of autologous EBV-specific cytotoxic T lymphocytes (time frame: 6 weeks)

Principal Investigator: Helen E. Heslop, MD, Baylor College of Medi-cine/Center for Cell and Gene Thera-py; 832-824-4662, [email protected]



Study Title: Phase I Dose-Escala-tion Study of CPI-613, in Combination With Bendamustine, in Patients With Relapsed or Refractory T-Cell Non-Hodgkin Lymphoma or Classic Hodg-kin Lymphoma

Study Sponsor and Collabora-tors: Comprehensive Cancer Center of Wake Forest University; National Cancer Institute

Purpose: To test the side effects and best dose of CPI-613 when given to-gether with bendamustine hydrochlo-ride (Treanda) in patients with relapsed or refractory T-cell non-Hodgkin lym-phoma or Hodgkin lymphoma



Maximum tolerated dose of 6,8-bis (benzylthio) octanoic acid when used in combination with bendamustine hy-drochloride, defined as the dose level immediately below the dose level that induced a dose-limiting toxicity in pa-tients (time frame: up to 28 days)

Principal Investigator: Zanetta S. Lamar, MD, Comprehensive Cancer Center of Wake Forest University; 336-716-7448, [email protected]

The information contained in this Clinical Trials Resource

Guide includes clinical studies actively recruiting people with Hodgkin lymphoma, non-Hodg-kin lymphoma (NHL), including AIDS-related NHL, as well as stud-ies that are also recruiting patients with multiple myeloma and mantle cell lymphoma. The studies include pilot, phase I, II, and interventional trials evaluating gene therapy; ther-apies in the relapsed/refractory set-ting; single-agent and combination chemotherapies; and a geriatric as-sessment to predict chemotherapy or chemoimmunotherapy toxicity in older patients with NHL. All of the studies are listed on the Na-tional Institutes of Health website at ClinicalTrials.gov.
























Clinical Trials Resource Guide

Hodgkin and Non-Hodgkin Lymphomacontinued from page 125



Study Title: Phase I Study of Cel-lular Immunotherapy Using Central Memory-Enriched T Cells Lentivi-rally Transduced to Express a CD19-Specific, Hinge-Optimized, CD28-Co-stimulatory Chimeric Receptor and a Truncated EGFR Following Peripheral Blood Stem Cell Transplantation for Patients With High-Risk Intermedi-ate Grade B-Lineage Non-Hodgkin Lymphoma

Study Sponsor and Collaborators: City of Hope Medical Center; National Cancer Institute

Purpose: To investigate the highest possible dose of central memory en-riched T cells that can be given follow-ing standard stem cell transplant before unmanageable side effects are seen in patients with B-cell non-Hodgkin lym-phoma that has returned after previous treatment



Incidence of dose-limiting toxicities defined as any grade 3 or higher tox-icity requiring the use of steroids, any grade 3 or greater autoimmune toxic-ity, or failure for a research participant with documented T-cell persistence to engraft by day 21 post–hematopoietic stem cell transplant (time frame: up to 28 days)

Principal Investigator: Leslie L. Popplewell, MD, City of Hope Medical Center; 800-826-4673



Study Title: Phase I and Pharma-cokinetic Study of Ibrutinib in HIV-Infected Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lym-phoma or Multiple Myeloma


Purpose: To study the side effects and best dose of ibrutinib (Imbruvica) in the treatment of B-cell non-Hodgkin lymphoma that has recurred or does

not respond to treatment in patients with human immunodeficiency virus (HIV) infection


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: Inci-

dence of toxicities assessed using NCI Common Terminology Criteria for Ad-verse Events version 4.0 (time frame: 28 days)

Principal Investigator: Yvette L. Kasamon, MD, AIDS Associated Ma-lignancies Clinical Trials Consortium; 410-955-8839, [email protected]


PHASE II

Study Type: Phase II/Intervention-al/Single Group Assignment

Study Title: A Phase 2 Multicenter Study of High Dose Chemotherapy With Autologous Stem Cell Transplant Followed by Maintenance Therapy With Romidepsin for the Treatment of T-Cell Non-Hodgkin Lymphoma

Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Cen-ter; University of Washington; Weill Medical College of Cornell University

Purpose: To test the benefit of ro-midepsin (Istodax) in patients with T-cell non-Hodgkin lymphoma who have undergone autologous transplantation



Progression-free survival for patients with high-risk histologies (time frame: 2 years)

Principal Investigator: Steven Horowitz, MD, Memorial Sloan Ketter-ing Cancer Center; 212-639-3045


Study Type: Phase II/intervention-al/single-group assignment

Study Title: A Phase II Trial of Pros-taglandin E2 Inhibition, Using Meloxi-cam, Plus Filgrastim for Mobilization of Autologous Peripheral Blood Stem Cells in Patients With Multiple Myelo-ma and Non-Hodgkin’s Lymphoma

Study Sponsor and Collabora-tors: Indiana University; National Cancer Institute

Purpose: This trial is an open-label

Simon optimal two-stage phase II trial of fixed doses of oral meloxicam and subcutaneous filgrastim (Neupogen) to assess the safety and efficacy in mo-bilizing autologous peripheral blood stem cells from patients with multiple myeloma and non-Hodgkin lymphoma who are planning to undergo high-dose chemotherapy with stem cell support. Clinical data regarding the cellular composition and function of the graft mobilized by this combination will be obtained.



Number of patients who mobilize and collect at least half of the total target CD34-positive cell dose in the first apheresis (time frame: 4 years)

Principal Investigator: Sherif Far-ag, MBBS, PhD, Indiana University; 317-944-1781, [email protected]


Study Type: Phase II/intervention-al/single-group assignment

Study Title: Once Daily Intrave-nous Busulfex as Part of Reduced-tox-icity Conditioning for Patients With Relapsed/Refractory Hodgkin’s and Non-Hodgkin’s Lymphomas Under-going Allogeneic Hematopoietic Pro-genitor Cell Transplantation—A Multi-center Phase II Study

Study Sponsor and Collaborators: West Virginia University

Purpose: To investigate reduced toxicity conditioning with once daily intravenous busulfan (Busulfex) and fludarabine in patients with relapsed/refractory Hodgkin and non-Hodgkin lymphoma undergoing allogeneic he-matopoietic cell transplantation

Ages Eligible for Study: 18 to 70 years

Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: To

assess 1 year progression-free survival in patients with chemotherapy-refrac-tory Hodgkin and non-Hodgkin lym-phoma undergoing reduced-toxicity conditioning with once daily intrave-nous busulfan and fludarabine (time frame: 1 year)

Principal Investigator: Abraham Kanate, MD, West Virginia University. Contact: Crystal Stevens, MT; 304-598-4512, [email protected]

For More Information: Visit Clini-

calTrials.gov and refer to this study by its identifier: NCT01203020

INTERVENTIONAL

Study Type: Interventional/single-group assignment

Study Title: Personalized Monitor-ing of Intravenous Busulfan Dosing for Patients With Lymphoma Undergoing Autologous Stem Cell Transplantation

Study Sponsor and Collaborators: Case Comprehensive Cancer Center; National Cancer Institute

Purpose: To investigate personal-ized dose monitoring of busulfan (Bu-sulfex) and combination chemotherapy in treating patients with Hodgkin or non-Hodgkin lymphoma undergoing stem cell transplant


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: Fea-

sibility of performing real-time thera-peutic dose monitoring, determined by the proportion of enrolled patients who are able to have an area under the curve for busulfan calculated (time frame: up to day 6)

Principal Investigator: Brian T. Hill, MD, Case Comprehensive Cancer Center; 216-445-9451, [email protected]


Study Type: Interventional/non-randomized/parallel assignment

Study Title: Comprehensive Geriat-ric Assessment to Predict Toxic Events in Older Patients With Non-Hodgkin Lymphoma With Imbedded Pilot Study of Pre-Phase Therapy

Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center

Purpose: To evaluate the ability of a largely self-administered geriatric as-sessment to predict toxicity in patients 60 years and older with non-Hodgkin lymphoma receiving chemotherapy or chemoimmunotherapy


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: Tox-

icity assessment (time frame: 3 years)Principal Investigator: Paul Ham-

lin, MD, Memorial Sloan Kettering Cancer Center; 212-639-6143

For More Information: Visit Clini-calTrials.gov and refer to this study by its identifier: NCT01829958 n


Announcements

Fred Hutchinson Cancer Research Center Recruits D. Gary Gilliland, MD, PhD as New President and Director

Fred Hutchinson Cancer Research Center announced that it has

named D. Gary Gilliland, MD, PhD, an expert in cancer genetics and preci-sion medicine as its new President and Director. He will take the helm as the Center’s new leader on January 2.

Dr. Gilliland comes to Fred Hutchinson from the University of Pennsylvania’s Perelman School of Medicine, where he was the Vice President of Precision Medicine. Prior to that he was an executive at Merck Research Laboratories and also spent more than 20 years at Harvard Medi-cal School, where he was a Professor of Medicine and a Howard Hughes Medi-cal Institute investigator.

Seminal DiscoveriesDr. Gilliland has made seminal dis-

coveries that have shed light on the genetic basis of leukemias and other blood cancers. His work has led to the development of new investigational cancer treatments, including precise, molecularly targeted therapies tailored to the unique characteristics of each patient’s tumor.

He is deeply familiar with Fred Hutch’s innovative research in the areas of immunotherapy, personalized medi-cine, bone marrow transplantation and more, so when he was tapped for the position, he said he couldn’t resist.

“It feels like coming home,” he said. “It feels like I’ve been preparing my entire life for this job. This is the per-fect time and perfect place and oppor-tunity to truly target cures for cancer. Everything I’ve done in my career has pointed here.”

‘Deep Thinker’Fred Appelbaum, MD, Deputy

Director of Fred Hutchinson, who has known Gilliland for more than 25 years, said he couldn’t be happier about the new President and Director. “Gary is a really wonderful scientist who thinks deeply about problems,

comes up with ideas and a hypothesis before anyone else does, and has tech know-how,” he said.

Gilliland has received many honors and awards for his academic research,

including the William Dameshek Prize from the American Society of Hematology, the Emil J. Freireich Award from the MD Anderson Cancer Center and the Stanley J. Korsmeyer

Award from the American Society for Clinical Investigation, of which he is an elected member. He is also an elected member of the American As-sociation of Physicians. n

D. Gary Gilliland, MD, PhD

Key inclusion criteria• Metastatic or unresectable locally advanced NSCLC • T790M mutation-positive tumor • Progression after only one prior EGFR-targeted therapy • Previous treatment with ≤1 prior chemotherapy • No intervening treatment between prior EGFR-targeted therapy and rociletinib

Primary endpoint• Objective response rate

Rociletinib(CO-1686)

NOW ENROLLING: 2L T790M+ MUTANT EGFR NSCLC

Evaluating the safety and efficacy of rociletinib (CO-1686) in patients withnon–small cell lung cancer (NSCLC) with the T790M EGFR mutation

Call:• 1-855-262-3040 (inside the United States) • +1-303-625-5160 (outside the United States)

Visit:• TIGERtrials.com• clinicaltrials.gov (NCT02147990)

E-mail:• [email protected]

Learn more about all ongoing TIGER clinical trials at TIGERtrials.com.

Rociletinib (CO-1686) is an investigational product and is not approved in any country.

Copyright © 2014 Clovis Oncology. ROCI-201 10/14

For more details about the TIGER-2 trial or to refer a patient

26186_clovco_fa4_ascopst.indd 1 10/27/14 3:31 PM

http://www.clovisoncology.com


In the News

South Korean Study Sparks Warnings About the Hazards of OverscreeningBy Charlotte Bath

An “epidemic of diagnosis” of thy-roid cancer is occurring in South

Korea and “absolutely could happen here,” according to H. Gilbert Welch, MD, MPH, Professor of Medicine at the Dartmouth Institute for Health Pol-icy and Clinical Practice, Hanover, New Hampshire. Dr. Welch is coauthor of an article in The New England Journal of Medicine1 reporting that widespread and inexpensive thyroid cancer screening in South Korea led to a 15-fold increase in the rate of thyroid cancer diagnoses there over the past 2 decades. The authors sug-gest that if the United States and other countries “want to prevent their own ‘epidemic,’ they will need to discourage early thyroid-cancer detection.”

In an interview with The ASCO Post, Dr. Welch said, “As a profession, this is a place where we need to actively discour-age early detection, because so many people have thyroid nodules, and such a high proportion of them could be said to be cancer.” Virtually all of the tumors found in the South Korean screening program were papillary thyroid tumors,

“the vast majority of which will not pro-duce symptoms during a person’s life-time,” according to the journal article.

Problem Is Not Just Screening “The problem is not just screening,

as in people coming in for an ultra-sound,” Dr. Welch stated. Problems also arise when patients are encouraged to do neck exams. “We shouldn’t have the public starting to worry and systemati-cally try to feel bumps in their thyroid. That would be the wrong thing to do,” Dr. Welch said.

“We’ve got another issue,” he add-ed, “which is that we have enough im-aging going on near the thyroid that physicians stumble on to thyroid nod-ules” while performing carotid duplex or other scans. And “once they’re stumbled on,” it sets in motion the sequence of diagnosis and treatment. “It would be very useful for us also to discourage that kind of action,” Dr. Welch noted.

“The first thing is to mitigate as much unnecessary testing as possible.

We’ve got people going into scanners too frequently anyway. But when thy-roid abnormalities are identified, pa-tients shouldn’t be scared about them, and for most small thyroid nodules that are incidentally detected, we shouldn’t be pursuing them,” he said. “So it has to be broader than just saying, don’t screen for thyroid cancer using ultrasound.”

Dr. Welch applauds the recently re-leased guidelines from the American College of Radiology recommending that incidentally detected thyroid nod-ules less than 1.5 cm in size (< 1 cm in

patients younger than age 35) recieve no further evaluation.2

Consequences of Treatment“The majority of patients given di-

agnoses of thyroid cancer have their thyroid removed,” Dr. Welch wrote in an op-ed piece for The New York Times.3

According to the data for South Korea, virtually all are treated and roughly two-thirds of the patients had radical thy-roidectomy and require lifelong thyroid replacement therapy. “An analysis of

Expect Questions From Patients

S creening for thyroid cancer should be discouraged to prevent

an “epidemic of diagnosis”—like the one occurring in South Korea—from happening in the United States and other countries, according to the au-thors of an analysis of the South Kore-an screening program. That study was published in The New England Journal of Medicine.1

In an op-ed piece in The New York Times,2 one of the study’s authors, H. Gilbert Welch, MD, MPH, further ex-plained the implications of the study. Dr. Welch, Professor of Medicine at the Dartmouth Institute for Health Policy and Clinical Practice, Hanover, New Hampshire, cautioned readers, “Having doctors not look too hard for early cancer is in your interest.”

That message might seem jarring to patients used to hearing that early detection is their best defense against cancer. What they need to under-stand, Dr. Welch said in an interview with The ASCO Post, is that the vast majority of cancers discovered by thyroid cancer screening are papillary thyroid cancers, many of which will never become evident during a per-

son’s lifetime except through screen-ing or as incidental findings from im-aging tests near the thyroid.

Once found, these cancers are usu-ally treated with radical thyroidectomy,

requiring lifelong thyroid replacement. Hypoparathyroidism and vocal-cord paralysis has occurred as a surgical complication in a small percentage of patients.

Makes Sense in Some Cases“Of course, screening makes sense

in some situations: in particular for people who are at a genuinely high risk for the cancer—those with mul-tiple cancer deaths in their family his-tory. People at average risk who ex-pect to live long enough to experience

the potential benefit in the future—and who are willing to accept the chance of harm from unneeded treat-ment now—may also decide that the screening makes sense for them,” Dr.

Welch wrote in The New York Times.2 “It is not that all early detection is

bad,” he told The ASCO Post. “The question is: how early? If we always go in the same direction, looking for smaller and smaller lesions, it is a rec-ipe for finding something wrong with all of us. So we have to understand that this question of how early is going to become more important as we are increasingly able to identify tiny per-turbations in immune function or bio-chemical information, or genetic mark-er or imaging structural abnormalities.”

Understanding the Balances“When we are talking about screen-

ing, we are talking about trying to get ahead of symptoms. And whenever you try to get ahead of symptoms, you are going to be treating some people for something that is never going to bother them. That treatment may lead to anxiety. It may cost them a lot of money, and can even lead to death,” Dr. Welch said.

“There are balances, and it is a mat-ter of having people understand those balances, and also having the system understand those balances—so we are not always going to the most ex-treme, looking for the smallest abnor-mality, trying to find the most abnor-malities, and turning the most people into patients.” n

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

References1. Ahn HS, Kim HJ, Welch HG: Korea’s

thyroid-cancer “epidemic”—screening and overdiagnosis. N Engl J Med 371:1765-1767, 2014.

2. Welch HG: An epidemic of thyroid cancer? New York Times, November 5, 2014.

Thyroid Cancer

It is not that all early detection is bad. The question is: how early? If we always go in the same direction,

looking for smaller and smaller lesions, it is a recipe for finding something wrong with all of us.

—H. Gilbert Welch, MD, MPH


I think we need more balance in the messaging, because for years, the only message that the general public has been hearing is that you should be looking for early forms of every disease, the earlier the better. We need more nuance than that.

—H. Gilbert Welch, MD, MPH

For Your Practice

Get ASCO’s NewPalliative Care Booklet

for Your PatientsHelp teach patients and their families about how to maintain their

quality of life after a cancer diagnosis

21Palliative Care

Talking About Your CareTalking about cancer, cancer treatment, and your needs is an important part of palliative

care because it helps clarify your goals and expectations. This could mean wanting to

continue disease-directed treatment as long as possible, regardless of the difficulty

of treatment, or it could mean maintaining a specific quality of life, even if that means

stopping treatment at some point. The best palliative care occurs when patients and their

families work together with the health care team.

Never be afraid to ask your health care team questions or express your opinions,

preferences, and concerns. Tell the doctors and nurses about any pain, discomfort, or other

side effects, such as mouth sores, nausea, vomiting, and constipation you experience, even

if you feel they are not serious. Often there are many options for relieving these symptoms,

but doctors and nurses need to know you are in pain or discomfort to help you feel better.

If you are confused about your options, tell them. They can provide more information and

guide you through the decision-making process so you are able to make informed choices

about your care.

If you have been referred to a palliative care specialist, your palliative care team can help

you and your caregivers understand your diagnosis, treatment plan, and prognosis, which

is the chance of recovery. These may change throughout the course of your illness, so

continue to have honest discussions with both your oncologist and your palliative care team.

10 ASCO Answers

The Goals of Palliative CareUnlike disease-directed treatment, which aims to slow, stop, or eliminate the cancer, the

goal of palliative care is to improve quality of life. This means allowing you to live the way

you want during and after treatment and equipping your family and caregivers to support

you while taking care of themselves. Palliative care is able to do this by addressing a

number of different cancer-related challenges.

Managing Symptoms and Side EffectsCancer can cause physical and emotional symptoms, and cancer treatment, such as

chemotherapy, radiation therapy, and surgery, often causes side effects. The specific

symptoms and side effects you may experience and their level of severity depends on a

number of factors, including the type and stage of the cancer, its location, your treatment

plan, and your overall health. Palliative care aims to prevent, manage, and/or relieve

cancer-related discomfort no matter what the cause and regardless of whether that

discomfort is mild, moderate, or severe.

PHYSICAL

Physical symptoms of cancer, such as

pain, fatigue, difficulty breathing, and

weight loss, vary widely from person to

person. Your health care team will work

with you to find the best way to control

your physical symptoms, as well as

prevent or ease treatment-related side

effects, such as nausea and vomiting,

diarrhea, and appetite loss.

Before starting treatment, a member of your health care team can help you understand

which side effects are most likely to occur and put a personalized plan in place to prevent

or manage them. Often a combination of therapies is used to relieve physical symptoms

and side effects. These may include:

Palliative CareImproving Quality of Life for Patients and Families

Supported by the Conquer Cancer Foundation

ORDER COPIES TODAYwww.cancer.net/eStore

FREE SHIPPING Members Save 20%

Featured Content Includes:How palliative care is used to manage symptoms and side effects

The difference between palliative care and hospice care

Practical advice about accessing palliative care services

Questions to ask the health care team

For Your Practice

Get ASCO’s NewPalliative Care Booklet

for Your PatientsHelp teach patients and their families about how to maintain their

quality of life after a cancer diagnosis

21Palliative Care

Talking About Your CareTalking about cancer, cancer treatment, and your needs is an important part of palliative

care because it helps clarify your goals and expectations. This could mean wanting to

continue disease-directed treatment as long as possible, regardless of the difficulty

of treatment, or it could mean maintaining a specific quality of life, even if that means

stopping treatment at some point. The best palliative care occurs when patients and their

families work together with the health care team.

Never be afraid to ask your health care team questions or express your opinions,

preferences, and concerns. Tell the doctors and nurses about any pain, discomfort, or other

side effects, such as mouth sores, nausea, vomiting, and constipation you experience, even

if you feel they are not serious. Often there are many options for relieving these symptoms,

but doctors and nurses need to know you are in pain or discomfort to help you feel better.

If you are confused about your options, tell them. They can provide more information and

guide you through the decision-making process so you are able to make informed choices

about your care.

If you have been referred to a palliative care specialist, your palliative care team can help

you and your caregivers understand your diagnosis, treatment plan, and prognosis, which

is the chance of recovery. These may change throughout the course of your illness, so

continue to have honest discussions with both your oncologist and your palliative care team.

10 ASCO Answers

The Goals of Palliative CareUnlike disease-directed treatment, which aims to slow, stop, or eliminate the cancer, the

goal of palliative care is to improve quality of life. This means allowing you to live the way

you want during and after treatment and equipping your family and caregivers to support

you while taking care of themselves. Palliative care is able to do this by addressing a

number of different cancer-related challenges.

Managing Symptoms and Side EffectsCancer can cause physical and emotional symptoms, and cancer treatment, such as

chemotherapy, radiation therapy, and surgery, often causes side effects. The specific

symptoms and side effects you may experience and their level of severity depends on a

number of factors, including the type and stage of the cancer, its location, your treatment

plan, and your overall health. Palliative care aims to prevent, manage, and/or relieve

cancer-related discomfort no matter what the cause and regardless of whether that

discomfort is mild, moderate, or severe.

PHYSICAL

Physical symptoms of cancer, such as

pain, fatigue, difficulty breathing, and

weight loss, vary widely from person to

person. Your health care team will work

with you to find the best way to control

your physical symptoms, as well as

prevent or ease treatment-related side

effects, such as nausea and vomiting,

diarrhea, and appetite loss.

Before starting treatment, a member of your health care team can help you understand

which side effects are most likely to occur and put a personalized plan in place to prevent

or manage them. Often a combination of therapies is used to relieve physical symptoms

and side effects. These may include:

Palliative CareImproving Quality of Life for Patients and Families

Supported by the Conquer Cancer Foundation

ORDER COPIES TODAYwww.cancer.net/eStore

FREE SHIPPING Members Save 20%

Featured Content Includes:How palliative care is used to manage symptoms and side effects

The difference between palliative care and hospice care

Practical advice about accessing palliative care services

Questions to ask the health care team

http://www.cancer.net

http://store2.asco.org/b/5285085011


In the News

insurance claims for more than 15,000 Koreans who underwent surgery showed that 11% had hypoparathyroid-ism and 2% had vocal-cord paralysis,” according to The New England Journal article.

Dr. Welch noted that it “is a very use-ful step to move from” radical thyroid-ectomy to lobectomy (a less extensive surgery removing only half the thyroid) because “there is a good chance you will not need thyroid replacement, and your chance of hypoparathyroidism goes to almost 0.”

In this country, too, most people diagnosed with thyroid cancer “do get thyroid-directed surgery,” Dr. Welch said. From the Surveillance, Epidemiol-ogy, and End Results (SEER) data, “it looks like most are coded as radical thy-roidectomy,” he added.

Some Opt for Observation“Some doctors are willing to manage

these small cancers with observation. And, of course, that makes more sense,” Dr. Welch stated.

A news article about the thyroid

cancer screening study reported in The New York Times: “A few places, like Me-morial Sloan Kettering Cancer Center in Manhattan, offer patients with small tumors the option of simply waiting and having regular scans to see if the tumor grows. But few patients have joined the program.”4

“I understand that,” Dr. Welch said. “It is always hard once you say some-one has cancer; in some sense, the horse is out of the barn. But it does make it clear that more and more doc-tors are getting sensitized to this prob-lem—not just in thyroid cancer, but in early cancer detection in general. And that’s good.”

How Do We Know It’s Overdiagnosis?

Although the rate of diagnosis of thyroid cancer in South Korea has in-creased 15-fold since 1993, the mor-tality rate has remained stable. “If the screening were saving lives,” Dr. Welch noted, “the death rate would decline or increase more slowly as the epidemic spread—but not stay perfectly flat.”

The mass screenings for thyroid cancer in South Korea were not begun

as a result of any particular perceived high risk, Dr. Welch stated. As The New England Journal article pointed out, the screenings were an add-on to a 1999 national cancer-screening program. “Al-though thyroid-cancer screening was not included in the program, provid-ers frequently chose to offer screening with ultrasonography as an inexpensive add-on for $30 to $50,” according to the journal article.

“Remember, this is a single-payer system, but it has an active private sec-tor that is delivering it—fee-for-ser-vice doctors and hospitals—and this was an easy extra service for them to sell. They already had the ultrasound machines. They were very common, and there was all this messaging about early cancer detection. They could add on a thyroid ultrasound, and patients would pay for it out of pocket,” Dr. Welch said. “It just sort of worked well with the general promotion of screen-ing…. Then you generate a fair amount of money afterward, because you find a lot of nodules and get a lot of biopsies,” he continued.

“I think understanding this example could help people understand how far

wrong you can go with an early-detec-tion strategy,” Dr. Welch said. “You can end up treating a whole lot more people for something that was never going to bother them.”

He added, “I think we need more balance in the messaging, because for years, the only message that the gen-eral public has been hearing is that you should be looking for early forms of every disease, the earlier the better. We need more nuance than that.” n

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

References1. Ahn HS, Kim HJ, Welch HG: Korea’s

thyroid-cancer “epidemic”—screening and overdiagnosis. N Engl J Med 371:1765-1767, 2014.

2. Hoang JK, Langer, JE, Middleton WD, et al: Managing incidental thyroid nodules detected on imaging: White paper of the ACR Incidental Thyroid Findings Commit-tee. J Am Coll Radiol 2014 (in press).

3. Welch HG: An epidemic of thyroid cancer? New York Times, November 5, 2014.

4. Kolata G: Study points to overdiag-nosis of thyroid cancer, New York Times, November 5, 2014.

Hazards of Overscreeningcontinued from page 128










HarborsidePress.com


[email protected]



Phone: 631.935.7660


After progression following initial antiestrogen therapy in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer (mBC)...

Go with Conf dence

Learn more at www.FaslodexUpdatedData.com

Go with FASLODEX.

Please see additional Important Safety Information on reverse and brief summary of full Prescribing Information for FASLODEX on following pages.

Important Safety Information About FASLODEX

• FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema have been reported in association with FASLODEX

• Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants

• FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C)

At minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2

• Not statistically signif cant as no adjustments were made for multiplicity2At minimum 18-month follow-up, HR=0.80

(95% CI: 0.68-0.94) (P=0.006)2

Median 6.5 months with FASLODEX 500 mg vs 5.4 months

with 250 mg in CONFIRM2,†

Primary Endpoint: Progression-Free Survival (PFS)1,*


with 250 mg in CONFIRM2

A Secondary Endpoint: Overall Survival (OS)1

* PFS is def ned as the time between randomization and the

earliest evidence of progression or death from any cause.2

† COmparisoN of FASLODEX In Recurrent or Metastatic Breast Cancer.1

Now Available

Final OS Analysis From

CONFIRM*

ww

w.F

aslo

dexUpdatedD

ata.c

om


Announcements

NCCN Publishes 20th Annual Guidelines in NSCLC, Reflecting Advances in Screening, Diagnosis, Radiology, and Systemic Therapies

The National Comprehensive Can-cer Network (NCCN) has pub-

lished the 20th annual edition of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC), one of the eight original NCCN Guide-lines published in November 1996.

“Since the first NCCN Guidelines for NSCLC were published 20 years ago, there have indeed been many advances in the diagnosis, screening, and treat-ment of non–small cell lung cancer,” said

David S. Ettinger, MD, FACP, FCCP, Alex Grass Professor of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and NCCN Guidelines Panel Chair for NSCLC.

Dr. Ettinger, who has chaired the NCCN Guidelines Panel for NSCLC since 1996, notes major accomplish-ments in the diagnosis and treatment of NSCLC, including the use of low-dose computed tomography (CT) scan in screening for NSCLC, as well as positron-emission tomography (PET)/CT scan in diagnosis. According to Dr. Ettinger, notable radiotherapy advances include stereotactic body radiotherapy and inten-sity-modulated radiotherapy. In surgery, he said, the use of video-assisted thoracic surgery or minimally invasive surgery has been an important advance.

Other Key Advances“Today, clinicians understand the im-

portance of histology—adenocarcino-ma vs squamous cell carcinoma—as well as the use of molecular diagnostic stud-ies,” said Dr. Ettinger. “Systemic therapy has come a long way with innovations in adjuvant and maintenance therapies, as well as the use of bevacizumab [Avastin] and targeted therapies. In the future, we will likely look to further innovation in immunotherapy, as well.”

NCCN currently develops and pub-lishes a library of 60 NCCN Guidelines, covering 97% of malignant cancers. The NCCN Guidelines are developed and updated through an evidence-based pro-

cess in which the expert panels integrate comprehensive clinical and scientific data with the judgment of the multidis-ciplinary panel members and other ex-perts drawn from NCCN Member In-

stitutions. Access to the complete library of NCCN Guidelines is available free-of-charge at NCCN.org.

“Today, lung cancer is the second most common cancer in both men and

women, and NCCN is proud to have played a pivotal role in promoting the optimal care for these patients for 20 years,” said Robert W. Carlson, MD, Chief Executive Officer, NCCN. n

David S. Ettinger, MD, FACP, FCCP

Guidelines

After progression following initial antiestrogen therapy in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer (mBC)...

Go with Conf dence

Learn more at www.FaslodexUpdatedData.com

Go with FASLODEX.

Please see additional Important Safety Information on reverse and brief summary of full Prescribing Information for FASLODEX on following pages.

Important Safety Information About FASLODEX

• FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema have been reported in association with FASLODEX

• Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants

• FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C)

At minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2

• Not statistically signif cant as no adjustments were made for multiplicity2At minimum 18-month follow-up, HR=0.80

(95% CI: 0.68-0.94) (P=0.006)2


with 250 mg in CONFIRM2,†

Primary Endpoint: Progression-Free Survival (PFS)1,*


with 250 mg in CONFIRM2

A Secondary Endpoint: Overall Survival (OS)1

* PFS is def ned as the time between randomization and the

earliest evidence of progression or death from any cause.2

† COmparisoN of FASLODEX In Recurrent or Metastatic Breast Cancer.1

Now Available

Final OS Analysis From

CONFIRM*

ww

w.F

aslo

dexUpdatedD

ata.c

om

http://www.faslodexhcp.com/home.html


Announcements

Huntsman Cancer Institute Investigator Receives Leadership Award from the National Cancer Institute

Neeraj Agarwal, MD, a Huntsman Cancer Institute investigator and

Associate Professor of Medicine at the University of Utah, has received the 2014 Cancer Clinical Investigator Team

Leadership Award from the National Cancer Institute (NCI). This highly competitive award recognizes excep-tional cancer investigators for contri-butions to advancing clinical research

through collaborative team science.Only 12 physicians nationwide re-

ceived the $100,000 awards to support their clinical research leadership efforts over a 2-year period. Dr. Agarwal’s re-

search focuses on clinical trials in ad-vanced prostate cancer and other uro-logic cancers.

As Associate Director of Huntsman Cancer Institute’s Clinical Trials Office, Dr.

References: 1. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor–positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594-4600. 2. Full Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE.

FASLODEX is indicated for the treatment of hormone receptor-positive (HR+) metastatic breast cancer (mBC) in postmenopausal women with disease progression following antiestrogen therapy.

Go with Conf dence

* The CONFIRM trial was a randomized, double-blind, controlled phase III study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1

† PFS was the primary endpoint.1

‡ ORR is def ned as the number of patients with complete response or partial response.2

§ OS was a secondary endpoint.1

Please read brief summary of full Prescribing Information for FASLODEX on following pages.

FASLODEX is a registered trademark of the AstraZeneca group of companies. ©2014 MedImmune, Specialty Care Division of AstraZeneca. All rights reserved. 3017912 8/14

Dece

mber 9-13, 2

014

See more a

t

SABCS Booth #465

Prolonged PFS With FASLODEX 500 mg vs 250 mg in CONFIRM2,*,†

• Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg at minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2

• Objective response rates (ORRs)‡ were not signif cantly different between FASLODEX 500 mg (13.8%) and 250 mg (14.6%) (OR=0.94; 95% CI: 0.57-1.55) (P=0.795)1,2

— Only patients with measurable disease at baseline were analyzed (FASLODEX 500 mg: n=240; FASLODEX 250 mg: n=261)2

— ORRs in the full patient population were 9.1% and 10.2% for the FASLODEX 500 mg and 250 mg arms, respectively1

FASLODEX 500 mg vs 250 mg in the

Updated OS Analysis in CONFIRM2,§

• Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg at minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2

• Not statistically signif cant as no adjustments were made for multiplicity.2

• In the initial OS analysis after a minimum duration of 18 months, there was no statistically signif cant difference in OS between the 2 treatment groups2

FASLODEX 500 mg Showed a Comparable Safety Prof le to FASLODEX 250 mg in CONFIRM1

Additional Important Safety Information About FASLODEX

• Fetal harm can occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving FASLODEX

• The most common, clinically signif cant adverse reactions occurring in ≥5% of patients receiving FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot f ash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation

• Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were non dose-dependent

Indication For FASLODEX

• FASLODEX is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy

FASLODEX®

(fulvestrant)Injection

BRIEF SUMMARY For full Prescribing Information, see package insert.

INDICATIONS AND USAGEFASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer inpostmenopausal women with disease progression following antiestrogen therapy.

DOSAGE AND ADMINISTRATIONRecommended Dose The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and oncemonthly thereafter [see Clinical Studies (14) in full Prescribing Information].

Dose Modification Hepatic Impairment:A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh classB) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injectionon days 1, 15, 29 and once monthly thereafter. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C)[see Warnings and Precautions and Use in Specific Populations].

Administration TechniqueThe proper method of administration of FASLODEX for intramuscular use is described in the instructions that follow: 1. Remove glass syringe barrel from tray and check that it is not damaged.2. Remove perforated patient record label from syringe. 3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™

instructions refer below to the “Directions for Use of SafetyGlide™.”4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with

the attached rubber tip cap. 5. Twist to lock the needle to the luer connector.6. Remove needle sheath.7. Remove excess gas from the syringe (a small gas bubble may remain). 8. Administer intramuscularly slowly in the buttock.9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm

completely forward until needle tip is fully covered.10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to

activate, discard immediately into an approved sharps collector.11. Repeat steps 1 through 10 for second syringe. For additional directions for use, see Administration Technique (2.3) in full Prescribing Information.

CONTRAINDICATIONSFASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of itscomponents. Hypersensitivity reactions, including urticaria and angioedema, have been reported inassociation with FASLODEX.

WARNINGS AND PRECAUTIONSBlood DisordersBecause FASLODEX is administered intramuscularly, it should be used with caution in patients withbleeding diatheses, thrombocytopenia, or anticoagulant use.

Hepatic ImpairmentThe safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects withmoderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function.Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mgis recommended [see Dosage and Administration].FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C)[see Use in Specific Populations].

Use in PregnancyBased on its mechanism of action and findings in animals, FASLODEX can cause fetal harm whenadministered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals whenadministered during the period of organogenesis at doses significantly smaller than the maximumrecommended human dose based on the body surface area. There are no adequate and well-controlled studies in pregnant women using FASLODEX. Women of childbearing potential should beadvised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy,or if the patient becomes pregnant while receiving this drug, the patient should be apprised of thepotential hazard to the fetus [see Use in Specific Populations].

ADVERSE REACTIONSClinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction ratesobserved cannot be directly compared to rates in other trials and may not reflect the rates observedin clinical practice.

Comparison of FASLODEX 500 mg and FASLODEX 250 mg The following frequency categories for adverse reactions (ARs) were calculated based on the safetyanalysis of Study 1 that compared FASLODEX 500 mg with FASLODEX 250 mg. The most frequentlyreported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% ofpatients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reportedadverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain(10.7% of patients) and injection site pain (9.1% of patients). Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessedcausality, from the controlled clinical trial Study 1 comparing the administration of FASLODEX 500 mgintramuscularly once a month with FASLODEX 250 mg intramuscularly once a month.

Table 1: Summary of Most Commonly Reported Adverse Reactions in Study 1 (≥5% in either treatment group): Safety Population

Body System Number (%) of Patients

and Adverse Reaction Fulvestrant 500 mg Fulvestrant 250 mgN=361 N=374

Body as a Whole

Injection Site Pain 42 (11.6) 34 (9.1)

Headache 28 (7.8) 25 (6.7)

Back Pain 27 (7.5) 40 (10.7)

Fatigue 27 (7.5) 24 (6.4)

Pain in Extremity 25 (6.9) 26 (7.0)

Asthenia 21 (5.8) 23 (6.1)

Vascular System

Hot Flash 24 (6.6) 22 (5.9)

Digestive System

Nausea 35 (9.7) 51 (13.6)

Vomiting 22 (6.1) 21 (5.6)

Anorexia 22 (6.1) 14 (3.7)

Constipation 18 (5.0) 13 (3.5)

Musculoskeletal System

Bone Pain 34 (9.4) 28 (7.5)

Arthralgia 29 (8.0) 29 (7.8)

Musculoskeletal Pain 20 (5.5) 12 (3.2)

Respiratory System

Cough 19 (5.3) 20 (5.3)

Dyspnea 16 (4.4) 19 (5.1)

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg toFASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkalinephosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases wereobserved in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST,ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms.

Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3)The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups,regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (includingnausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation(hot flashes), and pharyngitis.Injection site reactions with mild transient pain and inflammation were seen with FASLODEX andoccurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantlyEuropean Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections(North American Trial Study 2). Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessedcausality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mgintramuscularly once a month with anastrozole 1 mg orally once a day.

Table 2: Combined Data from Studies 2 and 3, Adverse Reactions ≥ 5%

Body System FASLODEX 250 mg Anastrozole 1 mgand Adverse Reactiona N=423 N=423

(%) (%)

Body as a Whole 68.3 67.6Asthenia 22.7 27.0Pain 18.9 20.3Headache 15.4 16.8Back Pain 14.4 13.2Abdominal Pain 11.8 11.6Injection Site Painb 10.9 6.6Pelvic Pain 9.9 9.0Chest Pain 7.1 5.0Flu Syndrome 7.1 6.4Fever 6.4 6.4Accidental Injury 4.5 5.7

Cardiovascular System 30.3 27.9Vasodilatation 17.7 17.3

Digestive System 51.5 48.0Nausea 26.0 25.3Vomiting 13.0 11.8Constipation 12.5 10.6Diarrhea 12.3 12.8Anorexia 9.0 10.9

Hemic and Lymphatic Systems 13.7 13.5Anemia 4.5 5.0

—continued


Announcements

Agarwal facilitates development of innova-tive clinical trial protocols. The award will allow him to dedicate more time to men-toring junior faculty, fellows, and residents in both research and career development, as well as providing clinical trial education for faculty and community clinicians.

Dr. Agarwal will continue active par-ticipation in SWOG, one of the four

national adult cancer research groups in the NCI-funded National Clinical Trial Network, and in his own investigator-initiated clinical trials.

Early CareerAgarwal received his medical degree

from All India Institute of Medical Sci-ences in New Delhi, India, and com-

pleted a residency in internal medicine at the University of Iowa. He then com-pleted a hematology-oncology fellow-ship at Huntsman Cancer Institute.

Currently, he directs Huntsman Cancer Institute’s genitourinary medi-cal oncology program and coleads the urologic oncology multidisciplinary program. nNeeraj Agarwal, MD

References: 1. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor–positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594-4600. 2. Full Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE.

FASLODEX is indicated for the treatment of hormone receptor-positive (HR+) metastatic breast cancer (mBC) in postmenopausal women with disease progression following antiestrogen therapy.

Go with Conf dence

* The CONFIRM trial was a randomized, double-blind, controlled phase III study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1

† PFS was the primary endpoint.1

‡ ORR is def ned as the number of patients with complete response or partial response.2

§ OS was a secondary endpoint.1

Please read brief summary of full Prescribing Information for FASLODEX on following pages.

FASLODEX is a registered trademark of the AstraZeneca group of companies. ©2014 MedImmune, Specialty Care Division of AstraZeneca. All rights reserved. 3017912 8/14

Dece

mber 9-13, 2

014

See more a

t

SABCS Booth #465

Prolonged PFS With FASLODEX 500 mg vs 250 mg in CONFIRM2,*,†

• Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg at minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2

• Objective response rates (ORRs)‡ were not signif cantly different between FASLODEX 500 mg (13.8%) and 250 mg (14.6%) (OR=0.94; 95% CI: 0.57-1.55) (P=0.795)1,2

— Only patients with measurable disease at baseline were analyzed (FASLODEX 500 mg: n=240; FASLODEX 250 mg: n=261)2

— ORRs in the full patient population were 9.1% and 10.2% for the FASLODEX 500 mg and 250 mg arms, respectively1

FASLODEX 500 mg vs 250 mg in the

Updated OS Analysis in CONFIRM2,§

• Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg at minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2

• Not statistically signif cant as no adjustments were made for multiplicity.2

• In the initial OS analysis after a minimum duration of 18 months, there was no statistically signif cant difference in OS between the 2 treatment groups2

FASLODEX 500 mg Showed a Comparable Safety Prof le to FASLODEX 250 mg in CONFIRM1

Additional Important Safety Information About FASLODEX

• Fetal harm can occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving FASLODEX

• The most common, clinically signif cant adverse reactions occurring in ≥5% of patients receiving FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot f ash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation

• Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were non dose-dependent

Indication For FASLODEX

• FASLODEX is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy

FASLODEX®

(fulvestrant)Injection

BRIEF SUMMARY For full Prescribing Information, see package insert.

INDICATIONS AND USAGEFASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer inpostmenopausal women with disease progression following antiestrogen therapy.

DOSAGE AND ADMINISTRATIONRecommended Dose The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and oncemonthly thereafter [see Clinical Studies (14) in full Prescribing Information].

Dose Modification Hepatic Impairment:A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh classB) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injectionon days 1, 15, 29 and once monthly thereafter. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C)[see Warnings and Precautions and Use in Specific Populations].

Administration TechniqueThe proper method of administration of FASLODEX for intramuscular use is described in the instructions that follow: 1. Remove glass syringe barrel from tray and check that it is not damaged.2. Remove perforated patient record label from syringe. 3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™

instructions refer below to the “Directions for Use of SafetyGlide™.”4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with

the attached rubber tip cap. 5. Twist to lock the needle to the luer connector.6. Remove needle sheath.7. Remove excess gas from the syringe (a small gas bubble may remain). 8. Administer intramuscularly slowly in the buttock.9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm

completely forward until needle tip is fully covered.10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to

activate, discard immediately into an approved sharps collector.11. Repeat steps 1 through 10 for second syringe. For additional directions for use, see Administration Technique (2.3) in full Prescribing Information.

CONTRAINDICATIONSFASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of itscomponents. Hypersensitivity reactions, including urticaria and angioedema, have been reported inassociation with FASLODEX.

WARNINGS AND PRECAUTIONSBlood DisordersBecause FASLODEX is administered intramuscularly, it should be used with caution in patients withbleeding diatheses, thrombocytopenia, or anticoagulant use.

Hepatic ImpairmentThe safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects withmoderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function.Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mgis recommended [see Dosage and Administration].FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C)[see Use in Specific Populations].

Use in PregnancyBased on its mechanism of action and findings in animals, FASLODEX can cause fetal harm whenadministered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals whenadministered during the period of organogenesis at doses significantly smaller than the maximumrecommended human dose based on the body surface area. There are no adequate and well-controlled studies in pregnant women using FASLODEX. Women of childbearing potential should beadvised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy,or if the patient becomes pregnant while receiving this drug, the patient should be apprised of thepotential hazard to the fetus [see Use in Specific Populations].

ADVERSE REACTIONSClinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction ratesobserved cannot be directly compared to rates in other trials and may not reflect the rates observedin clinical practice.

Comparison of FASLODEX 500 mg and FASLODEX 250 mg The following frequency categories for adverse reactions (ARs) were calculated based on the safetyanalysis of Study 1 that compared FASLODEX 500 mg with FASLODEX 250 mg. The most frequentlyreported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% ofpatients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reportedadverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain(10.7% of patients) and injection site pain (9.1% of patients). Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessedcausality, from the controlled clinical trial Study 1 comparing the administration of FASLODEX 500 mgintramuscularly once a month with FASLODEX 250 mg intramuscularly once a month.

Table 1: Summary of Most Commonly Reported Adverse Reactions in Study 1 (≥5% in either treatment group): Safety Population

Body System Number (%) of Patients

and Adverse Reaction Fulvestrant 500 mg Fulvestrant 250 mgN=361 N=374

Body as a Whole

Injection Site Pain 42 (11.6) 34 (9.1)

Headache 28 (7.8) 25 (6.7)

Back Pain 27 (7.5) 40 (10.7)

Fatigue 27 (7.5) 24 (6.4)

Pain in Extremity 25 (6.9) 26 (7.0)

Asthenia 21 (5.8) 23 (6.1)

Vascular System

Hot Flash 24 (6.6) 22 (5.9)

Digestive System

Nausea 35 (9.7) 51 (13.6)

Vomiting 22 (6.1) 21 (5.6)

Anorexia 22 (6.1) 14 (3.7)

Constipation 18 (5.0) 13 (3.5)

Musculoskeletal System

Bone Pain 34 (9.4) 28 (7.5)

Arthralgia 29 (8.0) 29 (7.8)

Musculoskeletal Pain 20 (5.5) 12 (3.2)

Respiratory System

Cough 19 (5.3) 20 (5.3)

Dyspnea 16 (4.4) 19 (5.1)

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg toFASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkalinephosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases wereobserved in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST,ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms.

Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3)The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups,regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (includingnausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation(hot flashes), and pharyngitis.Injection site reactions with mild transient pain and inflammation were seen with FASLODEX andoccurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantlyEuropean Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections(North American Trial Study 2). Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessedcausality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mgintramuscularly once a month with anastrozole 1 mg orally once a day.

Table 2: Combined Data from Studies 2 and 3, Adverse Reactions ≥ 5%


(%) (%)

Body as a Whole 68.3 67.6Asthenia 22.7 27.0Pain 18.9 20.3Headache 15.4 16.8Back Pain 14.4 13.2Abdominal Pain 11.8 11.6Injection Site Painb 10.9 6.6Pelvic Pain 9.9 9.0Chest Pain 7.1 5.0Flu Syndrome 7.1 6.4Fever 6.4 6.4Accidental Injury 4.5 5.7

Cardiovascular System 30.3 27.9Vasodilatation 17.7 17.3

Digestive System 51.5 48.0Nausea 26.0 25.3Vomiting 13.0 11.8Constipation 12.5 10.6Diarrhea 12.3 12.8Anorexia 9.0 10.9

Hemic and Lymphatic Systems 13.7 13.5Anemia 4.5 5.0

—continued


Lab Notes

Ongoing Molecular Research in the Science of Oncology

NOVEL STRATEGIES

Antitumor Effect of Intratumoral Injection of Clostridium Spores

Species of Clostridium bacteria

have been shown to kill tumor cells growing under hypoxic conditions. In a study reported in Science Trans-lational Medicine, Roberts and col-leagues showed that intratumoral injection of an attenuated strain

of Clostridium novyi (C novyi-NT) produced a microscopically precise tumor-localized response in a rat or-thotopic brain tumor model.

In a study in naturally occurring canine solid tumors, intratumoral in-

jection of the spores was well tolerat-ed, with the most common toxicities being symptoms associated with bac-terial infection. Objective response occurred in 6 (37.5%) of 16 dogs, including three complete responses. Intratumoral injection of C novyi-NT spores in a patient with advanced leiomyosarcoma resulted in tumor shrinkage within and surrounding the bone.

The investigators concluded: “Together, these results show that C novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.”

Roberts NJ, et al: Sci Transl Med 6:249ra111, 2014.

Mitochondrial Respiration as Target in KRAS-Mutant Pancreatic Cancer

Targeting of oncogenes can pro-duce tumor shrinkage, but the fre-quency of relapse indicates that a population of tumor cells survives oncogene inhibition. In a study in a KRAS-mutant pancreatic ductal ad-enocarcinoma mouse model reported in Nature, Viale and colleagues found that a subpopulation of dormant tu-mor cells that survived oncogene ab-lation and were responsible for tumor relapse had features of cancer stem cells and relied on oxidative phos-phorylation for survival.

Transcriptomic and metabolic anal-yses of these surviving cells showed pronounced expression of genes reg-ulating mitochondrial function, au-tophagy, and lysosome activity, with increased reliance on mitochondrial respiration and reduced dependence on glycolysis in cellular energy use be-ing observed. The surviving cells were sensitive to oxidative phosphorylation inhibitors, which were found to inhibit tumor recurrence.

The investigators concluded: “Our integrated analyses illuminate a thera-peutic strategy of combined targeting of the KRAS pathway and mitochon-drial respiration to manage pancreatic cancer.”

Viale A, et al: Nature 514:628-632, 2014.

Selective Generation of Reactive Oxygen Species in Tumor Cells

In a study reported in Clinical Cancer Research, Shin and colleagues


(%) (%)

Metabolic and Nutritional Disorders 18.2 17.7Peripheral Edema 9.0 10.2

Musculoskeletal System 25.5 27.9Bone Pain 15.8 13.7Arthritis 2.8 6.1

Nervous System 34.3 33.8Dizziness 6.9 6.6Insomnia 6.9 8.5Paresthesia 6.4 7.6Depression 5.7 6.9Anxiety 5.0 3.8

Respiratory System 38.5 33.6Pharyngitis 16.1 11.6Dyspnea 14.9 12.3Cough Increased 10.4 10.4

Skin and Appendages 22.2 23.4Rash 7.3 8.0Sweating 5.0 5.2

Urogenital System 18.2 14.9Urinary Tract Infection 6.1 3.5

a A patient may have more than one adverse reaction.b All patients on FASLODEX received injections, but only those anastrozole patients who were in the North

American Study 2 received placebo injections.

Post-Marketing ExperienceFor FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently(<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivityreactions including angioedema and urticaria. Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeksafter changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists,further evaluation should be considered.Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).

DRUG INTERACTIONSThere are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro,drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics.Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or inducers [see ClinicalPharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category D [see Warnings and Precautions]FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetalloss or abnormalities in animals when administered during the period of organogenesis at dosessignificantly smaller than the maximum recommended human dose based on the body surface area(BSA). Women of childbearing potential should be advised not to become pregnant while receivingFASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant whilereceiving this drug, the patient should be apprised of the potential hazard to the fetus. In studies in female rats at intramuscular doses ≥0.01 mg/kg/day (0.6% of the human recom-mended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well aseffects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused anincreased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day;equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventraltubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day (6% the human dose based on BSA)when administered during the period of organogenesis. Rabbits failed to maintain pregnancy whendosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA)during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (30% the humandose based on BSA), increases in placental weight and post-implantation loss were observed.Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwardsdisplacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the humandose based on BSA) when administered during the period of organogenesis. Because pregnancycould not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, thisstudy was inadequate to fully define the possible adverse effects on fetal development at clinicallyrelevant exposures.

Nursing MothersIt is not known if fulvestrant is excreted in human milk. Fulvestrant is found in rat milk at levels significantly higher (approximately 12-fold) than plasma after administration of 2 mg/kg. Drugexposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the admin-istered dose. Because many drugs are excreted in human milk and because of the potential for seriousadverse reactions in nursing infants from FASLODEX, a decision should be made whether to discon-tinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric UseA multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCune-Albright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age atinformed consent was 6 years old (range: 1 to 8).The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients,all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received4 mg/kg from study entry.

Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian orlocal consultant. All measurements during the study period were collected prospectively. Patients’baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; amean rate of bone age advancement (change in bone age in years divided by change in chronologicalage in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26.Twenty-nine of 30 patients completed the 12-month study period. The following results wereobserved: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced acomplete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of boneage advancement during the 12-month study period compared to baseline (mean change = -0.9[95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared tobaseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes inmedian Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predictedadult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineraldensity in children has not been studied and is not known.Eight patients (27%) experienced adverse reactions that were considered possibly related toFASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash),abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%)patients reported an SAE, none of which were considered related to FASLODEX. No patients discon-tinued study treatment due to an AE and no patients died.

PharmacokineticsThe pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysiswith sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years withPPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breastcancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis.In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, thegeometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometricmean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680(1020) ng*hr/mL, respectively.

Geriatric UseFor FASLODEX 250 mg, when tumor response was considered by age, objective responses wereseen in 22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years ofage and older, who were treated with FASLODEX in Study 2 and Study 3, respectively.

Hepatic ImpairmentFASLODEX is metabolized primarily in the liver. The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects withmild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using ashorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (Child-Pugh class A) had comparable mean AUC and clearance values to those with normal hepaticfunction. In subjects with moderate hepatic impairment (Child-Pugh class B) the average AUC offulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positivelycorrelated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patientswith severe hepatic impairment (Child-Pugh class C). A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (Child-Pugh class B) [see Dosage and Administration and Warnings and Precautions].

Renal ImpairmentNegligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renalimpairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations inwomen with estimated creatinine clearance as low as 30 mL/min were similar to women with normalcreatinine.

OVERDOSAGEAnimal studies have shown no effects other than those related directly or indirectly to antiestrogenactivity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasmaconcentrations at the end of the infusion, that were approximately 10 to 15 times those seen afterintramuscular injection.

SafetyGlide™ is a trademark of Becton Dickinson and Company.

FASLODEX is a trademark of the AstraZeneca group of companies.© AstraZeneca 2013

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850

Manufactured for: AstraZeneca UK Limited, Macclesfield, Cheshire, EnglandBy: Vetter Pharma-Fertigung GMBH & Co. KG, Ravensburg, Germany

Rev. 11/12 2355400 2/13

FASLODEX® (fulvestrant) Injection 2


Lab Notes

synthesized a novel polyphenol con-jugate (DPP-23) that exerted antitu-mor effects by targeting the unfolded protein response in the endoplasmic reticulum via production of reactive oxygen species in cancer cells but not in normal cells. The polyphenol con-jugate was synthesized on the basis of quantitative structure-activity re-lationships, and its molecular targets were investigated using genome-wide expression profiling by DNA micro-array and real-time polymerase chain reaction array.

DPP-23 was found to inhibit the growth of various tumor cells in vitro and in vivo in Balb/c nude mice xe-nografts. The selective generation of reactive oxygen species resulted in tu-mor cell death via caspase-dependent apoptosis.

The investigators concluded: “The selective generation of [reactive oxy-gen species] in cancer cells could be an attractive strategy for the selective killing of cancer cells, while maintain-ing negligible cytotoxicity to normal cells. DPP-23 represents a promising novel therapeutic agent for the selec-tive production of [reactive oxygen species] in cancer cells.”

Shin SY, et al: Clin Cancer Res 20:4302-4313, 2014.

PRC2 Loss Amplifies RAS-Driven Transcription and Results in Sensitivity to Bromodomain Inhibition

PRC2 (polycomb repressive com-plex 2) has been shown to promote oncogenesis in many tumor types; however, loss of function mutations in PRC2 components has also been shown to occur in some hematopoi-etic malignancies, raising questions about the precise role of the complex in cancer.

In a study reported in Nature, De Raedt and colleagues showed that the polycomb group gene SUZ12 functions as a tumor suppressor in peripheral nervous system tumors, high-grade glioma, and melanoma by cooperating with mutations in NF1. Loss of NF1, which encodes a RAS GTPase-activating protein, drives tu-morigenesis by activating RAS. Loss of SUZ12 was shown to potentiate the effects of NF1 mutations by am-plifying RAS-driven transcription through effects on chromatin. How-ever, inactivation of SUZ12 was also associated with an epigenetic switch that resulted in sensitivity of these cancers to bromodomain inhibitors.

The investigators concluded:

“Collectively, these studies not only reveal an unexpected connection be-tween the PRC2 complex, NF1 and RAS, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.”

De Raedt T, et al: Nature 514:247-251, 2014.

TREATMENT RESISTANCE

Hyperthermia Reduces Gemcitabine Resistance

Removal of incorporated gem-citabine by DNA repair mechanisms may contribute to resistance to the agent in solid tumors. In a study re-ported in Journal of the National Can-cer Institute, Raoof and colleagues found that radiofrequency-induced hyperthermia blocked repair of gem-citabine-stalled replication forks and thus improved gemcitabine antitu-mor activity.

The study showed that Mre11-me-diated homologous recombination re-pair of gemcitabine-stalled replication forks was crucial to hepatocellular car-cinoma cell survival. Mre11 was inhib-ited by an exonuclease inhibitor and by radiofrequency field-induced hyper-thermia. In orthotopic mouse models of chemoresistant hepatocellular carci-noma, Hep3B tumor mass was signifi-cantly smaller with radiofrequency-in-duced hyperthermia plus gemcitabine vs gemcitabine alone (mean = 180 vs 661 mg, P = .0063).

The investigators concluded: “This study provides mechanistic un-derstanding of homologous recombi-nation inhibiting-strategies, such as noninvasive radiofrequency field-in-duced hyperthermia, to overcome re-sistance to gemcitabine in refractory human solid tumors.”

Raoof M, et al: J Natl Cancer Inst 106(8):dju183 2014.

Single-Nucleus Genome Sequencing Shows Early Aneuploid Rearrangement and Gradual Clonal Evolution in Breast Cancer

In a study reported in Nature, Wang and colleagues developed a whole-genome and exome single-cell sequencing approach (nuc-seq) using G2/M nuclei and used the method to sequence single normal and tumor nuclei from an estrogen receptor–positive breast cancer and a triple-negative ductal carcinoma. The investigators found that aneuploid

rearrangements occurred early in tu-mor evolution and remained highly stable as clonal expansion, reflecting gradual evolution of point mutations, occurred within tumor masses.

Use of targeted single-molecule sequencing showed that many of the point mutations occurred at low fre-quencies (< 10%) in tumor masses. Mathematical modeling showed that the triple-negative tumor cells had a 13-fold increased mutation rate, whereas the increased mutation rate was not observed in estrogen recep-tor–positive tumor cells.

The investigators concluded: “These findings have important im-plications for the diagnosis, therapeu-tic treatment and evolution of chemo-resistance in breast cancer.”

Wang Y, et al: Nature 512:155-160, 2014.

TARGETED THERAPY

mTOR Cotargeting Active in Cetuximab-Resistant Head/Neck Cancers With PIK3CA and RAS Mutations

In a study reported in Journal of the National Cancer Institute, Wang and colleagues found that adding an mTOR inhibitor to cetuximab (Er-bitux) resulted in marked improve-ment in antitumor activity in squa-mous cell carcinomas of the head and neck expressing PIK3CA and RAS oncogenes.

Cetuximab treatment of PIK3CA-

and RAS-expressing squamous cell head and neck carcinoma mouse xenografts resulted in initial tumor response followed by relapse within a few weeks. It was found that ce-tuximab did not reduce the activity of mTOR (a downstream signaling target of EGFR, PIK3CA, and RAS) in these tumors. The addition of an mTOR inhibitor to cetuximab pro-duced markedly greater antitumor activity, particularly in the head and neck cancer cells resistant to cetux-imab as a single agent; combined treatment produced prompt tumor collapse of both PIK3CA- and RAS-expressing head and neck carcinoma xenografts (P < .001), together with significant reductions in proliferation (P < .001) and lymphangiogenesis (P < .001).

The investigators concluded: “The presence of PIK3CA and RAS muta-tions and other alterations affecting the mTOR pathway activity in [squa-mous cell carcinomas of the head and neck] could be exploited to predict potential resistance to cetuximab and to select the patients who may benefit the most from the concomitant ad-ministration of cetuximab and PI3K and/or mTOR inhibitors as a preci-sion molecular therapeutic option for [patients with squamous cell carcino-ma of the head and neck].” n

Wang Z, et al: J Natl Cancer Inst 106(9):dju215, 2014.

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

©Leo Cullum/The New Yorker Collection/www.cartoonbank.com


(%) (%)

Metabolic and Nutritional Disorders 18.2 17.7Peripheral Edema 9.0 10.2

Musculoskeletal System 25.5 27.9Bone Pain 15.8 13.7Arthritis 2.8 6.1

Nervous System 34.3 33.8Dizziness 6.9 6.6Insomnia 6.9 8.5Paresthesia 6.4 7.6Depression 5.7 6.9Anxiety 5.0 3.8

Respiratory System 38.5 33.6Pharyngitis 16.1 11.6Dyspnea 14.9 12.3Cough Increased 10.4 10.4

Skin and Appendages 22.2 23.4Rash 7.3 8.0Sweating 5.0 5.2

Urogenital System 18.2 14.9Urinary Tract Infection 6.1 3.5

a A patient may have more than one adverse reaction.b All patients on FASLODEX received injections, but only those anastrozole patients who were in the North

American Study 2 received placebo injections.

Post-Marketing ExperienceFor FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently(<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivityreactions including angioedema and urticaria. Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeksafter changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists,further evaluation should be considered.Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).

DRUG INTERACTIONSThere are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro,drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics.Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or inducers [see ClinicalPharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category D [see Warnings and Precautions]FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetalloss or abnormalities in animals when administered during the period of organogenesis at dosessignificantly smaller than the maximum recommended human dose based on the body surface area(BSA). Women of childbearing potential should be advised not to become pregnant while receivingFASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant whilereceiving this drug, the patient should be apprised of the potential hazard to the fetus. In studies in female rats at intramuscular doses ≥0.01 mg/kg/day (0.6% of the human recom-mended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well aseffects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused anincreased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day;equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventraltubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day (6% the human dose based on BSA)when administered during the period of organogenesis. Rabbits failed to maintain pregnancy whendosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA)during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (30% the humandose based on BSA), increases in placental weight and post-implantation loss were observed.Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwardsdisplacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the humandose based on BSA) when administered during the period of organogenesis. Because pregnancycould not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, thisstudy was inadequate to fully define the possible adverse effects on fetal development at clinicallyrelevant exposures.

Nursing MothersIt is not known if fulvestrant is excreted in human milk. Fulvestrant is found in rat milk at levels significantly higher (approximately 12-fold) than plasma after administration of 2 mg/kg. Drugexposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the admin-istered dose. Because many drugs are excreted in human milk and because of the potential for seriousadverse reactions in nursing infants from FASLODEX, a decision should be made whether to discon-tinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric UseA multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCune-Albright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age atinformed consent was 6 years old (range: 1 to 8).The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients,all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received4 mg/kg from study entry.

Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian orlocal consultant. All measurements during the study period were collected prospectively. Patients’baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; amean rate of bone age advancement (change in bone age in years divided by change in chronologicalage in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26.Twenty-nine of 30 patients completed the 12-month study period. The following results wereobserved: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced acomplete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of boneage advancement during the 12-month study period compared to baseline (mean change = -0.9[95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared tobaseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes inmedian Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predictedadult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineraldensity in children has not been studied and is not known.Eight patients (27%) experienced adverse reactions that were considered possibly related toFASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash),abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%)patients reported an SAE, none of which were considered related to FASLODEX. No patients discon-tinued study treatment due to an AE and no patients died.

PharmacokineticsThe pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysiswith sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years withPPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breastcancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis.In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, thegeometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometricmean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680(1020) ng*hr/mL, respectively.

Geriatric UseFor FASLODEX 250 mg, when tumor response was considered by age, objective responses wereseen in 22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years ofage and older, who were treated with FASLODEX in Study 2 and Study 3, respectively.

Hepatic ImpairmentFASLODEX is metabolized primarily in the liver. The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects withmild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using ashorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (Child-Pugh class A) had comparable mean AUC and clearance values to those with normal hepaticfunction. In subjects with moderate hepatic impairment (Child-Pugh class B) the average AUC offulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positivelycorrelated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patientswith severe hepatic impairment (Child-Pugh class C). A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (Child-Pugh class B) [see Dosage and Administration and Warnings and Precautions].

Renal ImpairmentNegligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renalimpairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations inwomen with estimated creatinine clearance as low as 30 mL/min were similar to women with normalcreatinine.

OVERDOSAGEAnimal studies have shown no effects other than those related directly or indirectly to antiestrogenactivity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasmaconcentrations at the end of the infusion, that were approximately 10 to 15 times those seen afterintramuscular injection.

SafetyGlide™ is a trademark of Becton Dickinson and Company.

FASLODEX is a trademark of the AstraZeneca group of companies.© AstraZeneca 2013

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850

Manufactured for: AstraZeneca UK Limited, Macclesfield, Cheshire, EnglandBy: Vetter Pharma-Fertigung GMBH & Co. KG, Ravensburg, Germany

Rev. 11/12 2355400 2/13

FASLODEX® (fulvestrant) Injection 2


In the Literature

Emerging Clinical Data on Cancer Management

SMOKING

Over 14 Million Major Medical Conditions in U.S. Adults Linked to Cigarette Smoking

At least 14 million major medical

conditions among U.S. adults aged 35 years and older were attributed to ciga-rette smoking by a study estimating the disease burden of cigarette smoking, which, according to the study’s authors, “remains immense.” Among current and

former smokers, prevalence ratios were “particularly high for lung cancer,” re-ported Brian L. Roston, MD, MPH, and colleagues from the Center for To-bacco Products, U.S. Food and Drug Administration, Silver Spring, Mary-

land, and the Centers for Disease Con-trol and Prevention (CDC), Atlanta.

The study, published online in JAMA Internal Medicine, used U.S. Census Bu-reau population estimates from 2009, National Health Interview Survey data on smoking and smoking-related dis-ease prevalence from 2006 through 2012, and National Health and Nutri-tion Examination Survey spirometry data obtained from medical examina-tions of surveyed adults from 2007 through 2010. The researchers centered “the estimates around 2009 to allow for sufficient data to make accurate esti-mates,” they explained.

“Estimated prevalence ratios were higher for current and former smokers for most conditions,” the researchers reported. Prevalence ratios for lung can-cer ranged from 4.45 to 9.35. Prevalence rates for other types of cancer among current or former smokers ranged from 1.54 to 3.01 for bladder cancer, 1.94 to 3.65 for cervical cancer, 1.36 to 1.60 for colorectal cancer, 1.15 to 2.00 for kid-ney cancer, 2.02 to 3.40 for oral cancers, and 0.44 to 1.51 for stomach cancer.

Other medical conditions with high prevalence ratios for current or former smokers were chronic obstructive pul-monary disease (2.02–4.00), diabe-tes mellitus (1.17–1.30), heart attack (1.54–3.03), and stroke (1.17–2.43).

“Heart attack, stroke, chronic bron-chitis, emphysema, and cancers of the bladder, cervix, esophagus, kidney, lar-ynx, mouth and/or pharynx, and pan-creas have been previously identified as smoking-related conditions and were in-cluded in the previous CDC analysis of smoking-attributable morbidity. Stom-ach cancer was identified as a smok-ing-attributable condition in the 2004 Report of the Surgeon General, and colorectal and liver cancer and diabetes were identified as smoking attributable conditions in the 2014 Report of the Sur-geon General,” the authors noted.

“Cigarette smoking remains a lead-ing cause of preventable disease in the United States, underscoring the need for continuing and vigorous smoking-prevention efforts,” the investigators concluded.

Additional PerspectivesAlthough the prevalence of smok-

ing is declining, “that decline is excru-ciatingly slow, and there are still more than 40 million smokers in the United States,” Steven A. Schroeder, MD, of the University of California, San Fran-

T A R G E T I N G C A N C E R C A R E

This live activity has been approved for AMA PRA Category 1 Credit™.

gicasym.org

Hotel Reservation & Early Registration Deadline: December 10, 2014, at 11:59 PM (EST)

Meeting Highlights• Three keynote lectures - Immune Checkpoints for Upper GI Cancers - Genetic Landscape of Pancreatic Cancer - Molecular Characterization of Colorectal Cancer• Robust scientific program - All-day poster sessions, featuring Trials in Progress posters (new this year!) - Disease-specific oral abstract sessions• Tumor Board: Management of Challenging Cases of Upper GI Cancers (ARS)• Translational Research Sessions: - Tumor Microenvironment - Understanding Molecular Testing• Interactive Meet the Professor ticketed sessions• New this year: Opportunity for ABIM diplomates to earn up to 10 Maintenance of Certification (MOC) points• Networking luncheon for fellows, residents, and junior faculty

January 15-17, 2015 • Moscone West Building • San Francisco, California

2015 Gastrointestinal Cancers SymposiumBRIDGING CANCER BIOLOGY TO CLINICAL GI ONCOLOGY

http://gicasym.org


In the Literature

cisco, pointed out in an accompanying editorial. He continued:

Funds that should be dedicated to pre-vention and cessation are casualties of state budget crises, and there is no citizen advocacy movement such as those that exist with conditions like breast cancer and human immunodeficiency virus and AIDS. Physician involvement has been inconsistent, even among the subspecial-ties that most encounter smokers with disease: cardiologists, oncologists, and pulmonologists. The data from Rostron et al should serve to keep tobacco control and its 2-fold aims of preventing initia-tion and helping smokers quit as the most important clinical and public health pri-orities for the foreseeable future.

Lung Cancer ScreeningJAMA Internal Medicine online for

October 13 also includes an editor’s note and two special communications about whether lung cancer screening with low-dose computed tomography should be covered under Medicare. “At issue is not only whether low-dose CT will be covered but, if it is covered, the specifics, such as the number and fre-quency of scans, the beneficiaries who would be eligible, and the procedures to assure that scans are of high qual-ity and that false-positive results are minimized,” Robert Steinbrook, MD, wrote in the editor’s note.

Steven H. Woolf, MD, MPH, of Vir-ginia Commonwealth University and col-leagues argued that “implementation of national screening may be premature. The magnitude of benefit from routine screen-ing is uncertain,” and “potential harms—which could affect a large population—include false-positive results, anxiety, radiation exposure, diagnostic workups, and the resulting complications.”

It is unclear whether routine screen-ing would result in net benefit or net harm. Woolf et al also expressed con-cern that low-dose CT screening could “draw attention or resources away from the priority of tobacco control.

Douglas E. Wood, MD, of the Uni-versity of Washington, Seattle, argued that “a “decision to add lung cancer screening with low-dose CT as a cov-ered benefit for Medicare beneficiaries should be inevitable given the high level of evidence that screening can lead to early diagnosis and cure for thousands of patients each year in the United States. Professional societies,” he stated, “have great expertise and experience in screening and can help [the Centers for Medicare & Medicaid Services] re-sponsibly implement a program that is patient-centered and minimizes unin-

tended harms and costs.” Rostron BL, et al: JAMA Intern Med.

October 13, 2014 (early release online).Schroeder SA: JAMA Intern Med. Oc-

tober 13, 2014 (early release online). Wood DE: JAMA Intern Med. October

13, 2014 (early release online). Woolf SH, et al: JAMA Intern Med.

October 13, 2014 (early release online).

ESOPHAGEAL CANCER

Customizing Surveillance Strategy in Patients With Esophageal Adenocarcinoma

A surveillance strategy for patients with esophageal adenocarcinoma treated with chemoradiation and sur-

gery (trimodality therapy) can poten-tially be customized based on surgical pathology stage, according to an anal-ysis of 518 patients with esophageal adenocarcinoma who underwent tri-modality therapy at The University of Texas MD Anderson Cancer Center in Houston and were frequently sur-


SAFETY:7”

SAFETY:10”

TRIM:7.875”

TRIM:10.5”

BLEED:8.375”

BLEED:11.125”

Patients (N=286)• Advanced, recurrent, or metastatic ALK-positive NSCLC

Alectinib1

CrizotinibRan

dom

ize

1:1


Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC

Client: GenentechProduct: Alectinib Job#: 100173873Colors: 4C Sizes: Bleed: 8.375"” W x 11.125" H

Sm Trim: 7.875" W x 10.5" H Live: 7" W x 10" H Gutter: N/A

Publications:Journal of Thoracic Oncology:

Oncology Times:

The ASCO Post:

Journal of Clinical Oncology:

HEM/ONC Today:

The New England Journal of Medicine:

A Size

A Randomized, Phase III Study Comparing Alectinib With Crizotinib in Treatment-Naïve Anaplastic Lymphoma Kinase (ALK)-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

Now enrolling for alectinib

NCT02075840BO28984

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for the use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail [email protected].

Primary Endpoint: • Progression-free survival (PFS), investigator-assessed,

by RECIST 1.1

Key Inclusion Criteria2: • Advanced, recurrent, or metastatic ALK-positive NSCLC

• Life expectancy ≥12 weeks

• ECOG performance status of 0-2

• No prior systemic therapy for advanced, recurrent, or metastatic disease

• Measurable disease by RECIST 1.1

Secondary Endpoints: • Objective response rate, investigator-assessed,

using RECIST 1.1

• Time to CNS progression, IRC-assessed, using RECIST 1.1

• PFS, IRC-assessed, using RECIST 1.1

• Duration of response

• Overall survival

• Safety: incidence of adverse events

• AUC of alectinib

• Patient-reported outcomes

Key Exclusion Criteria2: • Prior malignancy in past 3 years

• Any ≥ grade 3 toxicity (NCI CTCAE 4.0) from a prior therapy

• Baseline QTc >470 ms or symptomatic bradycardia <45 beats per minute

• Concomitant strong cytochrome P4503A inhibitors/inducers or QT-prolonging medications

© 2014 Genentech USA, Inc. All rights reserved. BIO0002445101 Printed in USA.

100173873_GEN_Phase3_JRN_ad_FR.indd 1 8/5/14 11:48 AM



In the Literature

veyed. “The compelling data show an excellent association between surgical pathology stage and frequency/type/timing of relapses after trimodality therapy in patients with esophageal ad-enocarcinoma, Takashi Taketa, MD, and colleagues at MD Anderson wrote in the Journal of the National Compre-hensive Cancer Network.

All patients in the study had preoper-ative chemoradiation with intravenous or oral fluoropyrimidine with either a platinum compound or a taxane and a median total radiation dose of 50.4 Gy (range, 39.6–64.8 Gy) in daily fractions of 1.8 Gy. The median age of patients was 61 years (range 23–79 years) and most had clinical stage II (39%) or III (51.7%) cancer. The median follow-up time after esophageal surgery was 55.4 months, and disease relapse occurred in 215 patients (41.5%).

“The higher the [surgical pathology stage], reflecting the resistance of the primary tumor to chemoradiation, the higher the metastatic potential of esoph-ageal adenocarcinoma. The present data show that distant metastases are much more frequent than locoregional-only relapses and that a higher [surgical pa-thology stage] leads to higher rates of relapses,” the investigators reported.

“In addition, patients with a higher [surgical pathology stage] tend to devel-op metastases not only more frequently but also sooner than those with a lower [surgical pathology stage].” In the first 12 months after surgery, the fraction of all re-lapses in various surgical pathology stage categories were as follows: stage 0 = 41%, I = 42%, II = 61%, and III = 68%.

The authors proposed that “the fre-quency of relapses based on timing could be exploited in formulating future surveillance strategies.” For example, since almost all relapses among patients with surgical pathology stages 0 and I occurred within 36 months of surgery, surveillance might be terminated in these patients after 3 years.

“The quandary is whether it is rea-sonable to recommend any surveil-lance (and what the frequency should be and what tests should be performed) for [surgical pathology stage] II or III. Based on the present data,” the authors stated, “one could question the benefit of surveillance in patients with [surgi-cal pathology stage] III, because ap-proximately 60% of patients are likely to experience relapse and 86% of these relapses are anticipated to be metastatic. Considerable discussion would be nec-essary to establish guidance for patients

with [surgical pathology stage] II.”The authors called for “a serious na-

tional dialogue … to restructure the overall surveillance strategy for [esoph-ageal adenocarcinoma] (and this can be extended to a few other solid tumors). Such a dialogue may lead to the launch of a prospective trial to establish a firm evidence-based strategy.”

Taketa T, et al: J Natl Compr Canc Netw 12:1139-1144, 2014.

LYMPHOMA

Second-Line Gemcitabine the Preferred Option for Relapsed or Refractory Lymphoma

For patients with relapsed or refrac-tory aggressive lymphoma in a Nation-al Cancer Institute of Canada clinical trial, second-line treatment with GDP (gemcitabine, dexamethasone, and cis-platin) was as effective as DHAP (dexa-methasone, cytarabine, and cisplatin). Treatment with GDP “can be consid-ered the preferred treatment option for these patients,” Michael Crump, MD, of Princess Margaret Cancer Center in Toronto and colleagues concluded in the Journal of Clinical Oncology.

The trial “tested the hypothesis that comparable efficacy could be achieved with GDP and that this treatment, administered on an outpatient basis, would be associated with fewer ad-verse events and less frequent hospi-talization compared with DHAP,” the authors wrote. “Our trial is the largest randomized comparison of second-line chemotherapy regimens admin-istered before autologous stem-cell transplantation, to our knowledge, and the results confirmed our hypothesis.”

Most of the patients in the study had stage III or IV and high intermediate-risk or high-risk disease at random assign-ment to GDP or DHAP. Moreover, most patients “had either not achieved a re-mission with initial therapy or had recur-rence of lymphoma within 1 year of com-pleting treatment,” the authors noted.

Among the 619 intention-to-treat patients, 71% had diffuse large B-cell lymphoma, 15% had lymphoma that had transformed from an indolent B-cell histology, and 8% had T-cell or anaplastic large cell lymphoma. Among 554 B-cell lymphoma patients, 411 had previously been given ritux-imab (Rituxan). Patients with B-cell lymphoma also received rituximab along with GDP or DHAP. Patients who responded proceeded to stem cell collection and autologous stem cell transplantation.

The two primary endpoints of the study were response rate after two treat-ment cycles, with the noninferiority margin for the response rate to GDP relative to DHAP set at 10%, and trans-plantation rate. Among the intention-to-treat population, “the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, −9.0% to 6.7%), meeting protocol-defined criteria for noninferi-ority of GDP (P = .005),” the investiga-tors reported. “The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (hazard ratio [HR] = 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP.”

Grade 3 or 4 adverse events during the first two cycles of chemotherapy occurred in 47% of patients receiv-ing GDP vs 61% receiving DHAP (P < .001). Patients receiving GDP had fewer episodes of febrile neutropenia, reduced need for platelet transfusion support, less frequent hospitalizations related to toxicity, and less deteriora-tion of quality of life from baseline. “Eight patients died as a result of pro-tocol treatment–related complica-tions: two during treatment with GDP and six after receiving DHAP,” the re-searchers noted.

Crump M, et al: J Clin Oncol. October 6, 2014 (early release online)

Risk of Premature Menopause Raised by Some but Not All Hodgkin Lymphoma Therapies

An analysis of nonsurgical meno-pause risk among 2,127 women treat-ed for Hodgkin lymphoma found that “risk of premature menopause increased more than 20-fold” after ovarian radiotherapy, alkylating che-motherapy other than dacarbazine, or BEAM (carmustine [BiCNU], etopo-side, cytarabine, melphalan) chemo-therapy for stem cell transplantation but was not statistically significantly raised after ABVD (doxorubicin, bleo-mycin, vinblastine, dacarbazine). Re-sults were reported in the Journal of the National Cancer Institute by Anthony J. Swerdlow, DSc, of the Institute of Can-cer Research, Surrey, United Kingdom, and colleagues in the England and Wales Hodgkin Lymphoma Follow-up Group.

The authors concluded that patients treated for Hodgkin lymphoma “need to plan intended pregnancies using personalized information on their risk of menopause by different future time

points” and provided tables to give individualized information to women based on the type of treatment, dose, and age at treatment.

The women were first treated from 1960 through 2004, mainly in the 1980s and 1990s, and were followed to 2003 through 2012. All the women were younger than 36 years when treat-ed, with 5.5% younger than 15 and 50% aged 15 to 24 years. With increasing age at treatment, there was a moderate but statistically significant increased risk of premature menopause.

“During follow-up, 605 patients underwent nonsurgical menopause before age 40 years,” the investiga-tors reported. Menopause generally occurred sooner after ovarian radio-therapy (with 62.5% of women expe-riencing menopause within 5 years of ≥ 5 Gy treatment), and after BEAM (with 50.9% of women experiencing menopause within 5 years), than after alkylating chemotherapy (with 24.2% of women experiencing menopause within 5 years of at least six cycles).

“Compared with women who had received neither alkylating chemo-therapy nor pelvic radiotherapy, risk of premature nonsurgical menopause was increased about 20-fold in women who had received pelvic radiotherapy or classic alkylating chemotherapy, 36-fold in women who had received both, and over 50-fold in those who had received a stem cell transplant (more again if they had also received pelvic radiotherapy),” the investigators re-ported.

“Risk was greatly raised after treat-ment with each common classic alkyl-ating regimen,” the researchers added. The risk was greatest with mechloreth-amine, vinblastine, procarbazine, pred-nisone (hazard ratio [HR] = 37.1, 95% CI = 21.2–65.0, P < .001) and least for chlorambucil, vincristine, procarba-zine, prednisone (HR = 17.9, 95% CI = 10.8–29.9, P < .001).

“Risk was greater again after BEAM, the most common regimen for stem cell transplantation; almost all BEAM-treated patients had also received other classic alkylating treat-ments. Risk was also statistically sig-nificantly raised in patients treated with etoposide who had not received classic alkylating chemotherapy or pelvic radiotherapy (HR = 6.1, 95% CI = 1.7–21.4, P < .001).” n

Swerdlow AJ, et al: J Natl Cancer Inst 106(9):dju207, 2014.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

Emerging Clinical Datacontinued from page 137


Letters to the Editor

Unique Barriers to Pain Control

I read with great interest your in-terview with Virginia LeBaron,

PhD, APRN, about barriers to ad-equate pain control (“Despite Grow-ing Awareness, the Global Crisis of Untreated Cancer Pain Persists,” The ASCO Post, October 15, 2014).

Having served as the medical direc-tor of a hospice, I am passionate about palliative care and end-of-life issues. I worked in Saudi Arabia between 2001 and 2007 at the King Faisal Specialist Hospital as a medical oncologist, and I am recently retired. I would like to share a few additional unique barriers that I encountered and how they were over-come in Saudi Arabia.

Cultural ImpedimentsKing Faisal Specialist Hospital and

Research Center had a 30-bed pallia-tive care unit along with a 100-bed he-matology/oncology inpatient unit at that time. Since Saudi Arabia is a con-servative Muslim country, morphine was officially labeled as a narcotic and was not allowed to be imported, not even in medicinal form.

The palliative care team, with support of the hospital leadership, reached their way up to the King and

through him to the top religious au-thorities. They convinced the great mufti to issue a fatwa, or edict, that taking morphine for pain control was acceptable from the religious perspective.

The country’s import policy had to be rewritten so that medicinal mor-phine could be imported. Each patient was given a copy of the official edict to convince him that it was not a sin to take morphine for pain control.

On another cultural note, I re-member that one elderly man with advanced cancer and his family agreed to be admitted to the palliative care service but did not like to be in the palliative inpatient unit. He was from

the desert. To accommodate him, the hospital converted a large room into a desert abode. The bed and other fur-niture were removed from the room. Sand was brought in and laid on the floor. The man was asked to bring in his personal sheets and blankets to

spread on the sand and create his own bedding. He died in his own little des-ert tent some time later.

I admire Dr. LeBaron for pursuing a career in palliative care and her recent travels to India (I am originally from Pakistan) in pursuit of learning how

best to overcome the barriers to achiev-ing optimal pain control. I salute her. n—Khalid L. Rehman, MD, FACP, MPA

New York, New YorkDisclaimer: This letter represents the views

of the author and may not necessarily represent the views of ASCO.

I admire Dr. LeBaron for … [her] pursuit of learning how best to

overcome the barriers to achieving optimal

pain control. —Khalid L. Rehman, MD, FACP, MPA

JNCCN-N-0200-1114

March 12 – 14, 2015The Diplomat • Hollywood, Florida

2015

th REGISTER NOW!

ADVANCING THESTANDARD OFCANCER CARETMAnnual

ConferenceTrack Session Topics*:•Breast Cancer Early Stage | HER2-Positive and Triple Negative Cancer

| New Therapies for Hormone-Sensitive Advanced Disease

•Gastrointestinal (GI) Cancers Esophageal | Metastatic Colorectal Cancer | Pancreatic Cancer

•Genitourinary (GU) Cancers Castration-Recurrent Prostate Cancer | Bladder Cancer | Kidney Cancer

• Hematologic Cancers Chronic Myelogenous Leukemia | Chronic Lymphocytic Leukemia | Multiple Myeloma | B-cell Lymphomas

•Lung Cancers Non-Small Cell Lung Cancer: Minimally Invasive Techniques | Adjuvant Therapy and Treatment of Metastatic Disease | Small Cell Lung Cancer: Role of Radiation Therapy

•Skin Cancers Localized and Advanced Melanoma and Toxicities Associated with Targeted Therapies

•Supportive Care Fertility | Smoking Cessation | Anthracycline-Induced Cardiac Toxicity

* Subject to change.

Save the Date!Thursday, March 12, 2015

20 Years o f Improving Cancer

Care TogetherAn NCCN Roundtable

Discussion

Visit NCCN.org/AC2015 to register or to view more information for this educational program.

http://www.nccn.org/professionals/meetings/annual_conference.aspx


Letters to the Editor

Raising Consciousness About Drug Costs: A Call to Action

A s medical oncologists working in chemotherapy utilization man-

agement (Oncology Analytics, Inc), my colleagues and I find ourselves daily in the center of the drug-cost maelstrom.

While it is encouraging to see that more attention is being paid in the popular and medical press to this “unsustain-able” escalation of drug costs, it seems most of the articles (including recently in The ASCO Post) are long on bemoan-ing the problem and on theorizing

what might be done—while medical oncologists are short on creating and implementing actionable strategies to address drug costs. Indeed, the descrip-tor “unsustainable” has been around for

so long that it has become a hackneyed term that by now has lost most of its shock value.

U.S. Food and Drug Administra-tion (FDA) evaluations, National Comprehensive Cancer Network (NCCN) and ASCO guidelines, and

enthusiastic reports in The ASCO Post are, for the most part, devoid of cost information about the drugs or regimens referenced. True, ASCO’s “Choosing Wisely” initiative, and the NCCN Journal’s advice to select the most cost-effective approach if all else is equal, represent welcome at-tempts to focus oncologists’ attention on the cost of care. But where are the numbers, and where are the cost com-parisons that deserve to be front-and-center in the minds of patients, physi-cians, policymakers, and insurers?

I would propose that the The ASCO Post take the lead in calling out the el-ephant in the room. Though sometimes cost data are not immediately known upon FDA approval of new drugs, in most cases the sticker prices quickly become available and can be added eas-ily in parentheses ($10,000/month is usually fairly accurate!) to the clinical data presented. With The ASCO Post as

a trendsetter, how informative it would be if NCCN and ASCO Guidelines, and the Journal of Clinical Oncology, would follow TAP’s lead by similarly and consistently documenting the cost of chemotherapy care.

By not being tuned in to the eco-nomics of our profession, and not knowing the downstream financial consequences of every prescription we write, we physicians are complicit in the ultimate undoing of our society’s ability to continue providing the medical mar-vels now at hand. With the stroke of a pen or the click of a mouse, The ASCO Post’s editorial policy could become a transformative force in finally launch-ing us on a course we should have been on long ago. n

—William S. Shimp, MD Plantation, Florida

Disclaimer: This letter represents the views of the author and may not necessarily reflect the views of ASCO.

By not being tuned in to the economics of our profession, and not knowing the downstream

financial consequences of every prescription we write, we physicians are complicit in the ultimate undoing

of our society’s ability to continue providing the medical marvels now at hand.

—William S. Shimp, MD

Dawn a New Day, by Cindy Wemette: Best Oil by a Person

Diagnosed With Cancer

Monday, by Julie Miller: Best Oil by a Family Member

of a Person With Cancer

The 10th anniversary of the Lilly Oncology On Canvas Art Competition was celebrated with the presentation of awards and display of winning entries in New York’s Grand Central Terminal on October 23, 2014. First-, second-, and third-place winners were published in the November 15 issue of The ASCO Post. Here we present additional winning artwork from the competition.

Inspiration, by Amy Brewer: Best Mixed Media from a

Family Member of a Person Diagnosed With Cancer


Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC

Client: GSKProduct: Tafinlar Job#: 6GSK_DATR_10182326Colors: 4C Sizes: Bleed: 11.125”w x 15.25”h

Sm Trim: 10.5”w x 13.75”h Live: 9.5”w x 13”h

Publications:Hem/Onc TodayCAP TodayThe ASCO PostTargeted Therapies in OncologyValue Based Cancer Care

KING Size

BRIEF SUMMARYTAFINLAR® (dabrafenib) capsules, for oral useMEKINIST® (trametinib) tablets, for oral useThe following is a brief summary only; see Full Prescribing Information for each product to view the complete product information

1 INDICATIONS AND USAGETAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST.Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS5.1 New Primary MalignanciesNew primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type MelanomaIn vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 HemorrhageHemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous ThromboembolismVenous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 CardiomyopathyCardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular ToxicitiesRetinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.

5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.

5.7 Serious Febrile ReactionsThe incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

MEL156R0_ICAD_FR2.indd 5 7/24/14 4:06 PM


Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC




KING Size

BRIEF SUMMARYTAFINLAR® (dabrafenib) capsules, for oral useMEKINIST® (trametinib) tablets, for oral useThe following is a brief summary only; see Full Prescribing Information for each product to view the complete product information

1 INDICATIONS AND USAGETAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST.Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS5.1 New Primary MalignanciesNew primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type MelanomaIn vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 HemorrhageHemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous ThromboembolismVenous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 CardiomyopathyCardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular ToxicitiesRetinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.

5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.

5.7 Serious Febrile ReactionsThe incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.



Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC




KING Size

aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.bIncludes the following terms: peripheral edema, edema, and lymphedema.c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular.

d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.

e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage.

fIncludes the following terms: renal failure and renal failure acute.Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were:Eye Disorders: Vision blurred, transient blindness.Gastrointestinal Disorders: Stomatitis, pancreatitis.General Disorders and Administration Site Conditions: Asthenia.Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Tests

TAFINLAR plus MEKINIST 2 mg

N = 55


N = 54TAFINLAR

N = 53

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4a

HematologyLeukopenia 62 5 46 4 21 0Lymphopenia 55 22 59 19 40 6Neutropenia 55 13 37 2 9 2Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0

Liver Function TestsIncreased AST 60 5 54 0 15 0Increased alkaline phosphatase 60 2 67 6 26 2

Increased ALT 42 4 35 4 11 0Hyperbilirubinemia 15 0 7 4 0 0

ChemistryHyperglycemia 58 5 67 6 49 2Increased GGT 56 11 54 17 38 2Hyponatremia 55 11 48 15 36 2Hypoalbuminemia 53 0 43 2 23 0Hypophosphatemia 47 5 41 11 40 0Hypokalemia 29 2 15 2 23 6Increased creatinine 24 5 20 2 9 0Hypomagnesemia 18 2 2 0 6 0Hyperkalemia 18 0 22 0 15 4Hypercalcemia 15 0 19 2 4 0Hypocalcemia 13 0 20 0 9 0

aNo Grade 4 events were reported in patients receiving TAFINLAR as a single agent.ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent.

7 DRUG INTERACTIONS7.1 Effects of Other Drugs on DabrafenibDabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other DrugsDabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 TrametinibCoadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyTAFINLARPregnancy Category DRisk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. 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 Warnings and Precautions (5.11)].Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

MEKINISTPregnancy Category DRisk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical 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 [see Warnings and Precautions (5.10)].Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.

8.3 Nursing MothersIt is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST 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.

8.4 Pediatric UseThe safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC.

8.5 Geriatric UseOne hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

8.6 Females and Males of Reproductive PotentialTAFINLARContraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives



Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC




KING Size

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST.

5.8 Serious Skin ToxicitySerious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5.9 HyperglycemiaHyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase DeficiencyTAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.11 Embryofetal ToxicityTAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST.

6 ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in another section of the label:

• New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)]

6.1 Clinical Trials ExperienceBecause 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 described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST.BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Adverse Reactions


N = 55


N = 54TAFINLAR

N = 53

All Gradesa

Grades 3 and 4

All Gradesa

Grades 3 and 4

All Gradesa

Grades 3 and 4

General disorders and administrative site conditionsPyrexia 71 5 69 9 26 0Chills 58 2 50 2 17 0Fatigue 53 4 57 2 40 6Edema peripheralb 31 0 28 0 17 0

Skin and subcutaneous tissue disordersRashc 45 0 43 2 53 0Night Sweats 24 0 15 0 6 0Dry skin 18 0 9 0 6 0Dermatitis acneiform 16 0 11 0 4 0Actinic keratosis 15 0 7 0 9 0Erythema 15 0 6 0 2 0Pruritus 11 0 11 0 13 0

Gastrointestinal disordersNausea 44 2 46 6 21 0Vomiting 40 2 43 4 15 0Diarrhea 36 2 26 0 28 0Abdominal paind 33 2 24 2 21 2Constipation 22 0 17 2 11 0Dry mouth 11 0 11 0 6 0

Nervous system disordersHeadache 29 0 37 2 28 0Dizziness 16 0 13 0 9 0

Respiratory, thoracic, and mediastinal disordersCough 29 0 11 0 21 0Oropharyngeal pain 13 0 7 0 0 0

Musculoskeletal, connective tissue, and bone disordersArthralgia 27 0 44 0 34 0Myalgia 22 2 24 0 23 2Back pain 18 5 11 0 11 2Muscle spasms 16 0 2 0 4 0Pain in extremity 16 0 11 2 19 0

Metabolism and nutritional disordersDecreased appetite 22 0 30 0 19 0Dehydration 11 0 6 2 2 0

Psychiatric DisordersInsomnia 18 0 11 0 8 2

Vascular disordersHemorrhagee 16 5 11 0 2 0

Infections and infestationsUrinary tract infection 13 2 6 0 9 2

Renal and urinary disordersRenal failuref 7 7 2 0 0 0



Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC




KING Size

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINISTContraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR.

8.7 Hepatic ImpairmentTAFINLARNo formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].MEKINISTNo formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal ImpairmentNo formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].10 OVERDOSAGEThere is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR.There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Medication Guide) for TAFINLAR.See FDA-approved patient labeling (Patient Information) for MEKINIST.Inform patients of the following:

• Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated. • TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)]. • TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.MEKINIST is a registered trademark of GlaxoSmithKline.


© 2014, GlaxoSmithKline group of companies. All rights reserved. Revised: 01/2014 TFR:4BRS© 2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014



Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC

Client: GSKProduct: TafinlarJob#: 6GSK_DATR_10182326Colors: 4C Sizes: Bleed: 11.125”w x 15.25”h

Sm Trim: 10.5”w x 13.75”hLive: 9.5”w x 13”h


KING Size

twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%).The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%).Drug InteractionsEffects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.Effects of the Combination of Dabrafenib with Trametinib. Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages. Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination.Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST.Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd)

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703.

TAFINLARMEKINISTHCP.comTAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014

(trametinib)0.5 mg, 1 mg, 2 mg tablets

®

(dabrafenib)50 mg, 75 mg capsules

®

To learn more, visit TAFINLARMEKINISTHCP.com



Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC




KING Size

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINISTContraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR.

8.7 Hepatic ImpairmentTAFINLARNo formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].MEKINISTNo formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal ImpairmentNo formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].10 OVERDOSAGEThere is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR.There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Medication Guide) for TAFINLAR.See FDA-approved patient labeling (Patient Information) for MEKINIST.Inform patients of the following:

• Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated. • TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)]. • TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.MEKINIST is a registered trademark of GlaxoSmithKline.


© 2014, GlaxoSmithKline group of companies. All rights reserved. Revised: 01/2014 TFR:4BRS© 2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014


https://www.gsksource.com/gskprm/en/US/images/gsk_content/TAFMEK/index.html

and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR.Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often

Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST

bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent.In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd)

(trametinib)0.5 mg, 1 mg, 2 mg tablets

®

(dabrafenib)50 mg, 75 mg capsules

®

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

0

10

20

30

40

50

60

70

80

TAFINLAR as a single agent(N=54)

Res

pons

e R

ates

4%

CompleteResponse

PartialResponse

50%

CompleteResponse

9%

PartialResponse

67%

Overall Response

54%(95% CI: 40, 67)

Overall Response

76%(95% CI: 62, 87)

+ MEKINIST2 mg once daily

TAFINLAR150 mg twice daily

(N=54)

Major effi cacy outcome: Investigator-assessed response rate1

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1

• 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1

– Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39%

• Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1

Months

TAFINLAR 150 mg twice daily

+ MEKINIST 2 mg once daily

(N=54)

TAFINLAR as a single agent 5.6 months(95% CI: 5, 7)

10.5 months(95% CI: 7, 15)

Months

(N=54)

Effi cacy outcome: Investigator-assessed median duration of response1

TAFINLAR + MEKINIST demonstrateda 76% overall response rate1

TAFINLAR + MEKINIST achieved a medianduration of response of 10.5 months1



Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC


Sm Trim: 21.0”w x 13.75”hLive: 22”w x 15.25”h


KING Size

MEL156R0_ICAD_FR2.indd 2-3 7/24/14 4:06 PM


Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC


Sm Trim: 10.5”w x 13.75”hLive: 9.5”w x 13”h


KING Size

New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST.Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of

Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST.Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

The fi rst and only FDA-approved combination therapy

TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST.

Important Safety Information for TAFINLAR and MEKINIST when used in combination


2 AGENTS. 1 THERAPY.

DEMONSTRATED DURABLE RESPONSE RATEDEMONSTRATED DURABLE RESPONSE RATEIN A PHASE II STUDY 1,2

overall response

rate1

overall response

rate1

median durationof response1

median durationof response1

months(95% CI: 7, 15)

months(95% CI: 5, 7)

(95% CI: 62, 87)

(95% CI: 40, 67)

10.510.510.510.55.65.65.65.6

76%76%76%76%

54%54%TAFINLAR as a single agent

Investigator-assessed analysis

TAFINLAR150 mg twice daily

MEKINIST2 mg once daily

in combination

+


TAP Vol 5 Issue 19

Documents

Transcript of TAP Vol 5 Issue 19