TAP Vol 5 Issue 8 Supplement by Harborside Press LLC

SUPPLE M E NT

VOLUME 5, ISSUE 8

JUNE 10, 2014

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

ASCOPost.com

Narratives in Oncology The ASCO Post profiles leaders in cancer care and research

Peter P. Yu, MD

Kenneth C. Anderson, MD

Nancy E. Davidson, MD

Richard Hoppe, MD

Barbara L. McAneny, MD

John E. Niederhuber, MD

Olufunmilayo Falusi Olopade, MD, FACP

Richard Pazdur, MD

H.M. (Bob) Pinedo, MD, PhD

Peter Jacobs, MD, PhD In Memoriam

Celebrating ASCO’s History, 1964–2014, pages 37–39 A Supplement to The ASCO Post™

A Harborside Press® Publication

The ASCO Post | JUNE 10, 2014 | SUPPLEMENT

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Paul F. Engstrom, MD Fox Chase Cancer Center

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

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

Samuel Silver, MD, PhD University of Michigan Health System

Associate Editors

Bishoy Morris Faltas, MD Weill Cornell Medical College

Jame Abraham, MD Cleveland Clinic

John A. Fracchia, MD New York Urological Associates

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

Manmeet Ahluwalia, MD, FACP Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

Alison Freifeld, MD University of Nebraska Medical Center

Jamie Von Roenn, MD American Society of Clinical Oncology

Michael Buckley, Art Director Michael@harborsidepress.com

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

Lynn D. Wilson, MD Yale University School of Medicine

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center

Stanley H. Winokur, MD Singer Island, Florida

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

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

Terri Caivano, Kristina O’Toole, Alyson Prete, Layout Artists Terri@harborsidepress.com Kristina@harborsidepress.com Alyson@harborsidepress.com

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

International Editors

Joseph S. Bailes, MD Texas Oncology Laurence H. Baker, DO University of Michigan Comprehensive Cancer Center Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine and Public Health Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD National Comprehensive Cancer Network Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at 888.282.2552, 703.299.0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email shannon@harborsidepress.com 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-

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

George W. Sledge, MD Indiana University

Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com Sarah McGullam, Web Editor Sarah@harborsidepress.com

Gail van Koot, Editorial Coordinator Gail@harborsidepress.com

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

Norman Virtue, Production Manager Norman@harborsidepress.com

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

Shannon Meserve, Circulation Manager Shannon@harborsidepress.com

Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Frank Buchner, Chief Technology Officer Frank@harborsidepress.com Leslie Dubin, Vice-President, Director of Sales Leslie@harborsidepress.com

Jacek Jassem, MD Medical University of Gdansk, Poland

Anthony Cutrone, President Anthony@harborsidepress.com

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

John A. Gentile, Jr., Chairman Jack@harborsidepress.com

James L. Mulshine, MD Rush University Medical Center

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

Writer, Narratives in Oncology:

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

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

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

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

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

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

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center William T. McGivney, PhD Philadelphia, Pennsylvania

hibited. For permission inquiries, contact permissions@ harborsidepress.com.

Domestic: $335; Institutional International $587. Contact subscriptions@harborsidepress.com.

Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.

Correspondence: Address general inquiries to Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com.

Circulation: The ASCO Post is sent free of charge to approximately 27,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www. ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $271; Individual International: $523; Institutional

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and

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Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

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.

ASCOPost.com | JUNE 10, 2014 | SUPPLEMENT

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Peter P. Yu, MD

An Early Calling to Medicine That Never Wavered: ASCO President Peter P. Yu, MD

he road leading to a career in medicine is often a stepwise journey of multiple decision points and influences. However, sometimes the decision to become a doctor is hardwired from birth. Such was the case with 2014-2015 ASCO President Peter P. Yu, MD. Since his days in nursery school, Dr. Yu always wanted to be a doctor and care for sick people. “I never considered any other profession but medicine,” he said. Dr. Yu grew up in the Riverdale section of New York City. “Both sides of my family were engineers, so becoming a doctor was breaking the mold,” said Dr. Yu. He went to the Bronx High School of Science and during his senior year applied to Brown University. “The application had a check box that asked if you wanted to be considered for Brown’s new 7-year medical program. I checked the box and when I received my acceptance letter I was enrolled in medical school. So looking back, I had a very clear path to a career in medicine,” noted Dr. Yu.

A Fork in the Road “The first time I wrestled with a career decision was when I was an intern at St. Luke’s Hospital in New York City. I wanted a discipline that combined diagnostic skills with therapeutic decisions. But I also wanted a field that would continually expand and challenge me over a 30-year career. It took a little while to sort out, but when I added those factors, oncology became the natural choice,” said Dr. Yu.

Following his internship, Dr. Yu crossed from the West to the East side of Manhattan for an oncology fellowship at Mount Sinai Hospital, where his interest in oncology was firmly planted. “I was fortunate to work with Dr. James Holland, one of the giants in the field. He looks at clinical issues without any preexisting rules, so it was a great learning experience for me,” said Dr. Yu.

imab [Erbitux] to the market,” said Dr. Yu, remarking that it was exciting to be part of one of the first success stories in translational research, bringing an agent from the bench to the bedside.

Clinical Practice Calls “I realized if I stayed at Memorial I could continue this kind of research, but it would take a full-time commitment to the lab. But I also

If we keep the [big data] process going—creating, accepting, and disproving theories—we will discover clinical solutions and use them until the process comes up with something better. I’m confident it’s going to take us into new dimensions of care. —Peter P. Yu, MD

“While at Mount Sinai, I also began friendships with Drs. Larry Norton and Edward Ambinder, which, in large part, began my relationship with ASCO,” he added. After completing his clinical fellowship at Mount Sinai, Dr. Yu plunged into the exciting challenges of the newly emerging field of translational medicine. “I went downtown to Memorial Sloan Kettering and did bench research with Dr. John Mendelson. We worked on epidermal growth factor receptor and tyrosine signal transduction, which was a little known pathway at the time. The work in that lab eventually led to the clinical trials that brought cetux-

NAME: Peter P. Yu, MD TITLE: Director of Cancer Research, Palo Alto Medical Foundation; President-Elect, American Society of Clinical Oncology MEDICAL DEGREE: MD, Brown University RESEARCH INTERESTS: Medical oncology, hematology, health information technology, health-care policy

enjoyed patient care and I was only doing one clinic a week. I realized that to be successful I would have to choose between the lab or the clinic,” said Dr. Yu. Dr. Yu took time to examine this important fork in his career path, but in the end, he decided to concentrate on clinical practice. “In 1989, I went to California and joined a six-doctor community oncology practice. It was very rewarding to focus on clinical practice; however, after a while, an overriding desire to provide service to society on a larger scale kicked in, and I become involved in the state’s Association of Northern California Oncologists,” explained Dr. Yu. “When I was Chair of the Clinical Practice Committee, I caught the attention of ASCO. I was recruited for the Clinical Practice Committee, of which I became President. ASCO nurtured my interest about issues that affect the delivery of cancer care on a societal level,” said Dr. Yu.

A Changing Landscape Dr. Yu came onto the national stage during a time of change in health care. “Change usually happens first in California, then spreads across the nation. All of a sudden we had huge enrollments into HMOs and rapid consolidation of the healthcare delivery market, which put enormous stress on practices. My six-doctor practice, the El Camino Internal Medical Group, has become part of the 1,300-physician Camino Medical, which is a member of the Sutter Health System,” said Dr. Yu. The tectonic shift in size, scope, and complexity of his once small practice sparked yet another new direction in Dr. Yu’s career. “I wanted to understand how a massive and complex delivery care system functions without losing its precision and at the same time how you can use its vast size and resources to spur innovation. One way, of course, is by advancing the use of information technology. Paper charts simply cannot function efficiently when you reach that kind of patient volume,” said Dr. Yu. “We’ve been using electronic medical records for about 14 years, so our Foundation has been way ahead of the information technology curve. That’s given me a leg up in policy meetings on the Hill when the discussion turns to the implementation of health information technology and meaningful use,” said Dr. Yu.

Work in Health-Care Policy Dr. Yu noted that his combined knowledge of national public policy, health information technology, and coordination of care across large delivery systems, has given him keen insight into large-scale challenges faced by the oncology community. Besides his clinical practice, Dr. Yu maintains continued on page 4

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Peter P. Yu, MD continued from page 3

a whirlwind schedule of conference calls, workshops, and strategy meetings, from Capitol Hill to the National Institutes of Health and the Centers for Disease Control and Prevention. How does Dr. Yu balance clinical practice with his demanding policy work? He credits a close working relationship with his practice partners and electronic access to patient records. “With our electronic medical records, we can access patient records and read chart notes from the same day. So we have a built in backup system that allows us to care for each others patients when needed,” said Dr. Yu. He continued, “Being part of this national dialogue has been an enriching experience. Moreover, being a representative of ASCO, I try to advance the Society’s role as the ‘big tent’ under which the serious policy

discussions about cancer care take place. It makes sense, since ASCO has evolved into the preeminent professional society in the cancer world.”

Three-Year Process When asked how he was planning to approach his ASCO presidency, Dr. Yu responded, “ASCO typically runs its leadership through cycles for any work group or committee chair. For instance, there is a president-elect year, a presidential year, and a pastpresident year. So I look at this as a 3-year cycle. In the immediate past year as president-elect, I looked at the meetings and committees I attended from a high point of view so I could truly get an overview of all the sectors of the Society that I had not thus far been part of.” Dr. Yu said that along with helping him develop his own vision for the future direction of the Society, his year as president-elect provided

him insight into how ASCO’s Board of Directors works. “Part of a President’s job is to serve as Chairman of the Board. I see my role as not so much telling people what they should do, but more as an observer who helps the members distill the salient points of discussion into a working consensus so we can effectively move important agendas forward,” said Dr. Yu. Dr. Yu allowed that one of the challenges moving forward for ASCO is the collection of clinically relevant data that can be used at point-ofcare to enhance our delivery system. Asked if we are making progress to that end, he said a book he was reading offered a clue. “I’m reading The Quantum Universe [by Brian Cox and Jeff Forshaw], and what I’m struck by is the authors’ point of view. You make a clinical observation and create a theory to explain it, which may or may not be true. If it’s true you hold onto it until disproven. That’s

The ASCO Post SALUTES

The American Society of Clinical Oncology on its

50TH Anniversary 1964 –2014

sort of what CancerLinQ is doing except in a big-data process. And if we keep the process going—creating, accepting, and disproving theories—we will discover clinical solutions and use them until the process comes up with something better. I’m confident it’s going to take us into new dimensions of care.” ASCO’s new president brings an impressive resume to the Society. Dr. Yu understands the oncology world from the research bench to the clinic to intense health-care policy meetings on Capitol Hill, and the Society will certainly benefit from that rich experiential knowledge and energy. However, it will also benefit from a president who, from the age of 6, sought no other career than doctor. Dr. Yu recalled a day in medical school when a physician said to him and a few other classmates, “At, the end of the day when you leave the room with a patient, that patient should feel better because you were there.” n

VOTRIENT is indicated for the treatment of advanced renal cell carcinoma (RCC)1

EFFICACY AGAINST PROGRESSION

VOTRIENT demonstrated an overall median progression-free survival (PFS) of

9.2 months vs 4.2 months with placebo (HR 0.46; 95% CI 0.34-0.62; P<0.001)1*

*Phase 3, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efﬁcacy and safety of VOTRIENT in ﬁrst-line or cytokine-pretreated patients (N=435) with advanced RCC of clear cell or predominantly clear cell histology. Patients with locally advanced or metastatic RCC were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.

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

EFFICACY LIGHTS THE WAY

VOTRIENT® (pazopanib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).1

VOTRIENT: Significant PFS improvement in patients with advanced RCC1 Median PFS in patients with advanced RCC receiving VOTRIENT vs placebo1,2 12 10

VOTRIENT Placebo

11.1

MONTHS

9.2

MONTHS

7.4

Months

8 6 4

MONTHS

4.2

2.8

MONTHS

4.2

MONTHS

2 0

HR 0.46; 95% CI 0.34-0.62 (P<0.001) All patients

HR 0.40; 95% CI 0.27-0.60 (P<0.001) First-line patients

HR 0.54; 95% CI 0.35-0.84 (P<0.001) Cytokine-pretreated patients

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of VOTRIENT in patients (N=435) with advanced RCC. Patients with locally advanced or metastatic RCC of clear cell or predominantly clear cell histology were randomized (2:1) to receive either VOTRIENT 800 mg (n=290) once daily or placebo (n=145). The study included first-line patients receiving VOTRIENT (n=155) or placebo (n=78) as well as cytokine-pretreated patients receiving VOTRIENT (n=135) or placebo (n=67).1

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thromboembolic Events: Arterial thromboembolic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thromboembolic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have occurred, including venous thrombosis and fatal pulmonary

emboli. In the randomized RCC trial, VTEs were reported in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. • Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. • Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred in clinical trials. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence

of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In advanced RCC, initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced RCC trial, 42% of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose reduced • No dose adjustment is required in patients with mild hepatic impairment • In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • Monitor serum liver tests before initiation of treatment and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modifications based on drug interactions, please see Sections 2.2 and 7 of accompanying Brief Summary of Prescribing Information

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • Most common adverse reactions (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

VOTRIENT (pazopanib) has a Category 1 recommendation as a ﬁrst-line therapy in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for relapsed or Stage IV unresectable RCC of predominant clear cell histology.3 NCCN Guidelines® also include therapies other than VOTRIENT (pazopanib) as ﬁrst-line treatment options.

• Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. • Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax.

• Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT.

• Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. The most common adverse reactions (≥20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.2.2014. ©National Comprehensive Cancer Network, Inc. 2013. All rights reserved. Accessed December 9, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

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EFFICACY LIGHTS THE WAY

BRIEF BRIEF SUMMARY SUMMARY (pazopanib) tablets tablets VOTRIENT VOTRIENT®® (pazopanib) The The following following isis aa brief brief summary summary only; only; see see full full prescribing prescribing information information for for complete complete product product information. information. WARNING: WARNING: HEPATOTOXICITY HEPATOTOXICITY Severe Severe and and fatal fatal hepatotoxicity hepatotoxicity has has been been observed observed in in clinical clinical trials. trials. Monitor Monitor hepatic hepatic function function and and interrupt, interrupt, reduce, reduce, or or discontinue discontinue dosing dosing as as recommended recommended [See [See Warnings Warnings and and Precautions Precautions (5.1)]. (5.1)]. 11 INDICATIONS INDICATIONS AND AND USAGE USAGE VOTRIENT VOTRIENT isis indicated indicated for for the the treatment treatment of of patients patients with with advanced advanced renal renal cell cell carcinoma carcinoma (RCC). (RCC). 22 DOSAGE DOSAGE AND AND ADMINISTRATION ADMINISTRATION 2.1 2.1 Recommended Recommended Dosing: Dosing: The The recommended recommended starting starting dose dose of of VOTRIENT VOTRIENT isis 800 800 mg mg orally orally once once daily daily without without food food (at (at least least 11 hour hour before before or or 22 hours hours after after aa meal) meal) [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) of of full full prescribing prescribing information]. information]. The The dose dose of of VOTRIENT VOTRIENT should should not not exceed exceed 800 800 mg. mg. Do Do not not crush crush tablets tablets due due to to the the potential potential for for increased increased rate rate of of absorption absorption which which may may affect affect systemic systemic exposure exposure [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) of of full full prescribing prescribing information]. information]. IfIf aa dose dose isis missed, missed, itit should should not not be be taken taken ifif itit isis less less than than 12 12 hours hours until until the the next next dose. dose. 2.2 2.2 Dose Dose Modification Modification Guidelines: Guidelines: In In RCC, RCC, the the initial initial dose dose reduction reduction should should be be 400 400 mg, mg, and and additional additional dose dose decrease decrease or or increase increase should should be be in in 200 200 mg mg steps steps based based on on individual individual tolerability. tolerability. Hepatic Hepatic Impairment: Impairment: No No dose dose adjustment adjustment isis required required in in patients patients with with mild mild hepatic hepatic impairment. impairment. In In patients patients with with moderate moderate hepatic hepatic impairment, impairment, alternatives alternatives to to VOTRIENT VOTRIENT should should be be considered. considered. IfIf VOTRIENT VOTRIENT isis used used in in patients patients with with moderate moderate hepatic hepatic impairment, impairment, the the dose dose should should be be reduced reduced to to 200 200 mg mg per per day. day. VOTRIENT VOTRIENT isis not not recommended recommended in in patients patients with with severe severe hepatic hepatic impairment impairment [see [see Use Use in in Specific Specific Populations Populations (8.6) (8.6) and and Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) of of full full prescribing prescribing information]. information]. Concomitant Concomitant Strong Strong CYP3A4 CYP3A4 Inhibitors: Inhibitors: The The concomitant concomitant use use of of strong strong CYP3A4 CYP3A4 inhibitors inhibitors (e.g., (e.g., ketoconazole, ketoconazole, ritonavir, ritonavir, clarithromycin) clarithromycin) increases increases pazopanib pazopanib concentrations concentrations and and should should be be avoided. avoided. Consider Consider an an alternate alternate concomitant concomitant medication medication with with no no or or minimal minimal potential potential to to inhibit inhibit CYP3A4. CYP3A4. IfIf coadministration coadministration of of aa strong strong CYP3A4 CYP3A4 inhibitor inhibitor isis warranted, warranted, reduce reduce the the dose dose of of VOTRIENT VOTRIENT to to 400 400 mg. mg. Further Further dose dose reductions reductions may may be be needed needed ifif adverse adverse effects effects occur occur during during therapy therapy [see [see Drug Drug Interactions Interactions (7.1) (7.1) and and Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) of of full full prescribing prescribing information]. information]. Concomitant Concomitant Strong Strong CYP3A4 CYP3A4 Inducer: Inducer: The The concomitant concomitant use use of of strong strong CYP3A4 CYP3A4 inducers inducers (e.g., (e.g., rifampin) rifampin) may may decrease decrease pazopanib pazopanib concentrations concentrations and and should should be be avoided. avoided. Consider Consider an an alternate alternate concomitant concomitant medication medication with with no no or or minimal minimal enzyme enzyme induction induction potential. potential. VOTRIENT VOTRIENT should should not not be be used used in in patients patients who who cannot cannot avoid avoid chronic chronic use use of of strong strong CYP3A4 CYP3A4 inducers inducers [see [see Drug Drug Interactions Interactions (7.1)]. (7.1)]. 44 CONTRAINDICATIONS CONTRAINDICATIONS None. None. 55 WARNINGS WARNINGS AND AND PRECAUTIONS PRECAUTIONS 5.1 5.1 Hepatic Hepatic Toxicity Toxicity and and Hepatic Hepatic Impairment: Impairment: In In clinical clinical trials trials with with VOTRIENT, VOTRIENT, hepatotoxicity, hepatotoxicity, manifested manifested as as increases increases in in serum serum transaminases transaminases (ALT, (ALT, AST) AST) and and bilirubin, bilirubin, was was observed. observed. This This hepatotoxicity hepatotoxicity can can be be severe severe and and fatal. fatal. Transaminase Transaminase elevations elevations occur occur early early in in the the course course of of treatment treatment (92.5% (92.5% of of all all transaminase transaminase elevations elevations of of any any grade grade occurred occurred in in the the first first 18 18 weeks) weeks) [see [see Dosage Dosage and and Administration Administration (2.2)]. (2.2)]. In In the the randomized randomized RCC RCC trial, trial, ALT ALT >3 >3 XX ULN ULN was was reported reported in in 18% 18% and and 3% 3% of of the the VOTRIENT VOTRIENT and and placebo placebo groups, groups, respectively. respectively. ALT ALT >10 >10 XX ULN ULN was was reported reported in in 4% 4% of of patients patients who who received received VOTRIENT VOTRIENT and and in in <1% <1% of of patients patients who who received received placebo. placebo. Concurrent Concurrent elevation elevation in in ALT ALT >3 >3 XX ULN ULN and and bilirubin bilirubin >2 >2 XX ULN ULN in in the the absence absence of of significant significant alkaline alkaline phosphatase phosphatase >3 >3 XX ULN ULN occurred occurred in in 2% 2% (5/290) (5/290) of of patients patients on on VOTRIENT VOTRIENT and and 1% 1% (2/145) (2/145) on on placebo. placebo. Two-tenths Two-tenths percent percent of of the the patients patients (2/977) (2/977) from from trials trials that that supported supported the the RCC RCC indication indication died died with with disease disease progression progression and and hepatic hepatic failure. failure. Monitor Monitor serum serum liver liver tests tests before before initiation initiation of of treatment treatment with with VOTRIENT VOTRIENT and and at at Weeks Weeks 3, 3, 5, 5, 7,7, and and 9. 9. Thereafter, Thereafter, monitor monitor at at Month Month 33 and and at at Month Month 4, 4, and and as as clinically clinically indicated. indicated. Periodic Periodic monitoring monitoring should should then then continue continue after after Month Month 4. 4. Patients Patients with with isolated isolated ALT ALT elevations elevations between between 33 XX ULN ULN and and 88 XX ULN ULN may may be be continued continued on on VOTRIENT VOTRIENT with with weekly weekly monitoring monitoring of of liver liver function function until until ALT ALT return return to to Grade Grade 11 or or baseline. baseline. Patients Patients with with isolated isolated ALT ALT elevations elevations of of >8 >8 XX ULN ULN should should have have VOTRIENT VOTRIENT interrupted interrupted until until they they return return to to Grade Grade 11 or or baseline. baseline. IfIf the the potential potential benefit benefit for for reinitiating reinitiating treatment treatment with with VOTRIENT VOTRIENT isis considered considered to to outweigh outweigh the the risk risk for for hepatotoxicity, hepatotoxicity, then then reintroduce reintroduce VOTRIENT VOTRIENT at at aa reduced reduced dose dose of of no no more more than than 400 400 mg mg once once daily daily and and measure measure serum serum liver liver tests tests weekly weekly for for 88 weeks weeks [see [see Dosage Dosage and and Administration Administration (2.2)]. (2.2)]. Following Following reintroduction reintroduction of of VOTRIENT, VOTRIENT, ifif ALT ALT elevations elevations >3 >3 XX ULN ULN recur, recur, then then VOTRIENT VOTRIENT should should be be permanently permanently discontinued. discontinued. IfIf ALT ALT elevations elevations >3 >3 XX ULN ULN occur occur concurrently concurrently with with bilirubin bilirubin elevations elevations >2 >2 XX ULN, ULN, VOTRIENT VOTRIENT should should be be permanently permanently discontinued. discontinued. Patients Patients should should be be monitored monitored until until resolution. resolution. VOTRIENT VOTRIENT isis aa UGT1A1 UGT1A1 inhibitor. inhibitor. Mild, Mild, indirect indirect (unconjugated) (unconjugated) hyperbilirubinemia hyperbilirubinemia may may occur occur in in patients patients with with Gilbert’s Gilbert’s syndrome syndrome [see [see Clinical Clinical Pharmacology Pharmacology (12.5) (12.5) of of full full prescribing prescribing information]. information]. Patients Patients with with only only aa mild mild indirect indirect hyperbilirubinemia, hyperbilirubinemia, known known Gilbert’s Gilbert’s syndrome, syndrome, and and elevation elevation in in ALT ALT >3 >3 XX ULN ULN should should be be managed managed as as per per the the recommendations recommendations outlined outlined for for isolated isolated ALT ALT elevations. elevations. Concomitant Concomitant use use of of VOTRIENT VOTRIENT and and simvastatin simvastatin increases increases the the risk risk of of ALT ALT elevations elevations and and should should be be undertaken undertaken with with caution caution and and close close monitoring monitoring [see [see Drug Drug Interactions Interactions (7.4)]. (7.4)]. Insufficient Insufficient data data are are available available to to assess assess the the risk risk of of concomitant concomitant administration administration of of alternative alternative statins statins and and VOTRIENT. VOTRIENT. In In patients patients with with pre-existing pre-existing moderate moderate hepatic hepatic impairment, impairment, the the starting starting dose dose of of VOTRIENT VOTRIENT should should be be reduced reduced or or alternatives alternatives to to VOTRIENT VOTRIENT should should be be considered. considered. Treatment Treatment with with VOTRIENT VOTRIENT isis not not recommended recommended in in patients patients with with pre-existing pre-existing severe severe hepatic hepatic impairment, impairment, defined defined as as total total bilirubin bilirubin >3 >3 XX ULN ULN with with any any level level of of ALT ALT [see [see Dosage Dosage and and Administration Administration (2.2), (2.2), Use Use in in Specific Specific Populations Populations (8.6), (8.6), and and Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) of of full full prescribing prescribing information]. information]. 5.2 5.2 QT QT Prolongation Prolongation and and Torsades Torsades de de Pointes: Pointes: In In the the RCC RCC trials trials of of VOTRIENT, VOTRIENT, QT QT prolongation prolongation (≥500 (≥500 msec) msec) was was identified identified on on routine routine electrocardiogram electrocardiogram monitoring monitoring in in 2% 2% (11/558) (11/558) of of patients. patients. Torsades Torsades de de pointes pointes occurred occurred in in <1% <1% (2/977) (2/977) of of patients patients who who received received VOTRIENT VOTRIENT in in the the monotherapy monotherapy trials. trials. In In the the randomized randomized RCC RCC trial, trial, 1% 1% (3/290) (3/290) of of patients patients who who received received VOTRIENT VOTRIENT had had post-baseline post-baseline values values between between 500 500 to to 549 549 msec. msec. None None of of the the 145 145 patients patients who who received received placebo placebo on on the the trial trial had had post-baseline post-baseline QTc QTc values values ≥500 ≥500 msec. msec. VOTRIENT VOTRIENT should should be be used used with with caution caution in in patients patients with with aa history history of of QT QT interval interval prolongation, prolongation, in in patients patients taking taking antiarrhythmics antiarrhythmics or or other other medications medications that that may may prolong prolong QT QT interval, interval, and and those those with with relevant relevant pre-existing pre-existing cardiac cardiac disease. disease. When When using using VOTRIENT, VOTRIENT, baseline baseline and and periodic periodic monitoring monitoring of of electrocardiograms electrocardiograms and and maintenance maintenance of of electrolytes electrolytes (e.g., (e.g., calcium, calcium, magnesium, magnesium, potassium) potassium) within within the the normal normal range range should should be be performed. performed. 5.3 5.3 Cardiac Cardiac Dysfunction: Dysfunction: In In clinical clinical trials trials with with VOTRIENT, VOTRIENT, events events of of cardiac cardiac dysfunction dysfunction such such as as decreased decreased left left ventricular ventricular ejection ejection fraction fraction (LVEF) (LVEF) and and congestive congestive heart heart failure failure have have occurred. occurred. In In the the overall overall safety safety population population for for RCC RCC (N=586), (N=586), cardiac cardiac dysfunction dysfunction was was observed observed in in 0.6% 0.6% (4/586) (4/586) of of patients patients without without routine routine on-study on-study LVEF LVEF monitoring. monitoring. Blood Blood pressure pressure should should be be monitored monitored and and managed managed promptly promptly using using aa combination combination of of anti-hypertensive anti-hypertensive therapy therapy and and dose dose modification modification of of VOTRIENT VOTRIENT (interruption (interruption and and re-initiation re-initiation at at aa reduced reduced dose dose based based on on clinical clinical judgment) judgment) [see [see Warnings Warnings and and Precautions Precautions (5.10)]. (5.10)]. Patients Patients should should be be carefully carefully monitored monitored for for clinical clinical signs signs or or symptoms symptoms of of congestive congestive heart heart failure. failure. Baseline Baseline and and periodic periodic evaluation evaluation of of LVEF LVEF isis recommended recommended in in patients patients at at risk risk of of cardiac cardiac dysfunction dysfunction including including previous previous anthracycline anthracycline exposure. exposure. 5.4 5.4 Hemorrhagic Hemorrhagic Events: Events: Fatal Fatal hemorrhage hemorrhage occurred occurred in in 0.9% 0.9% (5/586) (5/586) in in the the RCC RCC trials. trials. In In the the randomized randomized RCC RCC trial, trial, 13% 13% (37/290) (37/290) of of patients patients treated treated with with VOTRIENT VOTRIENT and and 5% 5% (7/145) (7/145) of of patients patients on on placebo placebo experienced experienced at at least least 11 hemorrhagic hemorrhagic event. event. The The most most common common hemorrhagic hemorrhagic events events in in the the patients patients treated treated with with VOTRIENT VOTRIENT were were hematuria hematuria (4%), (4%), epistaxis epistaxis (2%), (2%), hemoptysis hemoptysis (2%), (2%), and and rectal rectal hemorrhage hemorrhage (1%). (1%). Nine Nine of of 37 37 patients patients treated treated with with VOTRIENT VOTRIENT who who had had hemorrhagic hemorrhagic events events experienced experienced serious serious events events including including pulmonary, pulmonary, gastrointestinal, gastrointestinal, and and genitourinary genitourinary hemorrhage. hemorrhage. One One percent percent (4/290) (4/290) of of patients patients treated treated with with VOTRIENT VOTRIENT died died from from hemorrhage hemorrhage compared compared with with no no (0/145) (0/145) patients patients on on placebo. placebo. In In the the overall overall safety safety population population in in RCC RCC (N=586), (N=586), cerebral/ cerebral/ intracranial intracranial hemorrhage hemorrhage was was observed observed in in <1% <1% (2/586) (2/586) of of patients patients treated treated with with VOTRIENT. VOTRIENT. VOTRIENT VOTRIENT has has not not been been studied studied in in patients patients who who have have aa history history of of hemoptysis, hemoptysis, cerebral, cerebral, or or clinically clinically significant significant gastrointestinal gastrointestinal hemorrhage hemorrhage in in the the past past 66 months months and and should should not not be be used used in in those those patients. patients. 5.5 5.5 Arterial Arterial Thromboembolic Thromboembolic Events: Events: Fatal Fatal arterial arterial thromboembolic thromboembolic events events were were observed observed in in 0.3% 0.3% (2/586) (2/586) of of patients patients in in the the RCC RCC trials. trials. In In the the randomized randomized RCC RCC trial, trial, 2% 2% (5/290) (5/290) of of patients patients receiving receiving VOTRIENT VOTRIENT experienced experienced myocardial myocardial infarction infarction or or ischemia, ischemia, 0.3% 0.3% (1/290) (1/290) had had aa cerebrovascular cerebrovascular accident accident and and 1% 1% (4/290) (4/290) had had an an event event of of transient transient ischemic ischemic attack. attack. No No arterial arterial thromboembolic thromboembolic events events were were reported reported in in patients patients who who received received placebo. placebo. VOTRIENT VOTRIENT should should be be used used with with caution caution in in patients patients who who are are at at increased increased risk risk for for these these events events or or who who have have had had aa history history of of these these events. events. VOTRIENT VOTRIENT has has not not been been studied studied in in patients patients who who have have had had an an arterial arterial thromboembolic thromboembolic event event within within the the previous previous 66 months months and and should should not not be be used used in in those those patients. patients. 5.6 5.6 Venous Venous Thromboembolic Thromboembolic Events: Events: In In trials trials of of VOTRIENT, VOTRIENT, venous venous thromboembolic thromboembolic events events (VTE) (VTE) including including venous venous thrombosis thrombosis and and fatal fatal pulmonary pulmonary embolus embolus (PE) (PE) have have occurred. occurred. In In the the randomized randomized RCC RCC trial, trial, the the rate rate of of venous venous thromboembolic thromboembolic events events was was 1% 1% in in both both arms. arms. There There were were no no fatal fatal pulmonary pulmonary emboli emboli in in the the RCC RCC trial. trial. Monitor Monitor for for signs signs and and symptoms symptoms of of VTE VTE and and PE. PE. 5.7 5.7 Thrombotic Thrombotic Microangiopathy: Microangiopathy: Thrombotic Thrombotic microangiopathy microangiopathy (TMA), (TMA), including including thrombotic thrombotic thrombocytopenic thrombocytopenic purpura purpura (TTP) (TTP) and and hemolytic hemolytic uremic uremic syndrome syndrome (HUS) (HUS) has has been been reported reported in in clinical clinical trials trials of of VOTRIENT VOTRIENT as as monotherapy, monotherapy, in in combination combination with with bevacizumab, bevacizumab, and and in in combination combination with with topotecan. topotecan. VOTRIENT VOTRIENT isis not not indicated indicated for for use use in in combination combination with with other other agents. agents. Six Six of of the the 77 TMA TMA cases cases occurred occurred within within 90 90 days days of of the the initiation initiation of of VOTRIENT. VOTRIENT. Improvement Improvement of of TMA TMA was was observed observed after after treatment treatment was was discontinued. discontinued. Monitor Monitor for for signs signs and and symptoms symptoms of of TMA. TMA. Permanently Permanently discontinue discontinue VOTRIENT VOTRIENT in in patients patients developing developing TMA. TMA. Manage Manage as as clinically clinically indicated. indicated. 5.8 5.8 Gastrointestinal Gastrointestinal Perforation Perforation and and Fistula: Fistula: In In the the RCC RCC trials, trials, gastrointestinal gastrointestinal perforation perforation or or fistula fistula occurred occurred in in 0.9% 0.9% (5/586) (5/586) of of patients patients receiving receiving VOTRIENT. VOTRIENT. Fatal Fatal perforations perforations occurred occurred in in 0.3% 0.3% (2/586) (2/586) of of these these patients patients in in the the RCC RCC trials. trials. Monitor Monitor for for signs signs and and symptoms symptoms of of gastrointestinal gastrointestinal perforation perforation or or fistula. fistula. 5.9 5.9 Reversible Reversible Posterior Posterior Leukoencephalopathy Leukoencephalopathy Syndrome: Syndrome: Reversible Reversible Posterior Posterior Leukoencephalopathy Leukoencephalopathy Syndrome Syndrome (RPLS) (RPLS) has has been been reported reported in in patients patients receiving receiving VOTRIENT VOTRIENT and and may may be be fatal. fatal. RPLS RPLS isis aa neurological neurological disorder disorder which which can can present present with with headache, headache, seizure, seizure, lethargy, lethargy, confusion, confusion, blindness, blindness, and and other other visual visual and and neurologic neurologic disturbances. disturbances. Mild Mild to to severe severe hypertension hypertension may may be be present. present. The The diagnosis diagnosis of of RPLS RPLS isis optimally optimally confirmed confirmed by by magnetic magnetic resonance resonance imaging. imaging. Permanently Permanently discontinue discontinue VOTRIENT VOTRIENT in in patients patients developing developing RPLS. RPLS. 5.10 5.10 Hypertension: Hypertension: In In clinical clinical trials, trials, hypertension hypertension (systolic (systolic blood blood pressure pressure ≥150 ≥150 or or diastolic diastolic blood blood pressure pressure ≥100 ≥100 mm mm Hg) Hg) and and

hypertensive hypertensive crisis crisis were were observed observed in in patients patients treated treated with with VOTRIENT. VOTRIENT. Blood Blood pressure pressure should should be be well-controlled well-controlled prior prior to to initiating initiating VOTRIENT. VOTRIENT. Hypertension Hypertension occurs occurs early early in in the the course course of of treatment treatment (40% (40% of of cases cases occurred occurred by by Day Day 99 and and 90% 90% of of cases cases occurred occurred in in the the first first 18 18 weeks). weeks). Blood Blood pressure pressure should should be be monitored monitored early early after after starting starting treatment treatment (no (no longer longer than than one one week) week) and and frequently frequently thereafter thereafter to to ensure ensure blood blood pressure pressure control. control. Approximately Approximately 40% 40% of of patients patients who who received received VOTRIENT VOTRIENT experienced experienced hypertension. hypertension. Grade Grade 33 hypertension hypertension was was reported reported in in 4% 4% to to 7% 7% of of patients patients receiving receiving VOTRIENT VOTRIENT [see [see Adverse Adverse Reactions Reactions (6.1)]. (6.1)]. Increased Increased blood blood pressure pressure should should be be treated treated promptly promptly with with standard standard anti-hypertensive anti-hypertensive therapy therapy and and dose dose reduction reduction or or interruption interruption of of VOTRIENT VOTRIENT as as clinically clinically warranted. warranted. VOTRIENT VOTRIENT should should be be discontinued discontinued ifif there there isis evidence evidence of of hypertensive hypertensive crisis crisis or or ifif hypertension hypertension isis severe severe and and persistent persistent despite despite anti-hypertensive anti-hypertensive therapy therapy and and dose dose reduction. reduction. Approximately Approximately 1% 1% of of patients patients required required permanent permanent discontinuation discontinuation of of VOTRIENT VOTRIENT because because of of hypertension hypertension [see [see Dosage Dosage and and Administration Administration (2.2)]. (2.2)]. 5.11 5.11 Wound Wound Healing: Healing: No No formal formal trials trials on on the the effect effect of of VOTRIENT VOTRIENT on on wound wound healing healing have have been been conducted. conducted. Since Since vascular vascular endothelial endothelial growth growth factor factor receptor receptor (VEGFR) (VEGFR) inhibitors inhibitors such such as as pazopanib pazopanib may may impair impair wound wound healing, healing, treatment treatment with with VOTRIENT VOTRIENT should should be be stopped stopped at at least least 77 days days prior prior to to scheduled scheduled surgery. surgery. The The decision decision to to resume resume VOTRIENT VOTRIENT after after surgery surgery should should be be based based on on clinical clinical judgment judgment of of adequate adequate wound wound healing. healing. VOTRIENT VOTRIENT should should be be discontinued discontinued in in patients patients with with wound wound dehiscence. dehiscence. 5.12 5.12 Hypothyroidism: Hypothyroidism: Hypothyroidism, Hypothyroidism, confirmed confirmed based based on on aa simultaneous simultaneous rise rise of of TSH TSH and and decline decline of of T4, T4, was was reported reported in in 7% 7% (19/290) (19/290) of of patients patients treated treated with with VOTRIENT VOTRIENT in in the the randomized randomized RCC RCC trial. trial. No No patients patients on on the the placebo placebo arm arm had had hypothyroidism. hypothyroidism. In In RCC RCC trials trials of of VOTRIENT, VOTRIENT, hypothyroidism hypothyroidism was was reported reported as as an an adverse adverse reaction reaction in in 4% 4% (26/586) (26/586) of of patients. patients. Proactive Proactive monitoring monitoring of of thyroid thyroid function function tests tests isis recommended. recommended. 5.13 5.13 Proteinuria: Proteinuria: In In the the randomized randomized RCC RCC trial, trial, proteinuria proteinuria was was reported reported as as an an adverse adverse reaction reaction in in 9% 9% (27/290) (27/290) of of patients patients receiving receiving VOTRIENT VOTRIENT and and in in no no patients patients receiving receiving placebo. placebo. In In 22 patients, patients, proteinuria proteinuria led led to to discontinuation discontinuation of of treatment treatment with with VOTRIENT. VOTRIENT. Baseline Baseline and and periodic periodic urinalysis urinalysis during during treatment treatment isis recommended recommended with with follow follow up up measurement measurement of of 24-hour 24-hour urine urine protein protein as as clinically clinically indicated. indicated. Interrupt Interrupt VOTRIENT VOTRIENT and and dose dose reduce reduce for for 24-hour 24-hour urine urine protein protein ≥3 ≥3 grams; grams; discontinue discontinue VOTRIENT VOTRIENT for for repeat repeat episodes episodes despite despite dose dose reductions reductions [see [see Dosage Dosage and and Administration Administration (2.2)]. (2.2)]. 5.14 5.14 Infection: Infection: Serious Serious infections infections (with (with or or without without neutropenia), neutropenia), including including some some with with fatal fatal outcome, outcome, have have been been reported. reported. Monitor Monitor patients patients for for signs signs and and symptoms symptoms of of infection. infection. Institute Institute appropriate appropriate anti-infective anti-infective therapy therapy promptly promptly and and consider consider interruption interruption or or discontinuation discontinuation of of VOTRIENT VOTRIENT for for serious serious infections. infections. 5.15 5.15 Increased Increased Toxicity Toxicity with with Other Other Cancer Cancer Therapy: Therapy: VOTRIENT VOTRIENT isis not not indicated indicated for for use use in in combination combination with with other other agents. agents. Clinical Clinical trials trials of of VOTRIENT VOTRIENT in in combination combination with with pemetrexed pemetrexed and and lapatinib lapatinib were were terminated terminated early early due due to to concerns concerns over over increased increased toxicity toxicity and and mortality. mortality. The The fatal fatal toxicities toxicities observed observed included included pulmonary pulmonary hemorrhage, hemorrhage, gastrointestinal gastrointestinal hemorrhage, hemorrhage, and and sudden sudden death. death. AA safe safe and and effective effective combination combination dose dose has has not not been been established established with with these these regimens. regimens. 5.16 5.16 Increased Increased Toxicity Toxicity in in Developing Developing Organs: Organs: The The safety safety and and effectiveness effectiveness of of VOTRIENT VOTRIENT in in pediatric pediatric patients patients have have not not been been established. established. VOTRIENT VOTRIENT isis not not indicated indicated for for use use in in pediatric pediatric patients. patients. Based Based on on its its mechanism mechanism of of action, action, pazopanib pazopanib may may have have severe severe effects effects on on organ organ growth growth and and maturation maturation during during early early post-natal post-natal development. development. Administration Administration of of pazopanib pazopanib to to juvenile juvenile rats rats less less than than 21 21 days days old old resulted resulted in in toxicity toxicity to to the the lungs, lungs, liver, liver, heart, heart, and and kidney kidney and and in in death death at at doses doses significantly significantly lower lower than than the the clinically clinically recommended recommended dose dose or or doses doses tolerated tolerated in in older older animals. animals. VOTRIENT VOTRIENT may may potentially potentially cause cause serious serious adverse adverse effects effects on on organ organ development development in in pediatric pediatric patients, patients, particularly particularly in in patients patients younger younger than than 22 years years of of age age [see [see Use Use in in Specific Specific Populations Populations (8.4)]. (8.4)]. 5.17 5.17 Pregnancy: Pregnancy: VOTRIENT VOTRIENT can can cause cause fetal fetal harm harm when when administered administered to to aa pregnant pregnant woman. woman. Based Based on on its its mechanism mechanism of of action, action, VOTRIENT VOTRIENT isis expected expected to to result result in in adverse adverse reproductive reproductive effects. effects. In In pre-clinical pre-clinical studies studies in in rats rats and and rabbits, rabbits, pazopanib pazopanib was was teratogenic, teratogenic, embryotoxic, embryotoxic, fetotoxic, fetotoxic, and and abortifacient. abortifacient. There There are are no no adequate adequate and and well-controlled well-controlled studies studies of of VOTRIENT VOTRIENT in in pregnant pregnant women. women. IfIf this this drug drug isis used used during during pregnancy, pregnancy, or or ifif the the patient patient becomes becomes pregnant pregnant while while taking taking this this drug, drug, the the patient patient should should be be apprised apprised of of the the potential potential hazard hazard to to the the fetus. fetus. Women Women of of childbearing childbearing potential potential should should be be advised advised to to avoid avoid becoming becoming pregnant pregnant while while taking taking VOTRIENT VOTRIENT [see [see Use Use in in Specific Specific Populations Populations (8.1)]. (8.1)]. 66 ADVERSE ADVERSE REACTIONS REACTIONS 6.1 6.1 Clinical Clinical Trials Trials Experience: Experience: Because Because clinical clinical trials trials are are conducted conducted under under widely widely varying varying conditions, conditions, adverse adverse reaction reaction rates rates observed observed in in the the clinical clinical trials trials of of aa drug drug cannot cannot be be directly directly compared compared to to rates rates in in the the clinical clinical trials trials of of another another drug drug and and may may not not reflect reflect the the rates rates observed observed in in practice. practice. Potentially Potentially serious serious adverse adverse reactions reactions with with VOTRIENT VOTRIENT included included hepatotoxicity, hepatotoxicity, QT QT prolongation prolongation and and torsades torsades de de pointes, pointes, cardiac cardiac dysfunction, dysfunction, hemorrhagic hemorrhagic events, events, arterial arterial and and venous venous thromboembolic thromboembolic events, events, thrombotic thrombotic microangiopathy, microangiopathy, gastrointestinal gastrointestinal perforation perforation and and fistula, fistula, Reversible Reversible Posterior Posterior Leukoencephalopathy Leukoencephalopathy Syndrome Syndrome (RPLS), (RPLS), hypertension, hypertension, infection, infection, and and increased increased toxicity toxicity with with other other cancer cancer therapies therapies [see [see Warnings Warnings and and Precautions Precautions (5.1-5.10, (5.1-5.10, 5.14-5.15)]. 5.14-5.15)]. Renal Renal Cell Cell Carcinoma: Carcinoma: The The safety safety of of VOTRIENT VOTRIENT has has been been evaluated evaluated in in 977 977 patients patients in in the the monotherapy monotherapy trials trials which which included included 586 586 patients patients with with RCC RCC at at the the time time of of NDA NDA submission. submission. With With aa median median duration duration of of treatment treatment of of 7.4 7.4 months months (range (range 0.1 0.1 to to 27.6), 27.6), the the most most commonly commonly observed observed adverse adverse reactions reactions (≥20%) (≥20%) in in the the 586 586 patients patients were were diarrhea, diarrhea, hypertension, hypertension, hair hair color color change, change, nausea, nausea, fatigue, fatigue, anorexia, anorexia, and and vomiting. vomiting. The The data data described described below below reflect reflect the the safety safety profile profile of of VOTRIENT VOTRIENT in in 290 290 RCC RCC patients patients who who participated participated in in aa randomized, randomized, double-blind, double-blind, placebo-controlled placebo-controlled trial trial [see [see Clinical Clinical Studies Studies (14.1) (14.1) of of full full prescribing prescribing information]. information]. The The median median duration duration of of treatment treatment was was 7.4 7.4 months months (range (range 00 to to 23) 23) for for patients patients who who received received VOTRIENT VOTRIENT and and 3.8 3.8 months months (range (range 00 to to 22) 22) for for the the placebo placebo arm. arm. Forty-two Forty-two percent percent of of patients patients on on VOTRIENT VOTRIENT required required aa dose dose interruption. interruption. Thirty-six Thirty-six percent percent of of patients patients on on VOTRIENT VOTRIENT were were dose dose reduced. reduced. Table Table 11 presents presents the the most most common common adverse adverse reactions reactions occurring occurring in in ≥10% ≥10% of of patients patients who who received received VOTRIENT. VOTRIENT. Table Table 1. 1. Adverse Adverse Reactions Reactions Occurring Occurring in in ≥10% ≥10% of of Patients Patients with with RCC RCC who who Received Received VOTRIENT VOTRIENT VOTRIENT VOTRIENT

Placebo Placebo

(N=290) (N=290)

(N=145) (N=145)

All All All All Grades Grades Gradesaa Gradesaa Grade Grade 33 Grade Grade 44 Grade Grade 33 % % % % % % % % % % Adverse Adverse Reactions Reactions Diarrhea Diarrhea 52 52 33 <1 <1 99 <1 <1 Hypertension Hypertension 40 40 44 00 10 10 <1 <1 Hair Hair color color changes changes 38 38 <1 <1 00 33 00 Nausea Nausea 26 26 <1 <1 00 99 00 Anorexia Anorexia 22 22 22 00 10 10 <1 <1 Vomiting Vomiting 21 21 22 <1 <1 88 22 Fatigue Fatigue 19 19 22 00 88 11 Asthenia Asthenia 14 14 33 00 88 00 Abdominal Abdominal pain pain 11 11 22 00 11 00 Headache Headache 10 10 00 00 55 00 aa National National Cancer Cancer Institute Institute Common Common Terminology Terminology Criteria Criteria for for Adverse Adverse Events, Events, version version 3. 3.

Grade Grade 44 % % 00 00 00 00 00 00 11 00 00 00

Other Other adverse adverse reactions reactions observed observed more more commonly commonly in in patients patients treated treated with with VOTRIENT VOTRIENT than than placebo placebo and and that that occurred occurred in in <10% <10% (any (any grade) grade) were were alopecia alopecia (8% (8% versus versus <1%), <1%), chest chest pain pain (5% (5% versus versus 1%), 1%), dysgeusia dysgeusia (altered (altered taste) taste) (8% (8% versus versus <1%), <1%), dyspepsia dyspepsia (5% (5% versus versus <1%), <1%), dysphonia dysphonia (4% (4% versus versus <1%), <1%), facial facial edema edema (1% (1% versus versus 0%), 0%), palmar-plantar palmar-plantar erythrodysesthesia erythrodysesthesia (hand-foot (hand-foot syndrome) syndrome) (6% (6% versus versus <1%), <1%), proteinuria proteinuria (9% (9% versus versus 0%), 0%), rash rash (8% (8% versus versus 3%), 3%), skin skin depigmentation depigmentation (3% (3% versus versus 0%), 0%), and and weight weight decreased decreased (9% (9% versus versus 3%). 3%). Additional Additional adverse adverse reactions reactions from from other other clinical clinical trials trials in in RCC RCC patients patients treated treated with with VOTRIENT VOTRIENT are are listed listed below: below: Musculoskeletal Musculoskeletal and and Connective Connective Tissue Tissue Disorders: Disorders: Arthralgia, Arthralgia, muscle muscle spasms. spasms. Table Table 22 presents presents the the most most common common laboratory laboratory abnormalities abnormalities occurring occurring in in >10% >10% of of patients patients who who received received VOTRIENT VOTRIENT and and more more commonly commonly (≥5%) (≥5%) in in patients patients who who received received VOTRIENT VOTRIENT versus versus placebo. placebo.

Table Table 2. 2. Selected Selected Laboratory Laboratory Abnormalities Abnormalities Occurring Occurring in in >10% >10% of of Patients Patients with with RCC RCC who who Received Received VOTRIENT VOTRIENT and and More More Commonly Commonly (≥5%) (≥5%) in in Patients Patients who who Received Received VOTRIENT VOTRIENT Versus Versus Placebo Placebo VOTRIENT VOTRIENT (N=290) (N=290) All All Grades Gradesaa % %

Grade Grade 33 % %

Placebo Placebo (N=145) (N=145) Grade Grade 44 % %

All All Grades Gradesaa % %

Parameters Parameters Hematologic Hematologic Leukopenia Leukopenia 37 37 00 00 66 Neutropenia Neutropenia 34 34 11 <1 <1 66 Thrombocytopenia Thrombocytopenia 32 32 <1 <1 <1 <1 55 Lymphocytopenia Lymphocytopenia 31 31 44 <1 <1 24 24 Chemistry Chemistry ALT ALT increased increased 53 53 10 10 22 22 22 AST AST increased increased 53 53 77 <1 <1 19 19 Glucose Glucose increased increased 41 41 <1 <1 00 33 33 Total Total bilirubin bilirubin increased increased 36 36 33 <1 <1 10 10 Phosphorus Phosphorus decreased decreased 34 34 44 00 11 11 Sodium Sodium decreased decreased 31 31 44 11 24 24 Magnesium Magnesium decreased decreased 26 26 <1 <1 11 14 14 Glucose Glucose decreased decreased 17 17 00 <1 <1 33 aa National National Cancer Cancer Institute Institute Common Common Terminology Terminology Criteria Criteria for for Adverse Adverse Events, Events, version version 3. 3.

Grade Grade 33 % %

Grade Grade 44 % %

00 00 00 11

00 00 <1 <1 00

11 <1 <1 11 11 00 44 00 00

00 00 00 <1 <1 00 00 00 00

T:14”

B:14.25”

S:13”

Diarrhea: Diarrhea: Diarrhea Diarrhea occurred occurred frequently frequently and and was was predominantly predominantly mild mild to to moderate moderate in in severity severity in in the the clinical clinical trials. trials. Patients Patients should should be be advised advised how how to to manage manage mild mild diarrhea diarrhea and and to to notify notify their their healthcare healthcare provider provider ifif moderate moderate to to severe severe diarrhea diarrhea occurs occurs so so appropriate appropriate management management can can be be implemented implemented to to minimize minimize its its impact. impact. Lipase Lipase Elevations: Elevations: In In aa single-arm single-arm RCC RCC trial, trial, increases increases in in lipase lipase values values were were observed observed for for 27% 27% (48/181) (48/181) of of patients. patients. Elevations Elevations in in lipase lipase as as an an adverse adverse reaction reaction were were reported reported for for 4% 4% (10/225) (10/225) of of patients patients and and were were Grade Grade 33 for for 66 patients patients and and Grade Grade 44 for for 11 patient. patient. In In the the RCC RCC trials trials of of VOTRIENT, VOTRIENT, clinical clinical pancreatitis pancreatitis was was observed observed in in <1% <1% (4/586) (4/586) of of patients. patients. Pneumothorax: Pneumothorax: Two Two of of 290 290 patients patients treated treated with with VOTRIENT VOTRIENT and and no no patient patient on on the the placebo placebo arm arm in in the the randomized randomized RCC RCC trial trial developed developed aa pneumothorax. pneumothorax. Bradycardia: Bradycardia: In In the the randomized randomized trial trial of of VOTRIENT VOTRIENT for for the the treatment treatment of of RCC, RCC, bradycardia bradycardia based based on on vital vital signs signs (<60 (<60 beats beats per per minute) minute) was was observed observed in in 19% 19% (52/280) (52/280) of of patients patients treated treated with with VOTRIENT VOTRIENT and and in in 11% 11% (16/144) (16/144) of of patients patients on on the the placebo placebo arm. arm. Bradycardia Bradycardia was was reported reported as as an an adverse adverse reaction reaction in in 2% 2% (7/290) (7/290) of of patients patients treated treated with with VOTRIENT VOTRIENT compared compared to to <1% <1% (1/145) (1/145) of of patients patients treated treated with with placebo. placebo. 6.2 6.2 Postmarketing Postmarketing Experience: Experience: The The following following adverse adverse reactions reactions have have been been identified identified during during post post approval approval use use of of VOTRIENT. VOTRIENT. Because Because these these reactions reactions are are reported reported voluntarily voluntarily from from aa population population of of uncertain uncertain size size itit isis not not always always possible possible to to reliably reliably estimate estimate the the frequency frequency or or establish establish aa causal causal relationship relationship to to drug drug exposure. exposure. Gastrointestinal Gastrointestinal Disorders: Disorders: Pancreatitis Pancreatitis 77 DRUG DRUG INTERACTIONS INTERACTIONS 7.1 7.1 Drugs Drugs That That Inhibit Inhibit or or Induce Induce Cytochrome Cytochrome P450 P450 3A4 3A4 Enzymes: Enzymes: In In vitro vitro studies studies suggested suggested that that the the oxidative oxidative metabolism metabolism of of pazopanib pazopanib in in human human liver liver microsomes microsomes isis mediated mediated primarily primarily by by CYP3A4, CYP3A4, with with minor minor contributions contributions from from CYP1A2 CYP1A2 and and CYP2C8. CYP2C8. Therefore, Therefore, inhibitors inhibitors and and inducers inducers of of CYP3A4 CYP3A4 may may alter alter the the metabolism metabolism of of pazopanib. pazopanib. CYP3A4 CYP3A4 Inhibitors: Inhibitors: Coadministration Coadministration of of pazopanib pazopanib with with strong strong inhibitors inhibitors of of CYP3A4 CYP3A4 (e.g., (e.g., ketoconazole, ketoconazole, ritonavir, ritonavir, clarithromycin) clarithromycin) increases increases pazopanib pazopanib concentrations concentrations and and should should be be avoided. avoided. Consider Consider an an alternate alternate concomitant concomitant medication medication with with no no or or minimal minimal potential potential to to inhibit inhibit CYP3A4 CYP3A4 [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) of of full full prescribing prescribing information]. information]. IfIf coadministration coadministration of of aa strong strong CYP3A4 CYP3A4 inhibitor inhibitor isis warranted, warranted, reduce reduce the the dose dose of of VOTRIENT VOTRIENT to to 400 400 mg mg [see [see Dosage Dosage and and Administration Administration (2.2)]. (2.2)]. Grapefruit Grapefruit or or grapefruit grapefruit juice juice should should be be avoided avoided as as itit inhibits inhibits CYP3A4 CYP3A4 activity activity and and may may also also increase increase plasma plasma concentrations concentrations of of pazopanib. pazopanib. CYP3A4 CYP3A4 Inducers: Inducers: CYP3A4 CYP3A4 inducers inducers such such as as rifampin rifampin may may decrease decrease plasma plasma pazopanib pazopanib concentrations. concentrations. Consider Consider an an alternate alternate concomitant concomitant medication medication with with no no or or minimal minimal enzyme enzyme induction induction potential. potential. VOTRIENT VOTRIENT should should not not be be used used ifif chronic chronic use use of of strong strong CYP3A4 CYP3A4 inducers inducers cannot cannot be be avoided avoided [see [see Dosage Dosage and and Administration Administration (2.2)]. (2.2)]. 7.2 7.2 Drugs Drugs That That Inhibit Inhibit Transporters: Transporters: In In vitro vitro studies studies suggested suggested that that pazopanib pazopanib isis aa substrate substrate of of P-glycoprotein P-glycoprotein (Pgp) (Pgp) and and breast breast cancer cancer resistance resistance protein protein (BCRP). (BCRP). Therefore, Therefore, absorption absorption and and subsequent subsequent elimination elimination of of pazopanib pazopanib may may be be influenced influenced by by products products that that affect affect Pgp Pgp and and BCRP. BCRP. Concomitant Concomitant treatment treatment with with strong strong inhibitors inhibitors of of Pgp Pgp or or breast breast cancer cancer resistance resistance protein protein (BCRP) (BCRP) should should be be avoided avoided due due to to risk risk of of increased increased exposure exposure to to pazopanib. pazopanib. Selection Selection of of alternative alternative concomitant concomitant medicinal medicinal products products with with no no or or minimal minimal potential potential to to inhibit inhibit Pgp Pgp or or BCRP BCRP should should be be considered. considered. 7.3 7.3 Effects Effects of of Pazopanib Pazopanib on on CYP CYP Substrates: Substrates: Results Results from from drug-drug drug-drug interaction interaction trials trials conducted conducted in in cancer cancer patients patients suggest suggest that that pazopanib pazopanib isis aa weak weak inhibitor inhibitor of of CYP3A4, CYP3A4, CYP2C8, CYP2C8, and and CYP2D6 CYP2D6 in in vivo, vivo, but but had had no no effect effect on on CYP1A2, CYP1A2, CYP2C9, CYP2C9, or or CYP2C19 CYP2C19 [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) of of full full prescribing prescribing information]. information]. Concomitant Concomitant use use of of VOTRIENT VOTRIENT with with agents agents with with narrow narrow therapeutic therapeutic windows windows that that are are metabolized metabolized by by CYP3A4, CYP3A4, CYP2D6, CYP2D6, or or CYP2C8 CYP2C8 isis not not recommended. recommended. Coadministration Coadministration may may result result in in inhibition inhibition of of the the metabolism metabolism of of these these products products and and create create the the potential potential for for serious serious adverse adverse events events [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) of of full full prescribing prescribing information]. information]. 7.4 7.4 Effect Effect of of Concomitant Concomitant use use of of VOTRIENT VOTRIENT and and Simvastatin: Simvastatin: Concomitant Concomitant use use of of VOTRIENT VOTRIENT and and simvastatin simvastatin increases increases the the incidence incidence of of ALT ALT elevations. elevations. Across Across monotherapy monotherapy studies studies with with VOTRIENT, VOTRIENT, ALT ALT >3 >3 XX ULN ULN was was reported reported in in 126/895 126/895 (14%) (14%) of of patients patients who who did did not not use use statins, statins, compared compared with with 11/41 11/41 (27%) (27%) of of patients patients who who had had concomitant concomitant use use of of simvastatin. simvastatin. IfIf aa patient patient receiving receiving concomitant concomitant simvastatin simvastatin develops develops ALT ALT elevations, elevations, follow follow dosing dosing guidelines guidelines for for VOTRIENT VOTRIENT or or consider consider alternatives alternatives to to VOTRIENT VOTRIENT [see [see Warnings Warnings and and Precautions Precautions (5.1)]. (5.1)]. Alternatively, Alternatively, consider consider discontinuing discontinuing simvastatin simvastatin [see [see Warnings Warnings and and Precautions Precautions (5.1)]. (5.1)]. Insufficient Insufficient data data are are available available to to assess assess the the risk risk of of concomitant concomitant administration administration of of alternative alternative statins statins and and VOTRIENT. VOTRIENT. 88 USE USE IN IN SPECIFIC SPECIFIC POPULATIONS POPULATIONS 8.1 8.1 Pregnancy: Pregnancy: Pregnancy Pregnancy Category Category DD [see [see Warnings Warnings and and Precautions Precautions (5.17)]. (5.17)]. VOTRIENT VOTRIENT can can cause cause fetal fetal harm harm when when administered administered to to aa pregnant pregnant woman. woman. There There are are no no adequate adequate and and well-controlled well-controlled studies studies of of VOTRIENT VOTRIENT in in pregnant pregnant women. women. In In pre-clinical pre-clinical studies studies in in rats rats and and rabbits, rabbits, pazopanib pazopanib was was teratogenic, teratogenic, embryotoxic, embryotoxic, fetotoxic, fetotoxic, and and abortifacient. abortifacient. Administration Administration of of pazopanib pazopanib to to pregnant pregnant rats rats during during organogenesis organogenesis at at aa dose dose level level of of ≥3 ≥3 mg/kg/day mg/kg/day (approximately (approximately 0.1 0.1 times times the the human human clinical clinical exposure exposure based based on on AUC) AUC) resulted resulted in in teratogenic teratogenic effects effects including including cardiovascular cardiovascular malformations malformations (retroesophageal (retroesophageal subclavian subclavian artery, artery, missing missing innominate innominate artery, artery, changes changes in in the the aortic aortic arch) arch) and and incomplete incomplete or or absent absent ossification. ossification. In In addition, addition, there there was was reduced reduced fetal fetal body body weight, weight, and and prepre- and and post-implantation post-implantation embryolethality embryolethality in in rats rats administered administered pazopanib pazopanib at at doses doses ≥3 ≥3 mg/kg/day. mg/kg/day. In In rabbits, rabbits, maternal maternal toxicity toxicity (reduced (reduced food food consumption, consumption, increased increased post-implantation post-implantation loss, loss, and and abortion) abortion) was was observed observed at at doses doses ≥30 ≥30 mg/kg/day mg/kg/day (approximately (approximately 0.007 0.007 times times the the human human clinical clinical exposure). exposure). In In addition, addition, severe severe maternal maternal body body weight weight loss loss and and 100% 100% litter litter loss loss were were observed observed at at doses doses ≥100 ≥100 mg/kg/day mg/kg/day (0.02 (0.02 times times the the human human clinical clinical exposure), exposure), while while fetal fetal weight weight was was reduced reduced at at doses doses ≥3 ≥3 mg/kg/day mg/kg/day (AUC (AUC not not calculated). calculated). IfIf this this drug drug isis used used during during pregnancy, pregnancy, or or ifif the the patient patient becomes becomes pregnant pregnant while while taking taking this this drug, drug, the the patient patient should should be be apprised apprised of of the the potential potential hazard hazard to to the the fetus. fetus. Women Women of of childbearing childbearing potential potential should should be be advised advised to to avoid avoid becoming becoming pregnant pregnant while while taking taking VOTRIENT. VOTRIENT. 8.3 8.3 Nursing Nursing Mothers: Mothers: ItIt isis not not known known whether whether this this drug drug isis excreted excreted in in human human milk. milk. Because Because many many drugs drugs are are excreted excreted in in human human milk milk and and because because of of the the potential potential for for serious serious adverse adverse reactions reactions in in nursing nursing infants infants from from VOTRIENT, VOTRIENT, aa decision decision should should be be made made whether whether to to discontinue discontinue nursing nursing or or to to discontinue discontinue the the drug, drug, taking taking into into account account the the importance importance of of the the drug drug to to the the mother. mother. 8.4 8.4 Pediatric Pediatric Use: Use: The The safety safety and and effectiveness effectiveness of of VOTRIENT VOTRIENT in in pediatric pediatric patients patients have have not not been been established. established. In In rats, rats, weaning weaning occurs occurs at at day day 21 21 postpartum postpartum which which approximately approximately equates equates to to aa human human pediatric pediatric age age of of 22 years. years. In In aa juvenile juvenile animal animal toxicology toxicology study study performed performed in in rats, rats, when when animals animals were were dosed dosed from from day day 99 through through day day 14 14 postpartum postpartum (pre-weaning), (pre-weaning), pazopanib pazopanib caused caused abnormal abnormal organ organ growth/maturation growth/maturation in in the the kidney, kidney, lung, lung, liver liver and and heart heart at at approximately approximately 0.1 0.1 times times the the clinical clinical exposure, exposure, based based on on AUC AUC in in adult adult patients patients receiving receiving VOTRIENT. VOTRIENT. At At approximately approximately 0.4 0.4 times times the the clinical clinical exposure exposure (based (based on on the the AUC AUC in in adult adult patients), patients), pazopanib pazopanib administration administration resulted resulted in in mortality. mortality. In In repeat-dose repeat-dose toxicology toxicology studies studies in in rats rats including including 4-week, 4-week, 13-week, 13-week, and and 26-week 26-week administration, administration, toxicities toxicities in in bone, bone, teeth, teeth, and and nail nail beds beds were were observed observed at at doses doses ≥3 ≥3 mg/kg/day mg/kg/day (approximately (approximately 0.07 0.07 times times the the human human clinical clinical exposure exposure based based on on AUC). AUC). Doses Doses of of 300 300 mg/kg/day mg/kg/day (approximately (approximately 0.8 0.8 times times the the human human clinical clinical exposure exposure based based on on AUC) AUC) were were not not tolerated tolerated in in 1313- and and 26-week 26-week studies studies and and animals animals required required dose dose reductions reductions due due to to body body weight weight loss loss and and morbidity. morbidity. Hypertrophy Hypertrophy of of epiphyseal epiphyseal growth growth plates, plates, nail nail abnormalities abnormalities (including (including broken, broken, overgrown, overgrown, or or absent absent nails) nails) and and tooth tooth abnormalities abnormalities in in growing growing incisor incisor teeth teeth (including (including excessively excessively long, long, brittle, brittle, broken broken and and missing missing teeth, teeth, and and dentine dentine and and enamel enamel degeneration degeneration and and thinning) thinning) were were observed observed in in rats rats at at doses doses ≥30 ≥30 mg/kg/day mg/kg/day (approximately (approximately 0.35 0.35 times times the the human human clinical clinical exposure exposure based based on on AUC) AUC) at at 26 26 weeks, weeks, with with the the onset onset of of tooth tooth and and nail nail bed bed alterations alterations noted noted clinically clinically after after 44 to to 66 weeks. weeks. Similar Similar findings findings were were noted noted in in repeat-dose repeat-dose studies studies in in juvenile juvenile rats rats dosed dosed with with pazopanib pazopanib beginning beginning day day 21 21 postpartum postpartum (post-weaning). (post-weaning). In In the the post-weaning post-weaning animals, animals, the the occurrence occurrence of of changes changes in in teeth teeth and and bones bones occurred occurred earlier earlier and and with with greater greater severity severity than than in in older older animals. animals. There There was was evidence evidence of of tooth tooth degeneration degeneration and and decreased decreased bone bone growth growth at at doses doses ≥30 ≥30 mg/kg mg/kg (approximately (approximately 0.1 0.1 to to 0.2 0.2 times times the the AUC AUC in in human human adults adults at at the the clinically clinically recommended recommended dose). dose). Pazopanib Pazopanib exposure exposure in in juvenile juvenile rats rats was was lower lower than than that that seen seen at at the the same same dose dose levels levels in in adult adult animals, animals, based based on on comparative comparative AUC AUC values. values. At At pazopanib pazopanib doses doses approximately approximately 0.5 0.5 to to 0.7 0.7 times times the the exposure exposure in in adult adult patients patients at at the the clinically clinically recommended recommended dose, dose, decreased decreased bone bone growth growth in in juvenile juvenile rats rats persisted persisted even even after after the the end end of of the the dosing dosing period. period. Finally, Finally, despite despite lower lower pazopanib pazopanib exposures exposures than than those those reported reported in in adult adult animals animals or or adult adult humans, humans, juvenile juvenile animals animals administered administered 300 300 mg/kg/dose mg/kg/dose pazopanib pazopanib required required dose dose reduction reduction within within 44 weeks weeks of of

dosing dosing initiation initiation due due to to significant significant toxicity, toxicity, although although adult adult animals animals could could tolerate tolerate this this same same dose dose for for at at least least 33 times times as as long long [see [see Warnings Warnings and and Precautions Precautions (5.16)]. (5.16)]. 8.5 8.5 Geriatric Geriatric Use: Use: In In clinical clinical trials trials with with VOTRIENT VOTRIENT for for the the treatment treatment of of RCC, RCC, 33% 33% (196/582) (196/582) of of patients patients were were aged aged ≥65 ≥65 years. years. No No overall overall differences differences in in safety safety or or effectiveness effectiveness of of VOTRIENT VOTRIENT were were observed observed between between these these patients patients and and younger younger patients. patients. However, However, patients patients >60 >60 years years of of age age may may be be at at greater greater risk risk for for an an ALT ALT >3 >3 XX ULN. ULN. Other Other reported reported clinical clinical experience experience has has not not identified identified differences differences in in responses responses between between elderly elderly and and younger younger patients, patients, but but greater greater sensitivity sensitivity of of some some older older individuals individuals cannot cannot be be ruled ruled out. out. 8.6 8.6 Hepatic Hepatic Impairment: Impairment: In In clinical clinical studies studies for for VOTRIENT, VOTRIENT, patients patients with with total total bilirubin bilirubin ≤1.5 ≤1.5 XX ULN ULN and and AST AST and and ALT ALT ≤2 ≤2 XX ULN ULN were were included included [see [see Warnings Warnings and and Precautions Precautions (5.1)]. (5.1)]. An An analysis analysis of of data data from from aa pharmacokinetic pharmacokinetic study study of of pazopanib pazopanib in in patients patients with with varying varying degrees degrees of of hepatic hepatic dysfunction dysfunction suggested suggested that that no no dose dose adjustment adjustment isis required required in in patients patients with with mild mild hepatic hepatic impairment impairment [either [either total total bilirubin bilirubin within within normal normal limit limit (WNL) (WNL) with with ALT ALT >> ULN ULN or or bilirubin bilirubin >1 >1 XX to to 1.5 1.5 XX ULN ULN regardless regardless of of the the ALT ALT value]. value]. The The maximum maximum tolerated tolerated dose dose in in patients patients with with moderate moderate hepatic hepatic impairment impairment (total (total bilirubin bilirubin >1.5 >1.5 XX to to 33 XX ULN ULN regardless regardless of of the the ALT ALT value) value) was was 200 200 mg mg per per day day (N=11). (N=11). The The median median steady-state steady-state CCmax and AUC AUC(0-24) achieved at at this this dose dose was was approximately approximately max and (0-24) achieved 40% 40% and and 29%, 29%, respectively, respectively, of of that that seen seen in in patients patients with with normal normal hepatic hepatic function function at at the the recommended recommended daily daily dose dose of of 800 800 mg. mg. The The maximum maximum dose dose explored explored in in patients patients with with severe severe hepatic hepatic impairment impairment (total (total bilirubin bilirubin >3 >3 XX ULN ULN regardless regardless of of the the ALT ALT value) value) was was 200 200 mg mg per per day day (N=14). (N=14). This This dose dose was was not not well well tolerated. tolerated. Median Median exposures exposures achieved achieved at at this this dose dose were were approximately approximately 18% 18% and and 15% 15% of of those those seen seen in in patients patients with with normal normal liver liver function function at at the the recommended recommended daily daily dose dose of of 800 800 mg. mg. Therefore, Therefore, VOTRIENT VOTRIENT isis not not recommended recommended in in these these patients patients [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) of of full full prescribing prescribing information]. information]. 8.7 8.7 Renal Renal Impairment: Impairment: Patients Patients with with renal renal cell cell cancer cancer and and mild/moderate mild/moderate renal renal impairment impairment (creatinine (creatinine clearance clearance ≥30 ≥30 mL/min) mL/min) were were included included in in clinical clinical trials trials for for VOTRIENT. VOTRIENT. There There are are no no clinical clinical or or pharmacokinetic pharmacokinetic data data in in patients patients with with severe severe renal renal impairment impairment or or in in patients patients undergoing undergoing peritoneal peritoneal dialysis dialysis or or hemodialysis. hemodialysis. However, However, renal renal impairment impairment isis unlikely unlikely to to significantly significantly affect affect the the pharmacokinetics pharmacokinetics of of pazopanib pazopanib since since <4% <4% of of aa radiolabeled radiolabeled oral oral dose dose was was recovered recovered in in the the urine. urine. In In aa population population pharmacokinetic pharmacokinetic analysis analysis using using 408 408 patients patients with with various various cancers, cancers, creatinine creatinine clearance clearance (30-150 (30-150 mL/min) mL/min) did did not not influence influence clearance clearance of of pazopanib. pazopanib. Therefore, Therefore, renal renal impairment impairment isis not not expected expected to to influence influence pazopanib pazopanib exposure, exposure, and and dose dose adjustment adjustment isis not not necessary. necessary. 10 10 OVERDOSAGE OVERDOSAGE Pazopanib Pazopanib doses doses up up to to 2,000 2,000 mg mg have have been been evaluated evaluated in in clinical clinical trials. trials. Dose-limiting Dose-limiting toxicity toxicity (Grade (Grade 33 fatigue) fatigue) and and Grade Grade 33 hypertension hypertension were were each each observed observed in in 11 of of 33 patients patients dosed dosed at at 2,000 2,000 mg mg daily daily and and 1,000 1,000 mg mg daily, daily, respectively. respectively. Treatment Treatment of of overdose overdose with with VOTRIENT VOTRIENT should should consist consist of of general general supportive supportive measures. measures. There There isis no no specific specific antidote antidote for for overdosage overdosage of of VOTRIENT. VOTRIENT. Hemodialysis Hemodialysis isis not not expected expected to to enhance enhance the the elimination elimination of of VOTRIENT VOTRIENT because because pazopanib pazopanib isis not not significantly significantly renally renally excreted excreted and and isis highly highly bound bound to to plasma plasma proteins. proteins. 13 13 NONCLINICAL NONCLINICAL TOXICOLOGY TOXICOLOGY 13.1 13.1 Carcinogenesis, Carcinogenesis, Mutagenesis, Mutagenesis, Impairment Impairment of of Fertility: Fertility: Carcinogenicity Carcinogenicity studies studies with with pazopanib pazopanib have have not not been been conducted. conducted. However, However, in in aa 13-week 13-week study study in in mice, mice, proliferative proliferative lesions lesions in in the the liver liver including including eosinophilic eosinophilic foci foci in in 22 females females and and aa single single case case of of adenoma adenoma in in another another female female was was observed observed at at doses doses of of 1,000 1,000 mg/kg/day mg/kg/day (approximately (approximately 2.5 2.5 times times the the human human clinical clinical exposure exposure based based on on AUC). AUC). Pazopanib Pazopanib did did not not induce induce mutations mutations in in the the microbial microbial mutagenesis mutagenesis (Ames) (Ames) assay assay and and was was not not clastogenic clastogenic in in both both the the in in vitro vitro cytogenetic cytogenetic assay assay using using primary primary human human lymphocytes lymphocytes and and in in the the in in vivo vivo rat rat micronucleus micronucleus assay. assay. Pazopanib Pazopanib may may impair impair fertility fertility in in humans. humans. In In female female rats, rats, reduced reduced fertility fertility including including increased increased pre-implantation pre-implantation loss loss and and early early resorptions resorptions were were noted noted at at dosages dosages ≥30 ≥30 mg/kg/day mg/kg/day (approximately (approximately 0.4 0.4 times times the the human human clinical clinical exposure exposure based based on on AUC). AUC). Total Total litter litter resorption resorption was was seen seen at at 300 300 mg/kg/day mg/kg/day (approximately (approximately 0.8 0.8 times times the the human human clinical clinical exposure exposure based based on on AUC). AUC). Post-implantation Post-implantation loss, loss, embryolethality, embryolethality, and and decreased decreased fetal fetal body body weight weight were were noted noted in in females females administered administered doses doses ≥10 ≥10 mg/kg/day mg/kg/day (approximately (approximately 0.3 0.3 times times the the human human clinical clinical exposure exposure based based on on AUC). AUC). Decreased Decreased corpora corpora lutea lutea and and increased increased cysts cysts were were noted noted in in mice mice given given ≥100 ≥100 mg/kg/day mg/kg/day for for 13 13 weeks weeks and and ovarian ovarian atrophy atrophy was was noted noted in in rats rats given given ≥300 ≥300 mg/kg/day mg/kg/day for for 26 26 weeks weeks (approximately (approximately 1.3 1.3 and and 0.85 0.85 times times the the human human clinical clinical exposure exposure based based on on AUC, AUC, respectively). respectively). Decreased Decreased corpora corpora lutea lutea was was also also noted noted in in monkeys monkeys given given 500 500 mg/kg/day mg/kg/day for for up up to to 34 34 weeks weeks (approximately (approximately 0.4 0.4 times times the the human human clinical clinical exposure exposure based based on on AUC). AUC). Pazopanib Pazopanib did did not not affect affect mating mating or or fertility fertility in in male male rats. rats. However, However, there there were were reductions reductions in in sperm sperm production production rates rates and and testicular testicular sperm sperm concentrations concentrations at at doses doses ≥3 ≥3 mg/kg/day, mg/kg/day, epididymal epididymal sperm sperm concentrations concentrations at at doses doses ≥30 ≥30 mg/kg/day, mg/kg/day, and and sperm sperm motility motility at at ≥100 ≥100 mg/kg/day mg/kg/day following following 15 15 weeks weeks of of dosing. dosing. Following Following 15 15 and and 26 26 weeks weeks of of dosing, dosing, there there were were decreased decreased testicular testicular and and epididymal epididymal weights weights at at doses doses of of ≥30 ≥30 mg/kg/day mg/kg/day (approximately (approximately 0.35 0.35 times times the the human human clinical clinical exposure exposure based based on on AUC); AUC); atrophy atrophy and and degeneration degeneration of of the the testes testes with with aspermia, aspermia, hypospermia hypospermia and and cribiform cribiform change change in in the the epididymis epididymis was was also also observed observed at at this this dose dose in in the the 6-month 6-month toxicity toxicity studies studies in in male male rats. rats. 17 17 PATIENT PATIENT COUNSELING COUNSELING INFORMATION INFORMATION See See Medication Medication Guide. Guide. The The Medication Medication Guide Guide isis contained contained in in aa separate separate leaflet leaflet that that accompanies accompanies the the product. product. However, However, inform inform patients patients of of the the following: following: •• Therapy Therapy with with VOTRIENT VOTRIENT may may result result in in hepatobiliary hepatobiliary laboratory laboratory abnormalities. abnormalities. Monitor Monitor serum serum liver liver tests tests (ALT, (ALT, AST, AST, and and bilirubin) bilirubin) prior prior to to initiation initiation of of VOTRIENT VOTRIENT and and at at Weeks Weeks 3, 3, 5, 5, 7,7, and and 9. 9. Thereafter, Thereafter, monitor monitor at at Month Month 33 and and at at Month Month 4, 4, and and as as clinically clinically indicated. indicated. Inform Inform patients patients that that they they should should report report signs signs and and symptoms symptoms of of liver liver dysfunction dysfunction to to their their healthcare healthcare provider provider right right away. away. •• Prolonged Prolonged QT QT intervals intervals and and torsades torsades de de pointes pointes have have been been observed. observed. Patients Patients should should be be advised advised that that ECG ECG monitoring monitoring may may be be performed. performed. Patients Patients should should be be advised advised to to inform inform their their physicians physicians of of concomitant concomitant medications. medications. •• Cardiac Cardiac dysfunction dysfunction (such (such as as CHF CHF and and LVEF LVEF decrease) decrease) has has been been observed observed in in patients patients at at risk risk (e.g., (e.g., prior prior anthracycline anthracycline therapy) therapy) particularly particularly in in association association with with development development or or worsening worsening of of hypertension. hypertension. Patients Patients should should be be advised advised to to report report hypertension hypertension or or signs signs and and symptoms symptoms of of congestive congestive heart heart failure. failure. •• Serious Serious hemorrhagic hemorrhagic events events have have been been reported. reported. Patients Patients should should be be advised advised to to report report unusual unusual bleeding. bleeding. •• Arterial Arterial thrombotic thrombotic events events have have been been reported. reported. Patients Patients should should be be advised advised to to report report signs signs or or symptoms symptoms of of an an arterial arterial thrombosis. thrombosis. •• Reports Reports of of pneumothorax pneumothorax and and venous venous thromboembolic thromboembolic events events including including pulmonary pulmonary embolus embolus have have been been reported. reported. Patients Patients should should be be advised advised to to report report ifif new new onset onset of of dyspnea, dyspnea, chest chest pain, pain, or or localized localized limb limb edema edema occurs. occurs. •• Advise Advise patients patients to to inform inform their their doctor doctor ifif they they have have worsening worsening of of neurological neurological function function consistent consistent with with RPLS RPLS (headache, (headache, seizure, seizure, lethargy, lethargy, confusion, confusion, blindness, blindness, and and other other visual visual and and neurologic neurologic disturbances). disturbances). •• Hypertension Hypertension and and hypertensive hypertensive crisis crisis have have been been reported. reported. Patients Patients should should be be advised advised to to monitor monitor blood blood pressure pressure early early in in the the course course of of therapy therapy and and frequently frequently thereafter thereafter and and report report increases increases of of blood blood pressure pressure or or symptoms symptoms such such as as blurred blurred vision, vision, confusion, confusion, severe severe headache, headache, or or nausea nausea and and vomiting. vomiting. •• GI GI perforation perforation or or fistula fistula has has occurred. occurred. Advise Advise patients patients to to report report signs signs and and symptoms symptoms of of aa GI GI perforation perforation or or fistula. fistula. •• VEGFR VEGFR inhibitors inhibitors such such as as VOTRIENT VOTRIENT may may impair impair wound wound healing. healing. Advise Advise patients patients to to stop stop VOTRIENT VOTRIENT at at least least 77 days days prior prior to to aa scheduled scheduled surgery. surgery. •• Hypothyroidism Hypothyroidism and and proteinuria proteinuria have have been been reported. reported. Advise Advise patients patients that that thyroid thyroid function function testing testing and and urinalysis urinalysis will will be be performed performed during during treatment. treatment. •• Serious Serious infections infections including including some some with with fatal fatal outcomes outcomes have have been been reported. reported. Advise Advise patients patients to to promptly promptly report report any any signs signs or or symptoms symptoms of of infection. infection. •• Women Women of of childbearing childbearing potential potential should should be be advised advised of of the the potential potential hazard hazard to to the the fetus fetus and and to to avoid avoid becoming becoming pregnant. pregnant. •• Gastrointestinal Gastrointestinal adverse adverse reactions reactions such such as as diarrhea, diarrhea, nausea, nausea, and and vomiting vomiting have have been been reported reported with with VOTRIENT. VOTRIENT. Patients Patients should should be be advised advised how how to to manage manage diarrhea diarrhea and and to to notify notify their their healthcare healthcare provider provider ifif moderate moderate to to severe severe diarrhea diarrhea occurs. occurs. •• Patients Patients should should be be advised advised to to inform inform their their healthcare healthcare providers providers of of all all concomitant concomitant medications, medications, vitamins, vitamins, or or dietary dietary and and herbal herbal supplements. supplements. •• Patients Patients should should be be advised advised that that depigmentation depigmentation of of the the hair hair or or skin skin may may occur occur during during treatment treatment with with VOTRIENT. VOTRIENT. •• Patients Patients should should be be advised advised to to take take VOTRIENT VOTRIENT without without food food (at (at least least 11 hour hour before before or or 22 hours hours after after aa meal). meal). VOTRIENT VOTRIENT isis aa registered registered trademark trademark of of GlaxoSmithKline. GlaxoSmithKline.

©2013, ©2013, GlaxoSmithKline. GlaxoSmithKline. All All rights rights reserved. reserved. Revised: Revised: 11/2013 11/2013 VTR:11BRS VTR:11BRS ©2014 ©2014 GlaxoSmithKline GlaxoSmithKline group group of of companies. companies. All All rights rights reserved. reserved. Printed Printed in in USA. USA. 3825R0 3825R0 January January 2014 2014

The ASCO Post | JUNE 10, 2014 | SUPPLEMENT

PAGE 10

Kenneth C. Anderson, MD

International Leader in Multiple Myeloma Was Inspired by an Early Mentor’s Lessons in Wisdom and Compassion

enneth C. Anderson, MD, grew up in Auburn, a small historic town in central Massachusetts that was settled by the English in 1714. His desire to become a doctor bloomed early. “My decision to possibly pursue a career in medicine was first inspired by my mother, who was a registered nurse, and by our town’s general practitioner, who befriended me,” said Dr. Anderson. Dr. Anderson explained that his

perimentation in the laboratory,” said Dr. Anderson. While studying at Boston University, Dr. Anderson volunteered as an orderly in the local hospitals’ emergency rooms. “From the start, I thoroughly enjoyed my experiences working in the hospital setting. It further strengthened my idea that I could pursue science and have it translate into treatments that benefited patient’s lives,” said Dr. Anderson.

It’s important for us in the community to manage expectations and our first step is to turn myeloma into a chronic illness, [which] has been done in many patients. We have maintenance therapies that are starting to look effective. Once we have the right combination of therapies starting early enough then I do think we will be able to have molecularly complete responses. —Kenneth C. Anderson, MD

keen childhood interest in science coupled with a desire to use science to help better human conditions was the driving force in his decision to pursue a medical career. His initial plan was to follow in his early mentor’s footsteps and practice family medicine in a small town similar to Auburn. It was in that setting that he felt he could best make a difference in the lives of his patients.

Education Dr. Anderson was the first member of his family to earn a college degree. After graduating high school in Auburn, he attended Boston University, majoring in biology. “I discovered that along with my excitement over science, I actually had quite a bit of natural ability in the discipline. Simply put, I just loved the discovery aspect of ex-

A Career Transformed Following his graduation from Boston University in 1973, Dr. Anderson said that he was “blessed” to be able to attend Johns Hopkins Medical School, which was a major turning point in his career. “At Hopkins, I was very fortunate to meet Dr. Richard L. Humphrey, who was one of my early teachers and ultimately became my major mentor and role model. He remains a close friend to this day,” said Dr. Anderson. “At the time, Dr. Humphrey was working on multiple myeloma and he taught me two lessons during my very first year of medical school that are still at the forefront of my academic life to this day: to make science count for patients and to treat patients as family,” noted Dr. Anderson. He continued, “Upon enter-

ing Hopkins my intention was to become a general practitioner in a small town, but learning about the joy of academic medicine in which laboratory experimentation could lead to new discoveries and ultimately improve the diagnosis, prognosis, and treatment of people with life-threatening diseases transformed my career decision,” said Dr. Anderson. He explained that before the Johns Hopkins experience, he didn’t have a true appreciation of how one could really undertake science, conduct clinical trials, and forever change things. After receiving his medical degree from Johns Hopkins Medical School in 1977, Dr. Anderson trained in internal medicine at Johns Hopkins Hospital and completed his hematology, medical oncology, and tumor immunology training at Dana-Farber Cancer Institute. He has remained at Dana-Farber to this day.

Groundbreaking Research in Multiple Myeloma It was at Dana-Farber where Dr. Anderson began in earnest his career in multiple myeloma and developed a re-

search program that has been involved in most of the advances in the treatment of multiple myeloma. “It is very exciting to have contributed and watched the natural history of a disease change. I have been working on multiple myeloma for about 40 years, and the progress has been nothing short of remarkable. When I began my work, multiple myeloma was virtually untreatable. Patients now live, on average, a decade longer postdiagnosis, with many living much longer,” said Dr. Anderson. Dr. Anderson explained that the advances have stemmed not only from knowledge of the genomics and molecular biology of the tumor cell itself, but also from the importance of the microenvironment and the means by which the tumor interacts with the microenvironment. Asked what aspect of multiple myeloma research he finds particularly exciting, Dr. Anderson replied, “In myeloma, we are privileged in that we can sample a patient’s bone marrow and tumor cells and from there create models in the laboratory. This gives us the opportunity to see how it grows in patients, letting us study the tumor and micro-

NAME: Kenneth C. Anderson, MD TITLE: Director of Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, and Vice Chair of the Joint Program in Transfusion Medicine, Dana-Farber Cancer Institute; Kraft Family Professor of Medicine, Harvard Medical School MEDICAL DEGREE: MD, Johns Hopkins Medical School RESEARCH INTERESTS: Multiple myeloma, B-cell malignancies, stem cell transplantation NOTABLE HONORS: Waldenström Award for Myeloma Research, International Myeloma Workshop (2003); Robert A. Kyle Lifetime Achievement Award, International Myeloma Foundation (2005); Joseph H. Burchenal Award for Clinical Research, American Association for Cancer Research (2007); William Dameshek Prize for Outstanding Contributions to Hematology, American Society of Hematology (2008); David A. Karnofsky Memorial Award, American Society of Clinical Oncology (2011); American Cancer Society Medal of Honor for Basic Research (2012); Warren Alpert Foundation Prize, Harvard Medical School (2012)

ASCOPost.com | JUNE 10, 2014 | SUPPLEMENT

environment, which is much more difficult to do in other cancers such as breast and brain malignancies.”

‘The United Nations Against Myeloma’ Dr. Anderson is internationally recognized for his research that has changed the human landscape of this once untreatable disease. However, recalling the early lessons from his mentor and friend, Dr. Richard L. Humphrey, the multitude of prestigious awards and accolades from colleagues are appreciated, but the true satisfaction comes from what his decades of research means to his patients. “The ability to take laboratory observations and translate them into meaningful differences for patients is incredibly rewarding. Getting to know my patients and their families and watching them enjoy milestones in their lives such as graduations or weddings is what makes what I do special to me,” said Dr. Anderson. Besides his ongoing research, Dr. Anderson eagerly approaches the challenge and rewards of mentoring the next generation of cancer doctors. “I have trainees from all over the United States and the rest of the world, many of whom are going back to their homelands to be leaders of hematology. We’ve actually gained the nickname ‘The United Nations Against Myeloma.’ Once they finish their training at Dana-Farber, many of these bright young doctors go around the world from South America to Europe and Asia, becoming leaders in myeloma research. Thanks to these shared experiences, we’ve developed international clinical trial collaborations and lifelong friendships. So, I’m watching the next generation of international clinicians being trained and at the same time I’m witnessing the history of this disease change. It doesn’t get any more rewarding than that!”

Looking Ahead Asked if he thinks he’ll see a cure for multiple myeloma over the course of his career Dr. Anderson sounded an optimistic but cautionary note. “Let me say that it’s important for us in the community to manage expectations, and our first step is to turn myeloma into a chronic illness. I think it has been done in many patients. We have maintenance therapies that are starting to look effective. Once we have the right combina-

tion of therapies starting early enough then I do think we will be able to have molecularly complete responses. It will then be a case of maintaining them,” said Dr. Anderson. What current challenges or obstacles concern Dr. Anderson? “I think the main obstacle in the current en-

PAGE 11

vironment is a dangerous lack of federal funding to promote the vigorous research needed if we want to not only continue the pace of our scientific advances but accelerate them,” said Dr. Anderson. He commented that another unfortunate byproduct of our fiscal malaise in funding is the

chilling effect it might have on recruiting the best and brightest into academic oncology. Those obstacles aside, Dr. Anderson remains a committed optimist. “I am very thankful for the opportunities and extraordinary colleagues I’ve continued on page 12

Now Enrolling

BIRCH

A Study of MPDL3280A (an engineered anti-PDL1 antibody) in Patients With PD-L1–positive Locally Advanced or Metastatic Non-small Cell Lung Cancer (NCT02031458, Study ID GO28754)

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com.

Locally advanced or metastatic NSCLC PD-L1–positive patients

N=300

MPDL3280A1 (an engineered anti-PDL1 antibody)

Central testing for PD-L1 IHC status

Primary Endpoints:

Secondary Endpoints:

• Objective response rate (ORR), IRF-assessed,

• Duration of response

according to RECIST v1.1

• Progression-free survival

• ORR, investigator-assessed, according to

• Overall survival

modified RECIST

• Safety: incidence of AEs • Pharmacokinetics: maximum serum concentration • Pharmacokinetics: minimum serum concentration

under steady-state conditions within a dosing interval

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Locally advanced or metastatic NSCLC (stage IIIB,

stage IV, or recurrent)

• History of autoimmune disease • Active hepatitis B or hepatitis C

• Representative FFPE tumor specimens

• HIV-positive

• PD-L1–positive status by IHC tested at a

• Prior treatment with CD137 agonists, anti-CTLA4,

central laboratory • Measurable disease, defined by RECIST v1

anti-PD1, or anti-PDL1 antibodies or pathwaytargeting agents

• ECOG performance status of 0 or 1 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.

The ASCO Post | JUNE 10, 2014 | SUPPLEMENT

PAGE 12

Nancy E. Davidson, MD

ASCO Past President and Breast Cancer Researcher Works to Unite the Oncology Community in the Fight Against Cancer

orld-renowned breast cancer researcher, Nancy E. Davidson, MD, was born in Denver, Colorado, the daughter of two geologists. “My mother was a geologist beginning in the 1940s, a time when women really didn’t pursue that kind of career. So, I was reared in a very scientifically oriented environment,” said Dr. Davidson, but noted that she did not yet have the exposure to biology or medicine that would inform her own career choice in medicine. When Dr. Davidson was 13 years old, her father was transferred to India. “His transfer, which uprooted us from Denver, was a life-changing event. After a year in India, he was transferred to the Washington, DC, area, working for the U.S. Geological Service. Both of my parents would spend the rest of their careers in DC,” said Dr. Davidson. While attending high school in Washington, DC, Dr. Davidson had the opportunity to attend a weekend

biology program at the Bethesda Naval Hospital, which she credits for sparking her interest in biology. “After high school, I attended Wellesley College in Boston. It was a liberal arts school with a large emphasis on science. As a result of the cross-registration program between Wellesley and MIT, I spent my last years as an undergraduate working part-time in a cancer research lab at MIT,” said Dr. Davidson. She continued, “The work in the laboratory introduced me to the liver cancer field, and I worked for 2 years with a graduate student who was doing his thesis project. It was not only very productive scientifically but it proved doubly beneficial since he was the man I eventually married.”

Harvard Medical School. At the end of my first year, I went back to the DC area to spend the summer with my parents. I applied for a job at the National Cancer Institute (NCI), and Dr. Kent Osborne pulled my CV out of the stack and offered me a job. I asked if it paid,

From the Lab to the Clinic

and when he said yes I accepted. So, the summer after my first year at medical school I had a summer job at a breast cancer lab at the NCI. It was a life-defining event,” said Dr. Davidson. As Dr. Davidson recalls, her job at the NCI occurred right at the critical juncture when the relationship between science and medicine was beginning to emerge in oncology. “I decided that I wanted to be in the breast cancer field, so I took the path from internal medicine straight to medical oncology, which led to an internship at the University of Pennsylvania, followed by a medical residency at Johns Hopkins. After my residency at Johns Hopkins, I returned to the NCI as a fellow. In total, I was at the Institute for about 5 years,” she said.

Instead of pursuing a PhD, Dr. Davidson decided that medical school would give her a broader palette of experiences. “I loved Boston so I attended

NAME: Nancy E. Davidson, MD TITLE: Director of the University of Pittsburgh Cancer Institute and UPMC Cancer Centers MEDICAL DEGREE: MD, Harvard Medical School RESEARCH INTERESTS: Breast cancer NOTABLE HONORS: Brinker International Award for Breast Cancer Research, Susan G. Komen (1999); Women in Cancer Research Charlotte Friend Memorial Lectureship, American Association for Cancer Research (2008); Rosalind E. Franklin Award, National Cancer Institute (2008); Association of American Physicians (2010), Gianni Bonadonna Breast Cancer Award, American Society of Clinical Oncology (2010), and Institute of Medicine (2011)

Kenneth C. Anderson, MD continued from page 11

worked with. Besides your own family legacy, what really matters is what you have done in your time to make the world different. In that spirit, I

would encourage bright young medical students to think about pursuing oncology. Despite some challenges, it offers the chance to truly help the sickest of our patients and conduct research that changes the history of this disease,” he said.

After leaving the NCI, Dr. Davidson was recruited by Johns Hopkins to oversee the development of a breast cancer program. There, Dr. Davidson noted, she was given the opportunity to pursue her dream career, which was to split time working in the lab and

We wanted all the disciplines in oncology to have a seat at the ASCO table….In essence, my presidential theme was one of inclusion. After all, everyone in the oncology community shares the same goals, reducing the burden of cancer and making sure our cancer patients get the best care possible. —Nancy E. Davidson, MD

Dr. Anderson’s remarkable research career and clinical contributions to patients with multiple myeloma have unquestionably changed the way we think and speak of this once untreatable disease. And after 40 rigorous years, his commitment to using science

the clinic and explore the interface between the two areas. “It was a traditional academic atmosphere in which I built my laboratory over time with several different teams. There is not a type of NIH grant that I didn’t receive, so the funding was not as challenging as today. Interestingly, the first grant I ever received when at Hopkins was a young investigator award from ASCO,” said Dr. Davidson.

Outside the Academic Environment “Pretty early on I was able to get involved with two organizations outside the walls of Johns Hopkins. One was the Eastern Cooperative Oncology Group, in which I was fortunate enough to be involved in the breast committee to better the lives of cancer patients is unflagging. Asked if he enjoyed any avocations or pastimes, Dr. Anderson replied, “Sports. I’m an avid golfer and I enjoy family golf outings. And I love football and baseball. I’m a Red Sox fan, of course.” n

ASCOPost.com | JUNE 10, 2014 | SUPPLEMENT

and ultimately to serve as its Chair for 5 years,” said Dr. Davidson. The second, she noted, was ASCO. “My early ASCO award…aligned me tightly with the Society. I’m incredibly grateful to then ASCO President John Glick, who gave me a chance to run for ASCO’s Board of Directors. I won, and served on the board from 1996 to 1999,” said Dr. Davidson. Following her position on ASCO’s board, Dr. Davidson served for several years on the Board of Directors of the American Association for Cancer Research. She would soon return to ASCO. “Right after leaving the AACR, I received a call from ASCO President Sandra Horning, MD, asking if I’d return to the organization and chair the publications committee. I said sure,” said Dr. Davidson. “During my committee work, I was given the chance to run for the presidency of ASCO, which was a fabulous opportunity. I also had the amazing good fortune to be President-Elect just as the decision was made to hire Dr. Allen Lichter as ASCO’s CEO. Working with Allen was a true pleasure. He’s been a long-time visionary for the organization and it was great to have his mentorship as I assumed the office of president [for the 2007–2008 term],” said Dr. Davidson.

One Community: Innovating Patient Care Asked why her presidential theme was “One Community,” Dr. Davidson replied, “I felt very keenly that at that point in ASCO’s history there were some potential rifts between our community physicians and those in academic settings. We wanted all the disciplines in oncology to have a seat at the ASCO table. Moreover, we made it clear that scientists in the

laboratory were just as important as the clinicians. Then there’s the international community. In essence, my presidential theme was one of inclusion. After all, everyone in the oncology community shares the same goals, reducing the burden of cancer and making sure our cancer patients get the best care possible.” Along with her unity theme, Dr. Davidson noted another signature ASCO initiative during her presidency that she is proud of: cost of

PAGE 13

we talk about toxicity all the time,” she continued. “Well, cost of care is as much of a toxicity as hair loss or nausea and vomiting. And in the ensuing years, the Cost of Cancer Care Task Force has advanced this crucial culture-changing initiative that has now moved into analyzing value in care, which is the essence of cost.”

Post-ASCO Career Move Dr. Davidson credits her ASCO presidency for allowing her to

Dr. Davidson is Director of the University of Pittsburgh Cancer Institute and UPMC Cancer Centers.

care. “Working together, Allen and I made the tough decision that ASCO needed to be more involved in the costs of cancer care. I think it was a bold initiative, one not too popular at the time. We started with the most basic stance that oncologists should discuss the costs of care with their patients. Again, that was not a widely held opinion at that time and it started some pretty tough conversations.” “I distinctly remember one ASCO meeting in which I pointed out that

move outside of the breast cancer world. “Shortly after my presidency I moved from Hopkins to become the Director of the University of Pittsburgh Cancer Institute and the UMPC CancerCenter. We’re one of the nation’s 41 NCI-designated comprehensive cancer centers,” said Dr. Davidson. “As principle investigator for our cancer center grant, I oversee the research directions for our cancer institute. I’m also the director of

our clinical practice network, which provides care across western Pennsylvania. So I think about all things oncology all of the time. My days are incredibly full,” said Dr. Davidson. The field of oncology is entering a time of practice-changing advances, Dr. Davidson noted. “During their introduction, I tell all our fellows that I wish I were just beginning my career. I can see the amazing transitions that were made during my own career in terms of cancer awareness as well as the coming realization that cancer is a chronic disease for so many of our patients. We have also gained a vast amount of knowledge in the biology of cancer, which is moving us rapidly into the age of targeted therapies. So having this terrific underpinning of knowledge serves as a launching pad for the next generation of oncologists, making it an incredibly exciting time to enter the field,” she said. Few careers are as demanding as directing a comprehensive cancer center. Not surprisingly, Dr. Davidson, the mother of a medical student and a cancer epidemiology PhD student, fills her off-hours with stimulating activities. “I’m an avid reader and a very big world traveler. And I love sports, so I support all the local teams, especially the Steelers and Penguins,” she said This year, as more than 30,000 cancer care specialists from around the world converge in Chicago to attend the 2014 ASCO Annual Meeting and commemorate the Society’s 50th anniversary, the theme of Dr. Davidson’s presidency, “One Community: Innovating Patient Care,” serves as a perpetual reminder about the importance of unity in the fight against cancer. n

Save the Date Best of ASCO® Boston

Best of ASCO® Chicago

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August 8-9, 2014

August 15-16, 2014

August 22-23, 2014

Renaissance Boston Waterfront Hotel

Hilton Chicago

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PAGE 14

The ASCO Post | JUNE 10, 2014 | SUPPLEMENT

Celidex - Glioblastoma

A more aggressive GBM may be hiding in plain sight

EGFRvIII has been shown to be a marker for more aggressive tumor growth and reduced survival1-3 • The epidermal growth factor variant three (EGFRvIII) mutation is associated with increased growth and more rapid recurrence in GBM1-3 • EGFRvIII may also be a negative predictor of survival3 – In a study of 196 GBM patients, those who survived beyond the first year and expressed EGFRvIII (n=32) had significantly shorter median overall survival times (1.12 years, P<0.0001) compared to those who either expressed EGFR wild type (n=19, 2.02 years) or lacked EGFR (n=38, 2.03 years). This effect remained significant in multivariate analysis after adjustment for other cofactors3 But could EGFRvIII also prove to be an important therapeutic target? Celldex Therapeutics is conducting research on EGFRvIII. Take a closer look at celldex.com. References: 1. Lal A et al. Cancer Res. 2002;62:3335-3339. 2. Nishikawa R et al. Proc Natl Acad Sci U S A. 1994;91:7727-7731. 3. Heimberger AB et al. Clin Cancer Res. 2005;11:1462-1466.

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Richard Hoppe, MD

A Coast-to-Coast Road to an Illustrious Career in Radiation Oncology

ationally regarded radiation oncologist and lymphoma expert Richard Hoppe, MD, was reared in Seaford, a small town hugging the South Shore of Long Island, New York. “I grew up in the early part of Long Island’s suburban sprawl, and my childhood was a fairly typical experience for that time,” recalled Dr. Hoppe. Asked about early influences that steered him toward a career in medicine, Dr. Hoppe explained, “When I was in the third grade, I wound up in the hospital with appendicitis and I had a very good hospital experience. And as a kid, I was impressed by our family physician who would do house calls when we were sick. My parents had a layperson’s medical textbook at home that I used to spend hours pouring over. So, those combined experiences help develop my early interest in the sciences.” Dr. Hoppe cited a very solid high school experience as another foundation for his career in medicine. “I had terrific teachers, not just in the science and math departments, but throughout every level of the learning process. Looking back, it seems like from an early age, becoming a doctor was always on my radar,” he said. Dr. Hoppe continued, “I went to Cornell as an undergrad, which was a popular choice for kids from Long Island; it was far enough from home to

get that feeling of independence, yet it wasn’t on the other side of the continent. I majored in what was initially called zoology, but later renamed biological sciences. It was a track that premed students would take.” The undergraduate experience at Cornell offered a rich environment for the intellectually inquisitive pre-med student, and Dr. Hoppe dove into diverse courses ranging from British literature to Southeast Asian politics. “I did pretty well in Cornell, capping it off during my senior year when I met my future wife on a blind date,” he said.

An Academic Career Path After graduating from Cornell in 1967, Dr. Hoppe applied to several top medical schools in the Northeast, eventually deciding on Cornell University Medical School. “My wife and I got married after my first year of medical school and we moved into the married student housing. At the time, my wife was pursing a BA at Columbia. She began working while I was still a student,” said Dr. Hoppe. “[After medical school,] I figured that I’d go into some subspecialty in internal medicine, perhaps neurology or gastrointestinal medicine, but there was nothing I was passionately drawn to,” said Dr. Hoppe. “I got an opportunity to do a special summer program with an anatomy professor

NAME: Richard Hoppe, MD TITLE: Henry S. Kaplan–Harry Lebeson Professor of Cancer Biology and Professor of Radiation Oncology, Stanford University MEDICAL DEGREE: MD, Cornell University Medical School RESEARCH INTERESTS: Radiation oncology, non-Hodgkin lymphoma, cutaneous lymphoma, mycosis fungoides, total body irradiation NOTABLE HONORS: The Gold Medal of the American Society for Radiation Oncology (ASTRO) 2006; The Gold Medal of the American College of Radiology (ACR) 2013; The Janeway Award of the American Radium Society (ACR) 2002

who was working on computer-aided instruction. Remember, this was at a time when we used Fortran and punch cards. The program didn’t go very far but being part of it stimulated my decision to work in an academic environment,” he said.

Introduction to Radiation Oncology At the end of medical school, Dr. Hoppe still had not decided on which field or medical specialty he wanted to pursue. “For medical students in the East, doing a residency in California was enticing. I was working as a

she’d put me in touch with him. Well, his name was Svi Fuks and he was on the faculty in the Radiology Department at Stanford,” said Dr. Hoppe. He continued, “I contacted Dr. Fuks. He was a great guy. He picked me up at the airport let me sleep on his couch until I found a room. The elective course in radiology didn’t start for a couple of weeks so the administrator suggested that I spend the interim in radiation oncology therapy with Dr. Fuks. Radiation therapy was in its early stages and very few medical students had that kind of opportunity, especially at Stanford, whose

The sophisticated technology of today, such as 3D imaging and high-tech targeted radiation therapies, would seem impossible to conceive of when I was a resident in the 1970s. And as [Department Chair], I’ve had the privilege to oversee the growth and development of these therapies that have translated into remarkable increases in patient survival and quality of life. —Richard Hoppe, MD

subintern at New York Hospital, and the doctor I was working with was a Stanford Medical School grad. He said that if I wanted to check out the West, I should go to Stanford, and he gave me the phone number of Les Zatz, a professor in radiology. I called Dr. Zatz and he said, ‘Yeah, sure, come on out.’ Things were pretty informal at that time,” explained Dr. Hoppe. As his departure date neared, Dr. Hoppe, who had never traveled west of the Mississippi, found himself overwhelmed at having to leave his wife back in New York. “A few days before leaving, my mother-in-law mentioned that her cousin’s son was in medicine somewhere in California. She said

faculty were the giants in the field. That experience really turned me on to radiation oncology.” After his elective at Stanford, Dr. Hoppe returned to New York. “I decided that I really needed to be sure if radiation oncology was for me, so I took my next elective at Memorial Sloan Kettering in radiation therapy. I actually may have been the first medical student to do an elective in radiation therapy at Sloan Kettering. Working there sealed my decision. There were so many new modalities being looked at. It was an exciting time to begin a career in oncology,” said Dr. Hoppe. continued on page 16

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Richard Hoppe, MD continued from page 15

The Move West Following his elective, Dr. Hoppe did an internship in medicine at North Shore Hospital-Memorial Hospital program. “During my internship, I applied to

MD Anderson and Stanford University School of Medicine along with several other radiation oncology programs. I was accepted by Stanford and given my great experience there it seemed like a natural fit for my career path,” said Dr. Hoppe. Relocating his family across the country for 4 years was a huge consideration,

but his wife was supportive, so he accepted the residency. “My wife was pregnant at the time, due almost any day. So when we boarded the airplane the stewardess gave bit of a startled a look and my wife said, ‘Oh that’s OK, my husband’s a doctor.’” Dr. Hoppe recalled. “Although the faculty at Stanford were

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all top researchers in the field of radiation oncology, they were doctors first and set an example that we carried into our own careers. Put simply, the patient came first, and they conveyed that philosophy by empathetic action at the patient’s bedside,” said Dr. Hoppe. During his residency which began in 1972, Stanford was in the midst of a series of prospective randomized clinical trials in lymphoma led by Drs. Saul Rosenberg and Henry Kaplan. “Early in our residency, the rigor of clinical investigation was set in our minds. We participated in the care of the patients on trial, so it was a rich period when I learned about discussing randomized studies and interacting with patients,” said Dr. Hoppe.

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As his Stanford residency drew to a close, Dr. Hoppe began searching for a position, first looking back East where his family and friends were firmly settled. However, just before his residency ended, the department chair, Dr. Malcolm Bagshaw, called to offer him a job at Stanford’s radiation oncology department. A recent faculty departure had opened a research position investigating mycosis fungoides, and Dr. Hoppe was asked to take over the program, which turned out to be a key point in the development of his academic career. “This was an important program at Stanford, and they were on the forefront of treating the disease with radiation, which was about the only effective treatment,” he said. Dr. Hoppe explained that because mycosis fungoides is such rare disease, he quickly became a nationally regarded expert. “It opened doors and gave me the opportunity to write papers and get my name recognized in the field. The lymphoma department at Stanford was so large that I was brought on as the number three researcher behind Drs. Henry Kaplan and Eli Glatstein.” Dr. Glatstein soon left for the National Cancer Institute, but before leaving he received a grant to study the pathologic classification systems for lymphomas. “This was an international, multi-institutional effort. Stanford was the center for aggregating the data, and I was deeply involved. The end result became The Working Formulation of Non-Hodgkin Lymphoma for Clinical Usage, which became the eligibility criteria for clinical trials,” said Dr. Hoppe, adding, “It was very important for my career, not only for name recognition, but it gave me the opportunity to meet the world leaders in lympho-

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Barbara L. McAneny, MD

Barbara L. McAneny, MD, Is Dedicated to Designing a Better Health-Care System

arbara L. McAneny, MD, grew up on the outskirts of Alton, a small city on the Mississippi River in Madison County, Illinois. It is an area rich in history, famous as the site of Abraham Lincoln and Stephen Douglas’s last debate and for its role preceding and during the American Civil War. “We lived outside of town, so there were not a lot of other kids to play with. Both my parents taught at Saint Louis University, my father as a physicist and my mother as a mathematician. Education was an important part of my early home life,” said Dr. McAneny.

A Hands-on Education “The schools in our area were not very good, so I left high school at 16 and went to college at Grinnell College for my first 2 years of undergrad. I planned to follow my father’s footsteps into physics, but I soon learned that my brain doesn’t work that way. My undergraduate major was in mathematics. In my junior year, I switched to the University of Minnesota,” she said.

Richard Hoppe, MD continued from page 16

ma, from Clara Bloomfield to Gianni Bonadonna and from Karl Lennert to Henry Rappaport.” Shortly after, the untimely death of Dr. Kaplan opened the door for Dr. Hoppe to become Dr. Saul Rosenberg’s senior partner. “It became a fabulous collaboration and friendship. Saul still comes to our clinic a few times a month and participates in our lymphoma conferences. Partnering with Saul was a huge part of my career’s growth path,” said Dr. Hoppe.

A Career-Defining Program Participating in an early translational program would further advance

When a friend asked about her postgraduation plans, Dr. McAneny recalled that it was a wakeup call. “Most mathematicians end up in computer science or in the insurance industry, which was not me. I’d taken a lot of science and I wanted something that interacted with people, so I decided

accepting any out-of-state medical students, so I pursued my MD at the University of Iowa. It was a great experience, a hands-on practical education which worked perfectly for me because I’m a practical hands-on kind of person,” said Dr. McAneny. After receiving her MD, Dr. McAneny

[W]hen doctors organize together [they can] accomplish some pretty remarkable things….[W]orking with the state’s medical society made me realize that medicine is a team sport; to get things done we need cooperation from all the specialties. —Barbara L. McAneny, MD

on medicine,” explained Dr. McAneny, adding, “I took the MCATS and applied, so I’m not someone who decided at age 3 to become a doctor.” “I really got to like Minnesota while there as an undergrad, but they weren’t

toured the country interviewing for residency positions. “But after spending all my money on travel, I realized that I really liked the University of Iowa’s approach to learning, so that’s where I did my internal medicine residency,” she said.

Dr. Hoppe’s illustrious career in lymphoma research. “We used extensive large-field radiation in Hodgkin disease and saw immune system changes in certain patients. Curiously, some of these changes were the exact transformations that transplant surgeons were trying to achieve pharmacologically to get organ transplant tolerance,” said Dr. Hoppe. This observation was taken to the laboratory and developed into mouse models for giving total lymphoid irradiation in conjunction with bone marrow transplantation. “I became involved in this research and together with Sam Strober and other colleagues we developed a number of animal models using total lymphoid irradiation, going up the scale from rats to primates. We tested different

concepts of using radiation to achieve successful transplantation. Those studies came back to the clinic and eventually became a key component of Stanford’s allogeneic transplant program program using total lymphoid irradiation and anti-thymocyte globulin (TLI plus ATG), which has been, which has been a central focus of my career,” said Dr. Hoppe. Dr. Hoppe entered medicine in the nascent days of radiation oncology when surgeons at some hospitals even defined the radiation field by drawing margins on the patient’s skin with a marker. “The sophisticated technology of today, such as 3D imaging and hightech targeted radiation therapies, would seem impossible to conceive of when I was a resident in the 1970s. And as

Treating the Whole Person During her residency, Dr. McAneny’s first rotation was on the acute leukemia ward, which had a profound influence on her decision to pursue a career in oncology. “I fell in love with all the leukemia patients on the ward. Dr. Jim Armitage was there doing work in bone marrow transplantation, and it was the most astounding thing I could ever think of. Plus, oncology appealed to me because you treat the whole person, not a specific organ like the heart,” said Dr. McAneny. “I loved the personal interaction with the patients,” she continued. “When I was on the leukemia ward, I learned that with cancer patients you bypass the 20 years of building a friendship and you get close very quickly. Cancer patients don’t sweat the small stuff; they focus on what matters, and their resilience continues to amaze me. Ultimately, my decision to become an oncologist was simply because I wanted to help cancer patients continued on page 19

Chair of our department at Stanford for 19 years, I had the privilege to oversee the growth and development of these therapies that have translated into remarkable increases in patient survival and quality of life,” said Dr. Hoppe. “Stanford has been a place of incredible enthusiasm, collaboration, and success. My days are full, from the clinic to the lab, and the lecture hall. But it’s a job I love. I’ve never not wanted to come to work on Monday,” said Dr. Hoppe, adding, “My daughter teaches math in public school and my son is a radiation oncologist on the faculty at the University of Florida Proton Therapy Center. My wife and I enjoy the cultural scene in San Francisco. I have a good life,” said Dr. Hoppe. n

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Barbara A. McAneny, MD continued from page 17

get through the scariest thing that had ever happened to them.” Asked about her oncology fellowship, Dr. McAneny recalled a subtle message permeating the inner sanctum of the university that guided her decision. “The professors let you know that the really good doctors are in academic medicine. But looking at the papers I was reading, I knew I’d never write a paper that I’d bother to read if I came across it in a journal. More important, my personal strength and source of professional satisfaction was one-to-one interaction with a patient over the course of their illness. So, at that point I decided against academics; I was going where I could take care of as many patients as possible.”

Drawn to the West One of Dr. McAneny’s professors told her that doctors going into private practice tend to locate their practice near where they did their fellowship. “For the first time in my life I started to think about which part of the country I wanted to live. I considered Minnesota, Iowa, and the upper Midwest. It’s a wonderful region, but I realized that I craved diversity and I was also tired of living with 7 months of winter so I decided to look at the Southwest and Southeast,” said Dr. McAneny. She traveled to the University of New Mexico, which she described as small, newly established, and “not very high on anybody’s academic list.” But it was love at first sight with the state of New Mexico. “I was immediately taken by the people and diversity of the cultures including 19 different Indian tribes. When you go into the desert, you either hate or love it. I loved it so much that it won a place in my heart that has never left,” said Dr. McAneny. In 1987, following her fellowship in hematology/oncology, Dr. McAneny opened a community practice, New Mexico Oncology Hematology Consultants Ltd, with a colleague from the University of New Mexico. “We built our two-oncologist practice into a large group practice and beyond. We’ve been partners ever since,” she said.

The Collective Power of Doctors Dr. McAneny eventually took over the practice management side of her growing clinic, a transition that was partly related to her serendipitous career move into organized medicine, she noted. “I was

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NAME: Barbara L. McAneny, MD TITLE: CEO, New Mexico Oncology Hematology Consultants; Chair-Elect, AMA Board of Trustees MEDICAL DEGREE: MD, University of Iowa College of Medicine RESEARCH INTERESTS: Health-care policy, community oncology, organized medicine, hematology/oncology NOTABLE HONORS: BizTECH Award, Albuquerque Business First (2013); Health Care Innovation Award, U.S. Centers for Medicare and Medicaid Services (2012); ASCO Statesman Award, American Society of Clinical Oncology (2010); ASCO Board (2005-2008); Council on Medicine Service (2003-2010); Governors Award for Outstanding New Mexico Women (1996)

in the hospital’s doctor’s lounge after a consult with a young lung cancer patient, bemoaning the fact that so many people still smoke. A urologist came over and said, ‘So, are you just going to bitch about smoking, or are you going to do something about it?’” The urologist was president of the local medical society, which worked with the Department of Health on smoking cessation initiatives. He invited Dr. McAneny to join the committee and push for antismoking legislation. She jumped at the opportunity. “It took about 15 years of hard work but we got a clean indoor air act passed city-by-city in New Mexico. The experience taught me that when doctors organize together they could accomplish some pretty remarkable things. And working with the state’s medical society made me realize that medicine is a team sport; to get things done we need cooperation from all the specialties,” said Dr. McAneny. “I’ve been as ASCO member, from the day I decided to become an oncologist,” she continued. “I just got one of the alarming 30-year-member badges, reminding me of how old I am. ASCO is essential in moving forward everything related to oncology. But I’ve also been a long-time member of the American Medical Association [AMA]. The current situation in health care does a very good job at dividing doctors and keeping us relatively powerless as we fight over pieces of a decreasing pie.”

Human Services. It was an enlightening experience that helped me design a system that works best for cancer patients,” said Dr. McAneny. Dr. McAneny’s philosophy of streamlining the care continuum so that the doctor-patient experience is as seamless and productive as possible was realized in 2000 when she got to design the New Mexico Cancer Center in Albuquerque. “I asked patients what they wanted in the center and they said color and beauty. So we built the center focusing on natural light and art. I pay a curator who brings in new art regularly. On Sundays we open the center as a gallery and serve wine and cheese and we sell art. The proceeds go to our foundation that helps patients with the nonmedical expenses of having cancer, such as gas and food,” said Dr. McAneny. She explained that the cancer center is currently having a war of sorts with the local hospital because the center wants to remain independent. “We’ve created ways to keep patients out of the hospital and ER by offering our cancer center as an alternative. We take emergency cancer patients so they don’t have to sit for hours in the hospital’s ER while doctors take care of people with a heart attack or gunshot wound. After a while, I looked at our data and saw that the money our approach was saving the payer was huge. We were eating the expenses, and the payer was reaping the profits,” said Dr. McAneny.

Designing a Better Health-Care System

The COME HOME Project

“Physicians sit in the exam room listening to their patient’s hopes and fears and struggles, so we should design our health-care system. To effect change I needed to learn how the current system works and its flaws, so I sat on the Practicing Physicians Advisory Counsel for 4 years. It was an organization of various specialties from across the country that advises the Secretary of Health and

Armed with her data, Dr. McAneny went to the local payer. “After showing the payers how much money the innovations in our cancer center had saved them, I said that they should share the savings with us to help us defer our center’s costs. They said ‘Thank you very much, but that money should be going to our hospital.’ So, I brought my data to Medicare. At the time, the agency

was creating awards for innovative health-care systems. I wrote a paper and waited,” said Dr. McAneny. In 2012, Dr. McAneny was awarded a $19.8 million Health Care Innovation Award from the Centers for Medicare and Medicaid Services to test how private practices could provide better cancer care at a lower cost. To that end, she created Innovative Oncology Business Solutions, serving as its Medical Director and CEO. The project, titled COME HOME (“Community Oncology Medical Homes”), aims to replicate the care and cost-saving practices that Dr. McAneny created at the New Mexico Cancer Center at six practices across the nation. Asked about the project’s status, Dr. McAneny replied, “We’re halfway through the project. We’re working to get certified as an oncology medical home. Everybody has extended hours, and we’ve created triage pathways to make sure that patients get to the right site of service. We’ve changed the mindset. If a patient calls with a problem, we don’t say ‘We’ll see you next Thursday,’ we tell them to come in today at 2. We can do that because of our increased efficiencies.”

A Day in The Life Along with patient care and her work on the COME HOME project, Dr. McAneny is also Chair-Elect of the Board of Trustees for the AMA. “The AMA is my third job. I’m running for re-election and if I win, I’m Chair of the Board. If I lose, I have no more role at the AMA, which would make me very sad.” Dr. McAneny, a self-proclaimed exercise hater, is on the elliptical at 5:00 AM every day. “The only way I talk myself onto the elliptical is by reading a good novel at the same time. I see patients at our Gallup clinic, which is the heart of the Navaho Nation. Most of my time is devoted to managing the clinics in the project and keeping the CMS Innovation Award up to date with our triage pathways and other requirements. And I work on AMA policy issues. So it all blends together to make for one hectic day after another,” said Dr. McAneny. She concluded with a parting message to her colleagues: “I encourage everyone to join the AMA for national issues, the state societies for state issues, and ASCO for oncology-specific issues. We are stronger when we work together.” n

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his year ASCO celebrates it's 50th Anniversary. Here is a list of past ASCO Presidents over these 50 years. For more on ASCO's History and the Society's Founders, see page 35.

ASCO Through the Years: Past Presidents 2014-2015: Peter P. Yu, MD

2010-2011: George W. Sledge, Jr, MD

2006-2007: Gabriel N. Hortobagyi, MD

2013-2014: Clifford A. Hudis, MD

2009-2010: Douglas W. Blayney, MD

2005-2006: Sandra J. Horning, MD

2012-2013: Sandra M. Swain, MD, FACP

2008-2009: Richard Schilsky, MD

2004-2005: David H. Johnson, MD

2011-2012: Michael P. Link, MD

2007-2008: Nancy E. Davidson, MD

2003-2004: Margaret A. Tempero, MD 2002-2003: Paul A. Bunn, Jr, MD 2001-2002: Larry Norton, MD 2000-2001: Lawrence H. Einhorn, MD 1999-2000: Joseph S. Bailes, MD 1998-1999: Allen S. Lichter, MD 1997-1998: Robert J. Mayer, MD 1996-1997: James O. Armitage, MD 1995-1996: John H. Glick, MD 1994-1995: Karen H. Antman, MD 1993-1994: George P. Canellos, MD 1992-1993: Bernard Fisher, MD 1991-1992: Martin D. Abeloff, MD 1990-1991: Harvey M. Golomb, MD 1989-1990: Robert C. Young, MD 1985-1986: John R. Durant, MD 1984-1985: Sydney E. Salmon, MD 1982-1983: Saul A. Rosenberg, MD 1981-1982: John E. Ultmann, MD 1980-1981: Emil J. Freireich, MD 1979-1980: Charles G. Moertel, MD 1978-1979: Albert H. Owens, MD 1977-1978: Vincent T. DeVita, Jr, MD 1976-1977: James F. Holland, MD 1975-1976: Joseph Bertino, MD 1974-1975: Rose Ruth Ellison, MD 1973-1974: Bayard Clarkson, MD 1972-1973: Paul P. Carbone, MD 1971-1972: Kenneth B. Olson, MD 1970-1971: Jesse L. Steinfeld, MD 1969-1970: Paul Calabresi, MD 1968-1969: Emil Frei, MD 1967-1968: George C. Escher, MD 1966-1967: Fred J. Ansfield, MD 1965-1966: Michael J. Brennan, MD 1964-1965: Harry F. Bisel, MD

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John E. Niederhuber, MD

Nationally Renowned Surgeon and Researcher, John E. Niederhuber, MD, Relishes the Challenges That Lie Ahead

ohn E. Niederhuber, MD, was born and grew up in Steubenville, Ohio, a steel mill town located along the Ohio River. Dr. Niederhuber had a childhood interest in engineering and chemistry, but it was the town’s general practitioner who made a lasting impact on his career path. “He was an old-style family doctor. He did everything from setting a broken bone to delivering babies. If one of us was sick, he’d just say, ‘OK, I’ll stop by on my way home.’ He was an early influence on my decision to pursue a medical career,” said Dr. Niederhuber. After high school, Dr. Niederhuber attended Bethany College, a small liberal arts college in West Virginia. “I was one of only eight chemistry majors at Bethany and in my senior year I was given the opportunity to design my own research project. The work actually led to a National Science Foundation grant,” said Dr. Niederhuber. It was while running his own research project at Bethany that Dr. Niederhuber decided to go to medical school. “Our family had limited resources, so I was delighted when I was accepted to Ohio State Univer-

sity School of Medicine, which, being a state school was relatively inexpensive. I decided to get my medical degree and then figure out how to go to graduate school and pursue my interest in biomedical research,” said Dr. Niederhuber.

From Orderly to Surgeon During the summer before his first year at Ohio State, Dr. Niederhuber got a job as an orderly in the operating room of a local community hospital in Columbus, Ohio, bringing patients to the operating room and cleaning up after surgery. By the end of the summer, Dr. Niederhuber’s responsibilities had expanded to among other tasks, working as a scrub technician. Working weekends and occasional nights in the operating room helped support Dr. Niederhuber throughout medical school. This experience also influenced Dr. Niederhuber’s decision to become a surgeon. He recalled one particular Saturday afternoon that first summer working as an orderly in the operating room when his interest in surgery was put to a serendipitous test. “A young man came into the

NAME: John E. Niederhuber, MD TITLE: Executive Vice President Inova Health System, Chief Executive Officer of Inova Translational Medicine Institute, Chief Executive Officer and Director Inova Comprehensive Cancer and Research Institute, Adjunct Professor Oncology and Surgery Johns Hopkins University School of Medicine and Deputy Director Johns Hopkins Clinical Research Network MEDICAL DEGREE: MD, The Ohio State University School of Medicine RESEARCH INTERESTS: Surgical oncology, gastrointestinal cancer, hepatobiliary cancer, breast cancers, cancer biology, genomics, personalized medicine NOTABLE HONORS: Honorary Degree Doctor of Science Bethany College, Bethany, West Virginia (2007), Institute of Medicine National Academy of Sciences (2008), Society of Surgical Oncology Annual Heritage Award (2009), Elected Alumni Member Alpha Omega Alpha (2009), Distinguished Public Service Award, American Association for Cancer Research (2010); Annual Achievement Award, Association of Community Cancer Centers (2011), Past President of Society of Surgical Oncology, Past President of Association of American Cancer Institutes

operating room with an open ankle fracture. The attending surgeon mistook me for a hospital intern. He asked if I wanted to scrub and assist. The nurse looked at me and winked, so I scrubbed and assisted in the operation. I actually placed

tention to detail regarding each patient was unmatched in my experience. I maintained a close relationship with Dr. Zollinger throughout my career,” said Dr. Niederhuber. After receiving his medical de-

The Cancer Genome Atlas remains a very successful project and during those early years we were able to learn a lot about infrastructure needs, bio-banking and bioinformatics. It certainly had a stimulatory effect on technology, advancing next-generation sequencing technologies which continue to give us a deeper knowledge of cancer genomics. — John E. Niederhuber, MD

a couple of surgical screws into the bone and helped close the incision. Years afterward, I ran into that surgeon who had later realized that I was only a student at the time I assisted him. We had a good laugh about it,” said Dr. Niederhuber.

A Mentor’s Influence Between his junior and senior years in medical school, Dr. Niederhuber worked in the Laboratory of Robert M. Zollinger, MD, Chairman of Surgery at Ohio State University. “Dr. Zollinger directed an elaborate research program studying gastric physiology and especially the role of gastrin. He had a large colony of beagle dogs and the projects required my doing gastric surgery creating different kinds of gastric pouches. I operated on these dogs every day so by the time I graduated from medical school, the technical aspects of performing abdominal surgery had become second nature,” said Dr. Niederhuber. He credits Dr. Zollinger as a valued mentor. “He taught me a lot about surgery, but he also helped me develop better patient care skills. His at-

gree from Ohio State, Dr. Niederhuber stayed on at the university for his first year of surgical residency. During that first year, he applied to graduate school, planning to pursue a PhD. However, it was 1967, and the escalating war in Vietnam put his plans on hold. Dr. Niederhuber was drafted into the Army. “I did my 2-year tour of duty at Fort Detrick in Frederick, Maryland, which was home to the U.S. Army’s Center for Biological Research focused on infectious agents. After that I went to the University of Michigan, enticed by a very attractive scientific research program,” said Dr. Niederhuber.

Best of Both Worlds Dr. Niederhuber’s decision to attend the University of Michigan was largely influenced by another valued mentor, C. Gardner Child, MD, the university’s Chair of Surgery, who ensured Dr. Niederhuber that he would have a robust research experience during his surgical training. “Dr. Child came through on his promise. The university sponsored me continued on page 25

To learn more, visit us at

www.IMBRUVICA.com CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IMBRUVICATM is indicated for the treatment of patients with CLL who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

MANTLE CELL LYMPHOMA (MCL) IMBRUVICATM is indicated for the treatment of patients with MCL who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage – Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily. 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. Infections - Fatal and non-fatal infections have occurred with IMBRUVICA™ therapy. At least 25% of patients with MCL and 35% 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.

Myelosuppression - Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly. Renal Toxicity - Fatal and serious cases of renal failure have occurred with IMBRUVICA™ therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration. Second Primary Malignancies - Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA™. Four percent of patients with MCL, had skin cancers, and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

Embryo-Fetal Toxicity - Based on findings 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 – MCL: The most commonly occurring adverse reactions (≥20%) in the clinical trial were thrombocytopenia*, diarrhea (51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%). *Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

IMBRUVICATM: the first-in-class covalent BTK inhibitor

DISCOVERING HOW FAR THERAPY CAN GO Encouraging response rates in previously treated CLL and MCL1 Durable responses1:

Most common adverse reactions (ARs) (≥20%)1:

• Median duration of response (DOR) not reached in CLL —Range: 5.6 to 24.2+ months • 17.5 months median duration of response (95% CI: 15.8, NR) in MCL Phase 2 MCL Trial:

open-label, multi-center, single-arm 1

100

60 40

ORR 58.3%

PR 58.3%

20 0

Response (%)

CLL Trial: open-label, multi-center 1

ORR 65.8%

60 40

PR 48.6%

CLL (N=48)

CR 17.1% MCL (N=111)

None of the patients achieved a complete response.

CLL: 95% CI (43.2, 72.4) MCL: 95% CI (56.2, 74.5) CR=complete response; ORR=overall response rate; PR=partial response. ORR and DOR were assessed using a modified version of the International Workshop on CLL (iwCLL) criteria by an Independent Review Committee. ORR was investigator-assessed according to the revised International Working Group (IWG) non-Hodgkin lymphoma (NHL) criteria.

The most common Grade 3 or 4 nonhematological adverse reactions (≥5%) were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin infections (5%). Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. 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. CLL: The most commonly occurring adverse reactions (≥ 20%) in the clinical trial were thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%).

• CLL: thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%) • MCL: thrombocytopenia†, diarrhea (51%), neutropenia†, anemia†, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%)

*Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions. † Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

The most common Grade 3 or 4 non-hematological ARs (≥5%) were1:

• CLL: pneumonia (8%), hypertension (8%), atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), dehydration (6.4%), and musculoskeletal pain (6%). Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients. Treatment-emergent Grade 3 or 4 cytopenias were reported in 35% of patients • MCL: pneumonia (7%), abdominal pain (5%), atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin infections (5%). Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111)

*Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions. The most common Grade 3 or 4 nonhematological adverse reactions (≥ 5%) were pneumonia (8%), hypertension (8%), atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), dehydration (6.4%), and musculoskeletal pain (6%). Treatment-emergent Grade 3 or 4 cytopenias were reported in 35% of patients. Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% 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. SPECIAL POPULATIONS - Hepatic Impairment - Avoid use in patients with baseline hepatic impairment. Reference: 1. IMBRUVICATM (ibrutinib) Prescribing Information. Pharmacyclics, Inc. 2014.

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

TMTM TMTM Brief BriefSummary SummaryofofPrescribing PrescribingInformation InformationforforIMBRUVICA IMBRUVICA (ibrutinib) (ibrutinib) IMBRUVICA IMBRUVICA (ibrutinib) (ibrutinib)capsules capsules TMTM TMTM Brief BriefSummary SummaryofofPrescribing PrescribingInformation InformationforforIMBRUVICA IMBRUVICA (ibrutinib) (ibrutinib) IMBRUVICA IMBRUVICA (ibrutinib) (ibrutinib)capsules capsules TMTM IMBRUVICA IMBRUVICA (ibrutinib) (ibrutinib) capsules, capsules, for for oral oral use use TMTM IMBRUVICA IMBRUVICA (ibrutinib) (ibrutinib)capsules, capsules,forfororal oraluse use See Seepackage packageinsert insertforforFull FullPrescribing PrescribingInformation Information Table Table2:2:Treatment-Emergent* Treatment-Emergent*Decrease DecreaseofofHemoglobin, Hemoglobin,Platelets, Platelets, See Seepackage packageinsert insertforforFull FullPrescribing PrescribingInformation Information Table Table2:2:Treatment-Emergent* Treatment-Emergent*Decrease DecreaseofofHemoglobin, Hemoglobin,Platelets, Platelets, ororNeutrophils NeutrophilsininPatients Patientswith withMCL MCL(N=111) (N=111) INDICATIONS INDICATIONSAND ANDUSAGE USAGE ororNeutrophils NeutrophilsininPatients Patientswith withMCL MCL(N=111) (N=111) INDICATIONS INDICATIONSAND ANDUSAGE USAGE IMBRUVICA IMBRUVICAisisindicated indicatedforforthe thetreatment treatmentofofpatients patientswith withmantle mantlecell celllymphoma lymphoma(MCL) (MCL)who whohave have Percent PercentofofPatients Patients(N=111) (N=111) IMBRUVICA IMBRUVICAisisindicated indicatedforforthe thetreatment treatmentofofpatients patientswith withmantle mantlecell celllymphoma lymphoma(MCL) (MCL)who whohave have Percent PercentofofPatients Patients(N=111) (N=111) received receivedatatleast leastone oneprior priortherapy. therapy.This Thisindication indicationisisbased basedononoverall overallresponse responserate. rate.AnAnimprovement improvement received receivedatatleast leastone oneprior priortherapy. therapy.This Thisindication indicationisisbased basedononoverall overallresponse responserate. rate.AnAnimprovement improvement All AllGrades Grades(%) (%) Grade Grade3 3oror4 4(%) (%) ininsurvival survivalorordisease-related disease-relatedsymptoms symptomshas hasnot notbeen beenestablished established[see [seeClinical ClinicalStudies Studies(14.1) (14.1)ininfull full All Grade AllGrades Grades(%) (%) Grade3 3oror4 4(%) (%) ininsurvival survivalorordisease-related disease-relatedsymptoms symptomshas hasnot notbeen beenestablished established[see [seeClinical ClinicalStudies Studies(14.1) (14.1)ininfull full Prescribing PrescribingInformation]. Information]. Platelets Platelets Decreased Decreased 57 57 17 17 Prescribing PrescribingInformation]. Information]. Platelets 5757 1717 PlateletsDecreased Decreased CONTRAINDICATIONS CONTRAINDICATIONS Neutrophils NeutrophilsDecreased Decreased 4747 2929 CONTRAINDICATIONS CONTRAINDICATIONS Neutrophils Decreased 47 2929 Neutrophils Decreased 47 None None None None Hemoglobin Decreased Hemoglobin Decreased 4141 99 Hemoglobin Decreased 4141 99 Hemoglobin Decreased WARNINGS WARNINGSAND ANDPRECAUTIONS PRECAUTIONS WARNINGS WARNINGSAND ANDPRECAUTIONS PRECAUTIONS * *Based Basedononlaboratory laboratorymeasurements measurementsand andadverse adversereactions reactions Hemorrhage: Hemorrhage:Five Fivepercent percentofofpatients patientswith withMCL MCLand and6% 6%ofofpatients patientswith withCLL CLLhad hadGrade Grade3 3ororhigher higher Basedononlaboratory laboratorymeasurements measurementsand andadverse adversereactions reactions Hemorrhage: Hemorrhage:Five Fivepercent percentofofpatients patientswith withMCL MCLand and6% 6%ofofpatients patientswith withCLL CLLhad hadGrade Grade3 3ororhigher higher * *Based bleeding bleeding events events (subdural (subdural hematoma, hematoma, ecchymoses, ecchymoses, gastrointestinal gastrointestinal bleeding, bleeding, and and hematuria). hematuria). Overall, Overall, Ten Tenpatients patients(9%) (9%)discontinued discontinuedtreatment treatmentdue duetotoadverse adversereactions reactionsininthe thetrial trial(N=111). (N=111).The Themost most bleeding bleeding events events (subdural (subdural hematoma, hematoma, ecchymoses, ecchymoses, gastrointestinal gastrointestinal bleeding, bleeding, and and hematuria). hematuria). Overall, Overall, Ten patients patients(9%) (9%)discontinued discontinuedtreatment treatmentdue duetotoadverse adversereactions reactionsininthe thetrial trial(N=111). (N=111).The Themost most bleeding bleedingevents eventsincluding includingbruising bruisingofofany anygrade gradeoccurred occurredinin48% 48%ofofpatients patientswith withMCL MCLtreated treatedTen with with frequent frequentadverse adversereaction reactionleading leadingtototreatment treatmentdiscontinuation discontinuationwas wassubdural subduralhematoma hematoma(1.8%). (1.8%). bleeding bleedingevents eventsincluding includingbruising bruisingofofany anygrade gradeoccurred occurredinin48% 48%ofofpatients patientswith withMCL MCLtreated treatedwith with frequent frequentadverse adversereaction reactionleading leadingtototreatment treatmentdiscontinuation discontinuationwas wassubdural subduralhematoma hematoma(1.8%). (1.8%). 560 560mg mgdaily dailyand and63% 63%ofofpatients patientswith withCLL CLLtreated treatedatat420 420mg mgdaily. daily. Adverse Adversereactions reactionsleading leadingtotodose dosereduction reductionoccurred occurredinin14% 14%ofofpatients. patients. 560 560mg mgdaily dailyand and63% 63%ofofpatients patientswith withCLL CLLtreated treatedatat420 420mg mgdaily. daily. Adverse Adversereactions reactionsleading leadingtotodose dosereduction reductionoccurred occurredinin14% 14%ofofpatients. patients. The Themechanism mechanismforforthe thebleeding bleedingevents eventsisisnot notwell wellunderstood. understood. Patients Patientswith withMCL MCLwho whodevelop developlymphocytosis lymphocytosisgreater greaterthan than400,000/mcL 400,000/mcLhave havedeveloped developedintracranial intracranial The Themechanism mechanismforforthe thebleeding bleedingevents eventsisisnot notwell wellunderstood. understood. Patients Patientswith withMCL MCLwho whodevelop developlymphocytosis lymphocytosisgreater greaterthan than400,000/mcL 400,000/mcLhave havedeveloped developedintracranial intracranial IMBRUVICA IMBRUVICAmay mayincrease increasethe therisk riskofofhemorrhage hemorrhageininpatients patientsreceiving receivingantiplatelet antiplateletororanticoagulant anticoagulant hemorrhage, hemorrhage, lethargy, lethargy, gait gait instability, instability, and and headache. headache. However, However, some some of of these these cases cases were were in in the the IMBRUVICA IMBRUVICA may mayincrease increasethe therisk riskofofhemorrhage hemorrhageininpatients patientsreceiving receivingantiplatelet antiplateletororanticoagulant anticoagulant hemorrhage, lethargy, gait instability, and headache. However, some of of these cases were in in the hemorrhage, lethargy, gait instability, and headache. However, some these cases were the therapies. therapies. setting settingofofdisease diseaseprogression. progression. therapies. therapies. setting of disease progression. setting of disease progression. Consider Considerthe thebenefit-risk benefit-riskofofwithholding withholdingIMBRUVICA IMBRUVICAforforatatleast least3 3toto7 7days dayspre preand andpost-surgery post-surgery Forty Fortypercent percentofofpatients patientshad hadelevated elevateduric uricacid acidlevels levelsononstudy studyincluding including13% 13%with withvalues valuesabove above Consider Considerthe the benefit-risk benefit-risk ofofthe withholding withholding IMBRUVICA for for atrisk atleast least 3bleeding 3tobleeding to7 7days days pre preand and post-surgery post-surgery percent percentofofpatients patientshad hadelevated elevateduric uricacid acidlevels levelsononstudy studyincluding including13% 13%with withvalues valuesabove above depending depending upon upon the type typeofofIMBRUVICA surgery surgeryand and the the risk ofof [see [see Clinical Clinical Studies Studies(14) (14)Forty inForty infull full 1010mg/dL. mg/dL.Adverse Adversereaction reactionofofhyperuricemia hyperuricemiawas wasreported reportedforfor15% 15%ofofpatients. patients. depending depending upon upon the the type type of of surgery surgery and and the the risk risk of of bleeding bleeding [see [see Clinical Clinical Studies Studies (14) (14) in in full full 1010mg/dL. mg/dL.Adverse Adversereaction reactionofofhyperuricemia hyperuricemiawas wasreported reportedforfor15% 15%ofofpatients. patients. Prescribing PrescribingInformation]. Information]. Prescribing PrescribingInformation]. Information]. Chronic ChronicLymphocytic LymphocyticLeukemia: Leukemia:The Thedata datadescribed describedbelow belowreflect reflectexposure exposuretotoIMBRUVICA IMBRUVICAinina a Infections: Infections:Fatal Fataland andnon-fatal non-fatalinfections infectionshave haveoccurred occurredwith withIMBRUVICA IMBRUVICAtherapy. therapy.AtAtleast least25% 25% ofof Lymphocytic Chronic Chronic LymphocyticLeukemia: Leukemia:The Thedata datadescribed describedbelow belowreflect reflectexposure exposuretotoIMBRUVICA IMBRUVICAinina a Infections: Infections: Fatal Fataland and non-fatal non-fatal infections infections have have occurred occurred with with IMBRUVICA IMBRUVICA therapy. therapy. Atleast least 25% 25% ofNCI of Common clinical clinicaltrial trialthat thatincluded included4848patients patientswith withpreviously previouslytreated treatedCLL CLLtreated treatedwith with420 420mg mgdaily dailywith witha a patients patients with with MCL MCLand and 35% 35%ofof patients patients with withCLL CLL had had infections infections Grade Grade3At3or orgreater greater NCI Common clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily witha a patients patientswith with MCL MCLand andCriteria 35% 35%ofofpatients patients with with CLL CLLhad had infections infections Grade Grade 3 3oror greater greaterNCI NCI Common Common median mediantreatment treatmentduration durationofof15.6 15.6months. months. Terminology Terminology Criteria for forAdverse Adverse Events Events (CTCAE) (CTCAE) [See [See Adverse Adverse Reactions]. Reactions]. Monitor Monitor patients patients forfor treatment median duration of 15.6 months. median treatment duration of 15.6 months. Terminology Terminology Criteria Criteria for forAdverse Adverse Events Events (CTCAE) (CTCAE) [See [SeeAdverse AdverseReactions]. Reactions].Monitor Monitorpatients patientsforfor The Themost mostcommonly commonlyoccurring occurringadverse adversereactions reactions(≥(≥20%) 20%)were werethrombo thrombo cytopenia, cytopenia,diarrhea, diarrhea,bruising, bruising, fever fever and andinfections infections and and evaluate evaluate promptly. promptly. The cytopenia, Themost mostcommonly commonlyoccurring occurringadverse adversereactions reactions(≥(≥20%) 20%)were werethrombo thrombo cytopenia,diarrhea, diarrhea,bruising, bruising, fever feverand andinfections infectionsand andevaluate evaluatepromptly. promptly. neutropenia, neutropenia,anemia, anemia,upper upperrespiratory respiratorytract tractinfection, infection,fatigue, fatigue,musculoskeletal musculoskeletalpain, pain,rash, rash,pyrexia, pyrexia, Myelosuppression: Myelosuppression:Treatment-emergent Treatment-emergentGrade Grade3 3oror4 4cytopenias cytopeniaswere werereported reportedinin41% 41%ofofpatients patients neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, Myelosuppression: Myelosuppression: Treatment-emergent Treatment-emergent Grade Grade 3CLL. 3orCLL. or4 4These cytopenias cytopenias were were reported reportedinin41% 41% ofofpatients patients constipation, constipation,peripheral peripheraledema, edema,arthralgia, arthralgia,nausea, nausea,stomatitis, stomatitis,sinusitis, sinusitis,and anddizziness dizziness(See (SeeTables Tables3 3 with withMCL MCL and and35% 35%ofofpatients patients with with These included included neutropenia neutropenia (29%), (29%), thrombocytopenia thrombocytopenia constipation, constipation,peripheral peripheraledema, edema,arthralgia, arthralgia,nausea, nausea,stomatitis, stomatitis,sinusitis, sinusitis,and anddizziness dizziness(See (SeeTables Tables3 3 with withMCL MCL(17%) and and35% 35% of of patients patients with with CLL. CLL.These These included included neutropenia neutropenia (29%), (29%), thrombocytopenia thrombocytopenia and and4).4). (17%) and and anemia anemia (9%) (9%) ininpatients patients with with MCL MCLand and neutropenia neutropenia (27%) (27%)and and thrombocytopenia thrombocytopenia (10%) (10%) 4).4). and (17%) (17%)and andin anemia anemia (9%) (9%) inin patients patientswith withMCL MCLand andneutropenia neutropenia(27%) (27%)and andthrombocytopenia thrombocytopenia(10%) (10%) and in patients patients with with CLL. CLL. The Themost mostcommon commonGrade Grade3 3oror4 4non-hematological non-hematologicaladverse adversereactions reactions(≥(≥5%) 5%)were werepneumonia, pneumonia, ininpatients patientswith withCLL. CLL. The Themost mostcommon commonGrade Grade3 3oror4 4non-hematological non-hematologicaladverse adversereactions reactions(≥(≥5%) 5%)were werepneumonia, pneumonia, hypertension, hypertension,atrial atrialfibrillation, fibrillation,sinusitis, sinusitis,skin skininfection, infection,dehydration, dehydration,and andmusculoskeletal musculoskeletalpain. pain. Monitor Monitorcomplete completeblood bloodcounts countsmonthly. monthly. hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain. hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain. Monitor Monitorcomplete completeblood bloodcounts countsmonthly. monthly. Adverse Adversereactions reactionsfrom fromthe theCLL CLLtrial trial(N=48) (N=48)using usingsingle singleagent agentIMBRUVICA IMBRUVICA420 420mg mgdaily dailyoccurring occurringatat Renal RenalToxicity: Toxicity:Fatal Fataland andserious seriouscases casesofofrenal renalfailure failurehave haveoccurred occurredwith withIMBRUVICA IMBRUVICAtherapy. therapy. Adverse Adversereactions reactionsfrom fromthe theCLL CLLtrial trial(N=48) (N=48)using usingsingle singleagent agentIMBRUVICA IMBRUVICA420 420mg mgdaily dailyoccurring occurringatat Renal RenalToxicity: Toxicity: Fatal Fataland andserious serious cases casesofinofin renal renal failure failure have have occurred with with IMBRUVICA IMBRUVICA therapy. therapy. a arate rateofof≥ ≥10% 10%are arepresented presentedininTable Table3.3. Treatment-emergent Treatment-emergent increases increases creatinine creatinine levels levels upoccurred upto to1.51.5times times the the upper upperlimit limitof of normal normaloccurred occurred a arate rateofof≥ ≥10% 10%are arepresented presentedininTable Table3.3. Treatment-emergent Treatment-emergent increases increases inincreatinine creatinine levels levels uppatients uptoto1.51.5with times times the theupper upper limit limit ofin of normal normaloccurred occurred inin67% 67%ofofpatients patients with with MCL MCLand and23% 23% ofofpatients with CLL. CLL. Increases Increases in creatinine creatinine 1.51.5toto3 3times timesthe the inin67% 67%ofofpatients patients with with MCL and and 23% 23%ofofpatients patients with CLL. CLL.Increases Increases inand increatinine creatinine 1.51.5totowith 3 with 3times times the the Table Table3:3:Non-Hematologic Non-HematologicAdverse AdverseReactions Reactionsinin≥ ≥10% 10%ofofPatients Patientswith with upper upperlimit limit ofMCL ofnormal normal occurred occurred in in9% 9%ofwith ofpatients patients with withMCL MCLand 4% 4%ofofpatients patients CLL. CLL. Periodically Periodically Table Table3:3:Non-Hematologic Non-HematologicAdverse AdverseReactions Reactionsinin≥ ≥10% 10%ofofPatients Patientswith with upper upperlimit limit ofmonitor ofnormal normal occurred occurred in in9% 9% ofMaintain ofpatients patients with withMCL MCLand and4% 4%ofofpatients patientswith withCLL. CLL.Periodically Periodically Chronic ChronicLymphocytic LymphocyticLeukemia Leukemia(N=48) (N=48) monitor creatinine creatinine levels. levels. Maintain hydration. hydration. Chronic ChronicLymphocytic LymphocyticLeukemia Leukemia(N=48) (N=48) monitor monitorcreatinine creatininelevels. levels.Maintain Maintainhydration. hydration. All AllGrades Grades Grade Grade3 3oror4 4 Second SecondPrimary PrimaryMalignancies: Malignancies:Other Othermalignancies malignancieshave haveoccurred occurredinin5% 5%ofofpatients patientswith withMCL MCLand and System AllGrades Grades Grade Grade3 3oror4 4 SystemOrgan OrganClass Class Preferred PreferredTerm TermAll Second SecondPrimary Primary Malignancies: Malignancies: Other Other malignancies malignancies have have occurred occurred in in 5% 5% of of patients patients with with MCL MCL and and System Preferred System OrganClass Class PreferredTerm Term (%) (%) (%) (%) 10% 10%ofofpatients patientswith withCLL CLLwho whohave havebeen beentreated treatedwith withIMBRUVICA. IMBRUVICA.Four Fourpercent percentofofpatients patients with with Organ (%) (%) (%) (%) 10% 10%ofofpatients patients with with CLL CLL who who have have been been treated treated with with IMBRUVICA. IMBRUVICA. Four Four percent percent of of patients patients with with MCL, MCL,had hadskin skincancers cancersand and1% 1%had hadother othercarcinomas. carcinomas.Eight Eightpercent percentofofpatients patientswith withCLL CLLhad hadskin skin 44 6363 Gastrointestinal Gastrointestinaldisorders disorders Diarrhea Diarrhea MCL, MCL,had hadskin skin cancers cancers and and 1% 1% had had other other carcinomas. carcinomas. Eight Eight percent percent of of patients patients with with CLL CLL had had skin skin 4 4 63 63 Gastrointestinal disorders Diarrhea Gastrointestinal disorders Diarrhea cancers cancersand and2% 2%had hadother othercarcinomas. carcinomas. 22 2323 Constipation Constipation cancers cancersand and2% 2%had hadother othercarcinomas. carcinomas. 22 2323 Constipation Constipation 22 2121 Nausea Nausea Embryo-Fetal Embryo-FetalToxicity: Toxicity:Based Basedononfindings findingsininanimals, animals,IMBRUVICA IMBRUVICAcan cancause causefetal fetalharm harmwhen when 22 2121 Nausea Nausea Embryo-Fetal Embryo-Fetal Toxicity: Toxicity:Based ononfindings findings ininanimals, animals, IMBRUVICA can cancause cause fetal fetal when when 1414times 00 2121 Stomatitis Stomatitis administered administered toBased toa apregnant pregnant woman. woman. Ibrutinib IbrutinibIMBRUVICA caused causedmalformations malformations inin rats ratsharm atharm atexposures exposures times 00 2121 Stomatitis Stomatitis administered administered to to a a pregnant pregnant woman. woman. Ibrutinib Ibrutinib caused caused malformations malformations in in rats rats at at exposures exposures 14 14 times times those thosereported reportedininpatients patientswith withMCL MCLand and2020times timesthose thosereported reportedininpatients patientswith withCLL, CLL,receiving receiving 22 1919 Vomiting Vomiting those thosereported reported in in patients patients with with MCL MCL and and 20 20 times times those those reported reported in in patients patients with with CLL, CLL, receiving receiving 2 2 19 19 Vomiting Vomiting the theibrutinib ibrutinibdose doseofof560 560mg mgper perday dayand and420 420mg mgper perday, day,respectively. respectively.Reduced Reducedfetal fetalweights weightswere were 00 1515 Abdominal Abdominalpain pain the theibrutinib ibrutinib dose dose of of 560 560 mg mg per per day day and and 420 420 mg mg per per day, day, respectively. respectively. Reduced Reduced fetal fetal weights weights were were 0 0 15 15 Abdominal pain Abdominal pain observed observedatatlower lowerexposures. exposures.Advise Advisewomen womentotoavoid avoidbecoming becomingpregnant pregnantwhile whiletaking takingIMBRUVICA. IMBRUVICA. 00 1313 Dyspepsia Dyspepsia observed observedatIfatIf lower lower exposures. exposures. Advise Advise women women to to avoid avoid becoming becoming pregnant pregnant while while taking taking IMBRUVICA. IMBRUVICA. 0 0 13 13 Dyspepsia Dyspepsia this thisdrug drugisisused usedduring duringpregnancy pregnancyororif ifthe thepatient patientbecomes becomespregnant pregnantwhile whiletaking takingthis thisdrug, drug,the the Infections Infectionsand andinfestations infestations Upper Upperrespiratory respiratory If Ifthis thisdrug drug is is used used during during pregnancy pregnancy or or if if the the patient patient becomes becomes pregnant pregnant while while taking taking this this drug, drug, the the Upper Infectionsand andinfestations infestations Upperrespiratory respiratory patient patientshould shouldbebeapprised apprisedofofthe thepotential potentialhazard hazardtotoa afetus fetus[see [seeUse UseininSpecific SpecificPopulations]. Populations].Infections 22 4848 patient patientshould shouldbebeapprised apprisedofofthe thepotential potentialhazard hazardtotoa afetus fetus[see [seeUse UseininSpecific SpecificPopulations]. Populations]. tract tractinfection infection 22 4848 tract tractinfection infection ADVERSE ADVERSEREACTIONS REACTIONS 66 2121 Sinusitis Sinusitis ADVERSE ADVERSEREACTIONS REACTIONS 66 2121 Sinusitis Sinusitis The Thefollowing followingadverse adversereactions reactionsare arediscussed discussedininmore moredetail detailininother othersections sectionsofofthe thelabeling: labeling: 66 1717 Skin Skininfection infection The Thefollowing followingadverse adversereactions reactionsare arediscussed discussedininmore moredetail detailininother othersections sectionsofofthe thelabeling: labeling: 66 1717 Skin Skininfection infection 88 1010 Pneumonia Pneumonia • • Hemorrhage [see Hemorrhage [seeWarnings Warningsand andPrecautions] Precautions] 8 8 10 10 Pneumonia Pneumonia • • Hemorrhage [see Hemorrhage [seeWarnings Warningsand andPrecautions] Precautions] 00 1010 Urinary Urinarytract tractinfection infection • • Infections [see Infections [seeWarnings Warningsand andPrecautions] Precautions] 00 1010 Urinary Urinarytract tractinfection infection • • Infections [see Infections [seeWarnings Warningsand andPrecautions] Precautions] • • Myelosuppression [see Myelosuppression [seeWarnings Warningsand andPrecautions] Precautions] 44 3131 General Generaldisorders disordersand andadministrative administrative Fatigue Fatigue • • Myelosuppression [see Myelosuppression [seeWarnings Warningsand andPrecautions] Precautions] 4 4 31 31 General disorders and administrative Fatigue General disorders and administrative Fatigue • • Renal Toxicity [see Renal Toxicity [seeWarnings Warningsand andPrecautions] Precautions] 22 2525 site siteconditions conditions Pyrexia Pyrexia • • Renal Toxicity [see Renal Toxicity [seeWarnings Warningsand andPrecautions] Precautions] 22 2525 site Pyrexia siteconditions conditions Pyrexia 00 2323 Peripheral Peripheraledema edema • • Second Primary Malignancies [see Second Primary Malignancies [seeWarnings Warningsand andPrecautions] Precautions] 00 2323 Peripheral Peripheraledema edema • • Second Primary Malignancies [see Second Primary Malignancies [seeWarnings Warningsand andPrecautions] Precautions] 44 1313 Asthenia Asthenia Because Becauseclinical clinicaltrials trialsare areconducted conductedunder underwidely widelyvariable variableconditions, conditions,adverse adverseevent eventrates rates 4 4 13 13 Asthenia Asthenia Because Becauseclinical clinical trials trials are areconducted conducted under widely widelyvariable conditions, conditions, adverse adverse event event rates rates trials 00 1313 Chills Chills observed observed ininclinical clinical trials trialsofofaunder adrug drugcannot cannot bevariable bedirectly directly compared compared with withrates rates ofofclinical clinical trialsofof 0 0 13 13 Chills Chills observed observedin in clinical clinical trials trials ofmay ofmay a adrug drug cannot cannot bebe directly directly compared compared with withrates ratesofofclinical clinicaltrials trialsofof 22 5454 Skin Skinand andsubcutaneous subcutaneoustissue tissuedisorders disorders Bruising Bruising another another drug drug and and not notreflect reflect the the rates rates observed observed ininpractice. practice. 22 5454 Skin Skinand andsubcutaneous subcutaneoustissue tissuedisorders disorders Bruising Bruising another anotherdrug drugand andmay maynot notreflect reflectthe therates ratesobserved observedininpractice. practice. 00 2727 Rash Rash Mantle MantleCell CellLymphoma: Lymphoma:The Thedata datadescribed describedbelow belowreflect reflectexposure exposuretotoIMBRUVICA IMBRUVICAinina aclinical clinicaltrial trial 00 2727 Rash Rash Mantle MantleCell Cell Lymphoma: Lymphoma: The The data data described described below below reflect reflect exposure exposure to to IMBRUVICA IMBRUVICA in in a a clinical clinical trial trial 00 1717 Petechiae Petechiae that thatincluded included111 111patients patientswith withpreviously previouslytreated treatedMCL MCLtreated treatedwith with560 560mg mgdaily dailywith witha amedian median 00 1717 Petechiae Petechiae that thatincluded included 111 111 patients patients with with previously previously treated treated MCL MCL treated treated with with 560 560 mg mg daily daily with with a a median median treatment treatmentduration durationofof8.38.3months. months. 00 1919 Respiratory, Respiratory,thoracic thoracicand andmediastinal mediastinal Cough Cough treatment treatmentduration durationofof8.38.3months. months. 00 1919 Respiratory, Cough Respiratory,thoracic thoracicand andmediastinal mediastinal Cough The Themost mostcommonly commonlyoccurring occurringadverse adversereactions reactions(≥(≥20%) 20%)were werethrombo thrombo cytopenia, cytopenia,diarrhea, diarrhea, 00 1515 disorders disorders Oropharyngeal Oropharyngealpain pain The Themost mostneutropenia, commonly commonly occurring occurring adverse adverse reactions reactions (≥ (≥ 20%) 20%) were were thrombo thrombo cytopenia, cytopenia, diarrhea, diarrhea, 0 0 15 15 disorders Oropharyngeal pain disorders Oropharyngeal pain neutropenia,anemia, anemia,fatigue, fatigue,musculo musculo skeletal skeletalpain, pain,peripheral peripheraledema, edema,upper upperrespiratory respiratorytract tract 00 1010 Dyspnea Dyspnea neutropenia, neutropenia, anemia, anemia, fatigue, fatigue, musculo musculo skeletal skeletal pain, pain, peripheral peripheral edema, edema, upper upper respiratory respiratory tract tract 0 0 10 10 Dyspnea Dyspnea infection, infection,nausea, nausea,bruising, bruising,dyspnea, dyspnea,constipation, constipation,rash, rash,abdominal abdominalpain, pain,vomiting vomitingand anddecreased decreased 66 2727 Musculoskeletal Musculoskeletaland andconnective connectivetissue tissue Musculoskeletal Musculoskeletalpain pain infection, infection,nausea, nausea, bruising, bruising, dyspnea, dyspnea, constipation, constipation, rash, rash, abdominal abdominal pain, pain, vomiting vomiting and and decreased decreased 66 2727 Musculoskeletal Musculoskeletaland andconnective connectivetissue tissue Musculoskeletal Musculoskeletalpain pain appetite appetite(See (SeeTables Tables1 1and and2).2). 00 appetite appetite(See (SeeTables Tables1 1and and2).2). 2323 disorders disorders Arthralgia Arthralgia 00 2323 disorders Arthralgia disorders Arthralgia The Themost mostcommon commonGrade Grade3 3oror4 4non-hematological non-hematologicaladverse adversereactions reactions(≥(≥5%) 5%)were werepneumonia, pneumonia, 22 1919 Muscle Musclespasms spasms The Themost mostabdominal common commonGrade Grade 3 atrial 3oror4fibrillation, 4fibrillation, non-hematological non-hematological adverse adverse reactions reactions (≥(≥5%) 5%)were werepneumonia, pneumonia, 22 1919 Muscle Musclespasms spasms abdominal pain, pain,atrial diarrhea, diarrhea,fatigue, fatigue, and and skin skininfections. infections. abdominal abdominalpain, pain,atrial atrialfibrillation, fibrillation,diarrhea, diarrhea,fatigue, fatigue,and andskin skininfections. infections. 00 2121 Nervous Nervoussystem systemdisorders disorders Dizziness Dizziness 00 2121 Nervous Dizziness Nervoussystem systemdisorders disorders Dizziness Adverse Adversereactions reactionsfrom fromthe theMCL MCLtrial trial(N=111) (N=111)using usingsingle singleagent agentIMBRUVICA IMBRUVICA560 560mg mgdaily dailyoccurring occurring 22 1919 Adverse Adversereactions reactions from the theMCL MCL trial trial(N=111) (N=111) using agentIMBRUVICA IMBRUVICA560 560mg mgdaily dailyoccurring occurring Headache Headache atata arate rate offrom of≥ ≥10% 10% are arepresented presented ininusing Table Tablesingle 1.single 1. agent 2 2 19 19 Headache Headache atata arate rateofof≥ ≥10% 10%are arepresented presentedininTable Table1.1. 00 1010 Peripheral Peripheral 00 1010 Peripheral Peripheral neuropathy neuropathy Table Table1:1:Non-Hematologic Non-HematologicAdverse AdverseReactions Reactionsinin≥ ≥10% 10%ofofPatients Patientswith with neuropathy neuropathy Table Table1:1:Non-Hematologic Non-HematologicAdverse AdverseReactions Reactionsinin≥ ≥10% 10%ofofPatients Patientswith with Mantle MantleCell CellLymphoma Lymphoma(N=111) (N=111) Metabolism Metabolismand andnutrition nutritiondisorders disorders Decreased Decreasedappetite appetite 1717 22 Mantle MantleCell CellLymphoma Lymphoma(N=111) (N=111) Metabolism Decreased 1717 22 Metabolismand andnutrition nutritiondisorders disorders Decreasedappetite appetite All AllGrades Grades Grade Grade3 3oror4 4 Neoplasms Neoplasms benign, benign, malignant, malignant, Second Second 10* 10* 0 0 All AllGrades Grades Grade Grade3 3oror4 4 System SystemOrgan OrganClass Class Preferred PreferredTerm Term Neoplasms Second 10* 00 Neoplasmsbenign, benign,malignant, malignant, Second 10* System Preferred SystemOrgan OrganClass Class PreferredTerm Term (%) (%) (%) (%) unspecified unspecified malignancies* malignancies* (%) (%) (%) (%) unspecified malignancies* unspecified malignancies* 55 5151 Gastrointestinal Gastrointestinaldisorders disorders Diarrhea Diarrhea Injury, Injury,poisoning poisoningand andprocedural procedural Laceration Laceration 1010 22 55 5151 Gastrointestinal Diarrhea Gastrointestinaldisorders disorders Diarrhea Injury, Laceration 1010 22 Injury,poisoning poisoningand andprocedural procedural Laceration 00 3131 Nausea Nausea complications complications 00 3131 Nausea Nausea complications complications 00 2525 Constipation Constipation Psychiatric Psychiatricdisorders disorders Anxiety Anxiety 1010 00 00 2525 Constipation Constipation Anxiety 1010 00 Psychiatricdisorders disorders Anxiety 5 5 Psychiatric 2424 Abdominal Abdominalpain pain Insomnia Insomnia 1010 00 55 2424 Abdominal Abdominalpain pain Insomnia 10 0 Insomnia 10 0 00 2323 Vomiting Vomiting Vascular Vasculardisorders disorders Hypertension Hypertension 1717 88 00 2323 Vomiting Vomiting Hypertension 1717 88 Vasculardisorders disorders Hypertension 1 1 Vascular 1717 Stomatitis Stomatitis 11 1717 Stomatitis Stomatitis *One *Onepatient patientdeath deathdue duetotohistiocytic histiocyticsarcoma. sarcoma. 0 0*One 1111 Dyspepsia Dyspepsia *Onepatient patientdeath deathdue duetotohistiocytic histiocyticsarcoma. sarcoma. 00 1111 Dyspepsia Dyspepsia Infections Infectionsand andinfestations infestations Upper Upperrespiratory respiratory Infections Upper Infectionsand andinfestations infestations Upperrespiratory respiratory Table Table 4: 4:Treatment-Emergent* Treatment-Emergent*Decrease DecreaseofofHemoglobin, Hemoglobin, 00 3434 tract tractinfection infection Table Table4:4:Treatment-Emergent* Treatment-Emergent*Decrease DecreaseofofHemoglobin, Hemoglobin, 00 3434 tract tractinfection infection Platelets, Platelets,ororNeutrophils NeutrophilsininPatients Patientswith withCLL CLL(N=48) (N=48) 33 1414 Urinary Urinarytract tractinfection infection Platelets, Platelets,ororNeutrophils NeutrophilsininPatients Patientswith withCLL CLL(N=48) (N=48) 33 1414 Urinary Urinarytract tractinfection infection Percent PercentofofPatients Patients(N=48) (N=48) 77 1414 Pneumonia Pneumonia Percent PercentofofPatients Patients(N=48) (N=48) 77 1414 Pneumonia Pneumonia 55 1414 Skin Skininfections infections All AllGrades Grades(%) (%) Grade Grade3 3oror4 4(%) (%) 55 1414 Skin Skininfections infections All Grade AllGrades Grades(%) (%) Grade3 3oror4 4(%) (%) 11 1313 Sinusitis Sinusitis 11 1313 Sinusitis Sinusitis Platelets PlateletsDecreased Decreased 7171 1010 7171 1010 PlateletsDecreased Decreased 5 5 Platelets 4141 General Generaldisorders disordersand andadministrative administrative Fatigue Fatigue 55 4141 General Fatigue Generaldisorders disordersand andadministrative administrative Fatigue 33 3535 site siteconditions conditions Peripheral Peripheraledema edema Neutrophils NeutrophilsDecreased Decreased 5454 2727 33 3535 site Peripheral siteconditions conditions Peripheraledema edema Neutrophils 5454 2727 NeutrophilsDecreased Decreased 11 1818 Pyrexia Pyrexia 11 1818 Pyrexia Pyrexia Hemoglobin Decreased Hemoglobin Decreased 4444 00 3 3 Hemoglobin Decreased 1414 Asthenia Asthenia 4444 00 Hemoglobin Decreased 33 1414 Asthenia Asthenia * *Based Basedononlaboratory laboratorymeasurements measurementsper perIWCLL IWCLLcriteria criteriaand andadverse adversereactions reactions 0 0* *Based 3030 Skin Skinand andsubcutaneous subcutaneoustissue tissuedisorders disorders Bruising Bruising Basedononlaboratory laboratorymeasurements measurementsper perIWCLL IWCLLcriteria criteriaand andadverse adversereactions reactions 00 3030 Skin Skinand andsubcutaneous subcutaneoustissue tissuedisorders disorders Bruising Bruising 33 2525 Rash Rash Five Fivepatients patients(10%) (10%)discontinued discontinuedtreatment treatmentdue duetotoadverse adversereactions reactionsininthe thetrial trial(N=48). (N=48).These These 33 2525 Rash Rash Five patients (10%) discontinued treatment due to adverse reactions ininthe Five patients (10%) discontinued treatment due to adverse reactions thetrial trial(N=48). (N=48).These These 00 1111 Petechiae Petechiae included included3 3patients patients(6%) (6%)with withinfections infectionsand and2 2patients patients(4%) (4%)with withsubdural subduralhematomas. hematomas.Adverse Adverse 00 1111 Petechiae Petechiae included included3 3patients patients(6%) (6%)with withinfections infectionsand and2 2patients patients(4%) (4%)with withsubdural subduralhematomas. hematomas.Adverse Adverse 11 3737 Musculoskeletal Musculoskeletaland andconnective connectivetissue tissue Musculoskeletal Musculoskeletalpain pain reactions reactionsleading leadingtotodose dosereduction reductionoccurred occurredinin13% 13%ofofpatients. patients. 11 3737 Musculoskeletal Musculoskeletaland andconnective connectivetissue tissue Musculoskeletal Musculoskeletalpain pain reactions reactionsleading leadingtotodose dosereduction reductionoccurred occurredinin13% 13%ofofpatients. patients. 00 1414 disorders disorders Muscle Musclespasms spasms Thirty-eight Thirty-eightpercent percentofofpatients patientshad hadshifts shiftsfrom fromnormal normaltotoelevated elevateduric uricacid acidlevels levelsononstudy studyincluding including 00 1414 disorders Muscle disorders Musclespasms spasms Thirty-eightpercent percentofofpatients patientshad hadshifts shiftsfrom fromnormal normaltotoelevated elevateduric uricacid acidlevels levelsononstudy studyincluding including 0 0Thirty-eight 1111 Arthralgia Arthralgia 4% 4%with withvalues valuesabove above1010mg/dL. mg/dL. 00 1111 Arthralgia Arthralgia 4% with values above 10 mg/dL. 4% with values above 10 mg/dL. 44 2727 Respiratory, Respiratory,thoracic thoracicand andmediastinal mediastinal Dyspnea Dyspnea 44 2727 Respiratory, Dyspnea Respiratory,thoracic thoracicand andmediastinal mediastinal Dyspnea DRUG DRUGINTERACTIONS INTERACTIONS DRUGINTERACTIONS INTERACTIONS 0 0DRUG 1919 disorders disorders Cough Cough 00 1919 disorders Cough disorders Cough Ibrutinib Ibrutinibisisprimarily primarilymetabolized metabolizedbybycytochrome cytochromeP450 P450enzyme enzyme3A. 3A. 0 0Ibrutinib 1111 Epistaxis Epistaxis Ibrutinibisisprimarily primarilymetabolized metabolizedbybycytochrome cytochromeP450 P450enzyme enzyme3A. 3A. 00 1111 Epistaxis Epistaxis CYP3A CYP3A Inhibitors: Inhibitors: In In healthy healthy volunteers, volunteers, co-administration co-administration of ofketoconazole, ketoconazole,a astrong strongCYP3A CYP3A Metabolism Metabolismand andnutrition nutritiondisorders disorders Decreased Decreasedappetite appetite 2121 2 2CYP3A CYP3AInhibitors: Inhibitors:InInhealthy healthyvolunteers, volunteers,co-administration co-administrationofofketoconazole, ketoconazole,a astrong strongCYP3A CYP3A Metabolism Decreased 2121 22 Metabolismand andnutrition nutritiondisorders disorders Decreasedappetite appetite inhibitor, inhibitor,increased increasedCmax Cmaxand andAUC AUCofofibrutinib ibrutinibbyby2929-and and24-fold, 24-fold,respectively. respectively.The Thehighest highestibrutinib ibrutinib Dehydration Dehydration 1212 4 4inhibitor, inhibitor,increased increasedCmax Cmaxand andAUC AUCofofibrutinib ibrutinibbyby2929-and and24-fold, 24-fold,respectively. respectively.The Thehighest highestibrutinib ibrutinib Dehydration 1212 44 Dehydration dose doseevaluated evaluated ininclinical clinicaltrials trialswas was12.5 12.5mg/kg mg/kg(actual (actualdoses dosesofof840 840– –1400 1400mg) mg)given givenforfor2828days days doseevaluated evaluatedininclinical clinicaltrials trialswas was12.5 12.5mg/kg mg/kg(actual (actualdoses dosesofof840 840– –1400 1400mg) mg)given givenforfor2828days days Nervous Nervoussystem systemdisorders disorders Dizziness Dizziness 1414 0 0dose with withsingle singledose doseAUC AUCvalues valuesofof1445 1445± ±869 869ngng• hr/mL • hr/mL which whichisisapproximately approximately50% 50%greater greaterthan thansteady steady Nervous Dizziness 1414 00 Nervoussystem systemdisorders disorders Dizziness withsingle singledose doseAUC AUCvalues valuesofof1445 1445± ±869 869ngng• hr/mL • hr/mL which whichisisapproximately approximately50% 50%greater greaterthan thansteady steady Headache Headache 1313 0 0with state stateexposures exposuresseen seenatatthe thehighest highestindicated indicateddose dose(560 (560mg). mg). Headache 1313 00 Headache state stateexposures exposuresseen seenatatthe thehighest highestindicated indicateddose dose(560 (560mg). mg).

TMTM IMBRUVICA (ibrutinib) (ibrutinib)capsules capsules IMBRUVICA TMTM (ibrutinib) (ibrutinib)capsules capsules IMBRUVICA IMBRUVICA

Activeingredient ingredientmade madeininChina. China. Active Active Activeingredient ingredientmade madeininChina. China. Distributedand andMarketed Marketedby: by: Distributed Distributed Distributedand andMarketed Marketedby: by: Pharmacyclics,Inc. Inc. Pharmacyclics, Pharmacyclics, Pharmacyclics,Inc. Inc. Sunnyvale,CA CAUSA USA94085 94085 Sunnyvale, Sunnyvale, Sunnyvale,CA CAUSA USA94085 94085 and and and and Marketedby: by: Marketed Marketed Marketedby: by: JanssenBiotech, Biotech,Inc. Inc. Janssen Janssen JanssenBiotech, Biotech,Inc. Inc. Horsham, PA USA 19044 Horsham, PA USA 19044 Horsham, PA USA 19044 Horsham, PA USA 19044 Patenthttp://www.imbruvica.com http://www.imbruvica.com Patent Patent Patenthttp://www.imbruvica.com http://www.imbruvica.com IMBRUVICA™isisa atrademark trademarkowned ownedbybyPharmacyclics, Pharmacyclics,Inc. Inc. IMBRUVICA™ IMBRUVICA™ IMBRUVICA™isisa atrademark trademarkowned ownedbybyPharmacyclics, Pharmacyclics,Inc. Inc. ©Pharmacyclics,Inc. Inc.2014 2014 ©Pharmacyclics, ©Pharmacyclics, ©Pharmacyclics,Inc. Inc.2014 2014 PRC-00339 PRC-00339 PRC-00339 PRC-00339

Issued:February February2014 2014 Issued: Issued: Issued:February February2014 2014

ASCOPost.com | JUNE 10, 2014 | SUPPLEMENT

John E. Niederhuber, MD continued from page 21

as a visiting fellow in the division of immunology at The Karolinska Institute in Stockholm, Sweden. These were the early days of being able to isolate T-cells and Bcells from mouse tissues and to use these cells in vitro to model antibody response to antigens. The immunology environment in Sweden and Europe was electric in those years and the laboratory, headed by Göran and Erna Möller, had a steady stream of visiting immunology stars,” Dr. Niederhuber related. After completing his fellowship, Dr. Niederhuber returned to the University of Michigan to finish his surgical training and to consider his career direction. That’s when Dr. Child intervened again. “He had gone to the Chairman of the Department of Microbiology at the university and worked out an arrangement that gave me a full faculty appointment as an Assistant Professor in Microbiology and a full appointment as Assistant Professor of Surgery. Further, they arranged for my research laboratory to be located in the Department of Microbiology. I was to teach at the graduate level and was approved to train doctoral students. This combined experience, working in a basic science department and in a clinical department, gave me the fantastic opportunity to grow up professionally on both sides of the medical campus. It was, I am convinced, the most significant turning point in my career,” said Dr. Niederhuber. What attracted Dr. Niederhuber to oncology? “Working in cancer addressed my desire to perform surgery, which I dearly loved, but I also very much enjoyed being involved in internal medicine. And I always felt the best oncology surgeons were also talented internists as well. Oncology requires a team approach to clinical problem solving that is at once challenging and rewarding. I loved working side by side with my colleagues in medical oncology, radiation oncology, imaging and pathology to bring the very best care to complex cancer cases. I’ve always tried to instill that philosophy in the residents I’ve trained over the years,” said Dr. Niederhuber. “I spent 19 very exciting years at the University of Michigan. Those years included serving as the Associate Dean for Research (1982-85), Senior Associate Dean and as interim dean along with Professor Peter Ward (1983-85). Dr. Ward, was also a tremendous mentor. For this service, University President Shapiro allowed me to take a sabbatical and I did so

PAGE 25

in Professor Tom Kelley’s department of Molecular Biology and Genetics at Johns Hopkins. The sabbatical got me back to the bench for a year and gave me a great chance to catch up on the rapid advances in molecular biology and genetics occurring at that time. At the end of the sabbatical year, I accepted an invitation to stay on the faculty at Hopkins. In 1991, I accepted an invitation by Dr. David Korn, Dean Stanford School of Medicine to head the Department of Surgery. This was followed by an opportunity to relocate to the University of Wisconsin to help them bring two separate NCI-designated cancer centers together under one NCI core grant and to direct that Center,” he recounted.

Road to the NCI Throughout his career, Dr. Niederhuber has had many career-changing opportunities. In 2002, his friend and colleague, then–NCI Director Andrew von Eschenbach, MD, began recruiting Dr. Niederhuber to join him at the Institute, but Dr. Niederhuber needed to stay close to home to care for his young son and niece after his wife died from breast cancer in 2001. “In 2005 I finally felt that things with the children had stabilized so I took a leave of absence from the University of Wisconsin and accepted a Deputy Director position at the NCI with Andy. I hadn’t been there more than a few weeks when President Bush appointed Andy as acting FDA commissioner and I became the acting Director of the NCI. I never expected that to happen and I must say it was a tremendous honor to have President Bush ask me in the summer of 2006 to become the Director. I remained in the position until the summer of 2010,” said Dr. Niederhuber. During his tenure at the NCI, Dr. Niederhuber, working with Dr. Francis Collins, was instrumental in beginning The Cancer Genome Atlas (TCGA), an ambitious project that catalogs mutations responsible for cancer using genome sequencing and bioinformatics. TCGA has a number of different centers that are funded to generate and analyze data. “It remains a very successful project and during those early years we were able to learn a lot about infrastructure needs, biobanking and bioinformatics. It certainly had a stimulatory effect on technology, advancing next-generation sequencing technologies which continue to give us a deeper knowledge of cancer genomics,” said Dr. Niederhuber. Dr. Niederhuber is continued on page 26

sT:

Avoid Avoidconcomitant concomitantadministration administrationofofIMBRUVICA IMBRUVICAwith withstrong strongorormoderate moderateinhibitors inhibitorsofofCYP3A. CYP3A.For For Avoid Avoidconcomitant concomitantadministration administrationofofIMBRUVICA IMBRUVICAwith withstrong strongorormoderate moderateinhibitors inhibitorsofofCYP3A. CYP3A.For For strong strongCYP3A CYP3Ainhibitors inhibitorsused usedshort-term short-term(e.g., (e.g.,antifungals antifungalsand andantibiotics antibioticsforfor7 7days daysororless, less,e.g., e.g., strong strongCYP3A CYP3Ainhibitors inhibitorsused usedshort-term short-term(e.g., (e.g.,antifungals antifungalsand andantibiotics antibioticsforfor7 7days daysororless, less,e.g., e.g., ketoconazole,itraconazole, itraconazole,voriconazole, voriconazole,posaconazole, posaconazole,clarithromycin, clarithromycin,telithromycin) telithromycin)consider consider ketoconazole, ketoconazole, ketoconazole,itraconazole, itraconazole,voriconazole, voriconazole,posaconazole, posaconazole,clarithromycin, clarithromycin,telithromycin) telithromycin)consider consider interruptingIMBRUVICA IMBRUVICAtherapy therapyduring duringthe theduration durationofofinhibitor inhibitoruse. use.Avoid Avoidstrong strongCYP3A CYP3Ainhibitors inhibitors interrupting interrupting interruptingIMBRUVICA IMBRUVICAtherapy therapyduring duringthe theduration durationofofinhibitor inhibitoruse. use.Avoid Avoidstrong strongCYP3A CYP3Ainhibitors inhibitors thatare areneeded neededchronically. chronically.If Ifa amoderate moderateCYP3A CYP3Ainhibitor inhibitormust mustbebeused, used,reduce reducethe theIMBRUVICA IMBRUVICAdose. dose. that that thatare areneeded neededchronically. chronically.If Ifa amoderate moderateCYP3A CYP3Ainhibitor inhibitormust mustbebeused, used,reduce reducethe theIMBRUVICA IMBRUVICAdose. dose. Patientstaking takingconcomitant concomitantstrong strongorormoderate moderateCYP3A4 CYP3A4inhibitors inhibitorsshould shouldbebemonitored monitoredmore moreclosely closely Patients Patients Patientstaking takingconcomitant concomitantstrong strongorormoderate moderateCYP3A4 CYP3A4inhibitors inhibitorsshould shouldbebemonitored monitoredmore moreclosely closely signsofofIMBRUVICA IMBRUVICAtoxicity toxicity[see [seeDosage Dosageand andAdministration Administration(2.4) (2.4)ininfull fullPrescribing PrescribingInformation]. Information]. forforsigns forforsigns signsofofIMBRUVICA IMBRUVICAtoxicity toxicity[see [seeDosage Dosageand andAdministration Administration(2.4) (2.4)ininfull fullPrescribing PrescribingInformation]. Information]. Avoidgrapefruit grapefruitand andSeville Sevilleoranges orangesduring duringIMBRUVICA IMBRUVICAtreatment, treatment,asasthese thesecontain containmoderate moderate Avoid Avoid Avoidgrapefruit grapefruitand andSeville Sevilleoranges orangesduring duringIMBRUVICA IMBRUVICAtreatment, treatment,asasthese thesecontain containmoderate moderate inhibitorsofofCYP3A CYP3A[see [seeDosage Dosageand andAdministration Administration(2.4), (2.4),and andClinical ClinicalPharmacology Pharmacology(12.3) (12.3)ininfull full inhibitors inhibitors inhibitorsofofCYP3A CYP3A[see [seeDosage Dosageand andAdministration Administration(2.4), (2.4),and andClinical ClinicalPharmacology Pharmacology(12.3) (12.3)ininfull full PrescribingInformation]. Information]. Prescribing Prescribing PrescribingInformation]. Information]. CYP3AInducers: Inducers:Administration AdministrationofofIMBRUVICA IMBRUVICAwith withstrong stronginducers inducersofofCYP3A CYP3Adecrease decreaseibrutinib ibrutinib CYP3A CYP3A CYP3AInducers: Inducers:Administration AdministrationofofIMBRUVICA IMBRUVICAwith withstrong stronginducers inducersofofCYP3A CYP3Adecrease decreaseibrutinib ibrutinib plasmaconcentrations concentrationsbybyapproximately approximately10-fold. 10-fold. plasma plasma plasmaconcentrations concentrationsbybyapproximately approximately10-fold. 10-fold. Avoidconcomitant concomitantuse useofofstrong strongCYP3A CYP3Ainducers inducers(e.g., (e.g.,carbamazepine, carbamazepine,rifampin, rifampin,phenytoin phenytoinand and Avoid Avoid Avoidconcomitant concomitantuse useofofstrong strongCYP3A CYP3Ainducers inducers(e.g., (e.g.,carbamazepine, carbamazepine,rifampin, rifampin,phenytoin phenytoinand and John’sWort). Wort).Consider Consideralternative alternativeagents agentswith withless lessCYP3A CYP3Ainduction induction[see [seeClinical ClinicalPharmacology Pharmacology St.St.John’s St.St.John’s John’sWort). Wort).Consider Consideralternative alternativeagents agentswith withless lessCYP3A CYP3Ainduction induction[see [seeClinical ClinicalPharmacology Pharmacology (12.3)ininfull fullPrescribing PrescribingInformation]. Information]. (12.3) (12.3) (12.3)ininfull fullPrescribing PrescribingInformation]. Information]. USEININSPECIFIC SPECIFICPOPULATIONS POPULATIONS USE USE USEININSPECIFIC SPECIFICPOPULATIONS POPULATIONS Pregnancy:Pregnancy PregnancyCategory CategoryD D[see [seeWarnings Warningsand andPrecautions]. Precautions]. Pregnancy: Pregnancy: Pregnancy:Pregnancy PregnancyCategory CategoryD D[see [seeWarnings Warningsand andPrecautions]. Precautions]. RiskSummary: Summary:Based Basedononfindings findingsininanimals, animals,IMBRUVICA IMBRUVICAcan cancause causefetal fetalharm harmwhen whenadministered administeredtoto Risk Risk RiskSummary: Summary:Based Basedononfindings findingsininanimals, animals,IMBRUVICA IMBRUVICAcan cancause causefetal fetalharm harmwhen whenadministered administeredtoto pregnantwoman. woman.If IfIMBRUVICA IMBRUVICAisisused usedduring duringpregnancy pregnancyororif ifthe thepatient patientbecomes becomespregnant pregnantwhile while a apregnant a apregnant pregnantwoman. woman.If IfIMBRUVICA IMBRUVICAisisused usedduring duringpregnancy pregnancyororif ifthe thepatient patientbecomes becomespregnant pregnantwhile while takingIMBRUVICA, IMBRUVICA,the thepatient patientshould shouldbebeapprised apprisedofofthe thepotential potentialhazard hazardtotothe thefetus. fetus. taking taking takingIMBRUVICA, IMBRUVICA,the thepatient patientshould shouldbebeapprised apprisedofofthe thepotential potentialhazard hazardtotothe thefetus. fetus. AnimalData: Data:Ibrutinib Ibrutinibwas wasadministered administeredorally orallytotopregnant pregnantrats ratsduring duringthe theperiod periodofoforganogenesis organogenesis Animal Animal AnimalData: Data:Ibrutinib Ibrutinibwas wasadministered administeredorally orallytotopregnant pregnantrats ratsduring duringthe theperiod periodofoforganogenesis organogenesis oraldoses dosesofof10,10,4040and and8080mg/kg/day. mg/kg/day.Ibrutinib Ibrutinibatata adose doseofof8080mg/kg/day mg/kg/daywas wasassociated associatedwith with atatoral atatoral oraldoses dosesofof10,10,4040and and8080mg/kg/day. mg/kg/day.Ibrutinib Ibrutinibatata adose doseofof8080mg/kg/day mg/kg/daywas wasassociated associatedwith with visceralmalformations malformations(heart (heartand andmajor majorvessels) vessels)and andincreased increasedpost-implantation post-implantationloss. loss.The Thedose doseofof visceral visceral visceralmalformations malformations(heart (heartand andmajor majorvessels) vessels)and andincreased increasedpost-implantation post-implantationloss. loss.The Thedose doseofof mg/kg/dayininanimals animalsisisapproximately approximately1414times timesthe theexposure exposure(AUC) (AUC)ininpatients patientswith withMCL MCLand and 8080mg/kg/day 8080mg/kg/day mg/kg/dayininanimals animalsisisapproximately approximately1414times timesthe theexposure exposure(AUC) (AUC)ininpatients patientswith withMCL MCLand and timesthe theexposure exposureininpatients patientswith withCLL CLLadministered administeredthe thedose doseofof560 560mg mgdaily dailyand and420 420mg mgdaily, daily, 2020times 2020times timesthe theexposure exposureininpatients patientswith withCLL CLLadministered administeredthe thedose doseofof560 560mg mgdaily dailyand and420 420mg mgdaily, daily, respectively.Ibrutinib Ibrutinibatatdoses dosesofof4040mg/kg/day mg/kg/dayororgreater greaterwas wasassociated associatedwith withdecreased decreasedfetal fetal respectively. respectively. respectively.Ibrutinib Ibrutinibatatdoses dosesofof4040mg/kg/day mg/kg/dayororgreater greaterwas wasassociated associatedwith withdecreased decreasedfetal fetal weights.The Thedose doseofof4040mg/kg/day mg/kg/dayininanimals animalsisisapproximately approximately6 6times timesthe theexposure exposure(AUC) (AUC)ininpatients patients weights. weights. weights.The Thedose doseofof4040mg/kg/day mg/kg/dayininanimals animalsisisapproximately approximately6 6times timesthe theexposure exposure(AUC) (AUC)ininpatients patients withMCL MCLadministered administeredthe thedose doseofof560 560mg mgdaily. daily. with with withMCL MCLadministered administeredthe thedose doseofof560 560mg mgdaily. daily. NursingMothers: Mothers:It Itisisnot notknown knownwhether whetheribrutinib ibrutinibisisexcreted excretedininhuman humanmilk. milk.Because Becausemany manydrugs drugsare are Nursing Nursing NursingMothers: Mothers:It Itisisnot notknown knownwhether whetheribrutinib ibrutinibisisexcreted excretedininhuman humanmilk. milk.Because Becausemany manydrugs drugsare are excretedininhuman humanmilk milkand andbecause becauseofofthe thepotential potentialforforserious seriousadverse adversereactions reactionsininnursing nursinginfants infants excreted excreted excretedininhuman humanmilk milkand andbecause becauseofofthe thepotential potentialforforserious seriousadverse adversereactions reactionsininnursing nursinginfants infants fromIMBRUVICA, IMBRUVICA,a adecision decisionshould shouldbebemade madewhether whethertotodiscontinue discontinuenursing nursingorortotodiscontinue discontinuethe the from from fromIMBRUVICA, IMBRUVICA,a adecision decisionshould shouldbebemade madewhether whethertotodiscontinue discontinuenursing nursingorortotodiscontinue discontinuethe the drug,taking takinginto intoaccount accountthe theimportance importanceofofthe thedrug drugtotothe themother. mother. drug, drug, drug,taking takinginto intoaccount accountthe theimportance importanceofofthe thedrug drugtotothe themother. mother. PediatricUse: Use:The Thesafety safetyand andeffectiveness effectivenessofofIMBRUVICA IMBRUVICAininpediatric pediatricpatients patientshas hasnot notbeen been Pediatric Pediatric PediatricUse: Use:The Thesafety safetyand andeffectiveness effectivenessofofIMBRUVICA IMBRUVICAininpediatric pediatricpatients patientshas hasnot notbeen been established. established. established. established. GeriatricUse: Use:OfOfthe the111 111patients patientstreated treatedforforMCL, MCL,63% 63%were were6565years yearsofofage ageororolder. older.No Nooverall overall Geriatric Geriatric GeriatricUse: Use:OfOfthe the111 111patients patientstreated treatedforforMCL, MCL,63% 63%were were6565years yearsofofage ageororolder. older.No Nooverall overall differencesinineffectiveness effectivenesswere wereobserved observedbetween betweenthese thesepatients patientsand andyounger youngerpatients. patients.Cardiac Cardiac differences differences differencesinineffectiveness effectivenesswere wereobserved observedbetween betweenthese thesepatients patientsand andyounger youngerpatients. patients.Cardiac Cardiac adverseevents events(atrial (atrialfibrillation fibrillationand andhypertension), hypertension),infections infections(pneumonia (pneumoniaand andcellulitis) cellulitis)and and adverse adverse adverseevents events(atrial (atrialfibrillation fibrillationand andhypertension), hypertension),infections infections(pneumonia (pneumoniaand andcellulitis) cellulitis)and and gastrointestinalevents events(diarrhea (diarrheaand anddehydration) dehydration)occurred occurredmore morefrequently frequentlyamong amongelderly elderlypatients. patients. gastrointestinal gastrointestinal gastrointestinalevents events(diarrhea (diarrheaand anddehydration) dehydration)occurred occurredmore morefrequently frequentlyamong amongelderly elderlypatients. patients. the4848patients patientstreated treatedforforCLL, CLL,52% 52%were were6565years yearsofofage ageororolder. older.No Nooverall overalldifferences differencesinin OfOfthe OfOfthe the4848patients patientstreated treatedforforCLL, CLL,52% 52%were were6565years yearsofofage ageororolder. older.No Nooverall overalldifferences differencesinin effectivenesswere wereobserved observedbetween betweenthese thesepatients patientsand andyounger youngerpatients. patients.A Agreater greaternumber numberofof effectiveness effectiveness effectivenesswere wereobserved observedbetween betweenthese thesepatients patientsand andyounger youngerpatients. patients.A Agreater greaternumber numberofof adverseevents eventswere werereported reportedininthose those6565years yearsofofage ageand andolder. older.Grade Grade3 3ororhigher higheradverse adverseevents events adverse adverse adverseevents eventswere werereported reportedininthose those6565years yearsofofage ageand andolder. older.Grade Grade3 3ororhigher higheradverse adverseevents events occurredmore morefrequently frequentlyamong amongelderly elderlypatients patients(80% (80%ofofpatients patients6565and andolder olderversus versus61% 61%ofof occurred occurred occurredmore morefrequently frequentlyamong amongelderly elderlypatients patients(80% (80%ofofpatients patients6565and andolder olderversus versus61% 61%ofof youngerpatients). patients). younger younger youngerpatients). patients). RenalImpairment: Impairment:Less Lessthan than1% 1%ofofibrutinib ibrutinibisisexcreted excretedrenally. renally.Ibrutinib Ibrutinibexposure exposureisisnot notaltered alteredinin Renal Renal RenalImpairment: Impairment:Less Lessthan than1% 1%ofofibrutinib ibrutinibisisexcreted excretedrenally. renally.Ibrutinib Ibrutinibexposure exposureisisnot notaltered alteredinin patientswith withCreatinine Creatinineclearance clearance(CLcr) (CLcr)> >2525mL/min. mL/min.There Thereare arenonodata dataininpatients patientswith withsevere severe patients patients patientswith withCreatinine Creatinineclearance clearance(CLcr) (CLcr)> >2525mL/min. mL/min.There Thereare arenonodata dataininpatients patientswith withsevere severe renalimpairment impairment(CLcr (CLcr< <2525mL/min) mL/min)ororpatients patientsonondialysis dialysis[see [seeClinical ClinicalPharmacology Pharmacology(12.3) (12.3)ininfull full renal renal renalimpairment impairment(CLcr (CLcr< <2525mL/min) mL/min)ororpatients patientsonondialysis dialysis[see [seeClinical ClinicalPharmacology Pharmacology(12.3) (12.3)ininfull full PrescribingInformation]. Information]. Prescribing Prescribing PrescribingInformation]. Information]. HepaticImpairment: Impairment:Ibrutinib Ibrutinibisismetabolized metabolizedininthe theliver liverand andsignificant significantincreases increasesininexposure exposureofof Hepatic Hepatic HepaticImpairment: Impairment:Ibrutinib Ibrutinibisismetabolized metabolizedininthe theliver liverand andsignificant significantincreases increasesininexposure exposureofof ibrutinibare areexpected expectedininpatients patientswith withhepatic hepaticimpairment. impairment.Patients Patientswith withserum serumaspartate aspartatetransaminase transaminase ibrutinib ibrutinib ibrutinibare areexpected expectedininpatients patientswith withhepatic hepaticimpairment. impairment.Patients Patientswith withserum serumaspartate aspartatetransaminase transaminase (AST/SGOT)ororalanine alaninetransaminase transaminase(ALT/SGPT) (ALT/SGPT)≥ 3.0 ≥ 3.0x upper x upperlimit limitofofnormal normal(ULN) (ULN)were wereexcluded excludedfrom from (AST/SGOT) (AST/SGOT) (AST/SGOT)ororalanine alaninetransaminase transaminase(ALT/SGPT) (ALT/SGPT)≥ 3.0 ≥ 3.0x upper x upperlimit limitofofnormal normal(ULN) (ULN)were wereexcluded excludedfrom from IMBRUVICAclinical clinicaltrials. trials.There Thereisisinsufficient insufficientdata datatotorecommend recommenda adose doseofofIMBRUVICA IMBRUVICAininpatients patients IMBRUVICA IMBRUVICA IMBRUVICAclinical clinicaltrials. trials.There Thereisisinsufficient insufficientdata datatotorecommend recommenda adose doseofofIMBRUVICA IMBRUVICAininpatients patients withbaseline baselinehepatic hepaticimpairment impairment[see [seeClinical ClinicalPharmacology Pharmacology(12.3) (12.3)ininfull fullPrescribing PrescribingInformation]. Information]. with with withbaseline baselinehepatic hepaticimpairment impairment[see [seeClinical ClinicalPharmacology Pharmacology(12.3) (12.3)ininfull fullPrescribing PrescribingInformation]. Information]. Femalesand andMales MalesofofReproductive ReproductivePotential: Potential:Advise Advisewomen womentotoavoid avoidbecoming becomingpregnant pregnantwhile while Females Females Femalesand andMales MalesofofReproductive ReproductivePotential: Potential:Advise Advisewomen womentotoavoid avoidbecoming becomingpregnant pregnantwhile while takingIMBRUVICA IMBRUVICAbecause becauseIMBRUVICA IMBRUVICAcan cancause causefetal fetalharm harm[see [seeUse UseininSpecific SpecificPopulations]. Populations]. taking taking takingIMBRUVICA IMBRUVICAbecause becauseIMBRUVICA IMBRUVICAcan cancause causefetal fetalharm harm[see [seeUse UseininSpecific SpecificPopulations]. Populations]. PATIENTCOUNSELING COUNSELINGINFORMATION INFORMATION PATIENT PATIENT PATIENTCOUNSELING COUNSELINGINFORMATION INFORMATION SeeFDA-approved FDA-approvedpatient patientlabeling labeling(Patient (PatientInformation) Information) See See SeeFDA-approved FDA-approvedpatient patientlabeling labeling(Patient (PatientInformation) Information) Hemorrhage: • • Hemorrhage: • • Hemorrhage: Hemorrhage: Informpatients patientsofofthe thepossibility possibilityofofbleeding, bleeding,and andtotoreport reportany anysigns signsororsymptoms symptoms(blood (bloodininstools stools Inform Inform Informpatients patientsofofthe thepossibility possibilityofofbleeding, bleeding,and andtotoreport reportany anysigns signsororsymptoms symptoms(blood (bloodininstools stools urine,prolonged prolongedororuncontrolled uncontrolledbleeding). bleeding).Inform Informthe thepatient patientthat thatIMBRUVICA IMBRUVICAmay mayneed needtotobebe ororurine, ororurine, urine,prolonged prolongedororuncontrolled uncontrolledbleeding). bleeding).Inform Informthe thepatient patientthat thatIMBRUVICA IMBRUVICAmay mayneed needtotobebe interruptedforformedical medicalorordental dentalprocedures procedures[see [seeWarnings Warningsand andPrecautions]. Precautions]. interrupted interrupted interruptedforformedical medicalorordental dentalprocedures procedures[see [seeWarnings Warningsand andPrecautions]. Precautions]. Infections: • • Infections: • • Infections: Infections: Informpatients patientsofofthe thepossibility possibilityofofserious seriousinfection, infection,and andtotoreport reportany anysigns signsororsymptoms symptoms(fever, (fever, Inform Inform Informpatients patientsofofthe thepossibility possibilityofofserious seriousinfection, infection,and andtotoreport reportany anysigns signsororsymptoms symptoms(fever, (fever, chills)suggestive suggestiveofofinfection infection[see [seeWarnings Warningsand andPrecautions]. Precautions]. chills) chills) chills)suggestive suggestiveofofinfection infection[see [seeWarnings Warningsand andPrecautions]. Precautions]. Renaltoxicity: toxicity: • • Renal • • Renal Renaltoxicity: toxicity: Informpatients patientsofofthe thepossibility possibilityofofrenal renaltoxicity. toxicity.Advise Advisepatients patientstotomaintain maintainadequate adequatehydration hydration Inform Inform Informpatients patientsofofthe thepossibility possibilityofofrenal renaltoxicity. toxicity.Advise Advisepatients patientstotomaintain maintainadequate adequatehydration hydration [seeWarnings Warningsand andPrecautions]. Precautions]. [see [see [seeWarnings Warningsand andPrecautions]. Precautions]. Secondprimary primarymalignancies: malignancies: • • Second • • Second Secondprimary primarymalignancies: malignancies: Informpatients patientsthat thatother othermalignancies malignancieshave haveoccurred occurredininpatients patientswho whohave havebeen beentreated treatedwith with Inform Inform Informpatients patientsthat thatother othermalignancies malignancieshave haveoccurred occurredininpatients patientswho whohave havebeen beentreated treatedwith with IMBRUVICA,including includingskin skincancers cancersand andother othercarcinomas carcinomas[see [seeWarnings Warningsand andPrecautions]. Precautions]. IMBRUVICA, IMBRUVICA, IMBRUVICA,including includingskin skincancers cancersand andother othercarcinomas carcinomas[see [seeWarnings Warningsand andPrecautions]. Precautions]. Embryo-fetaltoxicity: toxicity: • • Embryo-fetal • • Embryo-fetal Embryo-fetaltoxicity: toxicity: Advisewomen womenofofthe thepotential potentialhazard hazardtotoa afetus fetusand andtotoavoid avoidbecoming becomingpregnant pregnant[see [seeWarnings Warnings Advise Advise Advisewomen womenofofthe thepotential potentialhazard hazardtotoa afetus fetusand andtotoavoid avoidbecoming becomingpregnant pregnant[see [seeWarnings Warnings andPrecautions]. Precautions]. and and andPrecautions]. Precautions]. Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and • • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and • • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and thatthe thecapsules capsulesshould shouldbebeswallowed swallowedwhole wholewith witha aglass glassofofwater waterwithout withoutbeing beingopened, opened,broken, broken, that that thatthe thecapsules capsulesshould shouldbebeswallowed swallowedwhole wholewith witha aglass glassofofwater waterwithout withoutbeing beingopened, opened,broken, broken, chewedatatapproximately approximatelythe thesame sametime timeeach eachday day[see [seeDosage Dosageand andAdministration Administration(2.1) (2.1)ininfull full ororchewed ororchewed chewedatatapproximately approximatelythe thesame sametime timeeach eachday day[see [seeDosage Dosageand andAdministration Administration(2.1) (2.1)ininfull full PrescribingInformation]. Information]. Prescribing Prescribing PrescribingInformation]. Information]. Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon • • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon • • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon possibleononthe thesame sameday daywith witha areturn returntotothe thenormal normalschedule schedulethe thefollowing followingday. day.Patients Patientsshould should asaspossible asaspossible possibleononthe thesame sameday daywith witha areturn returntotothe thenormal normalschedule schedulethe thefollowing followingday. day.Patients Patientsshould should nottake takeextra extracapsules capsulestotomake makeupupthe themissed misseddose dose[see [seeDosage Dosageand andAdministration Administration(2.5) (2.5)ininfull full not not nottake takeextra extracapsules capsulestotomake makeupupthe themissed misseddose dose[see [seeDosage Dosageand andAdministration Administration(2.5) (2.5)ininfull full PrescribingInformation]. Information]. Prescribing Prescribing PrescribingInformation]. Information]. Advise patients of the common side effects associated with IMBRUVICA [seeAdverse AdverseReactions]. Reactions]. • • Advise patients of the common side effects associated with IMBRUVICA [see • • Advise patients of the common side effects associated with IMBRUVICA [see Advise patients of the common side effects associated with IMBRUVICA [seeAdverse AdverseReactions]. Reactions]. Directthe thepatient patienttotoa acomplete completelist listofofadverse adversedrug drugreactions reactionsininPATIENT PATIENTINFORMATION. INFORMATION. Direct Direct Directthe thepatient patienttotoa acomplete completelist listofofadverse adversedrug drugreactions reactionsininPATIENT PATIENTINFORMATION. INFORMATION. Advise patients inform their health care providers all concomitant medications, including • • Advise patients to to inform their health care providers of of all concomitant medications, including • • Advise Advise patients patients to to inform inform their their health health care care providers providers of of all all concomitant concomitant medications, medications, including including prescriptionmedicines, medicines,over-the-counter over-the-counterdrugs, drugs,vitamins, vitamins,and andherbal herbalproducts products[see [seeDrug Drug prescription prescription prescriptionmedicines, medicines,over-the-counter over-the-counterdrugs, drugs,vitamins, vitamins,and andherbal herbalproducts products[see [seeDrug Drug Interactions]. Interactions]. Interactions]. Interactions]. Advise patients that they may experience loose stools or diarrhea, and should contact their doctor • • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor • • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor Advise patients that they may experience loose stools or diarrhea, and should contact their doctor theirdiarrhea diarrheapersists. persists. if iftheir if iftheir theirdiarrhea diarrheapersists. persists.

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PAGE 26

Olufunmilayo Falusi Olopade, MD, FACP

Internationally Renowned Oncologist Blazes a Trail in Breast Cancer Genetics and Risk Assessment

lufunmilayo Falusi Olopade, MD, FACP, the daughter of an Anglican pastor, was born in Nigeria. Dr. Olopade’s interest in oncology first surfaced while in medical school at the University College Hospital in Ibadan, where she helped care for patients with Burkitt’s lymphoma, which is common in sub-Saharan areas like Nigeria. “I was amazed at the power of chemotherapy to melt these tumors away, often in a matter of days,” Dr. Olopade said during an interview. After completing an internship in medicine, surgery, pediatrics, and obstetrics and gynecology, she served as a medical officer at the Nigerian Navy

Hospital in Lagos. Dr. Olopade noted that in medical school in Nigeria, students were always taught that prevention was better than a cure. This fundamental ideology has, in large part, guided much of Dr. Olopade’s career path.

John E. Niederhuber, MD

NCI or with cancer as a research problem. We were able to fund some unbelievable science in this new program we called Physical Sciences in Oncology,” Dr. Niederhuber stated.

continued from page 25

also recognized for his efforts to enhance the NCI’s intramural programs, the Cancer Center Program, and the SPORE program. He established the CTAC advisory committee to bring the leaders of clinical research together to address the many challenges of clinical research. When asked what accomplishments he was perhaps most excited about, he stated, “I believe there were two that would fall into the category.” Certainly, I enjoyed very much starting the NCI’s Community Cancer Center’s Program (NCCCP) to bring the NCI into a closer relationship with smaller community hospital cancer programs in order to address issues such as disparities and to give greater access to clinical trials to patients that normally did not have such access. When I visited those NCCCP hospitals and saw how much of a difference we were making I was overwhelmed,” he said. “The other program I am most proud of resulted from an opportunity to bring a group of physicists together and to get them excited about working in cancer research. They had never been involved with the

Looking for a Genetic Clue Since opportunities and resources were limited in her native country, Dr. Olopade left Nigeria in 1983 to do postgraduate training at Cook County Hospital and the University of Chicago. It was there that she began to advance her career and seek answers to some of the challenging issues she encountered during her

Pioneering Genomics Research In 2010, Dr. Niederhuber left the NCI for yet another challenging opportunity. “I was introduced to Knox Singleton, the CEO of Inova Health System in northern Virginia. He was trying to figure out where genomics and personalized medicine fit with the future of Inova. In short, he wanted to distinguish Inova as a premier healthcare system, to compete with more established local academic institutions such as Johns Hopkins, for example. I recommended he expand a significant component of Inova’s activities around research, individualized medicine and education,” said Dr. Niederhuber. After several discussions, Mr. Singleton approached Dr. Niederhuber with an offer. “He wanted me to build an institute within the Inova healthcare system centered on genomic medicine. It was a huge challenge, but since I could already see the impact of genomics on the future of

early training. When she came to the United States, Dr. Olopade encountered a va-

riety of larger, solid tumors that were more resistant to chemotherapy than continued on page 27

It wasn’t until the genomic revolution occurred that it was realized that physicians have treated breast cancer as a single disease when, in fact, from five to seven categories of breast cancer exist. Today, our focus is on individualizing breast cancer treatment and learning more about individuals and their specific cancers using genomic analyses. — Olufunmilayo Falusi Olopade, MD, FACP

cancer care, why wouldn’t I want to begin a large-scale predictive genomics project which started enrollment at birth and would follow patients over their lifetime to study a wide range of disorders? So I accepted,” said Dr. Niederhuber. As Executive Vice President and CEO of the Inova Translational Medicine Institute, Dr. Niederhuber is leading a team of clinicians and researchers working on ground breaking genetic studies including the problem of preterm birth, a growing public health issue in the United States that costs our healthcare system more than $28 billion per year. “We have more than 915 families enrolled in this study, where we’ve generated whole genome sequences looking for genetic markers that identify women at high risk of preterm births. We are seeing early results that indicate this information will help lead to better and faster diagnosis and care, as well as preventive therapies,” said Dr. Niederhuber. “We have also started a project which consents families during their early second trimester, follows them through delivery and then continues to follow the baby every six months. Again, this study involves family-trio whole genome sequencing and the integration of clinical

information. We have over 1,250 families enrolled on our way to a longitudinal cohort of 5,000 families,” he said.

What Lies Ahead During his illustrious career, Dr. Niederhuber has received numerous honors including election to the Institute of Medicine. He serves on several advisory boards, and continues to receive honorary professorships, and professional achievement awards. He has authored and coauthored more than 250 publications and edited 9 books, including serving as Editor-in-Chief of the highly regarded reference text Abeloff’s Clinical Oncology, currently in its fifth edition. But Dr. Niederhuber’s career is measured more by what lies ahead than his past accomplishments. “We’re preparing to break ground on a large 350,000 sq. ambulatory cancer center here at the Inova Fairfax Medical Center and to launch new genomic studies of cancer. Our goal is to predict those with a higher risk for cancer and pinpoint the exact therapies that the individual patient needs to successfully treat the disease,” said Dr. Niederhuber, with the energy in his voice indicating his relish for the challenges that lie ahead. n

ASCOPost.com | JUNE 10, 2014 | SUPPLEMENT

Olufunmilayo Falusi Olopade, MD, FACP continued from page 26

the lymphomas that she had treated in medical school. “I became really interested in the fundamental biology of cancer and finding ways to translate genetics research into practical ways to improve care in the clinic,” she said. “We already knew ways to do this effectively in patients with some leukemia and lymphomas, so I wanted to find these answers in solid tumors.” Dr. Olopade’s clinical advisor, Harvey Golomb, MD, suggested that she focus her medical and scientific interests on the field of genetics. From 1989 through 1991, she was a postdoctoral fellow in the laboratory of renowned geneticist Janet Rowley, MD. It was Dr. Rowley’s mentorship that bolstered Dr. Olopade’s conviction that the understanding of the genetic basis of cancer would lead to breakthroughs that the oncology community could use to treat and prevent the disease.

PAGE 27

her experiences in Chicago’s public hospitals, which led to her exploration of the genetic factors behind disparities in breast cancer that affect women of African descent. Picking up on research on the BRCA1 and BRCA2 genes, Dr. Olopade discovered that BRCA mutations are also prevalent among African

American and African women and, in part, explain the worse breast cancer outcomes in this population. She then helped teach oncologists to screen for these red flags in the clinic so that appropriate life-saving interventions could be developed. In 1992 at University of Chicago

NAME: Olufunmilayo Falusi Olopade, MD, FACP TITLE: Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics; Associate Dean, for Global Health; and Director of the Center for Clinical Cancer Genetics at The University of Chicago Medicine

OAK

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)

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com.

MPDL3280A1

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

Primary Endpoint:

(an engineered anti-PDL1 antibody) N=850 Randomized 1:1

Docetaxel

Secondary Endpoints: • Safety: incidence of adverse events

• Overall survival

• Overall response rate • Progression-free survival

MEDICAL DEGREE: MD, University of Ibadan RESEARCH INTERESTS: Cancer genetics, risk assessment, breast cancer, cancer prevention NOTABLE HONORS: National Honor, Officer of the Order of the Niger (2012); Clinical Research Professor Award, American Cancer Society (2010); ASCO– American Cancer Society Award and Lecture (2009); MacArthur Foundation “Genius” Fellowship, John D. and Catherine T. MacArthur Foundation (2005); Doris Duke Distinguished Clinical Scientist and Exceptional Mentor Award (2000); James S. McDonnell Foundation Scholar Award (1992); Young Investigator Award, American Society of Clinical Oncology (1991)

continued on page 28

Now Enrolling

Past Experience Guides Her Future Much of Dr. Olopade’s current work is motivated by her own ancestry and

Hospitals, Dr. Olopade also launched one of the first genetic-testing clinics in the country, the Cancer Risk Clinic. “We encountered some skepticism, but we thought that people are going to want to know whether they had an inherited predisposition to cancer, and

• Duration of response

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Locally advanced or metastatic NSCLC

(stage IIIB, stage IV, or recurrent)

• History of autoimmune disease • Active hepatitis B or hepatitis C

• Representative FFPE tumor specimens

• Prior treatment with docetaxel, CD137 agonists,

• Disease progression during or following

anti-CTLA4, anti-PD1, anti-PDL1 antibodies, or pathway-targeting agents

platinum-containing treatment regimen • Measurable disease, defined by RECIST v1.1 • ECOG performance status of 0 or 1

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.

The ASCO Post | JUNE 10, 2014 | SUPPLEMENT

PAGE 28

Richard Pazdur, MD

Enthusiasm and Vision Guide the Head of FDA’s Oncology Office

n 2005, Richard Pazdur, MD, was named the FDA’s Director of the Office of Hematology and Oncology Products. By any measure, being arbiter of the nation’s oncology drug pipeline is a daunting prospect, but Dr. Pazdur sees it as an opportunity to encourage his talented staff to work for the greater good of our nation’s cancer patients. After assuming this position, he initiated an open-door policy to foster collaboration. “I spend a good part of my day at the office talking to people at every level of the drug evaluation process. FDA staff spend many months involved in the review of an application, with multiple internal interactions involving the more than 50

medical oncologists who work in our office. When a drug is discussed at ODAC [Oncologic Drugs Advisory Committee], it is rare, if ever, that a question or concern arises that we have not already heard before,” said Dr. Pazdur.

A Childhood in a Tight-Knit Community “I grew up in a Chicago suburb called Calumet City, located 25 miles due south from the convention center where ASCO holds its Annual Meeting. It was a large Polish Catholic community. My parents were children of Polish immigrants. My mother was one of nine children, my father one of seven. We all lived within

NAME: Richard Pazdur, MD TITLE: Director of the Office of Hematology and Oncology Products, U.S. Food and Drug Administration MEDICAL DEGREE: MD, Loyola University Stritch School of Medicine, Chicago RESEARCH INTERESTS: Drug development, health-care policy, public health, colorectal cancer NOTABLE HONORS: Public Service Award, American Society of Clinical Oncology (2013); Cancer Research Leadership Award, Friends of Cancer Research (2012); Special Recognition Award, American Society of Clinical Oncology (2009)

Olufunmilayo Falusi Olopade, MD, FACP continued from page 27

when they’ve had cancer, they want to know whether their children or other family members are at risk,” she said.

Genetics Offers the Best Way Forward Dr. Olopade firmly believes that advances in genetics and cancer biomarkers will vastly increase the pace of cancer research. Finding these answers will both reduce the cost of cancer care and yield better treatments. “It wasn’t

until the genomic revolution occurred that it was realized that physicians have treated breast cancer as a single disease when, in fact, from five to seven categories of breast cancer exist. Today, our focus is on individualizing breast cancer treatment and learning more about individuals and their specific cancers using genomic analyses. An important goal is to identify breast cancer while it is local and curable, thus decreasing morbidity and costs,” said Dr. Olopade, speaking to Medscape. In 2005, Chicago’s John D. and Catherine T. MacArthur Foundation awarded Dr. Olopade one of its “Fel-

a few miles of each other, so there was always an aunt or older cousin watching out for you as a kid,” said Dr. Pazdur. Despite the tight-knit community, Dr. Pazdur commented that Calumet City had a past. “In the 1950s, Calumet City was known as “Sin City,” boasting more bars and taverns per square mile than any place in the nation. There were underworld connections from remnants of the Al Capone gang. On the outskirts of our community was a strip called State Street that was lined with after-hour’s bars and seedy men’s clubs,” said Dr. Pazdur. Dr. Pazdur credits an early experience with health care as a catalyst for his career. “When I was in grade school, my father began losing his eyesight and by the time I graduated he was completely blind. I accompanied him to his medical appointments, and much of my childhood was spent in doctor’s offices doing my homework waiting for my dad, so I had an early introduction into the world of medicine,” said Dr. Pazdur. He added, “The experience with my father influenced my decision to become a physician. Losing our breadwinner to blindness had significant emotional and financial effects on the family.”

Profound Influence of Early Mentors

lowship grants.” A large part of the grant was earmarked to advance her work studying cancer genetics in Nigeria and other places in Africa. “I also bought a really warm coat because now I was stuck in Chicago,” said Dr. Olopade in an interview. Dr. Olopade was the recipient of the 2009 ASCO–American Cancer Society Award and Lecture for her extraordinary contributions to the prevention and management of cancer. And in 2011, President Obama appointed Dr. Olopade as one of five new members of the National Cancer Advisory Board (NCAB). Members

of the board advise the Secretary of Health and Human Services and the Director of the National Cancer Institute (NCI). Regarding the NCI, the NCAB gives advice on reviewing and recommending support grants and cooperative agreements following technical and scientific review. Dr. Olopade credits her drive and relentless optimism to her spiritual upbringing in Nigeria. “More than anything, my spiritual discipline has always grounded me. Ever since I was young, it’s helped me to wake up every day wanting to do my best for society, and also for my patients.” n

Dr. Pazdur regards his education as an enriching community experience. He went to the same grade school and high school that his mother and her sisters and most of his cousins attended. “In high school I was editor of the school newspaper and yearbook. I still keep in contact with my journalism teacher, Ms. Beverly Stanislawski. I received an email from her just the other day. I use the skills I learned in her class every day at the FDA, when writing or editing papers and drug application reviews.” After high school, Dr. Pazdur entered Northwestern University in Evanston, Illinois. “During my college years, I was interested in sociology. A sociology professor, Dr. Zena Smith Blau, impressed me by her pure love of academics. I distinctly remember her telling me that to be successful in academics you need enthusiasm and a vision for what you’re doing. The enthusiasm of her lectures and her interest in sociology mesmerized me. Zena Blau and her husband were major figures in the national and international academic world of sociology, and their work is still cited in continued on page 30

N OW E N RO L L I N G

Pivotal Trial in gpNMBOverexpressing Metastatic Triple-Negative Breast Cancer • METRIC is a pivotal, open-label, prospectively controlled, randomized trial of glembatumumab vedotin in glycoprotein NMB-overexpressing triple-negative breast cancer (TNBC)

• gpNMB is an internalized transmembrane glycoprotein that is frequently overexpressed in TNBC tumors – gpNMB overexpression is associated with reduced recurrence-free survival in TNBC • Glembatumumab vedotin is an investigational antibody-drug conjugate (ADC) that targets tumors

1-4

Patients with metastatic TNBC overexpressing gpNMB* N=300

*Stratified

2:1 Randomization

expressing gpNMB4,5

Glembatumumab vedotin 1.88 mg/kg IV Day 1 of 21-day cycles Treat until unacceptable toxicity or disease progression Capecitabine 1250 mg/m2 BID Days 1-14 of 21-day cycles

by prior receipt of 0 or 1 line of therapy for advanced disease and anthracycline response.

Key Trial Endpoints

• Primary: Objective response rate (ORR) and/or progression-free survival (PFS) • Secondary: Duration of response (DOR) and overall survival (OS) Key Inclusion Criteria

• No more than one prior chemotherapy-containing regimen for advanced breast cancer • Prior receipt of anthracycline-containing chemotherapy in any setting, with no further anthracycline therapy indicated

• Taxane resistance after neoadjuvant/adjuvant therapy or in the advanced disease setting

For more information, visit www.metricstudy.com, www.clinicaltrials.gov/show/NCT01997333, or e-mail info@celldex.com.

References: 1. Weterman MAJ, Ajubi N, van Dinter IMR, et al. Int J Cancer. 1995;60:73-81. 2. Singh M, Del Carpio-Cano F, Belcher JY, et al. Crit Rev Eukaryot Gene Expr. 2010;20(4):341-357. 3. Rose AAN, Grosset A-A, Dong Z, et al. Clin Cancer Res. 2010;16(7):2147-2156. 4. Maric G, Rose AAN, Annis MG, Siegel PM. Onco Targets Ther. 2013;6:839-852. 5. Burris HA III. 2013 ASCO Educ Book. 2013:e99-e102. ©2014 Celldex Therapeutics, Inc.

MT1

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Richard Pazdur, MD continued from page 28

the literature,” said Dr. Pazdur. “When at Northwestern, I was contemplating a career in sociology. I’d worked with Dr. Blau on sociological projects examining the assimiliation of the Polish-American community in Chicago. Dr. Blau’s emphasis on enthusiasm and vision in an academic life has had a profound influence on my career to this day,” said Dr. Pazdur.

Decisions in Medical School Deciding on a career in medicine, but needing to stay close to home to help his family, Dr. Pazdur attended Loyola Stritch School of Medicine in Chicago. “Because of my father’s illness, my parents depended on me for help around the house, which was one reason I chose to stay in Chicago for medical school. When I interviewed there, I really had a sense that the faculty took a personal interest in every medical student. The spirit of the school exemplified a Jesuit philosophy of combining the academic and personal growth of the student with a personal commitment to improve society. This commitment influenced my work at the FDA. It isn’t a coincidence that we have four Loyola Stritch School of Medicine graduates who work in our oncology office at the FDA. This probably reflects the Jesuit commitment to professional service to the public,” said Dr. Pazdur. Dr. Pazdur noted that upon entering medical school, he initially wanted to become a psychiatrist. “I changed my mind and decided to become a cardiologist. I did a 4-month rotation in cardiac cath lab and did quite a few catheterizations. I was accepted to a cardiology fellowship; however, one of my last internal medicine rotations was in medical oncology and so I became interested in cancer care,” said Dr. Pazdur.

“I did my medical oncology solid tumor training at Rush-PresbyterianSt. Luke’s Medical Center and I did an additional year of hematology at the University of Chicago. But oncology in Chicago at that time was very different than now. There were no National Cancer Institute [NCI] phase I or phase II drug development programs in Chicago, so I referred patients to Wayne State in Detroit for these investigational drugs, since Wayne State had a contract with the NCI. During this time I was offered a position at Wayne State. I accepted the position and moved to Detroit in 1982, the same year I married my wife, Mary, who is an oncology nurse practitioner. Because time and money were tight, we spent our honeymoon in Detroit planning our move from Chicago,” said Dr. Pazdur.

Career at MD Anderson Dr. Pazdur worked at Wayne State University where he became the director of the fellowship program. “I trained many fellows who went on to become nationally recognized in oncology, which is still a source of pride. And after about 6 years at Wayne State, I applied for a position at MD Anderson Cancer Center in Houston,” said Dr. Pazdur. After interviewing with Dr. Bernard Levin, whom he’d met previously while at the University of Chicago, Dr. Pazdur accepted the position in gastrointestinal oncology at MD Anderson and moved with his wife to Houston. He spent 12 years at MD Anderson, once again serving as Director of the Fellowship Program. “Similar to my Wayne State experience, many of my fellows went on to very successful careers. I’m very proud of their accomplishments. I truly enjoyed every day I spent at MD Anderson, never dreaming that I’d leave the institution. However, I collaborated with several drug companies as a clinical investigator and I had the opportunity to present

my clinical trials to the FDA. During these visits, I began to understand the vital role the agency has in drug development,” said Dr. Pazdur.

A Vision for the FDA He continued, “I had a vision for the FDA to become a much greater participant in drug development and in the overall field of oncology. It was important to break down the walls that separate the FDA from its stakeholders and enhance the dialogue within the oncology community. In addition, my vision was to have our oncology reviewers develop expertise in specific malignancies. This led to the creation of our oncology office organized in disease-specific teams to review applications. Another goal was to have a more unified program since on-

to the market. “We’ve worked with ASCO, AACR, ASH and various patient advocacy groups. We have conducted workshops both at the Annual Meeting and throughout the year to inform the community about our current and future initiatives. Developing cancer agents is more complex than other drugs because we are dealing with a different risk-benefit profile. Our drugs are often toxic, and our patients have different expectations regarding the timeliness of approval and the kind of side effects they’re willing to accept. So, it is important that the process is as transparent as possible,” said Dr. Pazdur. Drug approval is an exhaustive iterative process requiring collaboration among multiple parts of the FDA. Cancer patients need new drugs, so the approval process is one of urgen-

Developing cancer agents is more complex than other drugs because we are dealing with a different risk-benefit profile. Our drugs are often toxic, and our patients have different expectations regarding the timeliness of approval and the kind of side effects they’re willing to accept. So, it is important that the process is as transparent as possible. — Richard Pazdur, MD

cology applications were previously dispersed between different offices and centers at the FDA. This was in part accomplished with the establishment of the oncology office in 2005, as well as the oncology program, which coordinates both internal FDA oncology activities and our activities with stakeholders, ” said Dr. Pazdur. Dr. Pazdur also stressed that his vision included a need to explain to the oncology community exactly how the FDA works to bring cancer drugs

cy tempered by necessary resolve to make sure that every drug that goes to market has proven benefit. Dr. Pazdur anticipates a bright future ahead. “We’re seeing a transformation in the way we develop and deliver cancer therapies. These are very exciting times.” Are there any regrets? “Yes, only one though. Someday in the future I’ll have to retire, and I won’t be able to participate in this vital process that will ultimately lead to cures in many cancers,” said Dr. Pazdur. n

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H.M. (Bob) Pinedo, MD, PhD

Understanding the Relationship Between the Lab and the Clinic is Key to 2014 Karnofsky Memorial Award Honoree’s Success

he island nation of Curaçao is nestled in the southern Caribbean Sea off the Venezuelan coast. Curaçao was first settled by the Arawaks, an Amerindian people that inhabited the island for hundreds of years before the arrival of Europeans. Amid one wave of settlers from Portugal and Spain that landed on the island in 1715 were the descendants of this year’s David A. Karnofsky Memorial Award honoree, H.M. (Bob) Pinedo, MD, PhD. Dr. Pinedo remembered a wonderful childhood on Curaçao, surrounded by breathtaking natural beauty. “I grew up in a Jewish neighborhood in Curaçao. The synagogue is the oldest in the Western hemisphere. We later moved out of town to a plantation house when I was in high school,” said Dr. Pinedo. “At that time in Curaçao we had very good Dutch teachers. I attended the Pieter Stuyvesant High School, named for the Director-General of New Netherland—which was later renamed New York—in the 1600s,” he continued. “Our schools emphasized language; English, Spanish, French, and German were mandatory. Curaçao is multilingual, but it has its own language called Papiamentu, which is a mixture of Spanish, Portuguese, Dutch, and Africian. At

school it was all Dutch, but at home we spoke Papiamentu.”

The Road to Medicine However, there were no universities in Curaçao at that time, so after graduating high school Dr. Pinedo had to make a decision. He had two choices before him: attend university in the United States or Holland. “My cousins decided on the States, but our family went to Holland where I initially attended Delft University of Technology. I had a terrific chemistry teacher in high school who really got me excited about the field. When I entered Delft, I majored in chemistry, but I found it too dry and I switched to medicine at Leiden University, which is the oldest univerity in the Netherlands. My interest in chemistry would resurface later in my career when I worked in drug development,” said Dr. Pinedo. He continued, “I think my decision to study medicine was influenced, in part, by family illness. My grandmother had breast cancer. She spent her last year of life in our home and being confronted with cancer care daily certainly affected my thoughts about becoming a doctor.” Dr. Pinedo explained that when he was attending university, an undergraduate medical program was 7 years, after which you chose a specialty. “I

NAME: H.M. (Bob) Pinedo, MD, PhD TITLE: Professor Emeritus of VU University Medical Center (VUmc); Consultant to the Board of the VUmc Cancer Center Amsterdam MEDICAL DEGREE: MD, Leiden University; PhD, Leiden University RESEARCH INTERESTS: Translational research, drug development NOTABLE HONORS: David A. Karnofsky Memorial Award (2014); Netherlands American Foundation Award (2012); Commander in the order of Orange Nassau (2008); Spinoza Prize, The Netherlands Organisation for Scientific Research (1997); Josef Steiner Award, The Dr. Josef Steiner Cancer Research Foundation (1995); Two Decorations awarded from the Netherlands Knight in the order of the Netherlands Lion (1995)

went into an internal medicine program. During that time I also did my doctoral work. Actually, my PhD was not in cancer, but in nephrology. After

he was a terrific mentor who clearly influenced my career in research. We remain close friends to this day. I had 2 excellent years of scientific research

One of the secrets to my research success was that basic scientists understood how we explained things to patients as they entered phase I trials. Understanding is the basis of trust and collaboration. — H.M. (Bob) Pinedo, MD, PhD

12 years at Leiden, I graduated at 29 years old with my MD and PhD,” said Dr. Pinedo.

Confronting Unmet Needs in Cancer Care After graduating, Dr. Pinedo was offered a position as Chief of Residents at the University Medical Center Utrecht. “When I arrived at Utrecht in 1972, it was clear that the cancer patients on my ward were neglected. Not purposely, but oncology was not a specialty at the time, so many doctors didn’t know how to treat these very sick patients, especially those with metastatic disease. The new drugs, like [doxorubicin], were coming along, but they weren’t widely used. Nephrology was well taken care of at the university, and I didn’t see a real challenge in that specialty, so I decided to go into oncology where there were many unmet needs,” said Dr. Pinedo. He went right to work, creating a division of oncology within the internal medicine department. Four years later, seeking to gather more information and knowledge about the nascent field of oncology, Dr. Pinedo journeyed to the United States, determined to work at the National Cancer Institute (NCI). “I got a position as a visiting scientist in the Division of Pharmacology. Dr. Bruce Chabner headed the division;

at the NCI, doing pharmacology of methotrexate. I also published five papers in leading journals. I worked very long hours, a habit I kept during my whole career,” said Dr. Pinedo. Dr. Pinedo was quick to point out that his workaholic regimen in the lab and clinic would have been impossible without the full support of his wife whom he met while working at the NCI. “My wife is originally from Washington, DC. She was an intensive care nurse so she understood the kind of dedication it took for me to conduct research and see patients.”

The Importance of Understanding In 1976, Dr. Pinedo returned to the University of Utrecht and, with the help of his friend Dr. Chabner, set up a research laboratory to continue his pharmacologic work with methotrexate. Three years later he was offered a position by the administration of VU University Amsterdam. “I moved to Amsterdam and set up another laboratory in my oncology department. The lab was actually in my clinic. One of my rules was that any clinician on my staff had to have worked 2 years in a lab. Also, the biologists and chemists in my lab were required to work continued on page 32

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H.M. (Bob) Pinedo, MD continued from page 31

at least 1 week in the clinic so they could truly understand the intimate relationship between patient and research. I think one of the secrets to my research success was that basic scientists understood how

we explained things to patients as they entered a phase I trials. Understanding is the basis of trust and collaboration, which is why I titled my Karnofsky Lecture “Understanding,” said Dr. Pinedo.”

An Obligation to Give Back The subject of the doctor-human-

itarian is part of the philosophical framework of Dr. Pinedo’s approach to medicine. “One reason I am honored to be this year’s recipient of the David A. Karnofsky Memorial Award is because more than just a great doctor, David Karnofsky was a humanitarian who stimulated those around him to be bet-

Building a Pipeline of Possibilities in Oncology For more than 25 years, Gilead has worked to develop medicines in areas of unmet medical need for patients worldwide. We are now conducting approximately 15 ongoing clinical trials in oncology, studying 4 small molecules and 2 monoclonal antibodies. Our pipeline comprises novel, targeted investigational agents across many pathways to treat a wide range of cancers. Together with our scientific and medical partners, we share a common focus—advancing the discovery, development, and delivery of new medications for people around the world.

Learn more about our oncology pipeline at http://www.gilead.com/ research/pipeline

ter researchers and doctors. Throughout my career in the lab and the clinic, I’ve always maintained a relationship with the patients that goes beyond treating cancer,” said Dr. Pinedo. He continued, “I retired a few years ago because in Holland, retirement is required at age 65. But I’m as busy as I was prior to official retirement. Now I divide my time between Holland and Curaçao, and after serving Holland for 50 years I wanted to do certain things that were neglected on the island. There was no cancer screening so I set up breast and cervical cancer screening programs, which are running very well,” said Dr. Pinedo.

Continued Interests “I’ve been involved in translational research throughout my career. In fact, about 7 years ago I co-founded the Center for Translational Molecular Medicine in the Netherlands. It’s a publicly-privately funded center that has €400 million available for grants,” said Dr. Pinedo. Asked about his late-career research pursuits, Dr. Pinedo responded, “My current interests are in epigenetics and immunology. In fact, I was a pioneer in the field of immunology. In 1999, I published a paper in The Lancet that described using an autologous tumor cellBCG vaccine on patients with Dukes’ B colon cancer. We used it as adjuvant treatment, and it worked.” During the time he spends in Holland, Dr. Pinedo chairs an international advisory board at VU University Medical Center Amsterdam to build an imaging center. “The imaging center takes up a lot of time, but I still see patients. I see patients outside of the university, partly second-opinion patients and also those that I’ve been following for more than 10 years. It’s a busy schedule,” Dr. Pinedo said. Even after such a long and illustrious career, Dr. Pinedo’s schedule allows little free time for hobbies. But while in Curaçao he takes advantage of the therapeutic waters surrounding the island. “I have scoliosis, and swimming in the tropical sea is very soothing. There’s also a naturalist there we call Dutch who has a submersible that dives to 1,000 feet. He collects samples of the algae along the undersea cliff. I go down in the ocean with "Dutch" once in a while. Other than that, my life centers on my work. My wife helps me keep track of my schedule,” said Dr. Pinedo. n

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David A. Karnofsky: The Man Behind the Karnofsky Memorial Award and Lecture

Early Contributions to Cancer Research Helped Establish Oncology as a Medical Discipline

avid A. Karnofsky, MD, dedicated himself to the pursuit of scientific excellence and the investigation of more effective therapies for cancer for nearly 30 years, from the time he was a young resident at the Collis P. Huntington Memorial Hos-

Disciplined Approach to Oncology Dr. Karnofsky’s meticulous attention to the clinical evaluation of drugs, which brought hard-data reliant objectivity and discipline to cancer research, is one reason he is credited with helping establish the field of oncology as a specific medical discipline. His creation in 1949 of the Karnofsky Performance Scale (along with another early pioneer of cancer chemotherapeutics, Joseph H. Burchenal, MD) is another.

Modern Age of Chemotherapy David A. Karnofsky, MD

pital for Cancer Research of Harvard University, until his death from lung cancer on August 31, 1969. Dr. Karnofsky’s early research discoveries at Memorial Hospital– Sloan-Kettering Institute (now Memorial Sloan Kettering Cancer Center) in New York led to the development of numerous chemotherapeutics, including the first oral alkylating agent triethylenemelamine, the glutamine antagonists azaserine (NSC 742) and 6-diazo-5-oxo-L-norleucine (DON), and two breakthrough agents widely used today in the treatment of childhood leukemias, daunorubicin and asparaginase (Elspar).

In 1942, Dr. Karnofsky began studying the biological activities of mustard gas, a chemical warfare agent, at the Mount Desert Island Biological Labo-

tard (mechlorethamine [Mustargen]), which had been found to be effective, albeit briefly, against lymphoma. His commanding officer at the time was C.P. Rhodes, MD, on leave as Medical Director of the Memorial Hospital for Cancer. At the end of World War II, in 1945, Dr. Karnofsky joined Dr. Rhodes at Memorial Hospital and, with Dr. Burchenal, launched the first organized clinical chemotherapy program in the country, and continued studies of nitrogen mustard and other antitumor cancer drugs. “It was these experiences, many of us believe, that initiated the modern era of cancer chemotherapy,” said Irwin H. Krakoff, MD, in his remarks at the 24th Annual David A. Karnofsky Memorial

The relevant matter in examining any form of treatment is not the reputation of its proponent, the persuasiveness of his theory, the eminence of its lay supporters, the testimony of patients, or the existence of public controversy, but simply … does the treatment work? ratory in Maine. He continued that research after joining the Army Chemical Warfare Service, then a branch of the U.S. Army. It was while in the Army that Dr. Karnofsky became interested in the antineoplastic activity of nitrogen mus-

Lecture, which were later published in the Journal of Clinical Oncology.1

Honoring the Early Cancer Pioneers After Dr. Karnofsky’s death, a group

of his friends donated money to ASCO to fund a yearly lecture at ASCO’s Annual Meeting, and in 1970, ASCO launched a permanent memorial to honor Dr. Karnofsky’s body of work with the David A. Karnofsky Memorial Award and Lecture. The Award, which is presented at ASCO’s Annual Meeting, recognizes oncologists who have made outstanding contributions in the areas of cancer research, diagnosis, and/or treatment and is the Society’s highest scientific honor. The 2014 recipient of the Karnofsky Award is H.M. (Bob) Pinedo, MD, PhD, a pioneer in the field of immunotherapy. At the time of his death, Dr. Karnofsky was Chief of the Medical Oncology Service and Head of the Division of Chemotherapy Research at the Sloan-Kettering Institute for Cancer Research, Professor of Medicine at Cornell University Medical Center, and a physician at The New York Hospital. The 2014 Karnofsky lecture was presented on May 31, 2014, at the ASCO Annual Meeting. n Reference 1. Krakoff IH: The 24th annual David A. Karnofsky memorial lecture. Progress and prospects in cancer treatment: The Karnofsky legacy. J Clin Oncol 12:432-438, 1994.

Recipients of the David A. Karnofsky Memorial Award and Lecture 2014: H.M. (Bob) Pinedo, MD, PhD 2013: Martine J. Piccart, MD, PhD 2012: Kanti R. Rai, MD 2011: Kenneth Anderson, MD 2010: Daniel D. Von Hoff, MD, FACP 2009: Clara D. Bloomfield, MD 2008: V. Craig Jordan, OBE, PhD, DSc 2007: Robert A. Kyle, MD, MACP 2006: Dennis J. Slamon, MD, PhD 2005: Charles L. Sawyers, MD 2004: Larry Norton, MD 2003: Brian J. Druker, MD

2002: John Mendelsohn, MD 2001: Charles A. Coltman, Jr., MD 2000: Waun Ki Hong, MD 1999: Ronald Levy, MD 1998: Kathleen Foley, MD 1997: Alfred G. Knudson, MD, PhD 1996: Judah Folkman, MD 1995: Bert Vogelstein, MD 1994: Samuel Hellman, MD 1993: Irwin Krakoff, MD 1992: Joseph Bertino, MD 1991: Steven Rosenberg, MD

1990: Lawrence H. Einhorn, MD 1989: Gianni Bonadonna, MD 1988: Robert C. Gallo, MD 1987: Janet D. Rowley, MD 1986: Charles G. Moertel, MD 1985: Bruce A. Chabner, MD 1984: Saul A. Rosenberg, MD 1983: E. Donnall Thomas, MD 1982: James F. Holland, MD 1981: Emil Frei, III, MD 1980: Bernard Fisher, MD 1979: Vincent T. DeVita, Jr., MD

1978: Donald Pinkel, MD 1977: Frank J. Rauscher, Jr., PhD 1976: Emil J. Freireich, MD 1975: Henry Rappaport, MD 1974: Joseph H. Burchenal, MD 1973: Robert A. Good, MD, PhD, DSc, FACP 1972: Henry S. Kaplan, MD 1971: Sidney Farber, MD 1970: Sir Alexander Haddow

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About the Writer

onald Piana is an independent writer and reporter with more than 15 years of experience in oncology communications and publishing. In addition to the profiles published

in this special anniversary issue of The ASCO Post, Ron has written more than 100 articles, interviews, and profiles for leading medical publications. A native New Yorker, in his

WHAT CREATES A GREAT SURVIVAL CURVE?

earlier years Ron lived in Paris before traveling worldwide as a merchant seaman, later working as a laborer, truck driver, and chef. His life-long boxing aspirations were halted after going a round in Gleason’s Gym with the legendary Roberto Duran on “one thrilling but boxing career–ending day.” Ron is also a writer of fiction and is currently working on his second novel. He lives in Huntington, New York with his wife Kristine.

■

L E V I N E C A N C E R INS TITUTE’S

About the Artist

eith Witmer received his Bachelor’s degree in Fine Arts from Otis/Parsons School of Design. He subsequently launched his career in advertising and publication with a commanding presence, initially using pen and ink and scratchboard mediums. Working with clients such as FedEx, Apple Computer, Hewlett-Packard,

MO DEL OF C ARE

Hematologic Oncology and Blood Disorders Program The Hematologic Oncology and Blood Disorders program at Levine Cancer Institute, part of Carolinas HealthCare System, has built its foundation not only on providing excellent care, but on changing the delivery model of that care. Reaching patients – no matter where they live – through the newest treatments delivered by world-class oncologists has been its priority since day one. The result? Improving the survival curve and changing the course of cancer itself.

CLINICAL EXPERTISE More than a dozen of the Institute’s nationally recruited physicians, from the top cancer programs in the country, are dedicated to hematology and blood cancers. This team of subspecialists provides cutting-edge care and expertise in specific malignancies, including leukemia, plasma cell disorders, transplantation and lymphoma, and non-malignant hematology. Our Leadership Team Ed Copelan, MD, FACP CHAIR

Hematologic Oncology and Blood Disorders program

Belinda Avalos, MD VICE-CHAIR

Hematologic Oncology and Blood Disorders program

TRANSPLANTATION In addition to multiple care locations across the Carolinas, Levine Cancer Institute opened a new transplantation unit in early 2014. Staffed by some of the world’s foremost experts in hematological malignancies, the 16-bed unit also includes:

CLINICAL TRIALS AND RESEARCH Physicians at the Institute participate in leading-edge clinical trials related to most types of blood cancers and blood disorders. The Institute is expected to be one of the leading enrolling sites for blood cancer clinical trials in the country by the end of 2014. Our specialized Phase 1 unit provides:

• Six-bed apheresis unit, adjacent to the transplant unit, to obtain stem • First-in-man clinical trials testing cells for peripheral blood transplants novel therapies and treatment options • Four ICU beds integrated with Carolinas HealthCare System’s • Access to high-quality care, and virtual ICU, which provides 24/7 expertise from physicians who oversight of all patients subspecialize in treating specific • Patient support, including familydiseases friendly patient rooms, an exercise • The ability to enroll patients in room, a laundry room and lounge the newest, most promising trials, • Patient navigation whether that patient lives down the street or out of state, through the Institute’s decentralized model of care

For more information, visit CarolinasHealthCare.org/ModelOfCare

Keith Witmer

and National Geographic, Keith refined his skills and developed new illustration techniques which combined both traditional and digital mediums. Today, Keith works exclusively with his trusty Stylus and Wacom Tablet to execute every illustration. Keith addresses every portrait with absolute professionalism and uncompromising attention to detail. When Keith is not at the drawing board, he can be found on his mountain bike or in a sushi bar somewhere in the beautiful city of Portland, Oregon. n

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

considered for publication

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In Memoriam

Peter Jacobs, MD, PhD 1934–2013

eter Jacobs, MD, PhD, regarded as the father of hematology in his native country of South Africa, began each day at 3 AM in the gym. During his workout, Dr. Jacobs would routinely call the nursing staff for updates on patients in his ward. Before sunup, Dr. Jacobs was on his way to the hospital. “Every morning before leaving for work, Peter would read from the Bible, which he’d already read coverto-cover. Then he would pray to the ‘Big Hematologist’ upstairs for guidance, patience, and understanding for the day that lay ahead,” said Dr. Jacobs’ wife, Di Jacobs. Dr. Jacobs was born March 21, 1934, in Pretoria, South Africa, the year the Status of the Union Act was passed, declaring South Africa “a sovereign, independent state” and removing the last vestiges of British rule. Dr. Jacobs then moved with his family to Rhodesia— now Zimbabwe—where he completed his high school education at the Prince Edward School in Salisbury.

of the University of Nebraska Medical Center, Omaha, wrote a letter supporting the nomination of Dr. Jacobs for Mastership in the American College of Physicians, in which he opened a candid window into Dr. Jacobs’ youth. He noted, “There is probably no other candidate this year for Mastership in the American College of Physicians who earned the money to attend medical school by working as a game control officer, whose responsibility it was to track down and

1960, through a nursing friend of mine. We became engaged the same week we met each other and were married 2 months later on January 21, 1961,” said Mrs. Jacobs. It soon became clear that an academic career was in Dr. Jacobs’ future. He was appointed as a Senior Research Bursar of the Council for Scientific and Industrial Research (CSIR) Iron and Red Cell Metabolism Unit while working toward his MD at the University of the Witwa-

With a career spanning the entire history of hematology and medical oncology in South Africa from the 1960s until now, [Dr. Jacobs] worked tirelessly to bring the best of modern health care to those with hematologic malignancies….All of us should aspire to emulate his compassion for patients and his commitment to education and learning. — Joseph M. Connors, MD

An Early Passion for Research From his days in high school and throughout much of his undergraduate study, Dr. Jacobs worked as a lab assistant and technician, which nurtured his passion for clinical research. In 1949, he began his working career as a medical laboratory technologist at the Pasteur Institute and Government Health Laboratory in Salisbury. Two years later, he was appointed Chief Medical Laboratory Technologist at GV Blaine Laboratories in the same city. In 1954, he returned to South Africa to study medicine at the University of the Witwatersrand in Johannesburg, graduating in 1959. Dr. Jacobs also had a deep love of nature and worked part-time as a game warden to help pay for his education. In March 2010, his associate and friend, James O. Armitage, MD,

destroy dangerous animals that were killing humans or ruining crops.” In an interview, Dr. Armitage elaborated on Dr. Jacobs’ adventurous past. “Peter had great stories about being a game control officer. One time he tracked a leopard that had been marauding the nearby villages. The big cat had gone into a cave, so Peter followed with a flashlight and a shotgun, because it would be a close-quarters shot. He said that he was concerned that the leopard might get the jump on him in the dark, but Peter got him first.”

A Man of Decision After his internship at Johannesburg General Hospital in 1960, Dr. Jacobs met the woman who would almost overnight become his wife. “Peter and I met on November 20,

tersrand, which he received in 1966. In 1967, he left for the United States to become a Senior Research Fellow in Hematology in the Department of Medicine at the University of Washington in Seattle, where he worked until 1969. He then returned to South Africa, where his research on iron supply and hemoglobin synthesis earned him a PhD from the University of the Witwatersrand in 1974.

The Father of South African Hematology Dr. Jacobs became the founding Head of the Hematology Department at the University of Cape Town, a post he held until 1994. He then continued in private practice and developed the world renowned Bone Marrow Trans-

plant Unit at Cape Town’s Constantiaberg Hospital, which he headed until his final retirement in February 2011. Some of Dr. Jacobs’ most groundbreaking achievements occurred during his tenure as Foundation Professor of Hematology at the University of Cape Town, Chief Specialist and Consultant Hematologist at Groote Schuur Hospital, and Director of the Cape Town Leukemia Centre, and rotating Chairperson of the Division of Pathology. Fellow South African and mentee, Matthew Seftel, MD, MBChB, MPH, MRCP, FRCPC, of the University of Manitoba, said, “Dr. Jacobs’ major achievement was the introduction of experimental and clinical blood and bone marrow transplantation. Throughout his career, he trained and mentored countless physicians and basic scientists, and in the midst of political and economic instability in South Africa, many of these trainees progressed to academic careers worldwide.” “His longstanding interest in lymphoma was influenced in recent years by the region’s HIV epidemic,” Dr. Seftel continued. “Despite these challenges, he continued to practice medicine with a tireless, orderly, and scholarly approach. Lymphoma experts of international repute regularly attended his biennial South African Lymphoma Study Group meetings. In 2009, the South African Academy of Arts and Science awarded him the centenary medal in recognition of his outstanding national and international academic profile.”

A Rich, Work-Centered Life Dr. Jacobs’ wife, Di, stressed that their whole life revolved around her husband’s academic career, his research, patients, their families, the nurses, students, and colleagues. “He loved to play golf on Saturday afternoons, but with his beeper continually going continued on page 36

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Peter Jacobs, MD, PhD continued from page 35

off during play, it often resulted with him leaving in the middle of a game if a patient needed him. He also loved to play tennis on Sunday mornings, but would only allow himself an hour be-

fore heading back to the hospital to see every patient in the unit. This he did mornings and evenings, 7 days a week,” she said. She continued, “We never managed to go away on vacations, so the only time he broke this routine would be to attend conferences or meetings locally

or overseas, flying back on the next available flight.” Mrs. Jacobs said that her husband would return home from the hospital between 7:00 PM and 8:30 PM every night. After a quick supper, together they would go through any mail, papers, or chapters Dr. Jacobs was writ-

ing. “I would type most of his drafts and work late at night and in the mornings when our sons were at school. The rest of my time was spent with my boys’ schooling, scouts, life-saving, and sport activities. They were both provincial surfers and, as a team judge, I would accompany them to national and provincial surfing events around South Africa,” she said.

A Very Busy Retirement In 2011, Dr. Jacobs retired from clinical patient care to become a consultant and Director of the Hematology Research Group at PathCare. He continued giving weekly tutorials to final-year medical students and remained involved in the medical student exchange program between Cape Town and Nebraska. In 2012, he received a Special Achievement Award from the Sunflower Fund, an organization that recruits donors for bone marrow transplantation, and in 2013, the Fellowship in Arts and Science of Medicine Award from the South African Medical Association. At the end of March 2013, Dr. Jacobs was diagnosed with pancreatic cancer and passed away 8 months later on November 18, 2013.

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Immediately following Dr. Jacobs’ death, tributes came pouring in from around the world, a testament to his global reach in the oncology community. From Canada, longtime colleague Joseph M. Connors, MD, of BC Cancer Agency Centre for Lymphoid Cancer, remembered Dr. Jacobs with the following reflections: “Dr. Peter Jacobs was an inspiration to all of us who endeavor to help lymphoma patients even in the most challenging circumstances. With a career spanning the entire history of hematology and medical oncology in South Africa from the 1960s until now, he worked tirelessly to bring the best of modern health care to those with hematologic malignancies. My every encounter with Peter was an inspiration. All of us should aspire to emulate his compassion for patients and his commitment to education and learning. We have lost an irreplaceable colleague.” From Germany, colleague Volker Dielh, MD, PhD, Founder and Honorary Chairman of the German Hodgkin Study Group, said, “Peter Jacobs was one of the most passionate, engaged, and knowledge-hungry doctors I have known. There were no meetings for

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PAGE 37

CELEBRATING

ASCO’s History, 1964–2014

ASCO’s Visionary Founders By Jo Cavallo

n April 9, 1964, seven physicians—Jane Cooke Wright, MD, FASCO; Arnoldus Goudsmit, MD, PhD; Fred J. Ansfield, MD, FASCO; Harry F. Bisel, MD, FASCO; Herman H. Freckman, MD, FASCO; Robert W. Talley, MD, FASCO; and William Wilson, MD, FASCO—met for lunch at the Edgewater Beach Hotel in Chicago. They wanted to discuss the formation of a medical organization that focused on the clinical care of cancer and gave physicians treating patients with cancer a forum to share ideas and information. At the time of that initial meeting— the first of four organizational meetings—there were not many physicians treating cancer. In fact, oncology was not yet a recognized discipline, and attending physicians were all general medicine doctors. Treatment for the disease centered on surgery and radiotherapy, and pessimism about making progress in cancer was high, but cure rates were low.1 Although the term “chemotherapy” had been coined more than halfa-century before by German chemist Paul Ehrlich to describe the use of chemicals to treat disease, the era of chemotherapy did not begin until 1942, when physicians at New Haven Hospital in Connecticut successfully used nitrogen mustard to treat a patient with advanced lymphosarcoma. A decade later, Dr. Goudsmit used nitrogen mustard to treat a woman diagnosed with cancer at the Cleveland Clinic. Told by the institution’s physicians that there was no therapy available for her disease, she sought treatment from Dr. Goudsmit, an internist in Youngstown, Ohio. She lived for at

least another 10 years. Dr. Goudsmit, along with Dr. Ansfield, is largely credited with organizing the effort to establish the Society.2 It was his belief that the advent of drugs in the treatment of cancer called for a new breed of physicians who focused on chemotherapy. They would later become known as medical oncologists. “If it hadn’t been for the drugs, there would have never been an organization as what we have now,” said Dr. Goudsmit. “It’s only when … anticancer drugs became available that there was an opportunity for the oncologists.”

of Clinical Oncology—the founders held the fourth and final organizational meeting on November 5, 1964, at the Lakeshore Hotel in Chicago. They sent invitations to join ASCO to 134 physicians. The invitations included a copy of Dr. Goudsmit’s essay, “Some Considerations Relative to the Present Status of Clinical Oncology,” in which he outlined shifting attitudes

• Provide physicians with proper professional educational background material and the opportunity to facilitate their own improved management of neoplastic diseases. • Sponsor or cosponsor the publication of photographs, books, and/or articles on the subject of clinical oncology. The publication of a special journal … is particularly appropri-

Peter Jacobs, MD, PhD

order to give the best treatment possible for the many lymphoma and leukemia patients for whom he lived and fought. Nearly every month, I got an email from Peter, asking for help with a very special and difficult patient with a completely unusual leukemia or an absurd lymphoma, or he asked for advice

on the third- or fourth-line therapy of a patient who had become a dear friend.” Mrs. Jacobs said that her husband had tremendous respect for all his nursing staff; he would tutor, encourage, and help them in every way possible. In fact, she said, everyone in Dr. Jacobs’ department, from the

continued from page 36

malignant lymphomas in which Peter was not sitting in the first row from early in the morning until the last talk in the evening, listening intensively and taking notes for his practice, in

ASCO’s Defining Goals Initially called the American Association of Clinical Oncologists—Dr. Wright later suggested the new organization be called the American Society

about the diagnosis and treatment of cancer and “the trend toward a greater patient-related orientation,” necessitating the need for an organization such as ASCO. Although some physicians declined the invitation to join the fledgling clinical oncology organization, claiming the formation of a new society was unnecessary, 90 physicians joined ASCO, and 51 charter members attended the Nov ember meeting. During the meeting, Dr. Goudsmit announced six ambitious goals he had developed for ASCO: • Provide the form, meeting ground, and means for formal and informal communication and mutual education for and among clinically oriented individuals with special knowledge and training in the field of human neoplastic diseases.

Dr. Goudsmit, along with Dr. Ansfield, is largely credited with organizing the effort to establish the Society. It was his belief that the advent of drugs in the treatment of cancer called for a new breed of physicians who focused on chemotherapy. They would later become known as medical oncologists.

ate. (The Journal of Clinical Oncology was launched January 1, 1983.) • Collaborate with other medical and research organizations, national and otherwise, with a view of enhancing professional education in the area of diagnosis and treatment of patients with neoplastic diseases. • Initiate, coordinate, and cooperate in projects of investigation of human neoplastic disease. • Provide a corporate framework for the pursuit of these and related activities.

ASCO’s Evolution ASCO’s first scientific Annual Meeting was held the following year on April 9, 1965, in the Bellevue Stratford Hotel in Philadelphia. More than 70 members and invited guests attended the inaugural event, which featured three presentations on leukemia and multiple myeloma. Today, ASCO has grown to become the world’s leading professional society of multidisciplinary medical professionals who treat people with cancer. Among ASCO’s 35,000 members, including those in the United States and internationally, are clinical oncologists from all oncology disciplines and subspecialties; physicians and other health-care professionals participating in approved oncology training programs; oncology nurses; and other practitioners with an interest in oncology. Each year, ASCO’s Annual Meeting, which is now held over the course of 5 days, attracts more than 25,000 oncology professionals and features the presentation of more than 4,000 scientific abstracts. continued on page 39

cleaners to the most senior members, were known and treated as part of the “Heme Team.” “Peter’s whole life was centered on his work, his patients, the students, his nursing staff, and his colleagues,” she said. n Editor's note: See pages 40-43 for additional tributes to leaders in oncology.

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ASCO’s History continued from page 37

Meet the Founders Fred J. Ansfield, MD, FASCO Along with Dr. Goudsmit, Dr. Ansfield is considered the driving force behind the founding of ASCO. At the time of the formation of ASCO, Dr. Ansfield was Associate Professor of Surgery, Cancer Research Hospital at the University of Wisconsin in Madison. An early pioneer in the use of chemotherapy, Dr. Ansfield led early clinical studies of fluorouracil (5-FU) in patients with several types of advanced solid-tumor cancers. He later studied

Fred J. Ansfield, MD, FASCO

the effect of adding vincristine to cyclophosphamide, 5-FU, methotrexate, and prednisone in advanced breast cancer. During the formation of ASCO, Dr. Ansfield was responsible for outlining a long-range plan for the institution of clinical oncology as a specialty in medicine, with a primary focus on the training of specialists in the field. Dr. Ansfield served as ASCO’s third President, from 1966 to 1967. Harry F. Bisel, MD, FASCO Dr. Bisel was born on June 17, 1918, in Manor, Pennsylvania. He received his medical degree from the University of Pittsburgh in 1942 and did graduate

Harry F. Bisel, MD, FASCO

work at the University of Pennsylvania and Harvard Medical School. Dr. Bisel was the first formally trained oncologist

hired by the Mayo Clinic. He went on to found the Mayo Clinic Section of Medical Oncology and was chairman from 1963 to 1972. He retired from the Mayo Clinic in 1983. Dr. Bisel was an early researcher in advanced breast cancer, investigating the efficacy in clinical trials of combinations of agents, including 5-FU, cyclophosphamide, and prednisone with or without vincristine, among others. As a founding member of ASCO, Dr. Bisel was charged with outlining a long-range plan for the institution of clinical oncology as a specialty in medicine. He also conceptualized the idea that “one full day … be held annually for scientific meetings.” Dr. Bisel was elected the first President of ASCO, serving from 1964 to 1965. Herman A. Freckman, MD, FASCO Dr. Freckman was Director of Cancer Chemotherapy at The Christ Hospital in Cincinnati and an early researcher in such chemotherapeutics as intra-aortic infusion of 5-FU and

Herman A. Freckman, MD, FASCO

cyclophosphamide in the treatment of lung cancer; chlorambucil and prednisolone for disseminated breast carcinoma; and intra-aortic infusion of 5-FU, methotrexate, cyclophosphamide, vinblastine, and vincristine, alone or in combination for advanced colorectal cancer. Dr. Freckman was responsible for organizing a membership committee and recruiting new members into ASCO. Arnoldus Goudsmit, MD, PhD, FASCO A native of Amsterdam, Dr. Goudsmit earned his medical degree in 1931 from the University of Amsterdam and moved to New York 2 years later to study at Cornell University Medical College, where he received his PhD degree in biochemistry. He

PAGE 39

later studied internal medicine at the Mayo Clinic in Rochester, Minnesota. As an internist in Youngstown, Ohio, in the 1950s, Dr. Goudsmit was the first physician there to use nitrogen mustard to treat a woman with cancer. Dr. Goudsmit credited his experience as the first President of the Ohio chapter of the American Society of Internal Medicine with helping him to establish ASCO.

develop scientific programming for the ASCO Annual Meeting and other Society-sponsored educational initiatives. William Wilson, MD, FASCO At the early organizational meetings in the establishment of ASCO,

William Wilson, MD, FASCO Arnoldus Goudsmit, MD, PhD, FASCO

A pioneer in advancing the field of chemotherapy, Dr. Goudsmit published a report of studies of heparin and cyclophosphamide in the treatment of lung cancer while he was organizing the launch of ASCO, drafting its constitution and organizational bylaws, and arranging for the Society to be incorporated. Dr. Goudsmit remained dedicated to advancing research in chemotherapy throughout his career, and as late as the 1980s, he was involved in an Eastern Cooperative Oncology Group study of combinations of chemotherapy agents for advanced gastric cancer.

Dr. Wilson was tasked with proposing a budget that would address the creation of a Society journal and other educational initiatives, including the Annual Meeting. Jane Cook Wright, MD, FASCO The only woman and the only African American among the original ASCO founders, Dr. Wright served as the Secretary-Treasurer during the formation and

Jane Cook Wright, MD, FASCO

Robert W. Talley, MD, FASCO When Dr. Goudsmit was planning for the establishment of ASCO, he asked Dr. Talley to be responsible for the area of “clinical science,” including the development of a comprehensive list of contemporary drugs and their application in the treatment of cancer. The list compiled by Dr. Talley was used to

early years after ASCO’s establishment. Dr. Wright was the last surviving member of the original seven founders, and she died on February 19, 2013, at the age of 93. In recognition of Dr. Wright’s contribution to cancer research, ASCO and the Conquer Cancer Foundation created the Jane C. Wright, MD, Young Investigator Award in 2011.n

Robert W. Talley, MD, FASCO

References 1. DeVita VT, Chu E: A history of cancer chemotherapy. Cancer Res 68:86438653, 2008. 2. Krueger GM, Alexander LI, Whippen DA, et al: Arnoldus Goudsmit, MD, PhD: Chemotherapist, visionary founder of the American Society of Clinical Oncology, 1909-2005. J Clin Oncol 24:40334036, 2006.

Visit The ASCO Post website at ASCOPost.com

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PAGE 40

In Memoriam

he ASCO Post honors the following specialists in oncology who passed away in 2013-2014. Please write to editor@ASCOPost. com to recognize and pay tribute to others in a future issue.

Donald L. Morton, MD

September 12, 1934– January 10, 2014 Donald L. Morton, MD, transformed the management of melanoma and breast cancer by intro-

ducing the sentinel node biopsy, giving surgeons an accurate roadmap for treatment, and sparing generations of cancer patients from the morbidity associated with unnecessary surgery. Throughout his distinguished career,

his work and discoveries have profoundly changed the treatment of cancer. Dr. Morton died on January 10, 2014, in Santa Monica, California. He was 79.

Overcoming Poverty Dr. Morton was born in 1934 in Richwood, West Virginia, a small coal-mining town tucked away in the Appalachians. The son of a coal miner, Dr. Morton grew up dirt poor during the Great Depression, reared in a house built by his father that had no electricity or indoor plumbing. He tended pigs, cows, and chickens

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in the morning before school, and then again after school. “Only after all my chores were done could I do my homework by the light of a kerosene lamp,” noted Dr. Morton in an interview with Innovations, a publication of the John Wayne Cancer Institute. Dr. Morton’s self-determination and a supportive mother overcame the limitations imposed by poverty. His searing intellect was seen early on, and following high school he enrolled in Berea College in Kentucky, which provided free education to qualified students from poor families. After graduating from Berea, Dr. Morton completed his undergraduate education at the University of California, Berkeley, in 1955 and then received his medical degree from the University of California, San Francisco (UCSF), in 1958.

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Dr. Morton interned at UCSF Medical Center and began a surgical residency in general surgery, which was put on hold by a fellowship grant at the National Cancer Institute (NCI). Following his fellowship, Dr. Morton completed his surgical residency at UCSF Medical Center, after which he returned to the NCI in 1960 to serve as senior surgeon in the surgery branch. He eventually became the head of NCI’s tumor immunology section.

ASCOPost.com | JUNE 10, 2014 | SUPPLEMENT

During this period, Dr. Morton’s lifelong interest in surgical oncology and melanoma began to bloom. Also at the NCI, Dr. Morton’s observations of spontaneous remissions in melanoma sparked his interest in immunotherapy, which would become a central line of inquiry during his career. In 1971, Dr. Morton assumed the role of Professor and Chief of the Division of Surgical Oncology, UCLA School of Medicine. At that time, surgical oncology was not yet recognized as a specialty within general surgery. Dr. Morton’s work changed the approach to melanoma surgery by introducing cutaneous lymphoscintigraphy to identify the regional lymphatic basin receiving drainage from a primary cutaneous melanoma. During the late 1970s, Dr. Morton further refined lymphatic mapping, defining the sentinel lymph node as the first tumor-draining node, leading to the development of the sentinel lymph node biopsy, which has become the standard of care for patients with early-stage malignant melanoma and breast cancer. It is widely accepted that the sentinel node concept saves the U.S. health-care system about $3.8 billion per year in unnecessary procedures and their subsequent harms.

Groundbreaking Research Dr. Morton’s early interest in immunotherapy led to his pioneering work with intratumoral bacille Calmétte-Guerin (BCG) for nonspecific melanoma immunotherapy, the first successful application of immunotherapy in metastatic cancer. His studies also laid the foundation for the use of intravesical BCG in superficial bladder cancer, which became the first U.S. Food and Drug Administration–approved cancer immunotherapy. During this period of groundbreaking research, Dr. Morton also became known as being one of the last physicians to treat the Hollywood icon John Wayne, who died in 1979 of stomach cancer. Dr. Morton—who slightly resembled Wayne in his stature and rugged good looks—became quite close to the famous actor. In later interviews, Dr. Morton would remark about Wayne’s dignity in dealing with his terminal condition. In 1981, with the help of the Wayne family, Dr. Morton established the John Wayne Cancer Clinic at UCLA. Ten years later, seeking more space for patients and research, Dr. Morton, along with John Wayne’s eldest son, Michael Wayne, moved to St. John’s Health Center, founding the John Wayne Cancer Institute.

Valued Mentor In a 2011 editorial in the Journal of Surgical Oncology, former ASCO Executive Vice President, Charles M. Balch, MD, of Johns Hopkins University wrote, “Donald Morton is truly a legend in surgical oncology, an icon as a surgical investigator, a pioneer in melanoma, a valued mentor, an authentic role model, and a cherished friend.” “I’m proud that about 80% of those I’ve trained are now deans or department chairs and are widely distributed throughout the country. They will continue to make contributions to cancer long after I’m gone,” Dr. Morton said during his interview in Innovations.

Dedication to Patients Dr. Morton’s scientific contributions to the field of oncology will endure as a living legacy, carried on by generations of future doctors. That said, his groundbreaking research work in the lab did not separate him from cancer patients; it brought him closer to them. His dedication to patients was best captured during an interview in the Los Angeles Daily News, when he said, “Cancer patients are the nicest patients in the world. I truly believe there is a genetic link between kindness and those who are diagnosed with cancer. After all of these years, I still cannot help but get emotionally involved with my patients and their situations. It is truly rewarding when a patient with a fatal diagnosis is still alive after 5 years, but it is crushing when I lose a patient because, in essence, I am losing a friend.”

Geoffrey P. Herzig, MD

December 6, 1941– December 20, 2013 Many of the advances that have bettered mankind are attributed to those who were driven by a primary passion. Geoffrey P. Herzig, MD, lived the better part of his life with a primary passion: conducting research to increase the cure rate of leukemia and lymphoma patients. His friend and colleague, Robert Peter Gale, MD, PhD, who has contributed greatly to basic science and clinical research in bone marrow transplantation, commented, “If you’re a young physician who does bone marrow transplants or treats people with leukemia, you may not realize how much you and your patients owe to Geoff Herzig.” Dr. Herzig was born on December 6, 1941, the day before Japan launched its infamous strike on Pearl Harbor, signal-

PAGE 41

ing the beginning of World War II. He and his brother Roger had an itinerant childhood, growing up in Cincinnati, Cleveland, and Georgia. Dr. Herzig attended the University of Cincinnati, where he graduated with honors in chemistry. He then pursued a career in medicine at the Case Western Reserve University School of Medicine in Cleveland.

Early Cryopreservation Efforts After receiving his medical degree, Dr. Herzig did his internship and residency at Albert Einstein College of Medicine in New York. Following his residency, he trained in hematology and oncology at the National Cancer Institute and later at Washington University in St. Louis, where he joined the faculty. While at Washington University, he further developed his concept of using high doses of anticancer drugs in leukemia, whose dose-limiting toxicity was bone marrow suppression, which he could overcome with an autologous transplant. However, the bone marrow

Geoffrey P. Herzig, MD

cells needed to be cryopreserved at an appropriate time before the side effects of multiple cycles of chemotherapy. To accomplish this, the ever-inventive and extremely handy Dr. Herzig built his own cryopreservation device. Gordon L. Phillips, MD, Dr. Herzig’s mentee, colleague, and friend added some clarity to these early efforts in cryopreservation. “Geoff did not invent cryopreservation of bone marrow, but he worked diligently to perfect the process at a time well before computerized, rate-controlled freezing. He also created the ‘software’ (long before this word was widely used), hand-calibrating the freezing curve and putting some of the machinery in one of his old cigar boxes,” he recounted. “One of my most enduring memories is of Geoff working late in the lab, refining the ‘software,’ smoking a cigar, and cursing (mildly and softly) at his slow progress. Finally, we ‘perfected’ it—meaning it was usable—but it was very labor-intensive and nerve-wracking as Geoff and I froze our first marrows together,” Dr. Phillips continued.

Transplant Program Director In 1975, Dr. Herzig founded the adult bone marrow transplant program at Barnes Hospital, one of the earliest programs of its type in the country. And in 1980 he was named first Director of Washington University’s Bone Marrow Transplant Program. In 1991, Dr. Herzog, along with others including Dr. Bloomfield, joined Roswell Park Cancer Institute in Buffalo, NY, to concentrate on clinical trials in acute leukemia, particularly his special interest, acute myeloid leukemia (AML). When Dr. Herzig was at Roswell Park, he worked closely with Dr. Bloomfield to define the predictive role of cytogenetics and molecular abnormalities in predicting AML therapy outcomes. He was also an important contributor to evolving concepts in how to best treat Hodgkin lymphoma, including novel drug regimens and autologous transplants. Dr. Herzig was an avid sailor, keeping a boat in New York Harbor. A man of interesting contradictions, he could be a very demanding mentor, but hundreds of mentees remember an underlying gentleness and random acts of kindness. He is survived by his son Andrew, his grandchildren, and his brother Roger, who is a Professor of Hematology at the University of Louisville and the Director of the University’s Blood and Bone Marrow Program.

Janet L. Rowley, MD

April 5, 1925–December 17, 2013 Dr. Janet L. Rowley’s groundbreaking research in the translocation of genetic material bucked scientific convention and heralded a new understanding that cancer is indeed a genetic disease. Her research was largely responsible for the discoveries that led to the development of the targeted cancer therapies used today. A powerful advocate for cancer research, she also built a strong relationship between the scientific community and those at the forefront of public policy. Dr. Rowley stood next to President Barack Obama in 2009, when he lifted the federal moratorium on funding for stem cell research; later that year, she would return to the White House to accept the Presidential Medal of Freedom. Dr. Rowley died on December 17, 2013.

Academic Upbringing Dr. Rowley was born in New York on April 5, 1925, the only child of two Ivy continued on page 42

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In Memoriam continued from page 41

League–educated parents, both of whom were teachers at the high school and college levels. At age 2, she moved with her family to Chicago. Reared in an intensely academic environment, Dr. Rowley was an earnest student and an avid reader.

Granted a scholarship at the University of Chicago, she finished her last 2 years of high school and first 2 years of college in an advanced placement program. She remained at the University of Chicago, earning a Bachelor of Philosophy degree in 1946, and a Doctor of Medicine degree in 1948. She mar-

ried Dr. Donald Adams Rowley the day after graduation from medical school. At the time Dr. Rowley entered the University of Chicago medical school, the quota for women was 3 in a class of 65 medical students. The quota was filled for the class she wanted to enter, so she had to wait another 9 months.

An Accidental Scientist She would spend the next 20 years working part-time, as she reared her four sons. For much of the late 1950s, Dr. Rowley had worked part-time at the Cook County Hospital clinic for

Janet L. Rowley, MD

mentally handicapped children. Then, in 1961, she went with her husband to England, where he went on sabbatical; it would prove to be a pivotal point in Dr. Rowley’s career. “I needed something to do for the year we’d be in England. Because of my work with retarded children, I was interested in inherited diseases. A friend arranged an introduction to Laszlo Lajtha, a hematologist in Oxford who was doing groundbreaking work on the pattern of replication of bone marrow cells. Lajtha allowed me to work in his lab to extend his study of the replication of chromosomes and learn more about the emerging field of cytogenetics,” Dr. Rowley said in a 2011 New York Times interview. Prior to her work with Dr. Lajtha, Dr. Rowley had been a practicing medical doctor, but she enjoyed the laboratory experience so much that upon returning to the University of Chicago the next year, genetic research would become her life’s work. She became an Associate Professor in 1969, and a full Professor in 1977. During the 1970s, Dr. Rowley demonstrated that the abnormal Philadelphia chromosome implicated in certain types of leukemia was involved in a translocation with chromosome 9 in some cases. She also identified a translocation between chromosomes 9 and 21 in myeloblastic leukemia. Going against the science establishment’s view that genetics had little role in causing cancer, she published her findings and argued that specific translocations caused specific cancers. Resistance eventually gave way to praise, and by 1990, more than 70 translocations had been identified across a host of cancers.

Celebrated Life In 1984, Dr. Rowley was made the Blum-Riese Distinguished Service Professor at the University of Chicago, a position she held for the remainder of her career. In 1998, she was honored

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with the Lasker Award for her work on translocation. The author of hundreds of papers and book chapters, she also gave generously of her time to serve on public scientific advisory committees, including the National Cancer Advisory Board, the President’s Council on Bioethics, the National Human Genome Research Institute Board of Scientific Counselors, and the National Advisory Council on Human Genome Research. Awards and accolades, however, do not define her legacy. Rather, it is the huge footprint she left on the science of cancer genetics and the role model she served as for those who continued her work in the field. Dr. Rowley will also be remembered as a person who celebrated every aspect of life. Outside of the lab, she kept on gardening, bicycling, skiing, swimming, and sailing well into her 80s. And despite the fame that followed her indelible contributions to genetic cancer that translated into lifesaving agents, she was simply a nice person to be around.

Jane Weeks, MD, MSc

August 12, 1952– September 10, 2013 On September 10, 2013, Jane Carrie Weeks, MD, MSc, a prominent researcher at Dana-Farber Cancer Center, died of cancer in her Boston home. She was 61. At the time of her death, Dr. Weeks was Professor of Medicine at Harvard Medical School, Professor of Health Policy and Management at the Harvard School of Public Health, Director of the Mc-GawPatterson Center for Population Sciences, and Chief of the Division of Population Sciences in the Department of Medical Oncology at Dana-Farber. While Dr. Weeks’ legacy in oncology is replete with achievements, it is her groundbreaking work in the field of outcomes research and health-care disparities that will perhaps have the longest lasting impact on cancer care. Outcomes research is the applied investigation that provides evidence about which interventions are most effective in a given patient population. The results of outcomes research are often used to inform legislative bodies that make crucial decisions about health-care policy. Although outcomes research is a heady discipline of macro-analysis and statistics, it all boils down to delivering better and more equitable care for patients with cancer, taking into consideration their experiences and preferences. Last June, when Dr. Weeks received a 2012-2013 William Silen Lifetime

Achievement in Mentoring Award from Harvard Medical School, her Dana-Farber colleague Deborah Schrag, MD, said, “Jane asks the critical questions about how we deliver clinical care—questions that have changed the way we think about and practice cancer medicine at its most profound level. In addition to her power-

Jane Weeks, MD, MSc

ful intellect and analytic rigor, Jane is the consummate mentor. Her trainees now populate the field of health services research in oncology across the country.”

Advancing Comparative Effectiveness Research In 1995, Dr. Weeks founded DanaFarber’s Center for Outcomes and Policy Research, which fosters cross-disciplinary health services research in cancer. An early researcher in the causes of disparities in care, in 2001 Dr. Weeks had a leadership role in creating Dana-Farber’s Initiative to Eliminate Cancer Disparities, which provided a centralized and coordinated structure for addressing the complexities of cancer disparities. Understanding the need for adding more value to the clinical care continuum, Dr. Weeks was also a pioneer in comparative effectiveness research. Her original work in this field enabled an understanding of the population-wide impact of cancer treatments and has helped guide decision-making at the clinical as well as policy level.

Cost-Effectiveness In a chapter of Holland-Frei Cancer Medicine, 6th Edition (B C Decker, Inc., July 2003), Dr. Weeks wrote, “In the United States, although not necessarily in all the developed countries, it is generally believed that the physician should function as the patient’s advocate in these discussions and should offer any treatment likely to be of net benefit, regardless of the cost to society…but all practitioners must have some understanding of issues of cost and cost-effectiveness if they are to have any voice in the debate over allocation of health care dollars and other resources.” She made that important observation a decade ago, well ahead of today’s national discussions of escalating health-care costs.

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Nurturing the Next Generation of Scientists Dr. Weeks’ innovative approach at mentoring has improved the field of oncology. “I worked with Jane for many years; she was instrumental in my career,” said Stephanie J. Lee, MD, MPH, a bone-marrow transplant researcher at the Fred Hutchinson Cancer Researcher Center, and a former mentee of Dr. Weeks. “My work in allogeneic transplantation is very different from Jane’s work but she was able to easily bridge that gap and mentor me, applying all of her knowledge and insight into my work. Many people feel like you must be in the same field to be a good mentor, but a great mentor like Jane doesn’t have to have content expertise in your particular subspecialty. Jane was very good at understanding people’s needs, and her insights were always spectacularly correct.” Dr. Weeks is survived by her husband, Barrett Rollins, MD, PhD, Linde Professor of Medicine at Harvard Medical School and Chief Scientific Officer and Faculty Dean for Academic Affairs at Dana-Farber Cancer Institute.

Dr. Mazzaferri was a dedicated researcher, educator, and scholar. With an uncompromised drive to provide excellent care for patients, he led by example training and educating generations of physicians to do the same. Friend and former colleague Richard Kloos, MD, of Ohio Statue University said “Ernie is remembered as a caring and talented physician, an accomplished scholar and educator, as well as a loving husband, father, and grandfather. He was a luminary figure, and few people have had a greater impact in thyroidology.1” Dr. Mazzaferri was generally regarded as one of the world's experts on thyroid cancer. He won the prestigious Paul Starr Award from the American Thyroid Association in 2009 for his fundamental contributions to improving the care of patients with thyroid cancer. Under his leadership, Ohio

Ernest Louis Mazzaferri, Sr, MD

September 27, 1936–May 14, 2013 Ernest Louis Mazzaferri, Sr, MD, MACP, of Henderson, Nevada, passed away peacefully at home on May 14, 2013 after a short illness, surrounded by his family. He was born September 27, 1936 in Cleveland, Ohio. Dr. Mazzaferri spent most of his medical career at The Ohio State University, serving as Division Director of Endocrinology from 1974-1978, then Chairman of Internal Medicine from 1984-1999, during which time the Department of Medicine grew fivefold. From 19781984, he was Chairman of Internal Medicine at the University of NevadaReno, serving as Acting Dean from 1979-1981.

Dedicated Veteran, Researcher, Educator, Scholar Dr. Mazzaferri earned his MD degree at The Ohio State University in 1962. After a year of internship at Ohio State, he proudly served as a Captain in the United States Air Force from 19641966, and as a Lieutenant Colonel from 1970-1972. He continued to serve in the U.S. Army Reserves, and on active duty status, served during Desert Storm as a Colonel at Madigan Army Medical Center in Seattle, Washington. His military career concluded with the Meritorious Service Medal in 1991.

Ernest Louis Mazzaferri, Sr, MD

State became a world-class center for the study of thyroid disease. In 2009, Dr. Mazzaferri was awarded the Ohio State University Distinguished Service Award. He was elected as a Master in the American College of Physicians in 1996.

Personal Best After a romance that began in the ninth grade, Ernie married Florence Marolt, his best friend and lifelong partner, on November 23, 1957. Dr. Mazzaferri is survived by his wife, 4 children, 14 grandchildren, and 6 greatgrandchildren. Above all of his accomplishments in medicine, Dr. Mazzaferri was especially proud of the thousands of students, interns, residents, and fellows that he mentored throughout his illustrious career; however, he always said that his marriage to his wife and the accomplishments of his children were his greatest achievements in life. Reference 1. Kloos RT, et al: Ernest L. Mazzaferri, MD, MACP (1936-2013). Thyroid 23:917-923, 2013.

Adapted from The Columbus Dispatch, May 19, 2013.

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