PMO May 2013 Vol 2 No 3 by The Oncology Nurse

May 2013 Volume 2 • Number 3 A Peer-Reviewed Journal

The official publication of

Global biomarkers Consortium Clinical Approaches

PM O TM

to Targeted Technologies

Personalized Medicine in Oncology TM

COLON CANCER Crizotinib and Colorectal Cancer – A Couple to Be Tested?……………………....................Page 123

INTERVIEW WITH THE INNOVATORS Personalizing Cancer Care, Policy, and the Payer Perspective: An Interview With Peter F. Hayes of Healthcare Solutions ..................Page 134

CONTINUING MEDICAL EDUCATION Considerations in Multiple Myeloma. Ask the Experts: Maintenance Settings......................................................Page 138

RENAL CELL CARCINOMA Sequential Therapy for Renal Cell Carcinoma................................................. Page 146

ALSO IN THIS ISSUE… • The Last Word by Robert E. Henry.........Page 161

Implementing the Promise of Prognostic Precision into Personalized Cancer Care

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he Global Biomarkers Consortium™ (GBC) is a community of worldrenowned healthcare professionals who will convene in multiple educational forums in order to better understand the clinical application of predictive molecular biomarkers and advanced personalized care for patients.

Global biomarkers Consortium Clinical Approaches

Save the date for the Second Annual Conference, October 4-6, 2013 Visit www.globalbiomarkersconsortium.com to register

Professional Experience of GBC Attendees 56.7%

26.7%

Personalized Medicine in Oncology ™

CONFERENCE NEWS News From NCCN and AACR

to Targeted Technologies

PM O

May 2013 Volume 2 • Number 3

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NCCN Updates Its Clinical Practice Guidelines The Changing Oncology Landscape: Evolution or Revolution? Highlights From the American Association for Cancer Research Annual Meeting Higher HER2 Expression Leads to Better Outcomes With T-DM1 in HER2-Positive Metastatic Breast Cancer

COLON CANCER Crizotinib and Colorectal Cancer – A Couple to Be Tested?

PAGE 123

Sebastian Stintzing, MD; Heinz-Josef Lenz, MD, FACP The authors provide insights into molecularly defined subgroups and development of more effective therapies with the focus on the pathways targeted by crizotinib in mCRC.

INTERVIEW WITH THE INNOVATORS Personalizing Cancer Care, Policy, and the Payer Perspective: An Interview With Peter F. Hayes of Healthcare Solutions PAGE 134 PMO talks with Peter F. Hayes about the payer’s perspective in personalizing medicine in oncology practice.

6.7%

CONTINUING MEDICAL EDUCATION

3.2%

Considerations in Multiple Myeloma. Ask the Experts: Maintenance Settings

6.7%

1-3 years

Kenneth C. Anderson, MD; Tina Flaherty, ANP-BC, AOCN; Houry Leblebjian, PharmD, BCOP

3-5 years

RENAL CELL CARCINOMA

5-10 years

Sequential Therapy for Renal Cell Carcinoma

10-20 years >20 years

Volume 2 • No 3

PAGE 138

PAGE 146

Daniel C. Cho, MD Dr Cho reviews sequences of therapies that might maximize both duration of disease control and quality of life for individual patients.

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PUBLISHING STAFF Senior Vice President/Sales & Marketing Philip Pawelko phil@greenhillhc.com Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Publisher Russell Hennessy russell@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Strategic Editor Robert E. Henry

Current Treatment of Myelofibrosis: How Far We Have Come and How Far We Have Yet to Go

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A report from the 2012 conference of the Global Biomarkers Consortium.

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THE LAST WORD

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The MHealth Factor: A Bioinformatics Platform for Arming the Oncology Personalized Medicine Revolution PAGE 161 Robert E. Henry

Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs

Mr Henry explores the potential to transform smartphones into personalized medicine portals. OUR MISSION The mission of Personalized Medicine in Oncology is to deliver practice-changing information to clinicians about customizing healthcare based on molecular profiling technologies, each patient’s unique genetic blueprint, and their specific, individual psychosocial profile, preferences, and circumstances relevant to the process of care.

Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano

OUR VISION Our vision is to transform the current medical model into a new model of personalized care, where decisions and practices are tailored for the individual – beginning with an incremental integration of personalized techniques into the conventional practice paradigm currently in place.

Web Content Managers David Maldonado Anthony Travean Digital Programmer Michael Amundsen

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2013 by Green Hill Healthcare Communications, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

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Volume 2 • No 3

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HEMATOLOGY

Senior Copy Editor BJ Hansen

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EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO), 1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mention in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the editorial director.

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Interview With the Innovators A PMO Exclusive Series The world of personalized medicine is a rapidly changing, ever-evolving state involving many stakeholders on the front lines of its creation: physicians, industry, researchers, patient advocates, and payers. PMO seeks out the leaders in these sectors and brings you their game-changing strategies, missions, and impact on personalizing oncology care. To view Interview With the Innovators, or to nominate an interviewee, visit us at

www.personalizedmedonc.com

PMO Interviewees include:

Michael Pellini, MD Foundation Medicine Inno52013

Edith Perez, MD Mayo Clinic

Kimberly Popovits Genomic Health

Henry T. Lynch, MD Creighton University School of Medicine

Editorial Board

Editor in Chief Al B. Benson III, MD Northwestern University Chicago, Illinois

SECTION EDITORS Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida

Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee

Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts

Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts

Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut

Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana

Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio

Prostate Cancer Oliver Sartor, MD Tulane University New Orleans, Louisiana

EDITORIAL BOARD Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania

K. Peter Hirth, PhD Plexxikon, Inc. Berkeley, California

Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois

Gregory D. Ayers, MS Vanderbilt University School of Medicine Nashville, Tennessee

Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan

Hope S. Rugo, MD University of California, San Francisco San Francisco, California

Lyudmila Bazhenova, MD University of California, San Diego San Diego, California

Howard L. Kaufman, MD Rush University Chicago, Illinois

Danielle Scelfo, MHSA Genomic Health Redwood City, California

Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona

Katie Kelley, MD UCSF School of Medicine San Francisco, California

Lee Schwartzberg, MD The West Clinic Memphis, Tennessee

Kenneth Bloom, MD Clarient Inc. Aliso Viejo, California

Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota

John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas

Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts

Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington

Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts

Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Afsaneh Motamed-Khorasani, PhD Radient Pharmaceuticals Tustin, California

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Stephen Gately, MD TGen Drug Development (TD2) Scottsdale, Arizona Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland

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Gene Morse, PharmD University at Buffalo Buffalo, New York

Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts

Darren Sigal, MD Scripps Clinic Medical Group San Diego, California David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan

Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California

Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland

David A. Proia, PhD Synta Pharmaceuticals Lexington, Massachusetts

Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain

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Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida

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CONQUERING THE CANCER CARE

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CONQUERING THE CANCER CARE CONTINUUM CONQUERING CANCER CARTHE C E CONT I

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The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present our 2nd annual Conquering the Cancer Care Continuum series. Upcoming topics include:

Challenges Patients Face in Cancer Care: Implications for the Healthcare Team Lea Ann Hansen, PharmD, BCOP Associate Professor, Virginia Commonwealth University

cancer.1 More than half are living well beyond 5 years ancer is an illness associated with substantial physical, emotional, social, and financial ramafter diagnosis. Women comprise a majority of longifications for affected individuals and their term survivors due to the favorable outcomes with families. In a significant number of cases, the diagnosis breast, cervical, and uterine cancers.2 The number of of cancer is either preceded by a period people living with a history of cancer of gradual, nonspecific symptoms or is projected to grow considerably over

discovered by routine screening, and the next 20 years for 2 major reasons. individuals are then thrust into a First, the number of Americans over whirlwind of diagnostic testing, inage 65 is predicted to double between vasive procedures, and complicated the years 2000 and 2030.3 Consetreatments with very little warning or Lea Ann Han quently, as a disease primarily of older sen, Pha Associate opportunity to assimilate their circumProfessor, rmD, BCOP adults, cancer will also increase. SecVirginia Commond, stances. Frequently, a multidisciplinary as the effectiveness of cancer onweal versity â&#x201E;˘ th Uni approach to treatment is necessary, retreatments improves, the number of he past dec ade has seen quiring patients to engage with numerthe utilizat a drapatients matic upscured of the disease will in ion of spe urgan e in several ous medical teams comprising crease, and even larger percentage cialty pha types of Medic rma are Moder the cies for all Lea Ann Hansen, rapeutic nization Ac different specialties, often in different those for can will be living longer with the disease modalitie as cer. The BCOP â&#x20AC;&#x153;a part D PharmD, t defined s, including cost of can a specialty locations. Many patients have beenabout $125 bill receiving multiple â&#x20AC;&#x153;linesâ&#x20AC;?dru of g with plan-n cer carewhile ceed $40 drug ion in 201 may rise from egotiated 0 0 to (first-line, prices tha relatively healthy prior to the cancer lion eventbyand second-line, etc) fine over time. per Themonth.â&#x20AC;? 2 Oth thethere7 bilend of the therapy$20 t exspe er health cial dru dec ade. demand plans ma gs differe fore are not sophisticated consumerstim ofe,medical overall specialtyserBy that for oncology services is expected totyiny dently dru gs . In genera are accon predic ounhealthcare vices. Consequently, it is incumbent crease byted 48% l, they are t for 2 of toby 2020, while the supply of oncologists high cost, adminis eve ry 5 pha increase by only 14% based on current patterns.4or tered by inje lars spent. 1 professionals to be able to facilitate patientsâ&#x20AC;&#x2122; transition cy dolinfusion, The purpos willrma ction require spe e of this arti to expand cial handlin ersity intoBCO carePin order to minimize theirisdistress the need for a wide varietyor are used lain maxicle underscore the evoluti These statistics g, en, PharmD, Commonwealth Univ for comple 80%, cialty pha on nia their clinical outcomes. Lea Ann Hans ssor, Virgimize from 17% toand other support personnel torequire x diseases of range the of ens health professionals spe rmacycatio Profe regim that special mo ption andnthe Associate on assumeach oral mediand can nitoring. functio term serv cology, how Anscomm Challenges exist beyond diagnosis play a part and every patient to re.2-4 t initial e in the around 50% In onitin enabling treatmenthe be d eve mic trea ge woul r, syste tme avera ts the for an National andwith ntantic agen most com of can to the agents disp ance nt scenario period as well. According to quality all of their needs disc acerr care that addresses uss nistr mon oralceive the to ens admi he predomina treatment been e ed lved pot has renc by invo se, ent adheindividandthat a specialty disea ialityben macy pro the traditionally ofefit (NCI), more throughout of the illness. Patients demillion llen pharges oftothe highlythan 12cha s the continuum sever vider (SP of cancer has Cancer Institute thesyst ate the otherapy by due P) are the poi high er, ies indic em targeted from of view e. Stud venous chem United States fine quality of care based on are their ability to5: are a history untru nt.livingntwith the newer of theofpatproven agents tha the patie tion of intra uals in the py ient. t are adm ly monitored for cancer thera tered ora inisnnel who close lly. After adherence rates5 rence has trained perso in an The Evo a system view . Nonadhe atic redures took place lution of 15% to 97% Green Hill outc Healthcare omes Communications, LLC of the literature, Sp e When these proce infuDru ec wors ital one academ gs and group of ialt y iated with or in a hosp assoc authors pro ic s and with oncologistâ&#x20AC;&#x2122;s office of the Pharmac Specialtbeen y posed the critical des disease state Lea Ann sive education most y in a number of Hansen criptors er hossion center, exten , high More of a spe There is drug to be 3 ician visitsPha rmD, BCO , ly was possible. cialty a lack of : increased phys stays, P consen patient and fami specialty ly comsus on the â&#x20AC;˘ High cos , longer hospital drug. The n rates ver, an increasing definition t (prescri morFood andpitalizatio ased or recently, howe not one incre ptio of of and defined the a ns cost mo Drug Ad than $600 ening, wors involves the use min â&#x20AC;˘ re toDifficult term. Init disease istration has per month mon situation synonymo dminmedicatio ially, the6 ately one-third ) us with bio n delivery, Appl roxim cations and self-a tality. labe was virtuallcation-relatedâ&#x20AC;&#x201D; Special technology the such as more oral medi teins pro handling y Leain of all medi producs ts, duced by eous therapies Ann requiring n eitherdue recombin two-third istered subcutan strict tem pro-to medicatio control respon-Hansen,mo nocrmD Asstoci ant DNA ations are lonal, ant perature ate Profes Pha ent. The direc BCibo italiztechnique â&#x20AC;&#x201D; Restric OPdies pro hosp $100 bilsor,om nof home environm brid admi s Virg cost ted or a and duc n location for â&#x20AC;&#x201D;at as,inia ed wit but Co acquisitio dher h ence thismm cellular hy- ose of this ar- or distribu medication is noonw sibility for drug eanona nts and longer 7 The purp lth preparatio tion site theUni ng to the patie sity casver annu n â&#x20AC;&#x201D; e.ally. en, lion epts Th e ibe istration is shifti 200gene if avail 7 ral conc Restricted locatio he -previous Lea Ann Hans ort network, BCOP n for medic ticle is to descr insPhar tallmD, their social supp rch related totration ment in thi than 20 ation adm e and the resea nt time, more ries examin inis renc cannt adhe cer Gre , risk faccar for ed the gro regardingspatie able. 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Ac-erenceThe refirence on its article in this a number of lastsuc ll patand e, mo adhe n records bas terns over cess. for refractory tim re tha Netor are ica Atmaxi themizing poi time, and ed on ensive Cancern 20 oral me have relapsed tions are prehapp best practices thednt for adh 80% is an the National Com roved sbyinthe erence use arbitrary cut . cording to the all compound Dru omes of Foo d outc g by 25% Ad d and many investi min atio ately admin pipelinenare work, approxim linedevelopmentistr gat (FD sam ors A) .) 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in addition self-admin l outes in chroni to istered sub c myeloid cutaneous and childh leukemia pies for the theraood acute home env lymphobla leukemia. 5-8 ironment are under stic that For each of FDA review these diso . ders, prolon When can rged oral cer medic therapy has been the ations are ministered standard adLea Ann orally in the of care for Hansen, dec home env ronment rath ade or more. It a PharmD ier than in , BCOP is likely tha ativ the of adherence t nege consequen clinic or hos ces of non pital, the rate range from adherence with other 15% to 97% 2 s at the end will be doc oral cancer of the first . For examp umented in medicatio year of trea le, hormonal the future ns tment wit apy matur treatment as their role h adjuvant es. The pur (AHT) for in cer, only 79% the pos re ear the of ly-stage bre this article results of of patients ast canis to discuss available remained on a gap exceed adherence research therapy wit ing 60 day on maxim and sug hou s ges and t ceeding 180 t best practic izing 85% withou ical outcom days. By yea es to improv t a gap exes. r 5, only 27% e clinmained wit hout 60- and and 29% re180-day gap In anothe

s, respective 3 r study of ly. AHT, pat tion possess ients with ion ratio (M a medica PR) >80% significant Direct com had a statisti ly higher municatio 10-year sur cally n with all vival rate personal bar patients abo than those riers to tak ut their ing daily the period is an rapy for a pro important longed aspect to Gr maximizin een Hill Hea g adherlthcare Com munication s, LLC

Letter From the Board

Personalized Medicine in Oncology: Providing Insights to Optimally Utilize Personalized Medicine Concepts Dear Colleague,

want to welcome you to this issue of Personalized Medicine in Oncology (PMO) with a few facts concerning personalized medicine (PM): • 79% of late-stage oncology pipeline are targeted therapies • Molecular profiling is driving many new targeted cancer therapeutics, with over 500 compounds coming soon, and 140 targets in development • Companion diagnostics are playing an increasingly greater role in cancer product launches Taken alone, any of these developments would call for intensified efforts to Greg Kalemkerian, MD educate practicing oncologists in PM systems and resources. Taken together, they are a clarion call for extraordinary measures to ensure that this happens. PM is a medical art form requiring awareness of key diagnostic and therapeutic resources. The demand for excellence by patients and caregivers is matched by the demand for value by payers and purchasers. All of these parties recognize cancer as the deadly enemy and will go to great lengths to obtain patientcentered, value-based care. Enter PMO. We bring oncologists the insights into the key developments in PM needed to raise their clinical skills and stay competitive through the expert use of the breakthrough treatments and diagnostics. The greatest clinical armamentarium is meaningless without knowledge of its proper deployment…and that is what PMO brings to oncologists in every issue. Our balanced reviews and editorials give today’s oncologists the insight they need to optimally utilize the products that bring value to the patient-centered cancer care model that is taking shape before our eyes.

Sincerely,

Greg Kalemkerian, MD University of Michigan PMO Board Member

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NCCN Annual Conference

NCCN Updates Its Clinical Practice Guidelines Audrey Andrews

pdates to the Clinical Practice Guidelines of the National Comprehensive Cancer Network (NCCN) were presented at the NCCN 18th Annual Conference held in Hollywood, FL, March 13-17, 2013. For most tumor sites, the updates were few and minor, but the NCCN did introduce inaugural guidelines for survivorship.

New Guidelines for Penile Cancer The NCCN issued new guidelines for penile cancer, a rare malignancy (0.5% of all cancers) whose management has been quite heterogeneous. The standard of care remains complete tumor excision and eradication of negative margins. For more superficial disease, based on the stage and grade of the tumor, less invasive options can be considered. These include topical treatment with either imiquimod 5% or 5-fluorouracil cream, which can produce “excellent outcomes,” according to Philippe E. Spiess, MD, of the H. Lee Moffitt Cancer Center, Tampa, FL.

Penile-preserving surgery maintains function and quality of life in a select cohort with small lesions where negative margins can be obtained. For more extensive tumors, radical surgery is the chief recommendation. Options include wide local excision, laser, radiation therapy, glansectomy, and partial/total penectomy. Penile-preserving surgery maintains function and quality of life in a select cohort with small lesions where negative margins can be obtained. For bulky disease with positive lymph nodes, neoadjuvant chemotherapy has proven effective. A nomogram is recommended for predicting metastatic lymph node involvement, as it outperforms the conventional clinical risk stratification tools. The NCCN did not recommend dynamic sentinel node biopsy due to its low sensitivity and inadequacy in detecting occult inguinal disease.

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New Survivorship Guidelines A growing appreciation of the unmet needs of cancer survivors has led to a new set of guidelines for survivorship. Subtopics covered in the initial version are anxiety and depression, cognitive function, exercise, immunizations/infections, fatigue, pain, sexual function, and sleep disorders. The guidelines are meant to be a companion to the guidelines for the individual tumor sites. “The survivorship guidelines are intended as a library of tools for a provider to use when assessing a cancer survivor,” said Crystal S. Denlinger, MD, of Fox Chase Cancer Center, Philadelphia, PA. At the meeting, several of the topics were described. The NCCN recommends physical activity and return to daily activities as soon as possible after cancer treatment, tailored to the individual’s abilities and preferences. The general recommendation is at least 150 minutes of moderate-intensity activity a week, coupled with strength training and stretching. The document includes an assessment pathway, advice for specific populations (such as those with lymphedema), offers examples of light, moderate, and vigorous exercise, and suggests strategies to motivate patients. Cognitive dysfunction can occur as a complication of cancer treatment. The NCCN guidelines discuss general principles of cognitive dysfunction and provide an evaluation pathway, specific assessments, and practical interventional strategies but acknowledge that this is still an area that is not well understood and not backed by strong data. The guidelines encourage immunizations based on age and medical condition as part of standard practice. Vaccinations against influenza, pneumonia, meningitis, and hepatitis are considered safe for cancer patients, but live attenuated vaccines such as for measles, mumps, and rubella are contraindicated or should be used cautiously. Principles for zoster (shingles) vaccination in cancer or transplant survivors are included.

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NCCN Annual Conference

Sexual dysfunction is a common experience of cancer survivors, and clinicians should assess the level of sexual activity (past and present), the impact of cancer therapy, sexual concerns or symptoms, comorbidities, risk factors, and psychosocial factors. The guidelines include validated tools for assessment: a brief sexual symptom checklist for women and a sexual health inventory for men.

Acute Promyelocytic Leukemia: A Non-Chemo Option “For the first time, the NCCN guidelines have taken chemotherapy out of the up-front treatment for acute promyelocytic leukemia (APL),” said Margaret R. O’Donnell, MD, of City of Hope Comprehensive Cancer Center, Duarte, CA. The guidelines for APL were changed as a result of a study presented at the 2012 American Society of Hematology Annual Meeting (Lo-Coco F, et al. Blood. 2012;120. Abstract 6), which compared the gold standard for newly diagnosed non–high-risk APL – simultaneous all-trans-retinoic acid (ATRA) and chemotherapy (idarubicin) – with the chemotherapy-free combination of ATRA and arsenic trioxide (ATO). Complete responses were observed in 97% of each arm, but 2-year event-free survival was 97% in the experimental arm versus 87% in controls. For patients with low/intermediate-risk APL, the guidelines now recommend induction with ATRA plus ATO.

New Agents in Colorectal Cancer Two new agents recently approved for metastatic colorectal cancer are now included in the NCCN guidelines – ziv-aflibercept and regorafenib – though their overall benefit is relatively minor, Leonard Saltz, MD, of Memorial Sloan-Kettering Cancer Center, New York City, acknowledged. “We had hoped ziv-aflibercept would be the next step forward, but in the registration study it provided only a 1.5-month overall survival benefit,” he noted. When added to FOLFIRI as a second-line treatment in the VELOUR trial, ziv-aflibercept improved overall survival from 12 to 13.5 months (P=.0032) and pro-

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gression-free survival from 4.7 to 6.9 months (P=.0007) (Van Cutsem E, et al. J Clin Oncol. 2012;30:34993506). This benefit is similar to what is achieved with bevacizumab but at a higher toxicity and financial cost, Saltz noted. A 12-week regimen exceeds $30,000, whereas a course of bevacizumab costs less than $14,000. “This cost difference was a deal-breaker for our physicians at Sloan-Kettering. We decided there is no need for zivaflibercept at this time,” he added. In the updated guidelines, ziv-aflibercept is acceptable when added to FOLFIRI or irinotecan, but it should not be used as a single agent, in combination with FOLFIRI after failure of FOLFIRI/bevacizumab, or added to a failed regimen. Bevacizumab was also added as an option after first progression in combination with FOLFIRI, irinotecan, FOLFOX, or CapeOx. Regorafenib was added to the guidelines as a treatment option after first, second, or third progression, depending on previous lines of therapy, based on the 1.4-month survival advantage seen in the CORRECT trial (Grothey A, et al. Lancet. 2013;381:303-312).

Giant Cell Tumor of the Bone New treatment pathways for giant cell tumor of bone (GCTB) and chordoma debuted in the updated version of the guidelines for bone cancer. These are rare neoplasms; therefore, clinicians lack familiarity with them. While GCTB is considered a benign disease, it carries a 2% risk for metastasis. Intralesional excision with the use of a high-speed burr is advised over more extensive surgery that requires skeletal reconstruction. While recurrence is not uncommon, the use of adjuvant therapy, either thermal or chemical, ameliorates this risk. In patients with unresectable or recurrent disease, denosumab can help restore the skeletal architecture and allow a joint-conserving procedure or avoidance of surgery altogether. For localized disease, excision is recommended; if resection carries unacceptable morbidity or the tumor is unresectable, treatment can be with serial embolization, denosumab, interferon, pegylated interferon, and/or radio-

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therapy. For metastatic disease, surgery is indicated if feasible. The recommended workup includes history, physical examination, cross-sectional imaging of the primary site, chest imaging, and biopsy, with optional bone scan.

New Agents in Multiple Myeloma “We have wonderful new agents, at least a lot more potent than prior-generation drugs,” said Kenneth C. Anderson, MD, of Dana-Farber Cancer Institute, Boston, MA. The approval of the second-generation proteasome inhibitor carfilzomib led to its recent inclusion in the guidelines for transplant candidates in combination with lenalidomide/dexamethasone. This triplet joins a growing list of regimens that greatly increase response rates, he said. For relapsed/refractory disease, the updated guidelines also include carfilzomib as a preferred salvage therapy option, as well as the new immunomodulating drug pomalidomide plus low-dose dexamethasone. Other recommended regimens now also include bortezomib/vorinostat and lenalidomide/bendamustine/dexamethasone.

Updates in Non-Hodgkin Lymphoma The growing use of lenalidomide in non-Hodgkin lymphoma is reflected in the updated guidelines. New to the guidelines for the second-line treatment of stage I/II disease is lenalidomide with or without rituximab. For chronic lymphocytic leukemia, first-line therapy now includes lenalidomide (continuous or intermittent dosing) as a treatment option and bendamustine with or without rituximab. For relapsed/refractory disease, lenalidomide with or without rituximab is a treatment option.

New Tyrosine Kinase Inhibitors in Thyroid Cancer With the availability of 2 new tyrosine kinase inhibitors (TKIs), “these are exciting times in thyroid cancer,” said Robert I. Haddad, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, Boston, MA. The TKIs now offer an option after patients become refractory to radioactive iodine.

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In advanced or metastatic medullary thyroid cancer, cabozantinib and vandetanib have more than doubled progression-free survival. The guidelines now list both drugs as category 1 treatments for unresectable disease that is symptomatic or asymptomatic and structurally progressive. While not FDA approved for thyroid cancer, other small molecule TKIs (sorafenib, sunitinib) can be considered.

New Drugs Exploit Androgen Pathway in Prostate Cancer Two new drugs in prostate cancer take advantage of the persistence of androgen receptor expression, even in castration-resistant prostate cancer. Abiraterone acetate, an androgen synthesis inhibitor, and enzalutamide, an antiandrogen, have changed the treatment landscape, said Philip W. Kantoff, MD, of the Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA. The guidelines include abiraterone/prednisone as a category 1 recommendation in both the prechemotherapy and postchemotherapy settings, and enzalutamide as a category 2A recommendation for docetaxel-naive men and a category 1 recommendation after chemotherapy. “These drugs have a clinically meaningful impact on survival,” Kantoff said.

Melanoma: Thin Lesions Can Forego Sentinel Lymph Node Biopsy A substantial change to the melanoma guidelines pertains to the indication for sentinel lymph node biopsy (SLNB), which the panel concluded is not warranted for thin lesions, ie, those ≤0.75 mm. SLNB may be considered when conventional risk factors accompany these very thin lesions. Otherwise, patients with thin lesions undergo wide excision, while those with lesions 0.76 to 1.0 mm should be considered for SLNB, and those with lesions >1 mm require SLNB. The change has the potential to affect as many as three-quarters of patients in the average practice. u

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The Changing Oncology Landscape: Evolution or Revolution? Audrey Andrews

anelists at the 18th Annual Conference of the National Comprehensive Cancer Network view the oncology world as rapidly changing, and the impact of this – for better or for worse – will be felt by healthcare providers, payers, and patients alike. “Certainly, this landscape is shifting beneath our feet,” said Clifford Goodman, PhD, Senior Vice President of The Lewin Group, a national healthcare policy consulting firm. “There are tectonic forces, and these are unsteady times,” he said.

Disparities in Coverage and Care The population of the United States is not getting any healthier despite broadening access to care and efforts to eliminate disparities, the panelists agreed. This is largely because the socioeconomic gap is widening and healthcare is becoming less affordable, especially to the middle class. “In 3 years, the person who makes an average US salary will have to spend 50% of it to cover his out-of-pocket expenses and healthcare premium,” Lee N. Newcomer, MD, MHA, of UnitedHealth Group, pointed out. John Fox, MD, MHA, of Priority Health, further predicted, “In the future, there will be healthcare exchanges and subsidies for low-income persons, but the middle class may be squeezed. Their out-of-pocket costs could be up to $6000 for an individual or $12,000 for a family. Even Medicare and Medicaid will experience more cost sharing. This is a new disparity.” John J. Mahoney, MD, MPH, consultant to Pitney Bowes, elaborated, “The reality is, if you look at the plans – bronze, silver, gold, and private exchanges for employers – the designs are not as rich as in the past. For instance, a bronze plan pays 60% of the cost, so participants think they have coverage, and they do for routine things. But the reality is that the middle class is seeing higher out-of-pocket costs.”

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One result of this is a population of persons who bypass preventive care and screening, and thus enter or re-enter the workplace with a higher risk profile or more advanced disease. Susan A. Higgins, MD, MS, added that in her practice at Yale, she is seeing stage IV cervical cancer (a “third world country disease”) among her underprivileged patients. In contrast, her affluent patients are moving into concierge practices. While the Affordable Care Act will “ballast the very bottom,” she said, high copays for everyone else means “the bottom of the middle class is falling down.”

The population of the United States is not getting any healthier despite broadening access to care and efforts to eliminate disparities, the panelists agreed. Roy Beveridge, MD, of McKesson Specialty Health, predicted that healthcare reform will increase coverage for previously uninsured persons, “but it is going to create other types of problems for how we care for them.” Newcomer predicted it will broaden access to care but not affect the escalating cost of care. “Access may not be worth much if people cannot afford the deductible,” he pointed out.

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Meet the Panel Clifford Goodman, PhD, moderator: Senior Vice President of The Lewin Group, a healthcare policy consulting firm, and Director of its Evidence-Based Practice Centers Coordinating Center. Roy Beveridge, MD: Chief Medical Officer for McKesson Specialty Health; formerly Executive Vice President and Medical Director of US Oncology. John Fox, MD, MHA: Senior Medical Director and Associate Vice President of Medical Affairs for Priority Health. Susan A. Higgins, MD, MS: Associate Professor in the Department of Therapeutic Radiology and the Division of Obstetrics and Gynecology at Yale University School of Medicine. Marty Kohn, MD, MS: Chief Medical Scientist for Care Delivery Systems at IBM Research, and an emergency medicine physician. John J. “Jack” Mahoney, MD, MPH: Consultant to Pitney Bowes, where he was formerly the company’s Global Health Strategy Director and Chief Medical Officer. Lee N. Newcomer, MD, MHA: Senior Vice President at UnitedHealth Group, with strategic responsibility for oncology, genetics, and women’s health. Andrew von Eschenbach, MD: President of Samaritan Health Initiatives, Inc; former Commissioner of Food and Drugs for the FDA and former Director of the National Cancer Institute.

Beyond the Formulary Greater attention must be paid to early integration of palliative care, both for quality-of-life reasons and as a way to reduce the cost of end-of-life care. Better care at the end of life must be valued – by clinicians, patients, policy makers, and payers, the panelists said. Higgins spoke for many when she acknowledged, “The palliative care aspects are a little neglected in our system, and this includes training our physicians to talk to patients in a way that allows them to connect to their wishes for quality and quantity of life. We spend

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many healthcare dollars in the last 6 months of life, but talking is not reimbursed.” One positive sign is that employers are beginning to see its value and to expand benefits accordingly. Some are even subsidizing advanced care directives and living wills. “At Pitney Bowes, we provide incentives for this. It’s thinking outside the formulary,” Mahoney offered.

Involving the Patient Fox suggested that before cancer outcomes can be improved, oncology stakeholders need to determine “which outcomes are most valuable.” At Priority Health, he said, they are “those that are most valuable to our patients,” and this is not necessarily longer life expectancy. The patient’s list of priorities must be front and center of clinical decision making, and any treatment should be consistent with them. “The only way to know this is to ask the patient,” he said. Beveridge saw other obstacles to the successful integration of palliative care: the lack of manpower to effectively deliver it, and the fact that patients often fail to grasp its meaning. “Patients don’t want to make their caregivers unhappy. We have found in interviews that many will accept a third or fourth line of futile therapy because they don’t want to let their doctors down. Interestingly, physicians say they are giving futile therapy because they don’t want to let their patients down,” he said. Newcomer called this a “philosophical barrier.” “Americans still think death is an option,” he said. “We have a whole culture that says it is wrong to stop [treatment],” and this impedes a full and open exchange about prognosis. “When you throw in the family and cultural dynamic, you almost need the Department of State as a negotiator,” Beveridge added. “We have found that it is frequently better to have a nurse practitioner or social worker introduce the topic, because we as physicians are not trained to do this, and we don’t do it particularly well.” Tools to help initiate these discussions are becoming available, including the American Board of Inter-

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nal Medicine Foundation’s Choosing Wisely program, which includes the American Society of Clinical Oncology’s “Top Five” list of common, costly procedures in oncology that are not supported by evidence and that should be questioned. Some practices in the UnitedHealth network are asking patients to complete the Choosing Wisely form upon hospital admission. “These practices are achieving much more patient-oriented outcomes, far fewer days in the ICU, and more deaths at home, because they are having this discussion,” Newcomer reported. He said that he recently used the Choosing Wisely tool with his own parents and was surprised at what he learned. “I changed my viewpoint about their end-of-life care. This can be done,” he said. “It doesn’t require an army of palliative care specialists but a cultural commitment.”

How “Big Data” Is Personalizing Medicine “Big data” will revolutionalize cancer care, panelists predicted. The power of tools like Watson is already being realized, said Marty Kohn, MD, MS, of IBM. Watson is a computer learning system that self-corrects and self-improves with little human input. “Watson can read and comprehend thousands of articles in a few seconds,” according to Kohn. Watson’s future role in therapeutic decision making can be demonstrated in a joint venture between Memorial Sloan-Kettering Cancer Center and WellPoint. Watson is being taught to understand the critical attributes of a cancer patient’s history, to consult the literature and evidence-based guidelines, and come up with treatment recommendations. But big data and tools like Watson do far more than accumulate information, Kohn pointed out. They draw from multiple pathways to create a basis for making personalized decisions that are more likely to have value. It is not just “lots of data,” but data that encompass volume, velocity, variety, and variability. More real-world than Watson was the example given by Newcomer, who noted that UnitedHealth Group has access to a decade’s worth of information on 70 to 80

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million people that can be integrated with state tumor registries and insurance claims data to create longitudinal records for individuals. This will be used to profile chemotherapy regimens and their progression-free survival rates, he said. He expects this registry to be a more realistic picture than what is gained from clinical trial data and to be useful to third-party payers in determining coverage.

In clinical research, big data will allow for more sophisticated analyses that will “move us from information to real knowledge,” von Eschenbach predicted. Among the panelists, Andrew von Eschenbach, MD, of Samaritan Health Initiatives, was particularly enthusiastic. “Big data is the most critically important thing we could be talking about,” he said. “If we have any hope of improving outcomes, it’s in the big data.” The capturing of big data will revolutionalize basic research and allow for modeling in silico cellular processes, biological processes, and multiple oncologic pathways. In clinical research, big data will allow for more sophisticated analyses that will “move us from information to real knowledge,” he predicted. “Then, with physician engagement and interpretation, we get to wisdom,” he said, which should lead to the ultimate goal of giving the right treatment to the right patient for the right reason. “That is the difference between rational medicine and rationed medicine.” Others on the panel were more cautious. “The trick is not to acquire data alone,” according to Beveridge, but to assure that the integrity of the data is strong. Fox emphasized that data should not be used “in a vacuum,” but in the context of patient preferences, which may include no active intervention. “We think about how to improve overall survival, but the challenge is for us to think differently. Overall survival is not the sine qua non of cancer care.”

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How Brave the New World: The Evolving Ecosystem The future of cancer care requires a reformed “ecosystem,” in the words of Goodman. This means the integration of components in a multidisciplinary approach and a competitive collaboration to problem solving. As von Eschenbach described it, the evolving ecosystem is no longer centered on individual excellence but rather on interoperable performance. “We were trained to play golf. The game has switched to basketball,” he said. “It’s about interoperability, how to work together so that I can’t be as good as I need to be without Lee Newcomer,” he said. Goodman noted that von Eschenbach once headed up the National Cancer Institute: “Many competing

cancer institutions doing research.” von Eschenbach said the ideal scenario would not have been “61 separate phenomenal cancer centers but 61 playing together like a well-orchestrated team.”

Dr Goodman’s Summary “As we look toward a brave new world in oncology, it’s tempting to look at all the high-tech stuff we have for discovering the next cure, but in this roundtable we saw that in order to get to the next level, we can’t forget that we have disparities in care that drag the system down,” Goodman concluded. “We need to hold up that part of our at-risk population at the same time we advance the cutting edge with big data and reorganizing the cancer ecosystem. Our current incentives and disincentives are not providing for optimal care.” u

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Highlights From the American Association for Cancer Research Annual Meeting Alice Goodman

he American Association for Cancer Research (AACR) 2013 Annual Meeting was held in Washington, DC, April 6-10, 2013. Following are selected highlights of early studies presented at the meeting. The hope is that these encouraging preliminary findings will be confirmed by larger studies and lead to advances in cancer care.

Antibody-Drug Conjugate Encouraging in Platinum-Resistant Ovarian Cancer T-DM1 was the first antibody-drug conjugate to gain FDA approval for the treatment of HER2-positive metastatic breast cancer. Preliminary study suggests that a second antibody-drug conjugate is active in platinum-resistant ovarian cancer, and if the encouraging early results are confirmed by clinical trials, this would fulfill an unmet need for a difficult-to-treat cancer with limited treatment options. The antibody-drug conjugate DMUC5754A includes a monoclonal antibody that recognizes the MUC16 protein expressed by ovarian cancer cells and is linked to a potent antimitotic toxin called MMAE. The antibody targets MUC16, and the toxin is released selectively into tumor cells that express MUC16, limiting the effects of the toxin on healthy tissues and organs. MMAE is so potent that it could not be delivered directly to patients, explained lead author Joyce Liu, MD, MPH, Dana-Farber Cancer Institute, Boston, MA. The phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of DMUC5754A in 44 women with advanced, recurrent, platinum-resistant ovarian cancer. Among these heavily pretreated patients, there were 1 complete response and 4 partial responses. All 5 responses were observed in patients with high expression of MUC16 in their tumor cells. The maximum tolerated dose was identified as 2.4

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mg/kg, and the antibody-drug conjugate was given every 3 weeks. Dose-limiting toxicities included 1 grade 4 neutropenia and 1 grade 4 uric acid increase, occurring at a higher dose level. Grade 3 adverse events included fatigue in 9% of patients and neutropenia in 9%. Fatigue was the most common adverse event at all dose levels, occurring in 57% of patients. Nausea, vomiting, decreased appetite, diarrhea, and peripheral neuropathy were also reported.

The antibody-drug conjugate DMUC5754A includes a monoclonal antibody that recognizes the MUC16 protein expressed by ovarian cancer cells... “If the activity of this drug is confirmed in additional trials, this will represent a real step forward in finding new, effective treatments for advanced ovarian cancer,” Liu said. u

Reference

Liu J, Moore K, Birrer M, et al. Targeting MUC16 with the antibody-drug conjugate (ADC) DMUC5754A in patients with platinum-resistant ovarian cancer: a phase I study of safety and pharmacokinetics. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 6-10, 2013; Washington, DC. Abstract LB-290.

Genetically Engineered T Cells Show Promising Activity in Pediatric Leukemia A small preliminary study suggests that a unique immunotherapy called “anti-CD19 chimeric antigen receptor (CAR) T-cell therapy” can achieve complete remission in children with acute lymphocytic leukemia (ALL) who relapse after bone marrow transplantation (BMT). “Childhood ALL is the most common malignancy in pediatric patients. The majority of children can achieve remission, but this comes with the price of

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long therapy, toxicity, and cost, with no guarantee of long-term cure. Children who relapse have limited therapeutic options, and new therapies are sorely needed,” stated lead author of the study Daniel W. Lee III, MD, assistant clinical investigator in the Pediatric Oncology Branch of the National Cancer Institute, Bethesda, MD. Anti-CD19 CAR T-cell therapy is a new way to treat childhood cancer, he continued. This therapy uses the patient’s own immune cells that have been collected and then modified and expanded in the laboratory to attach to the CD19 protein expressed by leukemia cells. Activation of the T cells for immunity requires 2 signals, Lee explained. Leukemia cells do not generate the second signal required, and therefore the leukemia is not controlled. “Genetically engineered T cells get around this by being designed specifically to recognize the CD19 antigen. When they are reinfused into the patient, the receptor fires 2 signals and activates the T cells to kill the target tumor tissue,” he added.

Comprehensive genetic analysis by The Cancer Genome Atlas identified 4 different subtypes of squamous cell carcinoma of the head and neck. At AACR, Lee reported results in the first 4 patients treated with anti-CD19 CAR T-cell therapy. Three patients had ALL and had received BMT, and 1 patient had B-cell lymphoma. All patients received fludarabine and cyclophosphamide prior to receiving the CAR T cells. One ALL patient had a complete response, and a second ALL patient had a transient complete response, with minimal residual disease remaining. The B-cell lymphoma patient did not respond. The side effects were temporary and not seen in every patient, Lee continued. They included fever and low blood counts and were easily managed in the hospital. “Graft-versus-host disease is a side effect of concern in patients treated with BMT. We saw no evidence of

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this in the first 3 ALL patients we treated who had undergone previous BMT,” he said. “Anti-CD19 CAR T cells represent a new way to attack childhood leukemia. Preliminary evidence suggests that we can induce complete remission in patients refractory to other therapies,” Lee stated. u

Reference

Lee DW III, Shah N, Stetler-Stevenson M, et al. Autologous-collected anti-CD19 chimeric antigen receptor (CAR) T cells for acute lymphocytic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL) in children who have previously undergone allogeneic stem cell transplantation (HSCT). Presented at: American Association for Cancer Research 2013 Annual Meeting; April 6-10, 2013; Washington, DC. Abstract LB-138.

Genetic Analysis Identifies 4 Subsets of Squamous Cell Carcinoma of the Head and Neck Comprehensive genetic analysis by The Cancer Genome Atlas (TCGA) identified 4 different subtypes of squamous cell carcinoma of the head and neck (SCCHN). The analysis included 279 patients with previously untreated SCCHN. This is the 8th tumor type analysis of TCGA to be presented. “Our study will likely become a landmark research tool for SCCHN for many years as we gradually unlock the secrets of this massive data set,” said David N. Hayes, MD, MPH, a medical oncologist who is associate professor at the University of North Carolina in Chapel Hill. SCCHN is the 5th most common cancer worldwide and the 6th most common type in the United States. Forty-five thousand new cases are diagnosed each year. Smoking is a risk factor, as is the epidemic of human papilloma virus (HPV). Among the 279 patients included in the study, 80% had tobacco-related disease and 13% were HPV-positive. “We need to understand the mutations or individual alterations in the 15 most significant mutated genes in SCCHN,” Hayes said. In the study, significant mutations were found in the following genes: CDKN2A, TP53, PIK3CA, NOTCH1, HRAS, and NFE2L2. Looking at all gene expression subtypes of SCCHN, tumors organize themselves into 4 groups that tend

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to go along with differences in mutation patterns and chromosomal alterations, Hayes explained. The 4 subtypes are: 1. Atypical subtype with no amplification of EGFR, HPV positive, and a high rate of PI3 kinase mutations (PIK3CA); 2. Classical subtype, also seen in squamous cell lung cancer, associated with 2 key mutations: KEAP1 and NFE2L2; 3. Mesenchymal subtype, mostly FGR1 and FGR mutations; 4. Basal subtype, highly associated with SOX2 amplifications and overexpression. Some of these alterations overlap with squamous cell carcinoma of the lung, which is also a tobacco-related cancer. “We frequently see altered genomes in other tobacco-related cancers. One of the striking findings we observed was a high degree of similarity to other squamous tumors, including lung squamous cell carcinoma. Lessons learned from studying the similarities and differences between tumors, such as copy number alterations, will be an angle to pursue to better understand altered pathways in cancer. The idea that they share properties that go beyond the type of cancer means that this could be studied at a model systems level.” Other key observations of this study include: • HPV-positive and other patients have infrequent EGFR gene amplification • HPV-positive tumors have a high rate of PIK3CA gene mutations • HPV-infected patients almost never have p53 alterations • In HPV-negative patients, druggable mutations include EGFR, FGR, and CNCCC21 “We have made a lot of observations, but this also makes things more complicated. We are able to recognize patterns, and some of these patterns may turn out to be druggable, or actionable, in the future,” Hayes stated. “This is robust information that gives us data on mutational analysis and copy numbers, expression, promoter methylation, and other aspects of SCCHN. This data set confirms other publications indicating that there is

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a clear difference between HPV-positive patients who usually have a better prognosis and are easier to treat than HPV-negative patients. HPV-negative patients have many more mutations than HPV-positive patients,” stated Giuseppe Giaccone, MD, PhD, Georgetown University Medical Center’s Lombardi Comprehensive Cancer Center, Washington, DC. Giaccone moderated a press conference where these data were presented. u

Reference

Hayes DN, Grandis J, El-Naggar AK, et al. Comprehensive genomic characterization of squamous cell carcinoma of the head and neck in the Cancer Genome Atlas. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 6-10, 2013; Washington, DC. Abstract 1117.

Intermittent Vemurafenib May Overcome Resistance Vemurafenib is a relatively new effective option for the treatment of melanoma; unfortunately, most patients who respond will develop resistance. Studies by researchers at Novartis suggest that an intermittent dosing strategy may be able to overcome resistance that occurs with standard continuous dosing. “We were excited about the translational science that led to approval of the BRAF inhibitor vemurafenib, which extends survival in these patients. But most patients relapse with lethal drug-resistant disease,” explained Darrin Stuart, PhD, Novartis Institutes for Biomedical Research, Emeryville, CA, who presented results of early animal and human studies. In a previous study, Stuart and colleagues implanted xenografts of BRAF-expressing tumors in mice and found that the tumors developed resistance to vemurafenib. But possibly more important was the observation that the tumors were dependent on the drug for their proliferation. When drug treatment was withdrawn, the tumors stopped growing and regressed. The next step was to determine if the drug-dependency of the tumors was exhibited in humans. Stuart and colleagues collaborated with scientists at The Royal Marsden Hospital in London, United Kingdom, and evaluated 42 patients with vemurafenib-resistant tumors. Of these, 19 patients had CT scans obtained

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after drug treatment was stopped. Fourteen of 19 scans showed regression in the rate of tumor growth. Stuart and colleagues then performed another experiment on mice implanted with BRAF-expressing tumor xenografts; this time they treated them with vemurafenib 4 weeks on and 4 weeks off (intermittent strategy) or continuous vemurafenib. None of the tumors in the animals treated intermittently developed resistance. This suggests that a drug holiday and intermittent treatment could be beneficial in patients taking vemurafenib and might overcome resistance. Stuart was not at liberty to discuss Novartis’ plans for the future but stated that intermittent dosing was a strategy that he hopes researchers will pursue. u

Reference

Das Thakur M, Fisher R, Salangsang F, et al. Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 6-10, 2013; Washington, DC. Abstract LB-144.

Drug Combination Potentially Effective in BRCA-Deficient Solid Tumors Two orally available experimental drugs achieved response in patients with BRCA-deficient solid tumors in a phase 1 study of 31 patients. Responders were patients with BRCA mutations and incurable pancreatic, breast, and ovarian tumors. “There is definitely a group of responders who appear to benefit from this drug combination. This should be studied in a new, much larger prospective trial,” said lead author Geoffrey Shapiro, MD, PhD, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. Among the 31 patients, 16 had BRCA-deficient cancers. Patients received treatment with sapacitabine and seliciclib – 2 drugs developed by Cyclacel. Sapacitabine causes single-strand DNA breaks that are converted to double-strand DNA breaks during replication. The investigators in the phase 1 trial hypothesized that seliciclib would interfere with the repair of damaged DNA and enhance the cytotoxicity of sapacitabine, Shapiro explained. Patients were treated with sequential administration of both drugs for 10 days on, followed by an 11-day rest

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period. During the dose-escalation phase of the study, patients without BRCA mutations had stable disease. Two observations during the dose-escalation phase made researchers focus on the patients with BRCA mutations: 1) it was reported that the repair of DNA breaks caused by sapacitabine is depending on the homologous repair pathway, which includes BRCA proteins and is downregulated in their absence; and 2) a partial response was observed in a pancreatic cancer patient who was found to be a BRCA-mutation carrier. The trial was then limited to patients with BRCA-deficient cancers. Three additional partial responses (PRs) were observed (2 with breast cancer and 1 with ovarian cancer). The PRs have been durable in 3 patients (from 9 to 21 months). These 3 patients are continuing on study. In total, 6 of the 16 BRCA-mutation carriers benefitted from the drug combination (4 patients with PRs and 2 with stable disease). Shapiro said that nonresponders were heavily pretreated and too compromised to tolerate a cycle of the combination therapy and were therefore not evaluable. “Among the BRCA-proficient group, several patients had prolonged stable disease, but the response was not as dramatic as in the BRCA-deficient group,” he said. “Going forward, the combination therapy has the most chance of efficacy in BRCA-deficient patients.” Sequential administration of the 2 experimental agents was used in the trial. Concurrent administration of sapacitabine and seliciclib will be studied, as will different dosing schedules. PARP inhibitors are effective in BRCA-deficient patients. Shapiro said the responders in the trial had not been pretreated with a PARP inhibitor. “We need to determine if the combination works in patients pretreated with PARP. Finally, we have some drug classes that address inherited cancers,” Shapiro stated. u

Reference

Shapiro GI, Hilton J, Cleary JM, et al. Responses to sequential sapa citabine and seliciclib in patients with BRCA-deficient solid tumors. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 6-10, 2013; Washington, DC. Abstract LB-202.

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Higher HER2 Expression Leads to Better Outcomes With T-DM1 in HER2-Positive Metastatic Breast Cancer Phoebe Starr

mong women with HER2-positive metastatic breast cancer, those with the highest expression of HER2 had the best outcomes on treatment with T-DM1, according to a biomarker analysis of the phase 3 EMILIA trial presented at the American Association for Cancer Research 2013 Annual Meeting. Further, the analysis found that T-DM1 achieved superior outcomes in all patients enrolled in the trial versus capecitabine/lapatinib. The presence of PI3 kinase mutations (PIK3CA) had no effect on treatment with T-DM1, while these mutations compromised the effectiveness of capecitabine/lapatinib and are known to interfere with the effectiveness of trastuzumab. “HER2-positive breast cancer is the same in all patients. The data of our biomarker analysis will help personalize therapy for individuals with HER2-positive breast cancer and make informed treatment decisions,” stated José Baselga, MD, PhD, Physician in Chief at Memorial Sloan-Kettering Cancer Center in New York City. T-DM1 is the first antibody-drug conjugate to be approved by the FDA. The drug links the antibody trastuzumab to a highly potent toxic chemotherapy called emtansine. Trastuzumab attaches to the HER2 protein expressed in HER2-positive breast cancers and triggers the release of emtansine into the tumors, thereby killing tumor cells. Emtansine could not otherwise be administered to patients because it is so toxic, Baselga noted. EMILIA was designed to compare the effectiveness of T-DM1 versus capecitabine/lapatinib in patients with metastatic HER2-positive breast cancer previously treated with trastuzumab plus taxane chemotherapy. T-DM1 significantly improved both progression-free survival (PFS) and overall survival (OS) compared with capecitabine/lapatinib. Tumor samples were collected prospectively to study

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biomarkers. PFS and OS were correlated with biomarkers such as EGFR, HER2 mRNA, and PIK3CA. Median HER2 mRNA concentration ratios and PIK3CA mutation frequencies were similar across all treatment arms at baseline. T-DM1 achieved superior PFS and OS in all biomarker subgroups. However, high expressors of HER2 mRNA levels derived even more benefit from T-DM1 than those with lower levels of expression. In the high expressors, median PFS was 34.1 months with T-DM1 versus 24.8 months with capecitabine/lapatinib.

At present, the working hypothesis is that tumors with high HER2 overexpression are hypersensitive to anti-HER2 therapies and may not need additional chemotherapy. The presence of PIK3CA mutations had no effect on PFS or OS in patients treated with T-DM1, but in the capecitabine/lapatinib arm, the presence of PIK3CA mutations led to worse outcomes than with wild-type PIK3CA. “T-DM1 is PIK3CA mutation neutral,” Baselga told listeners. At present, the working hypothesis is that tumors with high HER2 overexpression are hypersensitive to anti-HER2 therapies and may not need additional chemotherapy. “But this is speculation at this point,” he explained. T-DM1 is currently being studied earlier in the course of disease as adjuvant therapy, and also as firstline therapy for metastatic disease. Novel antibody-drug conjugates are in development for other types of cancer, he noted. u

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Crizotinib and Colorectal Cancer – A Couple to Be Tested? Sebastian Stintzing, MD; Heinz-Josef Lenz, MD, FACP University of Southern California/Norris Comprehensive Cancer Center Keck School of Medicine Sharon Carpenter Laboratory Los Angeles, California

Key Points • It is estimated that about 2.4% of all CRCs bear an ALK fusion gene, but so far the biological and clinical relevance have not been revealed • c-Met expression levels are increased in pretreated CRC specimens • c-Met signaling has been shown to overcome anti-EGFR treatment and may therefore be an important factor of secondary resistance to anti-EGFR treatment

rizotinib, a multikinase inhibitor, has recently shown activity in the treatment of anaplastic lymphoma kinase (ALK) fusion gene positive non–small cell lung cancer (NSCLC)1 and has therefore been approved for the treatment of ALK-positive NSCLC by the medical agencies in the United States and Europe.2 Although only 3% to 5% of NSCLCs are EML4-ALK positive, this extended personalized treatment of lung cancer has changed clinical practice. Next to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib that are approved for the treatment of EGFR-mutated NSCLC,3-5 crizotinib is another class of kinase inhibitor, being approved for a molecularly defined subset of lung cancer fragmenting NSCLC. In metastatic colorectal cancer (mCRC), one of the most common tumors worldwide, kinase inhibitors targeting EGFR, vascular endothelial growth factor

Sebastian Stintzing, MD

Heinz-Josef Lenz, MD, FACP

receptor (VEGFR), and others, with the exception of regorafenib, have failed to demonstrate clinical effectiveness, and therefore treatment strategies have been

Dr Stintzing is currently a postdoctoral fellow of the German Cancer Aid at the University of Southern California/Norris Comprehensive Cancer Center. Dr Stintzing’s research focus is on predictive and prognostic factors in the treatment of metastatic colorectal cancer. Dr Lenz is the Associate Director for Clinical Research and Co-Leader of the Gastrointestinal Cancers Program at the University of Southern California/Norris Comprehensive Cancer Center. Dr Lenz is Professor of Medicine and Preventive Medicine, Section Head of GI Oncology in the Division of Medical Oncology and Co-Director of the Colorectal Center at the Keck School of Medicine of the University of Southern California.

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less successful. Whether this is a disease-specific issue or lack of patient selection is unknown. This review will provide insights into molecularly defined subgroups and development of more effective therapies, with the focus on the pathways targeted by crizotinib in mCRC.

Crizotinib – Mechanism of Action – the NSCLC Story Crizotinib (Xalkori) is an orally administered multikinase inhibitor that has been developed using a structure-based drug design program for inhibiting the hepatocyte growth factor receptor (c-Met)-signaling with a half maximal inhibitory concentration (IC50) of 5 to 20 nM.6,7 Further evaluation revealed inhibition of cell proliferation in an ALK-positive large cell lymphoma cell with an IC50 of about 30 nM.7 In xe-

Trials in lung cancer using crizotinib are testing the efficacy and safety of crizotinib against pemetrexed and platinum or with other kinase inhibitors. nograft mouse models crizotinib was able to inhibit nucleophosmin-ALK (NPM-ALK) phosphorylation in a dose-dependent manner and induced apoptosis in tumorous tissue.8 Furthermore, inhibition of the oncogene ROS1 signaling has been described as a target of crizotinib.9 EML4-ALK fusion genes are found in about 5% of NSCLC. Because there is a negative association with smoking history in the subgroup of nonsmokers or patients with only a light smoking history, the EML4-ALK fusion gene is found in up to 10%.10 A phase 1 clinical trial established 250 mg bid as the recommended dosage for crizotinib. This trial has been extended, and patients bearing the EML4-ALK mutation have achieved an unexpected tumor response and clinical improvement. To reach the total of 119 patients, a cohort of about 1500 patients had to be screened for ALK fusion genes. This trial, conducted in heavily pretreated NSCLC patients

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bearing an EML4-ALK fusion, demonstrated an overall response rate of 60.8%, a progression-free survival (PFS) of 9.7 months, and a 1-year survival rate of 75%. The most common National Cancer Institute Common Terminology Criteria for Adverse Events grade 3/4 adverse events were neutropenia, elevated alanine aminotransferase, hypophosphatemia, and lymphopenia.1 These data led to the approval of crizotinib in the treatment of EML4-ALK–positive NSCLC.2 Ongoing trials in lung cancer using crizotinib are testing the efficacy and safety of crizotinib in a randomized setting against standard chemotherapy with pemetrexed and platinum (NCT01154140)11 or with other kinase inhibitors. Efficacy in other tumor entities is to be tested as well. Among those are anaplastic large cell lymphoma, glioma, and other advanced tumors if ALK fusion genes, ROS aberrations, or elevated c-Met expression is determined.11

ALK Function – Fusion – Frequency ALK is a member of the insulin receptor proteintyrosine kinases superfamily. A detailed review of structure and oncogenic activation has recently been published.12 In short, ALK is involved in embryogenesis and is thought to be important for brain development,13 as ALK expression is seen during mouse embryogenesis. However, ALK knockout mice show no obvious abnormalities and have a normal lifespan.14 In adulthood, ALK is expressed in the brain, small intestine, testis, prostate, and colon,13 although the exact mechanism of action is not yet clear.15 Even the ligands to the ALK receptor in humans are still undiscovered, as ligands in animal models are lacking mammalian homologues. But the pathways to be activated by ALK signaling have been described using NPM-ALK fusion gene signaling in lymphoma cells. This fusion gene has the ability to activate ALK signaling by autophosphorylation. Among the pathways to be activated by ALK are the Ras/Raf/ MEK/ERK1, JAK/STAT, PI3K/Akt, and PLc pathways, which lead to cell survival and cell division.8,16 All these pathways are known to be important for oncogenesis and development of metastasis. The physiological signal

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Figure. ALK Fusion â&#x20AC;&#x201C; Intracellular Signaling Pathways in Solid Tumors

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Â&#x2022;â&#x20AC;˘ Â&#x2022;â&#x20AC;˘ Â&#x2022;â&#x20AC;˘ Â&#x2022;â&#x20AC;˘ Â&#x2022;â&#x20AC;˘

transduction has not yet been elucidated. In addition to the NPM-ALK fusion gene, which drives 50% to 60% of the anaplastic large cell lymphoma cases,17 many other fusion genes with the ability to induce ALK signaling have been described. Although inflammatory myofibroblastic tumors have a reported frequency of 27%,7 clinically the most important ALK fusion gene in solid tumors is the EML4-ALK fusion gene in NSCLC. It can be found in a number of variants (currently 13 described variants) in about 5% of NSCLC patients.18 EML4-ALK fusion genes are able to activate Ras/ERK1/2, Akt, and JAK/STAT.19 As crizotinib has shown efficacy and therefore been approved for the treatment of NSCLC

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Legend: , EGFR: epidermal growth factor receptor # ! , ! ! (# # ! ! AREG: amphiregulin , ! & EREG: epiregulin , ! & HGF: growth factor , hepatocyte # )# ! (# # ! c-Met: Met-transforming gene - #, #-#! " ! RTKI: receptor kinase , ! tyrosine # ! #)! " " , "$ ) " ALK: anaplastic lymphoma kinase , RAS: rat ! # " ! sarcoma , ! # - -! RAF: proto-oncogene-raf

, # $' # ! # " " MEK: mitrogen-activated protein kinase kinase ), " " PLCy: phospholipase C / , " $ ) " # /- " PI3K: phosphatidylinositol 3-kinase , ! # " AKT: protein kinase B , # ! # ! ) mTOR: mammalian target of rapamycin , " $ ) " # 0+1- " " # PIP 2: , . phosphatidylinositol " # #! - " 4,5-bisphosphate # / IP3: inositol tri-phosphate

tumors harboring an ALK fusion gene, this has pushed the research efforts in the field of ALK fusion genes. During the past few years, in addition to NSCLC, ALK fusion genes have been found in many other solid tumors, including inflammatory myofibroblastic tumors,20 breast cancer,21 esophageal squamous cell cancer,22 renal cell cancer,23 and colorectal cancer (CRC).21 The frequency in adult solid tumors is less than 5% but is still undetermined in many tumors. Another tyrosine kinase targeted by crizotinib is c-Met.

c-Met Function The MET proto-oncogene encodes for hepatocyte

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growth factor receptor (HGFR), also named c-Met, and has been described to be essential for embryonic development and can trigger invasive growth in cancer cells. In adulthood, c-Met signaling is important in many physiological processes such as wound healing, tissue regeneration, and morphogenic differentiation.24 The activity of c-Met as a receptor tyrosine kinase is usually low in normal tissue but tends to be dysregulated in tumorous tissue.25 Further experiments have shown that c-Met signaling by HGF facilitates cell proliferation, survival, differentiation, motility, and invasion,24 all of which are important for oncogenesis. Somatic mutations of c-Met were described for the first time in hereditary papillary renal cell carcinomas in 200324 and have later been reported in other solid cancers such as

The activity of c-Met as a receptor tyrosine kinase is usually low in normal tissue but tends to be dysregulated in tumorous tissue. gastric cancer, head and neck cancer, primary liver cancer, ovarian cancer, NSCLC, and thyroid cancer.26 In addition to those activating mutations, higher levels of HGF leading to increased c-Met signaling have been described in many solid tumors, and overexpression of c-Met has been established in many solid tumors.26 Among these are lung,27 breast,28 ovarian,29 kidney,30 colon,30 gastric,30 thyroid,30 pancreas,31 and head and neck cancer.32 Higher c-Met expression was associated with poorer prognosis or advanced stage26 in most of these solid tumors, making c-Met an interesting target for tumor growth inhibition.33 Furthermore, analyses investigating NSCLC patients who have become resistant to anti-EGFR treatment with EGFR TKIs were able to establish c-Met amplification as one possible mechanism of anti-EGFR resistance.34,35 Two possible bypass mechanisms have been proposed: 1) c-Met signaling might initiate downstream signaling via MAPK/ PI3K/Akt independent of the EGFR, or 2) c-Met may

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be activated via ErbB crosstalk and therefore amplify its protumorigenic signaling.26 Major downstream signaling pathways activated by c-Met include the PI3K/Akt pathway leading to proliferation and cell growth,36 and the MAPK pathway.37 Furthermore, receptor tyrosine kinase crosstalk, including EGFR, cell-cell adhesions, cell motility, and endocytosis, are influenced by c-Met signaling, emphasizing its potential role in cancer development.37 As c-Met signaling is known to have the ability to escape EGFR inhibition38 in vitro, it would be of interest to biopsy CRC metastases that became resistant to anti-EGFR treatment to find a possible treatment option for c-Met inhibitors. A recent report showing clinical efficacy of crizotinib in 2 patients suffering from esophagogastric adenocarcinoma with c-Met amplification39 does encourage testing this mechanism in CRC as well.

ROS1 Function ROS1 is a receptor tyrosine kinase of the insulin receptor superfamily. Structurally similar to ALK, with which it shares a similarity of 48.92% in amino acid sequence,40 the ligand is not yet known. It was first described in 1982,41 and its oncogenic potential was demonstrated in 198442 by transforming NIH3T3 cells to tumorous lesions in nude mice. Further investigations discovered ROS1 in glioblastoma cell lines.43 In glioblastoma the fusion gene was called fusion in glioblastoma (FIG-ROS1).44 Proving its importance in human solid tumors, ROS1 rearrangements have been described in NSCLC at a frequency of about 1.6%.45 In NSCLC, other fusion partners than in glioblastoma can be found. Different from FIG-ROS1, which is located in the Golgi apparatus,43 CD74-ROS1,46,47 SLC34A2ROS1,46 SDC4-ROS1, TPM3-ROS1, EZR-ROS1, and LRIG3-ROS1,48 which have been described in NSCLC patients, are all located on the cell surface. This might explain the difference in function and treatability. In gastrointestinal cancer, only the fusion genes FIGROS147 in cholangiocellular carcinoma and SLC34A2ROS149 in gastric cancer have been described. The signal pathways transduced by ROS1 are similar

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to those activated by ALK fusion genes. Most important is the activation of PI3K/Akt/mTOR50 and PLc pathways, leading to changes in differentiation and apoptosis and an increased translational capacity. The RAS/ MAPK/MEK pathway does not seem to be activated by ROS1 signaling.50 Interestingly, ROS1 is capable of phosphorylate cytoskeleton proteins and therefore interacts with alpha-, beta-, and delta-catenin,51 which may represent a possible interaction with the oncogenic potential of the beta-catenin-wnt pathway. Furthermore, ROS1 signaling can be inhibited by crizotinib.52

Metastatic Colorectal Cancer The treatment of mCRC has made notable progress during the past 10 years. Until recently, clinical effectiveness was based on chemotherapeutic combination regimens using 5-fluorouracil (5-FU) and leucovorin (folinic acid) in combination with either irinotecan (FOLFIRI regimen)53 or oxaliplatin (FOLFOX regimen).54 However, with the introduction of monoclonal antibodies to those combination therapies, median overall survival (OS) times of about 24 months have been reached.55-59 Targets for those antibodies are either vascular endothelial growth factor (VEGF) with bevacizumab59 or EGFR with cetuximab56,57 and panitumumab.55 Anti-EGFR antibodies do not have efficacy in the subset of patients with KRAS-mutated tumors and are therefore limited to the treatment of KRAS wild-type tumors. The activating KRAS mutation, with a frequency of about 40%, is the only accepted predictive factor in the treatment of CRC,60 although it has become clear during the past few years that CRC is not 1 disease but many, defined by their individual genomic landscape.61 Along with the use of targeted therapy, the expansion of the chemotherapeutic regimen to FOL FOXIRI has been successful in improving efficacy in randomized trials.62 TKI Experience in mCRC It has become evident that many CRCs are dependent on the activation of 3 signaling pathways that are in part overlapping and have the ability to crosstalk.

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RAS/RAF/MEK, PLCy/PIP2/IP3, and PI3K/AKT/mTOR signaling pathways have therefore become main targets of kinase inhibitor research. Furthermore, angiogenesis is an important mechanism in tumor growth and progression. Multiple inhibitors have been created63 and are being tested alone or in combination. The Table lists ongoing phase 2 and phase 3 trials. The combination approach tries to increase efficacy by inhibiting 2 or more of these pathways at once to circumvent possible mechanisms of resistance. Although some of these inhibitors have shown promising results in phase 2 studies, most of them have failed to demonstrate activity in phase 3 trials. Therefore, the only approved

Regorafenib, a multitarget angiogenesis inhibitor, has shown significantly increased survival in heavily pretreated colorectal cancer patients. multikinase inhibitor for the treatment of mCRC is regorafenib. Regorafenib, a multitarget angiogenesis inhibitor, has shown significantly increased survival in heavily pretreated CRC patients.64 Some multikinase inhibitors like the VEGFR TKI cediranib65 or the multitargeted angiogenesis inhibitor vatalanib66 made it to phase 3 trial level but failed to demonstrate significant treatment advance. The reasons for that may well be that the whole patient population and not a molecular subset of “favorable” patients was treated. For example, vatalanib showed efficacy especially in the subset of patients presenting with a lactate dehydrogenase elevation.66 Other interesting targets for kinase inhibitors in mCRC may be found in the EGFR-dependent pathway. Among those, the BRAF mutation with a frequency of about 4% is most likely a favorable target, as the BRAF inhibitor vemurafenib is already approved for the treatment of BRAF-mutated malignant melanoma.67 Many phase 1/2 trials are currently testing a wide variety of TKIs in CRC.63 The most important problem to be addressed is screening enough patients to define the

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Table. Ongoing Clinical Phase 2/3 Trials Using Kinase Inhibitors Company

Target

Cancer Type

Phase of Clinical Trial

AZD8055

AstraZeneca

mTORC1/2

Solid tumors

1/2

MK2206

Merck

Akt and MEK

mCRC enriched for PTEN loss 2 and PI3CA mutation

Everolimus

Novartis

mTORC1

mCRC

Temsirolimus

Pfizer

mTORC1

CRC

BEZ235 + MEK162

Novartis

PI3K, mTOR, and MEK1/2

CRC and other solid tumors

1/2

PX-866 + cetuximab

Oncothyreon

Pan-PI3K and EGFR

mCRC

1/2

Perifosine + capecitabine

Keryx

Akt

mCRC

MK2206 + AZD6244

Merck

Akt and MEK

mCRC

Everolimus + irinotecan + cetuximab

Novartis

mTOR, EGFR, and Topo-1

mCRC

Everolimus + bevacizumab

Novartis

mTOR + VEGF

mCRC

Everolimus + FOLFOX + bevacizumab

Novartis

mTOR + VEGF

mCRC

1/2

Everolimus + panitumumab + irinotecan

Novartis + Amgen

mTORC1, EGFR, and Topo-1

mCRC

1/2

Temsirolimus + irinotecan

Pfizer

mTORC1 and Topo-1

mCRC KRAS mutated

BKM120 + panitumumab

Novartis

PI3KI + EGFR

mCRC KRAS wild-type

MEK162 + AMG 479

Novartis

MEK + IGFR

mCRC KRAS or BRAF mutated

Regorafenib + FOLFIRI

Bayer

VEGFR-TIE2, multitarget angiogenesis

mCRC

Regorafenib + FOLFOX

Bayer

VEGFR-TIE2, multitarget angiogenesis

mCRC

Vatalanib + FOLFOX

Pfizer

Multitarget angiogenesis

mCRC

Nintedanib+ FOLFOX

Boehringer Ingelheim

Multitarget angiogenesis

mCRC

Bayer

RAF, VEGFR, and PDGFR

mCRC

Roche

EGFR

mCRC

eIF4E

mCRC

Drug Name PI3K pathway

Angiogenesis

RAF/RAS/ERK pathway Sorafenib + cetuximab EGFR inhibitor Erlotinib + chemo

Translation initiating inhibitors ISIS 183750 + irinotecan

Isis Pharmaceuticals

Source: www.clinicaltrials.gov. 5-FU indicates 5-fluorouracil; Akt, protein kinase B; EGFR, epithelial growth factor receptor; eIF4E, eukaryotic translation initiation factor 4E; FOLFOX, 5-FU, oxaliplatin, leucovorin; IGFR, insulin-like growth factor receptor; (m)CRC, (metastatic) colorectal cancer; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; PI3KI, phosphatidylinositide 3-kinase; PTEN, phosphatase and tensin homologue; RAF, raf serine/threonine-specific protein kinase; Topo-1, DNA topoisomerase-1; VEGF(R), vascular endothelial growth factor (receptor).

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patient cohort that most likely will benefit from those targeted therapies. The questions arise if crizotinib, a c-Met, ALK, and ROS1 inhibitor, would make sense in the treatment of mCRC; and if yes, which molecularly defined subset of patients would be most likely to benefit from crizotinib therapy? Using immunohistochemistry (IHC), c-Met is overexpressed in 78% of primary CRC specimens, but only 8% express phospho-Met as a sign of activity.30 c-Met gene amplification is known to be a marker for advanced CRC, and liver metastases tend to have higher c-Met expression than the primary tumor specimen.68 Furthermore, c-Met has been described to be a negative prognostic marker in mCRC69 and its ligand HGF to be a negative prognostic factor in Union for International Cancer Control stage III CRC.70 Primary resistance to the anti-EGFR antibody cetuximab has been linked to c-Met activation in NSCLC71 and CRC cell lines.72 Using fluorescence in situ hybridization technique in a retrospective analysis of 85 chemotherapy-refractory CRC patients, primary resistance to cetuximab could not be attributed to c-Met overexpression in the primary tumor specimen.73 This might well be due to a relatively rare occurrence of c-Met overexpression (7/76; 9.2%). This is supported by findings from a mouse xenograft model of mCRC in which no correlation between c-Met overexpression and therapeutic responsiveness to c-Met inhibitors could be established, but the transcriptional factor for c-Met, MACC1, was predictive for outcome.74 In contrast, another group reported a possible influence of IHC-detected c-Met on PFS and OS in cetuximab-treated mCRC patients.75 Because the relevance of c-Met in secondary resistance to anti-EGFR treatment in the clinical setting is still under discussion, a study investigating the evolution of the biology of CRC metastasis during antiEGFR treatment is needed. Therefore, serial tumor biopsies and a comprehensive program to detect gene expression levels are essential. ALK fusion genes being another target of crizo-

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tinib is a very rare event in CRC. The frequency of the EML4-ALK fusion gene is estimated to be 2.4%.21 Lately another ALK fusion gene (C2orf44-ALK) has been described by next-generation sequencing (NGS) screening of 40 CRC cases.76 Additional ALK mutations (E17K mutation) have been found at a frequency of 6% in a cohort of 51 mCRC patients.77 Therefore, there might be another group of CRC patients that could possibly benefit from an ALK inhibitor like crizotinib.

Primary resistance to the anti-EGFR antibody cetuximab has been linked to c-Met activation in NSCLC and CRC cell lines. To date, no published data on the frequency and biological relevance of ROS1 in CRC are available. Studies in mCRC currently testing the effect and safety of inhibitors of the c-Met signaling pathway include the following: • Tivantinib (Daiichi Sankyo Inc, ARQ 197); a small molecule inhibiting the c-Met tyrosine kinase; it is being tested in a phase 1/2 setting with the combination of irinotecan and cetuximab in patients in whom frontline chemotherapy has failed (NCT01075048)11 • LY2801653 (Eli Lilly); a small molecule inhibitor of c-Met being tested in a phase 1 setting in advanced cancers. It has shown antitumor activity in tumor xenografts.78 CRC patients may be recruited (NCT01285037)11 • Rilotumumab (Amgen, AMG 102); a fully human antibody that targets HGF and therefore inhibits c-Met signaling. It is being tested in a phase 1/2 setting alone and in combination with panitumumab in mCRC patients (NCT00788957)11 As with many TKIs, development of resistance to crizotinib has been demonstrated in several in vitro studies. So far, the following mechanisms of resistance have been described: 1) cells undergo an oncogenic switch and become EGFR dependent,79,80 2) cells ex-

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press increased levels of MET and amplify KRAS and therefore overcome the inhibition by c-Met inhibitors and sustain high MAPK and PI3K/Akt signaling,81 and 3) recently a mutation of c-Met (Y1230H) has been described to overcome kinase inhibition.82

It is estimated that about 2.4% of CRCs bear an ALK fusion gene, but so far the biological and clinical relevance have not been revealed. Conclusion ALK fusion genes are rare in mCRC, although with the NGS technique on its way this subgroup could grow as more ALK fusion genes may be identified. It is estimated that about 2.4% of all CRCs bear an ALK fusion gene, but so far the biological and clinical relevance have not been revealed. Also, ROS1 has not been described in CRC specimens. Both factors seem to be rare, and the screening for a trial targeting the ALK fusion gene in a randomized setting is difficult. There are emerging data that c-Met expression levels are increased in pretreated CRC specimens. Furthermore, c-Met signaling has been shown to overcome anti-EGFR treatment and may therefore be an important factor of secondary resistance to anti-EGFR treatment. Although in vivo data on the mechanism on EGFR resistance are still missing, there are strong in vitro data suggesting this receptor tyrosine kinase crosstalk and oncogenic switch to maintain MAPK and PI3K/Akt signaling is important for a subgroup of CRC tumors. As this switch works vice versa, crizotinib in CRC should be combined with an anti-EGFR strategy to prevent crizotinib resistance. This concept of double inhibition (anti-EGFR and anti–c-Met) is currently being tested in several studies on the phase 1/2 level. Furthermore, a recent case report has been published showing that the combination of high-dose pemetrexed and crizotinib is tolerable and might expand the usage

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of crizotinib in NSCLC,83 so a combination with chemotherapy seems to be an option to be tested in mCRC as well. It might be clinically meaningful to biopsy CRC patients at the time of progression to evaluate c-Met expression levels repeatedly and treat the subgroup of patients with elevated c-Met expression levels in a randomized trial testing a combination of anti-EGFR antibody and crizotinib. u

References

1. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13:1011-1019. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Non-Small Cell Lung Cancer. Version 2.2013. http://www.nccn.org/professionals/physician_gls/f_guide lines.asp#nscl. 3. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139. 4. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497-1500. 5. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101:13306-13311. 6. Ou SH. Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged nonsmall cell lung cancer and beyond. Drug Des Devel Ther. 2011;5:471-485. 7. Cui JJ, Tran-Dubé M, Shen H, et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011;54:6342-6363. 8. Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 2007;6(12 Pt 1):3314-3322. 9. Chin LP, Soo RA, Soong, R, et al. Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer. J Thorac Oncol. 2012;7:1625-1630. 10. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4ALK. J Clin Oncol. 2009;27:4247-4253. 11. www.clinicaltrials.gov. January 2013. 12. Roskoski R Jr. Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition. Pharmacol Res. 2013;68:68-94. 13. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1995;267:316-317. 14. Duyster J, Bai RY, Morris SW. Translocations involving anaplastic lymphoma kinase (ALK). Oncogene. 2001;20:5623-5637. 15. Iwahara T, Fujimoto J, Wen D, et al. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene. 1997;14:439-449. 16. Chiarle R, Voena C, Ambrogio C, et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8:11-23. 17. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994;263:1281-1284. 18. Sanders HR, Li HR, Bruey JM, et al. Exon scanning by reverse tran-

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scriptase-polymerase chain reaction for detection of known and novel EML4-ALK fusion variants in non-small cell lung cancer. Cancer Genet. 2011;204:45-52. 19. Palmer RH, Vernersson E, Grabbe C, et al. Anaplastic lymphoma kinase: signalling in development and disease. Biochem J. 2009;420:345-361. 20. Armstrong F, Duplantier MM, Trempat P, et al. Differential effects of X-ALK fusion proteins on proliferation, transformation, and invasion properties of NIH3T3 cells. Oncogene. 2004;23:6071-6082. 21. Lin E, Li L, Guan Y, et al. Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers. Mol Cancer Res. 2009;7:1466-1476. 22. Jazii FR, Najafi Z, Malekzadeh R, et al. Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer. World J Gastroenterol. 2006;12:71047112. 23. Debelenko LV, Raimondi SC, Daw N, et al. Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum. Mod Pathol. 2011;24:430-442. 24. Birchmeier C, Birchmeier W, Gherardi E, et al. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915-925. 25. Jung KH, Park BH, Hong SS. Progress in cancer therapy targeting c-Met signaling pathway. Arch Pharm Res. 2012;35:595-604. 26. Sierra JR, Tsao MS. c-MET as a potential therapeutic target and biomarker in cancer. Ther Adv Med Oncol. 2011;3(1 suppl):S21-S35. 27. Wang NS, Liu C, Emond J, et al. Annulate lamellae in a large cell lung carcinoma cell line with high expression of tyrosine kinase receptor and proto-oncogenes. Ultrastruct Pathol. 1992;16:439-449. 28. Tuck AB, Park M, Sterns EE, et al. Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. Am J Pathol. 1996;148:225-232. 29. Aune G, Lian AM, Tingulstad S, et al. Increased circulating hepatocyte growth factor (HGF): a marker of epithelial ovarian cancer and an indicator of poor prognosis. Gynecol Oncol. 2011;121:402-406. 30. Ma PC, Tretiakova MS, MacKinnon AC, et al. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer. 2008;47:1025-1037. 31. Furukawa T, Duguid WP, Kobari M, et al. Hepatocyte growth factor and Met receptor expression in human pancreatic carcinogenesis. Am J Pathol. 1995;147:889-895. 32. Liu N, Furukawa T, Kobari M, et al. Comparative phenotypic studies of duct epithelial cell lines derived from normal human pancreas and pancreatic carcinoma. Am J Pathol. 1998;153:263-269. 33. Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 2010;11:834-848. 34. Turke AB, Zejnullahu K, Wu YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010;17:77-88. 35. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A. 2007;104:20932-20937. 36. Ponzetto C, Bardelli A, Zhen Z, et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/ scatter factor receptor family. Cell. 1994;77:261-271. 37. Organ SL, Tong J, Taylor P, et al. Quantitative phospho-proteomic profiling of hepatocyte growth factor (HGF)-MET signaling in colorectal cancer. J Proteome Res. 2011;10:3200-3211. 38. Camp ER, Summy J, Bauer TW, et al. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res. 2005;11:397-405. 39. Lennerz JK, Kwak L, Ackerman A, et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol. 2011;29:4803-4810. 40. Ou SH, Tan J, Yen Y, et al. ROS1 as a ‘druggable’ receptor tyrosine kinase: lessons learned from inhibiting the ALK pathway. Expert Rev Anticancer Ther. 2012;12:447-456. 41. Shibuya M, Hanafusa H, Balduzzi PC. Cellular sequences related to three new onc genes of avian sarcoma virus (fps, yes, and ros) and their expression in normal and transformed cells. J Virol. 1982;42:143-152. 42. Fasano O, Birnbaum D, Edlund L, et al. New human transforming

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genes detected by a tumorigenicity assay. Mol Cell Biol. 1984;4:1695-1705. 43. Birchmeier C, Sharma S, Wigler M. Expression and rearrangement of the ROS1 gene in human glioblastoma cells. Proc Natl Acad Sci U S A. 1987;84:9270-9274. 44. Charest A, Lane K, McMahon K, et al. Association of a novel PDZ domain-containing peripheral Golgi protein with the Q-SNARE (Q-soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor) protein syntaxin 6. J Biol Chem. 2001;276:29456-29465. 45. Rimkunas VM, Crosby KE, Li D, et al. Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: identification of a FIG-ROS1 fusion. Clin Cancer Res. 2012;18:4449-4457. 46. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:11901203. 47. Gu TL, Deng X, Huang F, et al. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One. 2011;6:e15640. 48. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18:378-381. 49. Lee J, Lee SE, Kang SY, et al. Identification of ROS1 rearrangement in gastric adenocarcinoma. Cancer. 2013;119:1627-1635. 50. Nguyen KT, Zong CS, Uttamsingh S, et al. The role of phosphatidyl inositol 3-kinase, rho family GTPases, and STAT3 in Ros-induced cell transformation. J Biol Chem. 2002;277:11107-11115. 51. Zong CS, Chan JL, Yang SK, et al. Mutations of Ros differentially effecting signal transduction pathways leading to cell growth versus transformation. J Biol Chem. 1997;272:1500-1506. 52. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30:863-870. 53. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041-1047. 54. Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol. 1999;17:3560-3568. 55. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706-4713. 56. Van Cutsem E, Köhne CH, Láng L, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29:2011-2019. 57. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663-671. 58. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342. 59. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013-2019. 60. Di Fiore F, Blanchard F, Charbonnier F, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer. 2007;96:1166-1169. 61. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330-337. 62. Loupakis F, Cremolini C, Masi G, et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic co lorectal cancer (MCRC): results of the phase III randomized TRIBE trial. J Clin Oncol. 2012;30(suppl 34). Abstract 336. 63. Yu M, Grady WM. Therapeutic targeting of the phosphatidylinositol 3-kinase signaling pathway: novel targeted therapies and advances in the treatment of colorectal cancer. Therap Adv Gastroenterol. 2012;5:319-337. 64. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303-312.

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65. Schmoll HJ, Cunningham D, Sobrero A, et al. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol. 2012;30:3588-3595. 66. Hecht JR, Trarbach T, Hainsworth JD, et al. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011;29:1997-2003. 67. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809-819. 68. Zeng ZS, Weiser MR, Kuntz E, et al. c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett. 2008;265:258-269. 69. Kammula US, Kuntz EJ, Francone TD, et al. Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome. Cancer Lett. 2007;248:219-228. 70. Toiyama Y, Miki C, Inoue Y, et al. Serum hepatocyte growth factor as a prognostic marker for stage II or III colorectal cancer patients. Int J Cancer. 2009;125:1657-1662. 71. Krumbach R, Schüler J, Hofmann M, et al. Primary resistance to cetuximab in a panel of patient-derived tumour xenograft models: activation of MET as one mechanism for drug resistance. Eur J Cancer. 2011;47:1231-1243. 72. Liska D, Chen CT, Bachleitner-Hofmann T, et al. HGF rescues colorectal cancer cells from EGFR inhibition via MET activation. Clin Cancer Res. 2011;17:472-482. 73. Cappuzzo F, Varella-Garcia M, Finocchiaro G, et al. Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer. 2008;99:83-89. 74. Galimi F, Torti D, Sassi F, et al. Genetic and expression analysis of

MET, MACC1, and HGF in metastatic colorectal cancer: response to met inhibition in patient xenografts and pathologic correlations. Clin Cancer Res. 2011;17:3146-3156. 75. Inno A, Di Salvatore M, Cenci T, et al. Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer? Clin Colorectal Cancer. 2011;10:325-332. 76. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012;18:382-384. 77. Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448:439444. 78. Yang WJ, Credille K, Gao H, et al. LY2801653, an orally available small molecule inhibitor of c-Met, demonstrated broad antitumor efficacy in patient derived xenograft models. Cancer Res. 2010;70(suppl). Abstract 3611. 79. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039-1043. 80. Corso S, Ghiso E, Cepero V, et al. Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition. Mol Cancer. 2010;9:121. 81. Cepero V, Sierra JR, Corso S, et al. MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors. Cancer Res. 2010;70:7580-7590. 82. Qi J, McTigue MA, Rogers A, et al. Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors. Cancer Res. 2011;71:1081-1091. 83. Gandhi L, Drappatz J, Ramaiya NH, et al. High-dose pemetrexed in combination with high-dose crizotinib for the treatment of refractory CNS metastases in ALK-rearranged non-small-cell lung cancer. J Thorac Oncol. 2013;8:e3-e5.

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SECOND ANNUAL CONFERENCE

2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS

• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma

• Squamous Cell Carcinoma • Merkel Cell Carcinoma

July 26-28, 2013 Hyatt Regency La Jolla • at Aventine 3777 La Jolla Village Drive • San Diego, California

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Fourth Annual Navigation and Survivorship Conference Memphis, Tennessee â&#x20AC;˘ The Peabody Memphis

NOVEMBER 15-17, 2013 CONFERENCE CO-CHAIRS Lillie D. Shockney, RN, BS, MAS AONN Program Director University Distinguished Service Associate Professor of Breast Cancer Departments of Surgery and Oncology Administrative Director, Johns Hopkins Clinical Breast Programs Administrative Director, Johns Hopkins Cancer Survivorship Programs Department of Surgery and Oncology Associate Professor, JHU School of Medicine Departments of Surgery, Oncology, and Gynecology Associate Professor, JHU School of Nursing Johns Hopkins Avon Foundation Breast Center Baltimore, MD

Sharon Gentry, RN, MSN, AOCN, CBCN Breast Health Navigator Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

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Personalizing Cancer Care, Policy, and the Payer Perspective: An Interview With Peter F. Hayes of Healthcare Solutions Peter F. Hayes Healthcare Solutions Portland, Maine

he Association for Value-Based Cancer Care Much of the discussion of value revolves around the (AVBCC) held its annual conference on May evolution of personalizing cancer care and the associ2-5, 2013, in Hollywood, ated costs of achieving such an ideal. Florida. AVBCC is the fastest growThis was certainly true of the presentaing national specialty organization tions at this year’s AVBCC conference dedicated to improving the care of as evidenced by talks entitled, “Trends cancer patients and their quality of in Cancer Treatment Decision-Maklife by discussing, considering, and ing: Pathways, Personalized Medicine, evaluating the value equation as it and Stakeholder Collaborations” and relates to new and existing cancer “Personalized Medicine, Compantherapies. This organization, which ion Diagnostics, Molecular Profiling, currently consists of more than 450 Genomic Sequencing: The Impact members, was established to provide a on Cost, Treatment, and the Value forum for payers and healthcare proProposition.” Peter F. Hayes fessionals to consider and evaluate Personalized Medicine in Oncolthe cost/value issues specific to canogy had the pleasure of talking with cer treatments and their impact on patient care and AVBCC faculty member Peter F. Hayes, principal of outcomes. This unique focus is achieved through disHealthcare Solutions and former Director of Associate cussions and collaborations with those involved in evalHealth and Wellness at Hannaford Supermarkets, about uating therapies, treating patients, and paying for care. the payer perspective of personalizing cancer care.

PMO Thank you so much for making the time to talk with us. To start, we’d like to ask about the Affordable Care Act. Is the Affordable Care Act financially

compatible with the growth of personalized medicine, specifically in oncology? Or will the additional cost reduce the spread of personalized medicine?

Mr Hayes is currently a principal of Healthcare Solutions. Formerly, he served as Director of Associate Health and Wellness at Hannaford Supermarkets. Mr Hayes has over 20 years of experience in innovative, strategic benefit design. During his tenure at Hannaford, the company received numerous national awards in recognition of the company’s commitment to working collaboratively with healthcare providers and vendors to deliver health benefits that are focused on value. Mr Hayes has participated in healthcare reform leadership roles at both the national and regional levels. He is a cofounder of the Maine Health Management Coalition and has been appointed by 2 Maine governors to serve on the Maine Health Care Reform Commission to recommend public policies to improve access to and affordability of healthcare for Maine citizens.

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Mr Hayes The question is really what impact will ObamaCare, or the Affordable Care Act, have on all care, and in particular oncology care, going forward. I think all of us are really underestimating the impact. To give you a good example, there are estimates that healthcare cost premiums for all of us are going to go up, on average, 30% next year. Some states are facing 80% increases. There are new studies estimating that costs are going to double or triple for the young and healthy singles, anybody who’s 21 to 29. We have this healthcare crisis coming. It’s unaffordable. Unfortunately, we are just spending far more money than we have resources for in cancer care; we can’t afford it. This situation is going to force the discussion that nobody wants to have. We’re going to have to start deciding as a society what we will spend money on in healthcare and what we will not. Cancer care will be impacted. I’ll give you a good example. I recently had the privilege of participating in a fascinating panel discussion. Alan Garber, MD, PhD, from Stanford University, presented a case about a new drug for prostate cancer. The cost of the therapy is $900,000, and it adds 3 days of life at the margin. As a society, should we spend $900,000 for 3 days of life versus spending that on a young diabetic to make sure they’re at clinical guidelines so they have 40 or 50 years of life? Europe has already crossed this threshold. Europe has taken a look at quality of life, or the years of life we add for the therapy that’s being discussed. There is an equation stating a year of life is worth “X.” If the therapy cost is over that number, it’s not provided. I think ObamaCare or the Affordable Care Act is going to force those types of conversations. The sky is not the limit. We can’t do everything for everybody. How do we start making decisions as a society? I think it will absolutely impact cancer care. PMO Value is more than cost – we believe it is the balance of cost, quality, and access. In your opinion, how long will it take for personalized medicine to start paying dividends and become attractive to payers by showing value?

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Mr Hayes This is a tough but interesting question. The question really touches upon how do you define value – and what it means as we think about personalized medicine and how it’s delivered. Is it quality? Cost? Access? It builds on the theme that we just discussed, the other consideration that no one really talks about: quality of life. The problem involves an issue of perspective; what is a definition of value? Is it the definition of the individual, or of society? The answers are very different.

The sky is not the limit. We can’t do everything for everybody. How do we start making decisions as a society? I think it will absolutely impact cancer care. If you’re an individual, and you’re faced with the prostate cancer example I mentioned, a $900,000 therapy that may add a couple of days of life, you as a patient may think that’s value, you should have access to it, and it should be done. From a societal point of view, as Europe has explored, is that how we should be spending healthcare resources? Or should it go into helping a young diabetic, or some other condition? I think what’s really left out of that value conversation is much more complex than the 3 metrics you mentioned. The last metric we really need to think about is the value to society. What’s the value to the community of the dollars that we spend, for the whole population, not just an individual? PMO How would you articulate the value proposition or justify the cost of personalized medicine to the clinical, business, and government sectors – and the patients? Mr Hayes The question is, how do you define value to the various stakeholders, be it personal, business, government, or community? I think that becomes a really challenging issue, because each one of those perspectives is going to be very different.

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If you’re the individual who is ill, you’re probably going to want and expect that the system will provide whatever it can to help you, and the families will expect that as well. If you’re the government and you know Medicare has finite resources, you’re then faced with trying to decide how to take the available healthcare dollars and create the most value for the society. For example, if you have an 85- to 90-year-old person who needs a very complex procedure that may add a month of life, and the cost will be $1 million, should you use the money in this way? Or should you invest that money in someone who’s much younger with a health condition that may have 20 or 30 years of productive work life and community life ahead of them? That perspective of value, how you define that, and how you reconcile that, is going to be very challenging. They’re inherently at odds with each other.

We’re going to say that for this type of cancer, we will pay the medical providers “X.” It’ll be a fixed price, and that’s going to really change the game... PMO Is the pricing methodology of manufacturers for personalized medicine, therapies, and diagnostics becoming more sophisticated and skillful, and less arbitrary, in order to balance profit with product affordability? Mr Hayes These are really thought-provoking questions. The question is, as we develop new therapies for cancers, and we’re thinking about how that model gets paid for, what is it going to mean? I think it’s going to be really interesting. These therapies are becoming very expensive. In the past, the model has been that the current system is a pass-through payment model, and this is where there’s a real disconnect in the system, because the patient really doesn’t pay for the full cost of care. The drug manufacturers create a product and price it, the physicians use it, and the health plans pay for

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it. All those costs end up getting passed through to the ultimate person who’s paying the insurance premium, and that is usually someone totally different than any of those parties, so the incentives are really perverse. Everywhere along that supply chain, someone’s making money. I think this is going to change pretty rapidly. Although this example is not related to cancer care, the case still applies. I was a director of benefits for a Fortune 100 company in New England. We had a bunch of baby boomers who needed joint replacements, hips and knees. The costs were $75,000 to $100,000 to do a hip replacement. We looked outside the United States. Outside the United States, hip replacements can be done for up to 90% less. Singapore would do a hip for $10,000. They would guarantee it for a year, package price. As I said earlier, on pass-through, the hips that we do in the United States you pay for every aspirin, you pay for every meal that the patient eats. Think about buying a car a tire at a time, or a nut at a time. Instead, you pay a package price. In this case, we put a policy in place stating that if our folks wanted to go to Singapore to have a hip replaced, we’d pay 100%; we’d send a significant other, you could go on a vacation. The minute we announced it, the Wall Street Journal picked it up. The next day, I had calls from about 10 hospitals across the country saying they would also match the price. What I’m getting at is, we’re going to say that for this type of cancer, we will pay the medical providers “X.” It’ll be a fixed price, and that’s going to really change the game, because then there are no more passthroughs. Because someone’s going to be on the hook for delivering that high-quality cancer care for a fixed price, they’re going to have to spend a lot more time making sure that they’re using the most cost-effective therapy; they’re not going to be able to pass those prices on. That’s where I think the model’s going. PMO The oncologists and their compensation, are we moving to fee-for-service? Mr Hayes Specialists in this country make 3 to 4 times more than they do in any other country. Cardiol-

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ogists here are making close to 7 figures. Cardiologists in other countries are somewhere around $200,000, so huge differences. I think what you’re going to see is the Mayo Clinic Model, in which more and more of our specialists and oncologists will go on salary instead of being paid for each patient they see. It’s going to dramatically change their reimbursement model, and it’s also going to dramatically change their incentive model. For instance, I had a colleague who started to refer any patient who needed open heart surgery to Mayo Clinic. The cardiologists there are on salary, so it doesn’t matter whether they do the procedure or don’t do the procedure. As a result of that program, 30% of the time when the local cardiologists thought it necessary to do a procedure, Mayo Clinic said surgery didn’t need to be done. This model will dramatically change how we pay the oncologist and specialist, and how we deliver cancer care. PMO Does that model ultimately benefit the oncologist, or is that going to dissuade oncologists from participating in the healthcare system anymore or a new crop of graduates from choosing oncology as their specialty? Mr Hayes I think the question is, what’s going to happen to specialist pay? What’s going to happen to oncology in particular, as we move away from the feefor-service model to different reimbursement models? There’s lots of conversation about how to slow the increase of what we’re spending for healthcare. The reality is, in a competitive global marketplace, we have to get our healthcare costs significantly down. Don Berwick, MD, who just retired from Medicare and the Institute of Medicine, and the Dartmouth Atlas have both said for a long time that 30% to 50% of all medical services delivered in this country add no clinical value. We’re doing a lot of things that we don’t need to do.

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When you start talking about how ObamaCare, the Affordable Care Act, how this is all going to impact specialist salaries, their reimbursements are going to go down dramatically. Right off the bat, to finance ObamaCare, there has to be a 30% reduction in payments by Medicare to all providers. What’s going to happen over time is that, yes, oncologist salaries, all the specialists, are going to see their incomes reduced. There’s going to be a significant reallocation of how we pay primary care versus specialist.

30% to 50% of all medical services delivered in this country add no clinical value. We’re doing a lot of things that we don’t need to do. PMO If a drug is developed that treats a cancer in a large patient population so well that it keeps those patients alive for the rest of their normal life expectancy, how do we avoid bankrupting the healthcare system? Mr Hayes Great question. If we can develop different agents that make a remarkable difference and keep people alive longer, what do we do with that? How do we keep it from bankrupting the system? I think it goes back to the European marketplace as a model. We have to take a look at quality of life. What are we getting for that investment? We, as a society, should develop a way to look at healthcare as a finite resource, with the goal of maximizing quality of life. That’s how I think we should make decisions going forward as we develop new medical technologies. How do we make decisions about where we should invest and where we should not invest as a society? I think that’s where we’re heading. PMO Thank you so much for your time. Mr Hayes My pleasure. u

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MAY 2013 • VOLUME 6 • NUMBER 2

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Maintenance Settings PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen Grants/Project Associate Susan Yeager The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattanonont Ferris Vice President of Finance Andrea Kelly Director of Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore

LETTER

FROM THE

EDITOR-IN-CHIEF

Over the past decade, significant progress has been made in the management of multiple myeloma, including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances. In this sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this second issue, experts from Dana-Farber Cancer Institute answer questions related to the management of patients in the maintenance setting. Sincerely, Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Director, Quality Control Barbara Marino Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean

FACULTY Kenneth C. Anderson, MD Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics Kraft Family Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute, Boston, MA

Tina Flaherty, ANP-BC, AOCN Nurse Practitioner Division of Hematologic Malignancies Dana-Farber Cancer Institute Boston, MA

Houry Leblebjian, PharmD, BCOP Clinical Pharmacy Specialist in Hematology/Oncology Dana-Farber Cancer Institute Boston, MA

Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma

Supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.

Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

Center of Excellence Media, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour. Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-012-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients

• Describe the pharmacokinetics and pharmacodynamics of novel agents when integrating these agents into treatment regimens for MM • Evaluate adverse event management strategies for patients with MM receiving novel therapies and multidrug regimens Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures William J. Wong, MD, MLI Reviewer, has nothing to disclose. Bobbie Perrin, RN, OCN, MLI Reviewer, has nothing to disclose. Shelly Chun, PharmD, MLI Reviewer, has nothing to disclose. Faculty Disclosures Sagar Lonial, MD, is on the Advisory Board for and is a Consultant to Bristol-Myers Squibb, Celgene Corporation, Millennium: the Takeda Oncology Company, Novartis, Onyx Pharmaceuticals, and sanofi-aventis. He does not intend to discuss any non-FDA-approved or investigational use for any products/devices. Kenneth C. Anderson, MD, is on the Advisory Boards for Celgene Corporation, Gilead, Onyx Pharmaceuticals, and sanofi-aventis, and is a Scientific Founder for Acetylon Pharmaceuticals, Inc., and OncoPep, Inc. He does not intend to discuss any non-FDA-approved or investigational use for any products/devices. Tina Flaherty, ANP-BC, AOCN, has nothing to disclose. She does not intend to discuss any non-FDA-approved or investigational use for any products/devices. Houry Leblebjian, PharmD, BCOP, is on the Advisory Board for Teva Pharmaceuticals Industries, Ltd. She does not intend to

discuss any non-FDA-approved or investigational use for any products/devices. Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13008B. html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net. Estimated time to complete activity: 1.0 hour Date of initial release: May 14, 2013 Valid for CME/CPE/CE credit through: May 14, 2014

SCAN HERE to Download the PDF or Apply for Credit. To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

The Role of Consolidation and Maintenance Therapies for Improving Myeloma Care Kenneth C. Anderson, MD

Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics Kraft Family Professor of Medicine, Harvard Medical School Dana-Farber Cancer Institute, Boston, MA

Introduction With the advent of novel, targeted agents, consolidation and maintenance therapies have become a key component of care in multiple myeloma (MM). Lenalidomide, thalidomide, and bortezomib can consolidate response after stem cell transplantation and provide ongoing maintenance to prolong response duration. Improved outcomes result, but the efficacy of these agents must be weighed against the potential risks of additional treatment. In this article, Kenneth C. Anderson, MD, shares insights and best practices in the use of consolidation and maintenance in the age of molecularly targeted antimyeloma therapies.

How is maintenance therapy different from consolidation? Consolidation therapy is given to increase the depth of response following treatment. As the term consolidation implies, this therapy is commonly used

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after high-dose melphalan therapy and autologous stem cell transplantation (HDT/ASCT).1 Novel therapies—thalidomide, lenalidomide, or bortezomib—are currently used for consolidation, alone or in combination, for 1 or 2 cycles.2 Evidence shows that such consolidation does increase the depth of response,3 with a significant proportion of patients achieving a molecular complete response (CR).4 Maintenance therapy, in contrast, aims to prolong the duration of response. In the patient who has received HDT/ASCT, maintenance helps extend the response that has been previously achieved through induction, transplantation, and consolidation. Maintenance therapy can also be utilized to prolong response to initial therapy in the elderly population and others ineligible for transplant. Early explorations of maintenance therapy in MM began with interferon alfa-2 and then corticosteroids.5 More recently, thalidomide, lenalidomide, and bortezomib have all been explored and accepted as maintenance therapies.6-10 For example, lenalidomide maintenance has been shown to increase progression-free survival (PFS) in transplant candidates9,10 and in elderly patients with newly diagnosed MM.7 In a US trial of patients receiving HDT/ASCT, the use of lenalidomide as posttransplant maintenance therapy prolonged both PFS and overall survival (OS; Figure).10 In the HOVON-65/GMMG-HD4 trial, bortezomib-based induction (bortezomib/doxorubicin/dexamethasone) plus posttransplant maintenance with bortezomib improved CR, PFS, and OS compared with vincristine-based induction (vincristine/doxorubicin/dexamethasone) followed by thalidomide maintenance.8

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Figure. Three-year survival rates in the US randomized trial of lenalidomide maintenance post-HDT/ASCT (N=460).10

Placebo, n (%)

Attal 2012 (N=608)9

n=306

n=302

➢Hematologic malignancies

13 (4)

5 (2)

➢Solid tumors

10 (3)

4 (1)

McCarthy 2012 (N=460)10

n=231

n=229

➢Hematologic malignancies

8 (3.5)

1 (0.4)

➢Solid tumors

10 (4.3)

5 (2.2)

80%

Lenalidomide maintenance (n=231) Placebo (n=229)

66%

Patients (%)

Lenalidomide Maintenance, n (%)

88%

Table 1. Second Primary Cancers in Patients Receiving Lenalidomide Maintenance in Randomized, PlaceboControlled Trials9,10

39%

40 30 20 10 0

PFS*

*Deﬁned as freedom from progression or death. ASCT indicates autologous stem cell transplantation; HDT, high-dose therapy; OS, overall survival; PFS, progression-free survival.

Which factors must be considered when recommending maintenance and choosing a specific agent? Multiple clinical factors affect the decision to use maintenance therapy and the choice of agent. The first thing to consider is the patient’s response history. Trials have generally shown that patients with stable disease (SD), partial response, very good partial response (VGPR), or even CR all have benefited from maintenance therapy.6-10 This evidence suggests that patients who have at least SD as a result of initial treatment enjoy an advantage from maintenance treatment. So, the question that must be asked is: How likely is the patient to benefit, given his or her response to date? A second factor to consider is risk stratification, as determined by cytogenetic abnormalities. To date, the best-studied agent in the maintenance setting is lenalidomide, which has been compared with placebo in 2 randomized trials posttransplant (IFM 2005-02 and CALGB 100104)9,10; in both of these trials, lenalidomide maintenance extended PFS, and in the CALGB trial, OS was prolonged as well.10 This advantage, however, was not evident among the subgroup of patients with high-risk cytogenetics, especially in those with del(17p). For this reason, high-risk patients require more than lenalidomide for maintenance. At our center, these patients receive bortezomib maintenance, often in combination with lenalidomide or thalidomide. This decision is based on recent data suggesting that bortezomib may improve the adverse outcomes usually associated with cytogenetic abnormalities.8,11,12 A third factor in decision-making is the patient’s prior therapy. For instance, if an individual has already received thalidomide in the induction regimen, one might consider using an alternative such as lenalidomide for maintenance. This approach anticipates the potential for development of resistance to the prior therapy. It is also a strategy to use when there is concern about exacerbating an adverse event (AE) seen with prior therapy, such as peripheral neuropathy with thalidomide. Patients may now receive 2 or more novel agents during initial therapy before transplantation. The standard of care is becoming a 3-drug initial regimen, often combinations of targeted therapies. For example, high extent and frequency of response have been documented with lenalidomide/bortezomib/ dexamethasone (RVD)13 or cyclophosphamide/bortezomib/dexamethasone14 for induction in the transplant-eligible population. Regimens like this achieve very high overall response (OR) rates. After these patients receive a transplant, they may get consolidation therapy, often with the same combination of targeted therapies as they received during induction, then go on to receive maintenance therapy with lenalidomide or bortezomib. Similarly, in elderly patients and others who are ineligible for transplant, melphalan plus prednisone may be combined with novel agents (thalidomide, lenalidomide, or bortezomib), followed by maintenance with the same agents—an approach that appears to be effective.7,15,16

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In this context, it may be worth mentioning that, in the United States, the selection of thalidomide for initial therapy or maintenance is less common than in Europe. The United Kingdom’s Medical Research Council conducted a large trial (MRC IX) in patients who received initial therapy with thalidomide-containing regimens, with or without subsequent transplant, followed by thalidomide maintenance or no maintenance. In this trial, thalidomide maintenance enhanced survival outcomes compared with no maintenance—although this benefit did not fully extend to patients with adverse cytogenetics.17 The difference between the United States and Europe in the use of novel agents probably boils down to our ability, in the United States, to use drugs off-label. Lenalidomide, for example, is approved for treatment of relapsed and relapsed/refractory myeloma in the United States.18 Yet, we use lenalidomide commonly in the newly diagnosed patient, in consolidation, and in maintenance. In Europe, however, clinicians are required to use drugs on-label only. This helps explain the greater use in Europe of the older immunomodulatory drug thalidomide. How often do you recommend maintenance for your patients? I routinely recommend maintenance therapy to my patients. My main reason is the knowledge that, in the absence of this therapy, the disease is destined to relapse. My second reason for using maintenance is that randomized trials have demonstrated its value. As described above, lenalidomide maintenance posttransplant, as well as in elderly, nontransplant candidates, has been shown to prolong PFS and, in one major study, OS.7,9,10 Bortezomibbased maintenance has also been associated with longer PFS and OS in these settings,8,15,16 although maintenance with this agent is not as well studied as lenalidomide maintenance. I feel there is an overwhelming benefit to maintenance that outweighs the risks. Lenalidomide is well tolerated; its common AEs in the maintenance setting include neutropenia, diarrhea, upper respiratory infections, and fatigue.9,10 One noteworthy effect is a 2- to 3-fold increased risk of second primary cancers among patients who receive HDT/ASCT plus lenalidomide maintenance treatment (Table 1).9,10 It is important to point out, however, that there are additional risk factors for developing second primary cancer posttransplant when using lenalidomide, including male gender, advanced stage III International Staging System myeloma, and, most importantly, the use of a regimen of dexamethasone/cyclophosphamide/etoposide/cisplatin (DCEP) before transplant.9 The DCEP regimen contains multiple alkylating or DNAdamaging chemotherapeutic agents, so it stands to reason that the avoidance of this combination as induction would markedly reduce the risk of second primary cancers. In our patients, however, I believe that the risk of developing progressive myeloma and dying rapidly from the disease is far greater than any potential risk of a second primary cancer after lenalidomide maintenance. The use of bortezomib as maintenance also has a favorable benefit-to-risk ratio, especially in patients with high-risk cytogenetics. Bortezomib significantly improved PFS and OS in patients with del(13) and del(17p) in the HOVON-65/GMMG-HD4 trial (Table 2),8 identifying a potentially effective treatment option in these types of patients. Therefore, when cytogenetic risk is high, I think adding bortezomib to lenalidomide is a useful approach. The efficacy with less toxicity of subcutaneous bortezomib19 makes this drug more readily applied in the maintenance setting.

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Table 2. Efficacy Results: HOVON-65/GMMG-HD48 VAD (n=414)

PAD (n=413)

P value

All patients

.002

Subgroup with del(17p)

.01

Not reached at 66 mo

N/A

Not reached at 54 mo

.003

Median PFS,* mo

Median OS,* mo All patients Subgroup with del(17p)

*Median follow-up of 41 months. N/A indicates not available; OS, overall survival; PAD, bortezomib/doxorubicin/dexamethasone; PFS, progression-free survival; VAD, vincristine/doxorubicin/dexamethasone.

How will maintenance therapy for MM continue to evolve? An exciting development that may affect maintenance therapy is the advent of newer targeted agents, most notably, newer proteasome inhibitors such as carfilzomib and MLN9708 (ixazomib). These drugs represent alternative options to combine with lenalidomide in high-risk patients. Carfilzomib is now approved by the US Food and Drug Administration for use in the relapsed/refractory setting,20 and it is being used and evaluated as frontline treatment as well.21,22 Carfilzomib/lenalidomide/dexamethasone (CRd) is a promising combination,21 as well as a potential successor to the very effective induction regimen, RVD.13 For example, in a seminal trial, RVD induction in newly diagnosed MM attained 100% OR, with 67% to 74% of patients achieving VGPR or better.13 A comparable universal response was seen with CRd induction in newly diagnosed patients, with 78% enjoying CR or near CR.21 A clinical trial is currently evaluating CRd both as induction and as posttransplant consolidation therapy and maintenance.23 Another novel proteasome inhibitor, the oral agent MLN9708, can also be combined with lenalidomide and dexamethasone upfront to achieve high response rates.24 This is an all-oral regimen, which is appealing to patients and clinicians alike. An oral proteasome inhibitor would also be a useful option in the maintenance setting. In the near future, maintenance therapy may enable us to delay transplantation. A clinical trial is looking at RVD induction, collection of stem cells after 3 to 4 cycles, and then randomizing patients to receive either HDT/ ASCT plus lenalidomide maintenance or lenalidomide maintenance with no transplant.25 Our favorable experience with novel agents in initial therapy, consolidation, and maintenance has begun to shift the timing of ASCT away from the current standard of early transplant toward delayed transplant. We are gathering clinical evidence on the relative efficacy and safety of novelagent induction followed by early ASCT versus novel-agent induction with ASCT reserved until progression. Maintenance therapy is also becoming more crucial in our efforts to sustain the profound responses we now achieve with these newer drugs. The increasing depth, duration, and frequency of responses have made us more stringent in the way we assess response. We can now regularly attain molecular CR with novel targeted agents, as measured by polymerase chain reaction for the immunoglobulin gene rearrangement or multicolor flow cytometry. A further degree of stringency is evolving from the use of positron emission tomography/computed tomography (PET/CT) in MM. It is now incumbent on us to utilize maintenance therapy in an attempt to prolong the response stringently defined by molecular CR and PET/CT. In summary, novel agents will continue to help us achieve good rates of high-quality response that were never before possible in MM. Consolidation with combination targeted treatments will continue to increase the depth of response, producing molecular CR in a significant fraction of patients. Finally, maintenance therapies with novel agents will continue to prolong PFS and even OS. We will see more gains from ongoing trends. First, building upon 3-drug

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combinations such as RVD, we will see new combinations of immunomodulators, proteasome inhibitors, and steroids, with the addition of monoclonal antibodies, histone deacetylase inhibitors, and other targeted agents. As in other malignancies, a combination of 4 or 5 agents is likely to achieve CR in the majority of patients, if not all. Second, we will advance our ability to measure minimal residual disease and molecular CR, and we can use these metrics to determine the optimal duration of maintenance therapy in MM. Although we have already seen tremendous progress over the past few decades, I believe the best is yet to come in the care of the disease. ♦ References

1. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27:1788-1793. 2. San-Miguel JF. Consolidation therapy in myeloma: a consolidated approach? Blood. 2012; 120:2-3. 3. Cavo M, Pantani L, Petrucci MT, et al; for the GIMEMA Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012;120:9-19. 4. Ladetto M, Pagliano G, Ferrero S, et al. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010;28:2077-2084. 5. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology®: Multiple Myeloma. Version 1.2013. http://www.nccn.org. Accessed March 8, 2013. 6. Attal M, Harousseau J-L, Leyvraz S, et al; for the Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294. 7. Palumbo A, Hajek R, Delforge M, et al; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769. 8. Sonneveld P, Schmidt-Wolf IGH, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946-2955. 9. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791. 10. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781. 11. Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007; 21:151-157. 12. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940-948. 13. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010; 116:679-686. 14. Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115:3416-3417. 15. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28:5101-5109. 16. Niesvizky R, Flinn IW, Rifkin RM, et al. Phase 3b UPFRONT study: safety and efficacy of weekly bortezomib maintenance therapy after bortezomib-based induction regimens in elderly, newly diagnosed multiple myeloma patients. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 619. 17. Morgan GJ, Gregory WM, Davies FE, et al; on behalf of the National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012;119:7-15. 18. Revlimid [package insert]. Summit, NJ: Celgene Corporation; May 2012. 19. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 20. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012. 21. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120:1801-1809. 22. Palumbo A, Bringhen S, Villani O, et al. Carfilzomib, cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma (MM) patients. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 730. 23. Carfilzomib, lenalidomide, and dexamethasone before and after stem cell transplant in treating patients with newly diagnosed multiple myeloma, NCT01816971. http://www. clinicaltrials.gov. Accessed April 24, 2013. 24. Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 332. 25. Study comparing conventional dose combination RVD to high-dose treatment with ASCT in the initial myeloma up to 65 years (IFM/DFCI2009), NCT01191060. http://www. clinicaltrials.gov. Accessed April 24, 2013.

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Nursing Considerations in the Maintenance Setting for Multiple Myeloma Tina Flaherty, ANP-BC, AOCN

Nurse Practitioner Division of Hematologic Malignancies Dana-Farber Cancer Institute, Boston, MA

Introduction Maintenance therapy is becoming a well-accepted recommendation for patients with multiple myeloma (MM), in both the transplant and nontransplant settings. However, there are several factors that must be considered when deciding which specific drugs, doses, and schedules should be used for this line of treatment, including age, performance status, prior response to therapy, patient preferences, and comorbidities. Elderly patients tend to be at greater risk for age-related diabetes or organ dysfunction (eg, cardiovascular disease, renal impairment) than younger patients, which may make disease management especially challenging.1,2 In this article, Tina Flaherty, ANP-BC, AOCN, answers questions related to the use of novel agents as maintenance and discusses the monitoring and management of treatment-related adverse events (AEs), including myelosuppression, neurotoxicity, and thromboembolic events.

How do you monitor for and treat myelosuppression in the maintenance setting? We tend to see less hematologic toxicity in the maintenance setting than we do in the frontline and relapsed/refractory settings. This is because the novel agents being used are usually given at reduced doses and schedules. In addition, most patients have already achieved a complete or very good partial response when maintenance therapy begins; therefore, their disease is less likely to be causing myelosuppression. That being said, some patients will still be predisposed to hematologic toxicities due to age, preexisting conditions, or cumulative toxicities from previous treatments, and they will require appropriate management strategies to maintain safety and preserve quality of life. To effectively manage such hematologic AEs as neutropenia, thrombocytopenia, and anemia, it is important to monitor patient blood counts on a regular basis, especially in the first and second cycles of therapy. When lenalidomide is used as maintenance, we typically check blood counts every 2 weeks during cycles 1 and 2. When bortezomib is used, counts are checked every 2 weeks prior to each administration of the drug. The interventions to use will depend on the grade or severity of the specific hematologic AEs (Table 1).3,4 The most common hematologic toxicity associated with lenalidomide is neutropenia.3 Grade 1 neutropenia usually does not require an adjustment in dose or schedule, but we do continue to monitor blood counts carefully. Conversely, grade 4 neutropenia would prompt us to hold lenalidomide therapy until either the neutropenia returns to grade 1 or the absolute neutrophil count is in the normal range.2 If neutropenia continues at grade 2 or higher for 2 or more cycles, we typically reduce the dose of lenalidomide to 5 mg and may consider adjusting the schedule in certain patient populations. For example, we may administer lenalidomide 5 mg every Monday, Wednesday, and Friday. In patients with standard- to high-risk disease, it is important to try to at least maintain the customary dose of lenalidomide maintenance (10 mg every 21 days of a 28-day cycle) to ensure optimal benefit. In these individuals, granulocyte colony-stimulating factors such as filgrastim can be utilized in a once-weekly or once-monthly schedule, depending on the grade of neutropenia. In the maintenance setting, hematologic toxicity rates tend to be low with bortezomib because this agent is administered every other week. However,

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some patients may still develop thrombocytopenia. With grade 1 thrombocytopenia, there is typically no need to adjust the dose or schedule of bortezomib; however, careful monitoring of blood counts is recommended.3 Grade 4 thrombocytopenia usually necessitates holding treatment until the toxicity resolves. We may also consider a transfusion of platelets if there is an increased risk of bleeding. With grade 2 or 3 thrombocytopenia, we may consider holding the bortezomib dose, and if there is a continued trend of toxicity, we many change the dose from 1.3 mg/m2 to 1.0 mg/m2. If the patient has been receiving this drug intravenously, we will also consider switching to the subcutaneous (SC) mode of administration if possible. Anemia may also occur with the use of novel agents in the maintenance setting. Some individuals are predisposed to this toxicity, especially if they have renal impairment from the myeloma itself, earlier therapy, or a preexisting condition.5 Management of anemia should take into account that some patients can tolerate a greater degree of this condition than others can.3 In addition to testing the numeric values of hemoglobin and hematocrit, quality of life should also be routinely assessed. A provider should ask questions concerning performance status, shortness of breath, and fatigue, which will assist in determining the need for transfusion versus erythropoietin-stimulating agents, such as darbepoetin alfa. With grade 1 or 2 anemia, depending on clinical circumstances, a patient may benefit from these agents, especially if he or she has concomitant renal dysfunction.5 With grade 4 anemia (and in certain scenarios, grade 2 or 3), the decision to transfuse must be balanced with the associated risks.3 In patients receiving lenalidomide maintenance, if grade 2 or 3 anemia is present for 2 or more cycles of therapy, we typically reduce the dose to 5 mg, especially in patients with renal impairment. What other toxicities are commonly associated with newer agents used as maintenance? Peripheral neuropathy (PN) is a well-known AE associated with the use of certain novel drugs, including bortezomib.6 This fact must be considered when choosing a maintenance therapy that individuals might be treated with for up to 2 years. In patients who already have grade 4 PN, we typically do not consider bortezomib for maintenance. If bortezomib is the drug of choice for a particular patient, then we frequently recommend the SC route of administration to decrease the incidence of neuropathy; fortunately, the

Grade 1 neutropenia usually does not require an adjustment in dose or schedule, but we do continue to monitor blood counts carefully. majority of our patients do not experience an increase in PN if they receive biweekly dosing of SC bortezomib. However, monitoring for signs and symptoms of this toxicity at the beginning of maintenance therapy and throughout the course of treatment remains essential.3 When bortezomib-related PN develops, the goal is to alleviate symptoms and prevent progression. We may consider holding the dose if grade 2 or 3 PN develops, and if painful symptoms continue, we may also reduce the dose from 1.3 mg/m2 to 1.0 mg/ m2 (given every other week). Thromboembolic events, including deep-vein thrombosis (DVT) and pulmonary embolism (PE) are also seen in patients with MM in the maintenance setting.7 Patients can be at risk for these life-threatening events due to their disease, individual risk factors (eg, obesity, diabetes, blood-clotting disorders), and specific medications.7 The development of DVT and/or PE can permanently affect the lives of patients and their families, as well as interfere with

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Table 1. NCI CTCAE: Hematologic Toxicity Grades3,4 Toxicity Neutropenia Thrombocytopenia Anemia

Unit of Measure

Grade 1

Grade 2

Grade 3

Grade 4

ANC, ×109/L

<LLN to 1.5

<1.5-1.0

<1.0-0.5

<0.5

Platelet count, × 109/L

<LLN to 75

<75-50

<50-25

<25

Hb, g/dL

<LLN to 10.0

<10.0-8.0

<8.0-6.5

<6.5

ANC indicates absolute neutrophil count; Hb, hemoglobin; LLN, lower limit of normal; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.

Table 2. Symptoms of Venous Thromboembolic Event7 Pulmonary Embolism Anxiety Discomfort in the chest area Electrocardiogram right axis deviation or new right bundle branch block Low-grade fever

minimizing chronic diarrhea that patients may experience during treatment. For this reason, we offer probiotics to our patients, being sure to recommend products that contain strains of bacteria that are considered very safe for the general population.13 What additional factors are important to consider in the maintenance setting?

Positive Homan’s sign (pain in the calf and popliteal area on passive dorsiflexion of the foot)a

To provide optimal care and adherence during maintenance, providers must consider prior response to therapy, cumulative toxicities, patient preferences, and psychosocial factors. Some patients may prefer oral lenalidomide, so that they do not have to travel back and forth to the clinic every other week for treatment. If we determine that a patient can be compliant with an oral regimen and that there are no contraindications, we will most likely use lenalidomide. For other individuals, bortezomib may be a better option, based on individual patient- and disease-related factors, such as a poor response to previous lenalidomide therapy or specific cytogenetic abnormalities. Regardless of which agent is used, nurses play an important role in improving patient compliance and outcomes. This requires good communication with patients and caregivers, careful monitoring for signs and symptoms of toxicities, and the prompt initiation of supportive or corrective strategies when necessary. ♦

Tachycardia

References

Sudden onset dyspnea Tachypnea or tachycardia Deep-Vein Thrombosis Cyanosis and cool skin in the presence of venous obstruction Distention of superficial venous collateral vessels Dull pain or tight feeling over area and with palpation Low-grade fever Obvious swelling (may not be present early)

Unilateral swollen, erythematous, warm extremity a

Present in approximately 35% of patients; high false-positive rate.

future treatment.7 Therefore, it is critical that patients are assessed for specific signs and symptoms that may indicate these events (Table 2). Venous thromboembolism (VTE) has been reported in patients receiving treatment with bortezomib, but at a much lower rate than in patients receiving treatment with lenalidomide (with or without dexamethasone).7 Recommendations for prevention and prophylaxis of thromboembolic events in MM depend on institutional practices, drug combinations being used, and factors specific to each patient. Typically, if patients have no prior history of VTE and do not have individual factors that predispose them to clot, either baby aspirin or standard-dose aspirin can be considered when they are receiving lenalidomide maintenance.7-9 However, if patients do have an increased risk of clot or have had past thromboembolic events, low-molecular-weight heparin or warfarin should be utilized. It is important to remember that some antithrombotic agents may be contraindicated in the presence of thrombocytopenia, renal impairment, or other comorbidities, due to the MM itself or to specific antimyeloma therapy.7 A common but less-addressed AE that occurs during maintenance—especially with lenalidomide—is chronic diarrhea.10 This toxicity can directly affect adherence to therapy and can have a negative impact on a patient’s quality of life. Although the direct mechanism of action is not clearly understood, it may be a direct or indirect cumulative effect of lenalidomide on the intestinal microflora (population of microscopic organisms) of the gut. Over the past several years, we have seen emerging data on the importance of gastrointestinal (GI) and immune health.11,12 Recently, probiotics have been promoted as an aid to enhance GI health by regulating the digestive system and

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1. Mehta J, Cavo M, Singhal S. How I treat elderly patients with myeloma. Blood. 2010; 116:2215-2223. 2. Palumbo A, Gay F. How to treat elderly patients with multiple myeloma: combination of therapy or sequencing. Hematology Am Soc Hematol Educ Program. 2009:566-577. 3. Miceli T, Colson K, Gavino M, Lilleby K; IMF Nurse Leadership Board. Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20. 4. National Cancer Institute. Common Terminology Criteria for Adverse Events v.3.0 (CTCAE). http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Published August 9, 2006. Accessed May 3, 2013. 5. Birgegård G. Managing anemia in lymphoma and multiple myeloma. Ther Clin Risk Manag. 2008;4:527-539. 6. Tariman JD, Love G, McCullagh E, Sandifer S; IMF Nurse Leadership Board. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3): 29-36. 7. Rome S, Doss D, Miller K, Westphal J; IMF Nurse Leadership Board. Thromboembolic events associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):21-28. 8. Palumbo A, Rajkumar SV, Dimopoulos MA, et al; International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 9. Klein U, Kosely F, Hillengass J, et al. Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone. Ann Hematol. 2009;88:67-71. 10. Smith LC, Bertolotti P, Curran K, Jenkins B; IMF Nurse Leadership Board. Gastrointestinal side effects associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008; 12(suppl 3):37-52. 11. Cummings JH, Antoine JM, Azpiroz F, et al. PASSCLAIM—gut health and immunity. Eur J Nutr. 2004;43(suppl 2):ii118-ii173. 12. Fooks LJ, Gibson GR. Probiotics as modulators of the gut flora. Br J Nutr. 2002;88(suppl 1): S39-S49. 13. Piascik M, Sanders ME. Probiotic supplementation: what nurse practitioners need to know to recommend safe and effective formulations. Postgraduate Healthcare Education Web site. http://www.powerpak.com/course/preamble/108730. Accessed May 4, 2013.

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CONTINUING EDUCATION

Pharmacologic Perspectives on Maintenance Therapy in the Era of Novel Agents Houry Leblebjian, PharmD, BCOP

Clinical Pharmacy Specialist in Hematology/Oncology Dana-Farber Cancer Institute Boston, MA

Introduction Recently, maintenance therapy with novel antimyeloma agents has been shown to be effective for prolonging duration of response following initial therapy, consolidation, or autologous stem cell transplantation (ASCT). This approach to myeloma treatment not only has the potential to improve quality of life, but may also extend survival. In this article, Houry Leblebjian, PharmD, BCOP, responds to frequently asked questions regarding the safety and efficacy of novel drugs as maintenance, and discusses administration issues that must be considered when using these therapies in the clinical setting.

How is the dose and schedule of lenalidomide adjusted in the maintenance setting? In multiple myeloma (MM), the dose of lenalidomide used in the maintenance setting differs from that used in other lines of treatment. As initial therapy or consolidation, this drug is typically used at a dose of 25 mg, given daily on days 1 to 14 of therapy repeated every 21 days or at a dose of 25 mg given daily on days 1 to 21 of therapy repeated every 28 days. Of course, these doses sometimes need to be reduced in patients with specific comorbidities, such as renal dysfunction.1,2 In the maintenance setting, lenalidomide is usually given at a dose of 15 mg at the same schedule used for induction, or sometimes daily without any break from therapy, if tolerated. Again, in patients who may be having difficulty tolerating this therapy, we have the option of lowering the dose to 10 mg or 5 mg. Three phase 3 randomized trials have evaluated lenalidomide in the maintenance setting (2 in the posttransplant setting and 1 as consolidation in transplant-ineligible patients).3-5 In the IFM 2005-02 trial (N=614), following ASCT, patients were randomly assigned to receive either consolidation treatment with lenalidomide (25 mg per day, on days 1-21 of

each 28-day cycle, for 2 cycles), followed by maintenance therapy with lenalidomide (10 mg per day for the first 3 months, increased to 15 mg if tolerated), or the same consolidation treatment with lenalidomide, followed by maintenance therapy with placebo. At a median follow-up of 45 months, median progression-free survival (PFS) was 41 months in the lenalidomide maintenance group versus 23 months in the placebo group (P<.001). No improvement was seen in overall survival (OS).3 In the CALGB 100104 study (N=460), investigators also studied lenalidomide maintenance in the posttransplant setting. Patients were randomly assigned in a blinded manner to lenalidomide (10 mg per day, increased to 15 mg if tolerated) or placebo between day 100 and day 110 after ASCT. At a median follow-up of 34 months, median time to progression (TTP) was 46 months in the lenalidomide maintenance group versus 27 months in the observation group (P<.001). In this trial, an OS benefit was observed.4 In the MM-015 trial (N=459), transplant-ineligible patients were randomized to receive melphalan plus prednisone (MP), melphalan/prednisone/lenalidomide (MPR), or MPR followed by lenalidomide maintenance (MPR-R). At a median follow-up of 30 months, PFS was 13 months, 14 months, and 31 months with MP, MPR, and MPR-R, respectively (P<.001 for MPR-R vs MPR and MPR-R vs MP). No difference in OS was observed between the groups.5 As evidenced by these studies, maintenance lenalidomide improves PFS, although a consistent OS benefit has yet to be reported.

Another factor to consider when analyzing results from these studies is the other drugs that were used during treatment, as they can contribute to additional toxicity.

Adverse events (AEs) must be carefully considered when treating MM patients with long-term lenalidomide. The most common AEs seen with this agent are myelosuppression, venous thromboembolism, and gastrointestinal toxicities. Lenalidomide may cause both thrombocytopenia and neutropenia, which may require dose modifications or temporarily withholding treatment until symptoms subside. However, the incidence of these and other AEs tends to be lower when lenalidomide is used as maintenance, compared with when it is used as frontline therapy (Table 1).3-5 It should be noted that the rates of hematologic toxicities in the IFM and the CALGB trials seem high because the Table 1. Incidence of Select Adverse Events in Phase 3 Trials of Lenalidomide percentages reported included the AEs observed throughout Maintenance3-5 the whole study窶馬ot just during maintenance therapy. On Grade 3/4 Grade 3/4 Grade 3/4 the other hand, investigators in the MM-015 study reported Neutropenia Thrombocytopenia Venous Secondary the rates of neutropenia and thrombocytopenia for the mainClinical Trial (%) (%) Thromboembolism (%) Cancers (%) tenance portion of the study separately, and these percentages 3 IFM 2005-002 were much lower than what was reported during frontline 51 14 6 7.5 Lenalidomide therapy. Another factor to consider when analyzing results 18 7 2 2.9 Placebo from these studies is the other drugs that were used during 4 CALGB 100104 treatment, as they can contribute to additional toxicity.3-5 45 14 1 7.8 Lenalidomide Investigators have reported a higher incidence of secondary 15 4 0 2.6 Placebo cancers in the lenalidomide arms of maintenance studies.3-5 5 MM-015 This does not appear to be related to the dose of lenalidomide, 1 2 0 3 MP but rather to the duration of treatment, as well as the use of 0 2 1 7 MPR other alkylating agents during induction or conditioning prior 7 6 2 7 MPR-R to transplant. Additional follow-up is needed to continue assessing potential risk factors for secondary malignancies and MP indicates melphalan plus prednisone; MPR, melphalan/prednisone/lenalidomide; MPR-R, MPR followed by lenalidomide maintenance. to determine the optimal duration of treatment with lenalid-

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Table 2. Incidence of Peripheral Neuropathy in the Phase 3 MMY-3021 Trial8 SC Bortezomib (N=147) n (%)

IV Bortezomib (N=74) n (%)

P Value

Any peripheral neuropathy

56 (38)

39 (53)

.044

Grade ≥2

35 (24)

30 (41)

0.12

Grade ≥3

9 (6)

12 (16)

0.26

IV indicates intravenous; SC, subcutaneous.

omide. Fortunately, many studies are under way to evaluate the safety and efficacy of long-term lenalidomide in the maintenance setting for myeloma. How is the recent approval of subcutaneous (SC) bortezomib impacting the use of this agent in the maintenance setting? Bortezomib has shown efficacy when used in the maintenance setting. The phase 3 HOVON-65/GMMG-HD4 trial compared bortezomib/doxorubicin/ dexamethasone plus posttransplant maintenance followed by bortezomib versus vincristine/doxorubicin/dexamethasone followed by thalidomide maintenance.6 The phase 3 GIMEMA trial compared bortezomib/melphalan/prednisone/thalidomide followed by bortezomib and thalidomide maintenance for 2 years versus bortezomib/melphalan/prednisone without maintenance.7 Both of these trials showed a PFS benefit with maintenance therapy. Peripheral neuropathy (PN), a common toxicity associated with bortezomib, occurs more frequently when patients receive this agent at a dose of 1.3 mg/m2 given intravenously on days 1, 4, 8, 11 every 21 days. Bortezomibinduced PN is often reversible with dose or schedule reductions or upon discontinuation of therapy. To reduce the incidence and severity of PN, we now have another option—SC bortezomib. A large phase 3 trial (N=222) randomized patients in a 2:1 ratio to receive intravenous (IV) or SC bortezomib at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks for 12 weeks.8 Results from this study confirmed the noninferiority of SC bortezomib in terms of overall response rate after 4 cycles. In addition, after a median follow-up of 12 months, no significant differences in TTP or OS were observed between the 2 arms. Grade ≥3 PN was significantly lower in the SC arm compared with the IV arm (6% vs 16%; P=.026). Neuropathy of any grade was also lower in the SC arm (38% vs 53%; P=.044) (Table 2). Other AEs, including myelosuppression, fatigue, and GI toxicities, were comparable among treatment arms.8 Given these results, I think SC bortezomib will continue to be used more frequently in the maintenance setting. The use of SC bortezomib can cause local injection site reactions. Of the 159 patients in 2 trials of SC bortezomib, 60% reported at least 1 local SC injection site reaction during the study, with 56% having a reaction in the first cycle. Two patients (1%) experienced local reactions that were considered severe (1 case of pruritis and 1 case of redness). These reactions resolved in a median of 6 days. Local reaction led to study discontinuation in only 1 patient and reduction in dose concentration in another.8,9 The recommended concentration of bortezomib when administered intravenously is 1.0 mg/mL; with SC administration, the recommended concentration of bortezomib is 2.5 mg/mL. Because each route of administration has a different reconstituted concentration, caution must be used when calculating the volume to be administered. When the SC route is used, the site for each injection (thigh or abdomen) should be rotated. New injections should be given at least 1 inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated. Preparation times and administration for SC and IV bortezomib do not differ since both are prepared by reconstituting the vial of bortezomib with normal saline and administered to patients as a quick injection.10 How often is thalidomide being used in the maintenance setting for MM in 2013?

For years, thalidomide appeared to be a good choice for maintenance therapy due to its efficacy and the convenience of being an oral agent. Eight phase 3 studies assessed thalidomide in the maintenance setting, and the use of this agent led to improvement in event-free survival (EFS) and/or PFS.1118 However, only 2 studies showed improvement in OS. The first was the IFM 99-02 study (N=597) in which patients were randomized to receive 1 of the 3 treatment arms following double ASCT: (1) no maintenance, (2) pamidronate, or (3) thalidomide 400 mg daily plus pamidronate. Patients were to receive these treatments until progression. Increased EFS and OS was seen in patients in the thalidomide arm, but this benefit was observed only in patients who achieved less than a very good partial response after transplant and those without del(13) or high beta-2 microglobulin levels.11 A second trial, by Spencer and colleagues (N=269) randomized patients to receive thalidomide plus prednisone or prednisone alone following single ASCT. Patients were to receive thalidomide for 12 months. There was improvement in 3-year PFS and OS in the thalidomide arm (P<.001 and P =.004, respectively).12 Thalidomide maintenance has fallen out of favor in most clinics in the United States because of the high rates of treatment-related toxicity (especially PN) and the inconsistent data regarding OS benefit. Lenalidomide and bortezomib are now being used as maintenance therapy for almost all of the patients at our institution, either as monotherapy or in combination. Newly approved drugs such as pomalidomide and carfilzomib are also undergoing investigation as maintenance in clinical trials and may provide additional options in the near future. ♦ References

1. Niesvizky R, Jayabalan DS, Christos PJ, et al. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008;111:1101-1109. 2. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123-2132. 3. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791. 4. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781. 5. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769. 6. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946-2955. 7. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28:5101-5109. 8. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 9. Moreau P, Coiteux V, Hulin C, et al. Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica. 2008; 93:1908-1911. 10. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals Inc; May 2013. 11. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294. 12. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27:1788-1793. 13. Morgan G, Jackson G, Davies F. Maintenance thalidomide may improve progression free but not overall survival: results from the Myeloma IX Maintenance Randomisation. Blood (ASH Annual Meeting Abstracts). 2008;Abstract 656. 14. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021-1030. 15. Lokhorst HM, van der Holt B, Zweegman S, et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010;115:1113-1120. 16. Stewart AK, Trudel S, Bahlis NJ, et al. A randomized phase III trial of thalidomide and prednisone as maintenance therapy following autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM): the NCIC CTG MY.10 trial. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 39. 17. Ludwig H, Adam Z, Tothova E, et al. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica. 2010; 95:1548-1554. 18. Maiolino A, Hungria VT, Garnica M, et al. Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. Am J Hematol. 2012;87:948-952.

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Renal Cell Carcinoma

Sequential Therapy for Renal Cell Carcinoma Daniel C. Cho, MD Division of Hematology and Oncology Beth Israel Deaconess Medical Center Boston, Massachusetts

Key Points • Until a therapeutic strategy emerges that can result in durable remissions for the majority of patients with advanced RCC, sequential therapy remains a reality for most patients • With the increasing complexity of the therapeutic landscape of RCC, many critical questions remain unanswered • In the absence of data from large randomized trials, the decision on sequence of therapies must be individualized primarily based on clinical factors • With the rapid emergence of novel technologies, however, the sequence of agents may soon be largely dictated by the genetic characterization of an individual’s tumor specimens prior to initiating therapy

ith several agents now approved and ficacy. Therefore, accepting that the majority of adbroadly available for the treatment of pavanced RCC is incurable, efforts have been focused tients with advanced on identifying sequences of therapies renal cell carcinoma (RCC), a great that might maximize both duration of deal of attention has been focused disease control and quality of life for on determining the most appropriate individual patients. In this review, we sequence of therapies. The concept will summarize these efforts so far and of sequential therapy has developed discuss how these efforts might expand for several reasons, including: 1) The in the future. availability of molecularly targeted agents with distinct toxicities and Sequential Therapy Starting mechanisms of action; 2) The fact With Immunotherapy that responses to molecularly targeted Although the premise of a prospecagents in RCC are typically not comtive, defined, sequential regimen depends Daniel C. Cho, MD plete or durable; therefore, treatment on the assumption that advanced RCC is with these agents must be thought of incurable, it should be remembered that a as noncurative except in rare circumstances; and 3) The subset of patients can experience durable remissions from fact that combinational regimens of available agents immunotherapy. Although single-agent interferon-α have not yet demonstrated substantially improved ef(IFN) has largely been removed from the RCC treatment

Dr Cho is the Director of the Experimental Therapeutics Program and a member of the Biologics Therapy Program. His research is focused on clinical, translational, and laboratory-based investigations in novel therapeutics for renal cancer and melanoma. Dr Cho earned his medical degree from Washington University School of Medicine at St Louis and his master’s degrees from Yale University. He completed his Residency in Internal Medicine and fellowship in Hematology/Oncology at Beth Israel Deaconess Medical Center. Dr Cho is an Assistant Professor of Medicine at Harvard Medical School.

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algorithm by recent phase 3 trials, high-dose interleukin-2 (IL-2) is still frequently given to patients with RCC at specialized centers. While IL-2 has historically been felt to benefit only a small subset of patients, recent studies suggest that in the current era response to high-dose IL-2 exceeds 25%, with at least 10% of patients exhibiting complete responses that last in excess of 2 years.1 Therefore, high-dose IL-2 remains a viable therapeutic option for patients with advanced RCC. With respect to sequence of therapy, several clinical trials have shown that molecularly targeted therapies, both those targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR), have substantial activity in cytokine-refractory patients.2-5 At the same time, a small retrospective study has suggested that the efficacy of high-dose IL-2 following VEGF-targeted therapies may be limited.6 Although the later point must be validated independently, the data available thus far suggest that patients deemed appropriate for IL-2 should be treated with IL-2 as a primary therapy before molecularly targeted agents. The determination of which patients might be best suited for consideration for high-dose IL-2 is dependent upon many factors. Clinical factors that should favor IL-2 include younger age, good performance status, few medical comorbidities, and disease that is not rapidly growing. Although many efforts have focused on identifying pathologic or molecular factors that might predict for the likelihood of benefit from IL-2, so far only the presence of clear cell histology is regularly adhered to. Finally, the consideration of IL-2 may also depend on more practical factors such as proximity to an IL-2 specialty center and patient motivation. While existing data suggest that IL-2 should be considered as a primary therapy for appropriately selected patients with advanced RCC, more novel immunotherapies may have broader activity across treatment scenarios. More will be discussed regarding these novel agents in the following sections.

Sequential Therapy Starting With Molecularly Targeted Agents For most patients with advanced RCC, molecularly

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targeted agents will be selected as the primary therapy of choice. A subset of these patients will first be treated with temsirolimus, an allosteric inhibitor of mTOR, that is recommended by the National Comprehensive Cancer Network (NCCN) for the treatment of patients who have poor prognostic features (â&#x2030;Ľ3 of 6 of the following: Karnofsky performance status <80, time from diagnosis to randomization <12 months, serum lactose dehydrogenase >1.5 the upper limit of normal, hemoglobin less than the lower limit of normal, corrected serum calcium >10 mg/dL, and >1 metastatic site).7 The majority of patients, however, will begin therapy with a VEGF-targeted treatment. The NCCN currently gives category 1 recommendations for 3 such therapies (sunitinib, pazopanib, and bevacizumab plus IFN). In

In the current era response to high-dose IL-2 exceeds 25%, with at least 10% of patients exhibiting complete responses that last in excess of 2 years. the United States, most patients will likely be treated with sunitinib or pazopanib, which are both tyrosine kinase inhibitors (TKIs) with activity against VEGF receptor 2 and platelet-derived growth factor receptor. With respect to second-line therapy, the NCCN currently gives category 1 recommendations for 2 agents, everolimus and axitinib, for patients who have previously been treated with VEGF-targeted TKIs. This is further complicated by that fact that retrospective analysis has suggested that there is no definitive cross-resistance between agents such as sorafenib, sunitinib, and bevacizumab/IFN, and these agents also remain therapeutic options following initial TKI failure.8 Regardless, in principle the decision facing physicians with respect to a second-line therapy following failure of a first-line TKI is whether to prescribe another VEGF-targeted agent (axitinib or similar agent) or change to an mTOR inhibitor (everolimus). Some guidance on this decision is available from current data. First, the final analysis of the pivotal

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Renal Cell Carcinoma

Table. Ongoing Sequential Therapy Trials in Renal Cell Carcinoma Title of Trial

Phase

Agents

Primary End Point

Sequential Two-Agent Assessment in Renal Cell Carcinoma Therapy (NCT01217931)

Pazopanib, everolimus, bevacizumab

Time to overall treatment failure

Comparison of Sequential Therapies With Sunitinib and Sorafenib in Advanced Renal Cell Carcinoma (Cross-J-RCC) (NCT01481870)

Sorafenib, sunitinib

Progression-free survival on first-line agent

phase 3 trial of everolimus versus placebo (RECORD-1) suggests that everolimus has similar activity following the failure of 2 VEGF TKIs as after 1.9 At the same time, both retrospective analysis and prospective clinical trials suggest that VEGF-targeted agents may have activity following disease progression on other VEGF (or even the same) pathway inhibitors.10-13 Finally, the only comparative trial between VEGF TKIs and mTOR inhibitors was the recently reported INTORSECT trial in which 512 patients with advanced RCC in whom prior sunitinib therapy had failed were randomized to receive either temsirolimus or sorafenib. This phase 3 trial failed to show that temsirolimus was superior to sorafenib in median progression-free survival (PFS)

It is clear that any current understanding regarding sequential therapy of molecularly targeted agents in RCC is at risk of changing quite rapidly. (4.28 vs 3.91 months; hazard ratio [HR] 0.87; P=.1933) and was actually inferior in overall survival (12.27 vs 16.64 months; HR 1.31; P=.0144).14 Taken together, these data appear to favor the sequence of VEGFVEGF-mTOR over VEGF-mTOR-VEGF (where VEGF indicates VEGF-targeted therapy and mTOR indicates mTOR inhibitors). While the existing data supporting a certain sequence of therapies are drawn from the analysis of the outcomes in a large group of patients, the decision with

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respect to individual patients must of course take into account patient-specific factors. For example, a patient who experienced severe mechanism-specific toxicities from a VEGF-targeted agent (eg, hypertension, proteinuria, cardiac complications, etc) might benefit from changing to an mTOR inhibitor given the largely non-overlapping toxicities of these classes of agents.15 A patient’s clinical response to initial VEGF-targeted therapy might also be taken into account. For a patient who is primarily refractory to a VEGF TKI, it would seem logical to try a therapy with a different mechanism of action such as an mTOR inhibitor. Likewise, a patient who had a prolonged benefit from the first VEGF-targeted TKI might be more likely to benefit from a different VEGF-targeted agent. In a recently reported secondary end-point analysis of the phase 3 AXIS trial, it was shown that the median PFS for patients whose duration of prior sunitinib therapy was ≥9 months was significantly longer than for those whose prior sunitinib duration was <9 months whether they were treated with sorafenib (4.6 vs 2.9 months) or axitinib (6.3 vs 4.5 months).16 All of these findings must be validated prospectively and independently, however, before it is appropriate to incorporate them formally in selection algorithms. Ultimately, the field must be guided by prospective clinical trials investigating sequential therapy. Impor tant trials assessing sequential therapies are shown in the Table. Hopefully completion of these studies will provide more information on the most appropriate sequence of agents for patients with RCC. Unfortunately,

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May 2013

Renal Cell Carcinoma

the arena of molecularly targeted agents in RCC also remains quite fluid. It is possible that the more potent, next-generation VEGF-targeted TKI tivozanib will soon be approved by the FDA following its positive phase 3 trial.17 The broad availability of such an agent across treatment scenarios (axitinib is currently only approved after failure of at least 1 systemic agent) will engender even more questions with respect to sequential therapy. For example, does it make the most sense to use a less potent VEGF TKI first and then follow with the more potent agents (eg, axitinib)? Conversely, would it make more sense to use the most potent VEGF TKI first? If that is the case, will a less potent VEGF TKI have efficacy following failure on the more potent VEGF TKI? Or would the more appropriate sequence become a highly potent VEGF TKI followed by an mTOR inhibitor, followed by rechallenge with the same highly potent VEGF TKI? Regardless, it is clear that any current understanding regarding sequential therapy of molecularly targeted agents in RCC is at risk of changing quite rapidly.

Novel Therapeutic Agents in RCC Many novel therapeutic agents are planned for assessment in RCC. As if sequential therapy was not already complicated enough with just 2 primary therapeutic classes of agents (VEGF-targeted agents and mTOR inhibitors), clinicians may soon be faced with the challenge of integrating agents with completely novel mechanisms of action into their therapeutic algorithms. While some agents may be combined with VEGF TKIs (eg, ALK inhibitors, MET inhibitors) and others used in place of current therapies (novel PI3-kinase/mTOR inhibitors in place of the rapalogues), perhaps the most relevant class of agents with respect to sequential therapy is the novel immunotherapies given their distinct mechanism of action. In particular, the PD-1 antibodies are likely the closest to possibly gaining broad approval. Recently, the PD-1 antibody nivolumab (MDX-1106, BMS-936558) demonstrated preliminary activity in patients with advanced RCC, many of whom had been heavily pretreated.18 Interestingly, at the time of data

Volume 2 â&#x20AC;˘ No 3

analysis and publication, 5 of 8 patients with objective responses who had started treatment more than 1 year before had responses lasting at least 1 year. Thus, although these results are quite preliminary, there is a suggestion that responses to these novel immunotherapies may be durable in some cases. In addition to several combination studies (including with VEGF TKIs and ipilimumab), nivolumab is scheduled to be assessed in a phase 3 clinical trial versus everolimus in patients with advanced RCC in whom prior antiangiogenic therapy has failed. A positive trial and possible approval of this agent in the second-line setting would be anticipated to have a major effect on sequential algorithms. Should PD-1 (or PD-L1) antibodies demonstrate the ability to

Clinicians may soon be faced with the challenge of integrating agents with completely novel mechanisms of action into their therapeutic algorithms. induce durable remissions in even a subset of patients, there will likely be a push to move these agents into the first-line setting. In that case, the most appropriate sequence in most patients with clear cell RCC might become immune therapy (with PD-1/PD-L1 antibodies or high-dose IL-2) followed by sequential molecularly targeted therapy.

Novel Technologies In step with continued investigation of novel therapies is the development and broader availability of novel technologies. Perhaps the most directly applicable to personalizing sequential therapy are next-generation sequencing technologies for whole genome or whole exome sequencing. Preliminary work with such platforms has already proven fruitful. Voss et al recently reported the finding of mutations in tuberous sclerosis complex 2 and mTOR in tumor specimens from patients with RCC who had prolonged responses to rapalogues.19 More information on the frequency of these and other mutations will likely be available in the anticipated

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Renal Cell Carcinoma

publication of the results of The Cancer Genome Atlas project. While the large-scale utilization of whole genome or whole exome sequencing for the analysis of other clinically annotated groups of tumor specimens may currently be somewhat cost prohibitive, such work is progressively becoming more feasible. It is hoped that the subsequent interrogation of such genetic information will allow the identification of markers to direct individual patients to specific therapies. At the same time, it is becoming clear that there is both intratu-

The sequence of agents may soon be largely dictated by the genetic characterization of an individual’s tumor specimens prior to initiating therapy. moral and intermetastases genetic heterogeneity within an individual patient’s RCC tumor burden.20 Inasmuch as this heterogeneity may also emerge temporally following treatment with various systemic therapies, in the future the sequence of therapies for an individual patient may ultimately be determined by serial genetic analysis rather than depending on codified treatment algorithms.

Conclusion Until a therapeutic strategy emerges that can result in durable remissions for the majority of patients with advanced RCC, sequential therapy remains a reality for most patients. Efforts thus far have focused on identifying sequences among currently available therapies that may maximize control of tumor growth and maintenance of patient quality of life; however, with the increasing complexity of the therapeutic landscape of RCC, many critical questions remain unanswered. For now, in the absence of data from large randomized trials, the decision on sequence of therapies must be individualized mostly based on clinical factors. With the

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rapid emergence of novel technologies, however, the sequence of agents may soon be largely dictated by the genetic characterization of an individual’s tumor specimens prior to initiating therapy. u

References

1. McDermott DF, Ghebremichael MS, Signoretti S, et al. The high-dose aldesleukin (HD IL-2) “SELECT” trial in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2010;28(suppl). Abstract 4514. 2. Motzer RJ, Michaelson MD, Rosenberg J, et al. Sunitinib efficacy against advanced renal cell carcinoma. J Urol. 2007;178:1883-1887. 3. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134. 4. Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol. 2007;8:975-984. 5. Atkins MB, Hildago M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004;22:909-918. 6. Cho DC, Puzanov I, Regan MM, et al. Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted therapy in patients with advanced renal cell carcinoma. J Immunother. 2009;32:181-185. 7. Motzer RJ, Agarwal N, Beard C, et al. NCCN clinical practice guidelines in oncology: kidney cancer. J Natl Compr Canc Netw. 2009;7:618-630. 8. Dudek AZ, Zolnierek J, Dham A, et al. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer. 2009;115:61-67. 9. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116:4256-4265. 10. Stenner F, Chastonay R, Liewen H, et al. A pooled analysis of sequential therapies with sorafenib and sunitinib in metastatic renal cell carcinoma. Oncology. 2012;82:333-340. 11. Rini BI, Michaelson MD, Rosenberg JE, et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008;26:3743-3748. 12. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009;27:4462-4468. 13. Zama IN, Hutson TE, Elson P, et al. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer. 2010;116:5400-5406. 14. Hutson T, Escudier B, Esteban E, et al. Temsirolimus vs sorafenib as second line therapy in metastatic renal cell carcinoma: results from the INTORSECT trial. Presented at: 37th Congress of the European Society for Medical Oncology; September 28-October 2, 2012; Vienna, Austria. Abstract LB22. 15. Bracarda S, Hutson TE, Porta C, et al. Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis. Br J Cancer. 2012;106:1475-1480. 16. Rini BI, Escudier BJ, Michaelson MD, et al. Phase III AXIS trial for second-line metastatic renal cell carcinoma (mRCC): effect of prior firstline treatment duration and axitinib dose titration on axitinib efficacy. J Clin Oncol. 2012;30(suppl 5). Abstract 354. 17. Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: results from a phase III randomized, open-label, multicenter trial. J Clin Oncol. 2012;30(suppl). Abstract 4501. 18. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454. 19. Voss MH, Hakimi AA, Brannon AR, et al. Next-generation sequencing reveals genomic determinants of long-term response to mTOR inhibitors in patients with advanced RCC. BJU Int. 2012;110(suppl 2). Abstract 11. 20. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumoral heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883-892.

PERSONALIZED MEDICINE

ONCOLOGY

May 2013

For indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen

Established treatment, demonstrated results Single-agent TREANDA® (bendamustine HCl) for Injection provided durable responses that lasted a median of 9 months Median DR

9.2 months (95% CI: 7.1, 10.8)

All responders (n=74) Patients who achieved a CR/CRu

10.4 months (95% CI: 9.3, 13.6)

8.3 months (95% CI: 6.3, 10.8)

Patients who achieved a PR

Months

The efficacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. In 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176), the most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%).

TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. • TREANDA is administered with a convenient dosing schedule – The recommended dose is 120 mg/m² administered intravenously over 60 minutes on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA • The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia

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Please see accompanying brief summary of full Prescribing Information. Reference: 1. Data on file. Teva Pharmaceuticals.

Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin Lymphoma That Has Progressed INDICATION AND USAGE: TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176). System organ class, preferred term, and number (%) of patients* are shown. Total number of patients with at least 1 adverse reaction— All Grades: 176 (100); Grade 3/4: 94 (53). Cardiac disorders, All Grades and Grade 3/4—Tachycardia: 13 (7), 0. Gastrointestinal disorders, All Grades and Grade 3/4—Nausea: 132 (75), 7 (4); Vomiting: 71 (40), 5 (3); Diarrhea: 65 (37), 6 (3); Constipation: 51 (29), 1 (<1); Stomatitis: 27 (15), 1 (<1); Abdominal pain: 22 (13), 2 (1); Dyspepsia: 20 (11), 0; Gastroesophageal reflux disease: 18 (10), 0; Dry mouth: 15 (9), 1 (<1); Abdominal pain upper: 8 (5), 0; Abdominal distension: 8 (5), 0. General disorders and administration site conditions, All Grades and Grade 3/4—Fatigue: 101 (57), 19 (11); Pyrexia: 59 (34), 3 (2); Chills: 24 (14), 0; Edema peripheral: 23 (13), 1 (<1); Asthenia: 19 (11), 4 (2); Chest pain: 11 (6), 1 (<1); Infusion site pain: 11 (6), 0; Pain: 10 (6), 0; Catheter site pain: 8 (5), 0. Infections and infestations, All Grades and Grade 3/4—Herpes zoster: 18 (10), 5 (3); Upper respiratory tract infection: 18 (10), 0; Urinary tract infection: 17 (10), 4 (2); Sinusitis: 15 (9), 0; Pneumonia: 14 (8), 9 (5); Febrile Neutropenia: 11 (6), 11 (6); Oral Candidiasis: 11 (6), 2 (1); Nasopharyngitis: 11 (6), 0. Investigations, All Grades and Grade 3/4—Weight decreased: 31 (18), 3 (2). Metabolism and nutrition disorders, All Grades and Grade 3/4—Anorexia: 40 (23), 3 (2); Dehydration: 24 (14), 8 (5); Decreased appetite: 22 (13), 1 (<1); Hypokalemia: 15 (9), 9 (5). Musculoskeletal and connective tissue disorders, All Grades and Grade 3/4—Back pain: 25 (14), 5 (3); Arthralgia: 11 (6), 0; Pain in extremity: 8 (5), 2 (1); Bone pain: 8 (5), 0. Nervous system disorders, All Grades and Grade 3/4—Headache: 36 (21), 0; Dizziness: 25 (14), 0; Dysgeusia: 13 (7), 0. Psychiatric disorders, All Grades and Grade 3/4—Insomnia: 23 (13), 0; Anxiety: 14 (8), 1 (<1); Depression: 10 (6), 0. Respiratory, thoracic and mediastinal disorders, All Grades and Grade 3/4—Cough: 38 (22), 1 (<1); Dyspnea: 28 (16), 3 (2); Pharyngolaryngeal pain: 14 (8), 1 (<1); Wheezing: 8 (5), 0; Nasal congestion: 8 (5), 0. Skin and subcutaneous tissue disorders, All Grades and Grade 3/4—Rash: 28 (16), 1 (<1); Pruritus: 11 (6), 0; Dry skin: 9 (5), 0; Night sweats: 9 (5), 0; Hyperhidrosis: 8 (5), 0. Vascular disorders, All Grades and Grade 3/4—Hypotension: 10 (6), 2 (1). *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology Variable All Grades Grade 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates. TRE-2486a November 2012 (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

Hematology

Current Treatment of Myelofibrosis: How Far We Have Come and How Far We Have Yet to Go At the 2012 conference of the Global Biomarkers Consortium, which took place March 9-11, 2012, in Orlando, Florida, Charles Schiffer, MD, from the Barbara Ann Karmanos Cancer Institute and Wayne State University in Detroit, Michigan, discussed the management of myeloproliferative neoplasms.

Key Points • Until recently, the standard of care for patients with myelofibrosis has been largely palliative, including supportive measures directed toward reducing anemia or decreasing the degree of splenomegaly • The only potentially curative therapy for myelofibrosis is allogeneic stem cell transplantation (alloSCT); however, the majority of patients with myelofibrosis are not eligible for alloSCT • The discovery of the role of the JAK2-mutated signaling pathways resulted in the development and FDA approval of ruxolitinib, a first-in-class JAK2 inhibitor that has shown limited promise in the treatment of myelofibrosis • Other JAK2 inhibitors are in development, and preliminary studies show promising results in terms of spleen reduction and symptom improvement

ajor advances in understanding the biology of hematologic malignancies, such as the unraveling of the molecular pathophysiology of BCR-ABL and studies of the mechanisms of resistance in Philadelphia chromosome–positive chronic myeloid leukemia, have resulted in the rapid development of multiple selective BCR-ABL tyrosine kinase inhibitors (eg, imatinib, nilotinib, dasatinib), which improved 10year survival from the historic experience of approximately 20% to an estimated rate of 85%.1 In the case study of a patient with myelofibrosis that follows, the role of inhibition of the JAK2-mutated signaling pathway is discussed. The World Health Organization classification system for myeloid malignancies lists 8 disorders in the category of myeloproliferative neoplasms (MPNs), including the so-called “BCR-ABL1–negative MPN”: polycythemia vera, essential thrombocythemia, and primary myelofibrosis.2 The MPNs (previously referred to as myeloproliferative disorders) are clonal disorders arising in a pluripotent hematopoietic stem cell.3 The MPNs are rare diseases.4 The annual incidence of

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Case • A 58-year-old man who had been treated for essential thrombocytosis with hydroxyurea intermittently for 18 years is referred for advice about further treatment • Over the past year, he has had a decline in his platelet count (now 84,000 cells/μL), hemoglobin (now 9.7 g/dL), and elevation in his white blood cell count (now 36,000 cells/μL with 4% blasts) • He reports discomfort in his left upper quadrant with occasional episodes of sharp pain and easy satiety. He has lost 22 pounds and has begun to experience night sweats • On physical examination, his spleen is palpable just below the umbilicus and extends to the midline (Figure 1) • His peripheral blood and marrow are shown in Figure 2 • The marrow was inaspirable, but cytogenetics on the patient’s peripheral blood revealed monosomy 7 • A JAK2 mutation was not detected in the peripheral blood sample

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Case (cont) Figure 1. Patient’s Abdomen Is Characterized by Massive Splenomegaly and Concomitant Hepatomegaly

myelofibrosis ranges from 0.2 to 1.5 cases per 100,000 individuals.5,6 The majority of patients with myelofibrosis experience splenomegaly, which can lead to portal hypertension or splenic infarcts,7 and cytopenias.8 In addition, progressive splenomegaly is associated with an increased risk of transformation to secondary acute myeloid leukemia,9 which has a poor prognosis (ie, median survival is 2.6 months after transforming to blast phase).10 Symptoms related to splenomegaly (ie, early satiety, abdominal pain) can also impair physical function, such as walking, bending, eating, or breathing.11 Anemia, which is prevalent among those with myelofibrosis, is prognostic of decreased survival.12 Myelofibrosis is also characterized by fatigue, night sweats, pruritus, bone and muscle pain, and unintentional weight loss – all of which impair quality of life.11,13,14 The median survival time for patients with myelofibrosis ranges from 2 to 11 years; high-risk patients show a rapid progression of the disease and a median survival time of 12 to 24 months.12,15

MYELOFIBROSIS ELOFIBROSIS Figure 2. Peripheral Blood and Bone Marrow A

Traditional Therapies for Myelofibrosis Most of the traditional therapies for myelofibrosis are palliative and have demonstrated limited efficacy in the management of splenomegaly, cytopenias, or the often debilitating symptoms associated with the disease.16,17 Hydroxyurea has generally been used as the first-line treatment of myelofibrosis-associated splenomegaly.13 Results from 1 study showed that approximately 30% of patients receiving hydroxyurea achieved a reduction in spleen size.18 However, the duration of response with hydroxyurea is only approximately 13 months, and hydroxyurea treatment is associated with the development and/or worsening of anemia.13 Splenectomy has also been used for the management of splenomegaly; however, in 1 study, splenectomy in patients with myelofibrosis was associated with 9% mortality and 31% morbidity.19 The only potentially curative therapy for myelofibrosis is alloSCT.20 However, the use of alloSCT is restricted to a small percentage of patients, since not all patients are appropriate candidates. Ideal candi-

MYELOFIBROSIS Peripheral smear shows some anisocytosis and poikilocytosis and some characteristic “teardrop” cells.

Bone marrow is intensely fibrotic with increased reticulin and collagen on trichrome.

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dates should be young, without comorbidities, with a performance status ≥90%, and without peripheral blood blasts.13,21,22 In 2005, 4 research groups,23-26 using different approaches, independently discovered an acquired point mutation in the Janus kinase 2 (JAK2) gene at codon 617 within the JH2 domain, resulting in the substitution of a valine for a phenylalanine (Figure 3).27 Known as JAK2 V617F, this mutation is found in approximately 95% of patients with polycythemia vera, 50% to 60% of those with essential thrombocythemia, and 50% to 60% of those with myelofibrosis.28 The discovery of this mutation, a tyrosine kinase used by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders.3 After the discovery of the JAK2 V617F mutation, hematologists and oncologists expected that specific JAK2 inhibitors could change the natural course of MPNs, as selective BCR-ABL tyrosine kinase inhibitors (eg, imatinib, nilotinib, dasatinib) had done in chronic myeloid leukemia. Therefore, a flurry of research and drug development activity took place in search of JAK2 inhibitors in the hope that the therapeutic paradigm would change from palliation to cure.29

Figure 3. A: Involvement of Janus Kinases in B: Structural Map of A Unifying PCytokine E R S P ESignal C T I VTransduction; E Janus Kinase 2

find but s Ligand sides porte poly mye Bost with P P P P their SH2 senti JAK2 Phosphorylation myel ed K STAT 73 pa with Cytoplasm tient of pa Nucleus diffe P P obse tanc DNA A in a p B expe B V617F each prior Amino Carboxyl FERM SH2 Pseudokinase Kinase terminus terminus poly a res P P P P P ed t sear JH2 JH1 Ruxolitinib lowe Ruxolitinib (previously known as INCB018424), an From Goldman JM. A unifying mutation in chronic myeloproliferative disorders. N Engl J Med. 2005;352:1744-1746. Copyright © 2005 Massachusetts Medical Society. Reprinted Involvement of Janus Kinases in Cytokine Signal Transduction (Panel A)with per- vitro orally administered JAK1 and JAK2 inhibitor approved mission from Massachusetts Society.2 (Panel B). char and Structural Map ofMedical Janus Kinase by the FDA in 2011, is the first therapy approved for ed by On ligand binding by receptors (Panel A), Janus kinase (JAK) proteins make contact with the cytoplasmic domain of the receptor, where they the targeted treatment of intermediate- and highleagues, patients with intermediate-2 or high-risk my-catalyze the The phosphorylation of tyrosines. This action, in turn, recruits STAT (signal transvolve risk myelofibrosis, including primary myelofibrosis, elofibrosis were randomized to receive twice-daily oral ducer and activator of transcription) molecules, which are phosphorylated on myel 30 post-polycythemia vera myelofibrosis, and post-essenruxolitinib (n=155) or placebo (n=153). Astranslocate shown into the nucletheir SRC homology 2 (SH2) domains, dimerize, and mia, us, where they actof as patients transcription The JAK homology 1 (JH1) domain tial thrombocythemia myelofibrosis. The FDA approval Figure 4, 41.9% in factors. the ruxolitinib group vertook (Panel B) is the active kinase domain of JAK2, and the JAK homology 2 (JH2) doof ruxolitinib was based on the results of 2 randomized susmain 0.7% the placebo had a reduction in spleen is a in pseudokinase withgroup autoinhibitory properties. JAK2 also carries a band the a 4.1(f)-ezrin-radixin-moesin domain. P indicates a site ofat autophosphase 3 clinical studies: a placebo-controlled study in volume, as assessed by (FERM) MRI or CT scan, of ≥35% 85 ty phorylation. The position of the mutated V617F codon is indicated by the arrow. on th 309 patients with intermediate-2 or high-risk myelo24 weeks (P<.001). The response was durable and was mult fibrosis and a study of ruxolitinib versus best available observed not only in patients having the JAK2 V617F thus therapy in 219 patients with intermediate-2 or high-risk mutation but also in patients with wild-type JAK2. to-thymine mutation encoding a valine-to-phenyl- ther primary myelofibrosis, post-polycythemia vera myelofiA reduction inalanine spleen substitution volume was maintained in paat position 617 (V617F) in the T brosis, or post-essential thrombocythemia myelofibrosis. tients who received ruxolitinib; 67% of thedomain patientsof with JH2, or autoinhibitory, JAK2 (see dia- by fo Panel They found the same In the first study, conducted by Verstovsek and cola response had thegram, response forB). ≥48 weeks (Figure 5). mutation in ques 57 percent of patients with myelofibrosis and in 23 muta percent of patients with essential thrombocythe- myel mia. The mutation was found only in hematopoi- it dis Volume 2 • No 3 May 2013 WWW.PERSONALIZEDMEDONC.COM 155 leavi etic cells and must therefore be an acquired somatic mutation. vated Normally, one would say that such consistent cruit A Receptor dimer

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Figure 4. Reduction in Spleen Volume of ≥35% at 24 Weeks: Ruxolitinib vs Placebo A

e r d

e t

Patients With Patients with>35% ≥35%Reduction Reduction in Spleen in SpleenVolume Volume(%) (%)

41.9

Odds ratio, 134.4 (95% CI, 18.0–1004.9) P<0.001

40 30 20 10 0

0.7

Ruxolitinib (N = 155)

Placebo (N = 153)

From Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxoli80 tinib for myelofibrosis. N Engl J Med. 2012;366:799-807. Copyright © 2012 Massachusetts MediRuxolitinib (N=155) cal Society. ReprintedPlacebo with permission (N=153)from Massachusetts Medical Society. 60

Change in Spleen Volume from Baseline (%)

40 20 0 −20 −40 −60 −80

An improvement of ≥50% was seen in the total symptom score at 24 weeks in 46% of patients who received ruxolitinib versus 5% of patients who received placebo (P<.001). At the time of data cutoff, 10 deaths 35% Decrease were reported in the ruxolitinib group (6.5%) versus 14 deaths in the placebo group (9.1%) (hazard ratio [HR] 0.67; 95% CI, 0.30-1.50; P=.33). Subsequently, a survival analysis based on Patients a planned data cutoff with 4 Individual additional months of follow-up (median follow-up, 51 weeks) revealed a significant survival advantage (Figure 6) for patients who received ruxolitinib, with 13 Placebo deaths in the ruxolitinib group (8.4%) and 24 deaths

enced transformation to acute myeloid leukemia; both were in the ruxolitinib group. In the second study, conducted by Harrison and colleagues, 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis were randomized to receive oral ruxolitinib (n=146) or best available therapy (n=73).31 Results showed that, at week 24, 32% of the patients in the ruxolitinib group had ≥35% reduction in spleen volume, as assessed by MRI or CT, compared with no reduction in the patients receiving best available therapy (P<.001). At week 48, 28% of the patients in the ruxolitinib group had ≥35% reduction in spleen volume compared with no reduction in the patients receiving best available therapy (P<.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. Figure 7 shows mean changes from baseline at week 48 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire core model (QLQ-C30) symptom scores. Improvement is represented by negative numbers (ie, reduction in symptoms). The most common hematologic abnormalities of grade ≥3 in either group were thrombocytopenia and anemia, which were managed with dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment due to thrombocytopenia, and none discontinued due to anemia. Nonhematologic adverse events were rare and mostly grade 1/2. Two cases of acute myeloid leukemia were reported with best available therapy. In addition, Verstovsek and colleagues analyzed the long-term outcomes of 107 patients with intermediate-2 or high-risk myelofibrosis receiving ruxolitinib in a phase 1/2 trial.32 After a median follow-up of 32

Median Change in Spleen Volume from Baseline (%)

es K2 C ib 40 e20 uc0 re re −20 patients who received ruxolitinib, Among nd −40 and thrombocytopenia were the anemia he most−60 common adverse events, but they re Ruxolitinib rrarely−80led to discontinuation of the drug. ry Baseline 12 24 36 48 oWeeks oin the placebo group (15.6%) (HR 0.50; 95% CI, 0.25No. of Patients a Ruxolitinib 148 139 69 16 0.98; P=.04). Among patients who received ruxolitinib, Placebo 132 106 46 13 he anemia and thrombocytopenia were the most common bo events, butwho they received rarely ledplato discontinuation of week 48; patients r- and 21.5% at adverse increase of 3.5% at week 24 and re cebo had a mean the drug (1 patient in each group). Two patients experihe 6.3% at week 48 (Fig. S6 in the Supplementary Appendix). Furthermore, patients receiving ruxolitinib had reductions in plasma levels of PERSONALIZED C-reactive Volume 2 • No 3 MEDICINE 156 protein and the proinflammatory cytokines tumor ts necrosis factor α and interleukin-6, and they had

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A Patients with ≥35% Reduction in Spleen Volume (%)

60 41.9

Odds ratio, 134.4 (95% CI, 18.0–1004.9) P<0.001

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40 30 20

Figure 5. A: Change in Spleen Volume From Baseline: 10 Ruxolitinib vs Placebo; B: Median Change in Spleen 0.7 Volume0 From Baseline Over Time (%): Ruxolitinib Ruxolitinib Placebo vs Placebo (N = 155) (N = 153) BA 80

Change Volume ChangeininSpleen Spleen Volume From (%)(%) fromBaseline Baseline

Figure 1. Change in Spleen Volume. Panel A shows the results of the intention-to-treat analysis of the percentage of patients in each study group who reached the primary end point of a reduction of 35% or more in spleen volume as assessed by means of magnetic resonance imaging (MRI) or computed tomography (CT). Patients who discontinued the study drug before week 24 or crossed over before week 24 were counted as not having had a response. Only patients with baseline data were included in this analysis. I bars months, denote 58 patients (54%) were still receiving rux95% confidence intervals. CI denotes confidence olitinib, interval. with anPanel overall survival of 69%. Thefrom overall B shows the percent change basein spleen at week 24 myelofibrosis (in 139 patients was in the survival line in these 107volume patients with ruxolitinib group and 106 in the placebo group) or at significantly better (P=.005) than in 16 310 matched the last evaluation before weekthat 24 (in patients in the ruxolitinib group and 47 in the placebo group). Data for (based on trial enrollment criteria) historical control 1 patient with a missing baseline value are not included patients,on primarily because of a highly significant difthe graph. Most patients in the ruxolitinib group ference in in thein high-risk subgroup (150overall of 155) survival had a reduction spleen volume, wheremost patients among in the placebo group had either an in(P=.006).asFurthermore, the patients with myelocrease in spleen volume (102 of 153 patients) or no change fibrosis, those withpatients). high-risk myelofibrosis (15 of 153 Panel C shows the experienced median percent change in spleen volume as by means of MRI the same overall survival as thoseassessed with intermediate-2 or CT over time. Reductions in spleen volume were aprisk. Patients with ≥50% reduction in splenomegaly had parent at the first on-study measurement at 12 weeks significantly prolonged survival those with <25% and were maintained over versus the course of the study. The edge of each I (P<.0001). bar corresponds to the 75th perreductionupper in splenomegaly However, in ancentile, and the lower edge to the 25th percentile.

Ruxolitinib (N=155) Placebo (N=153)

40 20 0 −20

35% Decrease

−40

Median Change Change in Median inSpleen SpleenVolume Volume from Baseline Baseline(%) (%) From

other long-term study, Tefferi and colleagues reported −60 that among 51 patients with myelofibrosis treated longSubgroups −80 term with 18 patients (35%) had died,changes and Individual Patients In aruxolitinib, post hoc analysis of subgroups, mean 5 patients (10%) volume experienced transformation to the acute in spleen among patients with JAK2 CB 33 myeloidV617F leukemia. No significant difference seen mutation were −34.6% in the was ruxolitinib 40 8.1% group; the pacorrein the group survivaland rate for in thethe 51 placebo ruxolitinib-treated 20 Placebo sponding changes among of patients without the tients compared with a cohort 410 patients withmutation were −23.8% and 8.4% (P value for interacprimary myelofibrosis who were treated with standard 0 tion, 0.07). The changes in the total symptom score therapy (P=.43). among patients with the JAK2 V617F mutation were −20 −52.6% (improvement) in the ruxolitinib group and −40 42.8% (worsening) in the placebo group, and the changes among those without the mutation were Case (cont) Ruxolitinib −60 −28.1% and 37.2%, on respectively = 0.11 for inter• The patient is started treatment(P with ruxoli−80 action). Across myelofibrosis subtypes (primary tinib Baseline 12 24 36 48 myelofibrosis, post–polycythemia vera myelofibroWeeks • His spleen decreases in size by ~2 cm after 2 sis, and post–essential thrombocythemia myeloNo. of Patients months but is still painful times ruxolitinib had a fibrosis), patients who at received Ruxolitinib 148 139 69 16 • Hedecrease now has fevers requires 2in the Placebo 132 106 46 13 in low-grade spleen volume andand improvement units of symptom red blood cells every 3 weeks total score; patients receiving placebo From Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib 21.5% for myelofibrosis. N Engl J Med. 2012;366:799-807. Copyright pla© 2012 Massachusetts Medical at week 48; patients who received had increases in spleen volume (P = 0.52 for inter- and Society. Reprinted with permission from Massachusetts Medical Society. cebo had a mean increase of 3.5% at week 24 and action) and worsening of the total symptom score at week 48 (Fig. S6 in the Supplementary (P = 0.46 forand interaction) S5A and S5B in the 6.3% Conclusions Future(Fig. Directions splenomegaly and other myelofibrosis-related symptoms Appendix). Furthermore, patients receiving ruxoliSupplementary Appendix). This first JAK inhibitor therapy for myelofibrosis had upon the discontinuation of therapy.15 Thus, although tinib had reductions in plasma levels of C-reactive been long anticipated; however, the value of this treatruxolitinib improve patients’cytokines quality of tumor life by sigprotein and may the proinflammatory Biomarkers ment isInnot yet known. Ruxolitinib been unable to nificantly reducing necrosis factor α andsplenomegaly interleukin-6,and anddisease-related they had a prespecified analysis of has biomarkers, patients plasma for leptin and erythrowho received significantly decreaseruxolitinib peripheral had bloodmean blastreductions count, re- in increases symptoms,initlevels is notofcurative myelofibrosis. Therepoietin (Fig. S7 in the Supplementary Appendix). the JAK2 V617F allele burden of 10.9% at week 24 verse marrow fibrosis, induce cytogenetic remission, or fore, ruxolitinib may play a definite but limited role in 15 reduce JAK2 V617F allele burden. Other limitations the management of patients with myelofibrosis who are 803 n engl j med 366;9 nejm.org march 1, 2012 of the drug include hematologic toxicities, especially not eligible for alloSCT.15 The New England Journal of Medicine anemia and thrombocytopenia, and the rapid return of Several new JAK inhibitors are under clinical Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on January 26, 2013. For personal use only. No other uses without permission. Copyright © 2012 Massachusetts Medical Society. All rights reserved.

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Figure 6. Overall Survival: Ruxolitinib vs Placebo 1.0

Ruxolitinib

Probability of Survival

0.8 Placebo 0.6

0.4 The

0.2

n e w e ng l a n d j o u r na l

m e dic i n e

Hazard ratio, 0.50 (95% CI, 0.25-0.98)

Figure 2. Changes in Quality-of-Life and SymptomAssessment Scores, According to Treatment Group. Mean changes from baseline at week 48 are shown for A EORTC QLQ-C30 Core 0.0 Model Scores scores on the European Organization for Research and 0 4 8 12 16 20 24 28 32 36 40 of 44Cancer 48 (EORTC) 52 56 60of Life 64question68 72 76 12 Treatment Quality 9.9 10 naire core model (QLQ-C30) global health status–quality 9.1 Weeks of life and selected functioning scores (Panel A); selected 8 No. EORTC QLQ-C30 symptom scores (Panel B); and 6 at Risk Ruxolitinib 155 155 155 154 153 152 148 144 143 143 140 134 102 of 68Cancer 52 Therapy–Lymphoma 37 18 8 3 Functional Assessment 3.4 4 Placebo 154 152 151 148 147 147 142 139 132 131 123 115 83including 58 total 45 scores, 35 20 9 3 (FACT-Lym) scores, disease2 specific subscale (FACT-LymS) scores, Trial Outcome From0Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807. Copyright © 2012 MassaIndex (FACT-TOI) scores (a summary of physical, funcFigureMedical 3. Overall Survival. chusetts Society. Reprinted with permission from Massachusetts Medical Society. −2 tional, and disease-specific outcomes), and general Kaplan–Meier estimates of overall survival, including 4 months(FACT-G) of additional follow-up after Athe analysis, −4 scores (Panel C). In Panels andprimary C, improveFigure 7. Mean Changes at Week 48 development for patients with myelofibrosis. For during examare−6shown. There were 13 From deathsBaseline in the ruxolitinib group (8.4%) and 24 deaths in the placebo group (15.6%) ment is represented by positive numbers, whereas in −5.4 Panel B, improvement is represented by negative num−8 a median follow-up period of 51 weeks. Tick marks indicate censoring times for individual patients. in SymptomGlobal Assessment Scores: Ruxolitinib vs Best ple, SAR302503, formerly known as TG101348, is a Health Status Role Functioning bers (reduction in symptoms). For EORTC QLQ-C30 and Quality of Life Available Therapy JAK2 and inhibitor currently under evaluation functioning andFLT3 symptom subscales that are not shown, there were minimal between-group differences (i.e., in aonly phase 3 placebo-controlled study (JAKARTA). B EORTC QLQ-C30 Symptom Scores a difference of <10 points the mean scores an increase by inweek 24change toand a innew steady state detailed information). Principal causes of death in with Pacritinib (SB1518) is a JAK2 FLT3 inhibitor 15 between the ruxolitinib group and the best-availableBest available therapy g per liter). The prevalence grade the ruxolitinib group were muscle weakness and (101 under investigation inmonthly a 24 phase 3 study versus bestofavailtherapy [BAT] group at weeks and 48). The ranges 9.5 10 forable clinically important differences the 4minimal anemia and theaproportion of inhibitor, patientsisregeneral deterioration, subdural hematoma, renal 3 or therapy. CYT387, JAK1 and for JAK2 6.0 FACT-Lym are as follows: FACT-Lym total score, 6.5 to 4.8 5 transfusions more units red cells) failure, non–small-cell lung cancer, acute myeloid quiring undergoing evaluation inor phase 2total studies, including a 3.0 11.2; FACT-TOI score, 5.5 to(1 11; FACT-G score, of 19,20 0.4 3 to 7; and LymS score, 2.9 to 5.4. extension study.that LY2784544, which has been followed a pattern was consistent with leukemia (AML), pneumonia (in 2 patients), and alsolong-term Worsening Improvement

Mean From Baseline MeanChange Change from Baseline

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Mean Change from Baseline

Hazard ratio, 0.50 (95% CI, 0.25–0.98) P=.04 by log-rank BAT test Ruxolitinib P=0.04 by log-rank test

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tit

Improveme

Change from Baseline

In s

Pa i

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described a JAK2 V617F (mutation)-selective inhibi−1.9 in as the hemoglobin level over time (Fig. sepsis (in 2 patients). Principal causes of death in changes −5 13 tor, is in phase 1/2 studies. u Marrow Histomorphologic and Biomarker the placebo group were staphylococcal infection, S9A and S9B in the Supplementary Appendix). Ac−6.3 Ruxolitinib −8.2 −10 Assessments to the response criteria of the Internagastrointestinal hemorrhage, intestinal perfora- cording No References major changes in marrow histomorphologic −12.3 −12.8 −15 multiorgan failure, pneumonia, sepsis (in tional Working Group Research tion, 1. Kantarjian H, Schiffer C, A.Myelofibrosis Hematologic malignancies: where features were observed inBurnett a for prespecified secondary do we stand in 2011? J Clin Oncol. 2011;29:473-474. Treatment, 41.2% of patients in the ruxolitinib 2 patients), and disease progression (in 4 patients). and analysis of data from patientsneoplasms receiving2012: anythe therapy. 2. Tefferi A. Myeloproliferative John M. Bennett birthday anniversary lecture. Leuk Res. 2012;36:1481-1489. In a80th prespecified exploratory analysis, ruxolitinib and 46.9% of patients in the placebo group Overall, nonhematologic adverse events oc- group 3. Spivak JL. Narrative review: thrombocytosis, polycythemia vera, and treatment was associated with changes in plasma mutations: the phenotypic of chronic myeloproliferation. were dependent onmimicry transfusions at baseline curred at a similar rate in the two groups. Events whoJAK2 (Table 5 in the Supplementary AppenFrom Harrison Scores C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib biomarkers C FACT-Lym Ann Intern Med. 2010;152:300-306. as transfusion-independent during thatbest more frequently in Jthe versus available therapy for myelofibrosis. N Engl Med.ruxolitinib 2012;366:787-798. were Tefferi A, JW. Classification and diagnosis of myeloprolifer12occurred dix);4.classified levels ofVardiman several proinflammatory cytokines, 11.3 ative neoplasms: the 2008 World Health Organization criteria and pointCopyright © 2012 Massachusetts Medical Society. Reprinted with permission from study (Tablealgorithms. S4 intumor the necrosis Supplementary group were ecchymosis, dizziness, and headache the including interleukin-6, factor al- Appenof-care diagnostic Leukemia. 2008;22:14-22. Massachusetts Medical Society. 10 9.1 8.9 pha, and C-reactive protein were reduced, whereas with new(predominantly grade 1 or 2) (Table 2). The most dix). In the ruxolitinib group, patients 8 erythropoietin and leptin levels were increased. common grade 3 or 4 nonhematologic6.0adverse onset grade 3 or 4 anemia had improvements in 6 Volume 2 • No pain, 3 May 2013that PERSONALIZED MEDICINE INand ONCOLOGY 158 events (abdominal fatigue, and dyspnea) ocsymptoms reductions in spleen volume Symptoms and Other Patient-Reported Outcomes 4 In prespecified patient- anemia curred more frequently in the placebo group. were similar toexploratory those in analyses patientsofwithout

Hematology

5. National Institutes of Health (NIH). Office of Rare Diseases Research. Genetic and Rare Diseases Information Center (GARD). Myelofibrosis. http://rarediseases.info.nih.gov/GARD/Condition/8618/QnA/22942/My elofibrosis.aspx#1496. Accessed February 27, 2013. 6. Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008;112:45-52. 7. Pardanani A, Vannucchi AM, Passamonti F, et al. JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations. Leukemia. 2011;25:218-225. 8. Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;342:1255-1265. 9. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWGMRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115:1703-1708. 10. Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105:973-977. 11. Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer. 2007;109:68-76. 12. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895-2901. 13. Komrokji R, Verstovsek S. Assessing efficacy in myelofibrosis treatment: a focus on JAK inhibition. Expert Rev Hematol. 2012;5:631-641. 14. Mesa RA, Schwager S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res. 2009;33:1199-1203. 15. Jung CW. Will JAK1/2 inhibitors change the standard of care for myelofibrosis? Korean J Hematol. 2012;47:241-242. 16. Verstovsek S. Therapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis. Clin Cancer Res. 2010;16:19881996. 17. Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy. Am J Hematol. 2008;83:491-497. 18. Martínez-Trillos A, Gaya A, Maffioli M, et al. Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations

of myelofibrosis: results in 40 patients. Ann Hematol. 2010;89:1233-1237. 19. Tefferi A, Mesa RA, Nagorney DM, et al. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood. 2000;95:2226-2233. 20. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29:761-770. 21. Alchalby H, Kröger N. Reduced-intensity conditioning followed by allogeneic hematopoietic stem cell transplantation in myelofibrosis. Curr Hematol Malig Rep. 2010;5:53-61. 22. Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2010;16:358-367. 23. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-1061. 24. James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144-1148. 25. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005; 352:1779-1790. 26. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-397. 27. Goldman JM. A unifying mutation in chronic myeloproliferative disorders. N Engl J Med. 2005;352:1744-1746. 28. Lippert E, Boissinot M, Kralovics R, et al. The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood. 2006;108:1865-1867. 29. Harrison C, Verstovsek S, McMullin MF, et al. Janus kinase inhibition and its effect upon the therapeutic landscape for myelofibrosis: from palliation to cure? Br J Haematol. 2012;157:426-437. 30. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807. 31. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787-798. 32. Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood. 2012;120:1202-1209. 33. Tefferi A, Litzow MR, Pardanani A. Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med. 2011;365:1455-1457.

Interview With the Innovators An exclusive PMO series

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â&#x20AC;˘ Melanoma â&#x20AC;˘ Basal Cell Carcinoma â&#x20AC;˘ Cutaneous T-Cell Lymphoma â&#x20AC;˘ Squamous Cell Carcinoma â&#x20AC;˘ Merkel Cell Carcinoma

July 26-28, 2013

Hyatt Regency La Jolla â&#x20AC;˘ San Diego, California

PROGRAM OVERVIEW

CONFERENCE CO-CHAIRS

A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: â&#x20AC;˘ Epidemiology and genetic/environmental factors â&#x20AC;˘ Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies â&#x20AC;˘ Risk stratification based on patient and tumor characteristics â&#x20AC;˘ Principles of cancer prevention of melanoma and basal cell carcinoma â&#x20AC;˘ Current treatment guidelines â&#x20AC;˘ Emerging treatment options for personalized therapy â&#x20AC;˘ Future strategies in management based on translational data from current clinical trials and basic research

LEARNING OBJECTIVES Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma â&#x20AC;˘ Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics â&#x20AC;˘ Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

TARGET AUDIENCE This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, and pathologists actively involved in the treatment of cutaneous malignancies. Advanced practice oncology or dermatololgy nurses, oncology pharmacists, and researchers interested in the molecular biology and management of cutaneous malignancies are also encouraged to participate.

DESIGNATION OF CREDIT STATEMENTS SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Lukeâ&#x20AC;&#x2122;s Cancer Center Bethlehem, Pennsylvania

REGISTERED NURSE DESIGNATION Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.0 contact hours.

REGISTERED PHARMACY DESIGNATION The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.0 contact hours (1.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION EARLY BIRD REGISTRATION NOW OPEN! $175.00 UNTIL APRIL 30, 2013

www.CutaneousMalignancies.com

Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany

AGENDA* FRIDAY, JULY 26, 2013 3:00 pm â&#x20AC;&#x201C; 7:00 pm

Registration

5:30 pm â&#x20AC;&#x201C; 7:30 pm

Welcome Reception/Exhibits

SATURDAY, JULY 27, 2013 7:00 am â&#x20AC;&#x201C; 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am â&#x20AC;&#x201C; 8:15 am

BREAK

8:15 am â&#x20AC;&#x201C; 8:30 am

Welcome to the Second Annual World Cutaneous Malignancies Congress â&#x20AC;&#x201D; Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am â&#x20AC;&#x201C; 11:45 am General Session I: A Clinicianâ&#x20AC;&#x2122;s Primer on the Molecular Biology of Cutaneous Malignancies â&#x20AC;˘ Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway â&#x20AC;˘ Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD 12:00 pm â&#x20AC;&#x201C; 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm â&#x20AC;&#x201C; 1:15 pm

BREAK

1:15 pm â&#x20AC;&#x201C; 4:30 pm

General Session II: Current Treatment Guidelines in Cutaneous Malignancies â&#x20AC;˘ Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients â&#x20AC;˘ Panel Discussion Management Controversies and Accepted Guidelines for the Personalized Management of Cutaneous Malignancies â&#x20AC;˘ Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Antiâ&#x20AC;&#x201C;PD-1

4:30 pm â&#x20AC;&#x201C; 6:30 pm

Meet the Experts/Networking/Exhibits

PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 12.0 AMA PRA Category 1 Credits â&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Steven J. Oâ&#x20AC;&#x2122;Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California

SUNDAY, JULY 28, 2013 7:00 am â&#x20AC;&#x201C; 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am â&#x20AC;&#x201C; 8:15 am

BREAK

8:15 am â&#x20AC;&#x201C; 8:30 am

Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Todayâ&#x20AC;&#x2122;s Sessions

8:30 am â&#x20AC;&#x201C; 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General Session IV: Challenges for the Cutaneous Malignancies Clinician â&#x20AC;˘ Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies? 12:00 pm â&#x20AC;&#x201C; 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm â&#x20AC;&#x201C; 1:15 pm

BREAK

1:15 pm â&#x20AC;&#x201C; 2:45 pm

General Session V: â&#x20AC;&#x153;Hot Dataâ&#x20AC;? â&#x20AC;&#x201D; What I Learned at Recent Meetings: Focus on Cutaneous Malignancies

2:45 pm â&#x20AC;&#x201C; 3:00 pm

Closing Remarks - Steven J. Oâ&#x20AC;&#x2122;Day, MD

*Agenda is subject to change.

For complete agenda please visit www.CutaneousMalignancies.com

The Last Word

The MHealth Factor: A Bioinformatics Platform for Arming the Oncology Personalized Medicine Revolution

ersonalized medicine (PM) applied to cancer in third world countries have in common with the applidiagnosis and treatment is really all about incation of MHealth in PM? At the 10th Annual World formation: discovering it, synthesizing it, anaHealth Care Congress, there was no direct answer to lyzing it, translating it to cancer pathophysiology, and this burning question (of course, America is no longer finally sharing it with those who need perched on the edge of its seat wonderto know what is going on inside the ing when Dick Tracy’s futuristic wrist tumors. The rise of PM skill sets, as watch phone will become a reality). But I remarked in one of my first articles there was a clue. For MHealth was disfor Personalized Medicine in Oncology, cussed as a real-world technology unitrelates to this matter of information ing physicians with patients in remote – which forms the subject at hand in third world areas, and the implications this piece. I therefore quote a parafor oncology PM are profound. graph from that article, “Cancer Care What is becoming evident in examPersonalized Medicine and Value: ining the use of MHealth to transmit The Strength of Science Fulfilling Inpatient health photos, lab results, and novation,” as a starting point for this other diagnostically relevant informacolumn on mobile health technology: tion from patient location to physician Robert E. Henry A core focus of this research, and a location is the potential to transform source of the plethora of informasmartphones into personalized medicine tion involved in the PM process, is the ongoing “... portals with nearly limitless applications for remarkable marked rewiring of the signaling networks that deinformation technology apps that guide patients through termine the behavior of the cancer cell and patient their treatment pathway in cancer PM. The development outcomes. High throughput technologies generate of the software now in place suggests amazing possibilities incredible masses of data showing many potential abfor helping oncology PM information needs via a bioinerrations and connections and allowing visualization formatics tool with the compactness and immediacy of a and integration of the data into testable hypotheses.” smartphone – and a very smart phone it will be when it is This has led to the several “omics” technologies – developed to full potential. Its value rests in its ability to genomics, proteomics, and metabolomics – “...that provide a platform for linking cancer patients with their interrogate tumors at the DNA, RNA, protein, and providers who can monitor and transfer data seamlessly. metabolomics level...[but which] has not been paralThis would give PM a much needed technological boost leled by improvement in cell biology approaches to to achieve the 3 points of value: cost, quality, and access. understand the consequences of these changes on celThis MHealth technology is already fully operational lular, organ, and organismal outputs.” in many countries and is now making its appearance The question at hand now is the most translational more prevalent in the United States in 2013. It offers utilization imaginable concerning the sharing of cancer the advantages of telemedicine while overcoming the disease state information: mobile health, or MHealth. limitations imposed by ponderous, high-maintenance What do Dick Tracy’s telephonic wrist watch and the operating systems. Its methodology would use smarttelephonic sharing of various disease states information phones to deliver information while educating a new

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May 2013

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The Last Word

workforce, thus supplementing a shrinking oncologist workforce. Already used in cardiology and several other disease states, MHealth has reduced congestive heart failure hospital emergency department admissions by about two-thirds through point-of-care assessment that facilitates diagnosis and treatment by enabling remote physicians to advise on-site nurses, health workers, or caregivers. By sharing information on a patient’s status immediately, the software allows physicians to prioritize care, preventing deterioration of a patient’s condition and so head off disease progression. This track record suggests a myriad of possibilities that aggressive software development in this bioinformatics platform holds for PM in cancer, which is so dependent on informatics and personal counseling to achieve its treatment goals. Consider as a case in point 2 articles on prostate cancer risk factors that happened to appear in the same May 2013 issue of Cancer Epidemiology, Biomarkers & Prevention: “Sleep Disruption Among Older Men and Risk of Prostate Cancer” and “Obesity and Future Prostate Cancer Risk Among Men After an Initial Benign Biopsy of the Prostate.” The advantages of monitoring patients for exacerbation of either risk factor for prostate cancer speak volumes to the potential of MHealth to oncology PM. It also speaks to the issue staring oncology square in the face: finding the economies needed for the advance of PM informational sharing – whose complexity is suggested with all the subtlety of a sledgehammer in that first paragraph quoted at the beginning of this article. The cancer tumor/disease progression information updates that the oncologist, nurse, or pharmacist needs to receive is well suited to the MHealth bioinformatics platform. With apps developed relevant to the informational needs of practicing oncologists, MHealth can deliver on the promise of PM, which relies on an enriched patient population. The problem facing PM is trying to write this new chapter in the conquest of cancer using informational technology on the order of a clay tablet and stylus. It is time oncologists had technological weaponry equal to the complexity of the information they depend on in the PM arena. The breadth of functions that MHealth innovation can

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provide underscores the long list of tasks that oncology PM must satisfy. This bioinformatics platform can be outfitted with patient-oncologist contact and access capabilities appropriate to changes in a patient’s condition and signal oncologists, nurse navigators, pharmacists, hospitals, or any appropriate member of the treatment team/system to respond in a timely fashion. Alternately, an app could monitor adherence to treatment regimens or other ongoing trends affecting a patient’s condition. The patient in turn could reach out to the treatment team with questions or concerns. Either way, the flow of information is the essential PM linchpin for timing appropriate interventions – and this is the key to avoiding waste and achieving the pinpoint precision that PM requires. The benefits of MHealth to PM’s uptake are legion: timely responses, avoiding needless hospitalizations or ensuring quick hospitalization when needed, and the simple sharing of queries between patients and their providers to assuage fears and help keep patients and physicians clear on the goals of treatment. In short, a telemedicine platform has emerged with the potential to help PM deliver premier quality care while avoiding waste in resource allocation like never before. It is curious that information mobility could play so significant a part in bringing this about – but there it is: MHealth is a tactical element essential to bringing cost, quality, and access under control, and the data already exist, albeit in other disease states, to support this claim. A smartphone app that puts patient needs into clear and immediate focus, regardless of whether the patient or provider is at work or at the opera…now that’s a game changer. Dick Tracy, eat your heart out. The cancer apps for this tool appear certain to be written, and quickly. It will be interesting to see their order of progression. This will be an MHealth marvel worth watching. It appears we are ready to write that new chapter in the history of PM in cancer…with materials considerably more current than a clay tablet and stylus.

Robert E. Henry

PERSONALIZED MEDICINE

ONCOLOGY

May 2013

rso ser Vi na ies ew liz on th ed lin e Me e dO at nc .co m

Faculty Perspectives

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A 4-part series The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present Faculty Perspectives: The History of Bendamustine series. Upcoming topics include: â&#x20AC;˘ â&#x20AC;˘ â&#x20AC;˘ â&#x20AC;˘

Characterization of bendamustine Registration studies - efficacy Registration studies - safety Ongoing clinical investigations

Faculty Perspectives

Part 1 of a 4-Part Serie s

DECEMBER

2012 â&#x20AC;˘ VO LUME 4 â&#x20AC;˘ NUMBER 1

A Retrospectiv

e Review of th of Bendamus e Characterization tine

CONTRIBU

TING FACU LTY

Julie M. Vos e, MD, MBA

University of Nebraska Medical Cen ter

Colleen Ros s, RN, MSN, MHA, OC

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ERSONALIZ ED EDICINE IN ONCOLOGY

OP University of Nebraska Medical Cen ter

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