June 2012, VOL 1, NO 2

Rapid Changes in Reimbursement Protocols for Molecular Tests............................................Page 36

Management of Ipilimumab-Related Toxicities......................................................Page 43

Personalized Medicine Advances in Melanoma: AnInterview With K. Peter Hirth, PhD..................Page 15

Crizotinib Miracle: A Nursing Perspective ......Page 54

June 2012

Volume 1 • Number 2

A Peer-Reviewed Journal

www.PersonalizedMedOnc.com© 2012 Green Hill Healthcare Communications, LLC

IMPLEMENTING THE PROMISE OFPROGNOSTIC PRECISION INTO PERSONALIZED CANCER CARETM

REGULATORY ISSUES

MELANOMA

LUNG CANCER

PERSONALIZEDMEDICINE INONCOLOGYM

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INTERVIEW WITH THE INNOVATORS

The offical publication of

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Implementing the Promise of PersonalizedCancer Care: Highlights From the Inaugural Conference of the Global Biomarkers Consortium..................................................Page 22

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Dual Targeting in Advanced Melanoma Encouraging PAGE 10

Neoadjuvant Abiraterone Potential Approach PAGE 11

ALK-Targeted Agent Has High Activity in Some Childhood Cancers PAGE 12

Personalizing Therapeutics for Melanoma in the 21st Century PAGE 13

CONFERENCE NEWS

Personalized Medicine Advances in Melanoma: An Interview With K. Peter Hirth, PhD PAGE 15

PERSONALIZEDMEDICINE INONCOLOGY™

The Global Biomarkers Consortium™

(GBC) is a community of world-

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will convene in multiple educational fo-

rums in order to better understand the

clinical application of predictive molec-

ular biomarkers and advanced personal-

ized care for patients.

Save the date for the Second Annual Conference,

October 4-6, 2013Visit

www.globalbiomarkersconsortium.comto register

Who attends the GBC?

INTERVIEW WITH THE INNOVATORS

Implementing the Promise of Personalized Cancer Care: Highlights From the Inaugural Conference of the Global Biomarkers Consortium PAGE 22

lives of cancer patients everywhere.

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Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN ap-plied for (online) is published 6 times a year by Green Hill HealthcareCommunications, LLC, 241 Forsgate Drive, Suite 205C, MonroeTwp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copy -right ©2012 by Green Hill Health care Com muni cations, LLC. Allrights reserved. Personalized Medicine in Oncology logo is a trademarkof Green Hill Healthcare Communications, LLC. No part of thispublication may be reproduced or transmitted in any form or by anymeans now or hereafter known, electronic or mechanical, includingphotocopy, recording, or any informational storage and retrieval sys-tem, without written permission from the publisher. Printed in theUnited States of America.

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MEDICINE INONCOLOGY™

REGULATORY ISSUES

INTERVIEW WITHTHE INNOVATORSAn exclusive PMO series

Personalized Medicine in Oncology™

is pleased to offer insightful interviews withleaders in oncology about their approach

to personalized medicine.

To watch our interviews, visit www.PersonalizedMedOnc.com/videolibrary

Volume 1 • No 2 June 20124 PERSONALIZED MEDICINE IN ONCOLOGY

Rapid Changes in Reimbursement Protocols for Molecular Tests PAGE 36Bruce Quinn, MD, PhD

Management of Ipilimumab-Related Toxicities PAGE 43

Patrick A. Ott, MD, PhD; Howard L. Kaufman, MD, FACS; F. Stephen Hodi, MD

LUNG CANCER

Crizotinib Miracle: A Nursing Perspective PAGE 54

Tara L. Rich, MSN, RN, CNP

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PERSONALIZED MEDICINE IN ONCOLOGY6 Volume 1 • No 2 June 2012

Editor in ChiefAL B. BENSON III, MDNorthwestern University

Chicago, Illinois

Editorial Board

Breast CancerEDITH PEREZ, MD Mayo ClinicJacksonville, Florida

Hematologic MalignanciesGAUTAM BORTHAKUR, MDThe University of Texas MD Anderson Cancer CenterHouston, Texas

PathologyDAVID L. RIMM, MD, PHDYale Pathology Tissue Services Yale University School of MedicineNew Haven, Connecticut

Drug DevelopmentIGOR PUZANOV, MDVanderbilt UniversityVanderbilt-Ingram Cancer CenterNashville, Tennessee

Lung CancerVINCENT A. MILLER, MDFoundation MedicineCambridge, Massachusetts

Predictive ModelingMICHAEL KATTAN, PHD Case Western Reserve UniversityCleveland, Ohio

Gastrointestinal CancerEUNICE KWAK, MD Massachusetts General Hospital Cancer CenterHarvard Medical School Boston, Massachusetts

MelanomaDOUG SCHWARTZENTRUBER, MD Indiana University Simon Cancer CenterIndianapolis, Indiana

Prostate CancerOLIVER SARTOR, MD Tulane UniversityNew Orleans, Louisiana

SECTION EDITORS

SANJIV S. AGARWALA, MDSt. Luke’s HospitalBethlehem, Pennsylvania

TONY ALBINO, PHDSignal Genetics LLCNew York, New York

GREGORY D. AYERS, MS Vanderbilt University School of MedicineNashville, Tennessee

LYUDMILA BAZHENOVA, MDUniversity of California, San DiegoSan Diego, California

LEIF BERGSAGEL, MDMayo ClinicScottsdale, Arizona

KENNETH BLOOM, MDClarient Inc.Aliso Viejo, California

MARK S. BOGUSKI, MD, PHDHarvard Medical SchoolBoston, Massachusetts

GILBERTO CASTRO, MDInstituto do Câncer do Estado de São Paulo São Paulo, Brazil

MADELEINE DUVIC, MD The University of TexasMD Anderson Cancer CenterHouston, Texas

BETH FAIMAN, PHD(C), MSN, APRN-BC, AOCNCleveland Clinic Taussig Cancer CenterCleveland, Ohio

STEPHEN GATELY, MDTGen Drug Development (TD2)Scottsdale, Arizona

STEVEN D. GORE, MDThe Johns Hopkins University School of MedicineBaltimore, Maryland

K. PETER HIRTH, PHDPlexxikon, Inc.Berkeley, California

HOWARD KAUFMAN, MDRush UniversityChicago, Illinois

KATIE KELLEY, MDUCSF School of MedicineSan Francisco, California

MINETTA LIU, MD Georgetown University HospitalWashington, DC

KIM MARGOLIN, MDUniversity of WashingtonFred Hutchinson Cancer Research CenterSeattle, Washington

GENE MORSE, MDUniversity of RochesterRochester, New York

AFSANEH MOTAMED-KHORASANI, PHDRadient PharmaceuticalsTustin, California

NIKHIL C. MUNSHI, MD Dana-Farber Cancer InstituteBoston, Massachusetts

STEVEN O’DAY, MDJohn Wayne Cancer Institute Santa Monica, California

DAVID A. PROIA, PHDSynta PharmaceuticalsLexington, Massachusetts

RAFAEL ROSELL, MD, PHDCatalan Institute of OncologyBarcelona, Spain

STEVEN T. ROSEN, MD, FACP Northwestern UniversityChicago, Illinois

HOPE S. RUGO, MD University of California, San FranciscoSan Francisco, California

DANIELLE SCELFO, MHSAGenomic HealthRedwood City, California

LEE SCHWARTZBERG, MD The West ClinicMemphis, Tennessee

JOHN SHAUGHNESSY, PHDUniversity of Arkansas for Medical SciencesLittle Rock, Arkansas

LAWRENCE N. SHULMAN, MDDana-Farber Cancer Institute Boston, Massachusetts

JAIME SHUTTER, MDSouth Beach Medical Consultants, LLCMiami Beach, Florida

DARREN SIGAL, MDScripps Clinic Medical GroupSan Diego, California

DAVID SPIGEL, MDSarah Cannon Research InstituteNashville, Tennessee

MOSHE TALPAZ, MDUniversity of Michigan Medical CenterAnn Arbor, Michigan

SHEILA D. WALCOFF, JDGoldbug Strategies, LLCRockville, Maryland

ANAS YOUNES, MDThe University of Texas MD Anderson Cancer CenterHouston, Texas

EDITORIAL BOARD

Pancreatic Cancer: Progress and ChallengesJune 18-21, 2012Lake Tahoe, NV

An AACR Special Conference on: Chemical Systems Biology: Assemblingand Interrogating Computational Models ofthe Cancer Cell by Chemical PerturbationsJune 27-30, 2012Marriott Copley PlaceBoston, MA

Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention ResearchOctober 16-19, 2012Anaheim, CA

Fifth Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and theMedically UnderservedOctober 27-30, 2012San Diego, CA

EORTC-NCI-AACR International Symposium on Molecular Targets andCancer TherapeuticsNovember 6-9, 2012Dublin, Ireland

An AACR Special Conference on: Post-GWAS Horizons in MolecularEpidemiology: Digging Deeper into the EnvironmentNovember 11-14, 2012Hollywood, FL

An AACR Special Conference on: Tumor Immunology: MultidisciplinaryScience Driving Basic and Clinical AdvancesDecember 2-5, 2012Miami, FL

CTRC-AACR San Antonio Breast Cancer SymposiumDecember 4-8, 2012San Antonio, TX

An AACR Special Conference on: TumorInvasion and MetastasisJanuary 20-23, 2013San Diego, CA

Ninth AACR-Japanese Cancer AssociationJoint Conference: Breakthroughs in Basicand Translational Cancer ResearchFebruary 21-25, 2013Maui, HI

AACR-Society of Nuclear Medicine JointConference on State-of-the-art MolecularImaging in Cancer Biology and TherapyFebruary 27-March 2, 2013San Diego, CA

Please visit www.aacr.org/meetingscalendar for the complete calendar, as conferences are added and updated on a regular basis


Dear Reader,

It is my great pleasure to welcome you to Personalized Medicine in Oncology (PMO),the official publication of the Global Biomarkers Consortium (GBC).

The concept for this journal was born out of the need for oncologists to understandthe vast, highly complex body of information on personalized medical treatmentof oncologic diseases. This timely journal will explore innovations in oncologyand how they translate into clinical progress as well as the associated value of theseinnovations: the balance of cost, quality, and access. Our goal is to extract thegreatest value from the revolution in personalized medicine by providing the in-

formation on the performance realities of new diagnostic and treatment discoveries and clarifying the pro-ductivity of personalized medicine technologies. Articles will provide information for the implementationof personalized medicine by practicing physicians, according to evidence-based, value-based, patient-centered criteria. In addition to print and online media, we are pleased to host the annual GBC meeting.Please save the date for the Second Annual Conference of the Global Biomarkers Consortium on October4-6, 2013, in Boston, Massachusetts.

It is my hope that you will find PMO useful to your practice.

Sincerely,

Igor Puzanov, MDVanderbilt UniversityPMO Section Editor, Drug Development

Letter From the Board

The Offical Publication of the GBC

Igor Puzanov, MD

WWW.PERSONALIZEDMEDONC.COM 9Volume 1 • No 2 June 2012

Letter From the Strategic Editor

Dear Reader,

As strategic editor of Personalized Medicine in Oncology (PMO), it was my pleasureto conduct several interviews with experts from our editorial board about the con-cept of personalized medicine (PM) and its current state of application within dif-ferent oncologic diseases. The ensuing input was a tour de force of informationregarding the application of PM at the clinical level. We explored virtually everyaspect of this translational process, and they gave their insights into the governingdynamics of PM – always separating assumption from the facts driving this powerfulengine for progress. The goal of these interviews is to help you cultivate an under-standing of the biology, biochemistry, and other PM techniques that will help you

distinguish novelty from value; avoid being buried in the information explosion of PM mechanics irrelevantto practicing oncologists; and understand the forces for PM within the context of healthcare’s clinical, busi-ness, and policy sectors.

Through the interview process, the first lesson learned was to resist the urge to conclude that PM is alreadyin widespread practice. It is not. PM is only beginning, and much of cancer therapy is still being practicedusing conventional pre-PM clinical techniques because research has not yet unlocked the mysteries thatenable PM management specific to most aspects of cancer. Consequently, cancer clinical management is acoalition of conventional and PM techniques. Framing our expectations for PM in cancer must start withthe acknowledgment that we know little, rather than celebrating what we have discovered to date. Resistingthe urge to oversimplify the status of PM in cancer care punctures the notion that we can extrapolate theexperiences involving the interaction of genomics, tumor landscape, and other PM elements in one cancerto others. Only empirical research will show which PM rules of engagement will apply across the board andwhich will remain localized. At present we are only knocking on PM’s door and occasionally slippingthrough it.

It is my hope that the offerings of PMO provide you valuable insights to the concept of PM. I hope thatyou will share your experiences with us as you venture into this exciting new era of cancer care.

All the best,

Robert E. HenryStrategic Editor

On the Brink of Personalized Medicine

Robert E. Henry


ASCO Conference News

Hitting 2 targets may be better than 1 in ad-vanced melanoma, suggests a preliminarytrial of combination therapy with theBRAF inhibitor dabrafenib and the MEK

inhibitor trametinib. Combined targeting with these 2agents achieved tumor regression with a lower incidenceof skin side effects compared with published data onstandard single-agent BRAF inhibitor therapy with vemurafenib (Zelboraf).

These results are from an expanded phase 1 trial thatincluded 125 patients with advanced melanoma harbor-ing a BRAF mutation; 77 did not have previous BRAF-targeted therapy, and this subset is the population offocus, explained lead author Jeffrey Weber, MD, PhD,senior member at H. Lee Moffitt Cancer Center and director of the Donald A. Adam ComprehensiveMelanoma Research Center, Tampa, Florida. Weber reported the results at a pre-ASCO press telecast andalso at ASCO 2012 (Abstract 8510).About half of all melanomas have a V600Emutation

in the BRAF gene, and in these patients, the MEK path-way is also activated. Most patients with a BRAFmuta-tion will respond to treatment with vemurafenib, whichis now FDA-approved for advanced melanoma, but willeventually become resistant to the drug.The subgroup of 77 patients who never received

BRAF-targeted therapy received 4 different dose levelsof the 2 drugs; the dose chosen to go forward with in fu-ture studies is dabrafenib 150 mg and trametinib 2 mg.With the 150-mg/2-mg dose, median progression-free

survival (PFS) was 10.8 months, which is “extremely en-

couraging,” Weber said. Single-agent studies of vemu-rafenib showed median PFS of 7.4 months, he added.Looking at a waterfall plot that shows tumor shrink-

age, overall about 95% of patients had their disease con-trolled on the 2 agents, as reflected by stable disease(38%), partial response (PR, 49%), or complete re-sponse (CR, 8%). Looking at the group treated with the150-mg/2-mg dose, CR was 8%, PR was 54%, and stabledisease was 38%.“This waterfall plot shows the best responses I’ve seen

in advanced melanoma,” Weber said during the presstelecast.The rates of skin toxicities on combination therapy

were much lower than what has been reported withother BRAF inhibitors as single-agent therapy, Webercontinued. The rate of squamous cell cancer was 3%compared with 15% to 25% seen with other BRAF-in-hibiting agents; the rates of actinic keratosis (5%) andpapilloma (2%) were also much lower than with BRAFinhibition alone.Grade 3 or higher toxicities on the combination

therapy were as follows: pyrexia, 52% (23% requireddose reductions); chills, 38% (10% required dose reduc-tions); fatigue, 37%; and nausea, 34%.A phase 3 trial of the combination therapy is now under

way. “Look for the results,” Weber told the audience.Incoming ASCO President Sandra Swain, MD, com-

mented that the hope with dual targeted therapy is thatmore patients with advanced melanoma will be cured.“This combination reduced skin side effects [comparedwith vemurafenib],” she noted. Swain is the medical di-rector of the Washington Cancer Institute of the Wash-ington Hospital Center and professor of medicine atGeorgetown University in Washington, DC.“Cancers are smart and can get around 1 pathway

that is inhibited. Targeting 2 pathways is a smart approach and a creative strategy for treating cancers,”she stated. u

Dual Targeting in Advanced Melanoma EncouragingAlice Goodman

Rates of skin toxicities on combinationtherapy were much lower than what hasbeen reported with other BRAF inhibitorsas single-agent therapy.



Abiraterone, which is FDA-approved for thetreatment of advanced prostate cancer, hadencouraging results in one of the first stud-ies to evaluate use of this targeted agent

earlier in the course of disease. Targeted hormonal ther-apy with abiraterone plus leuprolide was able to eradicatecancer in the prostate in some high-risk prostate cancerpatients prior to radical prostatectomy in a phase 2 studyreported at ASCO 2012 (Abstract 4521).“Most patients with early prostate cancer are cured with

primary surgery and/or radiotherapy. However, patientswith high-risk features [such as those in this study] generallyprogress. The study was conducted to determine if neoad-juvant therapy with abiraterone plus leuprolide could in-crease the cure rate. To date, no other treatment has showna benefit in the neoadjuvant setting. Larger studies areneeded to validate this finding,” said lead author Mary-Ellen Taplin, MD, Harvard Medical School and Dana-Farber Cancer Institute in Boston, Massachusetts.Standard hormone therapy with injectable leuprolide

acts to suppress testosterone. Abiraterone, an oral in-hibitor of CYP17, has a different mechanism of action,blocking the synthesis of androgens in the testes, adre-nal glands, and prostate. In this neoadjuvant study, abi-raterone was given along with leuprolide and low-doseprednisone to abrogate the side effects of abirateroneprior to radical prostatectomy.The study included 56 men with localized high-risk

prostate cancer. High risk was defined as Gleason score≥8 (71% of the sample); PSA ≥20 mg/mL (19% of thesample); T3 or T4 bulky disease (24% of the sample);and high PSA velocity (16% of the sample). Slightlymore than one-third of patients also had lymph node in-volvement, which is associated with aggressive disease.Patients were treated with either 3 months of leupro-

lide or 3 months of abiraterone, leuprolide, and low-doseprednisone (5 mg) and then underwent biopsy of theprostate for analysis of androgen levels; patients then re-

ceived treatment with abiraterone/leuprolide/pred-nisone for another 3 months, after which radical prosta-tectomy was performed.In the prostate specimen obtained at prostatectomy,

pathological complete response (pCR) was observed in10% of those treated with 6 months of abiraterone ver-sus 4% in those treated with 3 months of abiraterone;near pCR was seen in 24% versus 11%, respectively.“It is rare to eliminate prostate cancer with hormone

therapy,” Taplin said at a pre-meeting press telecast.“pCR with hormonal therapy is usually 5% or less. Theresponse rate of 34% is impressive, given the high-riskfeatures of the patient population,” she noted.Grade 3 adverse events included elevated liver en-

zymes in 9% and hypokalemia in 5%. Use of low-doseprednisone appeared to prevent some of the side effectsassociated with abiraterone, she noted.

Other neoadjuvant trials with some of the newerprostate cancer agents are now being planned, includingMDV 3100, Taplin said.“This is an exciting step forward, showing that

neoadjuvant abiraterone can make cancer disappear ina percentage of high-risk patients,” stated Nicholas Vogelzang, MD, Chair of ASCO’s communicationscommittee and moderator of the press telecast.He explained that neoadjuvant therapy is standard

in the treatment of breast cancer, rectal cancer, andbladder cancer.“When cancer disappearance is achieved with pri-

mary treatment in these other cancers, long-term sur-vival is improved,” Vogelzang noted. u

Neoadjuvant Abiraterone Potential ApproachPhoebe Starr

Abiraterone, an oral inhibitor of CYP17, hasa different mechanism of action, blockingthe synthesis of androgens in the testes,adrenal glands, and prostate.



In a preliminary phase 1 study, the targeted drugcrizotinib (Xalkori) stabilized disease progressionand, in some children, eradicated cancer cells inrelapsed, refractory, aggressive childhood cancers

that are likely to harbor genetic abnormalities in theALK gene: anaplastic large cell lymphoma (ALCL),inflammatory myofibroblastic tumors (IMT), and ag-gressive neuroblastoma.Crizotinib, which is targeted to abnormalities in the

ALK gene, is FDA-approved for the treatment of ALK-driven non–small cell lung cancer (NSCLC), which ac-counts for about 5% of all NSCLC. ALK is also apotential target in childhood cancers, because ALK ab-normalities are present in 80% to 95% of ALCL cases,50% of IMT cases, and 10% to 15% of aggressive neuroblastomas.If these promising early findings are borne out in

larger, randomized trials, crizotinib will become the sec-ond effective molecularly targeted agent for pediatriccancers, explained lead author Yael Mosse, MD, assis-tant professor of pediatrics at the Children’s Hospital ofPhiladelphia and University of Pennsylvania.“Crizotinib had a high degree of activity. Larger trials

with this agent are in development for ALCL. This drugmay also find a role in selected subsets of patients withIMTs and neuroblastomas,” she said.The Children’s Oncology Group study included 70

children with progressive cancer despite standard treat-ment. Six different cohorts were treated with crizotinibdoses ranging from 100 to 365 mg/m2. The drug was ex-tremely well tolerated, Mosse said, and the dose chosenfor studies going forward was 250 mg/m2, which is twicethe dose used in adults with NSCLC.Results were as follows: 7 of 8 patients (88%) with

ALCL had a complete response (CR). These responseshave been long-lasting, with all patients on treatmentfor up to 18 months, she said. Of the 7 patients with

IMT (a rare sarcoma) enrolled in the trial, the majorityhave had a response, with some responses lasting for upto 2 years; all patients with IMT are still on the drug,and Mosse said it is too early to report results.“There is no other treatment that is effective in

IMT,” she said.Of the 27 patients with aggressive neuroblastoma, 8

had known ALKmutations; 2 of these patients achieveda CR and have been on therapy from 9 months to morethan 2 years with no sign of disease progression. Mossepointed out that most heavily pretreated neuroblastomapatients, such as those in this preliminary trial, wouldprogress within 1 to 2 months on other available thera-pies. Among the 19 patients with unknown ALK status,there was 1 CR and 6 with prolonged stable disease after7 to 29 cycles of treatment.Toxicity was acceptable and mostly low grade. At the

highest dose level, elevations in liver enzymes were re-ported, and 1 patient had a drop in white blood cell count. Mosse suggested that higher doses of crizotinib are more

likely to achieve responses in neuroblastoma patients.Summing up, Mosse said that the phase 1 study

showed dramatic activity in ALCL, “all you would wantin a phase 2 trial.”“For neuroblastoma, we need more study to deter-

mine which patients will benefit from crizotinib. Thedrug has dramatic potential in other ALK-driven tu-mors,” she added.ASCO President Michael P. Link, MD, said: “I am

delighted to hear these findings, which provide aglimpse at a new paradigm. Histology and the affectedorgan are not sufficient [treatment targets]. We need toidentify the particular molecular drivers of tumors. Thestudy shows that an inhibitor of genetic abnormalitiesmay work in different cancer types. The way forward iscollaboration – in this case, experts in lung cancer, pediatric cancer, lymphoma, and brain cancer.” u

ALK-Targeted Agent Has High Activity in SomeChildhood CancersAlice Goodman


Advocating for biomarker-driven “smart”trials, making the case for patient selec-tion for specific drugs, and the concept ofrational combinations as potential tar-

geted therapies in order to improve the efficacy of clin-ical trials were topics of an insightful presentationdelivered by Dr Aleksandar Sekulic onbehalf of Dr Pat LoRusso at the inau-gural conference of the World Cuta-neous Malignancies Congress.Sekulic reminded the audience that

historically, drugs were designed, pa-tients were treated, and individual pa-tients had different responses in earlyclinical trials. The goal in the new eraof personalized treatment is to shift toa different model; one that determinesthe molecular profile of the individualpatient’s tumor and then attempts tomatch that profile with the availablepanel of targeted drugs. This approach will refocus theefforts of early clinical trials.This pharmacodynamic approach of using predictive

biomarkers leads to patients who are more likely to re-spond to therapy, as well as other measurements such asintermediate end point biomarkers. Sekulic cited exam-ples of such “smart” trials: SMO in basal cell carcinoma,PARP in breast cancer, ALK and EGFR in non–smallcell lung cancer, BRAF in melanoma, and c-kit in gas-trointestinal stromal tumors. The objective responserates in these early trials are impressive, especially com-pared with the historic controls at this stage.Sekulic also pointed out possible issues with pre -

selecting patients: some patients who could benefit fromthe drug may inadvertently be excluded, and as we startbreaking down common diseases into smaller subsets,there are decreasing numbers of patients on the trial,

posing challenges in recruiting, biomarker cost, andquality of tissue processing.

Intratumoral HeterogeneityAnother issue Sekulic addressed is intratumoral het-

erogeneity. A single tumor biopsy may not represent theentire tumor population. One ap-proach is to look at mutations andmarkers that can be identified with tar-geted assays that can be designed eitherto a single gene, such as BRAF, or to apanel of genes.The next obvious step, which has

been explored by several groups, isnext-generation sequencing, whereone can identify multiple mutations,potentially differentiate drivers versuspassengers, and pursue functional studies. Sekulic pointed out that in order to

treat the entire cancer in a patient, we have to considercombination therapy. He cited a presentation by Vogel-stein at the recent American Association for Cancer

Research meeting describing some of the challenges thatface us in this area and summarized them in 4 points:• To better understand the pathways in human cancercells or humanized systems

• To rationally identify the combination therapiesusing new screening approaches

• To develop new biologic treatments combining bio-logic-, immunologic-, and genomic-defined therapies

Personalizing Therapeutics for Melanoma in the 21st CenturyKristin Siyahian

Dr Aleksandar Sekulic

Not only do we need to pick the right agentsand right doses and right schedules, but also the right drug combinations.

� ��

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WCMC Conference News

• It is not just about curing advanced cancer; preventionand early detection are a large part of the answersNot only do we need to pick the right agents and

right doses and right schedules, but also the right drugcombinations. These combination strategies may be re-quired to overcome not only cross-talk and feedback, as

we have seen with recent strategies of BRAF and MEK,but also intratumoral heterogeneity.

Personalized Medicine for PatientsWith Metastatic BRAF Wild-TypeMelanomaAll these considerations are being applied to a trial

designed for patients with BRAF wild-type melanomaled by Jeff Trent and Pat LoRusso. In the proposed flow-chart of the trial, the tissue is obtained, genome is pro-filed, data are processed, knowledge mining to identifypathways affected is performed, and clear validation as-says are conducted, after which the tumor board meetsand the therapy is selected. In conjunction, a set oftranslational experiments in mouse explants and celllines will be carried out to test some of the predictionsof responses.A simplified schema of the trial where the patient is

consented and screened, the tumor is biopsied, and mo-lecular profiling is done in the form of next-generationsequencing of genome and transcriptome is offered inthe Figure.In conclusion, Sekulic stated that responsibility rests

with us all. We must think about paradigm change andboth preclinical and clinical drug development. The chal-lenges we must meet are how to do this in humanized sys-tems and how to develop rational combinations. u

Figure. Clinical Trial Schema

(Optional crossover)

4-Week Timeframe

Patient consented and screened

Tumor biopsy

Molecular profiling

Drug target

identified?No

Patient not randomized,treated with physician’schoice

Yes

Treated with physician’schoice

Patient randomized

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PMOWe are delighted to talk with you today aboutPlexxikon’s approach to personalized medicine. We’dlike to start by asking how you define personalized med-icine, particularly as it relates to the treatment of pa-tients with melanoma.

Dr Hirth Personalized medicine in oncology is not anew concept, but in melanoma it is a very recent devel-opment with the breakthrough of the drug discoveredby Plexxikon and codeveloped with its partner Roche.A completely new concept was put forward, and we

are now able to dissect the melanoma population intosubsets based on molecular drivers. Today, we reclassifyand talk about melanomas, not just 1 melanoma.

As a result, we were able to focus on a particular sub-set of those melanomas, understand the moleculardriver, develop the drug, and realize that because thismolecular driver is only present in a subset of cancer pa-tients, we would need to come up with a way to identifythose patients through the development of a companiondiagnostic.

PMO Personalized medicine in action remains spo-radic and occurs mainly at well-funded academic med-ical centers or prompted by physicians who understandthe genetic principles behind molecular biomarkers andhow to assess them appropriately. How can this situationchange so that personalized medicine can be made avail-

Interview With the Innovators

Personalized Medicine Advances in Melanoma: An Interview With K. Peter Hirth, PhDK. Peter Hirth, PhDChief Executive OfficerPlexxikon, Inc.

Plexxikon, a member of theDaiichi Sankyo Group since2011, works in the structure-guided discovery and develop-

ment of novel small-molecule phar -ma ceuticals to treat human disease. Thecompany’s lead drug Zelboraf (vemu-rafenib/PLX4032) was approved by theFDA in August 2011 and is copromotedin the United States by Daiichi Sankyo,Inc. and Genentech. PLX3397, thecompany’s next oncology candidate, ad-vanced to phase 2 testing in 2011.Plexxikon is developing a portfolio ofpreclinical- and clinical-stage compounds to address sig-nificant unmet medical needs in oncology, as well as in

several other therapeutic indications.Plexxikon’s proprietary Scaffold-BasedDrug Discovery™ platform integratesmultiple state-of-the-art technologies,including structural screening, as a keycomponent that provides a significantcompetitive advantage over other drugdiscovery approaches.Personalized Medicine in Oncology

had the opportunity to meet with theCEO of Plexxikon, K. Peter Hirth,PhD, to talk about Plexxikon’s ap-proach to personalized medicine, thelandscape of care in melanoma, and the

process of biomarker discovery and drug development inniche markets.

Dr Hirth cofounded Plexxikon in December 2000 and has more than 25 years of biotechnology and pharmaceutical discoveryand development experience. Previously, he was president of Sugen, Inc., where he helped advance several kinase inhibitorsthrough clinical trials. Dr Hirth received his PhD in molecular genetics from Heidelberg University and completed his postdoctoralwork at the University of California, San Diego.

K. Peter Hirth, PhD


able broadly to patients managed by community oncol-ogists? What are the barriers and opportunities for thisto occur?

Dr Hirth Translating and managing the biomarkerexperiences and the personalized medicine that initiallystarted out in academic centers into the community re-mains a challenge. However, there are examples wherethis has been going really well. We are just beginning to

understand the barriers to community implementation.For example, the ease of a test is very important. It’s veryeasy for doctors to deal with binary test readouts; whenit’s a simple yes or no. But there are more complicatedtests that make for a much more difficult treatment de-cision. Education is absolutely key to give doctors thetools to interpret the test results.In addition, when we talk about novel biomarkers

and bringing them forward into development, we alsohave to realize that there are regulatory issues that we

have to deal with. The guidance from the FDA at thispoint is not very clear.If you look at barriers for the development of bio-

markers and their translation into personalized medicinefrom a business perspective, a biomarker without a drug,without a clinical trial and data, is just a biomarker, anddeveloping that into a full-fledged diagnostic test posesa certain financial risk that people like to measure outas they engage in the development, because it is achicken/egg situation. I have a biomarker, I might havea drug, but will this drug with this biomarker in combi-nation be successful?Considering bringing tests to the community oncol-

ogist, there is an institution in the US that is somewhatunderutilized, and that is the Clinical Laboratory Im-provement Amendments of 1988 (CLIA)-certified labs,which really do not fall under the jurisdiction of theFDA but have all the expertise and talent and are al-ready distributed throughout the country. From a distri-bution perspective, you would actually get much fasterpenetration into the community if you went that routeof involving CLIA-certified labs in the development ofthese biomarker assays. But this is still a subject of dis-cussion with the FDA, and they’re working on guidance.

PMOVemurafenib has clearly been a significant ad-vance in the treatment of melanoma, and one can makea case that this agent represents personalized medicinein oncology when used in patients with BRAF muta-tions. Are efforts by Plexxikon also directed at the di-agnostics industry to standardize, innovate, and improvelaboratory testing for molecular biomarkers?

Dr HirthWhat is the optimum use of identifying thebest companion diagnostic? That really depends on theproject, and I don’t think there is a one-size-fits-all so-lution. In the case of Zelboraf and the V600 mutation,it was clear that the genetic level probably would be themost appropriate test. Currently, there is developmentof further technologies beyond PCR [polymerase chainreaction] looking at high-sensitivity sequencing. Sothere is going to be a technology change.At Plexxikon, after looking at the various programs

that we are working on, we have decided that basically


We also have to realize that there areregulatory issues that we have to dealwith. The guidance from the FDA atthis point is not very clear.


each program requires a different approach to a com-panion diagnostic, and therefore we have decided notto engage in developing these tests ourselves but rathergo into the marketplace to look for optimum technologyavailable to us.There is really no single answer to the question of

how best to do that. This is our approach, and I think alot of other companies have gone down that path, andas a result there are a number of diagnostic companiesoffering their services.I’m not sure whether this approach will be financially

rewarding, because more and more indications are be-coming smaller and smaller. The cost for these tests can-not be astronomically high, or nobody would use them.But there is still a lot of work that needs to be dealt withto make this possible in a practical fashion. I believe thatwe will see platform technologies that will be test runon sequencing platforms. There are going to be plat-forms like the cell sorting, and individual markers thatwill be integrated into sets like that. Diagnostic plat-forms will be developed separately and validated once,so you don’t have to pay the price to develop and vali-date the entire platform for each new marker, but justthe part for the specific new marker for which you wantto test.

PMOHow is Plexxikon applying its platform to cre-ate other oncology compounds beyond vemurafenib?

Dr HirthThe Plexxikon platform that was used to de-velop Zelboraf has also been utilized for a number of addi-tional programs. Patients eventually develop resistancewith cancer treatment and become refractory. The big ad-vantage we have here is our targeted approach; we can goin and look at the resistant tumors and ask what’s changed,what’s different, how do cancers get around. And that nowleads to potential points of intervention that we can drugwith the technology that we have built at Plexxikon. Itwill again lead up to matching patients with the appropri-ate diagnostic test and molecular drivers.We have 1 compound that we will take forward into

development, hopefully early next year, that will be acompletely new class of drug in the melanoma space.In addition, we have PLX3397 that’s in phase 2 de-

velopment; it represents a very different approach – notby targeting primarily the tumor cell itself but by actu-ally targeting the tumor microenvironment. It’s similarto the concept of angiogenesis inhibition – there is acomponent of the microenvironment that is criticallysupporting the growth of tumors.There will be subsets of tumors that will respond to

that. We know that already. It’s a little more tricky anddelicate to define the cutoffs – so it’s not as easy as it

was for BRAF. I have to remind people that in theBRAF situation it’s really binary, it’s yes/no. Here we’redealing with more gradation, shades of gray that we haveto deal with, so these diagnostic tests will take a littlebit longer to define and move forward.

PMO Many of the “success stories” in personalizedmedicine in oncology have involved collaboration be-tween pharma and a diagnostics company (eg, crizotinibin ALK+ non–small cell lung cancer and vemurafenib inBRAF+ melanoma), and the FDA seems receptive to thissort of collaboration. Are FDA guidelines clear in theirrequirements for the simultaneous development of a phar-maceutical agent and an accompanying diagnostic test?

Dr HirthWhen we talk about personalized medicineand the development from a regulatory perspective, thekey features that one needs to consider are in the worksat the FDA.There are attempts to develop draft guidelines, but

it’s a case-by-case decision, and I must say that the FDAis very receptive to this companion diagnostic conceptbecause it makes a lot of sense. It is getting those patients with the most need the best and most likely opportunity to benefit from a drug, it shortens development time lines, and it eliminates the cost of un-necessary waste. All of that is very logical and clear.The question is how it is implemented on a case-by-


There are attempts to develop draftguidelines, but it’s a case-by-case decision,and I must say that the FDA is veryreceptive...


case basis. The Zelboraf example might not be the stan-dard case because this actually was a more straightfor-ward situation, and less complicated as you think aboutit from a development perspective, and therefore notnecessarily the standard to be measured against in thefuture.We will undoubtedly run into situations where we

will have to determine how critical new tests are in se-lecting patients for a particular drug. There’s also theconsideration of what regulators want, what payers arewilling to pay for, and the types of tests they would liketo see done.There’s a clear example in which payers in colorectal

cancer will not pay for EGFR inhibitor drugs: cases withknown mutations of KRAS, because studies have shownthat the drug is not worthwhile in those patients.

I think the FDA is committed to get this right. Theyhave invited comments. We made proposals, and wealso think there are ways to mitigate the initial financialinvestment by not having a Cadillac rolled out for initialclinical trials but maybe start with a tricycle until weknow we really have something that we can develop andthen send out around the world. And we think theCLIA labs are a very good setup for that.

PMO Will the collaboration between pharma anddiagnostic companies add significant cost to the devel-opment of personalized therapy in melanoma?

Dr Hirth The development of a therapeutic togetherwith a companion diagnostic obviously is a change inparadigm, and it does require additional financial com-mitments, but it also requires a lot more coordinationbetween the 2 companies developing the drug and thediagnostic.It also requires a lot more communication between

agencies at the FDA. The Center for Drug Evaluation and

Research is controlling regulating oncology products, whiletests are regulated by a very different body, so these groupsneed to come together and agree on an overall plan.

PMO Despite the fact that the incidence of malig-nant melanoma has been increasing over the past 30years, with 76,000 new cases and nearly 10,000 deathsexpected in 2012, the discovery of molecular biomarkersassociated with this malignancy is still relatively newand, thus far, confined almost exclusively to BRAF (al-though data are now being accumulated for the associ-ation of c-KIT and NRAS mutations with melanoma).Why do you think the discovery process of molecularbiomarkers in melanoma has been so slow?

Dr HirthWhy has melanoma been such a graveyardin drug development over the last year? Why did we nothave any drugs before Yervoy and Zelboraf? Does thishave to do with the lack of biomarkers? No, not really.Plenty of biomarkers were identified. There was inter-leukin-1a. There was the interferon. There were allkinds of interleukin-2 stories that were available. Butwe never came to the point where anything was testedto form hypotheses for subtypes. It was all looked at ina traditional drug development way in a heterogeneouspatient population.The other downside of melanoma is that it’s a disease

that is so aggressive. That may be why other cancers thathave a longer development time line before they be-come fatal have been better from a drug developmentperspective. Generally, the capability to generate potential bio-

markers over the last few years has gone up exponen-tially compared with the past, primarily because ofhigh-throughput sequencing, and I see throughput se-quencing getting cheaper and cheaper, so many aca-demic institutions are now collecting data. My concernhere is who’s sifting through all the data, who’s makingsense of it. And then from the data we need to build hypotheses to ask questions. Well, are these tests epi -phenomenal? Are these passenger mutations or do theyactually drive indications?Once we have identified driver mutations, if they’re

druggable, we know what to do in terms of drug devel-


There’s also the consideration of whatregulators want, what payers are willingto pay for, and the types of tests theywould like to see done.


opment. But it’s not going to be something that will bechanging overnight. I know there are some people whohave this expectation with sequencing. The field will bechanged in 2 years. I like to manage expectations; fromthe time we identify a potential target to having some-thing on the market is still many years away.We have shown that with a companion diagnostic

we can accelerate the drug development process quitesubstantially, but it will still be a number of years beforewe see the benefit of these new technologies comingthrough.

PMO It seems that education of providers, pharma-cists, payers, and patients is vital in achieving personal-ized medicine in oncology. What efforts is Plexxikonmaking in educating these stakeholders?

Dr Hirth Education about these new approaches topersonalized medicine obviously involves a variety ofdifferent parameters, functions, clinicians, payers, insur-ance, and advocacies. We have initially taken the roadthat we would start out in a scientific community, be-cause this is the culture that we live in, where new con-cepts are first tested in an academic environment beforethey trickle down into a community setting.But it has been going really well – especially in

melanoma, where patients have been so frustrated – be-cause there wasn’t anything else new on the horizon; theadvocacy groups were looking for new events and newapproaches that could change the outcomes.I would imagine that payers will have a huge interest

in embracing this concept, because it will reduce wasteddrug on patients who are unlikely to benefit, and I can-not see how that is not a very important argument forpayers.Now, where they would go with testing, whether they

would follow the FDA, or whether they would like theirown testing labs, this is still a subject of discussion, andI don’t know how this will come out.

PMOWhat do you foresee as the future of personal-ized medicine in oncology when sequencing the entirehuman genome will cost less than $1000 in the next fewyears? How will this impact drug development formelanoma and other cancers?

Dr Hirth We’re seeing huge progress in sequencingefforts, being able to sequence entire genomes, genomesof cancers, and at a price that is falling to a level thatmakes it realistic to apply it to a really large population.How will that change the way we treat patients? First

of all, clearly I’m looking forward to being able to betteridentify populations within, let’s say, melanoma tumorsor breast tumors that share certain characteristics. Wecan learn what the most likely molecular drivers are, andif they are druggable. We will have a huge opportunityto come up with new approaches to treatment. So what I think will happen is that we’ll get better

treatments, we will get safer treatments, but the treat-ments will be more selective. There will be more nichedrugs. There will be smaller groups of patients, and thathas some challenges in terms of conducting clinical tri-als and in the necessary investment. To develop a drugis a very expensive exercise that is justified mostly be-cause there’s an anticipated patient population that youcan treat and subsequently make money. But as thesepopulations get smaller and smaller, we have to ask our-selves to identify the break-even point.I think we need to have changes in the regulatory en-

vironment and in the reimbursement environment. Weneed to reconsider what our end points need to be, how


Dr K. Peter Hirth shares his views on personalized medicine inoncology.


much time and money we can afford to spend in someof these smaller niched indications.We already see this at Plexxikon, where we start

smaller trials – 10, 20 patients.It is more important for us to show early on in devel-

opment that we hit the target, that we can establish theconcept of how the drug is working. Even if that is asmall indication, but then later on, once we have un-derstood that, we can bring it to the broader audience.And I think what we do with Zelboraf is very similar.

We have shown in melanoma how that works. This isnow being tested in other tumors as well. We don’tknow the outcomes yet, but I’m positively optimistic asalways, otherwise I wouldn’t be in this business.

PMOWhat will you offer melanoma patients with-out a biomarker that directs a targeted therapy, espe-cially if this impacts a significant percentage of patients?

Dr HirthWhen we look at the melanomas and whatbiomarkers are present, we still have about a 40% pro-portion of the population where there is really no clearbiomarker identified that can lend itself to developinga targeted drug. This is unfortunate, because there is notmuch available now for those patients other than dacar-bazine and Yervoy.I would also like to say that even though we now

have these subpopulations based on V600 BRAF, this isnot a complete homogeneous population either. It’s en-riched, but it’s not black and white, so there are patientswho respond strongly and patients who have less of a re-sponse. So clearly there are further fractionations thatwill happen. In the future, I do see a more niched ap-proach to therapy.The other thing I would expect to see is that we will

have a much more rational approach to combining Zel -

boraf, for instance, with another drug, and we can startcalling these companion therapeutics. In the old days,everything was combined with everything available, butthere was very little logic and science behind it. We seethat changing. We already have very beautiful examplesin some of the BRAF-driven tumors, where the most ap-propriate companion therapeutic is basically already onthe market and should be tested.So this is a change there as well. It will be much more

rational. And again, it leads to better development,faster time lines to bring new products and benefit topatients in the clinic.But I think it also requires a rethinking in the indus-

try that has consequences in organizational forms. A pa-tient population consisting of 2000 patients doesn’trequire a 20,000 people sales force, for example. And sowe will see dramatic changes in the oncology businessas a result of the science driving the search for moreniched opportunities becoming better through the useof companion diagnostics approaches.

PMO Will it still make sense for Plexxikon to de-velop agents that impact only 5% to 10% of patients?

Dr Hirth What is the patient population in anygiven disease that is attractive for development? This isa very difficult question to answer. Personally I believethat whenever we can have a very dramatic impact onpatients who are in need of help, it’s worthwhile doing.We have some extreme examples with Genzyme, for ex-ample, which has developed really rare indications. We know that targeted therapies that have a high

impact usually are priced better. The value propositionis very different, and that is reflected in the investment.It can hopefully be developed faster so maybe it doesn’trequire the $800 million that it typically would take. So I think there are opportunities in the biotech

space to embrace concepts of developing drugs morequickly and more financially efficiently to make it aworthwhile proposition. I think it’s worthwhile any timewhen we can help people; it’s a worthwhile propositionfor me.

PMO Thank you so much for taking the time to talkwith us today. u


Personally I believe that whenever wecan have a very dramatic impact onpatients who are in need of help, it’sworthwhile doing.

PERSONALIZEDMEDICINE IN ONCOLOGYM

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Personalized Medicine in Oncology’s mission is to deliver practice-changing information to cliniciansabout customizing healthcare based on molecular profiling technologies and each patient’s unique genetic blueprint.

Our vision is to transform the old medical model of stratified medicine into a new model of personalized carewhere all decisions and practices are tailored to the individual.

The goal of Personalized Medicine in Oncology is to sensitize practitioners to the performance realities of new diagnostic and treatment discoveries and to clarify molecular profiling technologies as they relate to diagnostic,prognostic, and predictive medicine. PMOwill feature diagnostic and clinical treatment information concerningthese 3 root aspects of personalized medicine in oncology.

Readers are invited to submit articles for consideration in the following categories:

Biologicals in Trial• Exploring the challenges of clinical trial design and patient enrollment

• Presentation of emerging clinical data

Predictive Models and Diagnostics • A look at available diagnostic technologies andimplementation in the community practice setting

Genetics and Biomarkers• Exploring genetic discoveries and impact on predictors of disease and therapeutic response

The Cost of Personalized Medicine• Personalized medicine policy drivers

• Payer coverage of diagnostics and biologics

Genetic Profiling Technologies• What technologies are available to clinicians and consumers and their impact on diagnostic,prognostic, and predictive medicine

In Practice• A practical guide for community-based oncologists discussing clinical applications and strategies for incorporating personalizedmedicine techniques into practice

• Development of treatment algorithms

N=1 • Case studies, patient-reported outcomes, defining treatment goals, partnering with patientsand caregivers

Submit the entire manuscript and a cover letter stating the objectives of the article to [email protected] should follow the Author Guidelines available at www.PersonalizedMedOnc.com.

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Until recently, cancer treatment reliedsolely on histologic diagnosis for deter-mining systemic therapy. Aside from considerations related to a patient’s un-

derlying comorbidities and performance status, therewas minimal deviation from an organ-of-origin–basedtreatment strategy. This relatively primitive understand-ing of malignancy failed to exploit biological and mo-lecular differences within each cancer type to allow for

selection of a more rational therapy focused on individ-ual patient and tumor characteristics. However, excitingstrides are currently being made in the field of cancerresearch and treatment, both with solid tumors andhematologic malignancies. As our understanding of can-cer initiation, progression, and response to treatmenthas advanced, and technical achievements in bioinfor-matics and genome/proteome analysis have been made,the opportunities to tailor therapies to individual pa-

Continuing Medical Education

Implementing the Promise of Personalized Cancer CareHighlights From the Inaugural Conference of the Global BiomarkersConsortiumRüdiger Hehlmann, MD, PhDUniversity of Heidelberg, Mannheim, Germany

Hope S. Rugo, MDUniversity of California San Francisco, San Francisco, California

SponsorsThis activity has been planned and implemented in accordance withthe Essential Areas and policies of the Accreditation Council for Con-tinuing Medical Education (ACCME) through the joint sponsorship ofthe University of Cincinnati, Medical Learning Institute, Inc., Center ofExcellence Media, LLC, and Core Principle Solutions, LLC. The Univer-sity of Cincinnati is accredited by the ACCME to provide continuingmedical education for physicians.

Physician Credit DesignationThe University of Cincinnati designates this enduring material for a maxi-mum of 1 AMA PRA Category 1 Credit™. Physicians should only claim thecredit commensurate with the extent of their participation in the activity.

Registered Nurse DesignationMedical Learning Institute, Inc.Provider approved by the California Board of Registered Nursing,Provider Number 15106, for 1 contact hour.

Registered Pharmacy DesignationMedical Learning Institute (MLI) is accredited by the Accredita-tion Council for Pharmacy Education (ACPE) as a provider of

continuing pharmacy education. Completion of this activity provides

for 1.0 contact hour (0.1 CEU) of continuing education credit. The uni-versal activity number for this activity is 0468-9999-12-015-H01-P.

Commercial Support AcknowledgmentThis activity is supported by educational grants from Abbott Labora-tories, Daiichi Sankyo, Genentech, and Millennium: The Takeda On-cology Company.

Target AudienceThis activity was developed for medical oncologists and hematolo-gists, pathologists, geneticists, advanced practice oncology nurses,research nurses, clinical oncology pharmacists, and genetic coun-selors involved in the management of patients with solid tumors orhematologic malignancies, and interested in the use of moleculartumor biomarkers to help optimize patient care.

Educational ObjectivesAfter completing this activity, the participants should be better able to:• Assess emerging data and recent advances in the discovery oftumor biomarkers, their impact on the treatment of patients withsolid tumors and hematologic malignancies, and how to integratekey findings into clinical practice.

• Discuss the role of tumor biomarkers in designing personalized ther-apy for patients with cancer, including management of treatment-related adverse events.

CME/CE Information


To receive credit, complete the posttest at www.mlicme.org/P11077.html.

Instructions for CreditThere is no fee for this activity. To receive credit after reading thisCME/CE activity in its entirety, participants must complete the posttestand evaluation. The posttest and evaluation can be completed onlineat www.mlicme.org/P11077.html. Upon completion of the evaluationand scoring 70% or better on the posttest, you will immediately receiveyour certificate online. If you do not achieve a score of 70% or betteron the posttest, you will be asked to take it again. Please retain a copyof the Certificate for your records.

DisclosuresBefore the activity, all faculty and anyone who is in a position to havecontrol over the content of this activity and their spouse/life partnerwill disclose the existence of any financial interest and/or relationship(s)they might have with any commercial interest producing healthcaregoods/services to be discussed during their presentation(s): honoraria,expenses, grants, consulting roles, speakers bureau membership, stockownership, or other special relationships. Presenters will inform par-ticipants of any off-label discussions. All identified conflicts of interestare thoroughly vetted by University of Cincinnati and Medical LearningInstitute, Inc. for fair balance, scientific objectivity of studies mentionedin the materials or used as the basis for content, and appropriatenessof patient care recommendations.

Planners and Managers DisclosuresRick Ricer, MD, UC CME Content Reviewer, has nothing to disclose.Lorrie McSherry, RN, BSN, OCN, MLI Peer Reviewer, is on the advi-sory board for Onyx.

Patricia Woster, PharmD, MLI Peer Reviewer, is a former employeeof Eisai and has stock in Pfizer.

Faculty DisclosuresRüdiger Hehlmann, MD, PhD, has nothing to disclose.*Hope S. Rugo, MD, is a researcher for Genentech/Roche, GlaxoSmith-Kline, ImClone, Merck, Novartis, and Sanofi/BiPar, and is on the speak-ers bureau for Bayer, Intellikine, and Genomic Health.*Content will include non–FDA-approved uses.

The associates of University of Cincinnati, Medical Learning Institute,Inc., the accredited providers for this activity, Center of ExcellenceMedia, LLC, and Core Principle Solutions, LLC, do not have any finan-cial relationships to products or devices with any commercial interestrelated to the content of this CME/CE activity for any amount duringthe past 12 months.

DisclaimerThe information provided at this CME/CE activity is for continuing ed-ucation purposes only and is not meant to substitute for the independ-ent medical judgment of a healthcare provider relative to diagnosticand treatment options of a specific patient’s medical condition. Rec-ommendations for the use of particular therapeutic agents are basedon the best available scientific evidence and current clinical guide-lines. No bias toward or promotion for any agent discussed in this pro-gram should be inferred.

Estimated time to complete this activity: 1.0 hourInitial Release Date: June 15, 2012Expiration Date: June 15, 2013


To receive credit, complete the posttest at www.mlicme.org/P11077.html.

tients have markedly expanded. Indeed, an expandingpool of predictive biomarkers has now ushered in theera of personalized medicine for cancer patients. Severalof these markers have transformed patient care, and test-ing for these markers has become mandatory prior to ini-tiation of therapy. As a result, targeted therapeutics thatrely on the molecular characteristics of a malignancyoffer hope for personalized care in cancer with improvedpatient outcomes.However, because a rapidly increasing number of mo-

lecular biomarkers are now becoming clinically available,a significant need exists for healthcare pro fessionals whomanage patients with cancer to keep abreast of the latestinformation on tumor biomarkers and how to appropri-ately use them to optimize therapy for their patients. Inthis regard, the Global Biomarkers Consortium (GBC)was developed. The GBC is a community of world-renowned healthcare professionals coming together toprovide a forum for the improved understanding of the

clinical application of prognostic and predictive molecularbiomarkers toward optimal personalized care for patientswith cancer. The inaugural conference of the GBC washeld on March 9-11, 2012, in Orlando, Florida. This mono-

CME/CE Information (continued)

Hope S. Rugo, MD

FACULTY CHAIRS

Rüdiger Hehlmann, MD, PhD

graph will highlight the key findings from that meeting.

Biomarkers Today – the Link toTherapeuticsThe ultimate goals in individualized or personalized

cancer therapy are to:• Understand the biology of each tumor with respectto risk of recurrence, pathways that drive growth andresistance, and potential targets for therapy

• Identify patients who need treatment due to adversetumor biology characteristics (in addition to tradi-tional tumor characteristics)

• Identify benefits of a specific therapy or type of therapy

• Avoid ineffective therapiesOur current tools allow for an assessment of risk and

of the overall benefit of chemotherapy, but in order toachieve true, personalized cancer therapy, tools areneeded to predict benefit from a specific therapy and takeinto account patient preferences. In early-stage breastcancer, we learned from a retrospective analysis by theEarly Breast Cancer Trialists’ Collaborative Group that

estrogen receptor (ER) status could predict the grade ofdisease, extent of proliferation, likelihood of a responseto chemotherapy or hormone therapy, and overall sur-vival.1 Similarly, in prospective trials of patients withnode-positive early breast cancer, ER status was shownto predict response to enhanced chemotherapy regi-mens, including doxorubicin/cyclophosphamide pluspac litaxel, where only patients with ER-negative tumorsderived benefit from these enhanced regimens with re-spect to disease recurrence and overall survival.2 Subse-quently, multigene assays were developed (MammaPrintand Oncotype) that provided prognostic informationbut were not sufficient by themselves to predictchemotherapy benefit, merely complementing clinical-pathological factors.3-5 Unfortunately, breast cancer re-search has not moved forward from this point. Atpresent, while we can look broadly at the benefit fromchemotherapy, hormone therapy, and HER2-directedtherapy, we are not yet able to predict which patient willbenefit most from a specific therapy.However, there is a great deal of research ongoing in

this area. For example, in patients with HER2-positivemetastatic breast cancer, the combined blockade of theHER2 receptor with trastuzumab and pertuzumab re-sulted in the longest progression-free survival (PFS) inthe first-line setting of any subset of breast cancer otherthan ER-positive disease (Table 1).6-10 Thus, when atreatable target is identified (in this case, HER2), specificagents can be developed that result in improved clinical

Table 1. Targeting the HER2 Receptor: The First Druggable Target Since Estrogen Receptor6,8-10

Slamon et al6 Marty et al8 Baselga et al9 Gianni et al10

(N=469*) (N=186) (N=808) (N=424)

-Tr +Tr -Tr +Tr -P +P -B +B

PFS/TTP (mo) 4.6 7.3 6.1 11.7 12.4 18.5 13.7 16.5

OS (mo) 20 26 23 31 NR @ med FU 38.3 38.519.3 mo

Slamon et al: q3 wk paclitaxel or AC, all others q3 wk docetaxel.*FISH + subset.AC indicates doxorubicin and cyclophosphamide; B, bevacizumab; ER, estrogen receptor; FISH, fluorescence in situ hybridization; OS, overallsurvival; P, pertuzumab; PFS/TTP, progression-free survival/time to progression; Tr, trastuzumab.

When a treatable target is identified,specific agents can be developed thatresult in improved clinical outcomesand that can overcome drug resistance.




outcomes and that can overcomedrug resistance.Taking these results a step fur-

ther, 3 prospective clinical trials(NeoSphere, Neo-ALLTO, andGeparQuinto), in which patientswith HER2-overexpressing breastcancer were treated withtrastuzumab plus pertuzumab ortrastuzumab plus lapatinib, in-cluded serial sampling of tumor tis-sue. Subsequent biomarker analysisof the tissue samples taken duringthe NeoSphere trial revealed thatwhile HER2 overexpression was associated with sensi-tivity to pertuzumab, there was no predictive value inthe biomarkers tested for patients with specific treat-ment regimens.11 The challenge is in identifying the ap-propriate set of biomarkers that can be clearly related tobenefit from a specific therapy. Failure to do so up to thispoint may have contributed to the withdrawal of ap-proval for bevacizumab for HER2-negative disease, sim-ply because of the lack of a reliable biomarker to identifythe subset of breast cancer patients who would benefitfrom this drug.The area where we have had the greatest success is

in the use of inhibitors of the mammalian target of rapamycin (mTOR). As tumors become increasingly resistant to hormone therapy, they up-regulate signal -ing through the phosphoinositide 3-kinase (PI3K)/Aktpathway, and a recent study investigated biomarkersthat could help identify patients who would benefitfrom blocking that pathway. In the BOLERO-2 trial,patients with hormone receptor (HR)-positive breastcancer that had become resistant to hormonal therapywere randomized to treatment with everolimus (anmTOR inhibitor) plus exemestane versus placebo plusexemestane. As shown in Table 2, median PFS wassignificantly improved in patients treated witheverolimus plus exemestane compared with thosetreated with placebo plus exemestane, suggesting thatadding an inhibitor of the mTOR pathway can

overcome resistance to hormone therapy.12

There are a number of pathways for more effectivebreast cancer therapy that will require rethinking onhow drug candidates are tested in clinical trials and whatmolecular targets should be pursued. Efforts are beingmade in these directions – in the I-SPY 2 trial, in whichpromising agents are being screened in combinationwith standard chemotherapy in the neoadjuvant settingto accelerate the process of identifying drugs that are ef-fective for specific breast cancer subtypes; in attemptsto design agents that target deregulated pathways; andby development of clinically and molecularly appropri-ate treatment protocols based on multidisciplinary input

from clinical oncologists, surgeons, radiation oncolo-gists, molecular biologists, geneticists, pathologists, andpatient advocates.

Comprehending the Next Generationof Oncology CareA technological revolution is driving the expectation

that we are on the verge of a transformation of ap-proaches to cancer management with an attendant im-


Everolimus and Placebo andExemestane Exemestane(N=485) (N=239) P Value

Local assessmentProgression-free survivalEvents (%) 202 (42) 157 (66) <.001Median duration, mo 6.9 2.8

Central assessmentProgression-free survivalEvents (%) 114 (24) 104 (44) <.001Median duration, mo 10.6 4.1

Table 2. Everolimus in Hormone Receptor–Positive Advanced BreastCancer12

The area where we have had the greatestsuccess is in the use of inhibitors of themammalian target of rapamycin (mTOR).

provement in patient outcomes.13 In this regard, thereare an unprecedented number of targeted therapies inclinical trials – about 500 targeted therapies investigat-ing about 140 genomic alterations, with approximately40 potential genomic targets that will require clinicaltesting in the near future. In lung cancer, the recogni-

tion that EGFR mutations are correlated with clinicalresponse to gefitinib and erlotinib therapy is wellknown.14-16 However, this was not an isolated example– subsequent work showed that approximately 7% of pa-tients with non–small cell lung cancer (NSCLC) ex-pressed a transforming EML4-ALK fusion gene that wasdistinct from the EGFRmutations.17 This led to the dra-matic finding that 57% of NSCLC patients with theALK rearrangement responded to treatment with crizo-tinib, a small-molecule oral inhibitor of ALK tyrosine

kinase (Figure 1),18 which recently led to the drug’s ap-proval for ALK-positive NSCLC.However, this is an evolving process, as shown by

the recent identification of the ROS1 rearrangementthat defines a molecular subset of NSCLC (~2% of pa-tients) with distinct clinical characteristics and impres-sive clinical sensitivity to crizotinib,19 as well as theKIF5B-RET transformation in colorectal cancer andNSCLC cells that are sensitive to multikinase in-hibitors that inhibit RET.20

Our ability to characterize the majority of aberrationsin actionable cancer genes has made it possible to rapidlytest potential biomarkers based on targeting the patientsmost likely to benefit in a trial. However, implementationof molecular testing into patient care requires that all testsbe performed in a Clinical Laboratory ImprovementAmendments–certified laboratory with a high degree ofquality control and an understanding of the accuracy ofthe results. As our ability to characterize the genome oftumors from specific patients improves, the number ofaberrations discovered and the challenge to determinetheir relevance to response to targeted therapies will in-crease, demanding the development of bioinformatic ap-


Figure 1. Tumor Responses to Crizotinib in Patients With ALK-Positive Non–Small CellLung Cancer18

Precent Change in Tumor Burden

The future of cancer care also relieson the techniques that we are able to develop to uncover actionable cancer genes.

Patient No.

Percent Cha

nge From Baseline


Black: Disease progressionBlue: Stable diseaseYellow: Partial responseRed: Complete response


proaches to determine which aberrations are the driversof effective therapy, and novel, critically experimental ap-proaches designed to test the predictive value of the mo-lecular aberrations.The future of cancer care also relies on the tech-

niques that we are able to develop to uncover actionablecancer genes. The techniques should be used in a com-plementary effort and include both old and newmethodologies: cytomorphology, cytogenetics, im-munophenotyping, gene expression profiling, next-generation sequencing, histology, fluorescence in situhybridization (FISH), and molecular genetics.

Incorporating Personalized MedicineInto Practice: A Natural Evolution ofEvidence-Based and TranslationalMedicine to Personalized MedicineOver the past several years, there has been an in-

crease in our understanding of cancer pathogenesis atthe molecular level, along with an appreciation of nu-merous pathways that have been implicated in cancerdevelopment and growth. This knowledge has led to theconcept that we should be conducting biomarker en-richment trials to improve the efficiency of new thera-peutic development for personalized medicine. Inconducting biomarker enrichment trials, there are 2major considerations:• Does a therapeutic agent benefit “biomarker-posi-tive” and/or “biomarker-negative” patients?

• Was this the right biomarker to test, ie, what is theright marker, what are the appropriate materials orspecimens to test, and do we have a good biomarkerassay available?There are several possible trial designs in a biomarker

enrichment trial. A retrospective validation in whichperiodic tissue and serum specimens are collected frompatients enrolled in a trial in which they are followedfor several years. Biomarkers are then retrospectivelyevaluated and correlated to the pathophysiology andclinical outcomes for each patient. A prospective vali-dation can be carried out in several different ways: • Biomarker testing is performed on all patients, but

randomization is not based on the results from bio-marker testing

• Biomarker testing is performed on all patients priorto randomization, and randomization is based on thebiomarker-positive or biomarker-negative status ofeach patient. Each biomarker-randomized patient isthen rerandomized or stratified to an experimental

arm or a control. This design is especially interestingin the setting of VEGF inhibitors in breast cancer

• The most complex strategy involves a biomarker-guided randomization in parallel with a marker-blinded randomization. The biomarker-positivegroup is placed into the experimental arm, the bio-marker-negative group into the control group, andthe biomarker-blinded group is rerandomized to anexperimental arm or control. The challenge in thisdesign is in getting the physician and patient to agreeto follow a therapeutic approach based on biomarkeranalysis, ie, some patients may actually be resistantto the concept of personalized medicine! This typeof biomarker enrichment trial typically required alarger number of enrolled patientsTable 3 outlines several of the most important issues


• Prevalence of marker• Reproducibility and validity of assay• Validity of cutoff point marker (binary or continuous?)• Sensitivity and specificity of marker • Strength of preliminary evidence• Feasibility of real-time assessment• Specimen collection• Budget• Collaborators

Table 3. Important Issues to Consider in Designing Biomarker Enrichment Clinical Trials

The reproducibility and validity of thebiomarker assay is especially importantsince this is the basis for the concept ofpersonalized medicine.

to consider in designing biomarker enrichment trials.The reproducibility and validity of the biomarker assayis especially important since this is the basis for the con-cept of personalized medicine. Unfortunately, in breastcancer, for example, the discordance rate among differentlaboratories is ~10% for HR and progesterone receptor

and ~15% for HER2; variability among immunohisto-chemistry experts is ~8% for FISH testing, although thiscould be reduced to 3% to 4% if the pathologists exam-ined the specimens together (Perez E. Written commu-nication from the experience at Mayo Clinic).These types of trials are already prompting a rethink-

ing of how personalized cancer treatment can be accom-plished. For example, in breast cancer, early detectionof metastasis-prone tumors and characterization of resid-ual metastatic cancers are important in efforts to im-prove patient management. Applications of genome-scale molecular analysis technologies are making thesecomplementary approaches possible by revealing molec-ular features uniquely associated with metastatic disease.Assays that reveal these molecular features will facilitatedetection prior to metastatic spread, and knowledge ofthese features will guide development of therapeuticstrategies that can be applied when metastatic diseaseburden is low, thereby increasing the probability of acurative response.21 This so-called “Omic Approach” iscomplementary to the traditional anatomic and histo-logic analyses of breast cancer. However, the genomicapproach to the treatment of breast cancer is complexand must take into account gene expression profiles,RNA structure, genomic rearrangements, and gene se-quence mutations in order to integrate these featuresinto a model that predicts tumor behavior. Figure 2 out-lines the schema used at the Mayo Clinic in accomplish-ing this goal – DNA and RNA are collected, wholegenome sequencing is performed, and a multidiscipli-nary bioinformatics team is convened to make decisionson applying the data to research and clinical practice.While incorporation of translational medicine into

practice is essential for the future of personalized medi-cine in oncology, we must not lose sight of the fact thatincorporating evidence-based guidelines and pathwaysinto clinical practice is also important in improving pa-tient outcomes.There are 2 types of evidence-based guidelines:

• A process map of integrated interventions over time(eg, the National Comprehensive Cancer Network[NCCN] guidelines) that addresses the coordination ofcare and specifically illuminates the continuum of care

• Individual guidelines in which the scope is more re-stricted, and there may be as many as 1000 decisionpoints posing an enormous challenge in terms of acomprehensive review and analysis of the literature

How do guidelines fit into decisions about treatments?


Figure 2. Mayo Clinic Integrated Approach toDefining the Genomic Landscape of Breast Tumors for Research and Practice

RMLs registry and preparation of bothRNA and DNA at collection sites

Library preparation Library preparation

Data analysis Combined bioinformatics team

DNA for whole genome

RNA for wholetranscriptome

Hi-Seq sequence analysis

Tumor collection

This so-called “Omic Approach” iscomplementary to the traditionalanatomic and histologic analysesof breast cancer.

RMLs indicate regional medical libraries.



They should follow clinical decision-making pathwaysthat offer a range of appropriate treatments for specificsituations that are included in the guidelines, with thegoal of reducing variability in care.22

Reimbursement Challenges andStrategies for Personalized Medicine inOncology – Perspectives for Providersand PatientsTo achieve the reality of personalized medicine in

oncology, we need to understand how payers review mo-lecular biomarker data for coverage and how these cov-erage decisions impact providers and patients. Molecularbiomarkers are not a special category of test from a payerperspective, and payers evaluate and pay for biomarkertesting in the same way they manage all other diagnostictests (Pezalla E. Written communication of the regula-tions from Aetna Pharmacy Management). In general,diagnostic tests are always covered under the medicalbenefit even if they are being used to determine if thepatient should receive a specific pharmaceutical, butthey are not covered under the pharmacy benefit. Mo-lecular biomarker testing may even be required in someinstances by payers before approving a specific therapy;in those cases, the testing will always be covered. How-ever, providers and patients should be aware of channelmanagement by some payers, ie, a requirement to use aparticular source for the diagnostic test. This is notmerely a cost control issue, it also ensures access to thehighest quality laboratories available.Most payers review all testing, pharmaceuticals, and

procedures based on the supporting clinical evidence,primarily in the form of published literature, nationalprofessional guidelines (eg, NCCN), FDA findings, andinformation from developers or manufacturers (PezallaE. Personal communication of the regulations fromAetna Pharmacy Management). The results of these re-views are typically published in clinical policy bulletins,which are available online for providers and patients.These bulletins classify tests as experimental or clini-cally necessary, cite the conditions under which the di-agnostic test is deemed necessary, provide a review of

the literature to support the stated policy, and list pay-ment and diagnostic codes. These are invaluable forproviders in managing their patients with cancer. Themajor criteria for coverage of a molecular biomarker testare that the test accomplishes what it purports to do interms of accuracy, reliability, and reproducibility, andthat the test has a measurable impact on medical deci-sion making and patient outcomes.

ConclusionThe inaugural conference of the Global Biomarkers

Consortium represented a unique opportunity for a di-verse, world-renowned faculty to convene to discuss thecurrent state of the art in tumor biomarkers from theperspective of providers, payers, and patients. The meet-ing focused on the use of molecular biomarkers in an ef-fort to fully realize the promise of personalized medicinein oncology.Because of the wide range of topics discussed, this

overview has captured only a small portion of the topicsdiscussed and has avoided discussion of the developmentof molecular biomarkers for each specific solid tumorand hematologic malignancy discussed at the meeting.These topics will be reviewed in future editions of Per-sonalized Medicine in Oncology. u

References1. Early Breast Cancer Trialists’ Collaborative Group (EBCTG). Effects ofchemotherapy and hormonal therapy for early breast cancer on recurrenceand 15-year survival: an overview of the randomised trials. Lancet.2005;365:1687-1717.2. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor statusand outcomes of modern chemotherapy for patients with node-positivebreast cancer. JAMA. 2006;295:1658-1667.3. Sotriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009;360:790-800.4. Albain KS, Paik S, van’t Veer L. Prediction of adjuvant chemotherapybenefit in endocrine responsive, early breast cancer using multigene assays.Breast. 2009;18(suppl 3):141-145.5. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. BreastCancer Res Treat. 2010;120:655-661.6. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a


The meeting focused on the use ofmolecular biomarkers in an effort to fullyrealize the promise of personalizedmedicine in oncology.

monoclonal antibody against HER2 for metastatic breast cancer that over-expresses HER2. N Engl J Med. 2001;344:783-792.7. Mass RD, Press MF, Anderson S, et al. Evaluation of clinical outcomesaccording to HER2 detection by fluorescence in situ hybridization inwomen with metastatic breast cancer treated with trastuzumab. Clin BreastCancer. 2005;6:240-246.8.Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial ofthe efficacy and safety of trastuzumab combined with docetaxel in patientswith human epidermal growth factor receptor 2-positive metastatic breastcancer administered as first-line treatment: the M77001 study group. J ClinOncol. 2005;23:4265-4274.9. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Study Group. Per-tuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.10. Gianni L, Romieu G, Lichinitser M, et al. First results of AVEREL, arandomized phase III trial to evaluate bevacizumab (BEV) in combinationwith trastuzumab (H) + docetaxel (DOC) as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC). Presentedat the CTRC-AACR San Antonio Breast Cancer Symposium, December6-11, 2011, San Antonio, TX. Abstract S4-8.11. Gianni L, Bianchini G, Kiermaier A, et al. Neoadjuvant pertuzumab(P) and trastuzumab (H): biomarker analyses of a 4-arm randomized phaseII study (NeoSphere) in patients (pts) with HER2-positive breast cancer(BC). Presented at the CTRC-AACR San Antonio Breast Cancer Sym-posium, December 6-11, 2011, San Antonio, TX. Abstract S5-1.12. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal

hormone-receptor-positive advanced breast cancer. N Engl J Med.2012;366:520-529.13.Mills GB. An emerging toolkit for targeted cancer therapies. GenomeRes. 2012;22:177-182.14. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: corre-lation with clinical response to gefitinib therapy. Science. 2004;304:1497-1500.15. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epi-dermal growth factor receptor underlying responsiveness of non-small-celllung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139.16.Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are commonin lung cancers from “never smokers” and are associated with sensitivity of tumorsto gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101:13306-13311.17. Soda M, Choi YL, Enomoto M, et al. Identification of the transformingEML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-566.18.Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase in-hibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-1703.19. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements definea unique molecular class of lung cancers. J Clin Oncol. 2012;30:863-870.20. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALKand RET gene fusions from colorectal and lung cancer biopsies. Nat Med.2012;18:382-384.21. Griffith OL, Gray JW. ‘Omic approaches to preventing or managingmetastatic breast cancer. Breast Cancer Res. 2011;13:230.22. National Comprehensive Cancer Network; NCCN Guidelines.www.nccn.org.



Personalized medicine can be described as the ability to customize therapy by understand-ing the molecular and/or genetic characteristics of an individual patient. However, as PMOStrategic Editor Robert Henry points out in this month’s letter (page 9), currently cancer clin-ical management is a coalition of conventional and personalized medicine techniques.

In your practice, do you feel well prepared to provide personalized care to your patients if available?

To participate in this survey, please log on towww.PersonalizedMedOnc.com

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▼ The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE retained at least 60% of the overall response rate after 4 cycles relative to single-agent IV VELCADE

SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed MM. The primary endpoint was overall response rate at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival (OS), and safety.

* INDICATIONS: VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

†Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1

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

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients

with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope,

and those who are dehydrated▼ Closely monitor patients with risk factors for, or existing heart disease ▼ Acute diffuse infiltrative pulmonary disease has been reported▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal

medications or fluid replacement▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

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NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION IN ALL INDICATIONS*

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Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE

PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IVR

Please see Brief Summary for VELCADE on next page.

For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.comReference: 1. 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(5):431-440.

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▼ Starting VELCADE® (bortezomib) subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment

▼ Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness

▼ Patients experiencing new or worsening PN during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification guidelines for PN

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS CONTINUED▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the

potential harm to the fetus▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong

CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

IN ALL INDICATIONS*

2:18 PM

Brief Summary

INDICATIONS:VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

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

WARNINGS AND PRECAUTIONS:VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been

isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

(continued)

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE (bortezomib). Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA:Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs

were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.

DRUG INTERACTIONS:Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE (bortezomib) is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS:Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA V-12-0017 3/12

Regulatory Issues

Molecular tests have proliferated over thepast decade, bringing the precision of genomics into reality inthe clinic, but the pay-

ment system for nucleic acid–basedtests has been unchanging and primi-tive. This unfortunate state of affairshas limited the ability of payers to en-courage (or control) the use of genomictests and has seriously handicapped theability of researchers to understandwhat genomic tests are being adoptedinto clinical medicine, how they arebeing used, and whether they are hav-ing an impact on health outcomes. Inan era where there is increasing em-phasis on the need for “practice-based evidence” (fromobservational studies and pragmatic trials that can sup-plement formal randomized clinical trials), our elec-tronic medical records and our transaction systems for

healthcare claims must be up to the task of telling uswhat genomic tests are being adopted.

Fortunately, an entirely new codingsystem is being introduced into the UStransaction system for providers andpayers in 2012 and 2013. Since theregulations and policies governing theuse of medical procedure codes, espe-cially in laboratory medicine, may bearcane to many stakeholders, we willprovide an overview of how the cur-rent system works before describing theimpending changes. While policies forcoverage and payment may differsomewhat between private payers andfederal payers like Medicare, we will

focus on the standard-setting efforts of Medicare as theprototypic payment system for outpatient procedures.This article discusses why coding systems are really quiteimportant for the smooth functioning of our healthcare

Rapid Changes in Reimbursement Protocols forMolecular TestsBruce Quinn, MD, PhDFoley Hoag LLP, Boston, Massachusetts

Key Points

• Molecular tests have proliferated over the past decade, bringing the precision of genomics into reality in the clinic

• We are at the edge of a truly unprecedented increase in the available codes for genomic tests• During the 2012 calendar year, and perhaps into 2013, Medicare will create tables that match each new codeto a price

• The CPT coding system is not designed for rapid change, and the advances in genomic testing are already rapidlyaccelerating

• It may turn out that a coding system more granular than the CPT coding system can provide will be required

Dr Quinn is Senior Health Policy Specialist for the Foley Hoag law firm and is a national expert on Medicare policy, the impactof health reform on innovation, and the crafting of successful business strategies within the US healthcare reimbursement system.

Bruce Quinn, MD, PhD



system and how the coding system for genomic tests isbeing reengineered. We also sketch the shape of a policybattle among different stakeholders as to what paymentsystem should be employed from 2013 forward for genomic tests. Finally, we discuss a few problems thatthe proposed coding system cannot yet address.

Codes as a Scaffold for HealthcareProcedures and the Flow of FundsDespite calls for a more rational and holistic ap-

proach to payment for healthcare services in the UnitedStates, much of the reimbursement for outpatienthealthcare flows through line item reimbursement – thelongstanding “fee-for-service” system.1,2 Because thou-sands of individual services, drugs, and tests exist, theoperation of a modern fee-for-service system requires ahighly granular system of codes that allows providers tocommunicate with payers, informing the latter of whatparticular services have been performed on a given day.The US healthcare system has evolved a family of dif-ferent, independent, legally recognized coding systemsfor different types of items and services: there are differ-ent code sets to categorize hospitalizations, physicianservices, laboratory tests, drugs, and supplies. While theunderlying coding systems for government and privatepayment systems are fundamentally the same becausethey are set by law, a particular payer can determine themeans by which it negotiates or sets prices for the servicerepresented by a certain code. For the largest paymentsystem, the Medicare system, each set of codes (whichmay contain literally thousands of distinct codes) iscrosswalked to a publicly available pricing table inwhich each service is assigned a price. And eachMedicare pricing table reflects the result of the machi-nations and operations of one or another incredibly ar-cane set of Medicare policies – different sets of policies,often amazingly complex and granular, for hospital services, physician services, clinical laboratory tests, and drugs.From the perspective of an administrator, Medicare’s

prices are the result of a series of transformations from aclinical event to a coding system and finally to a pricing

system, resulting in a line item dollar reimbursementthat is sent back to the provider of the medical service.An economist’s view of the transaction would be differ-ent: it is a view where the dollar transaction is para-mount, because a price encompasses crucial signals as tohow the marketplace and recipient of a service valuethat service. Price tells the producer what to provide,when, where, and in what quantity. Prices are the invis-ible but powerful guiding hand of the market. Little ofthat wisdom is conveyed by Medicare’s prices, however,at least not intentionally, because Medicare’s pricesblindly follow one or another set of dry accounting rulesto distribute a limited pool of payments based on varioustables of data and rules that manipulate those bits ofdata into a price.

This background leads to how Medicare reimbursesfor genomic tests. Up until 2012, Medicare has used anextremely simplistic system to reimburse for humangermline and somatic genomic tests, consisting of ahandful of mostly 20-year-old codes that represent a fewbasic laboratory bench processes like “DNA extraction,”“nucleic acid amplification,” and “sequencing.” Al-though there was a bit of state-to-state variation in pric-ing, these molecular steps generally paid about $20 each.A genetic test that required 5 such steps usually was re-imbursed about $100, and a test that required 10 molec-ular steps was likely reimbursed about $200. Medicare(and most other governmental and private payers) re-imbursed for genomic tests in this way because a smallhandful of process-specific codes were the only meansprovided in the federally designated codebook for labo-ratory tests, the Current Procedural Terminology (CPT)manual of the American Medical Association (AMA).3

We are at the edge of a truly unprecedented increase

Regulatory Issues

Fortunately, an entirely new coding systemis being introduced into the US transactionsystem for providers and payers in 2012 and 2013.

in the available codes for genomic tests, and they willsoon be far more specific than in the past. By 2013, theAMA CPT manual will contain well over 100 specificCategory I codes for named genetic tests, and anotherset of 9 codes representing tiers of increasing complexity.These tiers will collectively represent many dozens toeventually hundreds of additional genetic tests, witheach named test assigned to a specific tier by text foundin the AMA manual. During the 2012 calendar year,and perhaps into 2013, Medicare will create tables thatmatch each new code to a price. Medicare policy staffwill laboriously assign a new, administratively specificprice to each of the AMA CPT genetic codes. This ar-ticle provides an orientation on how the laboratory test

coding system for oncologic genetic tests worked upuntil now, how it is changing, and explains some of thepolicy options that Medicare administrators will face in2012 as they apply one or another set of rules to theprice-setting process. The outcome of these delibera-tions is important for the future of personalized medicinein oncology, because price signals carry enormous weightin encouraging or discouraging the supply of new med-ically necessary tests. In addition, the weight of theseimplications carries beyond Medicare beneficiariesalone, since most private payers closely followMedicare’s tables for reimbursement, in lieu of the im-possible task of setting thousands of prices de novo ateach of hundreds of individual US insurers.

The Code Set: How It Was Through 2011The AMA CPT code set in its modern form with 5-

digit classifiers was initially established in 1970 and isupdated annually.4-6 While the Health Insurance Porta-bility and Accountability Act of 1996 is best known for

its privacy and security rules, it also required the US De-partment of Health & Human Services to specify by reg-ulation mandatory public code sets for transactionsbetween healthcare providers and payers. In 2000, reg-ulations finalized by the Centers for Medicare & Medi-caid Services (CMS) endorsed and locked in the AMACPT code set, the obligatory code set for most outpa-tient transactions such as physician and laboratory services.7

The CPT established the first molecular test processcodes in 1993. By 1997, there were still only 6 molecularprocess codes (such as 83890, molecular diagnostics: iso-lation or extraction) to convey the provision of genetictests to insurers.8 By 2010, despite enormous advancesin genomic technologies and the widespread use of ge-netic and genomic tests, the AMA CPT handbook stillprovided only 20 codes, each reflecting one or anothersingle generic process used at the laboratory bench (insome cases today, in electronic DNA test cartridges)during the workflow of genomic testing. There was in-creasing pressure from payers to provide a more compre-hensive and rational code that would correspond to theactual test being performed – for example, a KRAS ge-netic test for a lung cancer patient, a BRCA genetic testfor a woman at high risk of breast cancer.

The Code Set: How It Will Be in2012/2013The multidisciplinary AMA editorial panel that ap-

proves the entry of new codes into the CPT manualmeets 3 times a year, approving codes to be published inthe following year. Under the auspices of the editorialpanel, a workgroup was convened by the College ofAmerican Pathologists and the Association of Molecu-lar Pathologists. Over a 2-year period, the workgroupvetted the wording of over 100 new molecular CPTcodes, passing them on in groups of several dozen codesto be approved by the AMA editorial committee.9 Earlyon, the workgroup determined that there would be ap-proximately 100 gene-specific codes, representing genesthat were either tests for germline mutations or for so-matic mutations (eg, cancer).10 After those codes were

Regulatory Issues

The AMA CPT code set in its modern form with 5-digit classifiers wasinitially established in 1970 and isupdated annually.



established, the workgroup created another level of 9CPT codes that represent levels of complexity for mo-lecular tests and a list of multiple-named genes eligibleto be represented by that code. In the future, highly val-idated and relatively popular tests may be assigned newspecific CPT codes, and new but less common genetictests will be assigned in groups to the 9 levels of the Tier2 molecular codes. The new codes occupy 9 full pagesof the 2012 edition of the AMA CPT handbook.3

A Pricing Policy Dilemma BlocksMedicare’s Use of New CPT CodesFor policy purposes, Medicare has long divided labo-

ratory tests into 2 broad groups: laboratory tests that areviewed as physician pathology services, and clinical lab-oratory tests. Like MRI or PET scans, physician pathol-ogy services require a licensed physician to interpretthem and issue a report. Medicare must distinguish be-tween personal services of a physician (a Part B service)and services of an institution (eg, the technical compo-nent of a PET scan) in order to enforce longstandingdistinctions between Part A (institutional) and Part B(physician) services. Usually the choice to categorize alaboratory test as a physician pathology test and a clin-ical laboratory test is unequivocal: for example, only aphysician can sign out the intraoperative frozen sectionof a suspected tumor mass, while a thyroid hormone testin a blood sample is a benchtop laboratory service re-quiring the expertise of a technologist and a laboratorydirector (who may be a PhD or MD). However, as inmost matters when a bureaucracy becomes involved, afew decades ago Medicare found it had to write specificregulations to enforce this seemingly commonsensicalconcept. In 1980, during the Carter administration,Medicare issued a federal policy notice sharply limitingwhat services would be payable to a physician patholo-gist, resulting in a lawsuit against the US Departmentof Health & Human Services by the College of Ameri-can Pathologists. In 1982, during the Reagan adminis-tration, Congress passed a new law that gave Medicareline item statutory authority to determine what was, andwas not, payable as the services of a physician. The re-

sulting regulations survived a court challenge in 1983and are largely unchanged today. Medicare specified asa general rule that services payable to a physician (anyphysician) must be usually provided by physicians, fol-lowed by a more specific rule singular to pathologists:laboratory tests payable to a pathologist must be eithersurgical pathology services or specific cytology andhematology services determined to “require” a physician(such as the frozen section of a tumor mass notedabove). Medicare also allowed payment for a consulta-tion between a pathologist and a clinician in narrow cir-cumstances when the consultation is requested inwriting, not as a standing order, and required that sucha consultation be based on a test report outside the ex-pected range for the patient’s condition.

These 20-year-old regulations unexpectedly took ona new life in 2011 following activities at the AMA. Al-though the “stacking codes” for molecular tests had beenclassified since their initiation as clinical laboratory tests(ie, as a type of clinical chemistry test), the AMA’s newgenetic codes were taken for review by the AMA Rela-tive Value Update Committee, which exists to evaluateand value services paid on the Physician Fee Schedule,such as personal services of physician pathologists. Rel-ative value units were assigned to the codes, as they wereassigned to other new physician services, such as surger-ies, and the results were forwarded for the review andapproval of CMS. Faced with a dilemma of whether toevaluate the new genomic codes on the Clinical Labo-ratory Fee Schedule or on the Physician Fee Schedule –2 entirely different pricing processes with different rules– CMS announced on November 25, 2011, that it hadassigned the new genetic CPT codes to neither fee

Regulatory Issues

Highly validated and relatively populartests may be assigned new specific CPTcodes, and new but less commongenetic tests will be assigned in groups tothe 9 levels of the Tier 2 molecular codes.

schedule and would not use the codes at all in calendaryear 2012.11 In a response letter, the College of Ameri-can Pathologists criticized this decision (it was “aston-ished”) and urged CMS to use the codes, and to usethem under the valuation processes and rules of thePhysician Fee Schedule by classifying genetic tests as thepersonal service of a physician.12 In short, this requestwould have moved hundreds of millions of dollars worthof genetic tests from the ledgers of the Clinical Labora-tory Fee Schedule (and its associated policies) to thePhysician Fee Schedule.

What Will Happen in 2012?CMS shunts new CPT codes for laboratory tests into

1 of 2 different pathways for pricing. Most new labora-tory tests are of the clinical chemistry type, not pathol-ogist services. These tests follow regulations that requireannouncement of the new clinical laboratory codes inJuly, solicitation of public comments as to how theyshould be priced, and publication of the final agencyprices around December 1, effective for the upcoming

calendar year. CMS may assign prices for clinical chem-istry tests by “crosswalking” the codes to the price or sumof prices of existing (prior) codes, or may “gapfill” theprices by asking its claims processing contractors to as-sign prices in the first half of the coming year, fromwhich it calculates median prices for national use.Alternatively, CMS can treat the new laboratory test

as a physician pathology service, in which case it pub-lishes provisional values from the Relative Value UpdateCommittee for the professional interpretation compo-nent of the test and for the technical component of thetest in June. (The professional component is payable tothe physician even in cases, like that of a hospital inpa-

tient, where the technical component is bundled to aDiagnosis-Related Group and is not paid separately.)The assignment to a fee schedule has other policy im-plications. For example, as with other physician services,a 20% copayment is applied to physician pathologytests, whereas currently Medicare policy requires no co-payment for clinical laboratory tests. Medicare takescomments on these Physician Fee Schedule paymentvalues over the summer and publishes final prices for thecoming fiscal year about November 1. In some cases, theprices appear for the first time on November 1.While the outcome of Medicare’s policy decision will

play out in the rest of 2012 and may carry into 2013, itseems likely that the new genetic codes will end up onMedicare’s Clinical Laboratory Fee Schedule. This is be-cause of Medicare’s own regulations: Medicare wrote itsown rules that determined that services payable to apathologist must either be surgical pathology services or“require” a physician, and most genomic laboratory testsare signed out by PhD-holding lab professionals. There-fore, simply put, the tests do not meet the current legalbar of “requiring” a physician. However, the resolutionof the fee schedule question depends on Medicare pub-licly announcing provisional decisions, taking pub -lic comments, and then coming to a final decision. Arguments for assignment to the Physician Fee Sched-ule include the position that it is a “cost-saving methodology”12 and will result in copayment require-ments for patients, which could be a deterrent to testutilization.

Assessment of the New GenomicCodesThere is no question that the 100-plus new genomic

codes are a great improvement in precision over theprocess codes that bluntly described processes like DNAamplification and gave no clue to what gene was beingtested. However, the CPT coding system is not designedfor rapid change, and the advances in genomic testingare already rapidly accelerating. It is likely that at leastfor some specialized applications such as tumor exomeanalysis, techniques based on next-generation sequenc-

Regulatory Issues

Of some concern is the decision of AMA policy staff to include most futuregenomic tests in “bucket-like” categoriesof only a few codes...



ing will become a practical clinical methodology withinthe next few years, but the coding system for 2013 is al-ready set and makes no allowance for high-throughputsequencing approaches. To date, there have been noCPT codes for gene-expression algorithm–based tests,which are well accepted in US oncology practice forbreast cancer prognosis and clinical decision making.The AMA CPT editorial panel has proposed a newgroup of codes, called Multi-Analyte Assays with Algo-rithms (MAAAs), which will appear in the AMA CPTmanual for 2013. It may take a year or longer for theMedicare program to adopt these codes, but they will facilitate tracking the usage and utility of the tests inclinical practice.Of some concern is the decision of AMA policy staff

to include most future genomic tests in “bucket-like”categories of only a few codes, which are being calledTier 2 genomic codes. In this arm of the coding system,a dozen or potentially a hundred or more unique ge-nomic tests could be represented by only 1 code. Thiswould imply that it would be difficult for payers to pricediscriminate among tests represented by the same codeand impossible to differentiate coverage policies amongtests that are presented by Tier 2 codes.An additional concern voiced by some stakeholders

is that payers may want to know if a laboratory test isFDA-approved or not. The FDA has stated in guidancedocuments that it will, in general, only approve new in-dications of targeted drugs that require a genetic test ifthere is a corresponding and FDA-approved brand of thetest. However, the FDA generally cannot enforce whattest is used by clinicians and laboratorians. Payers willbe concerned whether the test being used for the pa-tient, and for which they are being billed, is appropri-ately validated. A fully validated and controlled testthat is sensitive and accurate could certainly be a labo-

ratory-developed test. However, there is no way for thelaboratory to signal the quality of its test nor for thepayer to cover a test it views as adequately validated. Itmay turn out that a coding system more granular thanthe CPT coding system can provide will be required.There are currently several efforts under way to developsuch alternative systems, one of the most advancedbeing a coding system for molecular tests developed byMcKesson, Inc and currently used by 1 Medicare con-tractor and being discussed in the trade press.13 Howquickly this system, or a similar highly granular system,could take its place in the coding and payment processremains to be seen. u

References1.Newcomer LN. Changing physician incentives for cancer care to rewardbetter patient outcomes instead of use of more costly drugs. Health Aff(Millwood). 2012;31:780-785.2. Landrum MB, Keating NL, Lamont EB, et al. Survival of older patientswith cancer in the Veterans Health Administration versus fee-for-serviceMedicare. J Clin Oncol. 2012;30:1072-1079.3. American Medical Association. Current Procedural Terminology – cpt.Chicago, IL: American Medical Association Press; 2012.4. Isetts BJ, Buffington DE; Pharmacist Services Technical Advisory Coali-tion. CPT code-change proposal: national data on pharmacists medicationtherapy management services. J Amer Pharm Assoc. 2007;47:491-495.5. CPTcodingbooks.com. CPT-4 code process – how a code becomes acode. www.cptcodingbooks.com/codes/information.html. Accessed April13, 2012.6. Department of Health & Human Services. www.ncvhs.hhs.gov/97041614.htm. Accessed April 13, 2012.7. 45 CFR 160, 162.8. Root CB. Medicare coding and reimbursement for clinical laboratoryservices. Clin Chem. 1998;44(8 Pt 1):1713-1727.9. Paxton A. Molecular CPT codes topple old ‘stacking’ codes. CAP Today.April 2011.10. Association for Molecular Pathology. http://amp.org/committees/economics/AMPCPTReformProposal_Final.pdf. November 2009. AccessedApril 13, 2012.11. Centers for Medicare & Medicaid Services. Medicare program; pay-ment policies under the physician fee schedule, five-year review of workrelative value units, clinical laboratory fee schedule: signature on requisi-tion, and other revisions to part B for CY 2012. Final rule with commentperiod. Fed Regist. 2011;76:73026-73474.12. College of American Pathologists. www.cap.org/apps/docs/statline/pdf/cms_payment_policies.pdf. December 21, 2011. Accessed April 13,2012.13. Ashford M. Harvard Pilgrim, Trustmark join other payors consideringoutsourcing MDx claims to specialty vendors. Genomeweb. Pharmacoge-nomics Reporter. www.genomeweb.com/mdx/harvard-pilgrim-trustmark-join-other-payors-considering-outsourcing-mdx-claims-s. April 18, 2012.

Regulatory Issues

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Pushing Your Limits

COEAsize30211CE©iStockphoto.com/altaykaya


Melanoma

Ipilimumab, a monoclonal anti-body that blocks the negativecostimulatory molecule CTLA-4on T cells, leading to augmented

T-cell activation and proliferation, im-proves overall survival (OS) in pa-tients with metastatic melanoma andwas approved by the regulatory agen-cies in the United States and severalother countries for the treatment of un-resectable melanoma. Consistent withits mechanism of action, the drug’s tox-icities are mainly manifestations of

organ-specific inflammation primarilyaffecting the skin, gastrointestinaltract, liver, and endocrine system.Rarely do these effects lead to seriouscomplications such as bowel perfora-tion and adrenal insufficiency. As ipi -limumab is moved from clinical trialsinto broader use by general medical on-cologists, it is critical that the clinicianhas comprehensive knowledge of thefull spectrum of these immune-relatedadverse events (irAEs; also called ad-verse events of special interest), in

Management of Ipilimumab-Related ToxicitiesPatrick A. Ott, MD, PhDDana-Farber Cancer Institute, Boston, Massachusetts

Howard L. Kaufman, MD, FACSRush University Medical Center, Chicago, Illinois

F. Stephen Hodi, MDDana-Farber Cancer Institute, Boston, Massachusetts

Dr Ott is a member of the Melanoma Disease Center at Dana-Farber Cancer Institute and Assistant Professor of Medicine atHarvard Medical School. He specializes in the treatment of melanoma and has a research interest in immunotherapy.Dr Kaufman is Director of the Rush University Cancer Center, Associate Dean of the Rush Medical College, and Professorof Surgery and Immunology & Microbiology at the Rush University Medical Center. His primary research interests are inmelanoma and tumor immunotherapy.Dr Hodi is Director of the Melanoma Disease Center at Dana-Farber Cancer Institute and Associate Professor of Medicine atHarvard Medical School. His professional interests are in gene therapy for cancer, melanoma, and tumor immunology.

Howard L. Kaufman, MD, FACS

Key Points

• The clinical efficacy of ipilimumab in patients with metastatic melanoma has been demonstrated in 2 phase 3trials, leading to approval of the drug given at 3 mg/kg every 3 weeks for 4 doses

• During the extensive clinical development program, a clear picture of the unique immune-related toxicity profileof this drug emerged

• The toxicities of ipilimumab are mainly manifestations of organ-specific inflammation primarily affecting theskin, gastrointestinal tract, liver, and endocrine system

• Diarrhea and rash, the most common side effects in patients treated with ipilimumab, are easily recognized andshould be managed as autoimmune enteritis/dermatitis irAEs while ruling out other etiologies

order to develop an individualized approach to theirmanagement. Physicians should maintain a high levelof awareness for signs of symptoms of these toxicities andbe prepared to intervene early and effectively whenappropriate.

CTLA-4 Is an Important Immune-Regulatory Molecule in T-CellActivationActive immunotherapy targeted at T cells relies on

the presentation or cross-presentation of antigens bytumor or antigen-presenting cells and on the inductionof T effector cells that are specific to these antigens,long-lived, and capable of killing tumor cells. T-cell ac-tivation requires 2 signals. The first signal constitutes

the binding of the T-cell receptor (TCR) to a tumorpeptide presented by the major histocompatibility com-plex (MHC). For full T-cell activation, this TCR-MHC-peptide interaction must be accompanied by a secondsignal, which is mediated by the binding of CD28 on Tcells to the costimulatory molecules CD80 and CD86(both members of the B7 protein family) on the surfaceof an antigen-presenting cell.1-3 T-cell stimulation resultsin the proliferation of T cells and initiates effector func-tions such as cytokine secretion and the release ofgranzyme B and perforin needed for cell killing. T-cellactivation also leads to up-regulation of the CD28 ho-molog CTLA-4 (a member of the immunoglobulin su-perfamily), which has a much higher binding affinitythan CD28 to B7, leading to T-cell inhibition. This in-terplay of positive and negative immune regulation onthe surfaces of T cells and antigen-presenting cells is atightly controlled, temporally restricted, and dynamicprocess aimed at containing a potentially hazardous T-cell response.4 The significance of CTLA-4 as an in-

hibitory molecule is illustrated by the association withautoimmune disease, as evidenced by an increased riskof autoimmunity in patients with single nucleotideCTLA-4 polymorphisms and massive lymphoprolifera-tion in mice lacking CTLA-4 function.5-7 Other inhibitorymolecules, such as programmed death (PD) molecules,are expressed on the surface of T cells and contribute tothis intrinsic control of T-cell activation; PD-1 is also atarget in clinical development.

Targeting CTLA-4 With Ipilimumab IsEffective in Patients With AdvancedMelanomaBlockade of CTLA-4 with the fully human mono-

clonal antibody (IgG1κ) ipilimumab impedes its bind-ing to B7 and thereby enhances T-cell responses. Theclinical efficacy of ipilimumab in patients with meta -static melanoma was initially demonstrated in a seriesof phase 2 studies in which the drug was given at 10mg/kg every 3 weeks for 4 doses, followed by mainte-nance therapy with infusions every 3 months.8,9 In 1study, 2 additional dose cohorts received ipilimumab ateither 0.3 or 3 mg/kg, respectively.10 These efficacy datawere confirmed in 2 phase 3 trials that revealed a sur-vival benefit. The first study was a randomized, double-blind trial in which 676 patients were enrolled on 3 armsat a 3:1:1 ratio: 1) ipilimumab at 3 mg/kg in combina-tion with an HLA-A2–restricted gp100 peptide vac-cine, 2) ipilimumab at 3 mg/kg and placebo, and 3)gp100 peptide vaccine combined with placebo.11 Pa-tients with clinical benefit defined as stable disease of≥3 months’ duration or an objective response (partialresponse or complete response) were eligible for addi-tional reinduction doses of the same regimen they pre-viously received. Ipilimumab with or without the gp100peptide vaccine led to an improvement in OS, with a32% to 34% risk reduction of death (hazard ratios [HRs]of 0.68 and 0.66, respectively) compared with gp100and placebo. The median OS was 10.1 months for ipi -limumab and placebo and 10.0 months for ipilimumaband gp100, compared with 6.4 months for gp100 andplacebo (P<.001 and P=.003, respectively). The lack of

Melanoma

Blockade of CTLA-4 with the fully humanmonoclonal antibody (IgG1κ) ipilimumabimpedes its binding to B7 and therebyenhances T-cell responses.



an OS difference between the ipilimumab arms suggeststhat the OS benefit is driven by ipilimumab alone.There is a subset of patients who apparently have a pro-longed and durable survival benefit of treatment. Theencouraging 2-year survival rate of 23.5% in this pre-treated population with a high proportion of poor-risk

prognostic criteria such as elevated lactate dehydroge-nase, M1c disease, and brain metastases is consistentwith data from prior phase 2 studies. The results fromthis trial led to approval of ipilimumab by the FDA forpatients with unresectable stage III or stage IVmelanoma. Similar findings were reported when ipi -

Melanoma

Phase 2

Wolchok et al10 O’Day et al8 Weber et al9

Ipilimumab 3 mg/kg Ipilimumab 10 mg/kg Ipilimumab 10 mg/kg Ipilimumab 10(n=71) (n=71) (n=155) mg/kg (n=57)

Total Grade 3-4 Total Grade 3-4 Total Grade 3-4 Total Grade 3-4Dermatologic 32 (45.1) 1 (1.4) 33 (42.3) 3 (4.2) 76 (49.0) 5 (3.2) 39 (68) 0Gastrointestinal 23 (32.4) 2 (2.8) 28 (39.4) 11 (15.5) 48 (31.0) 13 (8.4) 26 (46) 13 (22.8)Endocrine 4 (5.6) 2 (2.8) 3 (4.2) 1 (1.4) 9 (5.8) 2 (1.3) 6 (11) 3 (5)Hepatic 0 0 2 (2.8) 2 (2.8) 14 (9.0) 11 (7.1) 8 (14) 7 (12.3)

Phase 3

Hodi et al11 Robert et al12

Ipilimumab 3 mg/kg Ipilimumab 10 mg/kg+ gp100 + dacarbazine(n=380) (n=247)

Total Grade 3-4 Total Grade 3-4

Dermatologic 152 (40.0) 9 (2.4)Rash 67 (17.6) 5 (1.3) 55 (22.3) 3 (1.2)Pruritus 67 (17.6) 1 (0.3) 66 (26.7) 5 (2.0)

Gastrointestinal 122 (32.1) 22 (5.8)Diarrhea 115 (30.3) 14 (3.7) 81 (32.8) 10 (4.0)Colitis 20 (5.3) 12 (3.2) 11 (4.5) 4 (2.0)

Endocrine 15 (3.9) 4 (1.1)Hypothyroidism 6 (1.6) 1 (0.3)Hypopituitarism 3 (0.8) 2 (0.5)Hypophysitis 2 (0.5) 2 (0.5)Adrenal 3 (0.8) 2 (0.5)insufficiency

HepaticElevated AST 72 (29.1) 51 (20.6)Elevated ALT 66 (26.7) 43 (17.4)Hepatitis 4 (1.6) 3 (1.2)

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; irAE, immune-related adverse event.

Table 1. irAE Profile of Metastatic Melanoma Patients Treated With Ipilimumab in Phase 2 and 3 Trials

l imumab was given in the first-line setting. In a random-ized phase 3 trial, patients with previously untreatedmetastatic melanoma received ipilimumab 10 mg/kgevery 3 weeks for 4 doses plus dacarbazine or dacarbazinealone.12 Patients with an objective response or stable dis-ease and no dose-limiting adverse events received main-tenance treatment with ipilimumab or placebo every 3months. A significantly improved OS of 11.2 monthswith ipilimumab and dacarbazine over 9.1 months withdacarbazine alone was seen in this study. The HR fordeath with ipilimumab-dacarbazine treatment was 0.72(P<.001).

The toxicity profiles in the 2 phase 3 clinical trialswere different, with more gastrointestinal toxicity in thetrial using ipilimumab versus gp100 versus the combi-nation of both, and a higher rate of hepatic toxicity inthe ipilimumab-dacarbazine versus dacarbazine trial.10

The reasons for this shift are not clear but may be relatedto better recognition and management of immune-related diarrhea and colitis in the former trial and theuse of dacarbazine, which may also result in hepatic tox-icity, in the latter trial. These observations highlight thecomplexity of responses to ipilimumab and suggest thatcareful attention to each patient, their underlying med-ical comorbidities, and concurrent and previous treat-ment history is important for monitoring and managingcomplications from therapy.

Immune-Related Adverse EventsCTLA-4 blockade can break peripheral T-cell toler-

ance to self-antigens, which is an expected effect thatwas recognized early in the development of monoclonalantibodies specific for CTLA-4 in preclinical and initialclinical studies. Mice with B16 melanoma treated witha combination of anti–CTLA-4 antibody and a granu-

locyte-macrophage colony-stimulating factor–producingtumor cell vaccine developed autoimmune skin depig-mentation characterized by polymorphonuclear cells in-filtrating the dermis.13 Early clinical phase 1 and 2studies using ipilimumab consistently demonstrated autoimmune manifestations such as dermatitis, rash, vitiligo, enterocolitis, hepatitis, and hypophysitis.14-16

Rare autoimmune events such as Guillain-Barré–likesyndrome, myasthenia gravis, lupus nephritis, sarcoido-sis, and myositis/arthritis have also been reported aftertreatment with ipilimumab.17,18

Because of their distinct immunologic characteristics,these manifestations are referred to as irAEs. There issome correlation between ipilimumab dosing and theseverity and frequency of irAEs. This observation wasapparent in several of the earlier phase 1 and 2 trials andhas been the clinical experience of many investigatorsinvolved early in the clinical development of thedrug.10,19,20 Consistent with these observations, in the 2phase 3 trials discussed above, total irAEs were more fre-quent in the study in which ipilimumab was used at 10mg/kg in combination with dacarbazine compared withthe trial in which it was given without chemotherapy at3 mg/kg. However, the difference in total frequency ofirAEs was mainly driven by a hepatotoxicity rate of upto 30% of the patients treated with ipilimumab at 10mg/kg plus dacarbazine (Table 1). In contrast, hepato-toxicity was not reported in another phase 3 trial inwhich ipilimumab was given at 3 mg/kg. Moreover, noendocrinopathies were reported with ipilimumab at 10mg/kg in the phase 3 setting, which is somewhat unex-pected based on the phase 2 experience, in which en-docrinopathies consistently occurred across studies at arate of 4% to 11% (Table 1).8-10 The rates of high-grade(3/4) rash, colitis, and diarrhea were similar in the 2phase 3 trials despite their use of ipilimumab at differentdoses.11,12

The majority of irAEs occur during the 12-week in-duction period with ipilimumab. Fewer than 10% oflong-term survivors experienced a new irAE that man-ifested ≥10 weeks after ipilimumab, and all but 1 eventwere low grade.11 Skin and gastrointestinal events are

Melanoma

There is some controversy as to whetherthere is a correlation between the immune-related adverse events and theclinical activity of ipilimumab.



the most common irAEs and most commonly appearearlier after treatment initiation than endocrine eventsor hepatotoxicity. Most irAEs are low grade, can betreated symptomatically, and do not lead to dose delaysor reductions. Fifteen percent to 40% are high-gradeevents that require immediate treatment with highdoses of corticosteroids. In rare instances, irAEs are re-fractory to corticosteroid treatment; other immunosup-pressive agents, such as infliximab or mycophenolatemofetil, have been used successfully in this situation(Table 2).There is some controversy as to whether there is a

correlation between the irAEs and the clinical activityof ipilimumab. Early clinical studies seemed to supportthat notion,14,21-24 however, in a meta-analysis of 3 phase2 trials it was shown that patients with advancedmelanoma can achieve a clinical benefit with ipi -limumab treatment in the absence of irAEs.25,26

DermatitisRash and pruritus are the most frequent irAEs asso-

ciated with ipilimumab, occurring in 40% to 50% of pa-tients. The vast majority of events are low grade and aretreated symptomatically, eg, with antihistamines, whilethe patient remains on therapy. However, skin manifes-tations that persist for 1 to 2 weeks should be treatedwith topical or moderate doses of systemic cortico -steroids (eg, prednisone once daily). Severe rash or pru-ritus needs to be evaluated by a dermatologist, and abiopsy should be performed if appropriate; ipilimumabtreatment must be delayed. Toxic epidermal necrolysisresulting in death has been reported in a patient treatedwith ipilimumab.11 High-dose corticosteroids (eg,methylprednisolone 2 mg/kg once or twice per day) arerequired for persistent severe skin toxicity and shouldbe tapered over a period of at least 4 to 6 weeks oncethe rash or pruritus has been controlled. For grade 3 skinevents that have improved to grade ≤1, reinitiation ofipilimumab can be considered. For grade 4 toxicity,treatment must be discontinued indefinitely. In compli-cated cases, early consultation with a dermatologistshould be considered.

Gastrointestinal ToxicityGastrointestinal irAEs occur most commonly in the

lower gastrointestinal tract, with diarrhea being the hall-mark symptom. Abdominal pain, nausea and vomiting,anal/rectal pain, hematochezia, and fever have also beenreported. Upper gastrointestinal involvement manifestsas esophagitis and/or duodenitis. Endoscopically, thecolonic mucosa appears erythematous and ulcerated;lymphocytic and/or leukocytic infiltration on histologicexamination confirms an etiology of immune-mediatedenterocolitis in most cases.24 Ipilimumab-induced ente-

rocolitis can lead to intestinal perforation and death,particularly when therapeutic intervention with high-dose corticosteroids is delayed. In the phase 3 trials, all-grade diarrhea and colitis were seen in approximately35% of patients; high grades of diarrhea and colitis werereported in 6% to 10% of patients treated with ipi -limumab at 3 mg/kg and in 6% of patients treated with10 mg/kg. In 1 trial directly comparing different dosesof ipilimumab, there was a suggestion of a dose effect(15.1% gastrointestinal irAEs with 10 mg/kg, 4.2% with3 mg/kg, and none with 0.3 mg/kg).10 In the phase 2 ex-perience, with most patients receiving 10 mg/kg, grade3 and 4 gastrointestinal irAEs were seen in 8.4% to 23%of patients.8-10 Most cases of grade 1 and 2 diarrhea re-spond to symptomatic treatment with loperamide if ini-tiated early, preferably on the first day of occurrence. Itis critical that all patients who will receive ipilimumabare educated about the importance of this potentiallylife-threatening adverse event, and that symptoms arecommunicated to the clinician promptly and reliably.Ipilimumab can be continued for grade 1 diarrhea; ifgrade 2 improves to grade ≤1, ipilimumab should also becontinued. Other etiologies for diarrhea need to be ruled

Melanoma

High-dose corticosteroids are required forpersistent severe skin toxicity and should betapered over a period of at least 4 to 6weeks once the rash or pruritus has been controlled.

out and treated appropriately while continuing treat-ment. Endoscopy should be considered in all patientswith grade 3 or 4 diarrhea in addition to stool studies(WBC, calprotectin); if colitis is likely or confirmed by

endoscopy, high-dose IV corticosteroids followed by a4- to 6-week steroid taper need to be administered.Most high-grade gastrointestinal events respond to

corticosteroid therapy. In the phase 3 setting, the me-

Melanoma

Organ system Symptoms/Signs Diagnosis

Gastrointestinal Diarrhea, colitis: abdominal pain, nausea and • History • Colonoscopy • Rule vomiting, anal/rectal pain, hematochezia, fever out non-irAE–related etiologies

(stool WBC, culture, calprotectin)

Dermatitis Rash/pruritus • History • Dermatologic examination • Consider evaluation by a dermatologist/ skin biopsy for severe cases

Neuropathy Weakness, sensory loss, paresthesias, gait abnormality • History • Rule out non-irAE–related etiologies • Comprehensive neurologic exam • Neurology consult • EMG, nerve conduction studies

Endocrinopathy Nonspecific symptoms: headache, behavioral changes, • History • Serum levels for: TSH, fatigue, weakness, lethargy, constipation, decreased free T4, T3, ACTH, morning cortisol, libido, impotence, amenorrhea, hypotension, LH, FSH, testosterone, prolactin hypoglycemia, hyponatremia • MRI brain scan with pituitary cuts

• Thyroid imaging/functional testing, if appropriate • Rule out other etiologies

Hepatotoxicity Most often asymptomatic. Elevated transaminases • Baseline LFT • Hepatitis serologies and/or bilirubin • ANA, ASMA • Liver imaging

• Consider liver biopsy • Consider hepatology consult early

ACTH indicates adrenocorticotropic hormone; ANA, antibodies to nuclei; ASMA, antibodies to smooth muscle; EMG, luteinizing hormone; PE, physical examination; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone;

Table 2. Diagnosis and Management of irAEs Related to Treatment With Ipilimumab



dian time to resolution of grade 2-4 diarrhea was approx-imately 2 weeks.11 If no improvement is seen after 5 to7 days of moderate to severe diarrhea, the anti–TNF-αantibody infliximab at a dose of 5 mg/kg is indicated and

can be repeated after 2 weeks if no response is seen. Ifthe diarrhea is refractory to IV steroids and infliximab,a diverting ileostomy and/or partial or complete colec-tomy should be considered. Ipilimumab therapy must be

Melanoma

Management

Grade 1 Grade 2 Grade 3/4

• Symptomatic treatment (loperamide, • Symptomatic treatment • High-dose corticosteroids • IV fluids bismuth subsalicylate) (loperamide, bismuth subsalicylate) • Consider hospitalization and IV

• Continue ipilimumab • Hold ipilimumab administration of steroids • Infliximab • If no resolution to grade 1 within if no response to steroids after 5-7 days3-4 days, treat as grade 3/4 • Discontinue ipilimumab permanently

• Antihistamines, topical steroids, • Antihistamines, topical steroids, • High-dose corticosteroids • Hold moisturizing lotion moisturizing lotion ipilimumab • Permanently discontinue • Continue ipilimumab • Consider holding next dose until ipilimumab for grade 4 • Consider

resolution to grade 1 reinitiation for grade 3 resolved to grade 1

• Continue ipilimumab • Hold ipilimumab if related Sensory neuropathy: • Discontinue ipilimumab if related

Motor neuropathy: • Discontinue ipilimumab for motor

neuropathy regardless of etiology • If progressive symptoms, consider hospitalization and start high-dose corti-costeroids (both motor and sensory)

If strong suspicion for adrenal crisis: • Hospitalization • Administer stress-dose corticosteroids (with mineralocorticoid activity)

• IV fluids If no adrenal crisis suspected: • Await endocrine labs prior to initiation of corticosteroids

• Endocrinology consult• Hormone replacement as needed and guided by endocrinologist• Consider pulse corticosteroid treatment

LFT and/or total bilirubin grade ≥2 or ≥2x baseline: LFT ≥8x ULN and/or total bilirubin ≥5x ULN: • Hold ipilimumab • Hold ipilimumab

• Intensify monitoring (LFT q3 days) • Intensify monitoring (daily LFT) • Consider hospitalization

• High-dose corticosteroids• Mycophenolate mofetil, tacrolimus, or infliximab if no response to steroids

electromyogram; FSH, follicle-stimulating hormone; irAE, immune-related adverse event; LFT, liver function test; LH, ULN, upper limit of normal.

permanently discontinued in patients with high-gradegastrointestinal toxicity. There is some evidence thatthe implementation of treatment guidelines for themanagement of gastrointestinal irAEs has resulted in de-creased incidence in the rates of bowel perforation andthe need for colectomy.27 Prophylactic treatment withbudesonide does not appear to reduce the colitis rate, asdocumented in a randomized phase 2 trial.9

Although much less common, pancreatitis has alsobeen reported after treatment with ipilimumab. Themanagement consists of supportive care, early initiationof systemic corticosteroids, and close observation. Asearch for other causes should be considered in patientswho do not respond quickly to steroids.

HepatotoxicityImmune-mediated hepatitis usually manifests as

asymptomatic elevation in liver function tests (LFTs).Histologically, acute hepatic inflammation with bal-looning degeneration of hepatocytes and predominantlylymphocytic infiltration has been reported.14 In thephase 2 trials, liver toxicity (all grades) occurred in 7%to 14% of patients who were treated with ipilimumab at10 mg/kg. In the phase 3 setting, hepatotoxicity was re-ported in 4.5% of patients treated with ipilimumabmonotherapy or ipilimumab plus gp100,11 whereas al-most one-third of patients experienced immune-medi-ated hepatitis in the phase 3 trial in which ipilimumabwas given at 10 mg/kg in combination with dacar-bazine.12 The markedly higher incidence of hepatotox-icity when ipilimumab is given concurrently withdacarbazine highlights the importance of careful exam-ination of its toxicity profile when given concurrentlywith other agents. LFTs elevated to grade ≥2 (≥2.5 theupper limit of normal [ULN]) or ≥2x above grade 1/2

elevated baseline values in a patient on ipilimumabshould prompt closer monitoring with LFTs (at leastevery 3 days). A viral or idiopathic autoimmune hepa-titis should be ruled out by serologic testing for hepatitisantibodies/antigens and antibodies to nuclei and smoothmuscle. Furthermore, imaging should be performed torule out metastases, and a liver biopsy should be consid-ered. Ipilimumab must be held until LFTs have returnedto normal or baseline values.If LFTs rise to ≥8x ULN or bilirubin to ≥5x ULN,

ipilimumab should be held. Hospitalization should beconsidered for close monitoring of hepatic function,consideration of liver biopsy to confirm diagnosis, andhigh-dose corticosteroids be administered, starting at 2mg/kg of methylprednisolone daily. In the hospital, liverfunction must be monitored daily until stabilization ordecrease of LFT, and subsequently at least every 3 daysfor a minimum of 2 weeks post-LFT peak. For immunehepatitis refractory to corticosteroids, other immuno-suppressive agents such as mycophenolate mofetil,tacrolimus, or infliximab have shown efficacy in the ap-propriate setting in conjunction with supportive man-agement such as prophylaxis for opportunisticinfections.25 Early consultation with a gastroenterologistor hepatologist may also be useful.

EndocrinopathiesNonspecific symptoms such as fatigue, myalgia,

headaches, visual disturbances, decreased libido, weak-ness, asthenia, anorexia, and constipation should raisethe suspicion for an endocrinopathy of the thyroid, pi-tuitary gland, or adrenal gland in any patient treatedwith ipilimumab. Endocrinopathies were reported in 4%to 11% (all grades) and 1% to 5% (grades 3/4) of pa-tients treated in phase 2 trials with ipilimumab given at10 mg/kg. At 3 mg/kg dosing of ipilimumab alone or incombination with gp100 in the phase 3 setting, 4% to7% of patients experienced hypothyroidism, hypopitu-itarism, hypophysitis, or rarely adrenal insufficiency.Somewhat surprisingly, no cases of hypophysitis were re-ported with ipilimumab plus dacarbazine in a phase 3trial.12 Endocrine toxicity is generally diagnosed at a me-

Melanoma

In the phase 2 trials, liver toxicity(all grades) occurred in 7% to 14% of patients who were treated withipilimumab at 10 mg/kg.



dian of 10 weeks after treatment initiation, which islater than most dermatologic and gastrointestinal irAEsbecome apparent.Autoimmune hypophysitis in many cases manifests as

enlargement of the hypophysis with thickening of the hy-pophyseal stalk on an MRI scan,28 but it can also be non-apparent on imaging. Histologically, an infiltration withlymphocytes, plasma cells, and macrophages has been de-scribed.29 Radiologic findings may predate the onset ofclinical symptoms.30 Consistent with secondary adrenalinsufficiency, serum cortisol levels are low with inappro-priately low adrenocorticotropic hormone (ACTH) lev-els in addition to low thyroid-stimulating hormone(TSH), free thyroxine (T4), and testosterone. Autoim-mune thyroiditis is another relatively common en-docrinopathy that can manifest as hyperthyroidism as inGraves’ disease or in hypothyroidism as in the immune-mediated destruction of thyroid tissue in Hashimoto’sthyroiditis. Antithyroxin peroxidase antibody and thy-roglobulin antibody, TSH, triiodothyronine (T3), and T4serum levels as well as a thyroid exam, in addition to im-aging and more specific testing as indicated (such as radioiodine-123 thyroid uptake), will delineate the condition and determine whether sub stitution with thy-roxine is necessary. Symptoms of autoimmune hypophysi-tis and thyroiditis can be subtle in the beginning; theclinician therefore needs to maintain a high level of sus-picion in patients on ipilimumab therapy presenting withnonspecific symptoms as described above and have a lowthreshold for checking endocrine labs.If an endocrinopathy is suspected, one should first

determine whether the patient is in adrenal crisis, inwhich case empiric administration of corticosteroidswith mineralocorticoid activity and aggressive IV hy-dration must be started immediately pending biochem-ical confirmation. If the patient is not in adrenal crisis,serum should be tested for TSH, free T4, T3, ACTH,morning serum cortisol, luteinizing hormone, follicle-stimulating hormone, testosterone, and prolactin (priorto initiation of corticosteroids, if required). Early in-volvement of an endocrinologist may be helpful. AnMRI of the brain with pituitary cuts should be obtained,

and the patient should be started on high-dose cortico -steroids and hormone replacement guided by an endocrinologist. The recommended treatment for ipilimumab-induced hypophysitis is a short course ofhigh-dose corticosteroids with subsequent taper, al-though this may not reverse the pituitary dysfunction.Generally, endocrinopathies induced by ipilimumabtend to respond more slowly to steroid therapy com-pared with the much more commonly seen dermatologicand gastrointestinal adverse events. Most patients with

autoimmune hypophysitis require indefinite glucocorti-coid replacement therapy after completion of prolongedsteroid tapering, and some patients require additionalsupport with T4 and testosterone due to persistent sec-ondary adrenal insufficiency. In selected cases, pulsesteroid administration has been advocated to preservepituitary function, although this has not been validated.

NeuropathyPeripheral neuropathy and neuritis have been re-

ported with ipilimumab. In any patient on ipilimumabtherapy who presents with neuropathy, nonimmune-me-diated etiologies such as infection, medications, or meta-bolic derangements should be ruled out. Neurologictesting (electromyogram, nerve conduction studies) inaddition to a comprehensive neurologic exam in closecollaboration with a neurologist will help define the syn-drome, grade the severity, and establish an objectivebaseline from which to judge further evolution of theneuropathy. Ipilimumab should be discontinued forgrade 3/4 drug-related sensory neuropathy and any grade3/4 motor neuropathy. Ipilimumab dosing should beheld for grade 2 drug-related neuropathy. For any grade3 or 4 neuropathy considered to be caused by ipilim -umab or progressing, hospitalization and IV cortico -

Melanoma

The recommended treatment foripilimumab-induced hypophysitis is a shortcourse of high-dose corticosteroids withsubsequent taper.

steroids need to be considered. IV immunoglobulins arean alternative if the neuropathy is refractory to steroids.Although much less common, Guillain-Barré syn-

drome (GBS) and myasthenia gravis have been reportedin patients treated with ipilimumab. One case was re-cently reported of a patient who developed a rapidlyprogressing generalized sensory and motor polyneuropa-thy after the third dose of ipilimumab, with cere-brospinal fluid (CSF) findings consistent with GBS

(elevated protein, IgG, oligoclonal bands, normal glu-cose in the CSF).31 Importantly, high-dose cortico -steroids immediately halted further worsening of thesymptoms and led to complete recovery within 4 weeks.Of note, steroids are considered ineffective in classicGBS. Cases of GBS with fatal outcomes were also reported during the clinical development program of ipilimumab.

UveitisUveitis is a relatively rare irAE and presents, depend-

ing on the affected portion of the uveal tract, as ocularpain, redness, photophobia, and decreased visual acuity.Patients on ipilimumab therapy should be made awareof this possible irAE, and a referral to an ophthalmolo-gist should be made early if symptoms occur. Direct visualization by slit lamp examination reveals inflammation and/or the presence of leukocytes. Initialtreatment consists of topical corticosteroids for anterioruveitis and steroid injections for posterior uveitis, whilesystemic corticosteroids are reserved for the treatmentof resistant cases.

Concluding RemarksBlockade of the T-cell inhibitory molecule CTLA-4

with the monoclonal antibody ipilimumab leads to an

OS benefit in patients with advanced melanoma, witha subset of patients enjoying durable benefit. The drughas been approved by many regulatory agencies, includ-ing those of the United States, Canada, Europe, andAustralia, and is therefore widely available to clinicianstreating advanced melanoma. During the extensiveclinical development program, a clear picture of theunique immune-related toxicity profile of this drugemerged. A key lesson from this experience has beenthat the overwhelming majority of irAEs can be wellmanaged if they are recognized and treated early. Diar-rhea and rash, the most common side effects in patientstreated with ipilimumab, are easily recognized andshould be managed as autoimmune enteritis/dermatitisirAEs while ruling out other etiologies. Other side ef-fects that are less common include hepatotoxicity andperipheral neuropathy. A host of nonspecific signs andsymptoms that can be associated with endocrine toxi-city are missed more easily and therefore require a struc-tured patient assessment approach. Heightenedsuspicion and comprehensive knowledge of the ipi -limumab toxicity profile, including rare events such asuveitis and pancreatitis, should enable clinicians tolargely avoid complications from unrecognized andtherefore untreated autoimmune conditions. In orderto minimize risk and facilitate the transition to thebroader community of general medical oncologists, arisk evaluation and mitigation strategy has been devel-oped by the drug manufacturer, Bristol-Myers Squibb,in collaboration with the FDA and can be accessed atwww.yervoy.com/hcp/ rems.aspx.Ipilimumab is an exciting novel treatment option for

patients with advanced melanoma, representing a newclass of oncology drugs, that can be given safely by on-cologists who are familiar with the full spectrum of irAEsand diligent in the monitoring and appropriate treat-ment of these toxicities. u

References1. June CH, Ledbetter JA, Linsley PS, et al. Role of the CD28 receptor inT-cell activation. Immunol Today. 1990;11:211-216.2. Ledbetter JA, Imboden JB, Schieven GL, et al. CD28 ligation in T-cellactivation: evidence for two signal transduction pathways. Blood.1990;75:1531-1539.

Melanoma

The drug has been approved by manyregulatory agencies, including thoseof the United States, Canada, Europe,and Australia.



3. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol.2002;2:116-126.4. Saito T, Yokosuka T, Hashimoto-Tane A. Dynamic regulation of T cellactivation and co-stimulation through TCR-microclusters. FEBS Lett.2010;584:4865-4871.5. Tivol EA, Borriello F, Schweitzer AN, et al. Loss of CTLA-4 leads to mas-sive lymphoproliferation and fatal multiorgan tissue destruction, revealing acritical negative regulatory role of CTLA-4. Immunity. 1995;3:541-547.6. Scalapino KJ, Daikh DI. CTLA-4: a key regulatory point in the controlof autoimmune disease. Immunol Rev. 2008;223:143-155.7. Ueda H, Howson JM, Esposito L, et al. Association of the T-cell regu-latory gene CTLA4 with susceptibility to autoimmune disease. Nature.2003;423:506-511.8. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipi -limumab monotherapy in patients with pretreated advanced melanoma: amulticenter single-arm phase II study. Ann Oncol. 2010;21:1712-1717.9. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind,placebo-controlled, phase II study comparing the tolerability and efficacyof ipilimumab administered with or without prophylactic budesonide inpatients with unresectable stage III or IV melanoma. Clin Cancer Res.2009;15:5591-5598.10. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy inpatients with pretreated advanced melanoma: a randomised, double-blind,multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164.11. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med.2010;363:711-723.12. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazinefor previously untreated metastatic melanoma. N Engl J Med.2011;364:2517-2526.13. van Elsas A, Sutmuller RP, Hurwitz AA, et al. Elucidating the autoim-mune and antitumor effector mechanisms of a treatment based on cyto-toxic T lymphocyte antigen-4 blockade in combination with a B16melanoma vaccine: comparison of prophylaxis and therapy. J Exp Med.2001;194:481-489.14. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates withtumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043-6053.15.Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmu-nity in patients treated with cytotoxic T lymphocyte-associated antigen 4blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12:1005-1016.16. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoim-munity induced by cytotoxic T lymphocyte-associated antigen 4 blockadein patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372-8377.

17. Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibody-inducedlupus nephritis. N Engl J Med. 2009;361:211-212.18.Hunter G, Voll C, Robinson CA. Autoimmune inflammatory myopa-thy after treatment with ipilimumab. Can J Neurol Sci. 2009;36:518-520.19. Sanderson K, Scotland R, Lee P, et al. Autoimmunity in a phase I trialof a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol.2005;23:741-750.20. Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies ofclinical response and immune-related adverse events. Oncologist.2007;12:864-872.21. Downey SG, Klapper JA, Smith FO, et al. Prognostic factors relatedto clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13:6681-6688.22.Maker AV, Yang JC, Sherry RM, et al. Intrapatient dose escalation ofanti-CTLA-4 antibody in patients with metastatic melanoma. J Im-munother. 2006;29:455-463.23.Weber JS, O’Day S, Urba W, et al. Phase I/II study of ipilimumab forpatients with metastatic melanoma. J Clin Oncol. 2008;26:5950-5956.24. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients withcancer after antibody blockade of cytotoxic T-lymphocyte-associated anti-gen 4. J Clin Oncol. 2006;24:2283-2289.25. Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab:contribution to a new paradigm for cancer immunotherapy. Semin Oncol.2010;37:533-546.26. Lutzky J, Wolchok J, Hamid O, et al. Association between immune-related adverse events (irAEs) and disease control or overall survival inpatients (pts) with advanced melanoma treated with 10 mg/kg ipilimumabin three phase II clinical trials. J Clin Oncol. 2009;27(suppl):15s. Abstract9034.27. Lin R, Yellin MJ, Lowy I, et al. An analysis of the effectiveness of spe-cific guidelines for the management of ipilimumab-mediated diarrhea/col-itis: prevention of gastrointestinal perforation and/or colectomy. J ClinOncol. 2008;26(May 20 suppl). Abstract 9063.28. Kaehler KC, Egberts F, Lorigan P, et al. Anti-CTLA-4 therapy-relatedautoimmune hypophysitis in a melanoma patient. Melanoma Res.2009;19:333-334.29. Goudie RB, Pinkerton PH. Anterior hypophysitis and Hashimoto’sdisease in a young woman. J Pathol Bacteriol. 1962;83:584-585.30. Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-asso-ciated antigen-4 blockage can induce autoimmune hypophysitis in patientswith metastatic melanoma and renal cancer. J Immunother. 2005;28:593-598.31. Wilgenhof S, Neyns B. Anti-CTLA-4 antibody-induced Guillain-Barre syndrome in a melanoma patient. Ann Oncol. 2011;22:991-993.

Melanoma

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For every nurse there is a patient who you willnever forget; the details of that story will notblur over time. In the developing era of person-alized medicine, there is that 1 patient whose

story I will not easily forget. It is thestory of a 24-year-old male medical stu-dent who presented for initial consul-tation the same week that crizotinibwas approved by the FDA for the treat-ment of anaplastic lymphoma kinase(ALK)-positive non–small cell lungcancer.This young never-smoker was bliss-

fully unaware of the recent advances in identifying the echinoderm micro-tubule-associated protein-like 4 (EML4)-ALK oncogene and the associatedresponse to crizotinib. Upon initialevaluation, his tissue was sent for epidermal growth fac-tor receptor and EML4-ALK testing, but due to the ur-gent nature of his symptoms, the decision was made tostart standard platinum doublet chemotherapy. This is

when I first met him – he was sitting in the chemo chairwaiting for treatment to start. He was quickly becomingsymptomatic and was admitted to the hospital that dayfor evaluation. Over the course of the next couple ofdays he acutely developed a pericardial effusion thattamponaded, requiring emergent bedside pericardiocen-

tesis. He proceeded to develop pulmonary emboli, atrialfibrillation, and pleural effusions requiring bilateralchest tubes. The second day he was in the ICU we re-ceived the news that his tumor was ALK positive. He

was too sick to understand the news,and his family was too scared to under-stand the possible utility of this infor-mation.Our patient assistance team worked

feverishly with the pharmaceuticalcompany and his insurance companysince the drug was brand new. Twenty-four hours later he was taking crizo-tinib. His response was immediate andmiraculous. He was discharged home20 days later; he walked out of the hos-pital without any assistance or medicalequipment. Within 1 month of leaving

the hospital he had resumed his normal activities ofweekend outings and visiting his friends from medschool. I remember the day he called the office to in-quire whether he was allowed to have a beer, a once typ-ical social activity for a 24-year-old student. We allsmiled with relief, knowing that without crizotinib theoutcome would not have been the same. He continuesto do well and has become actively involved in educat-ing people about lung cancer and crizotinib. Speakingto the public has given him a purpose and focus whilehe decides whether to continue with medical school.As a nurse practitioner, being able to witness the life-

altering effects of crizotinib reminds me of the progressthat is being made each day in cancer research. We hopethat these advances in genomic testing and targetedagents continue to provide patients not only with indi-vidualized care but with increased treatment options. u

Lung Cancer

Crizotinib Miracle: A Nursing PerspectiveTara L. Rich, MSN, RN, CNPTaussig Cancer Institute, Cleveland Clinic, Ohio

Tara L. Rich, MSN, RN, CNP

…being able to witness the life-alteringeffects of crizotinib reminds me of theprogress that is being made each dayin cancer research.

Ms Rich is a certified nurse practitioner at the Cleveland Clinic in the department of hematology and medical oncology. Herspecialty is in thoracic oncology.


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