June 2012, VOL 1, NO 2

The offical publication of

June 2012 Volume 1 • Number 2 A Peer-Reviewed Journal

PM O

PERSONALIZED MEDICINE IN ONCOLOGY TM

INTERVIEW WITH THE INNOVATORS Personalized Medicine Advances in Melanoma: An Interview With K. Peter Hirth, PhD..................Page 15

CONTINUING MEDICAL EDUCATION Implementing the Promise of Personalized Cancer Care: Highlights From the Inaugural Conference of the Global Biomarkers Consortium ..................................................Page 22

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

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

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

IMPLEMENTING THE PROMISE OF PROGNOSTIC PRECISION INTO PERSONALIZED CANCER CARE

TM

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

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June 2012 Volume 1 • Number 2

PERSONALIZED MEDICINE IN ONCOLOGY ™

CONFERENCE NEWS

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

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

INTERVIEW WITH THE INNOVATORS

Who attends the GBC?

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

CONTINUING MEDICAL EDUCATION

10.3% 10.3%

44.8%

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

PAGE 22

24.1%

10.3%

MD/DO PhD RN/APN RPh/PharmD Other

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PUBLISHING STAFF SENIOR VICE PRESIDENT, SALES AND MARKETING Philip Pawelko phil@greenhill.com PUBLISHERS John W. Hennessy john@greenhillhc.com Russell Hennessy russell@greenhillhc.com DIRECTOR, CLIENT SERVICES Eric Iannaccone eric@greenhillhc.com MANAGING DIRECTOR Pam Rattananont Ferris

PERSONALIZED MEDICINE IN ONCOLOGY ™

REGULATORY ISSUES

EDITORIAL DIRECTOR Kristin Siyahian kristin@greenhillhc.com

Rapid Changes in Reimbursement Protocols for Molecular Tests

STRATEGIC EDITOR Robert E. Henry

MELANOMA

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Crizotinib Miracle: A Nursing Perspective

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO), 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mention in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician.

Please convey any errors to the editorial director.

Volume 1 • No 2

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Bruce Quinn, MD, PhD

SENIOR COPY EDITOR BJ Hansen

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Tara L. Rich, MSN, RN, CNP

INTERVIEW WITH THE INNOVATORS An exclusive PMO series Personalized Medicine in Oncology™ is pleased to offer insightful interviews with leaders in oncology about their approach to personalized medicine.

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

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June 2012

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Editorial Board Editor in Chief AL B. BENSON III, MD Northwestern University Chicago, Illinois

SECTION EDITORS Breast Cancer EDITH PEREZ, MD Mayo Clinic Jacksonville, Florida

Gastrointestinal Cancer EUNICE KWAK, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts

Drug Development IGOR PUZANOV, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee

Hematologic Malignancies GAUTAM BORTHAKUR, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Lung Cancer VINCENT A. MILLER, MD Foundation Medicine Cambridge, Massachusetts

Pathology DAVID L. RIMM, MD, PHD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut

Melanoma DOUG SCHWARTZENTRUBER, MD Indiana University Simon Cancer Center Indianapolis, Indiana

Predictive Modeling MICHAEL KATTAN, PHD Case Western Reserve University Cleveland, Ohio

Prostate Cancer OLIVER SARTOR, MD Tulane University New Orleans, Louisiana

EDITORIAL BOARD

TONY ALBINO, PHD Signal Genetics LLC New York, New York GREGORY D. AYERS, MS Vanderbilt University School of Medicine Nashville, Tennessee LYUDMILA BAZHENOVA, MD University of California, San Diego San Diego, California LEIF BERGSAGEL, MD Mayo Clinic Scottsdale, Arizona

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

K. PETER HIRTH, PHD Plexxikon, Inc. Berkeley, California

DANIELLE SCELFO, MHSA Genomic Health Redwood City, California

HOWARD KAUFMAN, MD Rush University Chicago, Illinois

LEE SCHWARTZBERG, MD The West Clinic Memphis, Tennessee

KATIE KELLEY, MD UCSF School of Medicine San Francisco, California

JOHN SHAUGHNESSY, PHD University of Arkansas for Medical Sciences Little Rock, Arkansas

MINETTA LIU, MD Georgetown University Hospital Washington, DC

KENNETH BLOOM, MD Clarient Inc. Aliso Viejo, California

KIM MARGOLIN, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington

MARK S. BOGUSKI, MD, PHD Harvard Medical School Boston, Massachusetts GILBERTO CASTRO, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil MADELEINE DUVIC, MD The University of Texas MD Anderson Cancer Center Houston, Texas BETH FAIMAN, PHD(C), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio STEPHEN GATELY, MD TGen Drug Development (TD2) Scottsdale, Arizona

STEVEN T. ROSEN, MD, FACP Northwestern University Chicago, Illinois

STEVEN D. GORE, MD The Johns Hopkins University School of Medicine Baltimore, Maryland

SANJIV S. AGARWALA, MD St. Luke’s Hospital Bethlehem, Pennsylvania

GENE MORSE, MD University of Rochester Rochester, New York AFSANEH MOTAMED-KHORASANI, PHD Radient Pharmaceuticals Tustin, California NIKHIL C. MUNSHI, MD Dana-Farber Cancer Institute Boston, Massachusetts

Volume 1 • No 2

STEVEN O’DAY, MD John Wayne Cancer Institute Santa Monica, California

DARREN SIGAL, MD Scripps Clinic Medical Group San Diego, California DAVID SPIGEL, MD Sarah Cannon Research Institute Nashville, Tennessee

SHEILA D. WALCOFF, JD Goldbug Strategies, LLC Rockville, Maryland

DAVID A. PROIA, PHD Synta Pharmaceuticals Lexington, Massachusetts

PERSONALIZED MEDICINE

JAIME SHUTTER, MD South Beach Medical Consultants, LLC Miami Beach, Florida

MOSHE TALPAZ, MD University of Michigan Medical Center Ann Arbor, Michigan

ANAS YOUNES, MD The University of Texas MD Anderson Cancer Center Houston, Texas

RAFAEL ROSELL, MD, PHD Catalan Institute of Oncology Barcelona, Spain

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LAWRENCE N. SHULMAN, MD Dana-Farber Cancer Institute Boston, Massachusetts

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June 2012

Pancreatic Cancer: Progress and Challenges June 18-21, 2012 Lake Tahoe, NV An AACR Special Conference on: Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations June 27-30, 2012 Marriott Copley Place Boston, MA Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research October 16-19, 2012 Anaheim, CA Fifth Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved October 27-30, 2012 San Diego, CA EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 6-9, 2012 Dublin, Ireland

An AACR Special Conference on: Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment November 11-14, 2012 Hollywood, FL An AACR Special Conference on: Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances December 2-5, 2012 Miami, FL CTRC-AACR San Antonio Breast Cancer Symposium December 4-8, 2012 San Antonio, TX An AACR Special Conference on: Tumor Invasion and Metastasis January 20-23, 2013 San Diego, CA Ninth AACR-Japanese Cancer Association Joint Conference: Breakthroughs in Basic and Translational Cancer Research February 21-25, 2013 Maui, HI AACR-Society of Nuclear Medicine Joint Conference on State-of-the-art Molecular Imaging in Cancer Biology and Therapy February 27-March 2, 2013 San Diego, CA

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

Letter From the Board

The Offical Publication of the GBC 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 understand the vast, highly complex body of information on personalized medical treatment of oncologic diseases. This timely journal will explore innovations in oncology and how they translate into clinical progress as well as the associated value of these innovations: the balance of cost, quality, and access. Our goal is to extract the Igor Puzanov, MD greatest value from the revolution in personalized medicine by providing the information on the performance realities of new diagnostic and treatment discoveries and clarifying the productivity of personalized medicine technologies. Articles will provide information for the implementation of personalized medicine by practicing physicians, according to evidence-based, value-based, patientcentered 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 October 4-6, 2013, in Boston, Massachusetts.

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

Sincerely,

Igor Puzanov, MD Vanderbilt University PMO Section Editor, Drug Development

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Letter From the Strategic Editor

On the Brink of Personalized Medicine Dear Reader, As strategic editor of Personalized Medicine in Oncology (PMO), it was my pleasure to conduct several interviews with experts from our editorial board about the concept of personalized medicine (PM) and its current state of application within different oncologic diseases. The ensuing input was a tour de force of information regarding the application of PM at the clinical level. We explored virtually every aspect of this translational process, and they gave their insights into the governing dynamics of PM – always separating assumption from the facts driving this powerful engine for progress. The goal of these interviews is to help you cultivate an underRobert E. Henry 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 irrelevant to practicing oncologists; and understand the forces for PM within the context of healthcare’s clinical, business, and policy sectors.

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

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

All the best,

Robert E. Henry Strategic Editor

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WWW.PERSONALIZEDMEDONC.COM

June 2012

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ASCO Conference News

Dual Targeting in Advanced Melanoma Encouraging Alice Goodman

H

itting 2 targets may be better than 1 in advanced melanoma, suggests a preliminary trial of combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. Combined targeting with these 2 agents achieved tumor regression with a lower incidence of skin side effects compared with published data on standard single-agent BRAF inhibitor therapy with vemurafenib (Zelboraf).

Rates of skin toxicities on combination therapy were much lower than what has been reported with other BRAF inhibitors as single-agent therapy.

These results are from an expanded phase 1 trial that included 125 patients with advanced melanoma harboring a BRAF mutation; 77 did not have previous BRAFtargeted therapy, and this subset is the population of focus, explained lead author Jeffrey Weber, MD, PhD, senior member at H. Lee Moffitt Cancer Center and director of the Donald A. Adam Comprehensive Melanoma Research Center, Tampa, Florida. Weber reported the results at a pre-ASCO press telecast and also at ASCO 2012 (Abstract 8510).

About half of all melanomas have a V600E mutation in the BRAF gene, and in these patients, the MEK pathway is also activated. Most patients with a BRAF mutation will respond to treatment with vemurafenib, which is now FDA-approved for advanced melanoma, but will eventually become resistant to the drug.

The subgroup of 77 patients who never received BRAF-targeted therapy received 4 different dose levels of the 2 drugs; the dose chosen to go forward with in future 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-

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couraging,” Weber said. Single-agent studies of vemurafenib showed median PFS of 7.4 months, he added.

Looking at a waterfall plot that shows tumor shrinkage, overall about 95% of patients had their disease controlled on the 2 agents, as reflected by stable disease (38%), partial response (PR, 49%), or complete response (CR, 8%). Looking at the group treated with the 150-mg/2-mg dose, CR was 8%, PR was 54%, and stable disease was 38%.

“This waterfall plot shows the best responses I’ve seen in advanced melanoma,” Weber said during the press telecast.

The rates of skin toxicities on combination therapy were much lower than what has been reported with other BRAF inhibitors as single-agent therapy, Weber continued. The rate of squamous cell cancer was 3% compared with 15% to 25% seen with other BRAF-inhibiting agents; the rates of actinic keratosis (5%) and papilloma (2%) were also much lower than with BRAF inhibition alone.

Grade 3 or higher toxicities on the combination therapy were as follows: pyrexia, 52% (23% required dose reductions); chills, 38% (10% required dose reductions); 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, commented that the hope with dual targeted therapy is that more patients with advanced melanoma will be cured.

“This combination reduced skin side effects [compared with vemurafenib],” she noted. Swain is the medical director of the Washington Cancer Institute of the Washington Hospital Center and professor of medicine at Georgetown 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

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Neoadjuvant Abiraterone Potential Approach Phoebe Starr

A

biraterone, which is FDA-approved for the treatment of advanced prostate cancer, had encouraging results in one of the first studies to evaluate use of this targeted agent earlier in the course of disease. Targeted hormonal therapy with abiraterone plus leuprolide was able to eradicate cancer in the prostate in some high-risk prostate cancer patients prior to radical prostatectomy in a phase 2 study reported at ASCO 2012 (Abstract 4521).

“Most patients with early prostate cancer are cured with primary surgery and/or radiotherapy. However, patients with high-risk features [such as those in this study] generally progress. The study was conducted to determine if neoadjuvant therapy with abiraterone plus leuprolide could increase the cure rate. To date, no other treatment has shown a benefit in the neoadjuvant setting. Larger studies are needed to validate this finding,” said lead author MaryEllen Taplin, MD, Harvard Medical School and DanaFarber Cancer Institute in Boston, Massachusetts.

Standard hormone therapy with injectable leuprolide acts to suppress testosterone. Abiraterone, an oral inhibitor of CYP17, has a different mechanism of action, blocking the synthesis of androgens in the testes, adrenal glands, and prostate. In this neoadjuvant study, abiraterone was given along with leuprolide and low-dose prednisone to abrogate the side effects of abiraterone prior 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 the sample); T3 or T4 bulky disease (24% of the sample); and high PSA velocity (16% of the sample). Slightly more than one-third of patients also had lymph node involvement, which is associated with aggressive disease.

Patients were treated with either 3 months of leuprolide or 3 months of abiraterone, leuprolide, and low-dose prednisone (5 mg) and then underwent biopsy of the prostate for analysis of androgen levels; patients then re-

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ceived treatment with abiraterone/leuprolide/prednisone for another 3 months, after which radical prostatectomy was performed.

In the prostate specimen obtained at prostatectomy, pathological complete response (pCR) was observed in 10% of those treated with 6 months of abiraterone versus 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. The response rate of 34% is impressive, given the high-risk features of the patient population,” she noted.

Grade 3 adverse events included elevated liver enzymes in 9% and hypokalemia in 5%. Use of low-dose prednisone appeared to prevent some of the side effects associated with abiraterone, she noted.

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

Other neoadjuvant trials with some of the newer prostate cancer agents are now being planned, including MDV 3100, Taplin said.

“This is an exciting step forward, showing that neoadjuvant abiraterone can make cancer disappear in a percentage of high-risk patients,” stated Nicholas Vogelzang, MD, Chair of ASCO’s communications committee and moderator of the press telecast.

He explained that neoadjuvant therapy is standard in the treatment of breast cancer, rectal cancer, and bladder cancer.

“When cancer disappearance is achieved with primary treatment in these other cancers, long-term survival is improved,” Vogelzang noted. u

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ASCO Conference News

ALK-Targeted Agent Has High Activity in Some Childhood Cancers Alice Goodman

I

n a preliminary phase 1 study, the targeted drug crizotinib (Xalkori) stabilized disease progression and, in some children, eradicated cancer cells in relapsed, refractory, aggressive childhood cancers that are likely to harbor genetic abnormalities in the ALK gene: anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumors (IMT), and aggressive neuroblastoma.

Crizotinib, which is targeted to abnormalities in the ALK gene, is FDA-approved for the treatment of ALKdriven non–small cell lung cancer (NSCLC), which accounts for about 5% of all NSCLC. ALK is also a potential target in childhood cancers, because ALK abnormalities 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 second effective molecularly targeted agent for pediatric cancers, explained lead author Yael Mosse, MD, assistant professor of pediatrics at the Children’s Hospital of Philadelphia and University of Pennsylvania.

“Crizotinib had a high degree of activity. Larger trials with this agent are in development for ALCL. This drug may also find a role in selected subsets of patients with IMTs and neuroblastomas,” she said.

The Children’s Oncology Group study included 70 children with progressive cancer despite standard treatment. Six different cohorts were treated with crizotinib doses ranging from 100 to 365 mg/m2. The drug was extremely well tolerated, Mosse said, and the dose chosen for studies going forward was 250 mg/m2, which is twice the dose used in adults with NSCLC. Results were as follows: 7 of 8 patients (88%) with ALCL had a complete response (CR). These responses have been long-lasting, with all patients on treatment for up to 18 months, she said. Of the 7 patients with

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IMT (a rare sarcoma) enrolled in the trial, the majority have had a response, with some responses lasting for up to 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 ALK mutations; 2 of these patients achieved a CR and have been on therapy from 9 months to more than 2 years with no sign of disease progression. Mosse pointed out that most heavily pretreated neuroblastoma patients, such as those in this preliminary trial, would progress within 1 to 2 months on other available therapies. Among the 19 patients with unknown ALK status, there was 1 CR and 6 with prolonged stable disease after 7 to 29 cycles of treatment.

Toxicity was acceptable and mostly low grade. At the highest dose level, elevations in liver enzymes were reported, 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 want in a phase 2 trial.”

“For neuroblastoma, we need more study to determine which patients will benefit from crizotinib. The drug has dramatic potential in other ALK-driven tumors,” she added.

ASCO President Michael P. Link, MD, said: “I am delighted to hear these findings, which provide a glimpse at a new paradigm. Histology and the affected organ are not sufficient [treatment targets]. We need to identify the particular molecular drivers of tumors. The study shows that an inhibitor of genetic abnormalities may work in different cancer types. The way forward is collaboration – in this case, experts in lung cancer, pediatric cancer, lymphoma, and brain cancer.” u

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WCMC Conference News

Personalizing Therapeutics for Melanoma in the 21st Century Kristin Siyahian

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dvocating for biomarker-driven “smart” posing challenges in recruiting, biomarker cost, and trials, making the case for patient selecquality of tissue processing. tion for specific drugs, and the concept of rational combinations as potential tarIntratumoral Heterogeneity geted therapies in order to improve the efficacy of clinAnother issue Sekulic addressed is intratumoral hetical trials were topics of an insightful presentation erogeneity. A single tumor biopsy may not represent the delivered by Dr Aleksandar Sekulic on entire tumor population. One apbehalf of Dr Pat LoRusso at the inauproach is to look at mutations and gural conference of the World Cutamarkers that can be identified with tarneous Malignancies Congress. geted assays that can be designed either Sekulic reminded the audience that to a single gene, such as BRAF, or to a historically, drugs were designed, papanel of genes. tients were treated, and individual paThe next obvious step, which has tients had different responses in early been explored by several groups, is clinical trials. The goal in the new era next-generation sequencing, where of personalized treatment is to shift to one can identify multiple mutations, a different model; one that determines potentially differentiate drivers versus the molecular profile of the individual passengers, and pursue functional Dr Aleksandar Sekulic patient’s tumor and then attempts to studies. match that profile with the available Sekulic pointed out that in order to panel of targeted drugs. This approach will refocus the treat the entire cancer in a patient, we have to consider efforts of early clinical trials. combination therapy. He cited a presentation by VogelThis pharmacodynamic approach of using predictive stein at the recent American Association for Cancer biomarkers leads to patients who are more likely to respond to therapy, as well as other measurements such as Not only do we need to pick the right agents intermediate end point biomarkers. Sekulic cited examand right doses and right schedules, but ples of such “smart” trials: SMO in basal cell carcinoma, also the right drug combinations.

PARP in breast cancer, ALK and EGFR in non–small cell lung cancer, BRAF in melanoma, and c-kit in gasResearch meeting describing some of the challenges that trointestinal stromal tumors. The objective response face us in this area and summarized them in 4 points: rates in these early trials are impressive, especially com• To better understand the pathways in human cancer pared with the historic controls at this stage. cells or humanized systems Sekulic also pointed out possible issues with pre• To rationally identify the combination therapies selecting patients: some patients who could benefit from using new screening approaches the drug may inadvertently be excluded, and as we start • To develop new biologic treatments combining biobreaking down common diseases into smaller subsets, logic-, immunologic-, and genomic-defined therapies there are decreasing numbers of patients on the trial,

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WCMC Conference News

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

Figure. Clinical Trial Schema

Patient consented and screened

Personalized Medicine for Patients With Metastatic BRAF Wild-Type Melanoma

Tumor biopsy 4-Week Timeframe

Molecular profiling

Drug target identified?

Yes

Patient not randomized, treated with physician’s choice

Patient randomized 2:1 Treated with molecularly guided therapy

No

Treated with physician’s choice

s

(Optional crossover)

• It is not just about curing advanced cancer; prevention and early detection are a large part of the answers Not only do we need to pick the right agents and right doses and right schedules, but also the right drug combinations. These combination strategies may be required to overcome not only cross-talk and feedback, as

We’re just a

All these considerations are being applied to a trial designed for patients with BRAF wild-type melanoma led by Jeff Trent and Pat LoRusso. In the proposed flowchart of the trial, the tissue is obtained, genome is profiled, data are processed, knowledge mining to identify pathways affected is performed, and clear validation assays are conducted, after which the tumor board meets and the therapy is selected. In conjunction, a set of translational experiments in mouse explants and cell lines will be carried out to test some of the predictions of responses.

A simplified schema of the trial where the patient is consented and screened, the tumor is biopsied, and molecular profiling is done in the form of next-generation sequencing of genome and transcriptome is offered in the Figure.

In conclusion, Sekulic stated that responsibility rests with us all. We must think about paradigm change and both preclinical and clinical drug development. The challenges we must meet are how to do this in humanized systems and how to develop rational combinations. u

click

away!

Please visit us at www.PersonalizedMedOnc.com

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Interview With the Innovators

Personalized Medicine Advances in Melanoma: An Interview With K. Peter Hirth, PhD K. Peter Hirth, PhD Chief Executive Officer Plexxikon, Inc.

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several other therapeutic indications. lexxikon, a member of the Daiichi Sankyo Group since Plexxikon’s proprietary Scaffold-Based Drug Discovery™ platform integrates 2011, works in the structureguided discovery and developmultiple state-of-the-art technologies, ment of novel small-molecule pharincluding structural screening, as a key component that provides a significant maceuticals to treat human disease. The competitive advantage over other drug company’s lead drug Zelboraf (vemudiscovery approaches. rafenib/PLX4032) was approved by the Personalized Medicine in Oncology FDA in August 2011 and is copromoted had the opportunity to meet with the in the United States by Daiichi Sankyo, CEO of Plexxikon, K. Peter Hirth, Inc. and Genentech. PLX3397, the PhD, to talk about Plexxikon’s apcompany’s next oncology candidate, adK. Peter Hirth, PhD proach to personalized medicine, the vanced to phase 2 testing in 2011. landscape of care in melanoma, and the Plexxikon is developing a portfolio of process of biomarker discovery and drug development in preclinical- and clinical-stage compounds to address signiche markets. nificant unmet medical needs in oncology, as well as in

PMO We are delighted to talk with you today about Plexxikon’s approach to personalized medicine. We’d like to start by asking how you define personalized medicine, particularly as it relates to the treatment of patients with melanoma.

Dr Hirth Personalized medicine in oncology is not a new concept, but in melanoma it is a very recent development with the breakthrough of the drug discovered

by Plexxikon and codeveloped with its partner Roche.

A completely new concept was put forward, and we are now able to dissect the melanoma population into subsets based on molecular drivers. Today, we reclassify and talk about melanomas, not just 1 melanoma.

As a result, we were able to focus on a particular subset of those melanomas, understand the molecular driver, develop the drug, and realize that because this molecular driver is only present in a subset of cancer patients, we would need to come up with a way to identify those patients through the development of a companion diagnostic.

PMO Personalized medicine in action remains sporadic and occurs mainly at well-funded academic medical centers or prompted by physicians who understand the genetic principles behind molecular biomarkers and how to assess them appropriately. How can this situation change so that personalized medicine can be made avail-

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

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able broadly to patients managed by community oncologists? What are the barriers and opportunities for this to occur?

Dr Hirth Translating and managing the biomarker experiences and the personalized medicine that initially started out in academic centers into the community remains a challenge. However, there are examples where this has been going really well. We are just beginning to

We also have to realize that there are regulatory issues that we have to deal with. The guidance from the FDA at this point is not very clear. understand the barriers to community implementation.

For example, the ease of a test is very important. It’s very easy for doctors to deal with binary test readouts; when it’s a simple yes or no. But there are more complicated tests that make for a much more difficult treatment decision. Education is absolutely key to give doctors the tools to interpret the test results.

In addition, when we talk about novel biomarkers and bringing them forward into development, we also have to realize that there are regulatory issues that we

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have to deal with. The guidance from the FDA at this point is not very clear.

If you look at barriers for the development of biomarkers and their translation into personalized medicine from a business perspective, a biomarker without a drug, without a clinical trial and data, is just a biomarker, and developing that into a full-fledged diagnostic test poses a certain financial risk that people like to measure out as they engage in the development, because it is a chicken/egg situation. I have a biomarker, I might have a drug, but will this drug with this biomarker in combination be successful?

Considering bringing tests to the community oncologist, there is an institution in the US that is somewhat underutilized, and that is the Clinical Laboratory Improvement Amendments of 1988 (CLIA)-certified labs, which really do not fall under the jurisdiction of the FDA but have all the expertise and talent and are already distributed throughout the country. From a distribution perspective, you would actually get much faster penetration into the community if you went that route of involving CLIA-certified labs in the development of these biomarker assays. But this is still a subject of discussion with the FDA, and they’re working on guidance.

PMO Vemurafenib has clearly been a significant advance in the treatment of melanoma, and one can make a case that this agent represents personalized medicine in oncology when used in patients with BRAF mutations. Are efforts by Plexxikon also directed at the diagnostics industry to standardize, innovate, and improve laboratory testing for molecular biomarkers?

Dr Hirth What is the optimum use of identifying the best companion diagnostic? That really depends on the project, and I don’t think there is a one-size-fits-all solution. In the case of Zelboraf and the V600 mutation, it was clear that the genetic level probably would be the most appropriate test. Currently, there is development of further technologies beyond PCR [polymerase chain reaction] looking at high-sensitivity sequencing. So there 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

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each program requires a different approach to a companion diagnostic, and therefore we have decided not to engage in developing these tests ourselves but rather go into the marketplace to look for optimum technology available to us.

There is really no single answer to the question of how best to do that. This is our approach, and I think a lot of other companies have gone down that path, and as a result there are a number of diagnostic companies offering their services.

I’m not sure whether this approach will be financially rewarding, because more and more indications are becoming smaller and smaller. The cost for these tests cannot be astronomically high, or nobody would use them.

But there is still a lot of work that needs to be dealt with to make this possible in a practical fashion. I believe that we will see platform technologies that will be test run on sequencing platforms. There are going to be platforms like the cell sorting, and individual markers that will be integrated into sets like that. Diagnostic platforms will be developed separately and validated once, so you don’t have to pay the price to develop and validate the entire platform for each new marker, but just the part for the specific new marker for which you want to test.

PMO How is Plexxikon applying its platform to create other oncology compounds beyond vemurafenib?

Dr Hirth The Plexxikon platform that was used to develop Zelboraf has also been utilized for a number of additional programs. Patients eventually develop resistance with cancer treatment and become refractory. The big advantage we have here is our targeted approach; we can go in and look at the resistant tumors and ask what’s changed, what’s different, how do cancers get around. And that now leads to potential points of intervention that we can drug with the technology that we have built at Plexxikon. It will again lead up to matching patients with the appropriate diagnostic test and molecular drivers.

We have 1 compound that we will take forward into development, hopefully early next year, that will be a completely new class of drug in the melanoma space.

In addition, we have PLX3397 that’s in phase 2 de-

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velopment; it represents a very different approach – not by targeting primarily the tumor cell itself but by actually targeting the tumor microenvironment. It’s similar to the concept of angiogenesis inhibition – there is a component of the microenvironment that is critically supporting 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 and delicate to define the cutoffs – so it’s not as easy as it

There are attempts to develop draft guidelines, but it’s a case-by-case decision, and I must say that the FDA is very receptive... was for BRAF. I have to remind people that in the BRAF situation it’s really binary, it’s yes/no. Here we’re dealing with more gradation, shades of gray that we have to deal with, so these diagnostic tests will take a little bit longer to define and move forward.

PMO Many of the “success stories” in personalized medicine in oncology have involved collaboration between pharma and a diagnostics company (eg, crizotinib in ALK+ non–small cell lung cancer and vemurafenib in BRAF+ melanoma), and the FDA seems receptive to this sort of collaboration. Are FDA guidelines clear in their requirements for the simultaneous development of a pharmaceutical agent and an accompanying diagnostic test?

Dr Hirth When we talk about personalized medicine and the development from a regulatory perspective, the key features that one needs to consider are in the works at the FDA. There are attempts to develop draft guidelines, but it’s a case-by-case decision, and I must say that the FDA is very receptive to this companion diagnostic concept because 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 unnecessary waste. All of that is very logical and clear.

The question is how it is implemented on a case-by-

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case basis. The Zelboraf example might not be the standard case because this actually was a more straightforward situation, and less complicated as you think about it from a development perspective, and therefore not necessarily the standard to be measured against in the future.

We will undoubtedly run into situations where we will have to determine how critical new tests are in selecting patients for a particular drug. There’s also the consideration of what regulators want, what payers are willing to pay for, and the types of tests they would like to see done.

There’s a clear example in which payers in colorectal cancer will not pay for EGFR inhibitor drugs: cases with known mutations of KRAS, because studies have shown that the drug is not worthwhile in those patients.

There’s also the consideration of what regulators want, what payers are willing to pay for, and the types of tests they would like to see done.

I think the FDA is committed to get this right. They have invited comments. We made proposals, and we also think there are ways to mitigate the initial financial investment by not having a Cadillac rolled out for initial clinical trials but maybe start with a tricycle until we know we really have something that we can develop and then send out around the world. And we think the CLIA labs are a very good setup for that.

PMO Will the collaboration between pharma and diagnostic companies add significant cost to the development of personalized therapy in melanoma?

Dr Hirth The development of a therapeutic together with a companion diagnostic obviously is a change in paradigm, and it does require additional financial commitments, but it also requires a lot more coordination between the 2 companies developing the drug and the diagnostic.

It also requires a lot more communication between agencies at the FDA. The Center for Drug Evaluation and

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

PMO Despite the fact that the incidence of malignant melanoma has been increasing over the past 30 years, with 76,000 new cases and nearly 10,000 deaths expected in 2012, the discovery of molecular biomarkers associated with this malignancy is still relatively new and, thus far, confined almost exclusively to BRAF (although data are now being accumulated for the association of c-KIT and NRAS mutations with melanoma).

Why do you think the discovery process of molecular biomarkers in melanoma has been so slow?

Dr Hirth Why has melanoma been such a graveyard in drug development over the last year? Why did we not have any drugs before Yervoy and Zelboraf? Does this have to do with the lack of biomarkers? No, not really.

Plenty of biomarkers were identified. There was interleukin-1a. There was the interferon. There were all kinds of interleukin-2 stories that were available. But we never came to the point where anything was tested to form hypotheses for subtypes. It was all looked at in a traditional drug development way in a heterogeneous patient population.

The other downside of melanoma is that it’s a disease that is so aggressive. That may be why other cancers that have a longer development time line before they become fatal have been better from a drug development perspective.

Generally, the capability to generate potential biomarkers over the last few years has gone up exponentially compared with the past, primarily because of high-throughput sequencing, and I see throughput sequencing getting cheaper and cheaper, so many academic institutions are now collecting data. My concern here is who’s sifting through all the data, who’s making sense of it. And then from the data we need to build hypotheses to ask questions. Well, are these tests epiphenomenal? Are these passenger mutations or do they actually drive indications?

Once we have identified driver mutations, if they’re druggable, we know what to do in terms of drug devel-

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opment. But it’s not going to be something that will be changing overnight. I know there are some people who have this expectation with sequencing. The field will be changed in 2 years. I like to manage expectations; from the time we identify a potential target to having something on the market is still many years away.

We have shown that with a companion diagnostic we can accelerate the drug development process quite substantially, but it will still be a number of years before we see the benefit of these new technologies coming through.

PMO It seems that education of providers, pharmacists, payers, and patients is vital in achieving personalized medicine in oncology. What efforts is Plexxikon making in educating these stakeholders?

Dr Hirth Education about these new approaches to personalized medicine obviously involves a variety of different parameters, functions, clinicians, payers, insurance, and advocacies. We have initially taken the road that we would start out in a scientific community, because this is the culture that we live in, where new concepts are first tested in an academic environment before they trickle down into a community setting.

But it has been going really well – especially in melanoma, where patients have been so frustrated – because there wasn’t anything else new on the horizon; the advocacy groups were looking for new events and new approaches that could change the outcomes.

I would imagine that payers will have a huge interest in embracing this concept, because it will reduce wasted drug on patients who are unlikely to benefit, and I cannot see how that is not a very important argument for payers.

Now, where they would go with testing, whether they would follow the FDA, or whether they would like their own testing labs, this is still a subject of discussion, and I don’t know how this will come out.

PMO What do you foresee as the future of personalized medicine in oncology when sequencing the entire human genome will cost less than $1000 in the next few years? How will this impact drug development for melanoma and other cancers?

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Dr K. Peter Hirth shares his views on personalized medicine in oncology.

Dr Hirth We’re seeing huge progress in sequencing efforts, being able to sequence entire genomes, genomes of cancers, and at a price that is falling to a level that makes 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 better identify populations within, let’s say, melanoma tumors or breast tumors that share certain characteristics. We can learn what the most likely molecular drivers are, and if they are druggable. We will have a huge opportunity to 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 treatments will be more selective. There will be more niche drugs. There will be smaller groups of patients, and that has some challenges in terms of conducting clinical trials and in the necessary investment. To develop a drug is a very expensive exercise that is justified mostly because there’s an anticipated patient population that you can treat and subsequently make money. But as these populations get smaller and smaller, we have to ask ourselves to identify the break-even point.

I think we need to have changes in the regulatory environment and in the reimbursement environment. We need to reconsider what our end points need to be, how

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much time and money we can afford to spend in some of 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 development that we hit the target, that we can establish the concept of how the drug is working. Even if that is a small indication, but then later on, once we have understood 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 is now being tested in other tumors as well. We don’t know the outcomes yet, but I’m positively optimistic as always, otherwise I wouldn’t be in this business.

Personally I believe that whenever we can have a very dramatic impact on patients who are in need of help, it’s worthwhile doing.

PMO What will you offer melanoma patients without a biomarker that directs a targeted therapy, especially if this impacts a significant percentage of patients?

Dr Hirth When we look at the melanomas and what biomarkers are present, we still have about a 40% proportion of the population where there is really no clear biomarker identified that can lend itself to developing a targeted drug. This is unfortunate, because there is not much available now for those patients other than dacarbazine and Yervoy.

I would also like to say that even though we now have these subpopulations based on V600 BRAF, this is not a complete homogeneous population either. It’s enriched, but it’s not black and white, so there are patients who respond strongly and patients who have less of a response. So clearly there are further fractionations that will happen. In the future, I do see a more niched approach to therapy.

The other thing I would expect to see is that we will have a much more rational approach to combining Zel-

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boraf, for instance, with another drug, and we can start calling these companion therapeutics. In the old days, everything was combined with everything available, but there was very little logic and science behind it. We see that changing. We already have very beautiful examples in some of the BRAF-driven tumors, where the most appropriate companion therapeutic is basically already on the 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 to patients in the clinic.

But I think it also requires a rethinking in the industry that has consequences in organizational forms. A patient population consisting of 2000 patients doesn’t require a 20,000 people sales force, for example. And so we will see dramatic changes in the oncology business as a result of the science driving the search for more niched opportunities becoming better through the use of companion diagnostics approaches.

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

Dr Hirth What is the patient population in any given disease that is attractive for development? This is a very difficult question to answer. Personally I believe that whenever we can have a very dramatic impact on patients who are in need of help, it’s worthwhile doing.

We have some extreme examples with Genzyme, for example, which has developed really rare indications.

We know that targeted therapies that have a high impact usually are priced better. The value proposition is very different, and that is reflected in the investment.

It can hopefully be developed faster so maybe it doesn’t require the $800 million that it typically would take.

So I think there are opportunities in the biotech space to embrace concepts of developing drugs more quickly and more financially efficiently to make it a worthwhile proposition. I think it’s worthwhile any time when we can help people; it’s a worthwhile proposition for me.

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

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PMPM O C

ERSONALIZED EDICINE IN ONCOLOGY

ALL FOR PAPERS

Personalized Medicine in Oncology’s mission is to deliver practice-changing information to clinicians about 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 care where 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. PMO will feature diagnostic and clinical treatment information concerning these 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

Genetic Profiling Technologies •

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

In Practice Predictive Models and Diagnostics •

Genetics and Biomarkers •

•

A practical guide for community-based oncologists discussing clinical applications and strategies for incorporating personalized medicine techniques into practice

•

Development of treatment algorithms

A look at available diagnostic technologies and implementation in the community practice setting

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

N=1 •

Case studies, patient-reported outcomes, defining treatment goals, partnering with patients and caregivers

Submit the entire manuscript and a cover letter stating the objectives of the article to PMO@greenhillhc.com.

Manuscripts should follow the Author Guidelines available at www.PersonalizedMedOnc.com. "

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

Implementing the Promise of Personalized Cancer Care Highlights From the Inaugural Conference of the Global Biomarkers Consortium Rüdiger Hehlmann, MD, PhD University of Heidelberg, Mannheim, Germany Hope S. Rugo, MD University of California San Francisco, San Francisco, California

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ntil recently, cancer treatment relied solely on histologic diagnosis for determining systemic therapy. Aside from considerations related to a patient’s underlying comorbidities and performance status, there was minimal deviation from an organ-of-origin–based treatment strategy. This relatively primitive understanding of malignancy failed to exploit biological and molecular differences within each cancer type to allow for

CME/CE Information Sponsors This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation The University of Cincinnati designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim the credit commensurate with the extent of their participation in the activity.

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

Registered Pharmacy Designation Medical Learning Institute (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides

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selection of a more rational therapy focused on individual patient and tumor characteristics. However, exciting strides are currently being made in the field of cancer research and treatment, both with solid tumors and hematologic malignancies. As our understanding of cancer initiation, progression, and response to treatment has advanced, and technical achievements in bioinformatics and genome/proteome analysis have been made, the opportunities to tailor therapies to individual pafor 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 0468-9999-12-015-H01-P. Commercial Support Acknowledgment This activity is supported by educational grants from Abbott Laboratories, Daiichi Sankyo, Genentech, and Millennium: The Takeda Oncology Company.

Target Audience This activity was developed for medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

Educational Objectives After completing this activity, the participants should be better able to: • Assess emerging data and recent advances in the discovery of tumor biomarkers, their impact on the treatment of patients with solid tumors and hematologic malignancies, and how to integrate key findings into clinical practice.

• Discuss the role of tumor biomarkers in designing personalized therapy for patients with cancer, including management of treatmentrelated adverse events.

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

tients have markedly expanded. Indeed, an expanding pool of predictive biomarkers has now ushered in the era of personalized medicine for cancer patients. Several of these markers have transformed patient care, and testing for these markers has become mandatory prior to initiation of therapy. As a result, targeted therapeutics that rely on the molecular characteristics of a malignancy offer hope for personalized care in cancer with improved patient outcomes.

However, because a rapidly increasing number of molecular biomarkers are now becoming clinically available, a significant need exists for healthcare professionals who manage patients with cancer to keep abreast of the latest information on tumor biomarkers and how to appropriately use them to optimize therapy for their patients. In this regard, the Global Biomarkers Consortium (GBC) was developed. The GBC is a community of worldrenowned healthcare professionals coming together to provide a forum for the improved understanding of the

CME/CE Information (continued) Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CE activity in its entirety, participants must complete the posttest and evaluation. The posttest and evaluation can be completed online at www.mlicme.org/P11077.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the Certificate for your records.

Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by University of Cincinnati and Medical Learning Institute, Inc. for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Planners and Managers Disclosures Rick Ricer, MD, UC CME Content Reviewer, has nothing to disclose.

Lorrie McSherry, RN, BSN, OCN, MLI Peer Reviewer, is on the advisory board for Onyx.

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FACULTY CHAIRS

Hope S. Rugo, MD

Rüdiger Hehlmann, MD, PhD

clinical application of prognostic and predictive molecular biomarkers toward optimal personalized care for patients with cancer. The inaugural conference of the GBC was held on March 9-11, 2012, in Orlando, Florida. This monoPatricia Woster, PharmD, MLI Peer Reviewer, is a former employee of Eisai and has stock in Pfizer.

Faculty Disclosures Rüdiger Hehlmann, MD, PhD, has nothing to disclose. *Hope S. Rugo, MD, is a researcher for Genentech/Roche, GlaxoSmithKline, ImClone, Merck, Novartis, and Sanofi/BiPar, and is on the speakers 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 Excellence Media, LLC, and Core Principle Solutions, LLC, do not have any financial relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months.

Disclaimer The information provided at this CME/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for any agent discussed in this program should be inferred.

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

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Table 1. Targeting the HER2 Receptor: The First Druggable Target Since Estrogen Receptor6,8-10 Slamon et al6 (N=469*)

Marty et al8 (N=186)

Baselga et al9 (N=808)

Gianni et al10 (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 19.3 mo

38.3

38.5

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, overall survival; P, pertuzumab; PFS/TTP, progression-free survival/time to progression; Tr, trastuzumab.

graph will highlight the key findings from that meeting.

Biomarkers Today – the Link to Therapeutics The ultimate goals in individualized or personalized cancer therapy are to: • Understand the biology of each tumor with respect to risk of recurrence, pathways that drive growth and resistance, and potential targets for therapy • Identify patients who need treatment due to adverse tumor biology characteristics (in addition to traditional tumor characteristics)

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

• Identify benefits of a specific therapy or type of therapy • Avoid ineffective therapies Our current tools allow for an assessment of risk and of the overall benefit of chemotherapy, but in order to achieve true, personalized cancer therapy, tools are needed to predict benefit from a specific therapy and take into account patient preferences. In early-stage breast cancer, we learned from a retrospective analysis by the Early Breast Cancer Trialists’ Collaborative Group that

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estrogen receptor (ER) status could predict the grade of disease, extent of proliferation, likelihood of a response to chemotherapy or hormone therapy, and overall survival.1 Similarly, in prospective trials of patients with node-positive early breast cancer, ER status was shown to predict response to enhanced chemotherapy regimens, including doxorubicin/cyclophosphamide plus paclitaxel, where only patients with ER-negative tumors derived benefit from these enhanced regimens with respect to disease recurrence and overall survival.2 Subsequently, multigene assays were developed (MammaPrint and Oncotype) that provided prognostic information but were not sufficient by themselves to predict chemotherapy benefit, merely complementing clinicalpathological factors.3-5 Unfortunately, breast cancer research has not moved forward from this point. At present, while we can look broadly at the benefit from chemotherapy, hormone therapy, and HER2-directed therapy, we are not yet able to predict which patient will benefit most from a specific therapy.

However, there is a great deal of research ongoing in this area. For example, in patients with HER2-positive metastatic breast cancer, the combined blockade of the HER2 receptor with trastuzumab and pertuzumab resulted in the longest progression-free survival (PFS) in the first-line setting of any subset of breast cancer other than ER-positive disease (Table 1).6-10 Thus, when a treatable target is identified (in this case, HER2), specific agents can be developed that result in improved clinical

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outcomes and that can overcome Table 2. Everolimus in Hormone Receptor–Positive Advanced Breast drug resistance.

Cancer12 Taking these results a step furEverolimus and Placebo and ther, 3 prospective clinical trials Exemestane Exemestane (NeoSphere, Neo-ALLTO, and (N=485) (N=239) P Value GeparQuinto), in which patients Local assessment with HER2-overexpressing breast Progression-free survival cancer were treated with Events (%) 202 (42) 157 (66) <.001 trastuzumab plus pertuzumab or Median duration, mo 6.9 2.8 trastuzumab plus lapatinib, inCentral assessment Progression-free survival cluded serial sampling of tumor tisEvents (%) 114 (24) 104 (44) <.001 sue. Subsequent biomarker analysis Median duration, mo 10.6 4.1 of the tissue samples taken during the NeoSphere trial revealed that while HER2 overexpression was associated with sensiovercome resistance to hormone therapy.12 tivity to pertuzumab, there was no predictive value in There are a number of pathways for more effective the biomarkers tested for patients with specific treatbreast cancer therapy that will require rethinking on ment regimens.11 The challenge is in identifying the aphow drug candidates are tested in clinical trials and what propriate set of biomarkers that can be clearly related to molecular targets should be pursued. Efforts are being benefit from a specific therapy. Failure to do so up to this made in these directions â&#x20AC;&#x201C; in the I-SPY 2 trial, in which point may have contributed to the withdrawal of appromising agents are being screened in combination with standard chemotherapy in the neoadjuvant setting proval for bevacizumab for HER2-negative disease, simto accelerate the process of identifying drugs that are efply because of the lack of a reliable biomarker to identify fective for specific breast cancer subtypes; in attempts the subset of breast cancer patients who would benefit to design agents that target deregulated pathways; and from this drug. by development of clinically and molecularly appropriThe area where we have had the greatest success is ate treatment protocols based on multidisciplinary input in the use of inhibitors of the mammalian target of rapamycin (mTOR). As tumors become increasingly resistant to hormone therapy, they up-regulate signalThe area where we have had the greatest ing through the phosphoinositide 3-kinase (PI3K)/Akt success is in the use of inhibitors of the pathway, and a recent study investigated biomarkers mammalian target of rapamycin (mTOR). that could help identify patients who would benefit from blocking that pathway. In the BOLERO-2 trial, from clinical oncologists, surgeons, radiation oncolopatients with hormone receptor (HR)-positive breast gists, molecular biologists, geneticists, pathologists, and cancer that had become resistant to hormonal therapy patient advocates. were randomized to treatment with everolimus (an mTOR inhibitor) plus exemestane versus placebo plus Comprehending the Next Generation exemestane. As shown in Table 2, median PFS was of Oncology Care significantly improved in patients treated with A technological revolution is driving the expectation everolimus plus exemestane compared with those that we are on the verge of a transformation of aptreated with placebo plus exemestane, suggesting that proaches to cancer management with an attendant imadding an inhibitor of the mTOR pathway can

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Figure 1. Tumor Responses to Crizotinib in Patients With ALK-Positive Non–Small Cell Lung Cancer18 Precent Change in Tumor Burden Percent Change From Baseline

Black: Disease progression Blue: Stable disease Yellow: Partial response Red: Complete response

Patient No.

provement in patient outcomes.13 In this regard, there are an unprecedented number of targeted therapies in clinical trials – about 500 targeted therapies investigating about 140 genomic alterations, with approximately 40 potential genomic targets that will require clinical testing in the near future. In lung cancer, the recogni-

The future of cancer care also relies on the techniques that we are able to develop to uncover actionable cancer genes. tion that EGFR mutations are correlated with clinical response to gefitinib and erlotinib therapy is well known.14-16 However, this was not an isolated example – subsequent work showed that approximately 7% of patients with non–small cell lung cancer (NSCLC) expressed a transforming EML4-ALK fusion gene that was distinct from the EGFR mutations.17 This led to the dramatic finding that 57% of NSCLC patients with the ALK rearrangement responded to treatment with crizotinib, a small-molecule oral inhibitor of ALK tyrosine

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kinase (Figure 1),18 which recently led to the drug’s approval for ALK-positive NSCLC. However, this is an evolving process, as shown by the recent identification of the ROS1 rearrangement that defines a molecular subset of NSCLC (~2% of patients) with distinct clinical characteristics and impressive clinical sensitivity to crizotinib,19 as well as the KIF5B-RET transformation in colorectal cancer and NSCLC cells that are sensitive to multikinase inhibitors that inhibit RET.20 Our ability to characterize the majority of aberrations in actionable cancer genes has made it possible to rapidly test potential biomarkers based on targeting the patients most likely to benefit in a trial. However, implementation of molecular testing into patient care requires that all tests be performed in a Clinical Laboratory Improvement Amendments–certified laboratory with a high degree of quality control and an understanding of the accuracy of the results. As our ability to characterize the genome of tumors from specific patients improves, the number of aberrations discovered and the challenge to determine their relevance to response to targeted therapies will increase, demanding the development of bioinformatic ap-

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proaches to determine which aberrations are the drivers of effective therapy, and novel, critically experimental approaches designed to test the predictive value of the molecular aberrations.

The future of cancer care also relies on the techniques that we are able to develop to uncover actionable cancer genes. The techniques should be used in a complementary effort and include both old and new methodologies: cytomorphology, cytogenetics, immunophenotyping, gene expression profiling, nextgeneration sequencing, histology, fluorescence in situ hybridization (FISH), and molecular genetics.

Incorporating Personalized Medicine Into Practice: A Natural Evolution of Evidence-Based and Translational Medicine to Personalized Medicine Over the past several years, there has been an increase in our understanding of cancer pathogenesis at the molecular level, along with an appreciation of numerous pathways that have been implicated in cancer development and growth. This knowledge has led to the concept that we should be conducting biomarker enrichment trials to improve the efficiency of new therapeutic development for personalized medicine. In conducting biomarker enrichment trials, there are 2 major considerations: • Does a therapeutic agent benefit “biomarker-positive” and/or “biomarker-negative” patients?

• Was this the right biomarker to test, ie, what is the right marker, what are the appropriate materials or specimens to test, and do we have a good biomarker assay available?

There are several possible trial designs in a biomarker enrichment trial. A retrospective validation in which periodic tissue and serum specimens are collected from patients enrolled in a trial in which they are followed for several years. Biomarkers are then retrospectively evaluated and correlated to the pathophysiology and clinical outcomes for each patient. A prospective validation can be carried out in several different ways: • Biomarker testing is performed on all patients, but

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Table 3. Important Issues to Consider in Designing Biomarker Enrichment Clinical Trials • 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 randomization is not based on the results from biomarker testing • Biomarker testing is performed on all patients prior to randomization, and randomization is based on the biomarker-positive or biomarker-negative status of each patient. Each biomarker-randomized patient is then rerandomized or stratified to an experimental

The reproducibility and validity of the biomarker assay is especially important since this is the basis for the concept of personalized medicine. arm or a control. This design is especially interesting in the setting of VEGF inhibitors in breast cancer • The most complex strategy involves a biomarkerguided randomization in parallel with a markerblinded randomization. The biomarker-positive group is placed into the experimental arm, the biomarker-negative group into the control group, and the biomarker-blinded group is rerandomized to an experimental arm or control. The challenge in this design is in getting the physician and patient to agree to follow a therapeutic approach based on biomarker analysis, ie, some patients may actually be resistant to the concept of personalized medicine! This type of biomarker enrichment trial typically required a larger number of enrolled patients Table 3 outlines several of the most important issues

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Figure 2. Mayo Clinic Integrated Approach to Defining the Genomic Landscape of Breast Tumors for Research and Practice Tumor collection

RMLs registry and preparation of both RNA and DNA at collection sites

DNA for whole genome

RNA for whole transcriptome

Library preparation

Library preparation

Hi-Seq sequence analysis

Data analysis Combined bioinformatics team

RMLs indicate regional medical libraries.

to consider in designing biomarker enrichment trials.

The reproducibility and validity of the biomarker assay is especially important since this is the basis for the concept of personalized medicine. Unfortunately, in breast cancer, for example, the discordance rate among different laboratories is ~10% for HR and progesterone receptor

This so-called “Omic Approach” is complementary to the traditional anatomic and histologic analyses of breast cancer. and ~15% for HER2; variability among immunohistochemistry experts is ~8% for FISH testing, although this could be reduced to 3% to 4% if the pathologists examined the specimens together (Perez E. Written communication from the experience at Mayo Clinic).

These types of trials are already prompting a rethink-

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ing of how personalized cancer treatment can be accomplished. For example, in breast cancer, early detection of metastasis-prone tumors and characterization of residual metastatic cancers are important in efforts to improve patient management. Applications of genomescale molecular analysis technologies are making these complementary approaches possible by revealing molecular features uniquely associated with metastatic disease.

Assays that reveal these molecular features will facilitate detection prior to metastatic spread, and knowledge of these features will guide development of therapeutic strategies that can be applied when metastatic disease burden is low, thereby increasing the probability of a curative response.21 This so-called “Omic Approach” is complementary to the traditional anatomic and histologic analyses of breast cancer. However, the genomic approach to the treatment of breast cancer is complex and must take into account gene expression profiles, RNA structure, genomic rearrangements, and gene sequence mutations in order to integrate these features into a model that predicts tumor behavior. Figure 2 outlines the schema used at the Mayo Clinic in accomplishing this goal – DNA and RNA are collected, whole genome sequencing is performed, and a multidisciplinary bioinformatics team is convened to make decisions on applying the data to research and clinical practice.

While incorporation of translational medicine into practice is essential for the future of personalized medicine in oncology, we must not lose sight of the fact that incorporating evidence-based guidelines and pathways into clinical practice is also important in improving patient 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 of care and specifically illuminates the continuum of care • Individual guidelines in which the scope is more restricted, and there may be as many as 1000 decision points posing an enormous challenge in terms of a comprehensive review and analysis of the literature How do guidelines fit into decisions about treatments?

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They should follow clinical decision-making pathways that offer a range of appropriate treatments for specific situations that are included in the guidelines, with the goal of reducing variability in care.22

Reimbursement Challenges and Strategies for Personalized Medicine in Oncology – Perspectives for Providers and Patients To achieve the reality of personalized medicine in oncology, we need to understand how payers review molecular biomarker data for coverage and how these coverage decisions impact providers and patients. Molecular biomarkers are not a special category of test from a payer perspective, and payers evaluate and pay for biomarker testing in the same way they manage all other diagnostic tests (Pezalla E. Written communication of the regulations from Aetna Pharmacy Management). In general, diagnostic tests are always covered under the medical benefit even if they are being used to determine if the patient should receive a specific pharmaceutical, but they are not covered under the pharmacy benefit. Molecular biomarker testing may even be required in some instances by payers before approving a specific therapy; in those cases, the testing will always be covered. However, providers and patients should be aware of channel management by some payers, ie, a requirement to use a particular source for the diagnostic test. This is not merely a cost control issue, it also ensures access to the highest quality laboratories available.

Most payers review all testing, pharmaceuticals, and procedures based on the supporting clinical evidence, primarily in the form of published literature, national professional guidelines (eg, NCCN), FDA findings, and information from developers or manufacturers (Pezalla E. Personal communication of the regulations from Aetna Pharmacy Management). The results of these reviews are typically published in clinical policy bulletins, which are available online for providers and patients.

These bulletins classify tests as experimental or clinically necessary, cite the conditions under which the diagnostic test is deemed necessary, provide a review of

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the literature to support the stated policy, and list payment and diagnostic codes. These are invaluable for providers in managing their patients with cancer. The major criteria for coverage of a molecular biomarker test are that the test accomplishes what it purports to do in terms of accuracy, reliability, and reproducibility, and that the test has a measurable impact on medical decision making and patient outcomes.

The meeting focused on the use of molecular biomarkers in an effort to fully realize the promise of personalized medicine in oncology.

Conclusion The inaugural conference of the Global Biomarkers Consortium represented a unique opportunity for a diverse, world-renowned faculty to convene to discuss the current state of the art in tumor biomarkers from the perspective of providers, payers, and patients. The meeting focused on the use of molecular biomarkers in an effort to fully realize the promise of personalized medicine in oncology.

Because of the wide range of topics discussed, this overview has captured only a small portion of the topics discussed and has avoided discussion of the development of molecular biomarkers for each specific solid tumor and hematologic malignancy discussed at the meeting.

These topics will be reviewed in future editions of Personalized Medicine in Oncology. u

References 1. Early Breast Cancer Trialists’ Collaborative Group (EBCTG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 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 status and outcomes of modern chemotherapy for patients with node-positive breast 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 chemotherapy benefit 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 70gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 2010;120:655-661.

6. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a

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monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-792.

7. Mass RD, Press MF, Anderson S, et al. Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab. Clin Breast Cancer. 2005;6:240-246.

8. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005;23:4265-4274.

9. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab 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, a randomized phase III trial to evaluate bevacizumab (BEV) in combination with trastuzumab (H) + docetaxel (DOC) as first-line therapy for HER2positive locally recurrent/metastatic breast cancer (LR/mBC). Presented at the CTRC-AACR San Antonio Breast Cancer Symposium, December 6-11, 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 phase II study (NeoSphere) in patients (pts) with HER2-positive breast cancer (BC). Presented at the CTRC-AACR San Antonio Breast Cancer Symposium, 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. Genome Res. 2012;22:177-182.

14. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497-1500.

15. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139.

16. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101:13306-13311.

17. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-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 inhibition 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 define a 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 ALK and 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 managing metastatic breast cancer. Breast Cancer Res. 2011;13:230.

22. National Comprehensive Cancer Network; NCCN Guidelines. www.nccn.org.

Reader Survey This month’s question presented by

Personalized medicine can be described as the ability to customize therapy by understanding the molecular and/or genetic characteristics of an individual patient. However, as PMO Strategic Editor Robert Henry points out in this month’s letter (page 9), currently cancer clinical 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 to www.PersonalizedMedOnc.com

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MAY 2-5, 2013

THIRD ANNUAL CONFERENCE

Influencing the Patient-Impact Factor May 2-5, 2013 Westin Diplomat Hollywood, Florida

For more information please visit

www.AVBCConline.org

NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION

Subcutaneous VELCADE Demonstrated Efficacy Consistent With IV for the Primary Endpoint RESPONSE RATES† IN RELAPSED MULTIPLE MYELOMA (MM): SUBCUTANEOUS AND IV AT 12 WEEKS (AFTER 4 CYCLES) Single-agent VELCADE® (bortezomib)

AT 24 WEEKS (AFTER 8 CYCLES) VELCADE±dexamethasone

53% 51%

43% 42%

11% 12%

7% 8% ORR Primary Endpoint

CR

SC (n=148) IV (n=74)

ORR

CR

▼ 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 INFORMATION CONTRAINDICATIONS VELCADE 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

IN ALL INDICATIONS*

Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IV GRADE ≥3

6%

SC (n=147) IV (n=74)

16% ALL GRADES

38% 53% ▼ 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

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.com Reference: 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.

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.

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Rapid Changes in Reimbursement Protocols for Molecular Tests Bruce Quinn, MD, PhD Foley 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 code to a price • The CPT coding system is not designed for rapid change, and the advances in genomic testing are already rapidly accelerating • It may turn out that a coding system more granular than the CPT coding system can provide will be required

M

olecular tests have proliferated over the healthcare claims must be up to the task of telling us past decade, bringing the precision of what genomic tests are being adopted. genomics into reality in Fortunately, an entirely new coding the clinic, but the paysystem is being introduced into the US ment system for nucleic acid–based transaction system for providers and tests has been unchanging and primipayers in 2012 and 2013. Since the tive. This unfortunate state of affairs regulations and policies governing the has limited the ability of payers to enuse of medical procedure codes, especourage (or control) the use of genomic cially in laboratory medicine, may be tests and has seriously handicapped the arcane to many stakeholders, we will ability of researchers to understand provide an overview of how the curwhat genomic tests are being adopted rent system works before describing the into clinical medicine, how they are impending changes. While policies for being used, and whether they are havcoverage and payment may differ Bruce Quinn, MD, PhD ing an impact on health outcomes. In somewhat between private payers and an era where there is increasing emfederal payers like Medicare, we will phasis on the need for “practice-based evidence” (from focus on the standard-setting efforts of Medicare as the observational studies and pragmatic trials that can supprototypic payment system for outpatient procedures.

This article discusses why coding systems are really quite plement formal randomized clinical trials), our electronic medical records and our transaction systems for important for the smooth functioning of our healthcare Dr Quinn is Senior Health Policy Specialist for the Foley Hoag law firm and is a national expert on Medicare policy, the impact of health reform on innovation, and the crafting of successful business strategies within the US healthcare reimbursement system.

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system and how the coding system for genomic tests is being reengineered. We also sketch the shape of a policy battle among different stakeholders as to what payment system should be employed from 2013 forward for genomic tests. Finally, we discuss a few problems that the proposed coding system cannot yet address.

Codes as a Scaffold for Healthcare Procedures and the Flow of Funds Despite calls for a more rational and holistic approach to payment for healthcare services in the United States, much of the reimbursement for outpatient healthcare flows through line item reimbursement – the longstanding “fee-for-service” system.1,2 Because thousands of individual services, drugs, and tests exist, the operation of a modern fee-for-service system requires a highly granular system of codes that allows providers to communicate with payers, informing the latter of what particular services have been performed on a given day.

The US healthcare system has evolved a family of different, independent, legally recognized coding systems for different types of items and services: there are different code sets to categorize hospitalizations, physician services, laboratory tests, drugs, and supplies. While the underlying coding systems for government and private payment systems are fundamentally the same because they are set by law, a particular payer can determine the means by which it negotiates or sets prices for the service represented by a certain code. For the largest payment system, the Medicare system, each set of codes (which may contain literally thousands of distinct codes) is crosswalked to a publicly available pricing table in which each service is assigned a price. And each Medicare pricing table reflects the result of the machinations and operations of one or another incredibly arcane 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 a clinical event to a coding system and finally to a pricing

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system, resulting in a line item dollar reimbursement that is sent back to the provider of the medical service.

An economist’s view of the transaction would be different: it is a view where the dollar transaction is paramount, because a price encompasses crucial signals as to how the marketplace and recipient of a service value that service. Price tells the producer what to provide, when, where, and in what quantity. Prices are the invisible but powerful guiding hand of the market. Little of that wisdom is conveyed by Medicare’s prices, however, at least not intentionally, because Medicare’s prices blindly follow one or another set of dry accounting rules to distribute a limited pool of payments based on various tables of data and rules that manipulate those bits of data into a price.

Fortunately, an entirely new coding system is being introduced into the US transaction system for providers and payers in 2012 and 2013.

This background leads to how Medicare reimburses for genomic tests. Up until 2012, Medicare has used an extremely simplistic system to reimburse for human germline and somatic genomic tests, consisting of a handful of mostly 20-year-old codes that represent a few basic laboratory bench processes like “DNA extraction,” “nucleic acid amplification,” and “sequencing.” Although there was a bit of state-to-state variation in pricing, these molecular steps generally paid about $20 each.

A genetic test that required 5 such steps usually was reimbursed about $100, and a test that required 10 molecular steps was likely reimbursed about $200. Medicare (and most other governmental and private payers) reimbursed for genomic tests in this way because a small handful of process-specific codes were the only means provided in the federally designated codebook for laboratory tests, the Current Procedural Terminology (CPT) manual of the American Medical Association (AMA).3 We are at the edge of a truly unprecedented increase

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in the available codes for genomic tests, and they will soon be far more specific than in the past. By 2013, the AMA CPT manual will contain well over 100 specific Category I codes for named genetic tests, and another set of 9 codes representing tiers of increasing complexity.

These tiers will collectively represent many dozens to eventually hundreds of additional genetic tests, with each named test assigned to a specific tier by text found in the AMA manual. During the 2012 calendar year, and perhaps into 2013, Medicare will create tables that match each new code to a price. Medicare policy staff will laboriously assign a new, administratively specific price to each of the AMA CPT genetic codes. This article provides an orientation on how the laboratory test

The AMA CPT code set in its modern form with 5-digit classifiers was initially established in 1970 and is updated annually. coding system for oncologic genetic tests worked up until now, how it is changing, and explains some of the policy options that Medicare administrators will face in 2012 as they apply one or another set of rules to the price-setting process. The outcome of these deliberations is important for the future of personalized medicine in oncology, because price signals carry enormous weight in encouraging or discouraging the supply of new medically necessary tests. In addition, the weight of these implications carries beyond Medicare beneficiaries alone, since most private payers closely follow Medicareâ&#x20AC;&#x2122;s tables for reimbursement, in lieu of the impossible task of setting thousands of prices de novo at each of hundreds of individual US insurers.

The Code Set: How It Was Through 2011 The AMA CPT code set in its modern form with 5digit classifiers was initially established in 1970 and is updated annually.4-6 While the Health Insurance Portability and Accountability Act of 1996 is best known for

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its privacy and security rules, it also required the US Department of Health & Human Services to specify by regulation mandatory public code sets for transactions between healthcare providers and payers. In 2000, regulations finalized by the Centers for Medicare & Medicaid Services (CMS) endorsed and locked in the AMA CPT code set, the obligatory code set for most outpatient transactions such as physician and laboratory services.7 The CPT established the first molecular test process codes in 1993. By 1997, there were still only 6 molecular process codes (such as 83890, molecular diagnostics: isolation or extraction) to convey the provision of genetic tests to insurers.8 By 2010, despite enormous advances in genomic technologies and the widespread use of genetic and genomic tests, the AMA CPT handbook still provided only 20 codes, each reflecting one or another single generic process used at the laboratory bench (in some cases today, in electronic DNA test cartridges) during the workflow of genomic testing. There was increasing pressure from payers to provide a more comprehensive and rational code that would correspond to the actual test being performed â&#x20AC;&#x201C; for example, a KRAS genetic test for a lung cancer patient, a BRCA genetic test for a woman at high risk of breast cancer.

The Code Set: How It Will Be in 2012/2013 The multidisciplinary AMA editorial panel that approves the entry of new codes into the CPT manual meets 3 times a year, approving codes to be published in the following year. Under the auspices of the editorial panel, a workgroup was convened by the College of American Pathologists and the Association of Molecular Pathologists. Over a 2-year period, the workgroup vetted the wording of over 100 new molecular CPT codes, passing them on in groups of several dozen codes to be approved by the AMA editorial committee.9 Early on, the workgroup determined that there would be approximately 100 gene-specific codes, representing genes that were either tests for germline mutations or for somatic mutations (eg, cancer).10 After those codes were

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established, the workgroup created another level of 9 CPT codes that represent levels of complexity for molecular tests and a list of multiple-named genes eligible to be represented by that code. In the future, highly validated and relatively popular tests may be assigned new specific CPT codes, and new but less common genetic tests will be assigned in groups to the 9 levels of the Tier 2 molecular codes. The new codes occupy 9 full pages of the 2012 edition of the AMA CPT handbook.3

A Pricing Policy Dilemma Blocks Medicare’s Use of New CPT Codes For policy purposes, Medicare has long divided laboratory tests into 2 broad groups: laboratory tests that are viewed as physician pathology services, and clinical laboratory tests. Like MRI or PET scans, physician pathology services require a licensed physician to interpret them and issue a report. Medicare must distinguish between personal services of a physician (a Part B service) and services of an institution (eg, the technical component of a PET scan) in order to enforce longstanding distinctions between Part A (institutional) and Part B (physician) services. Usually the choice to categorize a laboratory test as a physician pathology test and a clinical laboratory test is unequivocal: for example, only a physician can sign out the intraoperative frozen section of a suspected tumor mass, while a thyroid hormone test in a blood sample is a benchtop laboratory service requiring the expertise of a technologist and a laboratory director (who may be a PhD or MD). However, as in most matters when a bureaucracy becomes involved, a few decades ago Medicare found it had to write specific regulations to enforce this seemingly commonsensical concept. In 1980, during the Carter administration, Medicare issued a federal policy notice sharply limiting what services would be payable to a physician pathologist, resulting in a lawsuit against the US Department of Health & Human Services by the College of American Pathologists. In 1982, during the Reagan administration, Congress passed a new law that gave Medicare line item statutory authority to determine what was, and was not, payable as the services of a physician. The re-

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sulting regulations survived a court challenge in 1983 and are largely unchanged today. Medicare specified as a general rule that services payable to a physician (any physician) must be usually provided by physicians, followed by a more specific rule singular to pathologists: laboratory tests payable to a pathologist must be either surgical pathology services or specific cytology and hematology services determined to “require” a physician (such as the frozen section of a tumor mass noted above). Medicare also allowed payment for a consultation between a pathologist and a clinician in narrow circumstances when the consultation is requested in writing, not as a standing order, and required that such a consultation be based on a test report outside the expected range for the patient’s condition.

Highly validated and relatively popular tests may be assigned new specific CPT codes, and new but less common genetic tests will be assigned in groups to the 9 levels of the Tier 2 molecular codes.

These 20-year-old regulations unexpectedly took on a new life in 2011 following activities at the AMA. Although the “stacking codes” for molecular tests had been classified since their initiation as clinical laboratory tests (ie, as a type of clinical chemistry test), the AMA’s new genetic codes were taken for review by the AMA Relative Value Update Committee, which exists to evaluate and value services paid on the Physician Fee Schedule, such as personal services of physician pathologists. Relative value units were assigned to the codes, as they were assigned to other new physician services, such as surgeries, and the results were forwarded for the review and approval of CMS. Faced with a dilemma of whether to evaluate the new genomic codes on the Clinical Laboratory Fee Schedule or on the Physician Fee Schedule – 2 entirely different pricing processes with different rules – CMS announced on November 25, 2011, that it had assigned the new genetic CPT codes to neither fee

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schedule and would not use the codes at all in calendar year 2012.11 In a response letter, the College of American Pathologists criticized this decision (it was “astonished”) and urged CMS to use the codes, and to use them under the valuation processes and rules of the Physician Fee Schedule by classifying genetic tests as the personal service of a physician.12 In short, this request would have moved hundreds of millions of dollars worth of genetic tests from the ledgers of the Clinical Laboratory Fee Schedule (and its associated policies) to the Physician 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 laboratory tests are of the clinical chemistry type, not pathologist services. These tests follow regulations that require announcement of the new clinical laboratory codes in July, solicitation of public comments as to how they should be priced, and publication of the final agency prices around December 1, effective for the upcoming

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... calendar year. CMS may assign prices for clinical chemistry tests by “crosswalking” the codes to the price or sum of prices of existing (prior) codes, or may “gapfill” the prices by asking its claims processing contractors to assign prices in the first half of the coming year, from which it calculates median prices for national use.

Alternatively, CMS can treat the new laboratory test as a physician pathology service, in which case it publishes provisional values from the Relative Value Update Committee for the professional interpretation component of the test and for the technical component of the test in June. (The professional component is payable to the physician even in cases, like that of a hospital inpa-

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tient, where the technical component is bundled to a Diagnosis-Related Group and is not paid separately.)

The assignment to a fee schedule has other policy implications. For example, as with other physician services, a 20% copayment is applied to physician pathology tests, whereas currently Medicare policy requires no copayment for clinical laboratory tests. Medicare takes comments on these Physician Fee Schedule payment values over the summer and publishes final prices for the coming fiscal year about November 1. In some cases, the prices 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, it seems likely that the new genetic codes will end up on Medicare’s Clinical Laboratory Fee Schedule. This is because of Medicare’s own regulations: Medicare wrote its own rules that determined that services payable to a pathologist must either be surgical pathology services or “require” a physician, and most genomic laboratory tests are signed out by PhD-holding lab professionals. Therefore, simply put, the tests do not meet the current legal bar of “requiring” a physician. However, the resolution of the fee schedule question depends on Medicare publicly announcing provisional decisions, taking public comments, and then coming to a final decision.

Arguments for assignment to the Physician Fee Schedule include the position that it is a “cost-saving methodology”12 and will result in copayment requirements for patients, which could be a deterrent to test utilization.

Assessment of the New Genomic Codes There is no question that the 100-plus new genomic codes are a great improvement in precision over the process codes that bluntly described processes like DNA amplification and gave no clue to what gene was being tested. However, the CPT coding system is not designed for rapid change, and the advances in genomic testing are already rapidly accelerating. It is likely that at least for some specialized applications such as tumor exome analysis, techniques based on next-generation sequenc-

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ing will become a practical clinical methodology within the next few years, but the coding system for 2013 is already set and makes no allowance for high-throughput sequencing approaches. To date, there have been no CPT codes for gene-expression algorithm–based tests, which are well accepted in US oncology practice for breast cancer prognosis and clinical decision making.

The AMA CPT editorial panel has proposed a new group of codes, called Multi-Analyte Assays with Algorithms (MAAAs), which will appear in the AMA CPT manual for 2013. It may take a year or longer for the Medicare program to adopt these codes, but they will facilitate tracking the usage and utility of the tests in clinical 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 called Tier 2 genomic codes. In this arm of the coding system, a dozen or potentially a hundred or more unique genomic tests could be represented by only 1 code. This would imply that it would be difficult for payers to price discriminate among tests represented by the same code and impossible to differentiate coverage policies among tests 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 is FDA-approved or not. The FDA has stated in guidance documents that it will, in general, only approve new indications of targeted drugs that require a genetic test if there is a corresponding and FDA-approved brand of the test. However, the FDA generally cannot enforce what test is used by clinicians and laboratorians. Payers will be concerned whether the test being used for the patient, and for which they are being billed, is appropriately validated. A fully validated and controlled test that is sensitive and accurate could certainly be a labo-

We’re just a

ratory-developed test. However, there is no way for the laboratory to signal the quality of its test nor for the payer to cover a test it views as adequately validated. It may turn out that a coding system more granular than the CPT coding system can provide will be required.

There are currently several efforts under way to develop such alternative systems, one of the most advanced being a coding system for molecular tests developed by McKesson, Inc and currently used by 1 Medicare contractor and being discussed in the trade press.13 How quickly this system, or a similar highly granular system, could take its place in the coding and payment process remains to be seen. u

References 1. Newcomer LN. Changing physician incentives for cancer care to reward better 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 patients with cancer in the Veterans Health Administration versus fee-for-service Medicare. 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 Coalition. CPT code-change proposal: national data on pharmacists medication therapy management services. J Amer Pharm Assoc. 2007;47:491-495.

5. CPTcodingbooks.com. CPT-4 code process – how a code becomes a code. www.cptcodingbooks.com/codes/information.html. Accessed April 13, 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 laboratory services. 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/eco nomics/AMPCPTReformProposal_Final.pdf. November 2009. Accessed April 13, 2012.

11. Centers for Medicare & Medicaid Services. Medicare program; payment policies under the physician fee schedule, five-year review of work relative value units, clinical laboratory fee schedule: signature on requisition, and other revisions to part B for CY 2012. Final rule with comment period. 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 considering outsourcing MDx claims to specialty vendors. Genomeweb. Pharmacogenomics Reporter. www.genomeweb.com/mdx/harvard-pilgrim-trustmarkjoin-other-payors-considering-outsourcing-mdx-claims-s. April 18, 2012.

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Melanoma

Management of Ipilimumab-Related Toxicities Patrick A. Ott, MD, PhD Dana-Farber Cancer Institute, Boston, Massachusetts Howard L. Kaufman, MD, FACS Rush University Medical Center, Chicago, Illinois F. Stephen Hodi, MD Dana-Farber Cancer Institute, Boston, Massachusetts

Key Points • The clinical efficacy of ipilimumab in patients with metastatic melanoma has been demonstrated in 2 phase 3 trials, 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 profile of this drug emerged • The toxicities of ipilimumab are mainly manifestations of organ-specific inflammation primarily affecting the skin, gastrointestinal tract, liver, and endocrine system • Diarrhea and rash, the most common side effects in patients treated with ipilimumab, are easily recognized and should be managed as autoimmune enteritis/dermatitis irAEs while ruling out other etiologies

I

pilimumab, a monoclonal antibody that blocks the negative costimulatory molecule CTLA-4 on T cells, leading to augmented T-cell activation and proliferation, improves overall survival (OS) in patients with metastatic melanoma and was approved by the regulatory agencies in the United States and several other countries for the treatment of unresectable melanoma. Consistent with its mechanism of action, the drug’s toxicities are mainly manifestations of

Howard L. Kaufman, MD, FACS

organ-specific inflammation primarily affecting the skin, gastrointestinal tract, liver, and endocrine system.

Rarely do these effects lead to serious complications such as bowel perforation and adrenal insufficiency. As ipilimumab is moved from clinical trials into broader use by general medical oncologists, it is critical that the clinician has comprehensive knowledge of the full spectrum of these immune-related adverse events (irAEs; also called adverse events of special interest), in

Dr Ott is a member of the Melanoma Disease Center at Dana-Farber Cancer Institute and Assistant Professor of Medicine at Harvard 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 Professor of Surgery and Immunology & Microbiology at the Rush University Medical Center. His primary research interests are in melanoma and tumor immunotherapy.

Dr Hodi is Director of the Melanoma Disease Center at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School. His professional interests are in gene therapy for cancer, melanoma, and tumor immunology.

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order to develop an individualized approach to their management. Physicians should maintain a high level of awareness for signs of symptoms of these toxicities and be prepared to intervene early and effectively when appropriate.

CTLA-4 Is an Important ImmuneRegulatory Molecule in T-Cell Activation Active immunotherapy targeted at T cells relies on the presentation or cross-presentation of antigens by tumor or antigen-presenting cells and on the induction of T effector cells that are specific to these antigens, long-lived, and capable of killing tumor cells. T-cell activation requires 2 signals. The first signal constitutes

Blockade of CTLA-4 with the fully human monoclonal antibody (IgG1κ) ipilimumab impedes its binding to B7 and thereby enhances T-cell responses. the binding of the T-cell receptor (TCR) to a tumor peptide presented by the major histocompatibility complex (MHC). For full T-cell activation, this TCR-MHCpeptide interaction must be accompanied by a second signal, which is mediated by the binding of CD28 on T cells to the costimulatory molecules CD80 and CD86 (both members of the B7 protein family) on the surface of an antigen-presenting cell.1-3 T-cell stimulation results in the proliferation of T cells and initiates effector functions such as cytokine secretion and the release of granzyme B and perforin needed for cell killing. T-cell activation also leads to up-regulation of the CD28 homolog CTLA-4 (a member of the immunoglobulin superfamily), which has a much higher binding affinity than CD28 to B7, leading to T-cell inhibition. This interplay of positive and negative immune regulation on the surfaces of T cells and antigen-presenting cells is a tightly controlled, temporally restricted, and dynamic process aimed at containing a potentially hazardous Tcell response.4 The significance of CTLA-4 as an in-

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hibitory molecule is illustrated by the association with autoimmune disease, as evidenced by an increased risk of autoimmunity in patients with single nucleotide CTLA-4 polymorphisms and massive lymphoproliferation in mice lacking CTLA-4 function.5-7 Other inhibitory molecules, such as programmed death (PD) molecules, are expressed on the surface of T cells and contribute to this intrinsic control of T-cell activation; PD-1 is also a target in clinical development.

Targeting CTLA-4 With Ipilimumab Is Effective in Patients With Advanced Melanoma Blockade of CTLA-4 with the fully human monoclonal antibody (IgG1κ) ipilimumab impedes its binding to B7 and thereby enhances T-cell responses. The clinical efficacy of ipilimumab in patients with metastatic melanoma was initially demonstrated in a series of phase 2 studies in which the drug was given at 10 mg/kg every 3 weeks for 4 doses, followed by maintenance therapy with infusions every 3 months.8,9 In 1 study, 2 additional dose cohorts received ipilimumab at either 0.3 or 3 mg/kg, respectively.10 These efficacy data were confirmed in 2 phase 3 trials that revealed a survival benefit. The first study was a randomized, doubleblind trial in which 676 patients were enrolled on 3 arms at a 3:1:1 ratio: 1) ipilimumab at 3 mg/kg in combination with an HLA-A2–restricted gp100 peptide vaccine, 2) ipilimumab at 3 mg/kg and placebo, and 3) gp100 peptide vaccine combined with placebo.11 Patients with clinical benefit defined as stable disease of ≥3 months’ duration or an objective response (partial response or complete response) were eligible for additional reinduction doses of the same regimen they previously received. Ipilimumab with or without the gp100 peptide vaccine led to an improvement in OS, with a 32% to 34% risk reduction of death (hazard ratios [HRs] of 0.68 and 0.66, respectively) compared with gp100 and placebo. The median OS was 10.1 months for ipilimumab and placebo and 10.0 months for ipilimumab and gp100, compared with 6.4 months for gp100 and placebo (P<.001 and P=.003, respectively). The lack of

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Table 1. irAE Profile of Metastatic Melanoma Patients Treated With Ipilimumab in Phase 2 and 3 Trials Phase 2 Wolchok et al10 Ipilimumab 3 mg/kg Ipilimumab 10 mg/kg (n=71) (n=71)

Dermatologic Gastrointestinal Endocrine Hepatic

Total Grade 3-4 Total 32 (45.1) 1 (1.4) 33 (42.3) 23 (32.4) 2 (2.8) 28 (39.4) 4 (5.6) 2 (2.8) 3 (4.2) 0 0 2 (2.8)

Grade 3-4 3 (4.2) 11 (15.5) 1 (1.4) 2 (2.8)

Oâ&#x20AC;&#x2122;Day et al8

Weber et al9

Ipilimumab 10 mg/kg (n=155)

Ipilimumab 10 mg/kg (n=57)

Total 76 (49.0) 48 (31.0) 9 (5.8) 14 (9.0)

Grade 3-4 5 (3.2) 13 (8.4) 2 (1.3) 11 (7.1)

Total 39 (68) 26 (46) 6 (11) 8 (14)

Grade 3-4 0 13 (22.8) 3 (5) 7 (12.3)

Phase 3 Hodi et al11 Ipilimumab 3 mg/kg + gp100 (n=380)

Robert et al12 Ipilimumab 10 mg/kg + dacarbazine (n=247)

Total

Grade 3-4

Total

Grade 3-4

Dermatologic Rash Pruritus

152 (40.0) 67 (17.6) 67 (17.6)

9 (2.4) 5 (1.3) 1 (0.3)

55 (22.3) 66 (26.7)

3 (1.2) 5 (2.0)

Gastrointestinal Diarrhea Colitis

122 (32.1) 115 (30.3) 20 (5.3)

22 (5.8) 14 (3.7) 12 (3.2)

81 (32.8) 11 (4.5)

10 (4.0) 4 (2.0)

15 (3.9) 6 (1.6) 3 (0.8) 2 (0.5) 3 (0.8)

4 (1.1) 1 (0.3) 2 (0.5) 2 (0.5) 2 (0.5)

72 (29.1) 66 (26.7) 4 (1.6)

51 (20.6) 43 (17.4) 3 (1.2)

Endocrine Hypothyroidism Hypopituitarism Hypophysitis Adrenal insufficiency Hepatic Elevated AST Elevated ALT Hepatitis

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

an OS difference between the ipilimumab arms suggests that the OS benefit is driven by ipilimumab alone.

There is a subset of patients who apparently have a prolonged and durable survival benefit of treatment. The encouraging 2-year survival rate of 23.5% in this pretreated population with a high proportion of poor-risk

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prognostic criteria such as elevated lactate dehydrogenase, M1c disease, and brain metastases is consistent with data from prior phase 2 studies. The results from this trial led to approval of ipilimumab by the FDA for patients with unresectable stage III or stage IV melanoma. Similar findings were reported when ipi-

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limumab was given in the first-line setting. In a randomized phase 3 trial, patients with previously untreated metastatic melanoma received ipilimumab 10 mg/kg every 3 weeks for 4 doses plus dacarbazine or dacarbazine alone.12 Patients with an objective response or stable disease and no dose-limiting adverse events received maintenance treatment with ipilimumab or placebo every 3 months. A significantly improved OS of 11.2 months with ipilimumab and dacarbazine over 9.1 months with dacarbazine alone was seen in this study. The HR for death with ipilimumab-dacarbazine treatment was 0.72 (P<.001).

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

The toxicity profiles in the 2 phase 3 clinical trials were different, with more gastrointestinal toxicity in the trial using ipilimumab versus gp100 versus the combination of both, and a higher rate of hepatic toxicity in the ipilimumab-dacarbazine versus dacarbazine trial.10 The reasons for this shift are not clear but may be related to better recognition and management of immunerelated diarrhea and colitis in the former trial and the use of dacarbazine, which may also result in hepatic toxicity, in the latter trial. These observations highlight the complexity of responses to ipilimumab and suggest that careful attention to each patient, their underlying medical comorbidities, and concurrent and previous treatment history is important for monitoring and managing complications from therapy.

Immune-Related Adverse Events CTLA-4 blockade can break peripheral T-cell tolerance to self-antigens, which is an expected effect that was recognized early in the development of monoclonal antibodies specific for CTLA-4 in preclinical and initial clinical studies. Mice with B16 melanoma treated with a combination of anti–CTLA-4 antibody and a granu-

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locyte-macrophage colony-stimulating factor–producing tumor cell vaccine developed autoimmune skin depigmentation characterized by polymorphonuclear cells infiltrating the dermis.13 Early clinical phase 1 and 2 studies using ipilimumab consistently demonstrated autoimmune manifestations such as dermatitis, rash, vitiligo, enterocolitis, hepatitis, and hypophysitis.14-16 Rare autoimmune events such as Guillain-Barré–like syndrome, myasthenia gravis, lupus nephritis, sarcoidosis, and myositis/arthritis have also been reported after treatment with ipilimumab.17,18 Because of their distinct immunologic characteristics, these manifestations are referred to as irAEs. There is some correlation between ipilimumab dosing and the severity and frequency of irAEs. This observation was apparent in several of the earlier phase 1 and 2 trials and has been the clinical experience of many investigators involved early in the clinical development of the drug.10,19,20 Consistent with these observations, in the 2 phase 3 trials discussed above, total irAEs were more frequent in the study in which ipilimumab was used at 10 mg/kg in combination with dacarbazine compared with the trial in which it was given without chemotherapy at 3 mg/kg. However, the difference in total frequency of irAEs was mainly driven by a hepatotoxicity rate of up to 30% of the patients treated with ipilimumab at 10 mg/kg plus dacarbazine (Table 1). In contrast, hepatotoxicity was not reported in another phase 3 trial in which ipilimumab was given at 3 mg/kg. Moreover, no endocrinopathies were reported with ipilimumab at 10 mg/kg in the phase 3 setting, which is somewhat unexpected based on the phase 2 experience, in which endocrinopathies consistently occurred across studies at a rate of 4% to 11% (Table 1).8-10 The rates of high-grade (3/4) rash, colitis, and diarrhea were similar in the 2 phase 3 trials despite their use of ipilimumab at different doses.11,12 The majority of irAEs occur during the 12-week induction period with ipilimumab. Fewer than 10% of long-term survivors experienced a new irAE that manifested ≥10 weeks after ipilimumab, and all but 1 event were low grade.11 Skin and gastrointestinal events are

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the most common irAEs and most commonly appear earlier after treatment initiation than endocrine events or hepatotoxicity. Most irAEs are low grade, can be treated symptomatically, and do not lead to dose delays or reductions. Fifteen percent to 40% are high-grade events that require immediate treatment with high doses of corticosteroids. In rare instances, irAEs are refractory to corticosteroid treatment; other immunosuppressive agents, such as infliximab or mycophenolate mofetil, 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 activity of ipilimumab. Early clinical studies seemed to support that notion,14,21-24 however, in a meta-analysis of 3 phase 2 trials it was shown that patients with advanced melanoma can achieve a clinical benefit with ipilimumab treatment in the absence of irAEs.25,26

Gastrointestinal Toxicity Gastrointestinal irAEs occur most commonly in the lower gastrointestinal tract, with diarrhea being the hallmark symptom. Abdominal pain, nausea and vomiting, anal/rectal pain, hematochezia, and fever have also been reported. Upper gastrointestinal involvement manifests as esophagitis and/or duodenitis. Endoscopically, the colonic mucosa appears erythematous and ulcerated; lymphocytic and/or leukocytic infiltration on histologic examination confirms an etiology of immune-mediated enterocolitis in most cases.24 Ipilimumab-induced ente-

Dermatitis Rash and pruritus are the most frequent irAEs associated with ipilimumab, occurring in 40% to 50% of patients. The vast majority of events are low grade and are treated symptomatically, eg, with antihistamines, while the patient remains on therapy. However, skin manifestations that persist for 1 to 2 weeks should be treated with topical or moderate doses of systemic corticosteroids (eg, prednisone once daily). Severe rash or pruritus needs to be evaluated by a dermatologist, and a biopsy should be performed if appropriate; ipilimumab treatment must be delayed. Toxic epidermal necrolysis resulting in death has been reported in a patient treated with ipilimumab.11 High-dose corticosteroids (eg, methylprednisolone 2 mg/kg once or twice per day) are required for persistent severe skin toxicity and should be tapered over a period of at least 4 to 6 weeks once the rash or pruritus has been controlled. For grade 3 skin events that have improved to grade â&#x2030;¤1, reinitiation of ipilimumab can be considered. For grade 4 toxicity, treatment must be discontinued indefinitely. In complicated cases, early consultation with a dermatologist should be considered.

rocolitis can lead to intestinal perforation and death, particularly when therapeutic intervention with highdose corticosteroids is delayed. In the phase 3 trials, allgrade diarrhea and colitis were seen in approximately 35% of patients; high grades of diarrhea and colitis were reported in 6% to 10% of patients treated with ipilimumab at 3 mg/kg and in 6% of patients treated with 10 mg/kg. In 1 trial directly comparing different doses of ipilimumab, there was a suggestion of a dose effect (15.1% gastrointestinal irAEs with 10 mg/kg, 4.2% with 3 mg/kg, and none with 0.3 mg/kg).10 In the phase 2 experience, with most patients receiving 10 mg/kg, grade 3 and 4 gastrointestinal irAEs were seen in 8.4% to 23% of patients.8-10 Most cases of grade 1 and 2 diarrhea respond to symptomatic treatment with loperamide if initiated early, preferably on the first day of occurrence. It is critical that all patients who will receive ipilimumab are educated about the importance of this potentially life-threatening adverse event, and that symptoms are communicated to the clinician promptly and reliably.

Ipilimumab can be continued for grade 1 diarrhea; if grade 2 improves to grade â&#x2030;¤1, ipilimumab should also be continued. Other etiologies for diarrhea need to be ruled

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

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

Symptoms/Signs

Diagnosis

Gastrointestinal

Diarrhea, colitis: abdominal pain, nausea and vomiting, anal/rectal pain, hematochezia, fever

• History • Colonoscopy • Rule 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, fatigue, weakness, lethargy, constipation, decreased libido, impotence, amenorrhea, hypotension, hypoglycemia, hyponatremia

• History • Serum levels for: TSH, free T4, T3, ACTH, morning cortisol, LH, FSH, testosterone, prolactin • MRI brain scan with pituitary cuts • Thyroid imaging/functional testing, if appropriate • Rule out other etiologies

Hepatotoxicity

Most often asymptomatic. Elevated transaminases and/or bilirubin

• Baseline LFT • Hepatitis serologies • 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;

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

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endoscopy, high-dose IV corticosteroids followed by a 4- 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-

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Management Grade 1

Grade 2

Grade 3/4

• Symptomatic treatment (loperamide, bismuth subsalicylate) • Continue ipilimumab

• Symptomatic treatment (loperamide, bismuth subsalicylate) • Hold ipilimumab • If no resolution to grade 1 within 3-4 days, treat as grade 3/4

• High-dose corticosteroids • IV fluids • Consider hospitalization and IV administration of steroids • Infliximab if no response to steroids after 5-7 days • Discontinue ipilimumab permanently

• Antihistamines, topical steroids, moisturizing lotion • Continue ipilimumab

• Antihistamines, topical steroids, moisturizing lotion • Consider holding next dose until resolution to grade 1

• High-dose corticosteroids • Hold ipilimumab • Permanently discontinue ipilimumab for grade 4 • Consider 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 corticosteroids (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: • Hold ipilimumab • Intensify monitoring (LFT q3 days)

LFT ≥8x ULN and/or total bilirubin ≥5x ULN: • Hold ipilimumab • 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.

dian time to resolution of grade 2-4 diarrhea was approximately 2 weeks.11 If no improvement is seen after 5 to 7 days of moderate to severe diarrhea, the anti–TNF-α antibody infliximab at a dose of 5 mg/kg is indicated and

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

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permanently discontinued in patients with high-grade gastrointestinal toxicity. There is some evidence that the implementation of treatment guidelines for the management of gastrointestinal irAEs has resulted in decreased incidence in the rates of bowel perforation and the need for colectomy.27 Prophylactic treatment with budesonide does not appear to reduce the colitis rate, as documented in a randomized phase 2 trial.9

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

Although much less common, pancreatitis has also been reported after treatment with ipilimumab. The management consists of supportive care, early initiation of systemic corticosteroids, and close observation. A search for other causes should be considered in patients who do not respond quickly to steroids.

Hepatotoxicity Immune-mediated hepatitis usually manifests as asymptomatic elevation in liver function tests (LFTs).

Histologically, acute hepatic inflammation with ballooning degeneration of hepatocytes and predominantly lymphocytic infiltration has been reported.14 In the phase 2 trials, liver toxicity (all grades) occurred in 7% to 14% of patients who were treated with ipilimumab at 10 mg/kg. In the phase 3 setting, hepatotoxicity was reported in 4.5% of patients treated with ipilimumab monotherapy or ipilimumab plus gp100,11 whereas almost one-third of patients experienced immune-mediated hepatitis in the phase 3 trial in which ipilimumab was given at 10 mg/kg in combination with dacarbazine.12 The markedly higher incidence of hepatotoxicity when ipilimumab is given concurrently with dacarbazine highlights the importance of careful examination of its toxicity profile when given concurrently with other agents. LFTs elevated to grade ≥2 (≥2.5 the upper limit of normal [ULN]) or ≥2x above grade 1/2

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elevated baseline values in a patient on ipilimumab should prompt closer monitoring with LFTs (at least every 3 days). A viral or idiopathic autoimmune hepatitis should be ruled out by serologic testing for hepatitis antibodies/antigens and antibodies to nuclei and smooth muscle. Furthermore, imaging should be performed to rule out metastases, and a liver biopsy should be considered. Ipilimumab must be held until LFTs have returned to normal or baseline values.

If LFTs rise to ≥8x ULN or bilirubin to ≥5x ULN, ipilimumab should be held. Hospitalization should be considered for close monitoring of hepatic function, consideration of liver biopsy to confirm diagnosis, and high-dose corticosteroids be administered, starting at 2 mg/kg of methylprednisolone daily. In the hospital, liver function must be monitored daily until stabilization or decrease of LFT, and subsequently at least every 3 days for a minimum of 2 weeks post-LFT peak. For immune hepatitis refractory to corticosteroids, other immunosuppressive agents such as mycophenolate mofetil, tacrolimus, or infliximab have shown efficacy in the appropriate setting in conjunction with supportive management such as prophylaxis for opportunistic infections.25 Early consultation with a gastroenterologist or hepatologist may also be useful.

Endocrinopathies Nonspecific symptoms such as fatigue, myalgia, headaches, visual disturbances, decreased libido, weakness, asthenia, anorexia, and constipation should raise the suspicion for an endocrinopathy of the thyroid, pituitary gland, or adrenal gland in any patient treated with ipilimumab. Endocrinopathies were reported in 4% to 11% (all grades) and 1% to 5% (grades 3/4) of patients treated in phase 2 trials with ipilimumab given at 10 mg/kg. At 3 mg/kg dosing of ipilimumab alone or in combination with gp100 in the phase 3 setting, 4% to 7% of patients experienced hypothyroidism, hypopituitarism, hypophysitis, or rarely adrenal insufficiency.

Somewhat surprisingly, no cases of hypophysitis were reported with ipilimumab plus dacarbazine in a phase 3 trial.12 Endocrine toxicity is generally diagnosed at a me-

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dian of 10 weeks after treatment initiation, which is later than most dermatologic and gastrointestinal irAEs become apparent.

Autoimmune hypophysitis in many cases manifests as enlargement of the hypophysis with thickening of the hypophyseal stalk on an MRI scan,28 but it can also be nonapparent on imaging. Histologically, an infiltration with lymphocytes, plasma cells, and macrophages has been described.29 Radiologic findings may predate the onset of clinical symptoms.30 Consistent with secondary adrenal insufficiency, serum cortisol levels are low with inappropriately low adrenocorticotropic hormone (ACTH) levels in addition to low thyroid-stimulating hormone (TSH), free thyroxine (T4), and testosterone. Autoimmune thyroiditis is another relatively common endocrinopathy that can manifest as hyperthyroidism as in Gravesâ&#x20AC;&#x2122; disease or in hypothyroidism as in the immunemediated destruction of thyroid tissue in Hashimotoâ&#x20AC;&#x2122;s thyroiditis. Antithyroxin peroxidase antibody and thyroglobulin antibody, TSH, triiodothyronine (T3), and T4 serum levels as well as a thyroid exam, in addition to imaging and more specific testing as indicated (such as radioiodine-123 thyroid uptake), will delineate the condition and determine whether substitution with thyroxine is necessary. Symptoms of autoimmune hypophysitis and thyroiditis can be subtle in the beginning; the clinician therefore needs to maintain a high level of suspicion in patients on ipilimumab therapy presenting with nonspecific symptoms as described above and have a low threshold for checking endocrine labs.

If an endocrinopathy is suspected, one should first determine whether the patient is in adrenal crisis, in which case empiric administration of corticosteroids with mineralocorticoid activity and aggressive IV hydration must be started immediately pending biochemical confirmation. If the patient is not in adrenal crisis, serum should be tested for TSH, free T4, T3, ACTH, morning serum cortisol, luteinizing hormone, folliclestimulating hormone, testosterone, and prolactin (prior to initiation of corticosteroids, if required). Early involvement of an endocrinologist may be helpful. An MRI of the brain with pituitary cuts should be obtained,

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and the patient should be started on high-dose corticosteroids and hormone replacement guided by an endocrinologist. The recommended treatment for ipilimumab-induced hypophysitis is a short course of high-dose corticosteroids with subsequent taper, although this may not reverse the pituitary dysfunction.

Generally, endocrinopathies induced by ipilimumab tend to respond more slowly to steroid therapy compared with the much more commonly seen dermatologic and gastrointestinal adverse events. Most patients with

The recommended treatment for ipilimumab-induced hypophysitis is a short course of high-dose corticosteroids with subsequent taper. autoimmune hypophysitis require indefinite glucocorticoid replacement therapy after completion of prolonged steroid tapering, and some patients require additional support with T4 and testosterone due to persistent secondary adrenal insufficiency. In selected cases, pulse steroid administration has been advocated to preserve pituitary function, although this has not been validated.

Neuropathy Peripheral neuropathy and neuritis have been reported with ipilimumab. In any patient on ipilimumab therapy who presents with neuropathy, nonimmune-mediated etiologies such as infection, medications, or metabolic derangements should be ruled out. Neurologic testing (electromyogram, nerve conduction studies) in addition to a comprehensive neurologic exam in close collaboration with a neurologist will help define the syndrome, grade the severity, and establish an objective baseline from which to judge further evolution of the neuropathy. Ipilimumab should be discontinued for grade 3/4 drug-related sensory neuropathy and any grade 3/4 motor neuropathy. Ipilimumab dosing should be held for grade 2 drug-related neuropathy. For any grade 3 or 4 neuropathy considered to be caused by ipilimumab or progressing, hospitalization and IV cortico-

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steroids need to be considered. IV immunoglobulins are an alternative if the neuropathy is refractory to steroids.

Although much less common, Guillain-BarrĂŠ syndrome (GBS) and myasthenia gravis have been reported in patients treated with ipilimumab. One case was recently reported of a patient who developed a rapidly progressing generalized sensory and motor polyneuropathy after the third dose of ipilimumab, with cerebrospinal fluid (CSF) findings consistent with GBS

The drug has been approved by many regulatory agencies, including those of the United States, Canada, Europe, and Australia. (elevated protein, IgG, oligoclonal bands, normal glucose in the CSF).31 Importantly, high-dose corticosteroids immediately halted further worsening of the symptoms and led to complete recovery within 4 weeks.

Of note, steroids are considered ineffective in classic GBS. Cases of GBS with fatal outcomes were also reported during the clinical development program of ipilimumab.

Uveitis Uveitis is a relatively rare irAE and presents, depending on the affected portion of the uveal tract, as ocular pain, redness, photophobia, and decreased visual acuity.

Patients on ipilimumab therapy should be made aware of this possible irAE, and a referral to an ophthalmologist should be made early if symptoms occur. Direct visualization by slit lamp examination reveals inflammation and/or the presence of leukocytes. Initial treatment consists of topical corticosteroids for anterior uveitis and steroid injections for posterior uveitis, while systemic corticosteroids are reserved for the treatment of resistant cases.

OS benefit in patients with advanced melanoma, with a subset of patients enjoying durable benefit. The drug has been approved by many regulatory agencies, including those of the United States, Canada, Europe, and Australia, and is therefore widely available to clinicians treating advanced melanoma. During the extensive clinical development program, a clear picture of the unique immune-related toxicity profile of this drug emerged. A key lesson from this experience has been that the overwhelming majority of irAEs can be well managed if they are recognized and treated early. Diarrhea and rash, the most common side effects in patients treated with ipilimumab, are easily recognized and should be managed as autoimmune enteritis/dermatitis irAEs while ruling out other etiologies. Other side effects that are less common include hepatotoxicity and peripheral neuropathy. A host of nonspecific signs and symptoms that can be associated with endocrine toxicity are missed more easily and therefore require a structured patient assessment approach. Heightened suspicion and comprehensive knowledge of the ipilimumab toxicity profile, including rare events such as uveitis and pancreatitis, should enable clinicians to largely avoid complications from unrecognized and therefore untreated autoimmune conditions. In order to minimize risk and facilitate the transition to the broader community of general medical oncologists, a risk evaluation and mitigation strategy has been developed by the drug manufacturer, Bristol-Myers Squibb, in collaboration with the FDA and can be accessed at www.yervoy.com/hcp/ rems.aspx.

Ipilimumab is an exciting novel treatment option for patients with advanced melanoma, representing a new class of oncology drugs, that can be given safely by oncologists who are familiar with the full spectrum of irAEs and diligent in the monitoring and appropriate treatment of these toxicities. u

References Concluding Remarks Blockade of the T-cell inhibitory molecule CTLA-4 with the monoclonal antibody ipilimumab leads to an

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1. June CH, Ledbetter JA, Linsley PS, et al. Role of the CD28 receptor in T-cell activation. Immunol Today. 1990;11:211-216.

2. Ledbetter JA, Imboden JB, Schieven GL, et al. CD28 ligation in T-cell activation: evidence for two signal transduction pathways. Blood.

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3. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol.

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4. Saito T, Yokosuka T, Hashimoto-Tane A. Dynamic regulation of T cell activation 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 massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3:541-547.

6. Scalapino KJ, Daikh DI. CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev. 2008;223:143-155.

7. Ueda H, Howson JM, Esposito L, et al. Association of the T-cell regulatory 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 ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter 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 efficacy of ipilimumab administered with or without prophylactic budesonide in patients 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 in patients 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 dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.

13. van Elsas A, Sutmuller RP, Hurwitz AA, et al. Elucidating the autoimmune and antitumor effector mechanisms of a treatment based on cytotoxic T lymphocyte antigen-4 blockade in combination with a B16 melanoma vaccine: comparison of prophylaxis and therapy. J Exp Med. 2001;194:481-489.

14. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anticytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043-6053.

15. Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade 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 autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in 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-induced lupus nephritis. N Engl J Med. 2009;361:211-212.

18. Hunter G, Voll C, Robinson CA. Autoimmune inflammatory myopathy 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 trial of 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.

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20. Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist.

2007;12:864-872.

21. Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTLassociated antigen-4 blockade. Clin Cancer Res. 2007;13:6681-6688.

22. Maker AV, Yang JC, Sherry RM, et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother. 2006;29:455-463.

23. Weber JS, O’Day S, Urba W, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26:5950-5956.

24. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 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.

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26. Lutzky J, Wolchok J, Hamid O, et al. Association between immunerelated adverse events (irAEs) and disease control or overall survival in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in three phase II clinical trials. J Clin Oncol. 2009;27(suppl):15s. Abstract 9034.

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Lung Cancer

Crizotinib Miracle: A Nursing Perspective Tara L. Rich, MSN, RN, CNP Taussig Cancer Institute, Cleveland Clinic, Ohio

F

or every nurse there is a patient who you will tesis. He proceeded to develop pulmonary emboli, atrial never forget; the details of that story will not fibrillation, and pleural effusions requiring bilateral blur over time. In the developing era of personchest tubes. The second day he was in the ICU we realized medicine, there is that 1 patient whose ceived the news that his tumor was ALK positive. He story I will not easily forget. It is the was too sick to understand the news, story of a 24-year-old male medical stuand his family was too scared to underdent who presented for initial consulstand the possible utility of this infortation the same week that crizotinib mation. was approved by the FDA for the treatOur patient assistance team worked ment of anaplastic lymphoma kinase feverishly with the pharmaceutical (ALK)-positive non–small cell lung company and his insurance company cancer. since the drug was brand new. TwentyThis young never-smoker was blissfour hours later he was taking crizofully unaware of the recent advances tinib. His response was immediate and in identifying the echinoderm micromiraculous. He was discharged home tubule-associated protein-like 4 (EML4)20 days later; he walked out of the hosTara L. Rich, MSN, RN, CNP ALK oncogene and the associated pital without any assistance or medical response to crizotinib. Upon initial equipment. Within 1 month of leaving evaluation, his tissue was sent for epidermal growth facthe hospital he had resumed his normal activities of tor receptor and EML4-ALK testing, but due to the urweekend outings and visiting his friends from med gent nature of his symptoms, the decision was made to school. I remember the day he called the office to instart standard platinum doublet chemotherapy. This is quire whether he was allowed to have a beer, a once typical social activity for a 24-year-old student. We all smiled with relief, knowing that without crizotinib the …being able to witness the life-altering outcome would not have been the same. He continues effects of crizotinib reminds me of the to do well and has become actively involved in educatprogress that is being made each day ing people about lung cancer and crizotinib. Speaking in cancer research. to the public has given him a purpose and focus while he decides whether to continue with medical school. when I first met him – he was sitting in the chemo chair As a nurse practitioner, being able to witness the lifewaiting for treatment to start. He was quickly becoming altering effects of crizotinib reminds me of the progress symptomatic and was admitted to the hospital that day that is being made each day in cancer research. We hope that these advances in genomic testing and targeted for evaluation. Over the course of the next couple of days he acutely developed a pericardial effusion that agents continue to provide patients not only with individualized care but with increased treatment options. u tamponaded, requiring emergent bedside pericardiocenMs Rich is a certified nurse practitioner at the Cleveland Clinic in the department of hematology and medical oncology. Her specialty is in thoracic oncology.

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