PMO May 2014

Unifying Oncologists & Pathologists

A Peer-Reviewed Journal May 2014 • Volume 3 • Number 3

PM O

BIOMARKERS • TARGETED THERAPIES • DIAGNOSTICS

Personalized Medicine in Oncology TM

THE BIOMARKER JAK2 V617F in a Patient With AML................Page 136

INTERVIEW WITH THE INNOVATORS A Breakthrough Treatment for ALL and CLL: The New Biologic Agent, CTL019. An Interview With David L. Porter, MD, of the University of Pennsylvania..................................................Page 138 Perspectives on the Landscape of Personalized Medicine. An Interview With Gail E. Herman, MD, PhD; Barbara L. McAneny, MD; and Charles L. Sawyers, MD..................................Page 154

IMMUNOTHERAPY Anti–PD-1/PD-L1 Therapy: New Immunotherapy Options for Patients With a Variety of Cancers..............................................................Page 144

PEDIATRIC ONCOLOGY A Win for Pediatric Cancer Research: The Gabriella Miller Kids First Research Act and Smashing Walnuts Foundation.....................Page 160

THE LAST WORD The Affordable Care Act and Cancer Patients – Winners and Losers in an Unsteady Paradigm GLOBAL BIOMARKERS Shift: Part 2…................................................Page 181

CONSORTIUM Clinical Approaches to Targeted Technologies ™

The official publication of

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

WORLD CUTANEOUS MALIGNANCIES CONGRESS

© 2014 Green Hill Healthcare Communications, LLC An affiliation of The Lynx Group

WORLD CUTANEOUS

In partnership with

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• • • • •

Actionable Drug/Target Associations

• PyroSequencing - DNA Next-Generation Sequencing (NGS) - DNA Fluorescence in situ Hybridization (FISH) - DNA • Fragment Analysis - DNA & RNA Chromogenic in situ Hybridization (CISH) - DNA • Quantitative Polymerase Chain Reaction (qPCR - cobas®) - DNA Immunohistochemistry (IHC) - Protein Sanger Sequencing - DNA

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abarelix

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everolimus†

gemcitabine

leuprolide

panitumumab†

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cetuximab

docetaxel

exemestane

goserelin

liposomal-doxorubicin†

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afatinib

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afatinib cetuximab erlotinib gefitinib imatinib panitumumab

trastuzumab lapatinib pertuzumab T-DM1 everolimus

Sequencing (NGS, Sanger)

FISH IHC

dabrafenib trametinib vemurafenib

PCR everolimus hormone therapy lapatinib pertuzumab T-DM1 trastuzumab

FoundationOne™ from Foundation Medicine* Technologies Used: Next-Generation Sequencing (NGS) - DNA

19

Actionable Drug/Target Associations

††

afatinib

everolimus

temsirolimus

carboplatin

gefitinib

trametinib

cetuximab

imatinib

trastuzumab

cisplatin

oxaliplatin

vandetanib

dabrafenib

panitumumab

vemurafenib

dacarbazine

sunitinib

erlotinib

temozolomide

The same 19 drug/target associations are included in the 51 drug/target associations for Caris Molecular Intelligence. * Based on information found at www.foundationone.com. † † Drug/target associations supported by Levels 1, 2 or 3 evidence.

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FoundationOne™

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** CLIA & ISO launch Q3 2014. The same 236 NGS genes are included in the 600+ NGS profile for Caris Molecular Intelligence.

MAY 2014

VOLUME 3, NUMBER 3

TABLE OF CONTENTS THE BIOMARKER

136

JAK2 V617F in a Patient With AML

PMO is pleased to offer the department “The Biomarker” to discuss the identification of biomarkers in patients with cancer and the prognostic/predictive impact and clinical decision-making implications of that marker.

INTERVIEW WITH THE INNOVATORS

138 A Breakthrough Treatment for ALL and CLL: The New Biologic Agent,

CTL019. An Interview With David L. Porter, MD, of the University of Pennsylvania

PMO speaks with Dr Porter about the enthusiasm surrounding the results from early

trials of treatment with genetically modified T cells.

154

Perspectives on the Landscape of Personalized Medicine. An Interview With Gail E. Herman, MD, PhD; Barbara L. McAneny, MD; and Charles L. Sawyers, MD

PMO speaks with several faculty members at the recent Personalized Medicine

Coalition conference about personalized medicine and their direct involvement in this movement.

IMMUNOTHERAPY

144

Anti–PD-1/PD-L1 Therapy: New Immunotherapy Options for Patients With a Variety of Cancers Sangmee Bae, MD; Bartosz Chmielowski, MD, PhD The authors explore PD-1/PD-L1 blocking agents that have shown promising results in patients with metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma and are currently undergoing testing in multiple other malignancies.

OUR MISSION Personalized Medicine in Oncology provides the bridge between academic research and practicing clinicians by demonstrating the immediate implications of precision medicine – including advancements in molecular sequencing, targeted therapies, and new diagnostic modalities – to the management of patients with cancer, offering oncologists, oncology nurses, payers, researchers, drug developers, policymakers, and all oncology stakeholders the relevant practical information they need to improve cancer outcomes. This journal translates the new understanding of the biology of cancer into the day-to-day management of the individual patient with cancer, using a patient’s unique genetic makeup to select the best available therapy.

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

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www.PersonalizedMedOnc.com

PUBLISHING STAFF Senior Vice President/Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Publisher Russell Hennessy rhennessy@the-lynx-group.com Editorial Directors Kristin Siyahian ksiyahian@the-lynx-group.com Anne Cooper acooper@the-lynx-group.com Strategic Editor Robert E. Henry Senior Copy Editor BJ Hansen Copy Editor Rosemary Hansen Production Manager Marie RS Borrelli The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Jackie Luma Deanna Martinez IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Green Hill Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-656-7935 fax: 732-656-7938

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Your specialized oncology diagnostics provider Learn more about our molecular profiles for hematologic and solid tumor cancers: MDS, AML, lung, and melanoma.

Visit us at ASCO Booth 10045

Š2014, Genoptix, Inc. GenoptixŽ is a registered trademark of Genoptix, Inc.

MAY 2014

VOLUME 3, NUMBER 3

T

TABLE OF CONTENTS

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.

(Continued)

Global biomarkers Consortium Clinical Approaches

PEDIATRIC ONCOLOGY

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A Win for Pediatric Cancer Research: The Gabriella Miller Kids First Research Act and Smashing Walnuts Foundation

TM

Through the extraordinary personal effort of a 10-year-old girl, additional research funds will now be made available to advance pediatric cancer care.

to Targeted Technologies

TM

VALUE-BASED CANCER CARE

162

Promise of Personalized Care Hinges on Reimbursement Reform

PROSTATE AND CERVICAL CANCER UPDATES

166 168

14 New Genetic Markers Predict Risk for Prostate Cancer Routine Cervical Cancer Screening Warranted Beyond Age 64OOF

CONFERENCE COVERAGE

170

Important information from the National Comprehensive Cancer Network annual meeting, the Gastrointestinal Cancers Symposium, and the Hematology/ Oncology Pharmacy Association annual meeting

Save the date for the Third Annual Conference, October 29-November 1, 2014 Visit www.globalbiomarkersconsortium. com to register

181

T he Affordable Care Act and Cancer Patients – Winners and Losers in an Unsteady Paradigm Shift: Part 2

Professional Experience of GBC Attendees

Kip Piper, MA, FACHE, talks about the challenges presented by the ACA to oncologists and their patients.

26.7%

THE LAST WORD

Personalized Medicine in Oncology is included in the following indexing and database services: Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copy­right ©2014 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), 1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPART­MENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mention in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the editorial director.

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1-3 years 3-5 years 5-10 years 10-20 years >20 years May 2014

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Vol 3, No 3

SCIENTIFIC CONFERENCES 2014-2015

AACR Precision Medicine Series Drug Sensitivity and Resistance: Improving Cancer Therapy Co-Chairpersons: Gideon Bollag, Elaine R. Mardis, Gordon B. Mills, and David B. Solit June 18-21, 2014 Orlando, FL

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics Scientific Committee Co-Chairpersons: Jean-Charles Soria, Lee J. Helman, and Jeffrey A. Engelman November 18-21, 2014 Barcelona, Spain

Marsha Rivkin Center for Ovarian Cancer Research-AACR 10th Biennial Ovarian Cancer Research Symposium Co-Chairpersons: Kathleen Cho, Sandra Orsulic, Mary L. “Nora” Disis, and Saul E. Rivkin September 8-9, 2014 Seattle, WA

Tumor Immunology: A New Chapter Co-Chairpersons: Robert H. Vonderheide, Nina Bhardwaj, Stanley Riddell, and Cynthia L. Sears December 1-4, 2014 Orlando, FL

Targeting PI3K-mTOR Networks in Cancer Co-Chairpersons: Lewis C. Cantley, Jose Baselga, Joan S. Brugge, Brendan D. Manning, and Malte Peters September 14-17, 2014 Philadelphia, PA Hematologic Malignancies: Translating Discoveries to Novel Therapies Chairperson: Kenneth C. Anderson Co-Chairpersons: Scott Armstrong and Riccardo Dalla-Favera September 20-23, 2014 Philadelphia, PA Advances in Melanoma: From Biology to Therapy Co-Chairpersons: Suzanne L. Topalian, Keith T. Flaherty, and Levi A. Garraway, September 20–23, 2014 Philadelphia, PA 13th Annual International Conference on Frontiers in Cancer Prevention Research Program Committee Chairperson: Phillip A. Dennis September 28-October 1, 2014 New Orleans, LA

San Antonio Breast Cancer Symposium Co-Directors: Carlos L. Arteaga, Ismail Jatoi, and C. Kent Osborne December 9-13, 2014 • San Antonio, TX Myc: From Biology to Therapy Co-Chairpersons: James E. Bradner, Martin Eilers, Dean W. Felsher, and Carla Grandori January 7-10, 2015 • La Jolla, CA Translation of the Cancer Genome February 7-9, 2015 Co-Chairpersons: William Hahn, Lynda Chin, and William Sellers Computational and Systems Biology of Cancer February 9-11, 2015 Co-Chairpersons: Andrea Califano, Brenda Andrews, and Peter Jackson The Fairmont, San Francisco, CA AACR-Society of Nuclear Medicine and Molecular Imaging Joint Conference: Molecular Imaging in Cancer Biology and Therapy Co-Chairpersons: Carolyn J. Anderson, Christopher H. Contag, and David Piwnica-Worms February 2015 • San Diego, CA

EDITORIAL BOARD

EDITORS IN CHIEF Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania

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

Al B. Benson III, MD Northwestern University Chicago, Illinois

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

SECTION EDITORS Biomarkers Pranil K. Chandra, DO PathGroup Brentwood, Tennessee

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

Darren Sigal, MD Scripps Clinic Medical Group San Diego, California Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana

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Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona 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 Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan Howard L. Kaufman, MD Rush University Chicago, Illinois Katie Kelley, MD UCSF School of Medicine San Francisco, California Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota

Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois Hope S. Rugo, MD University of California, San Francisco San Francisco, California Lee Schwartzberg, MD The West Clinic Memphis, Tennessee John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas Lillie D. Shockney, RN, BS, MAS Johns Hopkins University Baltimore, Maryland Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington Gene Morse, PharmD University at Buffalo Buffalo, New York

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Now enrolling Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial.

Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

@ 2013 Genentech USA, Inc. All rights reserved. BIO0001961500 Printed in USA.

To learn more about this study, please visit www.ClinicalTrials.gov.

LETTER TO OUR READERS

The Full Spectrum of Knowledge Driving Personalized Medicine Dear Colleague,

O

ne of the fascinating aspects of personalized medicine is the recognition of how each component relates to all other components. Take this month’s “The Last Word” column, where one of healthcare’s premier policy authorities, Kip Piper, weighs in on the impact of the Affordable Care Act on cancer care in this second of a Darren Sigal, MD 2-part series. This leads us to reflect on the practical reality of healthcare’s triad of medical, business, and policy forces, intertwined and influencing the process of care. The editors of Personalized Medicine in Oncology (PMO) make certain to bring the whole picture of this process to practicing oncologists: • The clinical needs driving drug and device utilization One of the fascinating • The business and policy context influencing clinical practice aspects of personalized • The winners and losers in the wake of healthcare reform medicine is the recognition • Clarity of treatment options in a healthcare system undergoing of how each component a paradigm shift relates to all other Knowledge is power, and PMO is dedicated to increasing oncolcomponents. ogists’ power to heal in this changing paradigm. The extraordinary variety of knowledge we organize for our readers helps bridge the gap from drug discovery to real-world practice. We are pleased to have you in our reading community as we open the door to the full spectrum of knowledge driving personalized medicine in cancer.

Sincerely,

Darren Sigal, MD Scripps Clinic PMO Board Member

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Vol 3, No 3

Metastatic Cancer...

If the origin is uncertain or unknown… is it really a diagnosis?

Not for your patient.

An advanced microRNA-based testing service from Rosetta Genomics … enabling a personalized approach to cancer treatment.

Introducing the Rosetta Cancer Origin Test™, which may help accurately identify your metastatic patient’s cancer origin using advanced and proven microRNA technology. The Rosetta Cancer Origin Test™ identifies about 95% of all cancer origins with 90% sensitivity1. The Cancer Origin Test has the highest concordance with final clinicopathological diagnosis at world-renowned centers of excellence2.

The Rosetta Cancer Origin Test™ may help: • When you have patients with metastatic cancer of uncertain or unknown origin • When a patient with metastatic cancer fails to respond as expected to treatment • If there is atypical presentation or discordant findings • When a basic IHC panel does not yield a definitive diagnosis • When evaluation costs need to be managed • When family members fear genetic links to certain cancers

To learn more please visit RosettaGenomics.com or call us: 1.888.522.7971 | 1.215.382.9000 REFERENCES 1. Meiri E, Mueller WC, Rosenwald S, et al. A second-generation microRNA-based assay for diagnosing tumor tissue origin.

Oncologist. 2012; 17:801-812. 2. Pentheroudakis G, Pavlidis N, Fountzilas G, et al. Novel microRNA-based assay demonstrates 92% agreement with diagnosis based on clinicopathologic and management data in a cohort of patients with carcinoma of unknown primary. Mol Cancer. 2013;12:57.

Rosetta Genomics and Rosetta Cancer Origin Test are trademarks of Rosetta Genomics, Ltd. ©2013 Rosetta Genomics, Ltd. All rights reserved.

Rosetta Genomics is CAP Accredited and CLIA Certified.

RG- 24.0.0.15 Rev2 1/14

THE BIOMARKER

JAK2 V617F in a Patient With AML PMO is pleased to offer the department “The Biomarker” to discuss the identification of biomarkers in patients with cancer and the prognostic/predictive impact and clinical decision-making implications of that marker.

Do you have a unique case to share with our reading community? Please submit your biomarker-driven cases to us at thebiomarker@the-lynx-group.com.

T

hank you for returning to read the second installment of “The Biomarker,” a column to discuss the diagnostic, prognostic, and/or clinical applications of biomarkers in patients with cancer. This month we have a guest author, Jason Gottwals, who will be highlighting a very intriguing case.

Pranil K. Chandra, Jason is the technical director of marketing DO and provides leadership to the scientific training of our sales force at PathGroup.

Our patient presented with pancytopenia and underwent a diagnostic bone marrow biopsy and ancillary studies. Routine morphologic examination and flow cytometric analysis confirmed acute myeloid leukemia (AML).

Conventional and molecular (fluorescence in Jason Gottwals situ hybridization [FISH]-based) karyotyping demonstrated an interstitial deletion on the long arm of chromosome 7. FISH studies also revealed a deletion in 20q. Polymerase chain reaction (PCR) and next-generation molecular studies were

V617F mutation was seen more commonly in transformed myeloproliferative disease, although both studies identified de novo AML with V617F as well. negative for common mutations seen in AML, including FLT3, KIT, CEBPA, NPM1, IDH1, IDH2, PHF6, and DNMT3A. The sole mutation identified was a Pranil K. Chandra, DO, is Director, Molecular Pathology Services and Interim Medical Director, Clinical Pathology of PathGroup.

Jason Gottwals is Director of Training & Technical Marketing at PathGroup.

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JAK2 V617F mutation by targeted next-generation sequencing.

The JAK-STAT Pathway in Molecular Oncologic Practice The Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway transmits information received from extracellular polypeptide signals, through transmembrane receptors, directly to target gene promoters in the nucleus, providing a mechanism for transcriptional regulation without secondary messengers.1 A variety of cytokines and growth factors complete their physiological tasks through the JAKSTAT pathway, including hematopoiesis, immune regulation, fertility, lactation, growth, and embryogenesis.2 The activating mutation V617F of JAK2 tyrosine kinase is well documented and present in the majority of patients with polycythemia vera (97%), with subsequently declining incidence in essential thrombocythemia (57%) and primary myelofibrosis (50%).3,4 These myeloproliferative disorders are characterized by overactive hematopoiesis, with the major feature of poly­ cythemia vera and essential thrombocythemia being increased production of red cells and platelets, respectively. Deletion of 20q has also been associated with myeloproliferative myeloid stem cell disorders.

AML: Another Heterogeneous Disease on a Molecular Level WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition, from the World Health Organization (WHO), remains the standard text for diagnosis and classification of AML for hematopathologists. The WHO classification of AML integrates clinical features with morphology, flow cytometric immunophenotyping, conventional and molecular (FISH-based) cytogenetics, and PCR-based studies to guide diagnosis, prognosis, and therapeutic managment.5 High-throughput sequencing technologies have transformed the practice of hematopathology by being able to rapidly identify genomic aberrations that yield prognostic and therapeutic information. Recent work on AML demonstrated clonal heterogeneity that evolves upon disease progression and/or relapse.6 Surprisingly, a large number of these alterations appear to be in genes whose function is known, or suspected, to be involved in epigenetic regulation of gene transcription. In the April issue of PMO, there was a nice review of the clinical significance of FLT3 ITD mutations in AML,7 which is associated with an aggressive clinical course. Recent work has implicated

www.PersonalizedMedOnc.com

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THE BIOMARKER

other genes such as IDH1, IDH2, DNMT3A, PHF6, RUNX1, and TP53 to have diagnostic, prognostic, and/ or therapeutic significance. For example, AML with a PHF6 mutation has an aggressive clinical course, whereas the presence of an NPM1 or IDH1 mutation as the sole mutational abnormality is associated with a relatively favorable outcome. Furthermore, AML with mutations in MLL, DNMT3A, and/or NPM1 appear to benefit from high-dose induction chemotherapy.8

JAK2 V617F in AML: Implications for Precision Oncology A 2007 study by Vicente and colleagues screened 10 AML cell lines and 339 patients for the presence of the JAK2 V617F mutation and found an overall incidence of 3.2%, with all mutations documented in M1 or M2 subtypes, suggesting a correlation with less differentiated leukemias.9 This research mirrored previous studies

by Lee et al and Steensma et al in 2006, who found JAK2 V617F mutations in 2.7% and 8% of AML cases, respectively. In both studies, V617F mutation was seen more commonly in transformed myeloproliferative disease, although both studies identified de novo AML with V617F as well.10,11 The detection of a JAK2 mutation as well as the 20q deletion in this patient is highly suggestive of a background myeloproliferative or myelodysplastic/myeloproliferative disorder. Studies have demonstrated that AML arising in the background of chronic-phase myeloid stem cell disorders are distinct from de novo AML both genetically and clinically. This notion is supported by observed resistance to conventional antileukemic therapeutic regimens.12 Multiple pharmacotherapeutic agents are currently at various stages of development targeting the JAK-STAT pathway.13 Conclusion AML is extremely heterogeneous on a molecular level, and research continues to identify new and exciting genomic aberrations that have clinical utility. Mutations in the JAK-STAT pathway are, as a whole, rare in AML; however, advancement in targeted therapies may provide additional benefit when combined with conventional cytotoxic regimens in this aggressive disease course.14 Clinical management decisions in AML

in the near term will continue to rely on a foundation established by the WHO guidelines; however, modern technologies such as next-generation sequencing have enormous potential to inform prognosis and result in

AML is extremely heterogeneous on a molecular level, and research continues to identify new and exciting genomic aberrations that have clinical utility. increased precision with regard to risk stratification.

This information, in turn, will allow for more precise and scientifically driven treatment planning and hopefully improved outcomes in this highly deadly disease.

Indeed, the era of precision oncology is upon us in the setting of AML. u

References

1. Aaronson DS, Horvath CM. A road map for those who don’t know JAK-STAT. Science. 2002;296:1653-1655.

2. Furqan M, Mukhi N, Lee B, et al. Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomark Res. 2013;1:5.

3. Ihle JN, Gilliland DG. Jak2: normal function and role in hematopoietic disorders. Curr Opin Genet Dev. 2007;17:8-14.

4. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-1061.

5. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. World Health Organization. Lyon, France: IARC; 2008.

6. Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506-510.

7. Lewis MJ. Case study: molecular profiling in acute myeloid leukemia. Personalized Medicine in Oncology. 2014;3:86-87.

8. Fathi AT, Abdel-Wahab O. Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy. Adv Hematol.

2012;2012:469592.

9. Vicente C, Vázquez I, Marcotegui N, et al. JAK2-V617F activating mutation in acute myeloid leukemia: prognostic impact and association with other molecular markers. Leukemia. 2007;21:2386-2390.

10. Lee JW, Kim YG, Soung YH, et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene. 2006;25:1434-1436.

11. Steensma DP, McClure RF, Karp JE, et al. JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. Leukemia. 2006;20:971-978.

12. Rampal R, Mascarenhas J. Pathogenesis and management of acute myeloid leukemia that has evolved from a myeloproliferative neoplasm. Curr Opin Hematol.

2014;21:65-71.

13. My Cancer Genome. Anticancer agents. www.mycancergenome.org/content/ other/molecular-medicine/anticancer-agents/. Accessed April 22, 2014.

14. Eghtedar A, Verstovsek S, Estrov Z, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood. 2012;119:4614-4618.

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A Breakthrough Treatment for ALL and CLL: The New Biologic Agent, CTL019 An Interview With David L. Porter, MD, of the University of Pennsylvania

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he number of patients was small and the therapy still investigational, but the results of research on personalized cellular therapy CTL019 stunned the oncology community. With only 70 patients treated to date, a research team at the University of Pennsylvania announced the results of their David L. Porter, clinical trials that constitute a radical change coming to the leukemia treatment model, MD and the practicing oncologist should start getting ready for it now. The agent of change was the topic of an interview with study author David L. Porter, MD, from Penn’s Abramson Cancer Center.

Given the cautious, incremental pace of most current research, replete with understatement and qualifiers to substantiate claims of effectiveness, safety, and value, the announcement was unusually bold and sweeping. Thus, the announcement at last December’s American Society of Hematology annual meeting reverberated through the medical community. After decades of experimentation with T cells to make them vehicles for delivering a master stroke against cancer, a

new cellular agent has emerged to treat chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL) so effectively and distinct from precedent that its researchers bluntly describe it as “...a completely new modality, a completely new approach to leukemia that we believe certainly has the potential to change the paradigm of treating leukemia.”

“Completely new modality.” “Paradigm shift.” Lofty claims heard infrequently in today’s climate of modest advances and evidence-based scrutiny of research claims, making it seem as if research has retreated to a state of safe and unspectacular incrementalism. This breakthrough therefore has important implications for appreciating the power of personalized medicine to keep its promise to heal in ways thought impossible until very recently.

The modality is genetically modified T cells directed against CD19 in the treatment of both CLL and ALL. The research team making the discovery refers to them as CTL019 cells. In our interview, Dr Porter describes the cause of the enthusiasm surrounding the results of early trials.

PMO Thank you for meeting with us, Dr Porter. We understand you are quite encouraged by early results from the trials of CTL019.

Dr Porter Yes, we are seeing really impressive response rates with this therapy in CLL patients with far advanced, heavily pretreated disease. These patients often had extensive and bulky disease, and yet these cells were able to induce remission in a very significant number of patients. Even more remarkable is the response rate we’ve seen in patients with relapsed and refractory ALL. PMO Just how clinically significant is the advantage offered by CTL019?

Dr Porter For the ALL population there really have been no good, effective alternative treatment options; once somebody relapses with ALL, the prognosis is abysmal. Many of these patients have had 3 and 4 prior attempts at treatment – half of them actually relapsed after an allogeneic bone marrow transplant. The complete remission rates to CTL019 cell therapy were over 85%, which was astounding. When no other conventional therapy was effective, we were getting complete remission rates of over 80%, and there is really no precedent for this.

The consistently deadly nature of CLL and ALL makes the small numbers of patients take on a significant proportion in framing expectations for this remedy. In diseases consistently deadly, even small patient sample sizes provide useful expectations for the results of larger trials to follow. Hence the enthusiasm for treatment on this small scale. Between our adult and

David L. Porter, MD, is Jodi Fisher Horowitz Professor in Leukemia Care Excellence in the Perelman School of Medicine at the University of Pennsylvania; and Director, Blood and Marrow Transplantation at the Abramson Cancer Center.

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pediatric programs, we’ve treated just over 70 patients with both CLL and ALL – a little over 40 patients with CLL and almost 30 now with ALL. PMO Can you provide a description of the scientific dynamics in play that have produced these unprecedented clinical results?

Dr Porter The CTL019 cells have the capacity for dramatic in vivo expansion and proliferation, which is probably important for magnifying or amplifying any antitumor response. We have seen that these cells can expand up to 3 logs. At the peak of their expansion, they can represent over 70% of all the T cells in the body, or at least of all the T cells in the blood. And they persist for long periods, and this was one of the new findings presented in our CLL patients. We have now been able to detect these cells surviving out beyond 3 years.

CTL019 therapy provides components of other types of therapy; it uses antibody-directed targeting. Thus, through its antibody put on the T cell, you have all the advantages of targeting via antibody therapy. Because it is a living drug, if you will, it has the potential to grow and expand, and that magnifies and amplifies any potential response, which gives you all the advantages that people have hoped for with cell therapy. And we now know that these cells can persist for long periods and remain biologically active. It gives all the advantages of long-term control that you might get with vaccine therapy. Consequently, we think it has potential to combine antibody targeting, cell therapy amplification, and vaccine-like memory activity.

PMO How closely did the results in patients match your team’s expectations as they began formulating this new agent, and how much did they discover along the way?

Dr Porter We anticipated from mouse models that these cells could have very potent antileukemia activity and that they could proliferate. I don’t think any of us really anticipated the magnitude of cell killing that we’re seeing, and we certainly didn’t anticipate these really high response rates. It’s so unusual when testing new cancer therapies to see it actually be effective at this level with the first try, and while we knew that these cells could survive over periods of time, we had no expectation that they were going to survive on the order of many months or years.

Some activity was expected, but the extent of what we found really has been remarkable. In a fascinating way, we have discovered something different with every single patient we have treated, and it does get to the notion of personalized therapy. This is unique in the sense that every patient has a drug manufactured that’s unique for them. If you think of these cells just like we think of a drug, each lot is specific and individ-

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Small magnetic beads (yellow) force the newly engineered versions of patients’ own T cells to divide before they are infused into each patient to treat the cancer.

ual for the patient. In addition, each response has been unique and personal, and it has allowed us to learn something new with every single patient.

PMO The individualized response in each patient is absolutely remarkable in itself. It means you have an ongoing learning process the more the drug is used. Has this led you to the point where you are able to start summarizing a body of knowledge from this that can guide clinical practice nuances as well as future research of engineering T cells and other biotech agents?

The CTL019 cells have the capacity for dramatic in vivo expansion and proliferation, which is probably important for magnifying or amplifying any antitumor response.

Dr Porter Absolutely. Between our adult and pediatric programs, we can start to summarize expectations and anticipated side effects and even now have a good strategy and plan for toxicity management. So I do think it’s moving far enough along that we are understanding at least some of the early events, how to anticipate responses, and how to anticipate and mitigate side effects.

PMO Where do diagnostics enter into the picture to help you to identify which patients are most likely to respond to CTL019?

Dr Porter Diagnostics will be critical. We are doing

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extensive work to try and figure out why this may be effective in one patient and not another and how to predict when it may or may not be effective, and also how to predict which patients may not get significant side effects. As of yet, we have not been able to identify any specific characteristic that has correlated with response or has predicted which patient may or may not respond.

Again, we have treated relatively small numbers of patients, and in that setting patterns may not yet be obvious. But it’s pretty clear that it’s not related to patient age or the dose of T cells within some range for a particular patient. There is nothing that we have been able to identify about a patient specifically, no previous specific features that we have yet identified that predict why it works in one person or another. But that work is ongoing and is going to be critical through this whole endeavor.

Patients get very severe flu-like symptoms with high persistent fevers, but it can also evolve to hypotension and hypoxia, and we have had some patients become critically ill.

PMO Just how broad a net do you cast for diagnostics in terms of forming your expectations for a patient’s response to CTL019 treatment and explaining the underlying causes of these effects?

Dr Porter Diagnostics have been absolutely critical in understanding how this therapy is effective, what’s happening when patients are responding, and in fact what is causing some of the side effects. The vast majority of responding patients develop a cytokine syndrome.

They get very severe flu-like symptoms with high persistent fevers, but it can also evolve to hypotension and hypoxia, and we have had some patients become critically ill. Diagnostic testing has been critical to identify for us in a rapid fashion that these symptoms have been coincident with very rapid and aggressive T-cell proliferation. They happen right at the time when we see T cells expanding to very high levels, and we have identified very specific cytokines present at high levels in the blood that we think mediate these symptoms. One of the cytokines that was completely unexpected to be found at such high levels was interleukin-6 (IL-6). It turns out there are drugs that block IL-6 activity. Specifically, there’s a drug called tocilizumab, which is an IL-6 receptor antagonist and is an FDA-approved medication for arthritis.

PMO This is very important in informing physicians on the biological basis for the clinical effects and side effects of treatment. Would you please elaborate on this?

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Dr Porter We learned very early on at the height of this reaction that IL-6 levels were very high in patients who were critically ill, and we started treating patients in the throes of this reaction with the anti–IL-6 therapy. We found that it works dramatically in the vast majority of patients – in fact, responses were almost instantaneous. Within a matter of an hour or two, patients who had had high fevers for days suddenly became afebrile; those who had been hypotensive in an ICU suddenly normalized their blood pressure.

Therefore, diagnostics have been critical to understanding the activity of the cells and also some of the factors that resulted in toxicity, and furthermore how to intervene when those toxicities come about. I think that one of the unique things about our program at Penn is the ability to have these comprehensive analyses to try to understand this very early in the development of the therapy.

PMO What enabled you to hit the nail on the head immediately and select tocilizumab rather than any other agent as the appropriate companion drug to eliminate these side effects – and not only ameliorate but actually get to the root of them and understand their genesis? Why weren’t you stumbling around in the dark awhile before finding it?

Dr Porter We knew that T cells, when they become activated, have the potential to release cytokines, and this project was designed with correlative laboratory testing that would analyze the cytokine profile after T cells were infused. We saw the first few patients, in fact, the first pediatric patient treated with ALL, become critically ill. We looked in the lab at what some of these inflammatory cytokines were doing and found extraordinary high levels of IL-6 that were out of proportion to everything else, and out of proportion to what we expected.

We first tried corticosteroids, which are probably the most traditional way of inhibiting T-cell activity and cytokine-induced inflammation, and found that the steroids had little impact, at least for several hours. This led us to try to do something extraordinary, because in the very first case we had a patient who was critically ill. It worked almost immediately, which is what really gave us the clue to continue to use that in subsequent patients.

At this point, every patient we have treated has responded to 1 or sometimes 2 doses of the medication.

PMO And having administered that, is there a need for any other additional palliative care, or is this sufficient?

Dr Porter This is a relevant consideration, for in fact there is the need for very intensive care after the patient is treated. Another side effect that we have seen in these patients is a tumor lysis syndrome, which I think is really a testament to the potency of these cells.

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As the T cells are proliferating, they kill large numbers of cells very quickly. That requires very careful management and therapy, but that is quite feasible, and oncologists are very experienced in that complication. But these patients can become critically ill, and it requires a very high level of monitoring and supportive care, though anti–IL-6 therapy seems to be at the focus point of managing side effects. But the bottom line is that the strategy is really an anticytokine-directed approach to side effects. There may be other ways to do it, and this may not be the only drug. There are other anti–IL-6 drugs. There may be other anticytokine drugs, but I think the approach is to try to interrupt the cytokine-induced activity.

PMO Will you give us a thumbnail sketch of the history of researching genetically engineered T cells?

Dr Porter This idea of using genetically modified T cells against cancer in fact wasn’t new. It’s been around since the late 1990s. There have been several trials and iterations of this idea. Work to optimize and design this approach in a way that it would be clinically effective really has been led by Carl June in our group for the better part of the decade.

Previous attempts at this weren’t successful for a few reasons. Initially, there were no efficient ways to introduce new genetic material into the T cells, and even when you could, there were no efficient ways to grow those T cells in the lab to numbers high enough to be used therapeutically.

In the past several years, very effective and efficient methods have been developed to introduce new genetic material through the T cells. We are using a lentivirus vector, which is a retrovirus vector based on an HIV backbone. Others are using just more pure retroviruses, and there are other techniques like electroporation and other ways to get new genetic materials to cells efficiently.

Carl June and Bruce Levine, now at Penn, developed a technology a number of years ago that allows one to grow T cells in a physiologically appropriate manner through a process of activation and costimulation so that they don’t grow and become senescent or exhausted; they can grow several 100-fold in the laboratory in a matter of 2 weeks. So overall, the technology has improved dramatically.

One problem always had been that the cells would not proliferate very well in the body and would not persist for long periods. There were trials that showed these cells were detectable at low levels for a few weeks, and responses were very modest. One of the unique features about our therapy is using a chimeric antigen receptor that has a signaling domain and a very potent costimulating domain. It is the 4-1BB fragment of the CD137 molecule, and it is a very potent signaling molecule. This

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Staff in the University of Pennsylvania’s Clinical Cell and Vaccine Production Facility use genetic engineering techniques to reprogram patients’ own immune cells to hunt for cancer cells in their bodies.

Members of the University of Pennsylvania research team, from left to right: David L. Porter, MD; Bruce Levine, PhD; Carl June, MD; Stephan Grupp, MD, PhD; and Michael Kalos, PhD.

had been tested over a number of years in the lab and in mouse models, showing that when you include it as part of the signaling function of the protein of the chimeric antigen receptor, these cells grow to high levels, and they persist and survive for much longer periods.

We don’t know for sure, but we think that the biological properties of the specific chimeric antigen receptor that we are using drives this very high level of

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proliferation and expansion in the body and provides a survival signal to these T cells that allowed them to survive at relatively high levels for very long periods, and this really has not been seen with genetically modified cell therapy in prior trials.

PMO So there is a pull-through/push-through process between the technology and the drug development: technology making possible drug development, and drug development suggesting new ways to refine technology. Is this a good way to view the process?

Dr Porter Absolutely – that’s the dynamic interplay we’re benefitting from.

PMO How will this redefine the hierarchy of treatments for CLL and ALL?

“Our hope is that this might be a one-time therapy as opposed to a medication that one might have to take for life.”

– David L. Porter, MD Dr Porter I think in CLL this is a completely new modality. There are a lot of new and different therapies being developed for CLL. I think it’s very early to know where this might fit in with all the newer biological agents, but it is a completely new, very personalized approach. While it is too early to know, our hope is that this might be a one-time therapy as opposed to a medication that one might have to take for life, for instance.

PMO You hope it will be a once-and-done process?

Dr Porter It may be a once and done, but this will be determined in long-term follow-up. That is the intent, in any case. Whether that proves to be true, we don’t know yet. At this point, CTL019 has been limited to patients with multiple relapsed/refractory CLL, offering them a completely new approach that has shown significant response rates.

PMO When will CTL019 be nudged into earlier usage? How long do you think it should be held in reserve before it is used?

Dr Porter I think that given these kinds of results, and as we learn more about the short- and long-term stage usage, it is absolutely reasonable to think about moving this kind of therapy earlier in the course of disease before patients are highly refractory – before they have extensive, bulky disease. We have some preliminary evidence that the side effects may be less if they have less leukemia, and all of that lends some support to explore using this earlier in the course of their disease.

PMO What are the plans for continuing research, and what is the scenario for patient access to this treat-

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ment in terms of where and when it will be available to all patients who need it?

Dr Porter We are now considering doing a larger multicenter trial. Right now our specific therapy is only at the University of Pennsylvania, though there are other centers with similar types of therapy. The CTL019 cell technology has been licensed by Novartis. We all hope to be able to manufacture this in large scale: they like to say not scale up but scale out. Each product is made for an individual patient, and we believe there will be facilities and strategies to be able to make these cells, so this could be available really in a relatively short time frame to people all over the country and, in fact, all over the world.

PMO You have given us incredible clarity on the results, nature, and future of CTL019. To complete the picture, I was wondering if you might suggest any lessons that this discovery holds for the practicing hematologist or oncologist at this point in time, both biologically and empirically. By biologically, I mean what lessons could they learn in terms of how they can familiarize themselves with disease pathophysiology to help them appreciate what this is doing, and what they should know to understand how it is so personal in the way each patient responds to it; and empirically, what lessons are there for them to revise their treatment strategies for ALL and CLL. Dr Porter Biologically, one needs to understand that this therapy is targeted against a specific protein, so it is only effective if the cell has CD19. It’s biologically then expected that it results in B-cell aplasia, so these patients lose their B cells. Physicians have to be aware of that and learn how to manage that as a side effect. But it is also important to think that once we understand the biology of the cancer and identify unique molecules on the cancer surface, then this kind of technology can be applied not just for CLL or ALL but for other tumor types as well, and there is the potential for this to be a generalizable modality of cancer therapy in the future.

In terms of empiric lessons, I think mostly it’s impor­ tant to understand this is still in the early stages of testing. There are a number of side effects that may require some specialized management, but as we treat more and more patients and disseminate this into multicenter clinical trials, there will be much more information about anticipated side effects and toxicity management, so that we can envision this therapy being applicable truly to patients all over the country if not all over the world.

PMO Thank you for sharing this extraordinary personalized medicine experience with CTL019. We will be looking forward to its continued movement through the research and development cycle and wish you and the entire research team continued success.

Dr Porter Thank you. u

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IMMUNOTHERAPY

Anti–PD-1/PD-L1 Therapy: New Immunotherapy Options for Patients With a Variety of Cancers Sangmee Bae, MD; Bartosz Chmielowski, MD, PhD University of California, Los Angeles Los Angeles, California

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here is a continued need for the development of new therapies for cancer; immunotherapy, a treatment modality in which cancer cells are not targeted directly but rather through altered immune cells such as T cells, has been in testing for several decades. Despite hundreds of clinical trials using Sangmee Bae, MD various forms of vaccines, cytokines, adoptive cell transfer, and checkpoint inhibitors, only a few agents (interferon, high-dose interleukin-2, ipilimumab, and sipuleucel-T) in certain types of cancer (melanoma, renal cell carcinoma [RCC], and prostate cancer) have been approved by the FDA, and not all of them showed an improvement in overall survival (OS) in randomized clinical trials. Recently, there has been increased enthusiasm Bartosz Chmielowski, MD, that immunotherapeutic strategies designed PhD to enhance endogenous antitumor properties of the adaptive immune system are becoming a therapeutic option for a variety of cancers. Ipilimu­ mab (CTLA-4–blocking antibody; CD152) was the first drug that targeted one of the immune checkpoint proteins, which under normal physiological conditions is crucial to maintaining self-tolerance to prevent autoimmunity, and showed the treatment can lead to an improvement in OS and durable responses.1 There has been even more excitement with the targeting of programmed death protein 1 (PD-1; CD279), another inhibitory coreceptor expressed by activated T cells.

Blockade of inhibitory immune checkpoint proteins would imply continued activation and amplification of tumor-specific T-cell responses and may lead to tumor elimination. In this review, we will focus on immunotherapeutic agents that target the PD-1 pathway.

Sangmee Bae, MD, is a Resident in the Internal Medicine Department at the Ronald Reagan UCLA Medical Center in Los Angeles, California.

Bartosz Chmielowski, MD, PhD, is Clinical Assistant Professor in the Division of Hematology and Medical Oncology of the University of California at Los Angeles. He specializes in the treatment of patients with melanoma and sarcoma.

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KEY POINTS PD-1/PD-L1 blocking agents are a new form of immunotherapy that have shown promising results in patients with metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma and are currently undergoing testing in multiple malignancies ➤ Pembrolizumab (MK-3475) and nivolumab are currently in randomized phase 3 clinical trials and may receive FDA approval by the end of 2014 ➤ Multiple combination therapies with PD-1/PD-L1 blocking agents are also in clinical testing ➤

Mechanism of Action T cells have remained the major focus of cancer immunotherapy given their ability to selectively recognize and orchestrate various immune responses. There is a close bidirectional communication between T cells and antigen-presenting cells (APCs; namely the dendritic cells) when T-cell receptors recognize antigens presented by the major histocompatibility complex (MHC) molecule. Once the T-cell receptor/MHC-mediated first signal is delivered, many ligand-receptor interactions mediate secondary stimulatory or inhibitory signals to further fine-tune the immune response.

Many of the secondary signals are mediated via the B7 molecule family on the surface of APCs binding with various receptors on the T-cell surface. Inhibitory signal mediators, namely CTLA-4 and PD-1, are frequently referred to as “immune checkpoints,” as such negative regulation is crucial in terminating the immune response and preventing inappropriate activation of immunity. There have been many studies regarding the mechanism of CTLA-4 blockade in cancer immunotherapy as a means to interrupt the negative signal mediated by CTLA-4 and restore T-cell activity against tumor antigens.2-5 Large clinical trials have validated the safety and efficacy of ipilimumab (MDX-010), a monoclonal antibody against CTLA-4, which led to its approval in melanoma, and further clinical trials are under way in other malignancies.6,7 The PD-1 receptor also mediates an inhibitory signal

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but unlike CTLA-4 is expressed by T cells during longterm antigen exposure and takes effect in the peripheral tissues. Thus, this signal is mainly implicated in T-cell exhaustion, which is characterized by impaired cytokine production, decreased proliferation, and reduced killing activity.8 There are 2 distinct ligands of PD-1, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273), which are frequently expressed within the tumor microenvironment, and antibodies that block the interaction between PD-1 and PD-L1 result in preferential activation of cancer-specific T cells. Mouse models show that blocking PD-1/PD-L1 interaction between T cells and APCs leads to T-cell activation, and blocking the interaction between T cells and target cells leads to increased target cell elimination.9 Although the clinical experience with PD-1 blockade is less extensive compared with the CTLA-4 pathway, the initial results appear quite promising, and the PD-1 pathway­–targeted therapy is now viewed as a viable treatment option with less systemic toxicity given its increased selectivity and ability to predominantly target the effector phase of T cells.10,11

Drugs in Development Anti–PD-1 Therapy Nivolumab (BMS-936558, MDX-1106) is a human IgG4 antibody against the PD-1 receptor. Brahmer and colleagues presented the results of the first phase 1 study conducted with nivolumab at single doses of 0.3, 1, 3, and 10 mg/kg and reported evidence of clinical activity with a favorable safety profile in 39 patients with advanced melanoma, non–small cell lung cancer (NSCLC), colorectal cancer (CRC), castrate-resistant prostate cancer, and RCC.12 Based on this, a large phase 1 study was conducted in 296 patients with heavi­ly pretreated solid malignancies receiving doses of 1, 3, and 10 mg/kg every 2 weeks in 8-week cycles. The study showed an objective response (complete and partial responses) in 18% to 28% of patients (14 of 76 in NSCLC, 26 of 94 in melanoma, and 9 of 33 in RCC), but no responses in patients with CRC or prostate cancer.13 Responses in the majority of patients were durable and evident by week 16; progression-free survival (PFS) at 24 weeks was 41% (95% CI, 30-51) for melanoma, 26% (95% CI, 16-36) for NSCLC, and 56% (95% CI, 39-73) for RCC. The maximum tolerated dose (MTD) was not defined; the most common adverse events (AEs) were fatigue, decreased appetite, nausea, vomiting, diarrhea, and rash; grade 3/4 AEs were observed in 14% of patients and included pneumonitis, vitiligo, colitis, hepatitis, thyroiditis, and hypophysitis. Immunohistochemical analysis showed a significant difference in response rates between PD-L1–

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negative and PD-L1–positive tumors, suggesting that a survival benefit may only be demonstrated in a select group of patients. Updated phase 1 trial (CA209-003) data on 129 patients with NSCLC presented at the 15th World Conference on Lung Cancer in October 2013 showed an overall response rate of 24.3%, with a median survival of 14.9 months. OS rates were 42% at 1 year and 24% at 2 years.

Although the clinical experience with PD-1 blockade is less extensive compared with the CTLA-4 pathway, the initial results appear quite promising.

These encouraging results have led to extensive clinical development of nivolumab. Currently, singleagent nivolumab is in testing in multiple malignancies; the list of clinical trials includes a trial comparing nivolumab with chemotherapy in patients with melanoma whose disease progressed on standard therapies, trials of nivolumab versus chemotherapy as first-line or second-line treatment in patients with NSCLC, a trial of nivolumab versus everolimus in RCC, and single-agent trials of nivolumab in hepatocellular carcinoma, follicular lymphoma, diffuse large B-cell lymphoma, and hematologic malignancies.

Pembrolizumab (MK-3475; previously called lambrolizumab) is a highly selective humanized monoclonal IgG4 kappa isotype antibody against PD-1. First studied in a dose-escalation phase 1 study in patients with various advanced solid tumors, it was shown to be safe at doses up to 10 mg/kg every 2 weeks, with objective clinical responses noted.14 Based on this study, Hamid and colleagues reported the safety and efficacy data of pembrolizumab in 135 patients with advanced melanoma.15 Once patients reached 10 mg/kg every 2 weeks in the initial dose-escalation period, patients were enrolled to an expansion cohort and received either 10 mg/kg or 2 mg/kg every 3 weeks. The overall response rate was higher in the group that received the higher dose (52% vs 25%), as was the rate of AEs. Common AEs included fatigue, rash, pruritus, and diarrhea, but cases of pneumonitis, myocardial infarction, renal failure, hypothyroidism and hyperthyroidism, and adrenal insufficiency were also seen. Median PFS was estimated to be more than 7 months. The data were updated at the annual meeting of the Society for Melanoma Research in November 2013. The study showed that 74% of patients with melanoma experienced a reduction in tumor size; the overall response rate was

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41% (51% in patients treated with 10 mg/kg every 2 weeks, 31% with 10 mg/kg every 3 weeks, and 40% with 2 mg/kg every 2 weeks), median PFS was 8.2 months (95% CI, 5.3-12.8), and most importantly, the 1-year survival rate was 81%. The preliminary report of pembrolizumab 10 mg/kg every 3 weeks in previously treated NSCLC showed an overall response rate of 24% using immune-related response criteria, 21% using RECIST, and a median OS of 51weeks, while median PFS had not yet been reached in responders.16 AEs overall were manageable, with 53% of patients experiencing AEs such as rash, pruritus, fatigue, diarrhea, and arthralgia, but no grade 3/4 AEs or treatment-related deaths. These trials used different doses of pembroliz­ umab (10 mg/kg and 2 mg/kg) and different schedules of drug administration (every 3 weeks and every 2 weeks). Nonrandomized data suggest that pembroliz­ umab at the higher dose might be more active, but this question will be answered by the ongoing trials comparing higher and lower dosing.

Ongoing clinical trials are evaluating combinations of pidilizumab with vaccines or chemotherapeutic agents in other solid malignancies.

Pembrolizumab is currently in clinical trials comparing its activity with chemotherapeutic agents and assessing its activity in other cancers such as breast, head and neck, gastric, and bladder, as well as in hematologic malignancies and in special patient populations such as patients with melanoma or NSCLC with brain metastasis.

Pidilizumab (CT-011) is a humanized IgG1 monoclonal antibody that was shown to induce a potent antigen-specific tumor response when combined with cyclophosphamide and vaccines in mouse models. A phase 1 study of pidilizumab in patients with advanced hematologic malignancies showed that treatment with pidilizumab with escalating doses from 0.2 to 6 mg/kg was generally well tolerated, and the MTD was not defined.17 Clinical benefit was seen in 33% (6 of 17) of the patients, with 1 complete response that was maintained for >68 weeks. Blood CD4+ levels remained elevated for up to 21 days following therapy. Ongoing clinical trials are evaluating combinations of pidilizu­ mab with vaccines or chemotherapeutic agents in other solid malignancies.

AMP-224, a PD-L2/IgG1 fusion protein that targets PD-1 signaling, is currently undergoing phase 1 testing.

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This trial has an expansion cohort in patients with melanoma and ovarian cancer.

Anti–PD-L1 Therapy In contrast to CTLA-4 ligands, PD-L1 is selectively expressed on cells in the tumor microenvironment and upregulated in solid tumors, inhibiting cytokine activity of tumor-targeting T cells.18-20 To further support the significance of the PD-1/PD-L1 pathway in immune tolerance, studies have demonstrated that the degree of PD-L1 expression on tumor cells correlated with poor clinical outcomes in various malignancies, including RCC and melanoma.21-24 Targeting the primary ligand of PD-1 is another way of blocking the PD-1 pathway, leading to ongoing antitumor activity.

MPDL3280A (RG7446) is a human anti–PD-L1 monoclonal antibody containing an engineered Fc domain. Because of the Fc optimization, the antibody does not induce either antibody-dependent cytotoxicity or complement-dependent cytotoxicity. Preliminary results from an ongoing phase 1 study with 85 heavily pretreated patients with advanced NSCLC showed that MPDL3280A was generally well tolerated, with grade 3/4 AEs in 12.6% of patients, including fatigue, dyspnea, nausea, and vomiting.25 Efficacy data were assessed in 53 patients, of whom 23% achieved an objective response, and 24-week PFS was 44.7%.

Objective response as well as disease control rate were associated with PD-L1 expression levels. The responses were also seen in patients with RCC, melanoma, CRC, and gastric cancer. The data on use of the drug in patients with melanoma were presented at the annual meeting of the Society for Melanoma Research in November 2013. The expansion cohort of the phase 1 study of MPDL3280A included 45 patients with metastatic melanoma; 11 patients with cutaneous melanoma responded to the treatment, the 24week PFS was 41%, and patients who previously received immunotherapy were more likely to benefit from the treatment with MPDL3280A (44% vs 19%).

Based on these encouraging results, MPDL3280A is being studied in other malignancies such as melanoma and RCC, and so far, results appear quite promising with overall responses of 13% to 29% and AEs including hyperglycemia, increased liver enzymes, colitis, dyspnea, and fatigue. Ongoing phase 2 and 3 trials are looking at combination regimens as well as comparing the efficacy with current treatment options in advanced solid tumors and hematologic malignancies.

BMS-936559 (MDX-1105) is a high-affinity human PD-L1–specific IgG4 monoclonal antibody that inhibits the binding of PD-L1 to PD-1 but spares the interaction of PD-L2. The safety and efficacy has been

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studied in a phase 1 dose-escalation trial including 207 patients with advanced solid tumors (NSCLC, CRC, melanoma, RCC, ovarian, gastric, pancreatic, and breast cancer) who received escalating doses ranging from 0.3 to 10 mg/kg every 2 weeks.26 MTD was not reached, and median duration of therapy was 12 weeks.

Objective responses were observed in 17% of melanoma, 10% of NSCLC, 6% of ovarian, and 12% of RCC patients, but no response was seen in patients with CRC or pancreatic cancer. Stable disease was observed in 12% to 41% at 24 weeks. Among patients who achieved an objective response, responses lasted for 1 year or more in 8 of 16 patients. Common AEs included fatigue, infusion reactions, diarrhea, arthralgia, and rash; grade 3/4 AEs were reported in 9% of patients, and 6% of patients discontinued therapy due to toxicity. Bristol-Myers Squibb has made the decision to concentrate on the development of nivolumab and not develop BMS-936559 in oncology.

MEDI4736 is another monoclonal antibody being studied against PD-L1. This antibody also has an optimized Fc region and therefore does not activate antibody-dependent cell-mediated cytotoxicity. Ongoing phase 1 and 2 studies are looking at the safety and efficacy of MEDI4736 as monotherapy as well as combination therapy in solid tumors.

Combination Therapy The available results from treatment with PD-1/ PD-L1 blocking agents are encouraging and have caused a lot of excitement, but there is still room for improvement. It is a natural development in oncology that after single-agent activity is seen with an agent, it is often later used in combination with other therapies.

Multiple clinical trials with combination regimens are ongoing; they can be divided into 3 groups: 1) combination with another form of immunotherapy, 2) combination with standard chemotherapy, and 3) combination with targeted therapy.

The first data on combination treatment come from the trial of nivolumab plus ipilimumab. PD-1 blockade therapy has been shown to enhance efficacy of CD8 T-cell responses and regulate tumor growth, and thus it has been postulated that it may have synergistic effects when combined with other immunotherapeutic agents.

CTLA-4 is another negative regulator of immune cell activation, and blockade of the CTLA-4 molecule has been shown to improve survival in patients with metastatic melanoma.6,7 Unlike PD-1 blocking agents, CTLA-4 blockers, such as ipilimumab, inhibit at earlier points of T-cell activation (during ligation with B7 costimulatory molecules) and also target regulatory T cells, leading to reduced T-cell regulatory activity. As

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CTLA-4 and PD-1 appear to play complementary roles in regulating T-cell function, combined blockade of PD-1 and CTLA-4 has been studied and suggested to have more pronounced antitumor activity than either agent alone in preclinical studies and in patients with chronic viral infections.27,28 Wolchok and colleagues reported the results of concurrent therapy with nivolu­ mab-ipilimumab and showed that 53% of patients with advanced melanoma had achieved an objective response and a tumor burden reduction of 80% or more.29 The combination of nivolumab and ipilimu­mab was also associated with increased toxicity: serious treatment-related AEs were seen in 49% of patients, and the most common grade 3/4 events included hepatic events (15%), gastrointestinal events (9%), renal events (6%), elevation of lipase (13%), aspartate aminotransferase (13%), and alanine aminotransferase (11%). The phase 3, blinded, randomized clinical trial comparing ipilimumab to nivolumab to the combination of both drugs has completed its accrual. This trial will confirm if the combination therapy is more active than either drug alone and if the combination results in increased toxicity.

Ongoing phase 1 and 2 studies are looking at the safety and efficacy of MEDI4736 as monotherapy as well as combination therapy in solid tumors.

Similarly, pembrolizumab is also being tested in combination with ipilimumab and also in combination with pegylated interferon-α in patients with melanoma and RCC. Preclinical data in the tumor mouse model showed that interferon-α increased PD-1 expression in tumor-infiltrating lymphocytes, which led to increased tumor activity.30 Other proposed immune escape mechanisms by tumor cells include LAG-3 and Tim-3 signaling pathways, which are also inhibitory molecules, and blocking antibodies have been shown to improve T-cell immunity in chronic infections.31-33 Combined blockade with PD-1 pathways synergistically restored the function of exhausted T cells, having positive antitumor effects in mouse models.34 The drugs blocking LAG-3 and Tim-3, as well as other molecules such as B7-H3 and B7-H4, are in early development, and trials combining nivolumab with an anti-KIR antibody, lirilumab, or with an anti–LAG-3 antibody have started accrual.

Other interesting approaches of combination im-

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munotherapy currently in clinical trials include the combination of pidilizumab with dendritic cell vaccine in patients with multiple myeloma or RCC and with sipuleucel-T in patients with advanced prostate cancer.

Chemotherapy has been a standard treatment for all unresectable malignancies for several decades and is known to prolong life or provide palliation in patients with a variety of cancers. Therefore, there are attempts to improve efficacy of chemotherapy by combining it with anti–PD-1 therapy – pidilizumab and gemcitabine in pancreatic cancer, pidilizumab and FOLFOX (leucovorin, 5-fluorouracil, and oxaliplatin) in colorectal cancer, and nivolumab or pembrolizumab and chemotherapy in NSCLC.

Data from the early trials of the new PD-1/PD-L1 blocking agents are very encouraging. It appears that the responses are frequent, rapid, and probably durable.

In the past decade, targeted therapy has emerged as the standard systemic therapy for patients with a variety of malignancies. Targeted therapy is usually very active, and rapid responses are achieved, but eventually tumors develop resistance. Immunotherapy is known to produce durable responses, if not a cure, in patients with metastatic cancer, but these responses are much less frequent and less rapid. Thus, it is not a surprise that there are ongoing attempts to combine immunotherapy with targeted therapy. In patients with melanoma, it was shown that treatment with a BRAF inhibitor or the combination of a BRAF inhibitor and a MEK inhibitor was associated with increased melanoma antigen expression, increased T-cell infiltration, decreased expression of immunosuppressive cytokines, and an increase in PD-L1 expression.35 This observation led to a clinical trial of the combination of MEDI4736 (anti– PD-L1 antibody) with dabrafenib and trametinib in patients with BRAF-mutated melanoma and with trametinib alone in patients with non–BRAF-mutated melanoma. Similar studies are being done with a combination of MPDL3280A and vemurafenib in patients with BRAF-mutated melanoma and with cobimetinib (GDC-0973; a MEK inhibitor) and vemurafenib in patients with solid tumors. Other clinical trials add anti–PD-1 therapy to standard targeted therapy in multiple cancers. There are attempts to combine MPDL3280A with bevacizumab in RCC or with erlotinib in NSCLC, nivolumab with sunitinib or pazopanib in

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RCC, pembrolizumab with pazopanib in RCC, and pidilizumab with lenalidomide in multiple melanoma or with rituximab in follicular lymphoma.

Questions and Future Directions The data from the early trials of the new PD-1/ PD-L1 blocking agents are very encouraging. It appears that the responses are frequent, rapid, and probably durable. The experience with these new drugs shows that most, if not almost all, patients with cancer have T cells that can potentially eliminate the tumor, and only the tumor cells that developed an active mechanism of immune tolerance such as PD-L1 expression survive immune surveillance. It suggests that the combination of PD-1/PD-L1 blocking agents with other forms of immunotherapy or targeted therapy can be even more efficacious, and it is only a matter of time before the most active combinations are discovered.

However, it is still unknown how durable these responses are and what the mechanisms of escape are when tumors progress after an initial response. We must expect that these mechanisms will be heterogeneous.

Much research has been devoted to studying the expression of PD-L1 on the tumor cells as a biomarker for these new agents, and preliminary data suggest that the level of expression predicts for response, but we should remember that biomarkers must be tested with the same scrutiny as new therapeutic agents. u References

1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.

Nat Rev Cancer. 2012;12:252-264.

2. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985-988.

3. 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.

4. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734-1736.

5. Bour-Jordan H, Esensten JH, Martinez-Llordella M, et al. Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family. Immunol Rev. 2011;241:180-205.

6. 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.

7. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.

8. Araki K, Youngblood B, Ahmed R. Programmed cell death 1-directed immunotherapy for enhancing T-cell function [published online March 3, 2014]. Cold Spring Harb Symp Quant Biol.

9. Mueller SN, Vanguri VK, Ha SJ, et al. PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice. J Clin Invest. 2010;120:2508-2515.

10. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012;366: 2517-2519.

11. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813-824.

12. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167-3175.

13. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.

14. Patnaik A, Kang SP, Tolcher AW, et al. Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. J Clin Oncol.

2012;30(suppl). Abstract 2512.

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15. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambro­ lizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-144.

16. Garon EB, Balmanoukian A, Hamid O, et al. Preliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer (NSCLC). Paper presented at: IASLC 15th World Conference on Lung Cancer; October 27-30, 2013; Sydney, Australia. Abstract MO18.02.

17. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14:3044-3051.

18. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793800.

19. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

Proc Natl Acad Sci U S A. 2002;99:12293-12297.

20. Fife BT, Pauken KE, Eagar TN, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol.

2009;10:1185-1192.

21. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra37.

22. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A. 2004;101:17174-17179.

23. Hino R, Kabashima K, Kato Y, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer.

2010;116:1757-1766.

24. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467-477.

25. Soria JC, Cruz C, Bahleda R, et al. Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): additional analyses from

a clinical study of the engineered antibody MPDL3280A (anti-PDL1). Paper presented at: European Cancer Congress; September 27-October 1, 2013; Amsterdam, Netherlands. Abstract 3408.

26. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-2465.

27. Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107:4275-4280.

28. Gardiner D, Lalezari J, Lawitz E, et al. A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection.

PLoS One. 2013;8:e63818.

29. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133.

30. Terawaki S, Chikuma S, Shibayama S, et al. IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol. 2011;186:2772-2779.

31. Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29-37.

32. Butler NS, Moebius J, Pewe LL, et al. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat Immunol.

2011;13:188-195.

33. Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207:2175-2186.

34. Sakuishi K, Apetoh L, Sullivan JM, et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207:2187-2194.

35. Frederick DT, Piris A, Cogdill AP, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19:1225-1231.

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ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

RECHARGE THE POSSIBILITIES

• Efficacy and safety evaluated in the largest prospective single-arm PTCL study (Study 3, N=131)1 • Studied in a pretreated, histologically diverse PTCL population1 • Patients could be treated until disease progression at their discretion and that of the investigator1

Important Safety Information WARNINGS AND PRECAUTIONS • Treatment with ISTODAX® (romidepsin) has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX. The risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D)

ADVERSE REACTIONS Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

ISTODAX® is a registered trademark of Celgene Corporation. © 2013 Celgene Corporation 07/13 US-IST130001a

www.istodax.com

Demonstrated efficacy in PTCL after at least 1 prior therapy in Study 3a1

15% ~60% 25%

(19/130) Complete Response Rate (CR+CRu) by independent central review (95% CI: 9.0, 21.9) • Similar complete response rates in the 3 major PTCL subtypes (NOS, AITL, ALCL)

9.2 months

(11/19) of Complete Responses (CR+CRu) exceeded • Follow-up was discontinued in the remaining 8 patients prior to 9.2 months (33/130) Objective Response Rate (CR+CRu+PR) by independent central review (95% CI: 18.2, 33.8)

1.8 months a

(~2 cycles) median time to Objective Response

Efficacy based on 130 patients with histological confirmation by independent central review.1

Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.

The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

DRUG INTERACTIONS • Monitor prothrombin time and International Normalized Ratio in patients concurrently administered ISTODAX (romidepsin) and warfarin sodium derivatives • Romidepsin is metabolized by CYP3A4 Monitor patients for toxicity related to increased romidepsin exposure and follow dose modifications for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors Avoid co-administration of ISTODAX with rifampin and other potent inducers of CYP3A4 • Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors

USE IN SPECIFIC POPULATIONS • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see Brief Summary of Full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, on the following pages.

Reference: 1. ISTODAX [package insert]. Summit, NJ: Celgene Corp; 2013.

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monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate.

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a Brief Summary of the Prescribing Information for the peripheral T-cell lymphoma indication only; see Full Prescribing Information for complete product information.

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman.

In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles.

Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

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1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle.

Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug.

2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.

• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.

• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.

Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.

• Grade 4 febrile (≥38.5° C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)].

5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)].

In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.

Potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)].

5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden should be closely

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Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).

In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus.

Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.

8.3 Nursing Mothers It is not known whether romidepsin 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 ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.

8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were >65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted.

Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)].

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted.

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)].

10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required.

There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 or Baxter Oncology GmbH Halle/Westfalen, Germany ISTODAX® is a registered trademark of Celgene Corporation © 2010-2013 Celgene Corporation. All Rights Reserved.

U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBSPTCL.005 06/13

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Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)].

7.2 Drugs that Inhibit Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25% [See Clinical Pharmacology (12.3)]. Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [see Dosage and Administration (2.2)] when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).

7.3 Drugs that Induce Cytochrome P450 3A4 Enzymes Avoid co-administration of ISTODAX with rifampin. In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively [See Clinical Pharmacology (12.3)].

Typically, co-administration of CYP3A4 inducers decrease concentrations of drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of ISTODAX. It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) would alter the exposure of ISTODAX. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible.

7.4 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)].

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman.

8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established.

INTERVIEW WITH THE INNOVATORS

Perspectives on the Landscape of Personalized Medicine Gail E. Herman, MD, PhD

An Interview With Gail E. Herman, MD, PhD; Barbara L. McAneny, MD; and Charles L. Sawyers, MD

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he Personalized Medicine Coalition (PMC) was launched in 2004 to educate the public and policymakers and to promote new ways of thinking about healthcare. Today, PMC represents a broad spectrum of more than 225 innovator, academic, industry, patient, provider, and payer communities seeking to advance the understanding and adoption of personalized medicine concepts and products for the benefit of patients.

Through our partnership with PMC, the publisher of Personalized Medicine in Oncology (PMO) had the pleasure of interviewing several faculty members at the recent PMC conference about personalized medicine and their direct involvement in this movement. Those interviewed include a geneticist, Gail E. Herman, MD, PhD; a community oncologist, Barbara L. McAneny, MD; and an academic oncologist, Charles L. Sawyers, MD. The insightful exchange is presented below.

PMO Thank you all very much for meeting with us today. To start our discussion, we’d like each of you to provide your definition of personalized medicine.

Charles L. Dr Herman I would define it as using the Sawyers, MD information in our genome to make better healthcare decisions, both as healthcare providers and also as patients.

Dr Sawyers I prefer the term precision medicine rather than personalized medicine as this term implies a more accurate diagnosis. Further, using information in the tumor genome to better understand the root cause of the cancer has been shown to predict the best therapy. “Personalized” implies that every patient’s tumor is different and might even need a different treatment, and while it’s true that every tumor might be different at the DNA level, I think it’s impractical to assume everyone would receive a custom treatment.

Dr McAneny I think patients tend to think of personalized medicine as a nurse navigator who’s going to hold your hand through your process. So I think we’re going to have to work to change that definition. As a cancer doctor, I think of finding the right treatment to fit

that exact patient’s needs. That’s where personalized medicine comes in, being able to use genomic markers of the patient and the tumor to find the right treatment that works best for that individual.

PMO Dr McAneny and Dr Sawyers, how have your practices, the New Mexico Cancer Center and the Human Oncology & Pathogenesis Program at Memorial Sloan Kettering, incorporated personalized medicine principles into patient care? Have there been obstacles to their adoption?

Dr McAneny We stay current on the markers that will lead to a change in therapy. We have created a pathway system to integrate this information into the care.

An obstacle we face is economic, with denials by the payers. In some cases, the labs may charge the payers for 1 test at a time, and sometimes that’s not acceptable to the payers, who question why a patient is receiving a second test and a third test.

Interestingly, the patients are not an obstacle. When we ask to test their genome to find out if their cancer will respond to a very specific drug that targets our finding, patients are very accepting. I occasionally work in a clinic in the Navajo Nation, and they do not like the idea of taking private information and making it more accessible. But when we explain the utility, there’s no problem.

They’re willing to go ahead with the tests and thrilled to have less toxic treatments.

Dr Sawyers I’m the inaugural chair of a research program at Sloan Kettering called Human Oncology & Pathogenesis Program (HOPP). Its purpose is to attract the best and the brightest physician scientists who have

Barbara L. McAneny, MD

Gail E. Herman, MD, PhD, is President of the American College of Medical Genetics and Genomics (ACMG).

Barbara L. McAneny, MD, is Chief Executive Officer of New Mexico Cancer Center, New Mexico Oncology Hematology Consultants, Ltd. Charles L. Sawyers, MD, is Chair of the Human Oncology & Pathogenesis Program at Memorial Sloan Kettering Cancer Center.

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1 foot in the lab and 1 foot in the clinic to help bridge the movement of new exciting ideas into the clinic.

Personalized medicine in the form of genomic sequencing of tumors has been a major part of the research by almost all the investigators in the HOPP program. I would say it’s mostly been positive. Some of the obstacles have been just the pace at which the technology is changing. In order to move something into the clinic, you have to secure a method and prove that it’s reliable and effective. It’s a challenge to remain constantly innovative and also still be impacting the clinic.

PMO Also for Drs Sawyers and McAneny, in your tenure as oncologists, can you describe the most significant advances that impacted your ability to provide better care for your patients?

Dr McAneny It is difficult to identify just one because there’s a tsunami of information that’s coming at us now, allowing us to fine-tune treatments for patients. I would think that the most significant scientific change is the genomic markers and being able to tailor treatment for a given patient.

I think the most significant process-oriented change is bringing many of the services that a patient needs together under 1 roof so that we can provide care in a way that’s very convenient and easy for patients.

Dr Sawyers I was involved at the very beginning of the development of the drug Gleevec for chronic myeloid leukemia in the late 1990s when most people were predicting that the drug would not work for a couple of reasons. One, cancers are complicated. Why would a drug that only is blocking 1 alteration in a cancer be expected to work? Obviously, that proved to be a concern that was not warranted. Second, this was the first tyrosine kinase inhibitor. Tyrosine kinases all do 1 thing: they take ATP [adenosine triphosphate] and put it onto a substrate. Even though Gleevec appeared to be relatively specific for BCR-ABL, the driver in chronic myeloid leukemia, it did work by blocking ATP binding, so it was assumed that there would be horrible toxicity, but that was not the case.

This was a remarkable experience. I’m very proud of our role in moving the field forward, and I think it’s going to continue to drive the way we develop cancer drugs in the future.

PMO And Dr Herman, from the geneticist’s perspective, can you describe the most significant advances you have witnessed that impact our ability to care for patients?

Dr Herman Given my background in pediatrics, the first advance that comes to mind is expanded newborn screening. When I started training, there were many rare metabolic disorders that we couldn’t treat, and as a result, children died. The standardized newborn screening

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panel tests for more than 30 disorders. There are kids that would have died prior to this panel that now are growing up, living normal lives. The college [ACMG] was central to this progress, establishing the criteria for adding a disorder to the panel. And now the college has obtained a grant to look at outcomes. It’s the newborn screening translational network.

Of course, other advances are new targeted drugs, options in treating genetic diseases, and the revolution in diagnostics.

PMO As we gain increased understanding of genetics in cancer, it’s increasingly important to incorporate molecular measurements into clinical trials for all kinds of cancer. Can you describe how the introduction of companion diagnostics and the discovery of biomarkers in oncology will impact clinical trial enrollment and design?

“I think that the most significant scientific change is the genomic markers and being able to tailor treatment for a given patient.”

– Barbara L. McAneny, MD Dr Sawyers The companion diagnostic model has already had a huge impact on not just clinical trial design but also clinical practice. The idea is that if you’re giving a targeted agent, you need to give it to patients whose tumor has the target. The clinical trials have to demonstrate 2 things; the first is that you can measure the target reliably with a diagnostic test, and second, that that test picks out a subpopulation of patients with that kind of cancer that respond dramatically to the treatment.

There are many examples now, particularly in lung cancer and melanoma in recent years, where this has worked beautifully. But it turns out that it actually is almost out of date as a concept even though it’s working well, because the new generation of molecular diagnostic tests is large panels of genes, whereas a typical companion diagnostic is just measuring 1 mutation.

I think the whole field recognizes this, including the regulatory authorities at the FDA, and I think we have to figure out how to capitalize on this new technology in a way that ensures the accuracy of the testing, so that patients are not misdiagnosed, but enables the power of these multigene panels to be deployed right away in the clinic.

Dr McAneny Also, I think our current system – where we have certain centers that are able to provide clinical trials, and patients are supposed to travel at the time of their life when they least want to travel away from their friends and family, to enroll in a trial – is perfectly designed to achieve the 3% that we enroll. If we

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want to continue enrolling only 3%, we should keep doing it as we are.

If we intend to use companion diagnostics and personalized medicine as a way to screen the population and find that subset of patients who will respond to a given therapy and therefore can be enrolled on a trial, then we need to widen that network so that it extends into the community practices, where we see the vast majority of the patients, and offer the trial to the patient in that setting. We need to restructure how we conduct clinical trials in this country, or we will never get better than 3% enrollment.

Payers respond to data. If we are able to demonstrate good outcomes in relation to reasonable costs, then we’ll be able to make a rational decision.

PMO Is the Affordable Care Act financially compatible with the growth of personalized medicine overall and specifically in oncology, or will its additional cost reduce the spread of personalized medicine overall and in oncology in particular?

Dr McAneny The Affordable Care Act basically is insurance reforms. People need to have better insurance policies that will allow us to do what we need to do as physicians.

I think the Affordable Care Act will expand the group of people for whom personalized care is available.

Right now, if I have patients who are uninsured, I can’t get them the drugs, I can’t get them the testing. I can give them some of my time, but frankly, as a cancer doctor, that’s useless unless I have my tools.

I’m excited about this. In my state with 24% uninsured, this opens up good therapy to a lot of people, so I think it will help.

I don’t think the cost of this is going to be exorbitant.

What we have to prove is that if you order a personalized medicine test, a genomic marker test, and you find a specific treatment that works, that provides a lot more value than treating people with the random chemotherapies that we try to use in the one-size-fits-all model. The value we’ll prove will be in better outcomes.

Dr Sawyers I think this question is getting at not so much whether personalized medicine is incompatible with the Affordable Care Act but whether the price of new oncology-targeted drugs can be sustained.

I think payers are willing to pay for treatments where the evidence overwhelmingly supports their effectiveness, and targeted therapies given to the right patient

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tend to be remarkably effective. The problems arise when a targeted therapy has a rather modest benefit and perhaps in only a small number, a minority of patients, yet the clinical trial demonstrates superiority over the standard treatment, but only by a small amount. I personally feel it’s hard to justify paying $80,000 to $100,000 a year for such a treatment.

I’m much more in favor of rewarding real game-changing treatments where we understand the reasons patients benefit, and we can select those patients. I think in the long run that will prove to be an economically cost-effective model of delivering care.

PMO Value is more than cost, it is the balance of cost, quality, and access. How long will it take for personalized medicine to begin paying dividends economically, as it already pays dividends clinically, and become attractive to payers by showing value?

Dr McAneny I think we’re going to have to prove the case with data. And I think a lot of the value will come in avoiding therapies that do not work. That obviously has value for the patients who spend some of their remaining life span receiving a treatment that isn’t working, enduring the toxicities and getting no value, and for the payers who end up paying for something that isn’t working.

Payers respond to data. If we are able to demonstrate good outcomes in relation to reasonable costs, then we’ll be able to make a rational decision.

Dr Sawyers This is the major question. Why shouldn’t payers pay for molecular diagnostic testing right away?

Because we don’t have the evidence that it is beneficial to all patients. With roughly 10 years of experience in lung cancer with different targeted agents, it’s pretty clear that a patient with lung cancer should have a panel of mutations run.

I don’t think a payer is going to argue with that, because it’s going to directly impact the treatment decision, and it’s going to be cost-effective in the long run because patients won’t get put on 1 or 2 or 3 drugs empirically and fail them and then finally get the right drug. But arguing that every cancer patient should have such a gene panel covered by the payer won’t happen until we, as a community, generate the evidence through research.

How do we generate those research projects? That’s another very difficult question, particularly in this era of restricted medical research budgets. I think it actually may be in some payers’ interest to join some funding consortia, perhaps with the drug development community, the academic community, and the government, to build the evidence base, or at least build the infrastructure, so that the occasional examples of one-offs of genomes and treatments that are done in cancer practice get collected and can be learned from.

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PMO How would you articulate the value proposition justifying the cost of personalized medicine to the clinical business and government sectors and to patients?

Dr Sawyers The value proposition to government is in the savings downstream to Medicare by more costefficient delivery of care. But in order to realize that economy, I think a lot of R&D money needs to be spent to generate the evidence base.

In some ways I think patients might have to be the catalyst to drive this issue, because patients are the ones who stand to benefit the most. We live in a world where data sharing is difficult for a number of reasons, including privacy, but at least in cancer the dominant theme I hear from patients is they want to share their data.

I think our field should seriously consider patient-driven efforts to deposit genomic data in a secure way and correlate it with clinical outcome so that this evidence base can start to be generated.

Dr McAneny We will be able to justify costs by identifying that subset of patients who are very likely to respond, use that drug in that population and only in that population; then the value proposition will become obvious.

I also think that it’s going to become necessary for us to figure out a way to better subsidize the process of getting a drug to market, because we cannot have drugs that cost $100,000 a year, $200,000 a year, to be able to keep a patient alive. That’s an unfair burden to put on patients and the system.

PMO Dr McAneny, you were awarded a grant from the Center for Medicare & Medicaid Innovation to test how private oncology practices could better care for patients with cancer at lower costs. Can you provide an update on your findings and how they can be incorporated into other cancer centers?

Dr McAneny It requires a basic mindset change of the way practices are structured. This is our goal as we create an oncology medical home. The idea is that “home” is a place that’s centered around you, the patient.

Instead of the current structure of a patient being sick today, but the doctor will see that patient a week from next Thursday, we encourage every person in the practice to have the mindset that if the patient is sick, our job is to get the patient what they need when they need it; to intervene early and to be the place where patients go early in the course of their illness. This will ultimately keep patients out of emergency departments, shorten length of stays in hospitals, and build that doctor/patient relationship so the patient regards the oncology practice as their home.

We succeeded in implementing this philosophy with some very specific triage pathways that look at the common problems that patients on chemotherapy or radia-

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tion therapy encounter. We set up processes to intervene early and then aggressively manage those side effects so that we have fewer patients in the hospital. We prevent 2 to 3 emergency department visits just in my practice per evening by being open until 8:00 o’clock and aggressively getting patients to come to the office. That’s a huge amount of savings.

We cannot have drugs that cost $100,000 a year, $200,000 a year, to be able to keep a patient alive. That’s an unfair burden to put on patients and the system.

We will also be using the pathways to improve the quality of what we do, and we’re embedding the genetic markers into these pathways.

PMO Dr Herman, the ACMG has put forth policy statements and guidelines regarding next-generation sequencing. Can you give us a glimpse of the types of guidelines the college will work toward during your tenure as president?

Dr Herman We are focusing on next-generation sequencing for clinical efforts, and we just recently published a guide for laboratories performing next-generation or exome sequencing. There is discussion of how far the depth of coverage should be and how to approach incidental findings. These are findings that may be medically actionable or important but are unrelated to the reason or diagnosis for which the test was ordered. One of the recommendations we received was to put a work group together to figure out how to add additional genes. We’re in the process of doing just that.

We have a work group now that’s writing an update to interpretation of genomic variants, ie, DNA sequence changes. They’re working very hard in the next-generation area and figuring out how to categorize variants and whether they are pathogenic or benign.

Also, we just recently started a work group focused on the issues surrounding informed consent for clinical exome and genomic sequencing.

PMO Dr Herman, you brought up an issue of particular interest – the college’s recent recommendations for reporting of incidental findings in clinical exome and genome sequencing reports. The college points out that there are insufficient data on clinical utility to fully support these recommendations. Considering this, can you briefly discuss the potential utility in secondary findings discovered in the course of research in a clinical context?

Dr Herman That’s a really important issue. The re-

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port touched on the fact that they were talking about clinical sequencing and not research. I think the National Human Genome Research Institute at NIH is very interested in trying to come up with some guidance and standards on what the research community should be doing or thinking about in this regard.

interpretation may not be up to the standards in the clinical lab. Not all research labs have the same standards, and I think the worst thing we could do is to give out information that’s wrong or premature.

PMO Dr Sawyers, with the new immunotherapy products coming down the pipeline, do you view that as a personalized or precision approach to treating cancer patients?

Dr Sawyers Immunotherapies are potentially a different kettle of fish because they don’t work by targeting the tumor. Checkpoint blockade inhibitors, such as ipilimumab, and different antibodies that target PD-1 or PD-1 ligand don’t work in every patient, but there might be some profile within the tumor that would predict who’s going to respond to checkpoint blockade therapy. The tools of genomics that we have available should lead to the answer, and I expect in the next couple of years we’ll know a lot more.

PMO We’d like to thank you each for your time today. Your insights on the dynamics of personalized medicine are much appreciated. Our very best to you for continued success in your endeavors. u

Not all research labs have the same standards, and I think the worst thing we could do is to give out information that’s wrong or premature.

There was a time years ago when we, as researchers, tried to give research results out to families. Now there’s a big push again to provide research results in a responsible fashion – meaning, results that are known to be of significance and are validated in a CLIA-approved clinical lab should be given to families.

I think the problem with research results, including DNA sequencing, is the quality of the sequencing and

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Over the past decade, significant progress has been made in the management of multiple myeloma, including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances.

In this sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this second issue, experts from Dana-Farber Cancer Institute answer questions related to the management of patients in the maintenance setting.

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PEDIATRIC ONCOLOGY

A Win for Pediatric Cancer Research: The Gabriella Miller Kids First Research Act and Smashing Walnuts Foundation

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n April 3, 2014, President Obama signed the Gabriella Miller Kids First Research Act. This act was introduced last year by representatives Peter Welch (D-VT) and Gregg Harper (R-MS) and strongly supported by House Majority Leader Eric Cantor (R-VA). After being introduced, the bill was renamed to include the name of a 10-year-old girl who became an activist for children’s cancer research after her diagnosis with brain cancer last year.

“You may have a bad day today, but there’s always a bright shining star to look forward to tomorrow.”

– Gabriella The Gabriella Miller Kids First Research Act The Congressional Research Service, a nonpartisan division of the Library of Congress, offered a summary of this act as follows: Gabriella Miller Kids First Research Act – Amends the Internal Revenue Code to terminate the entitlement of any major or minor political party to a payment from the Presidential Election Campaign Fund for a presidential nominating convention.

Transfers amounts in each account maintained for such purpose for the national committee of a party to a 10-Year Pediatric Research Initiative Fund, making them available only for allocation to national research institutes and national centers through the Common Fund for making grants for pediatric research under this Act. Amends the Public Health Service Act to require the Director of the National Institutes of Health (NIH), through the Division of Program Coordination, Planning, and Strategic Initiatives, to allocate funds appropriated under this Act to the national research institutes and national centers for making grants for pediatric research representing important areas of emerging scientific opportunities, rising pub-

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lic health challenges, or knowledge gaps that deserve special emphasis and would benefit from conducting or supporting additional research that involves collaboration between two or more national research institutes or national centers, or would otherwise benefit from strategic coordination and planning.

Authorizes $12.6 million out of the 10-Year Pediatric Research Initiative Fund for each of FY2014FY2023 for pediatric research through the Common Fund. Requires such funds to supplement, not supplant, funds otherwise allocated by NIH for pediatric research. Prohibits the use of such amounts for any purpose other than allocating funds for making grants for pediatric research described in this Act.

What this boils down to is that the government will divert $12.6 million to the common fund at the National Institutes of Health to support research efforts focused on childhood cancer and other pediatric diseases.

We at Personalized Medicine in Oncology and others in our field are of course delighted to hear of additional research funds made available to advance pediatric cancer care. The extraordinary component of this story, however, is the personal effort of a 10-year-old girl to increase funding for cancer research.

Meet Gabriella Her name is Gabriella Miller. In November 2012, at the age of 9 years, she learned that she had a walnut-sized, inoperable brain tumor. Despite exhausting chemotherapy and radiation treatments, she quickly became a national childhood cancer advocate and worked to raise money for cancer research through public speaking engagements and through the establishment of a foundation called Smashing Walnuts. A powerful image, Gabriella and her family literally began smashing walnuts with frying pans as a symbolic gesture to support her battle against the tumor.

In the year following her diagnosis, and while undergoing treatments, Gabriella accomplished more than some adults accomplish in a lifetime. She helped raise $275,000 for the Make-A-Wish Foundation, $15,000 for a childhood brain tumor foundation, spoke at a variety of local and national awareness events, and authored a special writing in a children’s book about

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cancer, Beamer Learns About Cancer, by Cindy Chambers, which was released in September 2013.

Gabriella recently lost her battle to cancer, but she remains an inspiration. She encouraged people to carry on the battle, suggesting that we will “win the war” even in her absence.

Pediatric Cancer Statistics We are now rapidly approaching 16,000 kids diagnosed with cancer annually. For 2014, the American Cancer Society has estimated 15,780 new cases of pediatric cancer. This number has increased from the estimated 12,500 children diagnosed in the year 2008.

Cancers that are most common in children 0 to 14 years of age are acute lymphocytic leukemia (26%), brain and central nervous system (CNS) (21%), neuroblastoma (7%), and non-Hodgkin lymphoma (6%). The most common cancers in adolescents 15 to 19 years of age are Hodgkin lymphoma (15%), thyroid carcinoma (11%), brain and CNS (10%), and testicular germ cell tumors (8%). The most common solid tumors are brain tumors.1 Recognizing an Advocate for Pediatric Research Funding To provide families with hope for better, more effective treatments, researchers need more funding. This is what Gabriella implored our government to do – invest in research. In recognition of his efforts to do just that and his leadership in getting the Gabriella Miller Kids First Research Act passed, House Majority Leader Eric Cantor received the 2014 Children’s Advocacy Award at the annual Children’s Ball to benefit Children’s National Health System. Mr Cantor was quoted, “Doctors, nurses, and researchers at Children’s National do outstanding work on behalf of children and their families every day. Providing quality care to children so that they can live brighter and healthier lives is a top priority. Over the last year, the Congress has advanced important legislation that puts kids first, including the PREEMIE Act, the Children’s Hospital GME Support Reauthorization Act, and the Gabriella Miller Kids First Research Act. I am committed to continue working together to find treatments and cures for our kids. It was an incredible honor to receive the Children’s Advocacy Award, and I will keep working to build support for pediatric research so we can help more children.”

How to Help To make a tax-deductible donation to the Smashing Walnuts Foundation, you can visit their website at www.smashingwalnuts.org. u Reference

1. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014.

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House Majority Leader Eric Cantor receives the 2014 Children’s Advocacy Award at the annual Children’s Ball to benefit Children’s National Health System.

Gabriella’s friends and family literally began smashing walnuts with a frying pan as a symbolic gesture to support her battle against her tumor.

Childhood Cancer Facts • The chance of a child under 20 being diagnosed with cancer is 1 in 285

• Cancer kills more children than any other disease in the Unit-

ed States, more than asthma, cystic fibrosis, diabetes, and pediatric AIDS combined • Pediatric brain tumors aren’t like those in adults. Children’s brain tumors require specific research and different treatments • 72% of young people diagnosed with a brain tumor are younger than age 15 • 7 children die every day of cancer Source: www.smashingwalnuts.org.

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Promise of Personalized Care Hinges on Reimbursement Reform Oncologists Must Lead the Way Charles Bankhead

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he promise of big data-driven personalized healthcare mandates reform of the oncology reimbursement system, suggested Jeffery C. Ward, MD, medical oncologist, Swedish Cancer Institute, Edmonds, WA, in a recent commentary (Ward JC. J Oncol Pract. 2014;10:83-86).

Oncologists must take the lead in moving past “medicine’s dark secret” of fee-for-service (FFS) reimbursement into a system that more accurately captures the full spectrum of service provided to patients, such as bundled payments, he noted.

“The real threat to bringing big data and personalized cancer care to the communities where the vast majority of oncology patients are treated is an antiquated reimbursement system that only pays for care when it involves physician touches and infusion of drugs,” Ward wrote.

data) is the driving force, providing the capability to accumulate, assemble, and analyze the massive amount of information that makes personalized care possible.

“The real threat to bringing big data and personalized cancer care to the communities where the vast majority of oncology patients are treated is an antiquated reimbursement system that only pays for care when it involves physician touches and infusion of drugs.”

– Jeffery C. Ward, MD

Transforming Oncology Practice “Personalized medicine and big data hold the promise to transform oncology practice more, and more rapidly, than anything that has happened in the first 50 years of the history of our specialty,” Ward noted in his article.

The amount of medical information doubles every 5 years, but the vast majority of digital medical data was developed in the past 2 years. Moreover, 80% of the data remains raw and unstructured. Bringing order to all of that information and making it useful and usable requires advanced computing capability, as represented

by IBM’s Watson, which has demonstrated great potential for processing information in real time to facilitate clinical decision making.

Big data has the potential to transform clinical practice and clinical research. Computer analysis will never replace a well-designed clinical trial but will augment and improve the trial process.

“Common characteristics that bind a few responders to a particular therapeutic from a sea of otherwise indifferent information, and then effortlessly seek out patients with similar characteristics, will allow for rapid and efficient validation trials,” said Ward. “Only when that happens can personalized medicine deliver on its promise.”

“It is not just FFS medicine that is the problem but a particular ilk of FFS that only pays for some services, failing to reimburse at all for other essential services provided in oncology offices and clinics.”

Before big data can transform the healthcare sector of the economy, the industry has to make fundamental changes that ensure stakeholders capture the full value, “and that begins with how we pay for it,” wrote Ward.

The emerging era of personalized medicine has its genesis in advances related to genetics, molecular biology, and other aspects of basic science and clinical medicine. However, the informatics revolution (big

Payment Reform and Big Data in Oncology To quote from an article on P4 (predictive, personalized, preventive, participatory) cancer medicine, “each patient will be surrounded by a ‘virtual cloud’ of billions of data points that will uniquely define their past medical history and current health status” (Hood L, et al. Nat Rev Clin Oncol. 2011;8:184-187). From the vast amount of data will come individualized algorithms that address a patient’s current clinical needs and provide for the patient’s future wellness.

To realize all that big data has to offer healthcare, reimbursement must be designed to complement personalized medicine, which will “incentivize processes

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VALUE-BASED CANCER CARE EDITORIAL

designed to improve value and measure and reward efficacy, quality, and efficiency of care,” Ward continued.

As an example, he cited ongoing work by the American Society of Clinical Oncology’s Clinical Practice Committee.

Still evolving, the Clinical Practice Committee model bases core payments on monthly episodes of care. The episodes are defined by multiple factors, including “the patient’s continuum of disease, new patient payments, treatment month payments, transition-of-care payments, and surveillance or nontreatment month payments,” Ward noted.

“When a margin proportionate to the cost of the drug is the provider’s reward for giving chemotherapy, it becomes quintessential FFS. The incentives to not only give more chemotherapy but to preferentially use high-margin drugs, usually more expensive drugs and parenteral therapies, can only partially be overcome by strict value-based pathway adherence or enforcement.”

– Jeffery C. Ward, MD “Any specific category of treatment may be expanded on the basis of acuity and/or complexity of the patient’s disease and the care given,” he said of the Clinical Practice Committee project. “Valuation of each core payment can be developed in a budget-neutral way to current reimbursement and increases and then tied to a medical inflation index.”

The payment system would provide for all the activities that go into various stages of the patient care process, from planning and initiation of treatment to follow-up and well care. Such bundled payments would

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account for a multitude of ancillary services, such as nurse educators, group sessions, and social work.

As currently conceived, treatment-month payments would have a built-in scale that could be adjusted in accordance with the complexity of the disease and treatment regimen. Transition payments would be incorporated to account for the extra time and service necessitated by a change in treatment plan.

“Fortunately, the electronic medical record and big data should make it much simpler to define the real work requirements and value of distinct bundles than the American Medical Association’s muchvilified Relative Value Scale Update Committee,” Ward added.

The core bundled payments would increase or decrease as a result of the adoption of value-based pathways and quality-improvement activities. Eventually, process measurements would be replaced by outcomes.

Inducements would be added over time, culminating in the development of a performance-based system.

Cancer Drug Pricing and Reimbursement Ward acknowledged that incorporation of cancer drugs into the reimbursement system will be problematic, given that drugs often constitute the most costly item in the care of a patient with cancer. Fundamental changes to the current “buy-and-bill” system of administration will be required.

“When a margin proportionate to the cost of the drug is the provider’s reward for giving chemotherapy, it becomes quintessential FFS,” said Ward. “The incentives to not only give more chemotherapy but to preferentially use high-margin drugs, usually more expensive drugs and parenteral therapies, can only partially be overcome by strict value-based pathway adherence or enforcement.”

“The era of personalized medicine will require that ASP [average sales price]-based pricing be replaced and that a margin on drugs be taken out of the reimbursement equation,” Ward added.

Oncologists must take the lead in developing the reimbursement system of the future. By failing to “answer the call,” oncologists risk allowing other parties – such as insurers and drug companies – to decide how oncology should be valued and reimbursed, Ward concluded. u

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ersonalized edicine in Oncology

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BIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

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PROSTATE AND CERVICAL CANCER UPDATES

14 New Genetic Markers Predict Risk for Prostate Cancer Of These Mutations, 5 Were Newly Discovered in This Study Neil Canavan

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mutation in any one of a suite of DNA repair pathway genes may predict not only the risk for familial prostate cancer but also indicate the presence of a particular aggressive form of the disease, according to results of a new UK study from the Institute of Cancer Research in London (Leongamornlert D, et al.

Br J Cancer. 2014;110:1663-1672.

“If we can more effectively screen these men, clinicians can potentially offer more tailored screening, staging and treatment pathways…men with deleterious germline mutations in these genes should be considered for more intensive screening and treatment.”

– Daniel Leongamornlert, PhD Candidate, and colleagues If validated, the clinical utility of these newly identified genetic markers will play a key role in the precautionary monitoring of men with the mutations, as well as guide treatment choice should disease onset occur.

“If we can more effectively screen these men,” wrote the investigators, “clinicians can potentially offer more tailored screening, staging and treatment pathways.”

Daniel Leongamornlert and colleagues from the Division of Genetics and Epidemiology at the Institute of Cancer Research in London, United Kingdom, found that the presence of even 1 of the so-called lossof-function mutations increased the risk for prostate cancer by almost 2-fold compared with men without any of these mutations.

Furthermore, these mutations were more frequently associated with nodal involvement, tumor metastasis, and/or advanced disease at the time of diagnosis.

Mechanism of Genetic Risk for Prostate Cancer Similar to Breast Cancer It has long been known that certain types of breast

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cancers run in families, in particular tumors associated with the BRCA1/BRCA2 mutations, which are observed in 10% of all breast cancer cases. However, mutations in these genes, and the resultant loss of function of the associated proteins, have been associated with other cancers, including ovarian and prostate cancer, which was only recently understood.

“This suggests that shared genetic and/or environmental factors may be causal for multiple cancer types,” wrote the investigators, a hypothesis thought to be particularly relevant for hormonal-related malignancies.

Because genomic instability is the hallmark of most cancers, the team expanded their focus to include a comprehensive set of genes related to DNA repair pathways.

New Mutations Identified A total of 191 men in the United Kingdom with a family history of prostate cancer were selected for this study; they were screened using the genetic assay known as the BROCA Cancer Risk Panel, in combination with second-generation DNA-sequencing technology, to spot deleterious mutations.

The 14 loss-of-function mutations were identified in 8 genes, including ATM, BRCA1, BRCA2, BRIP1, CHEK2, MUTYH, PALB2, and PMS2.

Of the mutations found, 5 were discovered for the first time in this investigation, and no enrolled patient had more than 1 loss-of-function mutation.

Although the predictive value of these mutations in cases of familial prostate cancer was less than that seen in the example of BRCA1/BRCA2 and breast cancer – roughly 10% in breast cancer versus 7.3% in prostate cance – the implications for disease prognosis are striking.

“There was a significant association between LoF [loss-of-function] carrier status and the presence of nodal involvement…and metastasis,” the investigators stated. Regarding involvement of the lymph nodes, there was an incidence rate of 42.9% for patients with prostate cancer and a loss-of-function mutation versus 1.3% for men without a mutation; for tumor metastasis, the rate was 30.0% versus 6.3%, respectively.

Loss-of-function mutation carriers also had a sig-

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nificantly greater risk for advanced disease (odds ratio, 15.09); even after the BRCA2 mutations known to be associated with poorer prognosis were excluded, the risk for advanced disease persisted.

Significant, Inherited Risk These newly revealed mutations also showed significant inherited genetic penetration in families. Of the 191 enrolled men with ≥3 cases of prostate cancer in their family, 128 also had ≥1 case of breast, ovarian, or colon cancer in their family.

One participant with a mutation in the CHEK gene had 2 brothers with prostate cancer; the family of

another enrolled man with a mutation in the ATM gene had a father with colon cancer, 4 of 8 brothers with prostate cancer, and his sister was reported to have had leukemia.

Overall, even after the most common loss-of-function mutations of BRCA1/BRCA2 were excluded from the analysis, the newly discovered mutations accounted for a 1.8 increased risk for prostate cancer.

“This finding could have important clinical implications as men with deleterious germline mutations in these genes should be considered for more intensive screening and treatment,” the investigators concluded. u

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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Routine Cervical Cancer Screening Warranted Beyond Age 64 Rosemary Frei, MSc

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esults of a new study investigating the probability of a cervical cancer diagnosis among women aged 65 to 83 years using data from the UK Cervical Screening Call/Recall System indicate that the current practice may need to be changed. The new data show that the odds of such a diagnosis were 25% lower in women who had regular screening between the ages of 50 and 64 years compared with women who did not have regular screening. Although the protective effect diminished gradually, it was still significant up to age 83 years, according to the investigators (Castañón A, et al. PLoS Med. 2014;11:e1001585).

Furthermore, the team calculated that there would be 149 fewer cervical cancers per 100,000 women if women continued to be screened for cervical cancer until age 75 instead of age 65.

“Based on these results, we believe women should be screened beyond age 50, with at least 1 screen after turning 60, and possibly continuing screening until age 75,” said lead investigator Peter Sasieni, PhD, professor of bio­ statistics and cancer epidemiology, Wolfson Insti­ tute of Preventive Medicine, Queen Mary University, London.

The methods used by Sasieni and colleagues included matching 1341 cases of invasive cervical cancer of women who were diagnosed at ages 65 to 83 years with 2646 controls matched for age and place of residence. A weighted logistic regression model was used to calculate the absolute risks for being diagnosed with cervical cancer.

The screening model involved the last 3 negative tests and having no high-grade cytology between the ages of 50 and 64 years.

The researchers could not collect data on potential confounding factors, such as sexual behavior and smoking, because this information is not gathered in the database they used. However, they made allowances for these factors by using sensitivity analyses.

Risk for Cervical Cancer Sasieni and coinvestigators calculated an odds ratio (OR) of 0.25 for the risk for cervical cancer between the ages of 65 and 83 years among women who had been screened at least once every 5.5 years between ages 50 and 64 years compared with those who had not been screened during those ages. Even women who had been

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CERVICAL CANCER AT A GLANCE New evidence suggests that women be screened for cervical cancer after age 50, with at least 1 screen after age 60, and possible screening until age 75 ➤ The odds of a cervical cancer diagnosis were 25% lower in women who were screened regularly up to age 64 years ➤ Based on these data, 149 fewer cervical cancers per 100,000 women would occur if women were screened regularly to age 75 ➤ Furthermore, if women stopped screening at age 55, there would be 182 additional cancers per 100,000 women ➤ Athough the protective effect of screening is reduced with age, the effect was still significant up to age 83 ➤

screened only once every 9 to 15 years between the ages of 50 and 64 years were at a lower risk for cervical cancer in later years, with an OR of 0.54.

However, the researchers also found that the protective effect of screening before age 64 years is reduced with advancing age. In women aged 50 to 64 years with a screening interval of 5.5 years or less compared with no screening, the OR for a cervical cancer diagnosis between the ages of 65 and 69 years was 0.12, compared with 0.27 for women aged 70 to 74 years, 0.46 for ages 75 to 79 years, and 0.49 for ages 80 to 83 years.

The team also estimated the possible effects of risk factors on which no data had been gathered, including on sexual behavior and smoking. They found that these factors could increase the risk by 18%. That translates into an OR of 0.14 instead of 0.12 of developing cervical cancer in women aged 65 to 69 years, 0.33 instead of 0.27 in women aged 70 to 74 years, and of 0.54 instead of 0.46 for women aged 75 to 79 years.

The team’s modeling of the effect of stopping screening at 75 years versus at 65 years per 100,000 women yielded 149 fewer cancers with the former scenario, based on cumulative incidence data from 1975.

In addition, the model suggests that there would be 182 additional cancers per 100,000 women if screening stopped at age 55 years. u

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Interview With the Innovators A PMO Exclusive Series The world of personalized medicine is a rapidly changing, ever-evolving state involving many stakeholders on the front lines of its creation: physicians, industry, researchers, patient advocates, and payers.

PMO seeks out the leaders in these sectors and brings you their game-changing strategies, missions, and impact on personalizing oncology care.

To view Interview With the Innovators, or to nominate an interviewee, visit us at

www.personalizedmedonc.com

PMO Interviewees include:

Lawrence M. Weiss MD, Clarient Diagnostic Services, Inc. Inno111313

Edith Perez, MD Mayo Clinic

Kimberly Popovits Genomic Health

Edward Abrahams, PhD Personalized Medicine Coalition

NCCN 2014

New Melanoma Guideline Adds BRAF Inhibitor, MEK Inhibitor to First-Line Systemic Therapy Options

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he BRAF inhibitor dabrafenib has been added as a category 1 recommendation for the primary treatment of BRAF-mutated metastatic melanoma in the latest version of the National Comprehensive Cancer Network (NCCN) guidelines. MEK inhibition with trametinib in BRAF-mutated melanoma was also added to the systemic John A. Thompson, MD therapy options for the treatment of advanced or metastatic melanoma.

NCCN melanoma guidelines were updated by John A. Thompson, MD, at the 2014 meeting of the NCCN. Dabrafenib was added as a recommendation only for patients with V600 mutation of the BRAF gene (as is vemurafenib), whereas the principal indication for primary treatment of BRAF-mutated melanoma with trametinib (plus dabrafenib) is intolerance to BRAF inhibitors. Single-agent trametinib is not indicated for the treatment of patients who have experienced progression of disease on prior BRAF inhibitor therapy.

Dabrafenib was compared with dacarbazine in a randomized study in 250 patients with metastatic BRAF-mutated metastatic melanoma.

The category 1 preferred regimens for advanced or metastatic melanoma now include ipilimumab, vemurafenib, and dabrafenib. The new guidelines note that dabrafenib can be associated with significant episodic and recurrent fevers, low-grade squamous carcinoma, and little if any significant photosensitivity.

The data to support these recommendations were presented by Thompson, medical director of the Phase 1 Clinical Trials Program and member of the Melanoma Clinic, Seattle Cancer Care Alliance.

Dabrafenib was compared with dacarbazine in a randomized study in 250 patients with BRAF-mutated metastatic melanoma (Lancet. 2012;380:358-365); median progression-free survival (PFS) was 5.1 months in the dabrafenib arm compared with 2.7 months

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in the dacarbazine arm, for a hazard ratio of 0.30.

Further downstream from BRAF, the next signaling molecule in melanoma is MEK. The first targeted MEK inhibitor to achieve FDA approval is trametinib. In a study in which 322 previously untreated patients with metastatic melanoma were randomized to trametinib or chemotherapy (dacarbazine or paclitaxel) (N Engl J Med. 2012;367:107-114), median PFS was 1.5 months in the chemotherapy arm and 4.8 months in the trametinib arm, and overall survival at 6 months was 67% and 81%, respectively.

A study of combined BRAF and MEK inhibition at 2 doses versus dabrafenib monotherapy in patients with metastatic melanoma revealed superior PFS with the combination regimens (~9.0 to 9.5 months) compared with dabrafenib monotherapy (~6 months) (N Engl J Med. 2012;367:1694-1703). The benefit of the combination regimen extended to all the clinical subgroups that were tested. Dual blockade increased the incidence of fever and chills compared with dabrafenib monotherapy.

“Oftentimes, the fever and chills require temporary cessation and resumption of therapy at lower doses and supportive therapy such as acetaminophen,” he said.

Potential for Immune-Related Adverse Events Thompson updated the field of immune checkpoint inhibitors in the treatment of melanoma. A recent multicenter retrospective review of ipilimumab in 39 patients with metastatic uveal melanoma resulted in a median overall survival of 9.6 months (Cancer.

2013;119:3687-3695). Grade 3/4 toxicity occurred in 18% of the patients.

“In treating patients with ipilimumab, we have to be very careful in managing the potential for immunerelated adverse events,” said Thompson. Skin, gastrointestinal (GI), liver, endocrine system, and neurologic toxicities may develop. The median time to skin toxicity is about 3 weeks, whereas GI toxicity tends to manifest at about week 6 and endocrine toxicity in the later stages of treatment, he said. GI toxicity, which occurs in up to 25% of patients treated with ipilimumab, can progress rapidly and requires active intervention.

Anti–PD-1 agents in development for the treatment of advanced melanoma are lambrolizumab and nivolu­ mab. The responses observed with lambrolizumab (N

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Engl J Med. 2013;369:134-144) were “quite dramatic,” he said, with approximately two-thirds of patients experiencing tumor shrinkage. The median duration of response had not been reached at the 11-month follow-up.

In patients with advanced melanoma, nivolumab received concurrently with ipilimumab was associated with a 53% objective response rate; a like percentage had immune-related grade 3/4 toxicities (N Engl J Med. 2013;369:122-133). Sixteen of 53 patients in this arm had tumor reduction >80% at 12 weeks.

First-Line Therapeutic Decisions At present, it is recommended that patients with BRAF wild type who have low-volume metastatic

melanoma and a performance status of 0 receive highdose interleukin-2 (IL-2) or ipilimumab as first-line systemic therapy or be entered into a clinical trial. For those with BRAF wild type who have more aggressive and symptomatic disease, ipilimumab or clinical trial enrollment (combining cytotoxic agents with immune checkpoint inhibitors) are recommended, said Thompson.

For patients with a documented mutation of BRAF, it is recommended that those with low-volume disease and a performance status of 0 receive IL-2, ipilimumab, or a targeted agent as first-line systemic therapy, or be enrolled into a clinical trial. Molecular targeted therapy (or enrollment into a clinical trial) is suggested for those with bulky disease who are symptomatic. u

The Affordable Care Act: Where Are We Now, What’s the Future?

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he Affordable Care Act (ACA) is in its infancy, but it is already changing oncology practice, said panelists during a roundtable discussion at the 2014 meeting of the National Comprehensive Cancer Network (NCCN). The changing composition of oncology patients, the risk pool of the exchanges, new payment and reimbursement models, acquisition fever, and oncology workforce demands were the real and potential consequences of the ACA discussed during the roundtable.

Forming the panel were moderator Clifford Goodman, PhD, senior vice president and principal, The Lewin Group, Falls Church, and panel members: • Christian G. Downs, JD, MHA, executive director, Association of Community Cancer Centers • Liz Fowler, PhD, JD, vice president, Global Health Policy, Johnson & Johnson • Michael Kolodziej, MD, national medical director of oncology strategy, Aetna • Lee H. Newcomer, MD, MHA, senior vice president, UnitedHealthcare • Mohammed S. Ogaily, MD, president, Michigan Society of Hematology and Oncology; clinical assistant professor, Michigan State University, East Lansing; medical director, Oakwood Center for Hematology and Oncology – Downriver • W. Thomas Purcell, MD, MBA, associate director for clinical services, University of Colorado Cancer

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Center, Denver; executive medical director, Oncology Services, University of Colorado Hospital • John C. Winkelmann, MD, private practice physician, Oncology Hematology Care, Cincinnati

Many patients who qualify for Medicaid and those selecting Bronze ACA plans have large co-pays and more out-of-pocket expenses than they did previously.

Since the rollout of the ACA, the composition of cancer patients hasn’t changed from the perspective of risk, said Purcell, but many patients covered by commercial insurance are for the first time participating in a narrow network. In addition, many patients who qualify for Medicaid and those selecting Bronze ACA plans have large co-pays and more out-of-pocket expenses than they did previously, and managing these expenses will be challenging.

The narrowing of networks has also had the consequence of interrupting continuity of care for some patients. “We’re getting situations in which patients are unable to come to us because they’re in a particular narrow network that we don’t cover,” he said.

Patients with rare or complex cancers best managed

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by an academic medical system that delivers multidisciplinary care may therefore not receive optimal care if the academic medical center is outside the patient’s narrow network, he said, “unless he pays out of pocket or we make an exception to treat him and cover the cost.”

Patients with immediate needs for care that could not be addressed previously are presenting at his clinic, said Ogaily. “Certainly, some [patients] are more complex because of the time that they have lacked coverage and did not seek medical care,” he said.

Razor-thin margins due to lower government reimbursement for oncology treatments are expediting hospital acquisition of physician practices.

Risk Pool Uncertainty In this early stage of the ACA, the risk pool is uncertain, creating a quandary for insurers, the panelists agreed. Because enrollment in ACA by younger persons is lagging, insurers may have insufficient data to make premium bids for next year, said Fowler.

“If the risk pool stays risky, does the thing fall apart?” asked Goodman.

Certain adjustments, such as a temporary reinsurance program, a temporary risk corridor program, and a permanent risk adjustment program may be necessary, said Fowler.

Other adjustments to the ACA, such as delaying the individual mandate, have been expensive to insurers as they continually reprogram their systems to comply with new regulations. Said Newcomer, “It has been an extremely expensive product to roll out. It takes a lot of our time, energy, and resources to keep making all of the changes that occur. It takes money away from other innovative programs.”

“One of the things that you’re starting to see is provider networks looking at doing things like accountable care organizations [ACOs], oncology medical homes, and broad medical homes,” said Downs. “I do worry a little bit though about providers going in risk, because that’s very difficult to manage, and it’s not necessarily their area of expertise. There is some concern about providers going too quickly into models they don’t fully understand.”

In Michigan, while ACOs are sprouting, the enthusiasm for oncology medical homes has not been robust, said Ogaily.

More Integrated Networks The new payment and reimbursement models with a

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shared savings environment will favor independent or group practitioners who have established relationships with payers, while putting at risk the practices that aren’t well integrated, said Downs. Acquisitions of oncology group practices and hospital mergers may be the new norm, a trend that started with the Medicare Modernization Act, he said.

“The concept of an integrated network becomes very important,” he said, noting the large number of disciplines involved in cancer care. The ACA may facilitate integration with its mandates for quality care measures and reporting requirements.

Razor-thin margins due to lower government reimbursement for oncology treatments are expediting hospital acquisition of physician practices, which are finding it difficult to survive on these low margins, said Newcomer. The consequence is an increase in prices as hospitals use their expanded leverage to negotiate fees.

“We’re seeing as much as a 10-fold increase in the price of a drug if a community practice is acquired by a hospital or facility,” he said. “That’s 10-fold on drugs that are not cheap in the first place. The patients pay for that with their co-payments and deductibles...and we also have to raise premiums to cover it.”

“One of the consequences of healthcare reform stimulated by the ACA is the requirement that, irrespective of site of service, you become sensitive to your price point and sensitive to quality metrics because network management is part of the strategy,” said Kolodziej.

The rapid rate of consolidation has resulted in less opportunity to negotiate appropriate site-of-service payment rates (ie, site-of-service differential), he added.

The cost differential between a community practice and a large hospital system may not reflect differences in services but “winds up being a contracting issue,” he said.

Even though the site of care, the services, and the patients may not change when a hospital system acquires a community oncology practice, “the fee schedules convert to the hospital’s negotiated fee schedule, which would be typically higher than we can get in community physician-based clinics,” said Newcomer.

The high rate of acquisition of community practices also runs the risk of leaving remote areas not adequately covered because larger hospital systems tend to focus on large metropolitan areas, said Ogaily. Traditionally, small community practices have been able to provide and extend coverage to remote areas.

Healthcare Demand and the Oncology Workforce The potential effect of a backlog of patient demand created by the ACA on the hematology and oncology workforce needed to meet this demand was raised by

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Goodman. When added to the demographic shift in the population, patient volumes may exceed the capability of the supply of hematologists and oncologists, necessitating increased use of physician extenders, said Winkelmann. Unfortunately, other specialties are scrambling to add physician extenders as well, creating competition for their services.

“We’ve got to start over and figure out how we can meet the needs of this large group of cancer patients coming forward into the system. That means a whole different way of approaching,” said Newcomer. Physicians may be the ones directing the care and devising treatment plans, with extenders administering treatments. The physician might then only be involved in the case of toxicity.

“If we rethink it, we can solve the problem, but it needs changing the financing and needs changing how we work with all of our other ancillary providers that care for cancer patients,” he said. “It can be done, but we’ll have to be innovative, and that’s the reason that all of us are toying with new ways of paying for cancer care.

Whether it be episodes, bundles, or capitation, we’re trying to find a way to realign the incentives to help physicians and hospital communities restructure how they deliver that care. The quicker we can get to that, the better off we’ll all be.”

Provisions under the ACA were geared toward moving providers from a fee-for-service system that warrants volume to one that values outcomes and quality instead, said Fowler. “It’s rough transition, particularly for providers that weren’t prepared or didn’t have the technology in place to do this,” she said.

Thirty percent of reimbursement incentives are based on patient satisfaction, she continued. “When you are thinking about what you need to do to meet the quality measures, you’ve got to start thinking about what matters to patients. That might be where survivorship and other issues come into play.”

ACA Shortcomings When asked where the ACA falls short, Newcomer mentioned the medical necessity clauses that prohibit taking cost into consideration when balancing treatment options that deliver equal outcomes.

“You have in any NCCN guideline multiple options for adjuvant breast cancer therapy or the treatment of non–small cell lung cancer. Some of them are far less expensive than others, but they have the same end results and often may have the same toxicities. In those scenarios, we should be thinking about using lower-cost alternatives,” he said. “We’re not allowed to do that in Medicare or the ACA.” u

Therapy for Castration-Resistant Prostate Cancer: Use Disease State as the Guide

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nderstanding the clinical disease states is essential when choosing therapy for patients with castration-resistant prostate cancer (CRPC), said Celestia S. Higano, MD. Patients with castration-resistant disease can be divided into those with metastatic disease and those with nonmetastatic disease. The focus of her presentation was on therapeutic options for metastatic CRPC, which can be further categorized into asymptomatic or symptomatic disease and prechemotherapy or postchemotherapy.

There are many approved treatment options from which to choose in the metastatic setting, including chemotherapy (docetaxel, cabazitaxel), immunotherapy (sipuleucel-T), hormonal therapy (abiraterone, enzalutamide), and a radioisotope (radium-223).

Sipuleucel-T, the only immunotherapy agent ap-

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proved by the FDA for the treatment of prostate cancer, is indicated for the treatment of metastatic CRPC that is asymptomatic or minimally symptomatic. Its approval

There are many approved treatment options in the metastatic setting, including chemotherapy, immunotherapy, hormonal therapy, and a radioisotope. was based on a significant survival advantage compared with placebo in the phase 3 trial known as IMPACT, said Higano, professor of medicine and urology, University of Washington, Seattle, WA.

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The median survival benefit with sipuleucel-T in IMPACT was 4.1 months, similar to the benefit achieved in 2 smaller phase 3 trials conducted in identical patient populations using the same trial design. “It’s consistent across all 3 trials,” she said. “I do believe the data.”

The placebo and sipuleucel-T survival curves in IMPACT overlapped for the first 6 months, which is likely “due to the fact that immunotherapy does not kick in right away like we see with chemotherapy or even hormonal therapy,” she said. “It takes time to actually make a difference.”

When prescribing sipuleucel-T, educate patients and their families not to expect a decline in PSA and of the lack of ability to predict benefit in individual patients.

The prostate-specific antigen (PSA) level does not decline with treatment with sipuleucel-T, she said, and it has no effect on progression-free survival (PFS), even though all 3 trials demonstrated significant survival benefit. Sipuleucel-T is very well tolerated; toxicities are mild and include infusion-related fever and/or chills. In the studies, there was a trend toward a delay in time to disease-related pain and a statistically significant delay in time to first opioid use.

A current challenge is to determine when to prescribe sipuleucel-T. “My own belief is that it should happen early in the course of metastatic castration resistance,” she said. Ideally, it should occur before initiation of numerous second-line hormonal manipulations and before corticosteroid use with chemotherapy and/ or abiraterone – at a time when patients are less likely to have symptoms or rapid progression and are less likely to have liver metastases, and when their immune system is more robust.

When prescribing sipuleucel-T, educate patients and their families not to expect a decline in PSA and of the lack of ability to predict benefit in individual patients, she said. Patients should be evaluated monthly for symptomatic progression. Imaging should be obtained at baseline and again at 3 months to monitor disease.

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Other Options: Hormonal Therapy, Chemotherapy, Radium-223 The 2 newest hormonal options are abiraterone and enzalutamide. Abiraterone is an oral CYP17 inhibitor that is recommended to be taken on an empty stomach in combination with prednisone. Enzalutamide is an oral pure antiandrogen that does not require prednisone. It is contraindicated in patients with a history of seizures or in those taking drugs that lower the threshold for seizures.

Both hormonal agents result in a decline in PSA levels.

In the postdocetaxel setting, both abiraterone and enzalutamide showed improvements in median overall survival compared with placebo and a delay in radiographic PFS, said Higano. Robust benefits were also observed in the predocetaxel setting, especially radiographic PFS. Docetaxel and cabazitaxel are the only chemotherapy options to demonstrate a survival benefit in metastatic CRPC, she said. Docetaxel is a first-line chemotherapy option for patients who are symptomatic or who have rapidly progressing disease.

Cabazitaxel is a semisynthetic taxoid derivative. It has poor affinity for P-glycoprotein (the drug efflux pump) and therefore may be active in docetaxel-refractory disease. Cabazitaxel is approved for use with prednisone and is indicated for patients with metastatic CRPC previously treated with docetaxel. Higano offered practical advice for the use of cabazitaxel: reduce the initial dose to 20 mg/m2, use growth factor in all patients, and appreciate that pain progression does not mean a lack of clinical benefit.

Radium-223 is an alpha particle–emitting radioisotope indicated for patients who have symptoms in the postdocetaxel setting (or who are unfit for docetaxel), a population that derived a significant survival benefit and a delay to a first skeletal-related event with radium-223 in the ALSYMPCA phase 3 study. Dosing in ALSYMPCA was monthly for 6 months. It is a calcium mimetic that targets new bone growth in and around metastases; thus, skeletal-related events may become a new end point in trials of radium-223 in the future, she said.

While radium-223 must be administered by a specialist in nuclear medicine, there are no restrictions on patient contact with other people. u

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Molecular Monitoring Can Provide Treatment Guidance in CML

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onitoring molecular response to tyrosine kinase inhibitor (TKI) therapy for chronic myelogenous leukemia (CML) may help guide the decision to switch therapy and the timing of progression to second- and third-line therapy, said Jerald P. Radich, MD, at the 2014 meeting of the National Comprehensive Cancer Network (NCCN).

Response rates to TKI therapy in CML are high, and many times these responses can be measured only at the molecular level. The reliance on molecular monitoring as a sensitive measure to monitor response is increasing. Molecular monitoring detects the presence of BCR-ABL1 mRNA using real-time quantitative polymerase chain reaction. A major molecular response (MMR) is defined as a reduction in BCR-ABL transcript levels of at least 3 logs compared with a standardized baseline obtained from patients with untreated newly diagnosed CML. “The concept of MMR...ended up having profound clinical utility,” said Radich, a member of the Clinical Research Division at the Fred Hutchinson Cancer Research Center and professor of medicine at the University of Washington, Seattle, WA. “It indicates patients who are very stable. Once you reach MMR, unless you discontinue medications, your chance of progressing to accelerated phase or becoming resistant is almost nil.”

A BCR-ABL transcript level <10% at 3 months predicts clinical outcome. The 8-year probability of survival after first-line imatinib therapy improved to 93% with a BCR-ABL transcript level ≤10%, compared with a 57% probability at a level >10%. Similar findings have been obtained with dasatinib and nilotinib.

The BCR-ABL transcript level at 3 months can also predict MMR, he said, with poor achievement of MMR with a BCR-ABL transcript level >10% as opposed to “an outstanding chance of achieving MMR in those who have their disease fall off the cliff in a few months.”

When to Switch Therapy The NCCN considers the lack of a complete molecular response at 3 months a treatment failure, at which time it recommends applying a different therapy. “If somebody has had an incomplete exposure to any of the TKIs at a few months, and they’re not at 10%, you can be patient,” he said. “But if somebody has been taking their drug religiously for 3 months, and they’re not below 10%, then you have to think [about switching].”

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The European LeukemiaNet (ELN) recommends waiting until 6 months to determine the need for a change. “The reason is because there are no data that show that early switching has anything to do with changing the natural history of the disease,” Radich continued. “A fair amount of people who don’t reach 10% by 3 months will progress to accelerated phase or blast crisis by 6 months. So you’ll lose some of those people if you’re too patient.”

Up to 200 resistance mutations have been found in CML. Mutational analysis may provide additional information for patients with inadequate response. The NCCN and ELN also recommend mutational analysis when patients lose response, progress to accelerated phase or blast crisis, or experience a 1-log increase in BCR-ABL transcript levels with loss of MMR. Salvage therapy with second-generation TKIs produce a complete cytogenetic response (CCyR) 25% to 50% of the time. Eventual relapse is common in patients who achieve CCyR with salvage therapy. “You have to think about what’s down the line for them, such as transplantation,” he said.

When starting salvage therapy, “3 months of therapy is enough to tell you how people are going to do. If they have a CCyR at 3 months, they do great,” he said, noting that CCyR is the only factor independently associated with event-free and overall survival in patients on second-line TKIs. “If they don’t achieve CCyR, you have to go to plan C. That turns out to be a really convenient time because most unrelated donor searches take around 3 to 4 months,” he said.

Median survival is about 10 months for patients who progress to accelerated phase or blast crisis. Undergoing transplantation is the only option for cure in these patients, with survival rates decreasing from 85% in patients in chronic phase to 40% in accelerated phase to 10% to 20% in blast crisis. “You have to make sure to move these people to more aggressive therapy, and you need to move them there in a timely fashion, not when they’ve blown up to advanced phase disease,” said Radich.

About 40% of patients can remain in complete molecular remission for up to 2 years after TKI discontinuation. Stopping TKI therapy after achievement of complete molecular remission should not be attempted outside of a clinical trial, he said. u

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Treatment Paradigm for NSCLC May Be Shifting

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river mutations, most commonly KRAS and EGFR, account for about half of non–small cell lung cancer (NSCLC), and this recognition is shifting the NSCLC treatment paradigm toward targeted therapy when possible, said Leora Horn, MD, MSc. In the future, immunotherapy may play a significant role in the NSCLC treatment armamentarium.

Chemotherapy hit a plateau in the treatment of metastatic NSCLC, with little difference in survival between the most frequently used regimens. Platinum-based doublet therapy as first-line therapy is associated with overall survival (OS) of about 1 year in NSCLC, said Horn, associate professor of medicine, Department of Hematology/Oncology, Vanderbilt University, Nashville, TN. Erlotinib, docetaxel, pemetrexed, and gemcitabine have each been shown to be effective as switch maintenance regimens. “There is still the option of delaying and careful observation of patients’ use of erlotinib, docetaxel, pemetrexed, or gemcitabine at the time of progression,” she said.

Chemotherapy hit a plateau in the treatment of metastatic NSCLC, with little difference in survival between the most frequently used regimens.

Targeted Therapy Evolving “What’s driving lung cancer these days and what’s happening, which is really exciting, is defining these multiple molecular subsets of NSCLC patients,” she said.

“About 55% of patients with lung cancer will have a driver mutation that we’re able to identify. That’s not necessarily a driver mutation for which we have a targeted therapy at this time.”

The most common molecular subtype is a KRAS mutation, observed in 15% to 25% of patients with NSCLC, followed by an EGFR mutation in 10% to 35%.

First-line treatment with an EGFR tyrosine kinase inhibitor (TKI) such as gefitinib, erlotinib, and afatinib outperformed chemotherapy in NSCLC patients with EGFR mutation on the end point of median progression-free survival (PFS), she said. “What they’ve also shown us is that there is no significant difference in overall survival, and that’s because in the majority of these trials, 80% of patients or more were crossing over to a TKI at the time of progression on chemotherapy,” said Horn.

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A common mechanism of acquired resistance to an EGFR TKI is a second site mutation, most often T790M, which is observed in about 50% of patients.

Disease flare, or rapid acceleration of disease resulting in hospitalization or death, occurs in about 20% of patients who go off EGFR TKIs. Patients with disease flares who resume their TKI treatment “can once again get control of these tumors because we know that they are oncogene addicted,” she said. Another treatment regimen that can control disease in patients who develop acquired resistance to a TKI is the combination of afatinib and cetuximab, she said.

Encouraging data in acquired resistance have been obtained with the third-generation TKI, AZD9291. Fifteen of the first 35 evaluable patients treated in a clinical study had a partial response, including 9 of 18 with T790M-positive tumors. CO-1686 is another agent being explored in clinical trials in patients with T790M-positive tumors and acquired resistance to EGFR TKIs. In patients with ALK-positive NSCLC, single-agent crizotinib more than doubled median PFS compared with chemotherapy. In patients with ALK-positive NSCLC with acquired resistance to crizotinib as well as those who are crizotinib-naive, the second-generation ALK inhibitor LDK378 has produced impressive response rates, said Horn, including in patients with central nervous system disease.

Immune Therapy Being Explored PD-1 and PD-L1 antibodies are being looked at in lung cancer. “There appears to be a reaction between PD-1 and its ligands that promotes an immunosuppressive tumor microenvironment,” said Horn. PD-L1 is broadly expressed in NSCLC patients with adenocarcinoma and squamous cell carcinoma.

Nivolumab, a PD-1 inhibitor, is an IgG4 monoclonal antibody that was associated with an overall response rate as high as 24% and a median OS of 14.9 months in heavily pretreated patients with NSCLC. The anti–PD-L1 monoclonal antibody, MPDL3280A, is also being explored in NSCLC. In a phase 1 study, “what we saw was rapid and durable responses in both squamous and nonsquamous NSCLC patients,” said Horn. A majority of patients respond by 12 to 21 weeks of therapy, at the time of their first CT scan. When responses were examined by PD-L1 immunohistochemistry (IHC) status, a higher response rate was observed in tumors that had an IHC score of 3 (83%) compared with IHC 2 and IHC 1. Some patients with tumors that were PD-L1 negative also exhibited a response. u

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WORLD CUTANEOUS MALIGNANCIES S CONGRESS

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THIRD ANNUAL October 29 - November 1, 2014 Marriott Marquis • San Francisco, California

CONFERENCE CHAIR World Cutaneous Malignancies Congress Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

CONFERENCE CO-CHAIR Global Biomarkers Consortium Jorge E. Cortes, MD

CONFERENCE CO-CHAIR Global Biomarkers Consortium Roy S. Herbst, MD, PhD

Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

Ensign Professor of Medicine Professor of Pharmacology Chief of Medical Oncology Director, Thoracic Oncology Research Program Associate Director for Translational Research Yale Cancer Center New Haven, CT 2014WCMC/GBC_Asize_111113

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2014 GASTROINTESTINAL CANCERS SYMPOSIUM

Investigational Angiogenesis Inhibitor Improves Survival as Second-Line Treatment in Gastric Cancer

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hase 3 data from a global study indicated an improvement in overall survival (OS) when the investigational angiogenesis inhibitor ramucirumab was added to chemotherapy as second-line therapy in patients with advanced gastric cancer.

The improvement in survival was more than 2 months with ramucirumab when used after progression on first-line therapy in the study known as RAINBOW, said lead investigator Hansjochen Wilke, MD, at the 2014 Gastrointestinal Cancers Symposium.

“This trial and the recently published REGARD trial demonstrate that ramucirumab is an effective new drug for the treatment of patients with metastatic or locally advanced unresectable gastric cancer and gastroesophageal junction [GEJ] cancer,” said Wilke, director of the Department of Oncology, Hematology and Center of Palliative Care, Kliniken Essen-Mitte, Essen, Germany.

Patients who received ramucirumab and paclitaxel also reported a reduction in pain and other improvements in their quality of life.

Ramucirumab, a human IgG1 monoclonal antibody that blocks the vascular endothelial growth factor receptor 2, represents the only second-line agent to extend life by as much as 2 months, noted Smitha Krishnamurthi, MD, who was not involved in the study.

“We’re excited to have what appears to be an active drug in the second-line setting that can be used instead of best supportive care or in addition to second-line chemotherapy for patients who can tolerate chemotherapy,” said Krishnamurthi, associate professor of medicine, Division of Hematology and Oncology, University Hospitals Case Medical Center, Cleveland, OH. RAINBOW involved 665 patients with metastatic GEJ or gastric adenocarcinoma who exhibited disease progression within 4 months after standard first-line chemotherapy with platinum- and fluoropyrimidine-based combinations. They were randomized to ei-

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ther a combination of ramucirumab and paclitaxel or paclitaxel alone. Treatment was administered in 4-week cycles until disease progression, unacceptable toxicity, or death.

Adding ramucirumab to second-line paclitaxel significantly improved response rates, OS, and progression-free survival (PFS). The overall response rates were 28% in patients randomized to ramucirumab and paclitaxel compared with 16% in patients randomized to paclitaxel alone (P=.0001).

The median OS was 7.4 months in the paclitaxel only arm and 9.6 months in the ramucirumab-paclitaxel arm, corresponding to a 20% reduction in the hazard ratio with ramucirumab (P=.0169). Six-month survival was 72% versus 57%, and 12-month survival was 40% versus 30% in the ramucirumab-paclitaxel and paclitaxel only arms, respectively.

Median PFS was 4.4 months for the combination of ramucirumab-paclitaxel compared with 2.9 months for paclitaxel alone, corresponding to a 36% reduction in risk (P<.0001).

Patients who received ramucirumab and paclitaxel also reported a reduction in pain and other improvements in their quality of life.

The most common side effects of treatment with ramucirumab and paclitaxel include neutropenia, leukopenia, hypertension, anemia, fatigue, abdominal pain, and asthenia. Although neutropenia was more frequently reported in the ramucirumab plus paclitaxel group, the incidence of febrile neutropenia was comparable to treatment with paclitaxel alone. All of these side effects were manageable, and very few patients discontinued treatment due to toxicities.

The most common grade ≥3 adverse events with ramucirumab were neutropenia (40.7% vs 18.8% in the placebo group), leukopenia (17.4% vs 6.7%), and fatigue (11.9% vs 5.5%); febrile neutropenia occurred with similar frequency in both groups (3.1% vs 2.4%).

Other grade ≥3 adverse events that occurred more often with ramucirumab compared with placebo were hypertension (14.7% vs 2.7%), bleeding/hemorrhage (4.3% vs 2.4%), gastrointestinal bleeding (3.7% vs 1.5%), proteinuria (1.2% vs 0%), and gastrointestinal perforation (1.2% vs 0%). u

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2014 HOPA ANNUAL CONFERENCE

It’s About Time: Monoclonal Antibodies for Multiple Myeloma

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ithin the oncology drug development pipeline, “multiple myeloma is one of the more intriguing spaces,” according to R. Donald Harvey, PharmD, who said one reason for his excitement is the emergence of monoclonal antibodies.

Harvey, associate professor of hematology/oncology at Emory University, Atlanta, GA, and director of the Phase I Clinical Trials Program, described investigational agents for myeloma and other cancers at the Hematology/Oncology Pharmacy Association 2014 Annual Conference.

Among the drugs for myeloma are not only better versions of current conventional classes of drugs but entirely new classes of agents for this malignancy. Early-phase trials suggest their impact will be huge, he said.

“It is odd to treat a disease of antibodies with antibodies,” Harvey said, “but improvements in our understanding of molecular biology and cell surface receptors has led to a number of impressive drug development stories.”

Monoclonal antibody inhibition is still in its early phases with respect to myeloma, but already a number of targets are in focus, including CS1, CD38, CD40, CD138, CD200, CD56, interleukin-6, and BAFF. Harvey said that besides monoclonal antibodies, he is also encouraged by early-phase data on histone deacetylase inhibitors (panobinostat, ricolinostat), a kinesin spindle protein inhibitor (filanesib), and an Akt inhibitor (afuresertib).

Targeting CS1 Elotuzumab targets CS1, a cell surface glycoprotein that is highly expressed on more than 95% of myeloma cells. In a myeloma xenograft mouse model, the combination of elotuzumab plus lenalidomide significantly reduced tumor volume compared with either agent alone, suggesting this drug will work best in combination regimens. In a study of 73 patients, the objective response rate was 82% for the combination, including 12% complete or stringent complete responses (Lonial S, et al.

2011 ASH Annual Meeting. Abstract 303).

Interestingly, elotuzumab displays “saturable receptor occupancy,” likely meaning that with this compound “the more drug you have, the more it knocks itself off the receptor”; therefore, 10 mg/kg is more active than 20 mg/kg.

Infusion reactions are not uncommon with elotuzu­ mab, which has led to the recommendation for aggressive premedication.

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Targeting CD38 Daratumumab targets CD38, a transmembrane glycoprotein and ectoenzyme with high receptor density on myeloma cells. The effects of CD38 inhibition include apoptosis after cross-linking, modulation of enzymatic activation, induction of cell-dependent cytotoxicity, and induction of antibody-dependent cell cytotoxicity.

“These things are generally good with respect to cancer but concerning with respect to infusion reactions, and adverse events do occur, including bronchospasm, but it is typically well managed,” Harvey indicated.

Among the drugs for myeloma are not only better versions of current conventional classes of drugs but entirely new classes of agents for this malignancy.

As a single agent, daratumumab showed strong activity in a phase 1/2 study in which 47% of patients derived benefit; at doses of 4 mg/kg, 66% had a minor response or better (Plesner T, et al. 2012 ASH Annual Meeting.

Abstract 73).

Due to encouraging results from phase 1 trials, a phase 2 trial has enrolled “at record numbers,” he noted, and the FDA has granted this agent breakthrough status.

SAR650984 is also an anti-CD38 antibody. In a phase 1 dose-escalation trial of patients who had received a median of 5 prior lines of therapy, 13 patients received the maximum dose (≥10 mg/kg every 2 weeks).

The overall response rate was 30.8%, with half of these a complete response (Martin TG III, et al. 2013 ASH Annual Meeting. Abstract 284).

Targeting CD138 Another interesting new drug is a potent antibody-drug conjugate that targets CD138, an antigen highly expressed on myeloma cells. Indatuximab ravtansine (BT062) is designed to deliver the maytansinoid cytotoxic agent DM4 specifically to these CD138-expressing cells. In a phase 1 trial of 21 relapsed/refractory patients, stable disease or better was observed in 100% of 15 evaluable patients, and 73% responded to BT062 plus lenalidomide/dexamethasone (Kelly KR, et al. 2013 ASH Annual Meeting. Abstract 758).

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“I think not only in hematology but in solid tumors as well, we are going to see an explosion in antibody-drug conjugates,” he said.

Harvey predicted that based on the activity of these monoclonal antibodies, myeloma may someday be treated more as lymphoma is treated, by adding an antibody. “We might someday be giving 5 or 6 drugs for induction, because we will get deep responses this way.

And we might be measuring myeloma like we do CLL [chronic lymphocytic leukemia], where we can say that we eradicated all measurable disease in the patient,” he said.

“I think not only in hematology but in solid tumors as well, we are going to see an explosion in antibody-drug conjugates.”

– R. Donald Harvey, PharmD Oral Proteasome Inhibitors In addition to new classes of drugs, conventional classes of agents are becoming even more effective and less toxic.

The oral proteasome inhibitor ixazomib (MLN9708) produced a highly impressive 94% response rate (after 4 cycles) when combined with lenalidomide and dexamethasone in treatment-naive patients (Kumar SK, et al. 2012 ASH Annual Meeting. Abstract 332). Sixty-five patients received ixazomib weekly in combination with lenalidomide (25 mg/day) and dexamethasone (40 mg weekly), then continued on ixazomib as maintenance therapy for up to 12 cycles. Only 2 cases of grade 3 peripheral neuropathy occurred at the recommended phase 2 dose of 2.97 mg/m2.

“This is an exciting 3-drug regimen that is fairly well tolerated. Ixazomib is not an ‘oral bortezomib.’ It is different in terms of activity and also toxicity,” he indicated.

Another oral proteasome inhibitor in development, oprozomib, is a structural analog of carfilzomib that comes in 2 formulations: powder-in-capsule split dose and once-daily modified-release formulation. The drug’s efficacy seems dependent on proteasome inhibition; more than 80% inhibition is achieved with 210 mg/day of oprozomib.

With oral proteasome inhibitors now becoming available, Harvey suggested that induction approaches will eventually look very different than they look now. “I think that ultimately,” he predicted, “we will have an all-oral regimen.” u

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The Affordable Care Act and Cancer Patients – Winners and Losers in an Unsteady Paradigm Shift: Part 2 The Conclusion of an Analysis of the ACA by Kip Piper, MA, FACHE

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n the April issue of PMO, Mr Kip Piper, a leading healthcare policy authority, addressed the benefits of the Affordable Care Act (ACA) for cancer patients and oncologists. In this second report, he addresses the problems the ACA presents. For the ACA’s sword does indeed cut both ways, particularly in terms of its economic feasibility. He now examines the challenges of finance and politics that attend the ACA’s implementation. Paying the bill for the benefits outlined in Mr Piper’s first article remains a stalwart opponent to the durability of the ACA. As discussed in last month’s article, the “good news” surrounding the ACA centers on ensuring widespread access to healthcare coverage. This, as we shall see, is not the same as guaranteed access to healthcare or even, ironically enough, to healthcare insurance. Increasing healthcare coverage access is done in part by expanding eligibility for Medicaid coverage in about half the states for low-income adults previously ineligible for Medicaid, and by providing substantial subsidies from the newly formed federal healthcare insurance exchanges at healthcare. gov and the state-run insurance exchanges. Individuals with income below 400% of the poverty level are eligible to apply for federal subsidies in the form of subsidized premiums, with patients between 100% and 200% of the poverty level receiving the most federal subsidies. In addition, individuals and families with incomes between 100% and 250% also receive subsidized cost sharing, ie, lower deductibles, copayments, and coinsurance from additional federal subsidies.

Medicaid for the most part has no premium, no deductible, no coinsurance, and only nominal copayments for prescription drugs. Other provisions for increasing access include the elimination of preexisting conditions as a criterion for coverage denial or increased premiums.

The net effect of these provisions is to remove the last pretense that healthcare under the ACA is linked to insurance, which would follow strict actuarial calculation of each person’s premium, coverage eligibility, and costs of benefits, all based on an individual’s or

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a company’s overall risk. Because this criterion is conspicuously absent from the ACA, healthcare insurance has been replaced by healthcare group purchasing – quite a different proposition, a distinction with real differences. Under the provisions of the ACA, those who are healthy and young will subsidize healthcare for older or infirm persons, whose premiums and coverage provisions would otherwise be prohibitively high.

The advantages of the ACA are not achieved without cost of another kind; this paradigm shift presents challenges across the entire healthcare spectrum.

The overall process of the ACA is therefore one focused on wealth redistribution, not health efficiency improvement, and this includes reducing the income of physicians. The ACA legislation is actually not medical legislation at heart but political, or more specifically ideological. It is centered not on medical imperatives but a political premise that “healthcare is a right” and then works backwards into the copious details of healthcare delivery to enforce this imperative.

The legislation does not attempt to examine the intricacies of each disease state, but instead treats all diseases as so many cogs in a wheel, identical in the process of redistributing healthcare coverage.

Feasibility of ACA in Oncology While the ACA was written with the intent of reforming all fields of medicine, oncologists know the special nature of cancer care, and so an in-depth reality check is in order. I will examine the factors involved in delivering on the promises made in the ACA and the basic problems to medicine posed by this insurance paradigm.

The advantages of the ACA are not achieved without cost of another kind; this paradigm shift presents

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THE LAST WORD

challenges across the entire healthcare spectrum. It comes down to the simple proposition: is the ACA sustainable, is it feasible financially?

The “advantages” side of the ACA have received the lion’s share of attention, and they are regulatory and financial in nature. They are all about how the government regulates the marketplace, how it uses taxpayer monies to subsidize coverage, and how it uses its police/regulatory power to ultimately require individuals, families, and businesses to subsidize other individuals, families, and businesses. Moving forward, the concerns with respect to access that the ACA raises are substantial, and many of these are a combination of both the direct and indirect effects of the incentives in the regulatory paradigm created by the ACA. These effects will be felt by cancer patients, and so oncologists need to understand them in order to anticipate the problems facing their patients over the long term.

We are also seeing much tighter drug formularies, with health plans under the ACA tightening up on drugs in different therapeutic classes.

One of these challenges is narrow networks. Each plan is required to have a network of providers, including an adequate number of oncologists participating in this network. What we are seeing in the health plans established to be in compliance with the ACA is that many insurers, though not all, have proceeded to devise fairly narrow networks – far fewer providers, by provider type, that a patient may access. Many academic medical centers, which provide much of the tertiary specialized and subspecialty care, do not have contracts with all of the ACA plans. We are seeing that insurers are trying to leverage their buying power in the marketplace, and responding to the regulatory and economic incentives of the ACA, by severely restricting the number of providers from which patients may choose care that are considered “in network,” with substantially increased copays and deductibles for going outside of network.

What this means to patients is that, when they are newly diagnosed, they have difficulty seeing all the different types of providers they need. They will be funneled into a narrower range of the multiple specialists and hospital facilities covered by their plan.

This, of course, will have an effect on the practical business of oncology and the ability of oncologists to

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serve their current patient base, because at a cer­tain point the patients will not have access to their doctors.

Another issue is that the ACA has resulted in many products having high deductibles. The government and the insurers are shifting many patients into high-deductible health plans. This perhaps may be one of the unintended consequences of the ACA, but one that is quite predictable. Analysts knew all along that the incentives and the market rules like guaranteed issue and adjusted community rating would necessitate a change in the benefit designs of the plans, with insurers moving to higher-deductible plans, since they are not able to affect revenue behavior in the old ways. We are also seeing a noticeable trend toward health plans having high coinsurance on biologics.

Where in the past a coinsurance of 20% or 30% of physician-administered drugs and biologics was common, we are now seeing more plans with 30%, 40%, or 50% coinsurance for biologics.

Here we see a good news/bad news scenario: many new biologics coming on the market, full of promise for improving patient longevity and quality of life, and so oncologists rely heavily on them to treat patients; but the biologics, particularly the newer ones, are quite expensive. Hence, many cancer patients will see much higher out-of-pocket costs owing to higher deductibles and higher coinsurance on biologics.

We are also seeing much tighter drug formularies, with health plans under the ACA tightening up on drugs in different therapeutic classes. We are also seeing health plans engage in more robust, stringent utilization management practices in order to limit spending. That will play out over time, but patients face a combination of narrow networks; higher out-of-pocket costs in the form of higher deductibles; higher coinsurance; a shift by plans away from copays to coinsurance, where the patient pays a percentage of the total drug cost rather than a modest, fixed dollar amount per prescription; tighter utilization management; and narrower drug formularies. These will all push back against the initial moves that were made to increase access, since these forces are designed to impede access to the newer, more expensive therapies.

The other disadvantage that we are seeing, of course, which was predictable, is lower reimbursement, a downward pressure on physician rates. Many of the health plans that devised products for the new health insurance exchanges were not offering traditionally accepted reimbursement rates for providers and in most cases were offering rates substantially lower than traditional commercial plans – in some cases closer to Medicare levels and even Medicaid

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rates. On average, they may not end up going as low as Medicaid but may approach Medicare or Medicare plus 10% or Medicare plus 5% rates. This further complicates matters since Medicare rates are not rising but are remaining stagnant, and when Congress has increased Medicare rates, it has tended to raise them only nominally, eg, 0.5% or 1%, which of course does not keep up with cost inflation. Consequently, over the past decade, physicians treating patients in Medicare Part B have lost substantial ground financially.

This will cause physicians to have to make difficult decisions concerning how many patients they will choose to serve in different markets. Take, for example, Medicaid: more people are going to be coming onto Medicaid; they will be insured. But access to insurance does not mean access to healthcare. This places physicians in the difficult position of either trying to limit the number of Medicaid patients they treat or trying to receive higher reimbursement rates from commercial insurers in order to compensate for gaps in Medicaid reimbursement. This is the plain, simple fact of cross-subsidies among the payers.

So there is all this money moving back and forth.

But as the highest boundary, traditionally the commercial payer, moves their pricing downward, there is simply less of an opportunity for oncologists and other

providers to shift losses – uncompensated or undercompensated care – from government programs to the higher-paying private sector because the commercial payer will not be providing that extra increment anymore. This is going to happen over time, and it will be further exacerbated as patients move from purely private plans into either government plans or government-paid or heavily subsidized plans. This increases the financial pressure, because the government is never going to be the highest payer.

The other disadvantage that we are seeing, of course, which was predictable, is lower reimbursement, a downward pressure on physician rates.

Change is upon us, and stepping up to the challenges requires understanding their dynamics first, then considering the downstream effects of the ACA, and finally, reconciling this legislation with the realities of medicine, putting the patient’s interests first and managing our resources realistically, compassionately, and intelligently. u

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