February 2013 Volume 2 • Number 1 A Peer-Reviewed Journal
The official publication of
Global biomarkers Consortium Clinical Approaches
PM O TM
to Targeted Technologies
TM
Personalized Medicine in Oncology TM
LUNG CANCER Resistance to Targeted Molecular Therapies in NSCLC ...................................Page 24
INTERVIEW WITH THE INNOVATORS Next-Generation Sequencing: An Interview With Michael J. Pellini, MD, of Foundation Medicine .............................. Page 34
LEGAL ISSUES IN HEALTHCARE The Drawn Out Process of the Medical Lawsuit ....................................................... Page 44
ALSO IN THIS ISSUE… • News from ASH, the GI Cancers Symposium, and the San Antonio Breast Cancer Symposium......................Page 10 • The Last Word by Robert E. Henry...........Page 46
Implementing the Promise of Prognostic Precision into Personalized Cancer Care www.PersonalizedMedOnc.com © 2013 Green Hill Healthcare Communications, LLC
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he Global Biomarkers Consortium™ (GBC) is a community of worldrenowned healthcare professionals who will convene in multiple educational forums in order to better understand the clinical application of predictive molecular biomarkers and advanced personalized care for patients.
Global biomarkers Consortium Clinical Approaches
Personalized Medicine in Oncology ™
CONFERENCE NEWS
TM
to Targeted Technologies
PM O
February 2013 Volume 2 • Number 1
TM
News from ASH, the GI Cancers Symposium, and the San Antonio Breast Cancer Symposium PAGE 10 Personalized Medicine Highlights From ASH 2012
Save the date for the Second Annual Conference, October 4-6, 2013 Visit www.globalbiomarkersconsortium.com to register
Progress in Personalized Approaches to Colorectal Cancer In Colon Cancer, Genomic Classifiers Aid in Prognosis Mayo Clinic Researchers Propose Screening Algorithm for HER2 in Esophageal Cancer Women With Triple-Negative Breast Cancer Highly Likely to Carry BRCA1 Gene Predicting Risk of Significant Side Effects Made Possible by OnPART
Professional Experience of GBC Attendees 56.7%
26.7%
Molecular Subtyping Reclassifies Early Breast Cancer in a Proportion of Patients
LUNG CANCER Resistance to Targeted Molecular Therapies in NSCLC PAGE 24 Melissa L. Johnson, MD; Ryan D. Gentzler, MD; Helena A. Yu, MD; Gregory J. Riely, MD, PhD The authors review current understanding of EGFRand ALK-driven lung adenocarcinoma, the mechanisms of acquired resistance in both groups of patients, and newer therapies being investigated for patients after the development of acquired resistance.
6.7% 3.2% 6.7%
1-3 years
INTERVIEW WITH THE INNOVATORS
3-5 years
Next-Generation Sequencing: An Interview With Michael J. Pellini, MD, of Foundation Medicine
5-10 years 10-20 years >20 years
Volume 2 • No 1
PAGE 34
PMO talks with Michael J. Pellini, MD, about the unique approach of Foundation Medicine to personalizing cancer treatment.
WWW.PERSONALIZEDMEDONC.COM
February 2013
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PUBLISHING STAFF SENIOR VICE PRESIDENT, SALES AND MARKETING Philip Pawelko phil@greenhillhc.com PUBLISHERS John W. Hennessy john@greenhillhc.com Russell Hennessy russell@greenhillhc.com DIRECTOR, CLIENT SERVICES Lou Lesperance, Jr lou@greenhillhc.com MANAGING DIRECTOR Pam Rattananont Ferris
The Drawn Out Process of the Medical Lawsuit
STRATEGIC EDITOR Robert E. Henry
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From the New York Times: Malpractice claims can affect doctors’ and patients’ lives.
SENIOR COPY EDITOR BJ Hansen
THE LAST WORD
PRODUCTION MANAGER Marie RS Borrelli QUALITY CONTROL DIRECTOR Barbara Marino BUSINESS MANAGER Blanche Marchitto
The Supportive Face of the FDA in the Advancement of Personalized Medicine
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Robert E. Henry
CIRCULATION DEPARTMENT circulation@greenhillhc.com Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copy right ©2013 by Green Hill Healthcare Communications, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. 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.
Volume 2 • No 1
Personalized Medicine in Oncology ™
LEGAL ISSUES IN HEALTHCARE
EDITORIAL DIRECTOR Kristin Siyahian kristin@greenhillhc.com
4
PM O
The move to enriched, personalized medicine in cancer is the child of 3 proud parents: medical, business, AND government.
OUR MISSION The mission of Personalized Medicine in Oncology is to deliver practice-changing information to clinicians about customizing healthcare based on molecular profiling technologies, each patient’s unique genetic blueprint, and their specific, individual psychosocial profile, preferences, and circumstances relevant to the process of care. 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.
PERSONALIZED MEDICINE
IN
ONCOLOGY
February 2013
• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma
July 26-28, 2013
Hyatt Regency La Jolla • San Diego, California
PROGRAM OVERVIEW
CONFERENCE CO-CHAIRS
A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: • Epidemiology and genetic/environmental factors • Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies • Risk stratification based on patient and tumor characteristics • Principles of cancer prevention of melanoma and basal cell carcinoma • Current treatment guidelines • Emerging treatment options for personalized therapy • Future strategies in management based on translational data from current clinical trials and basic research
LEARNING OBJECTIVES Upon completion of this activity, the participant will be able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies
TARGET AUDIENCE This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, and pathologists actively involved in the treatment of cutaneous malignancies. Advanced practice oncology or dermatololgy nurses, oncology pharmacists, and researchers interested in the molecular biology and management of cutaneous malignancies are also encouraged to participate.
DESIGNATION OF CREDIT STATEMENTS SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.
COMMERCIAL SUPPORT ACKNOWLEDGMENT Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.
Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Luke’s Cancer Center Bethlehem, Pennsylvania
REGISTERED NURSE DESIGNATION Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.0 contact hours.
REGISTERED PHARMACY DESIGNATION The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.0 contact hours (1.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).
CONFERENCE REGISTRATION EARLY BIRD REGISTRATION NOW OPEN! $175.00 UNTIL APRIL 30, 2013
www.CutaneousMalignancies.com
Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany
AGENDA* FRIDAY, JULY 26, 2013 3:00 pm – 7:00 pm
Registration
5:30 pm – 7:30 pm
Welcome Reception/Exhibits
SATURDAY, JULY 27, 2013 7:00 am – 8:00 am
Breakfast Symposium/Product Theater/Exhibits
8:00 am – 8:15 am
BREAK
8:15 am – 8:30 am
Welcome to the Second Annual World Cutaneous Malignancies Congress — Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD
8:30 am – 11:45 am General Session I: A Clinician’s Primer on the Molecular Biology of Cutaneous Malignancies • Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway • Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm – 1:15 pm
BREAK
1:15 pm – 4:30 pm
General Session II: Current Treatment Guidelines in Cutaneous Malignancies • Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expert’s Perspective on How I Treat My Patients • Panel Discussion Management Controversies and Accepted Guidelines for the Personalized Management of Cutaneous Malignancies • Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Anti–PD-1
4:30 pm – 6:30 pm
Meet the Experts/Networking/Exhibits
PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 12.0 AMA PRA Category 1 Credits ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Steven J. O’Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California
SUNDAY, JULY 28, 2013 7:00 am – 8:00 am
Breakfast Symposium/Product Theater/Exhibits
8:00 am – 8:15 am
BREAK
8:15 am – 8:30 am
Review of Saturday’s Presentations and Preview of Today’s Sessions
8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General Session IV: Challenges for the Cutaneous Malignancies Clinician • Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies? 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm – 1:15 pm
BREAK
1:15 pm – 2:45 pm
General Session V: “Hot Data� — What I Learned at Recent Meetings: Focus on Cutaneous Malignancies
2:45 pm – 3:00 pm
Closing Remarks - Steven J. O’Day, MD
*Agenda is subject to change.
For complete agenda please visit www.CutaneousMalignancies.com
Editorial Board Editor in Chief Al B. Benson III, MD Northwestern University Chicago, Illinois
SECTION EDITORS Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida
Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee
Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas
Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts
Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts
Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut
Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana
Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio
Prostate Cancer Oliver Sartor, MD Tulane University New Orleans, Louisiana
EDITORIAL BOARD Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania
K. Peter Hirth, PhD Plexxikon, Inc. Berkeley, California
Hope S. Rugo, MD University of California, San Francisco San Francisco, California
Gregory D. Ayers, MS Vanderbilt University School of Medicine Nashville, Tennessee
Howard L. Kaufman, MD Rush University Chicago, Illinois
Danielle Scelfo, MHSA Genomic Health Redwood City, California
Lyudmila Bazhenova, MD University of California, San Diego San Diego, California
Katie Kelley, MD UCSF School of Medicine San Francisco, California
Lee Schwartzberg, MD The West Clinic Memphis, Tennessee
Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona
Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota
John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas
Kenneth Bloom, MD Clarient Inc. Aliso Viejo, California
Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington
Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts
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
Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland
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Volume 2 • No 1
Afsaneh Motamed-Khorasani, PhD Radient Pharmaceuticals Tustin, California Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts
Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Stephen Gately, MD TGen Drug Development (TD2) Scottsdale, Arizona
Gene Morse, PharmD University at Buffalo Buffalo, New York
Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida Darren Sigal, MD Scripps Clinic Medical Group San Diego, California David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan
Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California
Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland
David A. Proia, PhD Synta Pharmaceuticals Lexington, Massachusetts
Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas
Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois
PERSONALIZED MEDICINE
IN
ONCOLOGY
February 2013
PMPM O C
ERSONALIZED EDICINE IN ONCOLOGY
TM
Implementing the Promise of Prognostic Precision into Personalized Cancer Care TM
ALL FOR PAPERS
Personalized Medicine in Oncology’s mission is to deliver practice-changing information to clinicians
about customizing healthcare based on molecular profiling technologies and each patient’s unique genetic blueprint. Our vision is to transform the old medical model of stratified medicine into a new model of personalized care where all decisions and practices are tailored to the individual.
The goal of Personalized Medicine in Oncology is to sensitize practitioners to the performance realities of new diagnostic and treatment discoveries and to clarify molecular profiling technologies as they relate to diagnostic, prognostic, and predictive medicine. PMO will feature diagnostic and clinical treatment information concerning these 3 root aspects of personalized medicine in oncology. Readers are invited to submit articles for consideration in the following categories:
Biologicals in Trial •
Exploring the challenges of clinical trial design and patient enrollment
•
Presentation of emerging clinical data
Predictive Models and Diagnostics •
A look at available diagnostic technologies and implementation in the community practice setting
Genetics and Biomarkers •
Exploring genetic discoveries and impact on predictors of disease and therapeutic response
The Cost of Personalized Medicine •
Personalized medicine policy drivers
•
Payer coverage of diagnostics and biologics
Genetic Profiling Technologies •
What technologies are available to clinicians and consumers and their impact on diagnostic, prognostic, and predictive medicine
In Practice •
A practical guide for community-based oncologists discussing clinical applications and strategies for incorporating personalized medicine techniques into practice
•
Development of treatment algorithms
N=1 •
Case studies, patient-reported outcomes, defining treatment goals, partnering with patients and caregivers
Submit the entire manuscript and a cover letter stating the objectives of the article to PMO@greenhillhc.com. Manuscripts should follow the Author Guidelines available at www.PersonalizedMedOnc.com.
PMOHouseAd2
Letter From the Board
Applying Personalized Medicine in the Overall Healthcare Environment Dear Reader,
W
elcome to the second year of publication of Personalized Medicine in Oncology (PMO)! We launched this journal with the goal of providing the practicing oncologist with a translational guide to personalized medicine’s research advances and system improvements that bring targeted treatment into practice, thereby transforming personalized medicine from a dream to a reality. In the coming year, we will continue to strive toward this goal and believe that PMO has a unique role in fostering clinical acumen for its readers. Lyudmila Bazhenova, The advances involving personalized medicine challenge the practicing oncolMD ogist’s knowledge of their value-based usage. The pace of research is demanding this value-based translational guidance, for healthcare cannot tolerate miscalculations in the use of expensive treatments and diagnostics. Faced with a deluge of data regarding personalized medicine products and techniques, the practicing oncologist needs help in the organization of resources. While the media tend to alternately overstate and complicate the degree to which personalized medicine is driving cancer treatment, PMO provides both the practical information and perspective that clinicians need to identify the advances that bring value – cost, quality, and access advantages – to their practice of medicine. Our editorial clarifies the broad spectrum of personalized medicine techniques and resources; whether they offer improved outcomes or just parity; their impact on costs, manpower, and systems; securing payer coverage; or their implications on health-related quality of life. Our Editorial Board appreciates that new technologies do not “run themselves,” and so we invite editorial that cultivates the requisite clinical expertise to use them well. Treatments and diagnostics will rise no higher than the acumen of the oncologists using them. Our editorial therefore focuses on the clinical relevance of new biomarkers and the potent alternatives that achieve the goal of an enriched patient population. Thank you for your readership. The Editorial Board looks forward to serving you well in this New Year to help you implement this remarkable new process of care. Sincerely,
Lyudmila Bazhenova, MD University of California, San Diego PMO Editorial Board Member
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Volume 2 • No 1
PERSONALIZED MEDICINE
IN
ONCOLOGY
February 2013
THIRD ANNUAL
Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor
This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.
May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS
AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm
Registration
FRIDAY, MAY 3, 2013
Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks
Gary M. Owens, MD President Gary Owens Associates
Burt Zweigenhaft, BS President and CEO OncoMed
7:00 am - 8:00 am
Simultaneous Symposia/Product Theaters
8:15 am - 9:15 am
Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS
9:15 am - 10:15 am
Keynote Address
10:15 am - 10:30 am
Break
10:30 am - 11:45 am
Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Marcus Neubauer, MD; Michael Kolodziej, MD
12:00 pm - 1:00 pm
Exclusive Lunch Symposium/Product Theater
1:15 pm - 2:00 pm
Session 3: Cost of Cure: When, How, and How Much? John Fox, MD; John Hennessy
2:00 pm - 2:45 pm
Session 4: Where Is Oncology Care Headed in the Future? Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD
Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery. • Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered. • Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively. • Examine the current trends in personalized care and companion diagnostics. • Analyze the patient issues around cost, quality, and access to care.
2:45 pm - 3:30 pm
Session 5: What Will the Cancer Delivery System Look Like in 2015? Ted Okon; John D. Sprandio, MD
TARGET AUDIENCE
PROGRAM OVERVIEW
Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.
LEARNING OBJECTIVES
This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.
DESIGNATION OF CREDIT STATEMENTS SPONSORS
This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.
COMMERCIAL SUPPORT ACKNOWLEDGMENT
Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.
3:30 pm - 3:45 pm
Break
3:45 pm - 4:30 pm
Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman
4:30 pm - 5:15 pm
Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO
5:15 pm - 5:45 pm
Summary/Wrap-Up of Day 1
6:00 pm - 8:00 pm
Cocktail Reception in the Exhibit Hall
SATURDAY, MAY 4, 2013 7:00 am - 8:00 am
Opening Remarks
8:30 am - 9:15 am
Session 8: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH
9:15 am - 10:00 am
Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow
10:00 am - 10:15 am
Break
10:15 am - 11:00 am
Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality Kip Piper
11:00 am - 11:45 am
Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher; Lillie Shockney, RN, BS, MAS
PHYSICIAN CREDIT DESIGNATION
The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
REGISTERED NURSE DESIGNATION
Simultaneous Symposia/Product Theaters
8:15 am - 8:30 am
12:00 pm - 1:00 pm
Exclusive Lunch Symposium/Product Theater
1:15 pm - 3:00 pm
Session 12: Meet the Experts Networking Roundtable Session
3:00 pm - 3:45 pm
Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH
3:45 pm - 4:15 pm
Summary/Wrap-Up of Day 2
4:30 pm - 6:30 pm
Cocktail Reception in the Exhibit Hall
Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.
SUNDAY, MAY 5, 2013
REGISTERED PHARMACY DESIGNATION
8:15 am - 8:30 am
Opening Remarks
8:30 am - 9:15 am
Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD
9:15 am - 10:00 am
Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson
The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).
CONFERENCE $375.00 until March 15, 2013 REGISTRATION $425.00 after March 15, 2013 REGISTER TODAY AT
www.regonline.com/avbcc2013
7:00 am - 8:00 am
Simultaneous Symposia/Product Theaters
10:00 am - 10:15 am
Break
10:15 am - 11:00 am
Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA
11:00 am - 11:45 am
Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and Challenges Thomas Marsland, MD; David Eagle, MD
11:45 am - 12:00 pm
Summary and Conclusion of Conference
*Agenda is subject to change. AVBCCAsize20413
2012 ASH Annual Meeting
Personalized Medicine Highlights From ASH 2012 Phoebe Starr Hematologic oncology is a fertile field for exploration of new targets for drug therapy. Below are summaries of presentations from the 54th Annual Meeting of the American Society of Hematology (ASH) on some new targeted therapies for hematologic malignancies currently in phase 2 testing.
Quizartinib: FLT3 Inhibitor in AML Quizartinib, an investigational oral FLT3 inhibitor, achieved high response rates in a difficult-to-treat cohort of patients with acute myelogenous leukemia (AML), and some of the responses were durable, according to results of a phase 2 trial. The FLT3 mutation is found in up to one-third of patients with AML and portends more aggressive disease and treatment failure on standard therapies. Although other FLT3 inhibitors have been studied in AML, quizartinib is the most potent of these in humans, said lead author Mark J. Levis, MD, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore, MD.
The FLT3 mutation is found in up to onethird of patients with AML and portends more aggressive disease and treatment failure on standard therapies. The phase 2 trial enrolled 2 cohorts of patients with a total number of 271 patients. Cohort 1 included patients aged 60 years or older with the FLT3 mutation who failed on standard chemotherapy or who had a recent first relapse. Cohort 2 included patients over age 18 years who presented with relapsed or refractory AML and had been given salvage chemotherapy after failure on prior treatment or had relapsed after a stem cell transplant. The majority of patients in both cohorts had the FLT3 mutation. Levis reported results from 137 patients (99 with FLT3 mutations and 38 without) in cohort 2. The complete response rate was 46% in patients with an FLT3-positive mutation and 32% in FLT3-negative patients. Median overall survival was 22.9 weeks for FLT3-positive patients and 25.6 weeks for FLT3-neg-
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ative patients. Quizartinib enabled 37% of all patients to go on stem cell transplant. The most common treatment-emergent adverse events were nausea (53%), vomiting (41%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), Q-T interval prolongation (27%), and fatigue (24%). Cohort 1 results, presented by Jorge Cortes, MD, MD Anderson Cancer Center, Houston, TX, showed that complete responses were achieved in more than 50% of FLT3-positive elderly patients. These results were considered clinically meaningful and allowed some patients to be bridged to stem cell transplant. Also, slightly fewer than one-third of FLT3-negative patients achieved a complete response. The side effect profile of quizartinib was similar to that in cohort 2. The investigators concluded that quizartinib may be an option for elderly AML patients who require further therapy. A phase 3 trial is planned. u
Pomalidomide Plus Carfilzomib Looks Promising in Relapsed/ Refractory Myeloma The combination of pomalidomide, carfilzomib, and dexamethasone achieved high response rates and delayed disease progression in heavily pretreated patients with multiple myeloma, according to results of a phase 1/2 trial. Study subjects had been previously treated with a median of 6 lines of therapy (range, 1-15). All were relapsed/refractory to lenalidomide and/or bortezomib. Overall response rate (ORR) was 50% (15/30), with 37% achieving a partial response, 13% achieving at least a very good partial response, and 67% attaining clinical benefit (minor response or better), reported Jatin Shah, MD, MD Anderson Cancer Center, Houston, TX. Median progression-free survival was 7.4 months, and overall survival at 1 year was 90%. “The combi-
PERSONALIZED MEDICINE
IN
ONCOLOGY
February 2013
2012 ASH Annual Meeting
nation has encouraging preserved response rates and survival independent of FISH [fluorescence in situ hybridization]/cytogenetic risk status,” he commented. The most common toxicities were neutropenia (84%), anemia (63%), and thrombocytopenia (57%). Febrile neutropenia occurred in 6%. Hematologic toxicities were reversible and manageable. The maximum tolerated dose of the regimen was carfilzomib 20/27 mg/m2, pomalidomide 4 mg, and dexamethasone 40 mg in relapsed/refractory myeloma. Enrollment is ongoing in a phase 2 study of 82 patients. u
Daratumumab Moving Forward in Myeloma Daratumumab, a monoclonal antibody that binds to CD38, is moving forward in studies of multiple myeloma. In a phase 1/2 study in 32 patients, clinical benefit was achieved in almost half the heavily pretreated relapsed/refractory population. Torben Plesner, MD, of Vejle Hospital in Vejle, Denmark, reported that 47% of patients demonstrated a reduction in the amount of monoclonal protein in the blood or urine, which corresponded to a 13% partial response rate, 19% minor response rate, and 16% stable disease rate. A reduction in plasma cell infiltration of the bone marrow was also observed. The maximum tolerated dose of the drug has not been established. Daratumumab infusion was surprisingly well tolerated. A dose-dependent reduction in natural killer cells was observed on treatment but was reversible upon treatment discontinuation. u
Brentuximab Vedotin Prolongs Survival in Hodgkin Lymphoma Several studies at ASH validated the use of brentuximab vedotin in Hodgkin lymphoma and suggested that indications for the drug may be expanded. Treatment with brentuximab after autologous stem cell transplant prolonged overall survival in relapsed/refractory Hodg kin lymphoma patients in a retrospective study that compared 102 patients treated with brentuximab versus 756 age-matched patients on standard therapy.
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A statistically significant overall survival benefit for brentuximab versus standard therapy was observed: median overall survival of 91.49 versus 27.99 months, respectively (P<.0001). Neither age nor sex had an impact on overall survival, said lead author Meghan S. Karuturi, MD, MD Anderson Cancer Center, Houston, TX. Among complete responders to brentuximab, positron emission tomography (PET) negativity after 7 cycles of treatment was correlated with longer progression-free survival (P<.013). PET status (negative vs positive) after both 4 and 7 cycles was significantly associated with improved progression-free and overall survival, she reported. u
Blinatumomab in Relapsed/ Refractory ALL Blinatumomab is a bispecific T-cell engager antibody that engages T cells and tumor cells, placing the T cells within reach to inject toxins into the tumor cell, triggering apoptosis. Blinatumomab directs the T cells to target cells that express CD19, a protein on the surface of most B-cell–derived leukemias and lymphomas.
Blinatumomab induced a high CR rate and prolonged overall survival in adults with relapsed/refractory B-cell ALL in a phase 2 single-arm study. Blinatumomab induced a high complete remission (CR) rate and prolonged overall survival in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) in a phase 2 single-arm study. The study established a dose regimen of 5 mcg/m2/day for week 1, followed by 15 mcg/m2/day thereafter. The most common adverse events were pyrexia, fatigue, headache, tremor, and leukopenia. Medically important, but fully reversible, adverse events included cytokine release syndrome and central nervous system events. Lead author Max S. Topp, MD, Wuerzburg University Medical Center, Germany, reported “unprecedented” single-agent activity of blinatumomab among
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36 patients enrolled in the phase 2 trial. CR was 69%. Molecular remission was achieved in 88% of hematologic responders. Median overall survival was 9.8 months, and median relapse-free survival was 9.8 months. A phase 2 trial has been launched in adults with relapsed/refractory B-cell ALL. u
Inotuzumab in ALL Inotuzumab is an antibody-antigen complex that binds to CD22 cells, releasing calicheamicin inside the tumor cell. Calicheamicin is a potent cytotoxic agent that binds to DNA, inducing double-stranded DNA breaks leading to apoptosis of the cell. Single-agent inotuzumab achieved an encouraging ORR of 57% in the treatment of relapsed/refractory ALL in a phase 2 trial. Response was independent of treatment schedule and correlated with clearance of leukemia cells from the bone marrow. The weekly schedule will be used in subsequent clinical trials, said lead author Susan O’Brien, MD, MD Anderson Cancer Center, Houston, TX. Additional studies of inotuzumab are under way. One is a pivotal trial of the weekly schedule versus the best
standard of care in relapsed/refractory ALL, and inotuzumab is also being studied in combination with low-intensity chemotherapy in elderly patients with ALL. Patients with refractory or relapsed CD22-positive ALL (n=89) were enrolled in this phase 2 trial. The first 10 patients were aged 18 years or older, and then the trial was opened to children. More than 90% of patients had CD22-expressing ALL. Weekly and monthly schedules were studied using the same total dose of inotuzumab for both schedules. Patients could be treated for up to 8 cycles. ORR of 57% was similar in the arms (weekly vs monthly schedule). CR was 18% in both arms; CR with the exception of platelets was 29% in the monthly arm and 30% in the weekly arm. Resistance was identified in 39% and 38% of patients, respectively, and 2 deaths occurred in each arm in less than 4 weeks. Cytogenetic CR was seen in 89% and 90% of patients, respectively. Overall, 63% and 70% of patients, respectively, were minimal residual disease negative. Median progression-free survival was 4.9 months, with a progression-free survival rate of 21% at 1 year. Median overall survival is 5.6 months; 20% are alive at 1 year, with no difference between the treatment arms. u
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SECOND ANNUAL CONFERENCE
2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS
TM
• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma
July 26-28, 2013 Hyatt Regency La Jolla • at Aventine 3777 La Jolla Village Drive • San Diego, California
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For indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen
Established treatment, demonstrated results Single-agent TREANDA® (bendamustine HCl) for Injection provided durable responses that lasted a median of 9 months Median DR
9.2 months (95% CI: 7.1, 10.8)
All responders (n=74) Patients who achieved a CR/CRu
10.4 months (95% CI: 9.3, 13.6)
1
8.3 months (95% CI: 6.3, 10.8)
Patients who achieved a PR
1
0
2
4
6
Months
8
10
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The efficacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. In 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176), the most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%).
TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. • TREANDA is administered with a convenient dosing schedule – The recommended dose is 120 mg/m² administered intravenously over 60 minutes on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA • The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia
Learn more at www.TREANDAHCP.com
Please see accompanying brief summary of full Prescribing Information. Reference: 1. Data on file. Teva Pharmaceuticals.
©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2577b January 2013
Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin Lymphoma That Has Progressed INDICATION AND USAGE: TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176). System organ class, preferred term, and number (%) of patients* are shown. Total number of patients with at least 1 adverse reaction— All Grades: 176 (100); Grade 3/4: 94 (53). Cardiac disorders, All Grades and Grade 3/4—Tachycardia: 13 (7), 0. Gastrointestinal disorders, All Grades and Grade 3/4—Nausea: 132 (75), 7 (4); Vomiting: 71 (40), 5 (3); Diarrhea: 65 (37), 6 (3); Constipation: 51 (29), 1 (<1); Stomatitis: 27 (15), 1 (<1); Abdominal pain: 22 (13), 2 (1); Dyspepsia: 20 (11), 0; Gastroesophageal reflux disease: 18 (10), 0; Dry mouth: 15 (9), 1 (<1); Abdominal pain upper: 8 (5), 0; Abdominal distension: 8 (5), 0. General disorders and administration site conditions, All Grades and Grade 3/4—Fatigue: 101 (57), 19 (11); Pyrexia: 59 (34), 3 (2); Chills: 24 (14), 0; Edema peripheral: 23 (13), 1 (<1); Asthenia: 19 (11), 4 (2); Chest pain: 11 (6), 1 (<1); Infusion site pain: 11 (6), 0; Pain: 10 (6), 0; Catheter site pain: 8 (5), 0. Infections and infestations, All Grades and Grade 3/4—Herpes zoster: 18 (10), 5 (3); Upper respiratory tract infection: 18 (10), 0; Urinary tract infection: 17 (10), 4 (2); Sinusitis: 15 (9), 0; Pneumonia: 14 (8), 9 (5); Febrile Neutropenia: 11 (6), 11 (6); Oral Candidiasis: 11 (6), 2 (1); Nasopharyngitis: 11 (6), 0. Investigations, All Grades and Grade 3/4—Weight decreased: 31 (18), 3 (2). Metabolism and nutrition disorders, All Grades and Grade 3/4—Anorexia: 40 (23), 3 (2); Dehydration: 24 (14), 8 (5); Decreased appetite: 22 (13), 1 (<1); Hypokalemia: 15 (9), 9 (5). Musculoskeletal and connective tissue disorders, All Grades and Grade 3/4—Back pain: 25 (14), 5 (3); Arthralgia: 11 (6), 0; Pain in extremity: 8 (5), 2 (1); Bone pain: 8 (5), 0. Nervous system disorders, All Grades and Grade 3/4—Headache: 36 (21), 0; Dizziness: 25 (14), 0; Dysgeusia: 13 (7), 0. Psychiatric disorders, All Grades and Grade 3/4—Insomnia: 23 (13), 0; Anxiety: 14 (8), 1 (<1); Depression: 10 (6), 0. Respiratory, thoracic and mediastinal disorders, All Grades and Grade 3/4—Cough: 38 (22), 1 (<1); Dyspnea: 28 (16), 3 (2); Pharyngolaryngeal pain: 14 (8), 1 (<1); Wheezing: 8 (5), 0; Nasal congestion: 8 (5), 0. Skin and subcutaneous tissue disorders, All Grades and Grade 3/4—Rash: 28 (16), 1 (<1); Pruritus: 11 (6), 0; Dry skin: 9 (5), 0; Night sweats: 9 (5), 0; Hyperhidrosis: 8 (5), 0. Vascular disorders, All Grades and Grade 3/4—Hypotension: 10 (6), 2 (1). *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category.
Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology Variable All Grades Grade 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50
Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates. TRE-2486c November 2012 (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDA full Prescribing Information.
GI Cancers Symposium
Progress in Personalized Approaches to Colorectal Cancer Alice Goodman Advances in the understanding of the molecular basis of colorectal cancer were featured at a pre-meeting Press Cast for the 10th Annual GI Cancers Symposium held January 24-26, 2013. Three separate presentations focused on: a new molecular classification system for colorectal cancer; gene expression profiling of circulating tumor cells as a prognostic strategy in pancreatic cancer; and the benefit of surgery after treatment with imatinib in gastrointestinal stromal tumors (GIST).
New Molecular Subtypes of Colorectal Cancer Molecular profiling has identified subtypes of breast cancer that have treatment implications. A study presented here showed that molecular profiling can also be applied to colorectal cancer, identifying 3 distinct gene expression patterns that are associated with different prognoses and responses to adjuvant chemotherapy. “This study clearly shows that there are different subtypes in colorectal cancer with completely different biological and clinical characteristics. We hope that with continued research, we’ll be able to develop new molecular tests based on this classification system, not only to identify patients needing more aggressive treatment, but also to predict which patients will respond to specific chemotherapy drugs and targeted agents, regardless of cancer stage,” stated study coauthor Josep Tabernero, MD, director of clinical research at Vall d’Hebron Institute of Oncology in Barcelona, Spain. Defining these subtypes may be especially helpful for stage II patients, since it is difficult to predict risk of relapse in this group of patients using clinical and pathological criteria. Gene array tests such as Oncotype DX and ColoPrint can be helpful, but it is not clear which patients should receive additional treatment, and these tests do not provide actionable information after relapse. At present, there is no good way to select treatments for individual patients, Tabernero explained. KRAS status is the only predictor of anti-EGFR treatment activity. Gene expression data were collected from 188 colo rectal cancer patients stages I through IV to develop a
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classification system based on hierarchical clustering of genes. Three types of gene signatures were found to be specific for subtype A, subtype B, and subtype C colo rectal cancer, and the subtypes were found to correlate with benefits from 5-fluorouracil (5-FU)-based therapy. The subtypes were characterized as deficient epithelial subtype A, associated with a good prognosis (no adjuvant treatment or 5-FU–based treatment needed); proliferative epithelial subtype B; and mesenchymal subtype C. Both subtypes B and C are associated with poor prognosis; subtype B is chemotherapy responsive, while subtype C is chemotherapy resistant, suggesting that new targeted therapies are needed.
Defining these subtypes may be especially helpful for stage II patients, since it is difficult to predict risk of relapse in this group of patients... The system was then validated in tumor samples from 543 patients with stages II and III colorectal cancer. The breakdown of tumor subtypes was: subtype A in 21.5%, subtype B in 62%, and subtype C in 16.5%. Ten-year follow-up showed that subtype C had the worst outcome, with no benefit from chemotherapy. Subtype A had a good prognosis with or without adjuvant chemotherapy. Subtype B had a significantly improved outcome with chemotherapy versus no chemotherapy. These subtypes are currently being evaluated in stage IV colorectal cancer, he said. “I predict that within the next 2 or 3 years, we and other research teams will have
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several gene expression signatures developed,” Tabernero said. u
Gene Expression Profiling of CTCs in Pancreatic Cancer Preliminary results from an ongoing prospective study suggest that gene expression profiling of circulating tumor cells (CTCs) in the bloodstream of pancreatic cancer patients may enable selection of personalized chemotherapy. The study suggests that specific gene expression profiles detected in CTCs may predict response to chemotherapy regimens. The researchers also identified key molecular pathways implicated in the development of treatment resistance and worsening cancer.
Investigators compared the gene expression differences in patients who continued to respond to chemotherapy and those who progressed on treatment. Survival remains poor in pancreatic cancer, with less than 5% of patients alive 5 years after diagnosis. New chemotherapy treatments are emerging, but as yet there are no validated biomarkers for treatment selection. CTCs are already being applied in breast cancer, and they would be useful as biomarkers for pancreatic cancer because it is difficult to biopsy. The study, reported by Kenneth Yu, MD, Memorial Sloan-Kettering Cancer Center, New York City, is the first to use pharmacogenomics modeling to analyze genetic response to chemotherapy regimens. “Pharmacogenomics modeling is a promising and exploratory tool for predicting treatment response in pancreatic cancer. This technique can be performed at initial diagnosis and at disease progression. Gene pathway analysis provides insights into pancreatic cancer prognosis and the development of drug resistance,” Wu said. The study enrolled 50 patients with unresectable stage II-IV pancreatic cancer. Patients were treated with 12 different chemotherapy regimens according to investigator’s choice. CTCs were collected prior to che-
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motherapy and at disease progression with Vita-Cap. Total RNA was extracted, and gene expression profiling was performed. A pharmacogenomics model for the 12 chemotherapy regimens was applied to gene expression profiles to predict sensitivity to chemotherapy. Investigators compared the gene expression differences in patients who continued to respond to chemotherapy and those who progressed on treatment. “The questions we asked were: 1) does the pharmacogenomic model predict treatment response and resistance, and 2) does the pharmacogenomic profile change when cancer progresses,” Wu explained. Among 20 patients who experienced disease progression, 6 had been treated with chemotherapy that the model predicted they would be sensitive to; 6 received treatment predicted to achieve an intermediate response; and 8 received treatment that was predicted to be resistant. “Patients treated predicted by our model to be more effective did better,” Wu said. Median time to progression, according to a preliminary analysis, was 7.3 months in the sensitive group, 5.3 months in the intermediate group, and 3.7 months in the resistant group. The chemosensitivity patterns were changed at disease progression, Wu continued, reflecting the development of resistance. A further analysis showed that the E2F1 pathway disruption was associated with longer treatment response, while disruption of the NF-κB pathway was associated with a shorter treatment response. Both the phospholipase C and retinoblastoma 1 pathways were disrupted at disease progression. The ultimate goal is to select the best treatment strategy for the individual patient, and to monitor patients during the course of therapy so that treatment can be adjusted according to molecular signs of worsening, he said. u
Surgery After Imatinib Imatinib was one of the first major advances in targeted therapy, providing the first life-extending effective treatment for GIST and chronic myeloid
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GI Cancers Symposium
leukemia. A retrospective study presented here found that patients whose residual lesions were resected after treatment with imatinib had improved survival compared with those who did not undergo resection. “This treatment strategy is worth trying as a clinical practice at centers with experienced surgical teams,” stated Seong Joon Park, MD, Asan Medical Center, Seoul, Korea. He noted that the study was retrospective and therefore cannot establish a treatment guideline, but it is supportive evidence for a strategy that is already being used. The study enrolled 134 patients with metastatic or recurrent GIST treated with imatinib alone or imatinib plus surgery to resect residual tumor, followed by additional imatinib. Patients were eligible for the study if they had maintained a response to prior imatinib for at least 6 months. Surgery was performed in 42 patients, and 92 patients were treated with imatinib until disease progression. Patient and tumor characteristics were similar in the groups, with 2 exceptions: median age was 51 years
in the surgically treated group and 58 years in those treated with imatinib alone; and peritoneal metastases were found in 12 and 56 patients, respectively. Median progression-free survival was 87.7 months in the patients who had surgical resection of residual disease after imatinib versus 42.8 months in those who were treated with imatinib alone (P=.001). Median overall survival had not yet been reached in the surgical group and was 88.8 months for imatinib alone (P=.001). Park said that about one-third of patients with residual disease can have a successful resection. “It is often recommended in younger patients with a good performance status. Surgery can be difficult if multiple peritoneal metastases are present,” he noted. Multivariate analysis showed that low initial tumor burden was associated with longer survival, while low initial tumor burden, female gender, and KIT exon 11 mutation were associated with delayed disease progression. The KIT mutation is also associated with response to therapy. u
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GI Cancers Symposium
In Colon Cancer, Genomic Classifiers Aid in Prognosis Caroline Helwick
G
enomic classifiers – in particular, ColoPrint and MSI-Print, and best when combined – can identify high-risk subsets among surgically resected stage II and stage III colon cancer patients, MD Anderson Cancer Center researchers reported at the 2013 GI Cancers Symposium. “The combination of ColoPrint and MSI-Print improves the prognostic accuracy in stage II and stage III patients and may help identify patients at higher risk who are more likely to benefit from additional treatment,” said Scott Kopetz, MD, PhD, lead author.
Genomic classifiers can identify high-risk subsets among surgically resected stage II and stage III colon cancer patients. “Although the benefit of chemotherapy in stage II and III colon cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment,” he added. ColoPrint is a gene expression classifier that distinguishes patients with low or high risk of disease recurrence. It was developed using whole genome expression data and has been validated in public data sets, independent European patient cohorts, and technical studies. The 64-gene MSI-signature, MSI-Print, is a genomic signature for the detection of colorectal cancer patients with microsatellite instability phenotype and high mutation frequency and is linked to deficient mismatch repair (dMMR). A dMMR system is present in 10% to 20% of patients with sporadic colon cancer and is associated with a favorable prognosis in early-stage disease. The population included 96 stage II patients and 94 stage III patients followed a median of 64 months. In this cohort, ColoPrint was prognostic for recurrence. The test classified 56% of stage II and stage III patients
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as being at low risk for recurrence. The 3-year recurrence-free survival (RFS) was 90.6% for low-risk and 78.4% for high-risk patients, with a hazard ratio of 2.33 (P=.012). In univariate and multivariate analyses, ColoPrint and stage (stage III vs stage II) were the only significant factors to predict outcome. The MSI-Print classified 24.6% of patients as MSIhigh (which is prognostically favorable), and most of these (81%) were low risk by ColoPrint. “Patients who were ColoPrint low risk and MSIhigh by signature had the best outcome, with a 3-year RFS of 95%, while patients with ColoPrint high risk had a worse outcome independently of the MSI status,” Kopetz reported. One-fourth of patients were characterized as “MSIPrint-high,” which was previously defined to incorporate both MSI-high tumors and additional tumors that share similar gene expression features. In this population, MSI-Print did not provide independent prognostic ability but did provide additional information when combined with ColoPrint. Low-risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment. RFS at 3 years was 90.1% for treated patients and 91.4% for untreated patients. ColoPrint high-risk patients treated with adjuvant chemotherapy had a 3-year RFS of 84%, compared with 70.1% for untreated patients (P=.037). Kopetz added that ColoPrint is independent of traditional American Society of Clinical Oncology (ASCO) high-risk features, with 50% of cases discordant based on the presence or absence of high-risk features and ColoPrint results. For example, among patients classified as high risk by ASCO clinical features, only 34% were high risk by ColoPrint and 41% were low risk. Among those at low risk by ASCO clinical features, 16% were low risk by ColoPrint and 9% were high risk. The genomic classifiers, therefore, add information above and beyond that obtained through conventional means, he said. u
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Mayo Clinic Researchers Propose Screening Algorithm for HER2 in Esophageal Cancer Caroline Helwick
T
he preferred screening test for HER2 status in surgical esophageal adenocarcinoma specimens is immunohistochemistry (IHC), with fluorescence in situ hybridization (FISH) restricted to cases with an indeterminate (2+) IHC score, according to investigators from the Mayo Clinic, Rochester, MN, who proposed a testing algorithm at the 2013 GI Cancers Symposium. “Our findings support a testing algorithm for resected esophageal adenocarcinomas where IHC is used for initial screening, and FISH testing is restricted to cases with equivocal IHC results,” said Harry H. Yoon, MD, lead investigator. HER2 oncoprotein overexpression is a known driver of tumor aggressiveness in esophageal adenocarcinoma; the HER2 gene is amplified in 7% to 22% of cases. HER2-positive patients treated with trastuzumab have improved survival; therefore, it is important to test for HER2 with IHC or FISH, he said. A previous exploratory, single-center study suggested that IHC is more predictive of trastuzumab benefit than FISH, but this superiority has not been established, and each testing method has its advantages. IHC is faster, less labor intensive, and less expensive (due to lower cost of reagents). FISH, on the other hand, is less vulnerable to tissue artifacts and offers a more objective scoring system, Yoon said. The current study evaluated the concordance of HER2 test results between IHC and FISH assays in 673 unselected surgically resected esophageal adenocarcinomas. Each tumor was evaluated by IHC in parallel with FISH in a blinded manner using FDA-approved assays. A consensus IHC score was determined by 2 pathologists using tumor-specific criteria (negative, 0-1+; equivocal, 2+; positive, 3+). Gene amplification by FISH was defined as a HER2/CEP17 (chromosome 17) ratio ≥2. By FISH, 17% of tumors tested positive. By IHC, 13%
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tested positive, 25% were indeterminate, 23% were negative by 1+, and 39% were negative by a 2+ score. Among the 89 patients with IHC 3+ scores, 79 were FISH+ and 10 were FISH–. Of the 167 indeterminate (2+) patients, 21 were FISH+ and 146 were FISH–. Of the 417 IHC– patients, 16 were FISH+ and 401 were FISH–. This yielded a concordance rate of 95% between FISH and IHC 3+ patients and IHC–negative patients, and a 74% concordance rate when IHC 2+ patients were included. HER2 amplification was detected in 89% of IHC 3+ cases, 13% of IHC 2+ cases, and 4% of IHC 0-1+ cases (Table). Accordingly, using FISH as the reference standard, the positive predictive value of a positive IHC test (3+) was 89%, and the negative predictive value of a negative test was 96%. Importantly, the positive predictive value of an equivocal IHC score (2+) for detecting HER2 amplification was 13%, he said. The sensitivity of IHC 2+ or 3+ was calculated to be 89%, and the specificity of IHC 3+ was 98%. “In the largest study to date comparing HER2 testing methods in esophageal adenocarcinoma, a negative IHC result nearly excludes the presence of gene amplification by FISH,” Yoon said, “whereas a positive result (3+) strongly predicts for the presence of amplification, and an equivocal IHC result (2+) is a weak predictor. u
Table. Predictive Value of IHC FISH Nonamplified
FISH Amplified
Total
IHC Score
N (%)
N (%)
(N)
Positive, 3+
10 (11)
79 (89)
89
Equivocal, 2+
146 (87)
21 (13)
167
Negative, 0 or 1+
401 (96)
16 (4)
417
FISH indicates fluorescence in situ hybridization; IHC, immunohistochemistry.
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2012 San Antonio Breast Cancer Symposium
Women With Triple-Negative Breast Cancer Highly Likely to Carry BRCA1 Gene Phoebe Starr
T
riple-negative breast cancer (TNBC) was strongly associated with BRCA1 status, but not with BRCA2 status, in a large study of medically insured women. The study showed that the number of patients with BRCA mutations with a TNBC profile is statistically significant. The authors of this poster, presented at the 2012 Annual CTRC-AACR San Antonio Breast Cancer Symposium, suggest that patients with TNBC should be referred to a genetics counselor for further evaluation and possible genetic testing.
Triple-negative breast cancer was strongly associated with BRCA1 status, but not with BRCA2 status, in a large study of medically insured women. Women with TNBC are thought to be more likely to be BRCA carriers, but it is controversial whether newly diagnosed women with TNBC should be referred to genetic counseling. The recommendation for genetic counseling in this group of patients rests only on studies with small numbers of BRCA carriers. Thus, there is no clear guideline, explained lead author Reina Haque, PhD, MPH, Department of Research and Development, Kaiser Permanente Southern California, Pasadena, CA. The study was conducted by investigators at Kaiser Permanente, a large nonprofit health plan serving over 3.5 million diverse members at more than 200 medical centers throughout southern California. The study was
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based on a retrospective cohort of 2105 women with breast cancer tested for BRCA mutations from 1997 to 2011. BRCA results were reported in the health plan’s clinical genetics registry. Of the 2105 breast cancer patients, 249 were BRCA mutation carriers: 143 BRCA1 carriers and 106 BRCA2 carriers. Data linkages were performed for all patients with the Surveillance, Epidemiology, and End Results–affiliated tumor registry; estrogen receptor (ER), progesterone receptor (PR), and HER2 status was captured and assessed by immunohistochemical or fluorescence in situ hybridization techniques. Patients were classified into 2 main biologic subtypes: TNBC (ER negative, PR negative, HER2 negative); and non-TNBC (luminal A, luminal B, and HER2 enriched). The association between TNBC and non-TNBC and BRCA1 or BRCA2 mutation status was examined. The investigators found that the TNBC subtype was strongly correlated with BRCA status (P<.0001). Women with TNBC tumors were 5 times more likely to be BRCA carriers than women with non-TNBC tumors (odds ratio [OR] 5.6; 95% CI, 4.1-7.5). The association between TNBC and BRCA1 was more robust (OR 12.2; 95% CI, 8.3-17.9). The association between TNBC and BRCA1 status was unchanged after adjusting for age, stage at diagnosis, and race/ethnicity. TNBC was not associated with BRCA2 status (OR 1.6; 95% CI, 0.9-2.7). These findings in a large sample of women suggest that TNBC patients should be referred for further evaluation and genetic testing, as results may inform treatment choice. u
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2012 San Antonio Breast Cancer Symposium
Predicting Risk of Significant Side Effects Made Possible by OnPART Alice Goodman
O
nPART can predict 6 common side effects of dose-dense doxorubicin plus cyclophosphamide and paclitaxel chemotherapy (ACT) with a high degree of accuracy in patients with breast cancer, according to a study presented at a poster session at the CTRC-AACR San Antonio Breast Cancer Symposium. The 78 breast cancer patients were part of a larger study with a total of 384 patients, including patients with colorectal and ovarian cancer. In the larger study, OnPART was able to predict the same 6 side effects with greater than 92% accuracy in patients receiving dose-dense 5-fluorouracil and oxaliplatin for colorectal cancer and carboplatin plus paclitaxel-based regimens for lung and ovarian cancer. OnPART utilizes Bayesian networks to identify single nucleotide polymorphisms (SNPs) from the DNA of patients’ saliva samples that identify whether the patients are at risk for the following 6 common side effects of dose-dense chemotherapy: oral mucositis, nausea and vomiting, diarrhea, fatigue, cognitive dysfunction, and peripheral neuropathy. “We can now identify patients at risk for 6 common side effects before they ever receive chemotherapy,” said lead author Lee Schwartzberg, MD, senior partner and medical director, The West Clinic in Memphis, TN. “This allows us to customize our chemotherapy regimens and side effect control interventions in a patient-centered care paradigm. These side effects can impair function, create inefficiencies in medical practice, and are costly to patients and payers. We look forward to working with Inform Genetics to help bring this novel product to the market as quickly as possible.” The rationale for this study was based on the hypothesis that the genetic impact on risk of side effects depends on “teams” of genes working synergistically, Schwartzberg explained. The study focused on 78 patients with breast cancer
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treated with at least 3 cycles of dose-dense ACT. Using a DNA Genotek collection tube, subjects provided a saliva sample from which DNA was extracted. SNP expression was determined using microarray technology. Patients received supportive care with each chemotherapy cycle. The Patient Care Monitor, a validated patient-reported symptom assessment tool, was used to measure the frequency and severity of the 6 side effects. Those rated ≥4 were considered to be significant. Bayesian methodological programming developed predictive SNP networks for each of the 6 side effects.
Accuracy of prediction ranged from 92% for predicting nausea and vomiting to 100% for predicting cognitive dysfunction and peripheral neuropathy. Based on the literature, the incidence of moderate-to-severe toxicity for all 6 side effects was higher than expected. Significant fatigue, oral mucositis, and nausea and vomiting were found in 25% of all patients who reported side effects, despite receiving recommended antiemetic supportive care prior to treatment. SNP-based Bayesian networks were highly predictive for each side effect of interest. Accuracy of prediction ranged from 92% for predicting nausea and vomiting to 100% for predicting cognitive dysfunction and peripheral neuropathy. The study showed that despite current supportive care options, the risk of side effects from common chemotherapy is significant. Previously, no method existed to predict which patients are at risk for these side effects from widely used chemotherapy regimens. The ability to identify prospectively the risk of side effects can lead to modifications in treatment regimens and aggressiveness of care. u
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2012 San Antonio Breast Cancer Symposium
Molecular Subtyping Reclassifies Early Breast Cancer in a Proportion of Patients Phoebe Starr
M
olecular subtyping of early breast cancers using MammaPrint and BluePrint allows precise and accurate prediction of the molecular phenotype of the disease, which has the potential to guide selection of personalized therapy if the tests are used prospectively. A retrospective study of 208 tumor samples found that molecular subtyping with these 2 platforms led to reclassification of 25% of the tumors, which would have been treated differently had the tests been applied prospectively. These findings have important therapeutic and prognostic implications.
Fifty-one patients were reclassified as a result of molecular subtyping. Of these, 28 were reassessed centrally for ER/PR/HER2 status by IHC and FISH. Retrospective classification showed that 39% of breast cancer classified clinically as HER2 disease should actually have been treated with therapies for luminal-type breast cancer (eg, endocrine therapy); and 20% of breast cancer classified clinically as triplenegative breast cancer could have been treated with therapies for luminal- and HER2-type disease, such as endocrine therapy and trastuzumab-based regimens. “The use of MammaPrint and BluePrint should be implemented in the management of primary breast cancer for the selection of adjuvant therapy in the era of personalized care,” stated lead author Massimo Cristo-
We’re just a
fanilli, MD, Fox Chase Cancer Center, Philadelphia, PA, and coauthors. The study used frozen tumor samples from 208 patients treated at 2 US institutions according to National Comprehensive Cancer Network standard guidelines between 1992 and 2010. Median follow-up was 11.3 years. Median age was 56 years (range, 28-89 years); 59% were hormone receptor positive (ER+/PR+), 20% were HER2+, and 24% were triple negative by locally assessed immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). All patients underwent lumpectomy or mastectomy with axillary staging. The microarray-based assays were as follows: BluePrint, an 80-gene assay that discriminates between luminal-type, basal-type, and HER2-type breast cancer. Luminal type is substratified by the 70-gene MammaPrint assay into low-risk luminal A and high-risk luminal B breast cancer. Breaking down results of molecular subtyping showed that 13 of 188 tumors that were ER+/PR+/ HER2– are not classified as luminal type by BluePrint; 24 of 41 clinical HER2+ patients are not classified as HER2 type by BluePrint; and 10 of 49 triple-negative tumors are not classified as basal type by BluePrint. Fifty-one patients were reclassified as a result of molecular subtyping. Of these, 28 were reassessed centrally for ER/PR/HER2 status by IHC and FISH. Patients with luminal-type early breast cancer identified by BluePrint have an excellent relapse-free survival: 97% for luminal A–type patients and 98% for luminal B–type patients. u
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Lung Cancer
Resistance to Targeted Molecular Therapies in NSCLC Melissa L. Johnson, MD; Ryan D. Gentzler, MD Feinberg School of Medicine, Northwestern University, The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois Helena A. Yu, MD; Gregory J. Riely, MD, PhD Department of Medicine, Division of Solid Tumors, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York
Key Points • Acquired resistance occurs after initial favorable response to EGFR-TKI therapy and develops despite active treatment with erlotinib or gefitinib • There is no standard treatment for patients once resistance to erlotinib or gefitinib develops, despite exhaustive attempts to identify an effective second-generation EGFR inhibitor • Reversing acquired resistance, or preventing its development, has become the focus of research efforts • Combination therapies, for example those that block both oncogene and bypass track signaling pathways, may prove to be effective for treating acquired resistance in NSCLC
O
ver the past decade, there has been enormous progress in our understanding of the molecular pathogenesis of non–small cell lung cancer (NSCLC), in particular among patients with lung adenocarcinoma. Approximately 60% of these patients’ tumors will be oncogene addicted.1 Those with mutated EGFR and ALK rearrangements can be treated with targeted inhibitors of the offending oncogene. While the success of the tyrosine kinase inhib-
Melissa L. Johnson, MD
itors (TKIs) – erlotinib and gefitinib directed against the epidermal growth factor receptor (EGFR) and crizotinib targeting the anaplastic lymphoma kinase (ALK) – has catalyzed significant changes in the treatment of patients with NSCLC, it has also introduced a new challenge: resistance that develops after TKI treatment (acquired resistance). Here, we review current understanding of EGFR- and ALKdriven lung adenocarcinoma, the mechanisms of acquired resistance
Dr Johnson is a thoracic oncologist at Northwestern Memorial Hospital and an Assistant Professor at Northwestern University Feinberg School of Medicine in the Department of Medicine, Division of Oncology/Hematology. Dr Gentzler is a fellow at Northwestern University Feinberg School of Medicine. He received his medical degree from Temple University School of Medicine and completed residency at Thomas Jefferson University Hospital. Dr Yu is a fellow at Memorial Sloan-Kettering Cancer Center. She received her medical degree from the University of Michigan Medical School and completed a residency at University of Pennsylvania Health System. Dr Riely is a medical oncologist at Memorial Sloan-Kettering Cancer Center. He specializes in treating patients with lung cancer and thymic tumors. His research focuses on the treatment of patients with thymic tumors as well as non–small cell lung cancer with specific mutations.
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Figure. EGFR and ALK Signaling Pathways in NSCLC
in both groups of patients, and newer therapies being investigated for patients after the development of acquired resistance.
EGFR Mutations and EGFR-Targeted Therapies EGFR is a receptor tyrosine kinase (RTK) that stimulates cellular growth, proliferation, and survival mediated by PI3K-AKT-mTOR and RAS-RAF-MEK-ERK pathways (Figure).2-5 Aberrant expression of EGFR is a well-established mechanism causing development of NSCLC tumors, in particular for the 10% to 15% of patients with activating mutations in the kinase domain
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of EGFR.6-9 The EGFR-TKIs gefitinib and erlotinib inhibit tumor growth by competing for the ATPbinding site of the kinase domain of EGFR.2 Although EGFR-TKIs have demonstrated modest antitumor activity in unselected patients with advanced NSCLC harboring EGFR mutations (response rates [RRs] 8%-9%10,11), these agents are capable of producing far greater responses (RRs 55%-91%, as reviewed by Pao and Chmielecki12 and Nguyen et al13). Female patients, never-smokers, and patients of East Asian ethnicity are more likely to respond to gefitinib or erlotinib, as discovered in early studies, and were subsequently found to be more likely to harbor activating mutations in EGFR.14-16
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The IPASS study was the first randomized phase 3 trial to demonstrate gefitinib to be superior to standard platinum chemotherapy in East Asian, never- or lightsmoker patients with advanced adenocarcinoma of the lung.17 Preplanned subgroup analysis showed that patients with EGFR mutations had longer progression-free survival (PFS) when treated with gefitinib (hazard ratio [HR] 0.48; P<.001), while those patients whose tumors were EGFR wild-type had shorter PFS when treated with gefitinib (HR 2.85; P<.001). First-SIGNAL, a second study of gefitinib in never-smoker patients conducted in Korea, demonstrated similar results to IPASS, where the presence of an EGFR mutation was predictive of higher overall RRs (84.6% [22/26] vs 25.9% [7/27]; P<.001) and longer PFS (HR; 0.377; 95% CI, 0.210-0.674; P<.001) among patients who received gefitinib.18 In addition to IPASS and First-SIGNAL, 2 phase 3 trials confirmed the superior efficacy of gefitinib versus chemotherapy in selected Japanese patients with lung adenocarcinoma and EGFR mutations (NEJ002 and WJTPG3405),19,20 and a third study verified the same results using erlotinib in Chinese patients (OPTIMAL).21 The EURTAC trial confirmed erlotinib was better than standard chemotherapy in a European Caucasian population with EGFR mutations (HR 0.37; P<.001).22 Erlotinib has been adopted into both the National Comprehensive Cancer Network and the
American Society of Clinical Oncology guidelines for initial treatment of patients with EGFR-mutated lung cancer.23,24
Acquired Resistance to EGFR-TKIs Acquired resistance occurs after initial favorable response to EGFR-TKI therapy and develops despite active treatment with erlotinib or gefitinib. Jackman and colleagues have defined criteria to help identify acquired resistance to TKIs.25 These criteria require an initial objective clinical benefit – either disease shrinkage or stable disease for at least 6 months – followed by progressive disease despite continuous TKI therapy within the last 30 days prior to development of progression. Using cell lines and mouse models with EGFR mutations treated with continuous EGFR-TKIs, several mechanisms of acquired resistance have been elucidated in the laboratory. Below we focus our discussion on those that have also been encountered clinically in patient specimens after rebiopsy. T790M “Gatekeeper” Mutations The most common mechanism of acquired resistance to EGFR-TKIs is a secondary mutation in exon 20 of EGFR, a single amino acid substitution at position 790 (methionine for threonine), first reported in 2005 in patients with advanced NSCLC previously treated with
Table. Gatekeeper Mutations in Oncogene-Addicted Malignancies Disease
Gate Keeper Mutation
Drug
Median TTP
References
CML
ABL T315I
Imatinib
10 months
28
GIST
KIT T670I
Imatinib
6-24 months
29
Lung
EGFR T790M
Erlotinib/Gefitinib
9-12 months
22,26,27,30
Lung
ALK L1196M
Crizotinib
10 months
31
To be determined
Vemurafenib
7 months
32
Melanoma
CML indicates chronic myelogenous leukemia; GIST, gastrointestinal stromal tumor; TTP, time to progression.
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gefitinib or erlotinib.26,27 Analogous to the “gatekeeper” mutations that develop in other oncogene-addicted cancers (Table), the T790M mutation confers drug resistance by altering drug binding within the ATP-binding pocket of EGFR; this mechanism accounts for roughly 50% of patients with acquired resistance to EGFR-TKIs.26,27,33 While other single-site mutations in EGFR, such as D761Y, L747S, and T854A, have also been identified as causing TKI resistance, they occur in less than 5% of patients. The mechanisms of resistance for these mutations remain unclear, but in vitro studies demonstrate that, unlike T790M, these less common mutations may exhibit weaker resistance that may be overcome with increasing doses of EGFR-TKIs.13 Despite developing resistance to TKI therapy, patients harboring T790M appear to have indolent, less aggressive clinical courses (19 months postprogression survival compared with 12 months in patients without T790M; P=.036) and seem more likely to progress within an existing site of disease rather than progressing to a new metastatic site.34 In a cohort of patients with acquired resistance who underwent repeat biopsies and molecular analysis (n=37), Sequist and colleagues reported 18 patients (49%) with T790M mutations, and a subset of these (n=3) were reported to have overamplification of EGFR, specifically the T790M allele.35 MET Amplification A second mechanism causing acquired resistance to EGFR-TKIs is the upregulation of an alternative signaling pathway, or “bypass track,” capable of activating the same intracellular pathways as EGFR.36,37 For example, upregulation of MET, an alternative RTK capable of activating the PI3K pathway and downstream effectors including AKT, provides the tumor an alternative means of signaling despite suppression of EGFR by EGFR-TKIs. MET amplification in combination with EGFR T790M occurs in 20% of EGFR-driven NSCLC with acquired resistance, but in isolation of the gatekeeper mutation, only about 5% of acquired resistance cases have MET amplification alone35,38 Insulin-like growth factor-1 receptor may be another RTK able to
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create a bypass track in the setting of acquired resistance to EGFR-TKIs, although this has only been suggested by preclinical data.39 PI3KCA Mutations Approximately 5% of patients with acquired resistance develop secondary mutations in PI3KCA.35 PI3KCA mutations were also reported in 2% of patients whose tumors were genotyped as part of the Lung Cancer Mutation Consortium, but these patients had not received prior EGFR-TKIs.1 PI3KCA mutations have been reported in another small cohort of TKI-naive patients to coexist with other driver mutations besides EGFR, such as KRAS and ALK, and predict inferior patient outcomes when expressed concurrently with one of these oncogenes.40
Despite developing resistance to TKI therapy, patients harboring T790M appear to have indolent, less aggressive clinical courses... Histologic Transformation Rarely, patients whose tumors have acquired resistance to EGFR-TKIs will exhibit histologic transformation of their primary tumor from adenocarcinoma to small cell or neuroendocrine differentiation, although the original EGFR mutation is preserved. This phenomenon has been observed in patient samples with a frequency ranging from 2% to 14%.35,38 Interestingly, these patients can be treated with small cell lung cancer chemotherapy regimens with favorable responses. The mechanism that triggers this change in histology is unclear but may be explained by a hypothesis that proposes that a pluripotent cancer stem cell underlies EGFR-mutant lung cancer development and resistance.35,41
Strategies for Overcoming EGFR-TKI Resistance Next-Generation EGFR-TKIs There is no standard treatment for patients once
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resistance to erlotinib or gefitinib develops, despite exhaustive attempts to identify an effective second-generation EGFR inhibitor (as reviewed by Oxnard et al42). One of the most heralded agents is afatinib, an irreversible inhibitor that forms a covalent bond in the ATPbinding site of EGFR, allowing inhibition of EGFR even in the presence of a secondary T790M resistance mutation. Gefitinib-resistant NSCLC cell lines are sensitive to afatinib in vitro and result in reduced EGFR pathway signaling and increased cellular apoptosis.43,44 This finding launched a series of clinical trials, named the LUX-Lung studies, to evaluate the efficacy of afatinib in EGFR-driven lung cancers. In the LUX-Lung 1
AP26113 is another novel TKI with potent activity against both mutated EGFR and EGFR T790M without affecting wild-type EGFR. study, patients with advanced NSCLC and prior treatment with chemotherapy and EGFR-TKIs were found to have an improved PFS when treated with afatinib compared with those who received best supportive care (HR 0.38; P<.0001),45 although RRs were only 7% and there was no improvement in overall survival (OS), the primary end point. While outcomes for patients with EGFR mutations and T790M-mediated resistance were not available, 34% of enrolled patients did meet Jackman criteria for acquired resistance.45 Importantly, afatinib and other quinazoline inhibitors of EGFR, such as erlotinib, bind wild-type and mutant EGFR, thereby causing well-known toxicities of skin rash and diarrhea. These dose-limiting toxicities may prevent afatinib and other irreversible EGFR-TKIs from reaching concentrations necessary to effectively inhibit T790M-mediated resistance. The discovery of novel covalent pyrimidine EGFR inhibitors that are more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, has led to an exciting new area of investigation against sec-
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ondary resistance to EGFR-TKIs using mutant-selective inhibitors that do not cause the expected toxicities.46 One such “third-generation” EGFR-TKI, CO-1686, is currently being studied in a phase 1/2 clinical trial for patients previously treated with EGFR-mutant NSCLC (NCT01526928). AP26113 is another novel TKI with potent activity against both mutated EGFR and EGFR T790M without affecting wild-type EGFR. AP26113 also inhibits NSCLC tumors driven by ALK rearrangements (described below). Preliminary results from a phase 1/2 study of AP26113 demonstrated it to be well tolerated with favorable antitumor activity.47 The ongoing phase 2 study is enrolling 4 cohorts: patients with NSCLC and acquired resistance to EGFR-TKIs, patients with ALK-rearranged NSCLC who are either treatment naive or have developed acquired resistance to ALK-targeted therapy, and patients with other cancers with ALK-rearrangements (NCT01449461). Cetuximab and Afatinib Studies evaluating the EGFR-directed monoclonal antibody cetuximab have shown mixed results in NSCLC – meager improvements in OS when com bined with first-line chemotherapy (11.3 months vs 10.1 months; HR 0.871; P=.044), and RRs of only 5% when used as a single agent.48-50In addition, the combination of erlotinib and cetuximab failed to lead to significant radiographic responses in patients with acquired resistance.51 However, preclinical mouse models of lung adenocarcinoma harboring T790M mutations have shown surprisingly potent synergy when combining cetuximab with the irreversible EGFR inhibitor afatinib.52 Early results of a phase 1b multicenter international trial testing this combination presented in 2011 showed a 31% confirmed partial response (PR) rate and 94% clinical benefit rate in patients with T790M-mutated NSCLC who had clinically defined acquired resistance to first-generation TKIs.53 Because of these promising results, enrollment was expanded to patients in a phase 2 study, which has recently closed to accrual (NCT01090011).
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MET Inhibition Direct targeting of MET is another possible therapeutic approach for overcoming resistance to EGFR-TKIs. Preclinical data suggest that inhibition of MET signaling in cell lines with EGFR resistance and MET amplification may restore sensitivity to EGFR inhibitors.37 Tivantinib (ARQ 197) and MetMAb have been combined with erlotinib and studied in large numbers of unselected patients. These data suggest that such a combination can be safely given, but there have been no tests of MET inhibitors with or without erlotinib in acquired resistance to EGFR-TKIs.54,55 HSP90 Inhibitors There is extensive preclinical rationale for the use of HSP90 inhibitors in acquired resistance to EGFR-TKIs. HSP90 chaperone proteins stabilize many oncoproteins important in NSCLC, including EGFR and MET, and when lung cancer cell lines are treated with HSP90 inhibitors, mutated EGFR can be effectively degraded.56 Mouse models harboring EGFR L858R and T790M mutations also undergo tumor regression when treated with HSP90 inhibitors.52 Two HSP90 inhibitors (IPI-504 and STA-9090) have been evaluated in phase 2 trials that included patients with EGFR mutations previously treated with erlotinib. In both of these studies, response rates were low among patients with EGFR mutations, although patients whose tumors were EGFR wild-type had impressive tumor shrinkage and were found retrospectively to harbor ALK rearrangements (described in more detail below).57,58 However, 2 additional studies investigating a third HSP90 inhibitor, AUY922, have recently been presented with more promising results for patients with EGFR mutations. Garon and colleagues reported the results of a single-agent phase 2 study evaluating AUY922 in previously treated patients with advanced NSCLC stratified by mutation subtype. Of 33 patients with EGFR mutations, 6 sustained a PR (18%).59 We reported the preliminary results of a phase 1 trial designed specifically for patients with acquired resistance to EGFR-TKIs in which patients were treated with the combination of
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AUY922 and erlotinib (to avoid disease flare associated with discontinuation of erlotinib in patients who develop acquired resistance).60 This drug combination was well tolerated, and 1 patient treated at the highest dose level achieved a PR. A phase 2 study evaluating the efficacy of erlotinib and AUY922 is ongoing.
ALK and Crizotinib Gene rearrangements involving ALK, most often with the echinoderm microtubule-associated protein-like 4, are found in 3% to 5% of patients with NSCLC. In these fusion genes, ALK is constitutively activated and drives tumor development through upregulation of cell survival pathways including PI3K-AKT and MEK-ERK (Figure).61,62 Patients harboring ALK rearrangements in
Two HSP90 inhibitors have been evaluated in phase 2 trials that included patients with EGFR mutations previously treated with erlotinib. their lung cancer tumors tend to be younger, never or light smokers with adenocarcinoma histology.63 ALK is the second molecular target to be validated in NSCLC64 and is targeted with crizotinib, a TKI with RRs of approximately 60% and a disease control rate of 80% in ALK-positive tumors.31,63 Based on phase 1 and 2 studies, the FDA granted crizotinib accelerated approval for the treatment of patients with NSCLC and ALK rearrangements in August 2011. Although most patients with ALK rearranged lung cancers will initially respond to crizotinib, a few cases of primary resistance have also been reported.65 Nevertheless, all patients develop acquired resistance at a median of 9 months,31 similar to EGFR-mutant lung cancer.26
Acquired Resistance to Crizotinib Several groups have reported molecular analysis of posttreatment tumors obtained from patients after development of acquired resistance to crizotinib,65-68 revealing multiple mechanisms of resistance including
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secondary mutations in ALK, increased ALK copy number gain, upregulation of parallel signaling pathways including EGFR and KIT, and acquisition of secondary oncogene mutations. ALK Mutations Choi and colleagues66 identified an acquired L1196M point mutation within ALK, analogous to gatekeeper mutations described in EGFR and BCR-ABL (Table). In addition to the L1196M point mutation, a second muta-
All secondary mutations in ALK reported in these 2 series were noted to be located within or near the binding pocket for ATP and crizotinib. tion, C1156Y, was also identified in the same patient’s sample. In the 2 largest series of postbiopsy specimen obtained from patients treated with crizotinib, additional mutations in the ALK kinase were reported. Katayama and colleagues observed 3 missense mutations (L1196M, G1202R, and S1206Y) and 1 insertion mutation (1151Tins) in 4 of 18 patients with acquired resistance to crizotinib; all of these were associated with crizotinib resistance in vivo.68 Doebele and colleagues identified 2 L1196M and 2 G1269A point mutations in 4 of 11 patients.65 All secondary mutations in ALK reported in these 2 series were noted to be located within or near the binding pocket for ATP and crizotinib. In contrast to the T790M gatekeeper mutation, which accounts for the vast majority of secondary resistance mutations in EGFR, the varied secondary mutations reported in ALK all occur at a relatively low prevalence (22%-36%). ALK Copy Number Gain ALK copy number gain, defined as a more than 2-fold increase in the mean of the rearranged gene per cell, has been identified as a mechanism of acquired resistance to crizotinib. Two of 11 patients in the series reported by Doebele et al exhibited a marked increase in both the number of the ALK rearrangements per cell as well as
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the number of cells with EML4-ALK rearrangements. One patient demonstrated ALK copy number gain in addition to an ALK mutation, while the second patient had only ALK copy number gain, suggesting that ALK copy number gain may be the primary event in developing resistance, followed by the accumulation of mutations within the ALK kinase.65 Bypass Signaling Analogous to the development of MET amplification in EGFR-resistant tumors, parallel signaling pathways that activate effectors downstream of ALK in the presence of crizotinib can also lead to the development of acquired resistance in ALK-positive patients.32 Upregulation of EGFR and KIT signaling have been identified as 2 potential bypass track signaling pathways.67,68 Using a cell line created from a patient with acquired resistance to crizotinib due to an acquired L1152R point mutation, tumor cells were found to secrete the EGFR ligand amphiregulin, indicating that dependence on EGFR signaling had developed in the setting of resistance to crizotinib.67 When comparing matched samples pretreatment and posttreatment with crizotinib, Katayama et al reported that increased EGFR expression measured by immunohistochemical staining was observed in 4 of 9 patients with ALK rearrangements, although no activating EGFR mutations were found.68 One of these patients had a secondary mutation in ALK in addition to increased EGFR activation. In the same study, marked KIT amplification by fluorescence in situ hybridization was measured in another patient’s tumor, suggesting a second avenue by which bypass signaling might develop. Finally, 1 additional patient was found to have both focal KIT amplification and a secondary ALK mutation, illustrating once again that multiple mechanisms of resistance may be encountered in a single patient’s tumor specimen.68
Methods for Overcoming Crizotinib Resistance ALK Inhibitors Several second-generation ALK inhibitors are cur-
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rently in clinical development for use in patients with acquired resistance to crizotinib, including CH5424802 (Chugai Pharmaceutical), LDK378 (Novartis), and AP26113 (ARIAD). Preliminary results from the phase 1 study of CH5424802 in ALK-positive NSCLC patients who were ALK inhibitor naive were recently reported.69 Although the phase 1 portion did not identify a maximum tolerated dose (MTD), at dose levels of 240 mg twice daily or higher, all 15 patients (100%) with measurable disease had a PR to treatment. The phase 2 study will enroll patients who are crizotinib resistant and ALK inhibitor naive to separate arms (NCT01588028). Interim results from the phase 1 trial of LDK378 in patients with ALK-positive NSCLC and prior exposure to crizotinib have also been reported.70 The MTD was determined to be 750 mg orally daily. In patients who received doses greater than 400 mg daily, 21 of 26 (81%) had PRs to treatment, and responses within the central nervous system were reported in patients treated with 750 mg daily. The phase 2 portion of this study will enroll several cohorts, including patients who are crizotinib naive, patients with acquired resistance to crizotinib, and patients with other ALK-positive solid tumors (NCT01283516). Preliminary results from a phase 1/2 clinical trial of AP26113, a dual inhibitor with activity in ALK-positive patients with acquired resistance to crizotinib as well as patients with resistance to EGFR-TKIs, were also recently reported. Of 11 patients with ALK rearrangements, 8 achieved a PR to treatment with AP26113, including 6 with acquired resistance to prior crizotinib.47 As described above, expansion of the phase 2 portion into 4 distinct molecular cohorts is ongoing (NCT01449461). HSP90 Inhibitors In addition to ALK inhibitors, HSP90 inhibitors are another drug class to show preferential activity in patients with ALK-rearranged NSCLC. Relevant HSP90 client proteins including KIT, EGFR, BRAF, AKT, and MET are key effectors of signaling pathways that may
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be upregulated in acquired resistance to crizotinib.71,72 A phase 2 trial investigating HSP90 inhibitor IPI-504 in patients with previously treated advanced NSCLC showed that the patients with the highest responses rates and longest PFS outcomes harbored ALK rearrangements in their tumors.57 Subsequent preclinical studies verified HSP90 inhibitors to be effective against ALK-positive NSCLC cell lines and mouse models, and perhaps more
In addition to ALK inhibitors, HSP90 inhibitors are another drug class to show preferential activity in patients with ALK-rearranged NSCLC. potent inhibitors against ALK-positive NSCLC than EGFR-mutant lung cancers.73 In another phase 2 trial evaluating HSP90 inhibitor STA-9090 in advanced NSCLC, responses were seen in 7 of 8 ALK-positive patients, with confirmed objective responses in 4 of 8 ALK-positive patients.58 HSP90 inhibitors have been shown effective in several models of crizotinib-mediated acquired resistance, and the combination of crizotinib and HSP90 inhibitors has synergistic antitumor activity in vitro.62,67,68 A trial of crizotinib and STA-9090 in the first-line setting is ongoing (NCT01579994).
Conclusion While the discovery of oncogenes such as EGFR and ALK has allowed important therapeutic advances for patients with lung adenocarcinoma, it has also catalyzed the development of tumor-mediated treatment resistance. Reversing acquired resistance, or preventing its development, has become the focus of research efforts, first to identify the variable mechanisms by which TKI resistance begins, and subsequently to identify novel small-molecule inhibitors capable of circumventing this phenomenon. Combination therapies, for example those that block both oncogene and bypass track signaling pathways, may prove to be effective for treating acquired resistance in NSCLC.
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Disclosures Dr Johnson: research funding (Novartis); consultant (Genentech); spouse contracted employee as Governmental Affairs lobbyist (Astellas). Dr Gentzler: no disclosures. Dr Yu: no disclosures. Dr Riely: research funding (Pfizer, Chugai 2012); consultant (Novartis, Daiichi Sankyo, Tragara, Chugai 2011, ARIAD, Celgene, Foundation Medicine, Abbott Molecular). u
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Next-Generation Sequencing: An Interview With Michael J. Pellini, MD, of Foundation Medicine Michael J. Pellini, MD Foundation Medicine Cambridge, Massachusetts
A
s the molecular drivers of cancer are better sequencing 236 genes known to be somatically altered understood and targeted therapies are develin human cancer. Genomic alterations are matched to oped against those drivers, relevant targeted therapies, either apthere is a growing need to perform proved or in clinical trials, that could comprehensive molecular analysis be a rational choice for the patient of tumors to determine the optimal based on the genomic profile of their treatment strategy for each patient. cancer. This information is reported to To this end, Foundation Medicine the patient’s physician via the Foundawas founded in April 2010 by leaders tionOne Interactive Cancer Explorer, in genome technology, cancer biology, the company’s online reporting platand medical oncology from the Broad form. This assay utilizes next-generaInstitute, the Dana-Farber Cancer Intion sequencing technology on small stitute, Harvard Medical School, and amounts of routine cancer tissue with the Massachusetts Institute of Techa reported >99% sensitivity and specnology. Their goal: to develop a comificity for alterations within relevant Michael J. Pellini, MD prehensive cancer diagnostic test that cancer genes. helps physicians recommend treatPMO recently had the great pleament options for each patient based on the molecular sure of meeting with Michael J. Pellini, MD, to dissubtype of their cancer. cuss the unique approach of Foundation Medicine to The company’s first assay, FoundationOne, became personalizing cancer treatment. To view the interavailable last year and is a genomic profile that idenview in its entirety, please visit www.personalizedmed tifies a patient’s individual molecular alterations by onc.com/.
PMO Thank you so much for taking the time to speak with us, Dr Pellini. To start, how do you define personalized medicine in oncology? Dr Pellini Personalized medicine in oncology is a concept that is relatively easy to define but difficult to implement. Let’s start with the physician’s perspective. If we im-
plement personalized medicine in oncology well, we enable each oncologist to select the appropriate therapy or therapies to target the drivers of each patient’s cancer. If we end with a patient in mind, then that patient is confident that he or she is getting the most effective therapy to prolong life. That’s how it has to come together. We select the right therapy, attack the molec-
Dr Pellini joined Foundation Medicine as President and Chief Executive Officer in May 2011. Previously, he was President and Chief Operating Officer of Clarient, a GE Healthcare Company. Dr Pellini received a BA from Boston College, an MBA from Drexel University, and an MD from Jefferson Medical College of Thomas Jefferson University. Dr Pellini serves as a member of the Boston College Technology Council and the Board of Trustees for the Coriell Institute for Medical Research.
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ular appropriate drivers, and hopefully prolong the life of the patient. PMO Personalized medicine is largely practiced in academic settings. In your opinion, what changes are needed to ensure that personalized medicine can be made broadly available to patients managed by community physicians? Dr Pellini That is a key question for all of us. How do we drive the practice of personalized medicine in oncology from the academic centers to the community setting? It’s certainly one of the motivating factors in establishing Foundation Medicine. Eighty percent to 85% of patients with cancer are treated in community practices around the United States; however, the key novel therapeutics tend to be used first within the academic medical centers and slowly roll out to community practices. But what we have to do as a company, what we have to do as a community, is drive this information to the community setting so those 80% to 85% of patients who are being treated in this country, and even outside the United States, are getting best-in-class testing and the most appropriate therapy for their disease. Foundation Medicine launched a test called FoundationOne last year. This is a test that takes a comprehensive snapshot of each patient’s cancer to help the oncologist identify the molecular drivers to treat. Now that sounds like something that should occur in an academic medical setting, and it is occurring in the academic medical setting, but there’s no reason why that can’t be driven into the communities around the United States and beyond. In fact, we’re already seeing it. There are additional issues to consider. One is that of reimbursement. How do we rethink the reimbursement challenge in the United States? Reimbursement is something that we have to tackle over the coming years because of the rapid technological changes in our space. And we also have to think about the regulatory side, the FDA. What role are they going to play in this transformation? So there are several different factors that we have to take into consideration, but again, if we do this well, we’ll start to take diagnostic tests and therapeutics that
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Foundation Medicine is dedicated to the health and well-being of patients with cancer.
are often only utilized in the key academic medical centers and gradually, or perhaps rapidly, drive them into communities. PMO As you mentioned, Foundation Medicine recently launched FoundationOne to deliver genomic profiles to oncologists to help them guide personalized therapy. Can you talk a little bit about FoundationOne and how it’s going to work for community oncologists?
Foundation Medicine launched a test called FoundationOne last year. This is a test that takes a comprehensive snapshot of each patient’s cancer... Dr Pellini FoundationOne is a comprehensive molecular profile that oncologists can use to help understand the key molecular drivers of their patients’ cancer. It’s unique in that we sequence the coding regions of 236 genes known to be somatically altered in human cancer. In addition, we capture all 4 major classes of alterations: insertions/deletions, base pair substitutions, translocations, and copy number alterations. There’s nothing else even close to it on the market today. When we initially launched the test, the first up-
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take came from the academic medical centers. What we’re starting to see, though, is this migration outside of the academic medical centers into the community setting. Currently, about 40% of the tests are ordered by oncologists in the academic medical centers, 40% by oncologists practicing in the community setting, and 20% from the international community.
We’re in a position to generate a significant amount of data with many of our collaborating academic medical center scientists and physicians. One of the reasons that this migration has occurred so rapidly is that in FoundationOne we have designed a test that is straightforward to use. Second, it’s impactful. In more than 70% of the cases that are reported out, oncologists are receiving information that is clinically actionable for their patients. So it’s not only the amount of information they are receiving; rational options open up when you have this information. It helps them think about treating a patient perhaps a little bit differently than they otherwise would have. We spent a lot of time on the development of this program, not just in terms of optimizing the test and making sure that the test has the robust sensitivity and specificity that is needed for the clinic, but we spent a lot of time making sure that it integrates easily into clinical practice, both in terms of the way the test is ordered and the way the test is reported back to the oncologist. It’s about taking very complex information that’s generated on each patient’s cancer sample and finding a way to translate that into information that is easily understood and then acted upon. PMO Confidence in the results of a program such as FoundationOne is extremely critical for a community uptake. What steps has Foundation Medicine taken to ensure that FoundationOne will provide the accuracy that patients and physicians are looking for? Dr Pellini When you come out with a new molecular test, especially a complex new molecular test
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that should have an impact on the way patients are ultimately treated, one needs to make sure that it has robust sensitivity and specificity. With the new technology advancements in this field, we have to think about new ways to generate that type of analytic information. So if we’re generating the data, how do we know that the data are accurate? A particular benefit, yet also challenge, of utilizing next-generation sequencing is that if you use this technology appropriately, it’s potentially better than the gold standard. For example, we routinely find an alteration in EGFR, or we’ll pick up a HER2 alteration or some type of translocation that might not have been identified by the standard molecular techniques that are used today. That presents us with a challenge, and 1 way to overcome that challenge is to go back and perform additional validation with specific molecular tests to confirm the next-generation sequencing results. But that can’t be done forever. We have developed new approaches to validate testing based on next-generation sequencing. We’ll present these data at AACR [American Association for Cancer Research], and we also recently submitted our validation approach to a prestigious journal. We’ve taken a very simplistic approach to getting the message out about the sensitivity and specificity, or the accuracy, of this approach. It’s all about generating and presenting the data. In the last year alone, we’ve had articles in Nature Medicine and Journal of Thoracic Oncology. We had a total of 8 presentations at ASCO [American Society of Clinical Oncology] last year. We’re in a position to generate a significant amount of data with many of our collaborating academic medical center scientists and physicians. Our aim is simply to publish these data to demonstrate to the broader community that this is a new approach, but this is a new approach that’s potentially going to change the way that we think about molecular testing. PMO Treating cancer patients has become an increasingly costly venture. How does incorporating new molecular profiling into that provide value? How do we justify those added costs to therapy?
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Dr Pellini How does this approach of utilizing next-generation sequencing add value? How do we deal with the additional costs? It’s a question today that’s front and center, so I’ll try to hit that question from a couple of different perspectives. Let’s first focus on the test itself. In terms of the cost of this type of testing, we often hear that the cost of doing the human genome is now coming down to under $1000. But I think it’s really important to understand what that is and what it isn’t. As we think about FoundationOne, consider the costs and the requirements that go into this test from 3 different perspectives. There’s an enormous amount of work that occurs before the sequencing. The sample preparation standard operating procedures that allow us to extract nucleic acid DNA and RNA from a very small piece of paraffin-embedded tissue is extremely challenging on its own. The library construction and hybrid capture procedures are the next presequencing components. These are procedures that our company has perfected over the past few years. Recognize there’s a real cost burden associated with this initial aspect of the testing. The second part is the cost and effort associated with the sequencing itself. These costs are coming down, but we really need to differentiate running a germline sample, which is basically a blood sample, versus applying sequencing to human cancer tissue. Sequencing from cancer tissue is a much more costly and complex enterprise than running it on a germline sample. Then there’s the final piece of the testing. Once we have all those data, what do we do with them? How do we take that information and translate it into something that’s actionable? These steps require complex informatics. I want to make sure that we separate this informatics component of the $1000 genome from all the other costs that actually go into running this type of test for patients diagnosed with cancer. It’s critically important for the payer community to understand how important informatics has become, because this is a complex and new consideration, and it’s something the payers and industry must continue to work through.
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Dr Michael Pellini discusses Foundation Medicine’s vision for the future of cancer care.
The reason that we have to push in this direction and figure this out together is that the current paradigm for molecular testing in the United States must change. First, we are running out of tissue to continue down the
If we think we’re going to run 3, 5, or 10 individual molecular tests and continue to do that on small biopsies, think again. current path. If we think we’re going to run 3, 5, or 10 individual molecular tests and continue to do that on small biopsies, think again. We’re running out of tissue, and we won’t get the answers that we ultimately need for patient care. Another challenge is the additional cost incurred every time a new molecular test is ordered. As you know, it’s not $100 per molecular test; it’s roughly $500 per new test on average. So, if I’m a thoracic oncologist, and I’m treating a patient with non–small cell lung cancer and want to run 10 individual molecular tests, that’s at least a $5000 price tag. Further, the number of tests that are being ordered is only growing. A final aspect of cost relates to the therapeutic deci-
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sions that are being made. This starts to get a little complicated, but today if patients are relatively late stage in their disease, chances are they’re getting a cytotoxic chemotherapy. Some of these chemotherapies have been around for a long time. The cost of the drug itself may not be that significant. The side effects, the emergency room visits, the impact on the patient, and even the broader cost to the healthcare system associated with those adverse events can become very significant. If we can use this approach to find a target therapy, or therapies, that are more effective and less toxic for the patient, the price of the diagnostic test becomes quite insignificant.
What I can tell you is that while we are in the early days of working with the payers, they have been receptive. Medicare has been receptive. If we utilize this technology to work with smaller sample sizes, if we utilize this technology to avoid the increasing costs associated with the growing number of individual molecular tests that are going to be ordered, and if we utilize this technology to select the right therapeutic up front, it might change some of the fears that we have around targeted therapies and the diagnostic workup. What I can tell you is that while we are in the early days of working with the payers, they have been receptive. Medicare has been receptive. They all understand that this is the next wave of molecular testing. They all understand the potential clinical value. We all know this approach is going to have an impact in the clinic, and they are with us, and now we’re simply starting the dialogue. Of course, that dialogue has to be backed up with clinical and pharmacoeconomic data to make sure that we all arrive at the appropriate end point. The reason that I’m optimistic is because it is the right thing to do. It’s the right thing to do for the patient, it’s the right thing to do for the oncologist, and in this case we can say we ultimately believe it’s going to be the right thing to do for the payer as well.
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PMO There are cancer patients who either don’t respond to therapy or have acquired resistance to therapy. How will FoundationOne specifically help those particular patients suffering from cancer? Dr Pellini The question is how could FoundationOne now change the treatment options or help patients who have maybe failed first-, second-, or third-line therapy. They have metastatic disease. What comes next? Often, those patients are relegated to broad-based cytotoxic chemotherapeutics. Sometimes there’s a benefit, but often there’s not, and there are significant side effects that typically go hand in hand with these drugs. It’s something the oncology community has been working through for decades. Let me turn to the data to answer the question about how FoundationOne and this technology can be used. We have a data set from 95 patients diagnosed with non–small cell lung cancer. What’s interesting is that we found alterations in 33 genes in those patients. That’s kind of scientifically interesting, but what does it really mean? Well, 22 of those altered genes can be directly tied to a therapeutic that is either on the market or in clinical trials. You may say there aren’t that many targeted therapeutics for non–small cell lung cancer, so what’s the benefit of this knowledge. Here’s the potential benefit: Today there are 3 tests that are routinely used for patients with non–small cell lung cancer in the community: EGFR, KRAS, and EML4-ALK. If you have patients who tested negative for those 3 biomarkers, they are relegated to broad-based chemotherapy. Second, if you have patients who have failed their first targeted therapy, and their next option is a chemotherapy with a marginal benefit, do you want to know that there might be an additional 20 drugs that are either in clinical trials or on the market that could potentially be helpful to your patients with that disease? That’s the way to think about FoundationOne; that’s the way to think about this next wave of molecular testing. It’s going to open up new doors for patients and for oncologists to select therapeutics and find clinical trials in a very rational setting. PMO Regarding heterogeneity, there was an arti-
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cle published last March in the New England Journal of Medicine about the nuances of intertumoral heterogeneity. How will FoundationOne help researchers address the heterogeneity of tumors? Dr Pellini While the heterogeneity of cancer became more of a mainstream topic thanks to the New England Journal of Medicine article and a New York Times follow-up article, it’s something that we’ve known for a long time in this community. It’s not surprising, especially if you have a pathology background, that tumors are, in fact, heterogeneous. We have to rethink the way that we’re testing these samples. We spent an enormous amount of time making sure that FoundationOne had the appropriate level of sensitivity and specificity to capture the alterations that are found at a very low mutant allele frequency. If you’re looking for an alteration that is found in 60% of the tumor’s cells, chances are you’re also going to capture it with a much simpler technology. But if the tumor is heterogeneous, as almost all are, the alterations may only be found in a very limited set of the tumor’s cells. If tissue is selected from 2 different areas, a technology is needed with an exquisite sensitivity and specificity to capture the alterations that are found at a low mutant allele frequency. That’s how we need to think about capturing this information. It’s just not practical in today’s clinical age to think about taking multiple biopsies from a patient and then running multiple tests. The payers aren’t going to pay for the multiple biopsies and tests, and we might not have access to enough tissue. What we have to do is utilize this technology to deliver results with the appropriate level of accuracy while minimizing the risk that we face with heterogeneous tissue that we work with every single day. PMO To achieve personalized medicine in oncology all healthcare professionals need to be educated. What efforts is Foundation Medicine making toward payers, physicians, patients, and other healthcare professionals to ensure that they’re up to speed on the newness of personalized medicine in oncology? Dr Pellini Education is such a key element of en-
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abling this approach to become mainstream. It’s not just the education of oncologists, it’s education of the payers, it’s education of the regulators. And a group that can play a vital role is the patient advocates. We recently invited 10 of the most well-respected patient advocacy groups in the country to Foundation Medicine and spent a day and a half talking with them
It’s just not practical in today’s clinical age to think about taking multiple biopsies from a patient and then running multiple tests. about this very issue. How do we educate patients? How do we educate oncologists? What role can they play? What role should we play? I’ll tell you that I learned more in that 1 day than I think I’ve learned in any 1 day in a long time because it really is a different perspective. It’s the patient’s perspective. The only thing they care about is driving the advancement of cancer therapy forward. That’s it. How can we maximize the benefit of this new technology, of everything that we’re learning about cancer for patients? It starts with education. Education is perhaps the
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single most important underpinning of that revolution in cancer care. We have to think about the advocacy groups, because if you work closely with them, they’ll help get the message out. That’s critical. Of course, we also have to think about oncologists. The oncologists are central to this migration of cancer care, especially out of the academic medical centers into the communities around the United States. Oncologists are data driven, and that’s why our company has spent so much time and effort on really developing the data and putting together the retrospective and prospective clinical studies. We’ve partnered with many
The FDA also understands that not only can this technology be impactful at the level of the clinical trial; it can be impactful at the level of the clinic... of the major cancer centers, in the United States and overseas, and pharmaceutical companies to generate the data to demonstrate that this approach will ultimately have a dramatic impact in the way that we think about caring for patients with cancer. Education also comes in the form of working with the FDA. We have met with certain groups at the FDA. The FDA has not completely sorted through how to work with next-generation sequencing. It’s a complex new technology. It’s going to take time, but they are receptive to it. There’s an understanding at the FDA that this technology will likely have a significant impact on the way pharmaceutical companies perform their clinical trials. It allows them to be much more targeted and ideally much more efficient in their approach to clinical trials. The FDA also understands that not only can this technology be impactful at the level of the clinical trial; it can be impactful at the level of the clinic, impacting how oncologists select therapies for each of their patients. Payers also understand these concepts. They might not be as focused on the clinical trials because that’s the world of the FDA and pharma, but they are focused on making sure that they do get the right therapy to the
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patient to maximize the benefit that patient is going to receive, and also to minimize the negative, the side effects that the patient might have if he or she receives the wrong therapy. So, we have a lot of different stakeholders when it comes to education. We have patient stakeholders, we have oncologist stakeholders, we have payer stakeholders, and we have regulators at the FDA. Patient advocacy groups can play a role with each of them, but we as a company, we as an industry, we as a community have to continue to focus on education for all these groups. If we do it well, we will see oncology continue to evolve extremely quickly. PMO Drug development is going to change in the future. What is your vision of the future of drug development as it relates to our pharmaceutical company colleagues utilizing next-generation sequencing technologies in drug development? Dr Pellini How might next-generation sequencing impact drug development? I’ll tell you, one of the most significant surprises that I’ve had in my 18 or 19 months at Foundation Medicine is the adoption of this approach by pharmaceutical companies. I have to admit that when I came here I was a little skeptical that pharma would readily adopt what Foundation Medicine was doing because, by design, this approach is going to take a therapeutic that might be used for a broader population and narrow that population. To my pleasant surprise, it’s not only the development groups within pharma that understand it, but the commercial teams get it as well. There have been a couple of very high-profile failed phase 3 trials, yet we know that there was a subset of patients who responded extremely well. How do we identify that subset? Well, if we have the molecular profile of those patients, we can look at the responders, match them up to the appropriate molecular alterations that were found, and determine whether there’s a match. If there is a match, think about how quickly that follow-up clinical trial can commence and how small that trial might need to be if it’s targeting a very specific population. The second thing that we’re seeing as the thera-
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peutics become more targeted is pharma looking for molecular information that continues to refine their patient populations. For example, we have at least 1 partnership where our test and our approach is being applied to most of their phase 1 and phase 2 patients in oncology on a global basis. That’s thousands of patients. That will add up to dozens of clinical trials, and a fully informative molecular profile is going to be run on each of those patients to help them continue to think about how to refine their therapeutic approach. That should be promising to all of us, and again, it’s been a very pleasant surprise to see the pharmaceutical industry’s response to this approach. Another path that I’ll go down touches on broadening their markets. We’re moving toward thousands of samples from patients with all different types of cancer. We’re running this information at a level of sensitivity and specificity that is helping us uncover new alterations, which means we have a treasure chest of new information that has emerged within Foundation Medicine. So why is that important? If I’m a pharmaceutical company and have a therapeutic that is targeting an alteration found in 10% of patients with breast cancer, I might want to know if that alteration is found in patients with pancreatic cancer, with colorectal cancer, with rare sarcomas, and so on, so we can think about additional markets for this therapeutic. We now receive regular requests from pharmaceutical companies regarding an alteration or the possibility of a combined trial with 2 therapeutics that are targeting 2 alterations, and they want to understand how often these alterations are found across various disease states. That’s information that we can provide in a timely fashion even with only several thousand patients in our database. What happens when our database goes to 10,000, 50,000, and 100,000 patients? You start to get a glimpse into the future of clinical trials and how pharmaceutical companies and companies like Foundation Medicine can work together and ultimately partner with oncologists and patients to refine clinical trials, thereby making them as efficient as possible.
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PMO Can you provide us with a couple of clinical examples from your experiences? Dr Pellini One of the things that drives us each and every day is that we get to see the impact that this approach can have in the clinic. It’s unusual that a day goes by when our head of clinical development or head of medical affairs or medical director doesn’t come to the senior team and says “guess what we learned today?” We’re learning a lot about this disease, and we’re learning a lot about how oncologists are treating their patients. Now we’ve been doing this long enough to understand the impact that it’s starting to have on some of these patients.
One of the things that drives us each and every day is that we get to see the impact that this approach can have in the clinic. Let me give you a couple of examples that probably would not be intuitive to even the best oncologists in the United States. Yesterday, I learned we received a specimen from a patient who was being treated for pancreatic cancer. The patient was not doing well. FoundationOne was run on this patient’s sample, and it identified a HER2 amplification. Not too many oncologists or scientists would think about testing for HER2 in a pancreatic cancer case. This finding was identified several months ago, and yesterday we learned that the patient has now been on Herceptin for a few months and was responding nicely. These experiences are the things that keep us going every single day. It’s still anecdotal evidence, though we’re conducting the outcomes studies that we’ll need over the long term and are generating more publishable case studies all the time. For example, last summer in the Journal of Thoracic Oncology we reported an extremely interesting case of a patient with non–small cell lung cancer who tested negative for EGFR, KRAS, and EML4-ALK. The pa-
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tient sample was then sent to Foundation Medicine for testing. We identified a novel ALK fusion, which ultimately led to the treatment of the patient with crizotinib. We now have data that are going out 6 months showing the radiographic response, not only the clinical but the radiographic response to crizotinib.
We see these interesting connections. We see these seemingly counterintuitive connections, but it just tells us that we have a lot to learn... I think it’s safe to say that most oncologists, if not all oncologists, would agree that without the type of approach that was applied with FoundationOne, there is no chance that the second patient would have received crizotinib, and there’s no chance that the patient with pancreatic cancer would have received Herceptin. We WCMC_2013Conf_horizontalV382012_Layout 1 8/20/12 9:22 AM are seeing these cases almost every day now that we’ve
been doing this long enough to receive patient follow-up. It’s not the ultimate answer, but it really does give us hope. It gives the oncology community a sense that, collectively, we really are moving this in the right direction. Another patient who comes to mind was in hospice care, and there was another response based on a finding. FoundationOne identified an EGFR mutation in a woman with late-stage breast cancer. That’s counterintuitive. You typically do not see EGFR alterations in patients with breast cancer, yet it was identified, and the patient was started on Tarceva. So we see these interesting connections. We see these seemingly counterintuitive connections, but it just tells us that we have a lot to learn about oncology and how we’re going to treat patients with cancer. We have a lot to learn about the approach of applying next-generation sequencing via FoundationOne. All of this is going to be an important part of cancer care in the future. PMO Thank you so much for your time. PageDr 1 Pellini My pleasure. u
SECOND ANNUAL CONFERENCE
2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS
TM
• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma
• Squamous Cell Carcinoma • Merkel Cell Carcinoma
July 26-28, 2013 Hyatt Regency La Jolla • at Aventine 3777 La Jolla Village Drive • San Diego, California 42
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ANNUAL CONFERENCE
"! ! !
! Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom
* 3:00 pm - 7:00 pm
Registration
5:30 pm - 7:30 pm
Welcome Reception and Exhibits
7:00 am - 8:00 am
Symposium/Product Theater
8:15 am - 8:30 am
Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP
8:15 am - 11:45 am
General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level
12:00 pm - 1:00 pm
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1:15 pm - 4:30 pm
This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.
General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology
4:30 pm - 6:30 pm
Meet the Experts/Networking/Exhibits
Jorge E. Cortes, MD 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
The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.
This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.
Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer
Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.
7:00 am - 8:00 am
Symposium/Product Theater
8:15 am - 11:45 am
General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)
12:00 pm - 1:00 pm
Symposium/Product Theater/Exhibits
1:15 pm - 3:00 pm
General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management â&#x20AC;˘ Reimbursement Challenges â&#x20AC;˘ Closing Remarks
3:00 pm
Departures
The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
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*Agenda is subject to change.
Legal Issues in Healthcare
The Drawn Out Process of the Medical Lawsuit Pauline W. Chen, MD
S
he was one of the most highly sought radiologists in her hospital, a doctor with the uncanny ability to divine the source of maladies from the shadows of black and white X-ray films. But one afternoon my colleague revealed that she had been named in a lawsuit, accused of overlooking an irregularity on a scan several years earlier. The patient suing believed she had missed the first sign of a now rampant cancer.
Most claims required almost two years from initiation of the lawsuit, and almost four years from the time of the event in question, to reach a resolution. While other radiologists tried to assure her that the “irregularity” was well within what might be considered normal, my colleague became consumed by the whatif’s. What if she had lingered longer on the fateful film? What if she had double-checked her reading before signing off on the report? She began staying late at the hospital to review, and re-review, her work. And she worried about her professional reputation, asking herself if colleagues were
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avoiding her and wondering if she would have trouble renewing her license or hospital privileges. At home she felt distracted, and her husband complained that she had become easy to anger. After almost a year of worry, my colleague went to court and was cleared of the charges. But it was, at best, a Pyrrhic victory. “I lost a year of my life,” she told me. “That lawsuit completely consumed me.” She was not the first colleague to recount such an experience. And far from overstating the issue, doctors may in fact be underestimating the extent to which malpractice not only consumes their time but also undermines their ability to care for patients, according to a new study in Health Affairs. For more than 150 years, the medical malpractice system has loomed over health care, and doctors, the vast majority of whom will face a lawsuit sometime in their professional lives, remain ever vocal in their criticism of the system. But with few malpractice claims resulting in payments and liability premiums holding steady or even declining, doctors have started to shift their focus from the financial aspects of malpractice to the untold hours spent focused on lawsuits instead of patient care. Now researchers are putting numbers to those doctors’ assertions. For the current study, they combed through the malpractice claims records of more than 40,000 doctors covered by a national liability insurer. They took note of the length of each claim, as well as any payments made, the severity of the injury and the specialty practiced by the physician being sued. Most claims required almost two years from initiation of the lawsuit, and almost four years from the time of the event in question, to reach a resolution. Cases that resulted in payment or that involved more severe patient injuries almost always took longer. The researchers then looked at the proportion of a doctor’s career spent on an open claim. They discovered that on average, doctors spent more than four years of their career – more time than they spent in medical
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February 2013
Legal Issues in Healthcare
school – working through one or more lawsuits. Certain specialists were more vulnerable than others. Neurosurgeons, for example, averaged well over 10 years, or over a quarter of their professional life, embroiled in lawsuits. These findings help to show why doctors care so intensely about malpractice and what they might face over the course of a lifetime, said Seth A. Seabury, lead author and a senior economist at the RAND corporation in Santa Monica, Calif. The results also underscore what plaintiffs must endure. Previous studies have shown that when medical errors occur, patients prefer to have physicians acknowledge the mistake quickly and apologize as soon as possible. Though less than 5 percent of all errors ever lead to a malpractice claim, lengthy claims drag out the process and, in certain cases, hold up what may be appropriate compensation. Patients not directly involved can be affected as well. A legitimate malpractice lawsuit sometimes results in doctors or even entire institutions changing how they
practice in order to prevent similar events from happening again. Lengthy legal wrangling can slow down these potentially important improvements. While these findings are only an indirect measure of the extent to which malpractice claims can affect doctors’ and patients’ lives, the study makes clear the importance of considering time, as well as cost, when looking at malpractice reform. “If we could get these cases resolved faster, we might be able to improve the efficiency of the system, lower costs and even improve quality of care for patients,” Dr. Seabury said. “Having these things drag on is a problem for doctors and patients.” u From The New York Times, Jan 24, 2013. ©2013. The New York Times. All rights reserved. Used by permission and protected by the Copyright Laws of the United States. The printing, copying, redistribution, or retransmission of this Content without express written permission is prohibited.
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The Last Word
The Supportive Face of the FDA in the Advancement of Personalized Medicine
I
n a presentation at the 2011 World Health Care consequence of confidential research causing this peCongress, Vicki Seyfert-Margolis, PhD, the FDA’s culiar form of insanity to be practiced by quite sane sciSenior Advisor for Science Innovation and Policy, entists. She then explained how the FDA is working to delivered information that demonstrated how the meddiminish this cycle of repeat failure that threatens the ical sector of healthcare has no exclueconomic viability of research into sive claim to creativity in methods for the biologicals so important to perfacilitating the success of personalized sonalized medicine in oncology. medicine. Her findings underscore the Tactical options for avoiding this fundamental makeup of healthcare as “research insanity” are extensive and a fusion of 3 sectors: clinical, business, under way. A central theme is a sciand government. Therefore, the move ence enclave and data repository “…to to enriched, personalized medicine in improve FDA’s management of sciencancer is the child of 3 proud parents: tific data about regulated products and medical, business, and government. improve regulatory decision-making She discussed the deep commit[to] facilitate integration of scientific ment by the FDA to helping pharma data – across studies, within studies, improve its research and development combine with outside data, [and] enRobert E. Henry process by reducing the cost of new able collaborations.” It would “create drug approvals, which had increased structured scientific data repositories by 60% from 2000 to 2005 – when the cost of failures that support the acquisition, validation, integration, is included. Failure, then, is a major culprit obstructing and extraction of data from the increasingly large and personalized medicine advances. The question becomes complex data sets received by the Agency [and] make how to accelerate fast-fail research? She brought eviuse of enhanced analytical tools and techniques that dence of something private researchers could not know: enable scientists, and ultimately reviewers, to search, model, and analyze data to enable personalized medicine and to conduct better safety and efficacy analyses.” In December 2012 the FDA issued a Seyfert-Margolis’ presentation in itself can go far to document that can help drug companies erase the stigma of the FDA as a force for impeding by accelerating approvals and reducing progress. Government is keenly aware that personalfailures. ized medicine in cancer care is not a passing fad, and it has no intention of watching passively while private that because outcomes are not shared among competresearch spends itself into insolvency and brings down ing companies, “…each failure is repeated many times.” the roof upon the heads of cancer treatment innovaNow, when Einstein was glibly making his point about tion. Witness another signal event – this one recent insanity being that matter of doing the same thing over and impressive. and over again while expecting a different result, he In December 2012 the FDA issued a document that may not have been thinking of including in this syncan help drug companies by accelerating approvals and drome the current reward system and its unintended reducing failures. Titled Guidance for Industry: Enrich-
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ONCOLOGY
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The Last Word
ment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products, this 42-page document draft advises pharma to select those patients most likely to show a benefit from a studied drug, enriching the patient study pool and so increasing the speed and accuracy of ascertaining the drug’s or biological’s potential to stop the cancer’s spread. It is axiomatic that personalized medicine is based on treating patients who are enriched through biomarker and other predictive methods, and the guidance document draft explores the clinical implications of this premise. The results demonstrate a desirable risk/benefit ratio. The guidance described several examples of the process of securing approval. One was trastuzumab, with a significant survival of 5 months for metastatic breast cancer in patients with high HER2/neu-expressing tumors (a quarter of breast cancer patients) but less than 2 months’ survival improvements in the overall patient population. The report states that focusing part of the trial on the enriched patients with high HER2/ neu-expressing tumors “…ultimately supported use of the drug in the marker-selected population despite the significant cardiotoxicity that emerged. The much smaller mean effect...that would have been observed in an unselected population, and the fact that only about one-fourth of patients would have benefited, might have made approval difficult to support in the face of the observed cardiotoxicity of the drug.” We find 2 lessons for personalized medicine from these examples. The first centers on the cause-andeffect application of these initiatives spawned thePM GBC_2013Conf_horizontal3_62512_Layout 1 8/16/12by1:06
FDA. The second is more diffuse, but no less valuable: the dispelling of stereotypes and consequent broadening of appreciation of the way in which healthcare works. Empirically, the guidance document draft underscores the time-honored premise of personalized medicine as an exercise in an enriched patient pool. The other lesson underscores the integrated, multistakeholder, trisector nature of the process of care: medicine, business, and government. The implication is to regard fellow stakeholders from different sectors as colleagues, not adversaries, with systems changes worthy of integrating
Guidance for Industry: Select those patients most likely to show a benefit from a studied drug, enriching the patient study pool. into those from other sectors and groups. The core beneficiary, of course, will be the patient, who has appeared with life-and-death questions that are best served by a multilateral process of care. Listening to one another increases the chances of patient survival exponentially. Collegiality, support, and respect are in order for those from other fields, who regard themselves as just what they are: fellow healers in the mysterious initiative that is personalized medicine in cancer care. Robert E. Henry
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