Advancing Progress in the Development of
Combination
Cancer Therapies
with
Immune Checkpoint
Inhibitors
PROCEEDINGS OF A WORKSHOP
Erin Balogh and Sharyl J. Nass, Rapporteurs
National Cancer Policy Forum
Board on Health Care Services
Health and Medicine Division
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001
This activity was supported by Contract No. 200-2011-38807 (Task Order No. 75D30118F00071) and Contract No. HHSN263201800029I (Task Order No. HHSN26300008) with the Centers for Disease Control and Prevention and the National Cancer Institute/National Institutes of Health, respectively, and by the American Association for Cancer Research, American Cancer Society, American College of Radiology, American Society of Clinical Oncology, Association of American Cancer Institutes, Association of Community Cancer Centers, Bristol-Myers Squibb, Cancer Support Community, CEO Roundtable on Cancer, Flatiron Health, Helsinn Therapeutics (U.S.), Inc., LIVESTRONG Foundation, Merck, National Comprehensive Cancer Network, Novartis Oncology, Oncology Nursing Society, and Pfizer Inc. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.
International Standard Book Number-13: 978-0-309-49086-3
International Standard Book Number-10: 0-309-49086-3
Digital Object Identifier: https://doi.org/10.17226/25405
Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu.
Copyright 2019 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America
Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2019. Advancing progress in the development of combination cancer therapies with immune checkpoint inhibitors: Proceedings of a workshop. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25405.
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WORKSHOP PLANNING COMMITTEE1
ROGER DANSEY (Co-Chair), Chief Medical Officer, Seattle Genetics
SAMIR N. KHLEIF (Co-Chair), Director, Loop Immuno-Oncology Lab, Biomedical Scholar, and Professor of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
AMY P. ABERNETHY, Chief Medical Officer, Chief Scientific Officer, and Senior Vice President, Oncology, Flatiron Health2
EDWARD J. BENZ, JR., President and Chief Executive Officer Emeritus, Dana-Farber Cancer Institute; Richard and Susan Smith Distinguished Professor of Medicine, Genetics and Pediatrics, Harvard Medical School
GIDEON BLUMENTHAL, Deputy Office Director (Acting), Office of Hematology and Oncology Products, Center for Drug Evaluation and Research; Associate Director, Precision Oncology, Oncology Center of Excellence, Food and Drug Administration
CHRIS BOSHOFF, Head and Senior Vice President, Immuno-Oncology, Early Development, and Translational Oncology, Pfizer Inc.
OTIS W. BRAWLEY, Bloomberg Distinguished Professor, Department of Epidemiology, Bloomberg School of Public Health, Department of Oncology, School of Medicine, Johns Hopkins University
CHRISTOPHER R. COGLE, Professor of Medicine, Pierre Chagnon Professor of Stem Cell Biology and Bone Marrow Transplant, University of Florida; Scholar in Clinical Research, Leukemia & Lymphoma Society
LISA KENNEDY SHELDON, Chief Clinical Officer, Oncology Nursing Society
LEE M. KRUG, Program Leader, NKTR-214, Oncology Clinical Development, Bristol-Myers Squibb
___________________
1 The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
2 In February 2019, Dr. Abernethy became Principal Deputy Commissioner of Food and Drugs at the Food and Drug Administration (FDA). The views expressed in this proceedings do not necessarily represent the official views or policies of FDA.
MARTIN J. MURPHY, Chief Executive Officer, CEO Roundtable on Cancer
DAVID REESE, Senior Vice President, Translational Sciences, Amgen Inc.
RICHARD L. SCHILSKY, Senior Vice President and Chief Medical Officer, American Society of Clinical Oncology
DAN THEODORESCU, Director, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center
GEORGE J. WEINER, C.E. Block Chair of Cancer Research, Professor of Internal Medicine, and Director, Holden Comprehensive Cancer Center, The University of Iowa
Project Staff
ERIN BALOGH, Senior Program Officer
RUTH COOPER, Senior Program Assistant (from October 2018)
NICOLE KASTELIC, Summer Intern (June–July 2018)
NATALIE LUBIN, Senior Program Assistant (until October 2018)
CYNDI TRANG, Research Assistant (until September 2018)
EMILY ZEVON, Associate Program Officer (from October 2018)
SHARYL J. NASS, Forum Director and Director, Board on Health Care Services
NATIONAL CANCER POLICY FORUM1
EDWARD J. BENZ, JR. (Chair), President and Chief Executive Officer Emeritus, Dana-Farber Cancer Institute; Richard and Susan Smith Distinguished Professor of Medicine, Genetics and Pediatrics, Harvard Medical School
LUCILE L. ADAMS-CAMPBELL, Professor of Oncology, Associate Director for Minority Health and Health Disparities Research, and Senior Assistant Dean, Community Outreach and Engagement, Georgetown University Lombardi Cancer Center
GARNET L. ANDERSON, Senior Vice President and Director, Public Health Sciences Division, Fred Hutchinson Cancer Research Center; Affiliate Professor, Department of Biostatistics, University of Washington
KENNETH ANDERSON, Kraft Family Professor of Medicine, American Cancer Society Clinical Research Director, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute
WILLIAM L. BAILEY, Vice President, Medical & Scientific Affairs Research & Development, Helsinn Therapeutics (U.S.), Inc.
KAREN BASEN-ENGQUIST, Annie Laurie Howard Research Distinguished Professor, Professor of Behavioral Science, and Director, Center for Energy Balance in Cancer Prevention and Survivorship, The University of Texas MD Anderson Cancer Center
CHRIS BOSHOFF, Chief Development Officer, Oncology, Global Product Development, Pfizer Inc.
CATHY J. BRADLEY, Associate Dean for Research, Colorado School of Public Health, Professor and Deputy Director, University of Colorado Cancer Center
OTIS W. BRAWLEY, Bloomberg Distinguished Professor, Department of Epidemiology, Bloomberg School of Public Health, Department of Oncology, School of Medicine, Johns Hopkins University
ROBERT W. CARLSON, Chief Executive Officer, National Comprehensive Cancer Network
___________________
1 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
NANCY E. DAVIDSON, President and Executive Director, Seattle Cancer Care Alliance; Senior Vice President, Director, and Full Member, Clinical Research Division, Fred Hutchinson Cancer Research Center; Head, Department of Medicine, Division of Medical Oncology, University of Washington
GEORGE D. DEMETRI, Professor of Medicine and Director, Ludwig Center, Harvard Medical School; Senior Vice President for Experimental Therapeutics, Dana-Farber Cancer Institute; Associate Director for Clinical Sciences, Dana-Farber/Harvard Cancer Center
JAMES H. DOROSHOW, Deputy Director for Clinical and Translational Research, National Cancer Institute
NICOLE F. DOWLING, Associate Director for Science, Division of Cancer Prevention and Control, Centers for Disease Control and Prevention
SCOT W. EBBINGHAUS, Vice President and Therapeutic Area Head, Oncology Clinical Research, Merck Research Laboratories
KOJO S. J. ELENITOBA-JOHNSON, Professor, Perelman School of Medicine; Director, Center for Personalized Diagnostics and Division of Precision and Computational Diagnostics, University of Pennsylvania
AWNY FARAJALLAH, Vice President, Head, US Medical Oncology, Bristol-Myers Squibb
STANTON L. GERSON, Director, Case Comprehensive Cancer Center; Professor of Hematological Oncology, Case Western Reserve University; Director, University Hospitals Seidman Cancer Center
LORI HOFFMAN HŌGG, Veterans Health Administration National Oncology Clinical Advisor and Program Manager, Prevention Policy, Department of Veterans Affairs
LINDA HOUSE, President, Cancer Support Community
HEDVIG HRICAK, Chair, Department of Radiology, Memorial Sloan Kettering Cancer Center
ROY A. JENSEN, President, Association of American Cancer Institutes; Director, The University of Kansas Cancer Center; William R. Jewell, M.D. Distinguished Masonic Professor, Kansas Masonic Cancer Research Institute
LISA KENNEDY SHELDON, Chief Clinical Officer, Oncology Nursing Society
SAMIR N. KHLEIF, Director, Loop Immuno-Oncology Lab, Biomedical Scholar, and Professor of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
RONALD M. KLINE, Medical Officer, Patient Care Models Group, Center for Medicare & Medicaid Innovation, Centers for Medicare & Medicaid Services
MICHELLE M. LE BEAU, Arthur and Marian Edelstein Professor of Medicine and Director, The University of Chicago Comprehensive Cancer Center
MIA LEVY, Director, Rush University Cancer Center; Associate Professor of Medicine, Division of Hematology and Oncology; and Systems Vice President, Cancer Services, Rush University Medical Center
J. LEONARD LICHTENFELD, Interim Chief Medical Officer, American Cancer Society
NEAL J. MEROPOL, Vice President, Research Oncology, Flatiron Health
MARTIN J. MURPHY, Chief Executive Officer, CEO Roundtable on Cancer
RANDALL A. OYER, Medical Director, Oncology, Ann B. Barshinger Cancer Institute, Lancaster General Penn Medicine
RICHARD PAZDUR, Director, Oncology Center of Excellence; Acting Director, Office of Hematology and Oncology Products, Food and Drug Administration
RICHARD L. SCHILSKY, Senior Vice President and Chief Medical Officer, American Society of Clinical Oncology
DEBORAH SCHRAG, Chief, Division of Population Sciences, Professor of Medicine, Department of Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute
LAWRENCE N. SHULMAN, Professor of Medicine, Deputy Director for Clinical Services, and Director, Center for Global Cancer Medicine, Abramson Cancer Center, University of Pennsylvania
DAN THEODORESCU, Director, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center
VERENA VOELTER, Head, United States Oncology Clinical Development & Medical Affairs, Novartis Pharmaceuticals Corporation
GEORGE J. WEINER, C. E. Block Chair of Cancer Research, Professor of Internal Medicine, and Director, Holden Comprehensive Cancer Center, The University of Iowa
ROBERT A. WINN, Associate Vice Chancellor, Community Based-Practice; Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Illinois at Chicago; Director, University of Illinois Health Cancer Center
National Cancer Policy Forum Staff
ERIN BALOGH, Senior Program Officer
RUTH COOPER, Senior Program Assistant
ANNALEE GONZALES, Administrative Assistant
NATALIE LUBIN, Research Assistant
MICAH WINOGRAD, Financial Officer
EMILY ZEVON, Associate Program Officer
SHARYL J. NASS, Forum Director and Director, Board on Health Care Services
Reviewers
This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process.
We thank the following individuals for their review of this proceedings:
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by ELI Y. ADASHI, Brown University. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies.
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Acknowledgments
Support from the many annual sponsors of the National Academies of Sciences, Engineering, and Medicine’s National Cancer Policy Forum is crucial to the work of the forum. Federal sponsors include the Centers for Disease Control and Prevention and the National Cancer Institute/National Institutes of Health. Non-federal sponsors include the American Association for Cancer Research, American Cancer Society, American College of Radiology, American Society of Clinical Oncology, Association of American Cancer Institutes, Association of Community Cancer Centers, Bristol-Myers Squibb, Cancer Support Community, CEO Roundtable on Cancer, Flatiron Health, Helsinn Therapeutics (U.S.), Inc., LIVESTRONG Foundation, Merck, National Comprehensive Cancer Network, Novartis Oncology, Oncology Nursing Society, and Pfizer Inc.
The forum wishes to express its gratitude to the expert speakers whose presentations helped further the dialogue and advance progress in the clinical development of combination cancer therapies with immune checkpoint inhibitors. The forum also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda.
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Contents
THE LANDSCAPE FOR IMMUNE CHECKPOINT INHIBITOR THERAPY
The Impact of Immune Checkpoint Inhibitors on Cancer Treatment
Understanding Resistance to Immune Checkpoint Inhibitor Therapy
STRATEGIES FOR COMBINATIONS WITH PD-1/PD-L1 INHIBITORS
Demonstration of Independent Action Versus Mechanism-Based Preclinical Data
Sequencing Administration of Combination Strategies
BIOMARKERS IN DEVELOPMENT OR IN USE FOR IMMUNE CHECKPOINT INHIBITOR THERAPIES
Challenges with Biomarker Development
Biomarker Development for Single-Agent Versus Combination Therapy
Defining Thresholds for Biomarker Results
Biomarkers for Site-Agnostic Indications
Availability of Biospecimens for Biomarker Discovery and Development
CLINICAL TRIAL DESIGN STRATEGIES FOR COMBINATION IMMUNOTHERAPY
Patient-Centered Trial Outcomes
Dosing, Sequencing Administration, and Treatment Duration for Combinations
Trial Designs to Promote Efficiency
Master Protocols for Combination Trials
Shared or External Control Arms
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Acronyms and Abbreviations
ASCO | American Society of Clinical Oncology |
BLA | Biologics License Application |
cHL | classical Hodgkin’s lymphoma |
CSC | Cancer Support Community |
DDR2 | discoidin domain receptor 2 |
FDA | Food and Drug Administration |
IHC | immunohistochemistry |
IND | Investigational New Drug |
INFORMED | Information Exchange and Data Transformation |
Lung-MAP | Lung Cancer Master Protocol |
MSI-H | high microsatellite instability |
NCCN | National Comprehensive Cancer Network |
NCI | National Cancer Institute |
NCI-MATCH | National Cancer Institute Molecular Analysis for Therapy Choice |
NCTN | National Clinical Trials Network |
NDA | New Drug Application |
NSCLC | non-small cell lung cancer |
PCR | polymerase chain reaction |
PET | positron emission tomography |
RCC | renal cell carcinoma |
RECIST | Response Evaluation Criteria In Solid Tumors |
SCLC | small cell lung cancer |
SITC | Society for Immunotherapy of Cancer |
TMB | tumor mutational burden |
VEGFR | vascular endothelial growth factor receptor |