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Suggested Citation:"Front Matter." 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: 10.17226/25405.
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Suggested Citation:"Front Matter." 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: 10.17226/25405.
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Suggested Citation:"Front Matter." 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: 10.17226/25405.
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Suggested Citation:"Front Matter." 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: 10.17226/25405.
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Suggested Citation:"Front Matter." 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: 10.17226/25405.
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Suggested Citation:"Front Matter." 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: 10.17226/25405.
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Suggested Citation:"Front Matter." 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: 10.17226/25405.
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Advancing Progress in the Development of Combination Cancer Therapies with Immune Checkpoint Inhibitors Erin Balogh and Sharyl J. Nass, Rapporteurs National Cancer Policy Forum Board on Health Care Services Health and Medicine Division PREPUBLICATION COPY—Uncorrected Proofs

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 Ameri- can 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 Thera- peutics (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-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X 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 check- point inhibitors: Proceedings of a workshop. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25405. PREPUBLICATION COPY—Uncorrected Proofs

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technol- ogy. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. C. D. Mote, Jr., is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY—Uncorrected Proofs

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The state- ments and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National A ­ cademies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY—Uncorrected Proofs

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 speak- ers. 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. v PREPUBLICATION COPY—Uncorrected Proofs

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 Institute, 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 vi PREPUBLICATION COPY—Uncorrected Proofs

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 round- tables do not issue, review, or approve individual documents. The responsibility for the pub- lished Proceedings of a Workshop rests with the workshop rapporteurs and the institution. vii PREPUBLICATION COPY—Uncorrected Proofs

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 viii PREPUBLICATION COPY—Uncorrected Proofs

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 Institute, Cedars-Sinai Medical Center VERENA VOELTER, Head, United States Oncology Clinical Development & Medical Affairs, Novartis Pharmaceuticals Corporation ix PREPUBLICATION COPY—Uncorrected Proofs

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 x PREPUBLICATION COPY—Uncorrected Proofs

Reviewers This Proceedings of a Workshop was reviewed in draft form by indi- viduals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical com- ments 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: ELIZABETH JAFFEE, Johns Hopkins University ALEXANDRA SNYDER, Merck Although the reviewers listed above provided many constructive com- ments 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 consid- ered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies. xi PREPUBLICATION COPY—Uncorrected Proofs

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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 ­ merican A Association for Cancer Research, American Cancer Society, Ameri- can College of Radiology, American Society of Clinical Oncology, Asso- ciation of American Cancer Institutes, Bristol-Myers Squibb, Cancer Sup- port 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 clini- cal 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. xiii PREPUBLICATION COPY—Uncorrected Proofs

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Contents ACRONYMS AND ABBREVIATIONS xix PROCEEDINGS OF A WORKSHOP 1 WORKSHOP OVERVIEW 1 THE LANDSCAPE FOR IMMUNE CHECKPOINT INHIBITOR THERAPY  3 The Impact of Immune Checkpoint Inhibitors on Cancer Treatment, 7 Understanding Resistance to Immune Checkpoint Inhibitor Therapy, 10 STRATEGIES FOR COMBINATIONS WITH PD-1/PD-L1 INHIBITORS  11 Demonstration of Independent Action Versus Mechanism-Based Preclinical Data, 12 Sequencing Administration of Combination Strategies, 15 Prioritization and Redundancy, 17 Regulatory Considerations, 19 BIOMARKERS IN DEVELOPMENT OR IN USE FOR IMMUNE CHECKPOINT INHIBITOR THERAPIES 23 Types of Biomarker Tests, 23 Immunohistochemistry Testing, 24 Genomic Testing, 25 xv PREPUBLICATION COPY—Uncorrected Proofs

xvi CONTENTS Expression Signatures, 27 Multiplex Fluorescence, 28 Circulating Tumor Markers, 29 The Microbiome, 30 Challenges with Biomarker Development, 31 Biomarker Development for Single-Agent Versus Combination Therapy, 31 Defining Thresholds for Biomarker Results, 31 Biomarkers for Site-Agnostic Indications, 32 Availability of Biospecimens for Biomarker Discovery and Development, 34 CLINICAL TRIAL DESIGN STRATEGIES FOR COMBINATION IMMUNOTHERAPY35 Patient-Centered Trial Outcomes, 36 Endpoints for Clinical Trials, 37 Dosing, Sequencing Administration, and Treatment Duration for Combinations, 38 Trial Designs to Promote Efficiency, 38 Master Protocols for Combination Trials, 38 Shared or External Control Arms, 41 REAL-WORLD DATA 43 Collaboration and Real-World Data Sharing, 45 WRAP-UP48 REFERENCES49 APPENDIX A: Statement of Task 61 APPENDIX B: Workshop Agenda 63 PREPUBLICATION COPY—Uncorrected Proofs

Boxes and Figures BOXES 1 Suggestions from Individual Workshop Participants to Improve the Development of Combination Cancer Therapies with Immune Checkpoint Inhibitors, 4 2 PD-1/PD-L1 Inhibitors in Combination with VEGFR Inhibitors, 16 3 Examples of Recent Cross-Labeling Approvals, 21 4 Examples of Master Protocol Trial Designs, 39 FIGURES 1 (a) The clinical trial landscape for PD-1/PD-L1 immune checkpoint inhibitor drugs. (b) Illustration of the 1,332 trials evaluating PD-1/PD-L1 drugs in combination with agents against the top 38 targets, 6 2 In a cohort of patients with lung cancer, PD-1/PD-L1 checkpoint inhibitor therapy was not observed in 2014, 8 3 Process to link clinical data from Flatiron Health to genomic data from Foundation Medicine, 47 xvii PREPUBLICATION COPY—Uncorrected Proofs

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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 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 xix PREPUBLICATION COPY—Uncorrected Proofs

xx ACRONYMS AND ABBREVIATIONS 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 SITC Society for Immunotherapy of Cancer TMB tumor mutational burden VEGFR vascular endothelial growth factor receptor PREPUBLICATION COPY—Uncorrected Proofs

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In recent years, significant progress has been made in the clinical development and use of various types of cancer immunotherapy, all of which rely on the immune system to fight cancer. The majority of new cancer drug applications submitted to the Food and Drug Administration (FDA) are for immunotherapies or combinations involving immunotherapies. One type of immunotherapy is an immune checkpoint inhibitor. Cells in the human body have proteins that regulate the immune system response to foreign invaders (e.g., cancer cells, microorganisms). However, cancer cells can coopt these “checkpoint” proteins and thwart the immune system’s ability to recognize and attack cancer cells. To help promote an immune response to cancer, researchers have developed immune checkpoint inhibitors that enable T-cells to recognize cancer cells as foreign and to prevent deactivation of an immune system response.

To examine the challenges and opportunities to develop combination cancer therapies that include immune checkpoint inhibitors, the National Cancer Policy Forum held a workshop on July 16–17, 2018, in Washington, DC. This workshop convened stakeholders with a broad range of expertise, including cancer researchers, clinicians, patient advocates, and representatives from industry, academia, and government. This publication summarizes the presentations and discussions from the workshop.

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