2019 SCIENTIFIC REPORT Regulatory Advancements for Patients REAL-WORLD EVIDENCE: CHARACTERIZING THE USE AND POWER OF REAL-WORLD DATA 11 An Exploratory Analysis of Real-World End Points for Assessing Outcomes Among Immunotherapy-Treated Patients with Advanced Non-Small-Cell Lung Cancer 26 Validating Real-World Endpoints for an Evolving Regulatory Landscape PATIENT-FOCUSED DRUG DEVELOPMENT: ALIGNING PATIENT NEEDS WITH ONCOLOGY DRUG DEVELOPMENT 45 The Promise of Immuno-oncology: Implications for Defining the Value of Cancer Treatment 56 How Oncologists Perceive the Availability and Quality of Information Generated from Patient-Reported Outcomes (PROs) 64 Improving Attribution of Adverse Events in Oncology Clinical Trials COMPLEX BIOMARKERS: INFORMING DEVELOPMENT AND STANDARDS FOR DIAGNOSTIC TESTS 73 Tumor Mutational Burden Standardization Initiatives: Recommendations for Consistent Tumor Mutational Burden Assessment in Clinical Samples to Guide Immunotherapy Treatment Decisions 84 Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology from Technical Artifacts 97 TMB standardization by alignment to reference standards: Phase II of the Friends of Cancer Research TMB Harmonization Project. 99 Data Generation (and Review Considerations) for Use of a Companion Diagnostic for a Group of Oncology Therapeutic Products OPTIMAL DRUG DEVELOPMENT: ADDRESSING EMERGING OPPORTUNITIES 117 Immuno-Oncology Combination Drug Development for Patients with Disease Progression After Initial Anti-PD-(L)1 Therapy 133 Characterizing the Use of External Controls for Augmenting Randomized Control Arms and Confirming Benefit. 170 Non-small cell lung cancer (NSCLC) case study examining whether results in a randomized control arm are replicated by a synthetic control arm (SCA). 171 Opportunities for Combination Drug Development: Data Sources and Innovative Strategies to Assess Contribution of Components 186 Designing the Future of Cell Therapies INTRODUCTION For more than two decades, Friends of Cancer Research (Friends) has been instrumental in the creation and implementation of policies ensuring patients receive the best treatments in the fastest and safest way possible. Friends has been successful due to convening the right people at the right time and putting forth revolutionary, yet realistic ideas. Through collaborative and meaningful initiatives, Friends’ programs foster solutions to issues encountered by researchers and regulators as they strive to translate discoveries into safe and effective new treatments. Each year, Friends convenes working groups, hosts scientific conferences, and conducts research on a range of topics to inform regulatory policy, oncology drug development, and clinical practice. These venues are vital to facilitating the creative partnerships and dialogue that ultimately yield many whitepapers, scientific abstracts, and peer-reviewed manuscripts led by Friends that infuse innovative ideas and strategies into the collective science and regulatory landscape. In 2019, we expanded our research portfolio with several large scale pilot projects that are represented in this book. These pilot projects are designed to expand our science un- derstanding as well as inform policy. The 2019 Scientific Report represents Friends’ ongoing mission to drive collaboration among partners from every healthcare sector to power advances in science, policy, and regulation that speed life-saving treatments to patients. This journal is intended to be a resource for those in the drug development and regulatory space and informative for those interested in science and regulatory issues in oncology. The scientific report contains the full text of the Friends 2019 publications and whitepapers, which focused on several key themes: 1 Real-world evidence: Characterizing the use and power of real-world data 2 Patient-focused drug development: Aligning patient needs with oncology drug development 3 Complex biomarkers: Informing development and standards for diagnostic tests 4 Optimal drug development: Addressing emerging opportunities REAL-WORLD EVIDENCE: CHARACTERIZING THE USE AND POWER OF REAL-WORLD DATA Only 35% of cancer Real-world evidence (RWE) is generated from data collected trials include sicker, from patients receiving routine care. This information is recorded in the patient’s medical record, medical billing and higher risk patients. claims documents, and patient registries. Although the type of Over 60% of RWE gathered varies depending on the source, this data can help researchers gather insights into patient characteristics, cancers occur in treatment patterns, and outcomes of patients treated outside people 65 and older of clinical trials. but only 22% Randomized controlled trials (RCTs) are the gold standard for of clinical trial demonstrating evidence of safety and efficacy in the development of new therapies. While this will always be the case, there may be patients are over 65. opportunities for real-world data (RWD) to provide important sup- plemental information to inform the use of therapies. For example, clinical trials use eligibility criteria to select for specific patient pop- ulations that help maximize the ability to measure treatment effica- cy. While this patient selection can improve the statistical quality of the clinical data, it may not reflect the broader patient population Specific patient that will likely receive the drug in clinical practice. The use of RWD can help assess the use and effectiveness of a therapy in “real- populations world” patients. and characteristics Increasingly, the healthcare community is grasping the capabilities can be collected of RWE and its potential role in facilitating drug development. Congress has also recognized this potential and has included man- from several RWD dates in the 21st Century Cures Act and the Prescription Drug User sources in a similar Fee of 2017 for FDA to explore the use of RWE in prescription drug regulation. The FDA’s Framework for Evaluating RWD/RWE for Use manner to produce in Regulatory Decisions will “evaluate the potential use of RWD to similar results— generate RWE of product effectiveness to help support approval of new indications for drugs… or to help to support or satisfy post this will increase approval study requirements.” confidence in results In response to this growing need, the Friends RWE Pilots 1.0 and from studies with 2.0 were first of their kind efforts that brought together a dozen real-world data. key stakeholders to study RWE for use in drug development and evalutation over time. The collective results of this work are help- ing inform the use of RWD/RWE. 4 friends of cancer research • Specific patient populations and characteristics can be collected from several RWD sources in a similar manner to produce similar RWE PARTNERS results—this will increase confidence in results from studies with real-world data Aetion • Some real-world endpoints correlate to endpoints commonly ASCO CancerLinQ & Concerto used in clinical trials—this suggests that real-world endpoints HealthAI Cancer Research Network could be used as proxies for clinical trial endpoints in real-world COTA data and warrants further investigation FDA Flatiron Health IQVIA™ PUBLICATIONS RELATED TO THIS TOPIC Mayo Clinic • An Exploratory Analysis of Real-World End Points for Assessing Outcomes McKesson Among Immunotherapy-Treated Patients with Advanced Non-Small-Cell Lung NCI SEER-Medicare Linked Cancer (Page 11) Database • Validating Real-World Endpoints for an Evolving Regulatory Landscape OptumLabs® (Page 26) PCORnet Syapse Tempus PATIENT-FOCUSED DRUG DEVELOPMENT: ALIGNING PATIENT NEEDS WITH ONCOLOGY DRUG DEVELOPMENT Patient engagement in research and clinical trials has evolved Some real-world over time. Patients are being actively sought as partners to help design, implement, and disseminate clinical trial findings. It is endpoints correlate estimated that less than 5% of adult cancer patients enroll in a clin- to endpoints ical trial despite many indicating a desire to participate. Engaging patients early and often throughout the entire research and drug commonly used in development process can help inform appropriate trial designs, clinical trials— answer patient relevant questions, and encourage participation. but are difficult to Designing clinical trials that answer questions important to patients measure. This and maximize the information gained are critical. Listening to patients and capturing their experience can help better characterize suggests that the patient’s health, quality of life, and functional status while on a real-world endpoints cancer treatment. Patient reported outcome (PRO) tools are helping better define the value of a treatment and enabling more informed could be used as patient decision-making. proxies for clinical Throughout 2019, Friends helped advance the understanding of endpoints in PRO use in treatment decision making as well as identify key real-world data. recommendations to improve safety monitoring in trials. friends of cancer research 5 • Improved characterization of treatment toxicities and how patients feel and function while on treatment can enable a more Improved character- thorough assessment of a therapy’s benefit and can help prioritize future clinical trials ization of treatment • Mechanisms for more rapid sharing of adverse events toxicities and how information during trials and improved consistency in reporting can help more precisely describe potential patients feel