E-Newsletter - November 2019
Alliance Committee Chair Perspectives

Optimizing Clinical Trials to Improve Anti-Cancer Immune Responses: Alliance IMMUNO-Oncology committee

By David Kozono, MD, PhD
Assistant Professor of Radiation Oncology
Senior Physician, Dana-Farber Cancer Institute
Dana-Farber/Brigham and Women’s Cancer Center
Co-Chair, Alliance Immuno-Oncology Committee

Andrew B. Nixon, PhD
Professor of Medicine
Director of the Phase I Biomarker Laboratory
Duke Cancer Institute
Co-Chair, Alliance Immuno-Oncology Committee

Elizabeth Mittendorf, MD, PhD
Rob and Karen Hale Distinguished Chair in Surgical Oncology
Director, Breast Immuno-Oncology Program
Dana-Farber/Brigham and Women’s Cancer Center
Co-Chair, Alliance Immuno-Oncology Committee

This decade has borne witness to the transformative effect of unleashing the body’s own immune system in the fight against cancer, leading to the U.S. Food and Drug Administration (FDA) approval of seven immune checkpoint inhibitors over the past eight years. With an unprecedented number of new agents being investigated in clinical trials, the Alliance Immuno-Oncology (IO) Committee was created in November 2018 with the goal of providing IO expertise to the Alliance for Clinical Trials in Oncology. The committee is comprised of a multi-disciplinary team of clinicians and researchers who seek to optimize IO trials and biomarkers. We serve an advisory role to disease site committees developing study concepts featuring IO agents to provide input as it relates to both trial design and incorporation of immune correlates. We also propose and conduct trials that investigate novel immunotherapeutic agents or strategies, particularly those that cross disease sites or address orphan interactions. Importantly, we are working to develop best-in-class approaches to harmonize biospecimen collection, processing and storage for present and future IO research, and interface with reference labs including the Cancer Immune Monitoring and Analysis Centers (CIMACs).

An example of an IO Committee-lead trial is Alliance Foundation Trials (AFT)-50, EndoMap: A phase IB/II umbrella study of targeted agents with atezolizumab for patients with recurrent or persistent endometrial cancer (PI: Brian Slomovitz, University of Miami). AFT is partnering with Genentech to sponsor this biomarker-driven study that combines immunotherapy (the PD-L1 inhibitor atezolizumab) with targeted agents that are selected based on molecular vulnerabilities predicted by FoundationOne next-generation sequencing. The primary endpoint of the study is overall response rate with each agent in its biomarker-selected arm. The study highlights our committee’s commitment to precision medicine and addressing unmet needs, since women with uterine cancers that do not respond to first-line therapy have suboptimal outcomes with existing approaches.

Immune checkpoint inhibitors have generally been well tolerated by most patients; however, a minority of patients, around 5-10 percent, experience one or more severe immune-related adverse events (irAEs) that can involve diverse organs including the heart, lungs, liver, intestines, kidneys, muscles, skin, brain, and nerves. On occasion, these rare but serious side effects that occur in response to immune activation can be rapidly fatal. Because of the relatively low occurrence and wide variety of irAEs, the establishment of an efficient centralized repository for acquisition and organized distribution of well-annotated biospecimens is vital. Once samples are collected, future translational studies will improve our understanding of the molecular pathogenesis and treatment of these significant toxicities. To this end, we are leading Alliance A151804, Establishment of a national biorepository to advance studies of immune-related adverse events (PI: David Kozono). We are partnering with the other cooperative groups of the National Clinical Trials Network (NCTN) to collect blood and tissue samples from patients at the time they experience these toxicities. This study affords us the unique opportunity to harmonize biospecimen acquisition for impactful IO research.

Along similar lines, clinical trials of immune checkpoint inhibitors have generally excluded patients with pre-existing autoimmune diseases, out of concern that they may be severely worsened. However, it is possible these often highly effective agents may remain safe in these patients. Together with the Alliance Respiratory Committee, we are conducting AFT-42, Safety, activity, and pharmacology of nivolumab in patients with advanced non-small cell lung cancer and pre-existing autoimmune disease (PI: Rebecca Heist, Massachusetts General Hospital). Dr. Nixon is leading the analysis of circulating immune cells obtained from subjects treated with the PD-1 inhibitor. These studies will help us better understand who can be safely treated with these effective therapies.

The Alliance IO Committee is eager to help design and conduct IO studies as safely and effectively as possible, using our expertise in trial design and immune correlative research. We look forward to serving the Alliance as a central IO resource and working with you!


For other articles in this issue of the Alliance E-News newsletter, see below.