Use of Patient-Reported Outcomes in Understanding Symptomatic Adverse Events in Early-Phase Trials of Combination Treatments that Include Immune Checkpoint Inhibitors and Targeted Therapy

PROJECT SUMMARY Breakthroughs in cancer immunotherapy have excited patients and clinicians and have brought optimism back into the oncology community. However, these therapies are often effective for only a percentage of patients, and some patients may even be at risk for serious and sometimes fatal toxicities related to the therapy. Unlike the toxicities induced by standard therapies, immune-related adverse events (irAEs) are just becoming appreci- ated, and side effect profiles for new immunotherapies are often poorly understood. Further contributing to this issue is the increasing use of therapies that combine immune checkpoint inhibitors approved by the US Food and Drug Administration (eg, nivolumab, pembrolizumab) with other checkpoint inhibitors or targeted thera- pies. The unique toxicities of such combination therapies remain largely unknown and need to be tracked, so that their immune-related safety profiles can be characterized and adequately managed. Researchers at The Uni- versity of Texas MD Anderson Cancer Center propose to use patient-reported outcomes (PROs) to capture symptomatic irAEs of combination therapies that include checkpoint inhibitors, taking advantage of the large number of early-phase trials of these therapies already in place in the institution's Department of Investigational Therapeutics, coupled with the expertise in longitudinal symptom assessment in the Department of Symptom Research. The Specific Aims of the study are: (1) to identify, track, and evaluate emerging symptomatic toxic- ities and symptom burden during early-phase clinical trials of treatments that include immune checkpoint in- hibitors in combination with other checkpoint inhibitors or targeted therapies; and (2) to investigate relation- ships between longitudinal patient-reported symptoms and clinical outcomes (eg, development of moderate-to- severe irAEs, time to treatment discontinuation, time to deterioration) in early-phase trials of combination treat- ments that include checkpoint inhibitors, and to investigate whether moderate to severe irAEs are predicted by increases in relevant symptoms prior to the event. The study's clinical impact will be early detection of irAEs associated with combination therapies that include checkpoint inhibitors, to facilitate proactive intervention. Worsening symptoms may presage the emer- gence of their clinical manifestations and allow for appropriate supportive care or for other treatment decisions to be made. PROs are an essential component of cancer drug development, without which clinicians and regu- lators have an incomplete picture of how patients are affected by a new agent. PROs will provide invaluable pa- tient perspectives on the symptomatic effects of combination treatments that include immune checkpoint in- hibitors to multiple stakeholders in early drug development (eg, patients, sponsors, regulators, and payers). This project addresses Recommendation F in the Cancer Moon Shot Blue Ribbon Panel 2016 report, which calls for accelerated research to monitor and manage patient-reported symptoms, not only for improving quality of life, but also for ensuring patient adherence to treatments that will improve therapeutic response. 1