Reporting of immune-related adverse events (irAEs) in US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors.

e14693 Background: Evaluating immune checkpoint inhibitor (ICI) toxicity is complex given the interplay between the host immune system and tumor microenvironment leading to unpredictable timing and severity of irAEs. Monitoring of irAEs is critical as they can cause significant impact on morbidity and quality of life. Thus, we evaluated the consistency and pattern of reporting of irAEs in trials leading to FDA drug approvals. Methods: Using the FDA website, we identified 73 primary articles for ICI FDA approvals over a 10-year period (2011-2021). Data were collected independently by all authors as categorical variables for reporting of any grade and grade 3 or higher toxicity in the trial arm that led to FDA approval for 29 irAEs classified by the National Comprehensive Cancer Network Version 1.2024 guidelines. Our analyses were based on a binary classification of reported versus not reported, including the manuscript text, tables, and supplement, and reporting trends were analyzed based on the study year, phase, primary tumor, and monotherapy versus combination ICI therapy. Results: The majority of approvals were associated with Phase II (N=22) or Phase III (N=39) studies. Approvals included 14 primary tumors and 2 tumor agnostic approvals with the most common tumors including lung (N=22) and skin (N=14). irAE reporting ranged between 0% and 100% with a mean of 40% and a standard deviation of 35. Across the 29 irAEs, 45% were categorized as severely underreported with less than 25% reporting in trials, 17% were classified as underreported in 26-50% of trials, 17% were moderately reported in 51-75% of trials, and 21% were well reported in at least 75% of trials. For example, fatigue, diarrhea, and hypothyroidism were well reported at 100%, 99%, and 93%, respectively, while myocarditis, aseptic meningitis, and giant cell arteritis were severely underreported at 18%, 4%, and 1%, respectively. Additionally, certain systems were more reported than others, including gastrointestinal (100%) and endocrine (97%), while other systems were inconsistently reported such as cardiology (15%) and neurology (48%) (see Table). Conclusions: Our study identified significant inconsistencies in irAE reporting in clinical trials that led to ICI FDA approvals. In particular, rarer irAEs were reported infrequently while more common irAEs were well reported. Unified efforts are needed to standardize the irAE reporting in the primary literature to ensure reliable dissemination of information for timely recognition and treatment in clinical practice. Table: see text