Toxicity surveillance in FDA pivotal registration trials for immune checkpoint inhibitors: Are we missing the mark?

215 Background: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for a multitude of malignancies, leading to prolonged survival and durable responses. Despite this, a significant number of patients will develop immune-related adverse events (irAEs) with significant associated morbidity and mortality. A retrospective study has previously demonstrated that 28% of patients can develop IrAEs from 6 months up to 2 years after starting therapy (1). Surveillance for toxicity is essential for understanding the long-term risk associated with ICIs. We aimed to analyze the reporting timeframes used in clinical trials of immuno-oncology agents leading to FDA approval. Methods: In this retrospective study, we interrogated the HemeOnc knowledgebase to curate a list of all clinical trial publications leading to FDA approval from 2011 to 2024. We manually selected from this list any trial including an immune checkpoint inhibitor either as monotherapy or in combination with another systemic therapy. The adverse event follow-up time was then extrapolated by manually reviewing the trial publication, supplemental materials or the trial protocol depending on where this information was listed. All trials were categorized based on trial initiation dates. Results: We identified 175 clinical trials leading to FDA approvals, with trial initiation dates ranging from 2004 to 2019. 165 trials were included in the analysis with 10 being excluded due to lack of language regarding follow-up. 62% of the trials included were Phase III trials with the remaining 38% Phase I/II trials. The median follow-up days for all trials across this timeframe was 90, with a range of 28 to 135. The median follow-up time for AE monitoring increased by nearly 30%, rising from 70 days in 2004 to 90 days in 2013. Subsequently, we observed a consistent median follow-up time of 90 days (28 to 130 days) from that point onward, with no further increase. Conclusions: To our knowledge this is the first systematic review of IrAE monitoring in clinical trials leading to FDA approval. In our study we revealed that, despite advancements in the understanding of IrAEs and their potential for late presentation, registration trials leading to regulatory approval remain inadequately designed to capture chronic and delayed immunotherapy toxicities. As these therapies advance into earlier stages of disease with longer life expectancy, it will be critical for regulatory bodies, study sponsors, and trial investigators to either redesign clinical trials or for there to be an alternative method that comprehensively captures the incidence and pattern of late-presenting toxicities. 1. Durbin, ASCO 2023.