Abstract 3228: Characterization of multi-organ system involvement of immune-related adverse events after anti-PD-(L)1 monotherapies: A pooled analysis of clinical trial data submitted to FDA

Abstract Background: Treatment with PD-(L)1 blocking antibodies has dramatically improved outcomes across multiple cancer types. Such benefits must be carefully weighed against the risks of serious immune-related adverse events (irAEs) involving various organs, the occurrence patterns of which have not yet been well characterized. This large novel analysis of pooled clinical trial data submitted to FDA aims at uncovering and gaining deeper insights into the multiorgan patterns of irAEs associated with these agents. Methods: This retrospective pooled analysis is based on patient-level, monotherapy, PD-(L)1 blocking antibody data from 18 clinical trials completed between 2019 and 2023, supporting FDA approvals across 7 cancer types. Only FDA authors had access to and analyzed patient level data. Patients with irAEs were identified using each PD-(L)1 development program’s pre-defined definitions based on MedDRA preferred terms. Preferred terms were grouped into 30 irAEs based on the involved organs. IrAEs starting before or within 7 days of the end date of the preceding irAE, were considered co-occurring. Results: Among the 5863 patients, 64% (n=3771) had at least one irAE; the most common irAEs (>10%) were skin reaction (53.5%), colitis/diarrhea (33.2%), hepatitis (23%), hypothyroidism (19.3%), and nephritis/renal dysfunction (11.7%). 50% (n= 1890) had more than one irAE type, with 59.7% experiencing 2, 24.8% experiencing 3, 9.7% experiencing 4, and 5.8% experiencing 5 to a maximum of 8 distinct irAE types, regardless of timing during their treatment course. Median time-to-onset of irAE in patients with a single type of irAE was 45 days while median time-to-onset of first irAE in subjects with more than one type of irAE was 30.5 days. Among the 1743 patients evaluable for co-occurrence analysis, 1285 (73.7%) experienced co-occurring irAEs. The 5 most frequently co-occurring irAEs were: skin reaction and colitis/diarrhea (15.8%); skin reaction and hepatitis (8.2%); skin reaction and hypothyroidism (7.5%); skin reaction and nephritis/renal dysfunction (4.8%); and colitis/diarrhea and hepatitis (4.2%). Conclusions: This is the largest study of patient level clinical trial data evaluating the incidence and occurrence patterns of multi-system irAEs. The study demonstrated that the median time-to-onset of the first irAE was shorter for patients who experienced multi-organ irAEs than in those with single organ irAEs. Notably, half of the patients with an irAE experienced more than one distinct irAE during treatment, the majority of whom demonstrated co-occurrence of irAEs. These findings underscore the importance of vigilant monitoring and comprehensive management strategies to address the interconnected nature of irAEs, aiding providers in understanding, predicting, and managing patients experiencing irAEs. Citation Format: Abhilasha Nair, Matthew J. Hadfield, Yue Huang, Flora Mulkey, Ilynn Bulatao, Marc R. Theoret, Kerry L. Reynolds. Characterization of multi-organ system involvement of immune-related adverse events after anti-PD-(L)1 monotherapies: A pooled analysis of clinical trial data submitted to FDA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3228.