Delayed immune-related adverse events associated with immune checkpoint inhibitors: A pharmacovigilance analysis of the FAERS database.

Abstract

e24093 Background: Treatment with immune checkpoint inhibitors (ICIs) has achieved extraordinary response rates and revolutionized the systematic management of mange malignancies. ICIs can lead to immune-related adverse events (irAEs) affecting different organ that occur quiet early, mostly within the first year of immunotherapy, but data on the spectrum and severity outcomes of delayed irAEs in long-term responders to ICIs are extremely lacking. Methods: We obtained delayed irAEs (onset > 12 months after commencement of ICIs) reports from the FDA Adverse Event Reporting System (FAERS) database between January 1, 2016 and June 30, 2024, to characterize the reporting trends, clinical features, risk factors, and severity outcomes. We performed a disproportionality analysis to calculate reporting odds ratios (RORs) that were used to evaluate correlations between ICIs and irAEs. Results: Reports of delayed irAEs accounted for 6.8% of all irAEs reports in the full FAERS database. The most commonly reported delayed irAEs were skin, respiratory, endocrine, gastrointestinal, and hepatic toxicities. Cases with indications for non-small cell lung cancer, melanoma, kidney cancer, gastroesophageal cancer, and liver cancer accounted for the majority. The majority of delayed irAEs (56.4%) occurred within the first 12–18 months after ICI initiation, 31.5% of which happened during the administration of ICIs. Non-anti-PD-1 ICI treatment, Eastern Asia country group, concomitant targeted therapy or chemotherapy were identified as risk factors for developing delayed irAEs. Furthermore, delayed irAEs was associated with a decreased fatality (OR = 0.72, 95% CI [0.62-0.83], P < 0.0001) compared to early irAEs. Delayed hepatic (OR = 1.78, 95% CI [1.20-2.64], P < 0.0001) and respiratory irAEs (OR = 2.34, 95% CI [1.68-3.28], P < 0.0001) tended to be more commonly occurred in the fatal group. The time to onset of fatal delayed irAEs was comparable to that of non-fatal delayed irAEs (518 vs 516 days, P = 0.967). Conclusions: This comprehensive pharmacovigilance study defines the spectrum, clinical characteristics, and severity outcomes of delayed irAE reporting. Multiple risk factors and clinical peculiarities for overall or fatal delayed irAE have been identified as signals to guide clinical practice and future research. However, the present findings need to be further confirmed in a large-scale prospective study.