Adverse reactions of immune checkpoint inhibitors combined with angiogenesis inhibitors: A pharmacovigilance analysis of drug–drug interactions

The combination of immune checkpoint inhibitors (ICIs) and angiogenesis inhibitors (AGIs) is widely used in cancer treatment; however, drug-drug reactions (DDIs) remain unknown. We aimed to identify interaction signals for the concomitant use of ICIs and AGIs. Data were obtained from the US FDA Adverse Event Reporting System (FAERS) from January 1, 2015, to December 31, 2023. Disproportionality analysis was used for data mining by calculating the reporting odds ratio (ROR) and 95% confidence interval (95% CI). Adjusted RORs were analysed using logistic regression analysis, considering age, sex and reporting year. Further confirmation was assessed via additive and multiplicative models. We identified 75,936 reports on ICIs combined with AGIs. Significant interaction signals were observed for hepatobiliary disorders (RORcrude: 5.25, 95% CI: 5.07-5.44, RORadj: 5.01, 95% CI: 4.82-5.22, additive models: 0.2323), investigations (RORcrude: 1.66, 95% CI: 1.62-1.70, RORadj: 1.63, 95% CI: 1.58-1.67, additive models: 0.2187, multiplicative models: 1.1265), renal and urinary disorders (RORcrude: 1.87, 95% CI: 1.80-1.95, RORadj: 1.72, 95% CI: 1.64-1.79, additive models: 0.3239, multiplicative models: 1.1799) and vascular disorders (RORcrude: 1.94, 95% CI: 1.87-2.02, RORadj: 1.87, 95% CI: 1.80-1.95, additive models: 0.5823, multiplicative models: 1.5676). Subset data analysis showed positive interaction signals for PDL-1/CTLA-4 inhibitors + AGI in hepatobiliary disorders, PD-1 inhibitors + AGI in investigations, or PD-1/PDL-1 inhibitors + AGI in renal and urinary/ vascular disorders. Based on FAERS data, four systemic disorders were identified as having DDIs related to the combined use of ICIs and AGIs. Pre-clinical trials are required to explore the mechanisms underlying these interactions.