Immune checkpoint blockade reshapes drug-associated toxicity: a pharmacovigilance atlas of drug-ICI interactions
Abstract
Background: Immune checkpoint inhibitors (ICIs) are usually treated as direct culprits in immune-related adverse events, but checkpoint blockade may also reset tolerance to other medications. We tested whether ICI exposure reshapes the organization, drug specificity and timing of reported treatment toxicity.
Methods: We analyzed 13,701,106 deduplicated FDA Adverse Event Reporting System reports from 2016 through 2025. Cancer-restricted reporting associations and cross-organ community detection characterized the ICI-associated toxicity landscape. Adjusted logistic models tested primary-suspect drug x ICI interactions for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, interstitial nephritis, drug-induced liver injury, anaphylaxis and vomiting. Accelerated failure-time models evaluated documented onset according to ICI exposure and checkpoint pathway.
Results: Among 2,365,278 cancer-associated reports, 256,940 contained an ICI. Of 3001 eligible Preferred Terms, 2091 differed between ICI-containing and non-ICI reports at false discovery rate (FDR) <0.05, and four cross-organ toxicity communities emerged. Drug-phenotype associations were reweighted: 71 of 147 eligible pairs had FDR-significant interactions, including 56 amplifications and 15 attenuations. Signals included marked moxifloxacin-SJS/TEN amplification (interaction OR 100.51, 95% CI 38.58 to…
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