Immune Checkpoint Blockade Modifies Drug-Associated Toxicity Across Phenotypes and Time
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Importance
Immune checkpoint inhibitors (ICIs) produce diverse immune toxicities, but whether checkpoint blockade also modifies associations between other drugs and adverse events is poorly understood.
Objective
To define ICI-associated toxicity organization and determine whether drug-associated adverse-event reporting and documented onset vary with ICI exposure and checkpoint pathway.
Design and Setting
Cross-sectional analysis of deduplicated FAERS reports from 2016 through 2025; analyses performed in 2026.
Participants
Among 13,701,106 deduplicated reports, 2,365,278 were associated with cancer and 256,940 contained an ICI. Median age among cancer reports with observed age was 66 years (IQR, 56-75 years).
Exposures
ICI exposure in any reported drug role, individual primary-suspect drugs, and checkpoint-pathway exposure.
Main Outcomes and Measures
Reporting odds ratios (ORs), cross-organ adverse-event communities, adjusted primary-suspect drug × ICI interaction ORs for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), interstitial nephritis, drug-induced liver injury (DILI), anaphylaxis, and vomiting, and accelerated failure-time model time ratios for documented onset.
Results
Of 3001 eligible Preferred Terms in cancer-associated reports, 2091 differed at a false discovery rate (FDR) less than .05, and 4 cross-organ toxicity communities were identified. Of 147 eligible drug-phenotype pairs, 71 had FDR-significant interactions (56 amplification and 15 attenuation), including moxifloxacin–SJS/TEN amplification (interaction OR, 100.51; 95% CI, 38.58-261.84), enfortumab vedotin–SJS/TEN attenuation (interaction OR, 0.17; 95% CI, 0.13-0.23), and omeprazole–interstitial nephritis amplification (interaction OR, 10.33; 95% CI, 7.60-14.04). Among 64,593 reports in the 1-to 365-day temporal cohort, ICI exposure was associated with longer adjusted documented onset for 5 of 7 phenotypes (time ratios, 1.37-1.58); AGEP and anaphylaxis were not significant. Of 19 estimable checkpoint-phenotype coefficients, 10 remained FDR significant.
Conclusions and Relevance
ICIs were associated with a structured cross-organ toxicity landscape, phenotype-specific modification of drug-associated adverse-event reporting, and distinct temporal patterns across checkpoint pathways. These findings support checkpoint blockade as a modifier of drug-associated toxicity and motivate longitudinal and mechanistic validation.
Key Points
Question
How does immune checkpoint inhibitor (ICI) exposure organize and modify drug-associated toxicity across phenotypes and time?
Findings
In this cross-sectional study of 13,701,106 deduplicated adverse-event reports, ICI exposure defined a broad toxicity landscape containing 4 cross-organ communities. Among 147 eligible primary-suspect drug-phenotype pairs across 7 focal phenotypes, 71 drug × ICI interactions were identified; documented time to onset also differed by phenotype and checkpoint pathway.
Meaning
Checkpoint blockade may create an altered treatment state in which the phenotype and timing of drug-associated toxicity depend on both the accompanying drug and the checkpoint pathway inhibited.
