Immune Checkpoint Blockade Modifies Drug-Associated Toxicity Across Phenotypes and Time
- 1Vanderbilt University Medical Center
Abstract
ImportanceImmune checkpoint inhibitors (ICIs) produce diverse immune toxicities, but whether checkpoint blockade also modifies associations between other drugs and adverse events is poorly understood.
ObjectiveTo define ICI-associated toxicity organization and determine whether drug-associated adverse events and onset vary with ICI exposure and checkpoint pathway.
Design and SettingCross-sectional analysis of deduplicated FAERS reports from 2016 through 2025; analyses performed in 2026.
ParticipantsAmong 13,701,106 deduplicated reports, 2,365,269 were cancer associated and 256,940 contained an ICI. Median age among cancer reports with observed age was 66 years (IQR, 56-75 years); 1,031,999 (43.6%) were female and 1,003,154 (42.4%) were male.
ExposuresICI exposure in any reported drug role, individual primary-suspect drugs, and checkpoint-pathway exposure.
Main Outcomes and MeasuresReporting odds ratios (ORs), cross-organ adverse-event communities, adjusted primary-suspect drug x 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), and vomiting (VOM), and accelerated failure-time model time ratios for documented onset.
ResultsOf 3001 eligible Preferred Terms in cancer-associated reports, 2091 differed at a false discovery rate (FDR) less than .05. Four cross-organ toxicity communities were identified. Of 138 eligible drug-phenotype pairs, 65 had FDR-significant interactions, including moxifloxacin-SJS/TEN amplification (interaction OR, 101.72; 95% CI, 39.11-264.55), enfortumab vedotin-SJS/TEN attenuation (interaction OR, 0.17; 95% CI, 0.13-0.23), and omeprazole-interstitial nephritis amplification (interaction OR, 10.35; 95% CI, 7.62-14.05). Among 60,324 reports contributing to temporal analyses, ICI exposure was associated with longer adjusted documented time to onset for 5 of 6 phenotypes (time ratios, 1.37-1.59) but not AGEP (time ratio, 0.99; 95% CI, 0.67-1.46). Temporal associations also differed across checkpoint pathways.
Conclusions and RelevanceICIs were associated with a structured cross-organ toxicity landscape, phenotype-specific modification of drug-associated adverse events, 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 PointsO_ST_ABSQuestionC_ST_ABSWhat is the structure of toxicity associated with immune checkpoint blockade?
FindingsIn this cross-sectional study of 13,701,106 deduplicated adverse-event reports, ICI exposure defined a broad toxicity landscape containing 4 cross-organ communities. Sixty-five drug x ICI interactions were identified across 5 immune-mediated phenotypes and a control (vomiting), and documented time to onset differed by phenotype and checkpoint pathway.
MeaningCheckpoint blockade may create an altered immune state in which the phenotype and timing of drug-associated toxicity depend on both the accompanying drug and the checkpoint pathway inhibited.
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BibTeX
@misc{mukherjee2026immune,
title = {{Immune Checkpoint Blockade Modifies Drug-Associated Toxicity Across Phenotypes and Time}},
author = {E. M. Mukherjee and A. Asiaee and D. Park and M. S. Krantz and C. A. Stone and M. Martin-Pozo and E. J. Phillips},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.26361880},
url = {https://www.medrxiv.org/content/10.64898/2026.08.31.26361880v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Immune Checkpoint Blockade Modifies Drug-Associated Toxicity Across Phenotypes and Time
AU - E. M. Mukherjee
AU - A. Asiaee
AU - D. Park
AU - M. S. Krantz
AU - C. A. Stone
AU - M. Martin-Pozo
AU - E. J. Phillips
PY - 2026
DA - 2026/08/31
PB - medRxiv
DO - 10.64898/2026.08.31.26361880
UR - https://www.medrxiv.org/content/10.64898/2026.08.31.26361880v1
AB - ImportanceImmune checkpoint inhibitors (ICIs) produce diverse immune toxicities, but whether checkpoint blockade also modifies associations between other drugs and adverse events is poorly understood. ObjectiveTo define ICI-associated toxicity organization and determine whether drug-associated adverse events and onset vary with ICI exposure and checkpoint pathway. Design and SettingCross-sectional analysis of deduplicated FAERS reports from 2016 through 2025; analyses performed in 2026. ParticipantsAmong 13,701,106 deduplicated reports, 2,365,269 were cancer associated and 256,940 contained an ICI. Median age among cancer reports with observed age was 66 years (IQR, 56-75 years); 1,031,999 (43.6%) were female and 1,003,154 (42.4%) were male. ExposuresICI exposure in any reported drug role, individual primary-suspect drugs, and checkpoint-pathway exposure. Main Outcomes and MeasuresReporting odds ratios (ORs), cross-organ adverse-event communities, adjusted primary-suspect drug x 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), and vomiting (VOM), and accelerated failure-time model time ratios for documented onset. ResultsOf 3001 eligible Preferred Terms in cancer-associated reports, 2091 differed at a false discovery rate (FDR) less than .05. Four cross-organ toxicity communities were identified. Of 138 eligible drug-phenotype pairs, 65 had FDR-significant interactions, including moxifloxacin-SJS/TEN amplification (interaction OR, 101.72; 95% CI, 39.11-264.55), enfortumab vedotin-SJS/TEN attenuation (interaction OR, 0.17; 95% CI, 0.13-0.23), and omeprazole-interstitial nephritis amplification (interaction OR, 10.35; 95% CI, 7.62-14.05). Among 60,324 reports contributing to temporal analyses, ICI exposure was associated with longer adjusted documented time to onset for 5 of 6 phenotypes (time ratios, 1.37-1.59) but not AGEP (time ratio, 0.99; 95% CI, 0.67-1.46). Temporal associations also differed across checkpoint pathways. Conclusions and RelevanceICIs were associated with a structured cross-organ toxicity landscape, phenotype-specific modification of drug-associated adverse events, 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 PointsO_ST_ABSQuestionC_ST_ABSWhat is the structure of toxicity associated with immune checkpoint blockade? FindingsIn this cross-sectional study of 13,701,106 deduplicated adverse-event reports, ICI exposure defined a broad toxicity landscape containing 4 cross-organ communities. Sixty-five drug x ICI interactions were identified across 5 immune-mediated phenotypes and a control (vomiting), and documented time to onset differed by phenotype and checkpoint pathway. MeaningCheckpoint blockade may create an altered immune state in which the phenotype and timing of drug-associated toxicity depend on both the accompanying drug and the checkpoint pathway inhibited.
ER -