Characteristics and predictors of multi-system immune-related adverse events in a large pan-cancer cohort: A retrospective analysis

Background: Immune checkpoint inhibitors (ICI) can cause complex, multi-system immune-related adverse events (irAEs) that remain poorly described. This study characterizes their frequency and clinical features in a large institutional cohort. Methods: Retrospective cohort of 2,134 metastatic cancer patients treated with ≥1 ICI at Brown University Health (2015-2025). IrAEs were identified and categorized by affected organ system. Multi-system irAEs were defined as ≥2 affected organ systems. Frequency was stratified by sex, cancer type, and treatment regimen. Fisher's exact tests assessed subgroup differences, and multivariable logistic regression identified independent predictors, reported as odds ratios (OR) with p-values. Results: Of 2,134 patients, 24.8% (n=530) developed an irAE; 22.4% (n=119) had multi-system involvement, most commonly with two organs (16.8%, n=89) and less commonly three or more (5.7%, n=30). Common pairings included dermatitis + endocrine (10%, n=12), colitis + dermatitis (9.2%, n=11), and colitis + pneumonitis (5.9%, n=7), with clustering across dermatologic, gastrointestinal, pulmonary, and endocrine systems. Multi-system irAEs differed significantly by treatment regimen (5.1% in monotherapy vs. 4.7% in “ICI + chemo/targeted” vs. 13.9% in dual-ICI; p<0.001), but not by sex (p=0.6). They were more frequent in melanoma/skin cancers (p=0.004) and genitourinary cancers (p=0.03). On multivariable logistic regression adjusting for treatment regimen, melanoma/skin cancers remained significantly associated with higher odds of multi-system irAEs (OR: 1.92, p=0.03), while the association with genitourinary cancers was attenuated (OR: 1.37, p=0.2). Conclusions: Multi-system irAEs comprised nearly one-quarter of all irAEs and were more frequent in melanoma/skin and genitourinary cancers, and among patients who received dual-ICI therapy, supporting the need for closer monitoring in these groups. Uni- and multivariate logistic regression model predicting risk of multi-system vs. single/no irAE Univariate OR (p-value) Multivariate OR (p-value) Treatment regimen ICI monotherapy 0.33 (<0.001) 0.36 (<0.001) 0.37 (<0.001) ICI + chemo/targeted 0.30 (<0.001) 0.35 (0.002) 0.36 (0.002) Dual ICI (reference group) Sex Male 0.89 (0.5) Female (reference group) Cancer type Thoracic (ref: non-thoracic) 0.80 (0.3) Melanoma/Skin (ref: non-melanoma/skin) 2.43 (0.002) 1.92 (0.03) GU (ref: non-GU) 1.62 (0.02) 1.37 (0.2) GI (ref: non-GI) 0.58 (0.08) Head & Neck (ref: non-head & neck) 0.66 (0.3)