e23398 Background: Immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICIs) can manifest at heterogeneous timepoints, reflecting distinct patterns of immune activation. Early-onset irAEs may require heightened surveillance, yet clinical determinants of early onset remain poorly characterized. Methods: We identified a real-world cohort of metastatic cancer patients treated with ≥1 ICI within the Brown University Health system from 2015-2025. Patients who developed ≥1 irAE were included. Time from ICI initiation to first irAE was calculated and dichotomized as early ( < 6 weeks) vs ≥6 weeks. Clinical and treatment characteristics were compared across timing groups, and multivariable logistic regression was used to identify predictors of early onset. Treatment regimen, cancer type, race, biological sex, smoking history, and baseline creatinine were included as prespecified covariates. Odds ratios (OR) and p-values were reported. Results: Among 2,134 ICI-treated patients, 510 (23.9%) developed an irAE (median age 70, IQR 63-80; 56% male; 89% White; 79% ever smokers). The most common cancers were thoracic (45%), genitourinary (25%), and melanoma/skin (10%). Treatment regimens included ICI monotherapy (63%), ICI + targeted/chemotherapy (26%), and dual-ICI (10%). Among irAEs, 137 (26.9%) were early-onset and 373 (73.1%) occurred ≥6 weeks. Treatment regimen was significantly associated with early-onset irAEs, with lower odds of occurring < 6 weeks for ICI + targeted/chemotherapy (OR 0.46, p = 0.02) and ICI monotherapy (OR 0.48, p = 0.02) compared to dual-ICI. Endocrine irAEs exhibited a delayed temporal pattern, with significantly lower odds of occurring < 6 weeks (OR 0.32, p = 0.001). In a multivariable model including treatment regimen and endocrine irAEs, both covariates retained statistical significance, indicating independent effects. Race, biological sex, smoking history, thoracic cancer, genitourinary cancer, and baseline creatinine were not associated with timing of onset. Conclusions: Approximately one-quarter of irAEs occurred within 6 weeks of ICI initiation, with early-onset events more frequent among patients receiving dual-ICI therapy, whereas endocrine irAEs occurred later in the treatment course. Dual-ICI regimens generate stronger early immune activation, consistent with early-onset irAEs, while endocrine irAEs reflect evolving autoimmune glandular injury. These temporal patterns may inform regimen-specific surveillance strategies and support timing-informed approaches to irAE risk assessment.
Koh et al. (Thu,) studied this question.