Seasonal variation in immune-related adverse events in advanced cancer patients

Immune checkpoint inhibitors (ICIs) improve outcomes across advanced cancers but can cause immune-related adverse events (irAEs). Seasonal environmental factors influence immune regulation and autoimmunity, yet its relationship with irAE development in non-melanoma cancers remains poorly defined.

We retrospectively analysed patients with advanced non-melanoma solid tumours treated with anti-PD-1/PD-L1 and/or anti-CTLA-4 monotherapy at two Australian tertiary centers between 2014-2024. Seasonal variation in irAE incidence, organ distribution, severity, and timing were evaluated using descriptive analyses, Kaplan-Meier estimates and Cox proportional hazards models.

Among 709 patients across 27 cancer types (median follow-up 12.7 months), 514 irAEs occurred, including 32% grade ≥ 3 events and 14% treatment discontinuation rate due to toxicity. Winter ICI initiation led to the highest irAE rate (0.89 events per treatment) versus summer (0.62), largely driven by seasonal variation in low-grade cutaneous and thyroid events. Summer ICI initiation showed the highest proportion of grade ≥ 3 irAEs, whereas winter had the lowest. Seasonal effects also differed by regimen intensity, with disproportionately more irAEs among patients commencing doublet ICIs in winter. Season of ICI initiation was not significantly associated with overall irAE risk (p = 0.174) or time to onset (p = 0.11). However, time to first irAE differed by season of toxicity onset (p = 0.019), with earlier irAEs occurring in spring and summer.

Although there was no significant association between season of ICI initiation and overall irAE risk, we observed seasonal variations in the phenotype, severity, and timing of irAEs. These exploratory findings may inform future investigation into seasonal influences on immune toxicity.