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Background Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, but they often lead to immune-related adverse events (irAEs) that differ by region due to genetic, environmental, and practice-based factors. 1 2 While prior studies suggest possible geographic variability in irAE incidence, a comprehensive cross-regional analysis across all ICI types and cancers remains lacking.Methods We conducted a pan-cancer meta-analysis of interventional trials registered on ClinicalTrials.gov between 2014 and 2024 evaluating approved ICIs (nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, ipilimumab, tremelimumab). Trials were classified as East-Asia-dominant (≥70% sites in East/Southeast Asia) or Western-dominant. Studies with ≥10 treated patients per arm and posted adverse-event tables were included. Arm-level incidence of any-grade and grade ≥3 irAEs was extracted using MedDRA immune toxicity terms. Meta-regression (random-effects) estimated pooled log-odds of irAE risk (West vs East), adjusting for ICI class and tumor type. 3 Heterogeneity was assessed using τ2 and I2, with small-study bias explored via Egger’s test, trim-and-fill, and PET-PEESE corrections.4 Results Of 9,128 trials screened, 1,359 arms (40 East-Asia, 1,319 West) contributed usable irAE data. For any-grade irAEs, unadjusted relative risk (RR) was 1.28 (95% CI 0.87–1.89; p = 0.22; τ 2 = 1.07; I2 = 88%). Class-adjusted RR was 1.27 (95% CI 0.87–1.87; p = 0.21), with minimal change after tumor type adjustment (RR 1.27; 95% CI 0.87–1.85; p = 0.21). Grade ≥3 irAEs showed a similar trend (adjusted RR 1.16; 95% CI 0.85–1.58; p = 0.35; I2 = 66%). Melanoma-specific analysis (168 arms) revealed a threefold higher risk in Western trials (RR 3.31; 95% CI 0.98–11.24; p = 0.055; I2 = 94.5%).5 Excluding melanoma reduced heterogeneity (RR 1.19; 95% CI 0.81–1.75; I2 = 84%). Egger’s test indicated asymmetry (z = –4.07; p < 0.0001), but PET/PEESE corrections confirmed result stability (RR ~1.32)4 (table 1) (figure 1).Conclusions Western trials exhibit a consistent 20–30% higher rate of irAEs, though not statistically significant after adjusting for confounders. Melanoma emerges as a distinct outlier, with Western cohorts showing disproportionately elevated irAE risk. These findings may reflect underlying genetic susceptibility, environmental exposures, or disparities in pharmacovigilance and AE reporting practices. Persistent heterogeneity across analyses (I 2 > 85%) suggests the influence of unmeasured trial-level variables or differences in data completeness. To improve the interpretability and global generalizability of ICI safety data, future studies should harmonize AE reporting standards, stratify outcomes by geography and tumor type, and integrate patient-level omics and biomarker data to uncover mechanisms driving geographic toxicity variation.1 2 References Semenov YR. Seasonal and geographic variation in cutaneous immune-related adverse events after treatment with immune checkpoint inhibitors. J Eur Acad Dermatol Venereol. 2025 Jul;39(7):e597-e599. doi: 10.1111/jdv.20484.Chandler GS, et al. Baseline risk factors associated with immune-related adverse events and atezolizumab. Front Oncol. 2023;13:1138305. doi: 10.3389/fonc.2023.1138305.Zhan Z, et al. The impact of immune checkpoint inhibitors on prognosis in unresectable hepatocellular carcinoma treated with TACE and lenvatinib: a meta-analysis. Front Immunol. 2025;16:1573505. doi: 10.3389/fimmu.2025.1573505.Johnson DB, et al. Incidence of cutaneous immune-related adverse events and outcomes in immune checkpoint inhibitor-containing regimens: a systematic review and meta-analysis. Cancers (Basel). 2024 Jan 13;16(2). doi: 10.3390/cancers16020340.Amaral T, et al. Discontinuation of immune checkpoint inhibitors for reasons other than disease progression and the impact on relapse and survival of advanced melanoma patients. A systematic review and meta-analysis. Front Immunol. 2025;16:1524945. doi: 10.3389/fimmu.2025.1524945.Abstract 1034 Figure 1Distribution of any-grade immune-related adverse event (irAE) rates by region. Each point represents a trial arm. Violin plots show density; box plots show median and IQR. Western arms exhibit higher median irAE rates and greater variability than Eastern armsAbstract 1034 Table 1Summary of meta-regression results for regional differences in irAE rates across checkpoint inhibitor trialsk = trial-arm count; RR = risk ratio (West vs East); τ2 = between-study variance; I2 = heterogeneity (% of total variability).