Multi-organ immune-related adverse events following immune checkpoint inhibitor therapy in patients with metabolic dysfunction–associated steatotic liver disease.

Abstract

e24203 Background: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Metabolic dysfunction–associated steatotic liver disease (MASLD) is a highly prevalent metabolic condition. As more patients with MASLD become candidates for ICI treatment, it is important to understand whether MASLD influences the development of irAEs. Methods: We conducted a retrospective cohort study using the TriNetX Research Network. Adults with cancer treated with ICI, including PD-1, PD-L1, or CTLA-4 inhibitors, between 2011 and 2026 were included. MASLD was defined by using diagnostic codes, with exclusion of other chronic liver diseases. Patients treated with ICIs were stratified into MASLD and non-MASLD cohorts and matched 1:1 using propensity score matching. Index date was the day of ICI initiation and patients were followed up in 1 year. Outcomes included organ-specific immune-related adverse events (irAEs). Multivariable analyses were performed to identify ICI regimens associated with a higher risk of irAEs among patients with MASLD. Analyses were conducted using Cox proportional hazards models, hazard ratios with 95% confidence intervals. Results: 11,097 patients with MASLD treated with ICIs were matched to patients without MASLD. MASLD was associated with higher risks of multiple irAEs, including endocrine (HR 1.17; 95% CI, 1.12–1.22; p < 0.001), musculoskeletal (HR, 1.16; 95% CI, 1.11–1.22; p < 0.001), hepatic (HR, 1.43; 95% CI, 1.34–1.52; p < 0.001), gastrointestinal (HR, 1.20; 95% CI, 1.15–1.26; p < 0.001), neurologic (HR, 1.10; 95% CI, 1.06–1.16; p < 0.001), and cutaneous irAEs (HR, 1.15; 95% CI, 1.10–1.20; p < 0.001). In contrast, MASLD was not associated with significantly different risks of renal (HR, 1.03; 95% CI, 0.97–1.09; p = 0.346), ocular (HR, 1.11; 95% CI, 0.99–1.25; p = 0.086), cardiac (HR, 1.02; 95% CI, 0.93–1.12; p = 0.716), respiratory (HR, 1.00; 95% CI, 0.94–1.06; p = 0.894), hematologic (HR, 1.03; 95% CI, 0.98–1.08; p = 0.224), or rheumatologic irAEs (HR, 1.10; 95% CI, 0.97–1.24; p = 0.150) compared with non-MASLD patients. In multivariable analyses, ipilimumab use was associated with a higher risk of hepatic irAEs (HR, 1.47; 95% CI, 1.03–2.11; p = 0.036). For endocrine irAEs, nivolumab (HR, 1.18; 95% CI, 1.02–1.36; p = 0.022) and pembrolizumab (HR, 1.11; 95% CI, 1.02–1.21; p = 0.014) were independently associated with increased risk. For cutaneous irAEs, ipilimumab (HR, 1.34; 95% CI, 1.03–1.75; p = 0.031) and cemiplimab (HR, 1.95; 95% CI, 1.21–3.14; p = 0.006) were independently associated with higher risk. Conclusions: MASLD is independently associated with an increased risk of multi-organ immune-related adverse events in patients receiving immune checkpoint inhibitors, supporting its role as a clinically important modifier of immunotherapy-related toxicity.