Stomatitis as a harbinger of harm: Long-term mortality and multiorgan adverse events associated with immune-related stomatitis in checkpoint inhibitor-treated melanoma—A propensity score–matched cohort study.

Abstract

e21600 Background: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for advanced malignant melanoma, but immune-related adverse events (irAEs) such as stomatitis may impact long-term outcomes. The association between stomatitis and subsequent morbidity, including mortality and systemic irAEs, remains underexplored. To evaluate the long-term effects of stomatitis on mortality and other adverse outcomes in melanoma patients receiving ICIs. Methods: Retrospective cohort study using the TriNetX federated database (deprecated COVID-19 Research Network, 88 healthcare organizations). Patients aged ≥18 years with malignant melanoma (ICD-10-CM C43) receiving ICIs (pembrolizumab, nivolumab, or ipilimumab) were divided into cohorts with (n = 1,719) and without (n = 22,228) stomatitis (ICD-10-CM K12). Propensity score matching (PSM) balanced cohorts on demographics, BMI, ECOG score, and comorbidities, yielding 1,708 patients per group. Exposures included-Stomatitis during ICI therapy. Main Outcomes and Measures--Primary outcome: all-cause mortality. Secondary outcomes: respiratory diseases, dysphagia, malaise/fatigue, trismus, fever, circulatory/respiratory symptoms, endocrine/metabolic diseases, circulatory diseases, and digestive diseases. Analyses included risk ratios (RRs), odds ratios (ORs), hazard ratios (HRs) from Kaplan-Meier survival, and mean instances, starting 1 day post-index event (first ICI administration). Results: After PSM, the stomatitis cohort had a higher mortality risk (37.3% vs 31.4%; RR, 0.842 [95% CI, 0.765-0.926]; HR, 0.829 [95% CI, 0.737-0.933]; P = 0.002 for log-rank). Respiratory diseases were more common (53.3% vs 43.3%; RR, 0.813 [95% CI, 0.721-0.917]; P = 0.001; HR, 0.711 [95% CI, 0.600-0.842]; P < 0.001). Dysphagia instances were higher (mean 2.913 vs 2.121; P = 0.023), though risk was borderline (11.2% vs 9.1%; RR, 0.806 [95% CI, 0.648-1.003]; P = 0.053). Circulatory/respiratory symptoms (49.2% vs 42.3%; RR, 0.860 [95% CI, 0.758-0.975]; P = 0.020) and circulatory diseases (59.5% vs 51.5%; RR, 0.866 [95% CI, 0.757-0.990]; P = 0.041; HR, 0.690 [95% CI, 0.562-0.847]; P < 0.001) were elevated in the stomatitis group. No significant differences for malaise/fatigue, trismus, fever, endocrine, or digestive diseases. Conclusions: Stomatitis during ICI therapy for melanoma is associated with increased long-term mortality and select irAEs, particularly respiratory and circulatory complications. These findings suggest stomatitis may signal broader immune dysregulation, warranting closer monitoring.