Second-generation H1 antihistamine use with survival and immune-related outcomes in lung cancer and melanoma patients receiving immune checkpoint inhibitors.

11153 Background: Immune checkpoint inhibitors (ICIs) are standard of care for melanoma and lung cancer but are associated with immune-related adverse events and variable outcomes. Previous studies suggest that H1 antihistamine use may be associated with improved outcomes, potentially through histamine-mediated modulation of the tumor microenvironment. However, real-world evidence is limited. Methods: We conducted a multicenter retrospective study using the TriNetX Global Collaborative Network. Adult patients (≥18 years) with melanoma or lung cancer receiving ICIs (pembrolizumab, nivolumab, ipilimumab, atezolizumab, durvalumab, cemiplimab, or avelumab) were identified. Patients were categorized by exposure to second-generation H1 antihistamines (cetirizine, loratadine, fexofenadine, desloratadine, or levocetirizine) within 3 months before or during ICI initiation. One-to-one propensity score matching was performed based on demographics, baseline comorbidities, cancer characteristics, prior treatments, and conditions commonly associated with antihistamine use, including allergic and atopic disorders. The index date was defined as first ICI exposure, and outcomes were assessed from day 1 to day 180. The primary outcome was overall survival. Secondary outcomes included hospitalization and immune-related adverse events (irAEs), defined using a composite endpoint of organ-specific immune-mediated toxicities based on prior published methodology. Results: After matching, 2,141 melanoma and 11,812 lung cancer patients were included. In lung cancer patients, H1 antihistamine use was associated with reduced all-cause mortality (HR 0.769, 95% CI 0.727–0.815), lower hospitalization rates (HR 0.862, 95% CI 0.821–0.906), fewer intensive care unit admissions (HR 0.867, 95% CI 0.797–0.943) and reduced emergency department use (HR 0.940, 95% CI 0.899–0.984). 6-month overall survival was 80.93% in antihistamine users vs 75.98% in non-users. It was also associated with decreased endocrine (HR 0.843, 95% CI 0.776–0.916), and musculoskeletal irAEs (HR 0.840, 95% CI 0.752–0.938). In patients with melanoma, H1 antihistamine use was associated with reduced all-cause mortality (HR 0.685, 95% CI 0.581–0.808), lower hospitalization rates (HR 0.837, 95% CI 0.734–0.955), and reduced neutropenia (HR 0.441, 95% CI 0.266–0.729). 6-month overall survival was 88.15% vs 83.20%, respectively. No statistically significant differences were observed across other major immune-related organ systems. Conclusions: Second-generation H1 antihistamine use was associated with improved early survival and reduced healthcare utilization among melanoma and lung cancer patients treated with ICIs, without a significant increase in irAEs. Despite the retrospective design and potential confounding, prospective validation is warranted.