Impact of proton pump inhibitor use on immune-related adverse events in patients with non- small cell lung cancer: A retrospective study

Background Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy; however, immune-related adverse events (irAEs) remain a critical concern. Proton pump inhibitors (PPIs) are frequently co-administered to patients with advanced lung cancer and PPI-induced alterations in the gut microbiota may impair immune responses, potentially affecting ICI efficacy and prognosis. However, the association between PPI use and irAE development remains unclear. Methods We retrospectively analyzed 228 patients with advanced non-small cell lung cancer who received first-line ICI therapy between April 2017 and December 2024. The impact of baseline PPI use on the incidence of irAEs, classified as checkpoint inhibitor pneumonitis (CIP) or irAEs without CIP (non-CIP irAEs), was evaluated. Results Multivariate logistic regression analysis demonstrated that PPI use was associated with a non-significant trend toward a lower incidence of overall irAEs (odds ratio [OR] = 0.625; 95% confidence interval [CI], 0.348–1.120; p  = 0.117). Notably, PPI exposure was significantly associated with a reduced incidence of non-CIP irAEs (OR = 0.510; 95% CI, 0.274–0.947; p  = 0.033), whereas no significant association was observed with the incidence of CIP. The PPI-exposed group showed a non-significant trend toward shorter median overall survival (OS) compared with the PPI-unexposed group (16.7 vs. 24.7 months; p  = 0.065). In multivariate Cox regression analysis, PPI exposure was not identified as an independent prognostic factor for OS (hazard ratio [HR] = 1.081; 95% CI, 0.743–1.573; p  = 0.674). In contrast, the occurrence of CIP (HR = 0.438; 95% CI, 0.232–0.824; p  = 0.011) and non-CIP irAEs (HR = 0.331; 95% CI, 0.215–0.508; p  < 0.0000005) was significantly associated with improved OS. Conclusions PPI use was potentially associated with a lower incidence of non-CIP irAEs, whereas no significant effect was observed for CIP. In contrast, PPI use was not an independent prognostic factor, suggesting that irAE occurrence is influenced by multiple factors beyond PPI use. This study highlights the importance of investigating the interplay between PPI exposure, irAE occurrence, and gut microbiome alterations.