Proton Pump Inhibitor Use and Survival Outcomes in Patients with Advanced Non-Small-Cell Lung Cancer Receiving...

Background and Objectives: Immune checkpoint inhibitors (ICIs) improve survival in advanced non-small-cell lung cancer (NSCLC), yet treatment responses vary. The potential influence of proton pump inhibitors (PPIs), metformin, statins, and nonsteroidal anti-inflammatory drugs (NSAIDs) on immunotherapy efficacy has gained increasing attention. This study aimed to evaluate the associations of these medications with survival outcomes. Materials and Methods: This retrospective cohort study included 179 patients with advanced NSCLC who received second-line nivolumab. The use of PPIs, metformin, statins, and NSAIDs was assessed within a ±30-day exposure window around nivolumab initiation. Sensitivity analyses were performed including all four studied medications. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox regression models. Results: Median follow-up was 19 months, and 52.5% of patients used PPIs. In univariable analysis, PPI use was significantly associated with worse PFS (HR = 2.01; p < 0.001), while PD-L1 ≥ 50% expression was associated with improved PFS (HR = 0.57; p = 0.034). In multivariable analysis, PPI use remained independently associated with worse PFS (HR = 2.22; p < 0.001), and male sex was associated with improved PFS (HR = 0.56; p = 0.013). For OS, PPI use (HR = 1.53; p = 0.043), ECOG ≥ 2 (HR = 2.09; p = 0.001), and male sex (HR = 0.53; p = 0.008) were significant factors in univariable analysis. In multivariable analysis, PPI use (HR = 2.01; p = 0.002) and ECOG ≥ 2 (HR = 2.21; p = 0.001) were independent adverse prognostic factors, while male sex was independently associated with improved OS (HR = 0.41; p = 0.001). Median PFS was 5 months in PPI users versus 9 months in non-users (p < 0.001); median OS was 9 versus 14 months (p = 0.036). The use of metformin, statins, and NSAIDs showed no significant relationship with PFS or OS. Sensitivity analyses supported an association between PPI use and worse outcomes. Conclusions: PPI use was associated with worse PFS and OS in patients with advanced NSCLC receiving second-line nivolumab. These findings suggest that unnecessary PPI use should be carefully reassessed during immunotherapy.