Proton Pump Inhibitor Use and Survival Outcomes in Patients with Advanced Non-Small-Cell Lung Cancer Receiving Immunotherapy: A Real-World Study.

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.