Impact of Proton Pump Inhibitors on Immune-related Adverse Events and Efficacy During Pembrolizumab Monotherapy

Background/Aim: Concomitant proton pump inhibitors (PPIs) have been inversely correlated with efficacy, including overall survival (OS) and progression-free survival (PFS), in patients with urothelial carcinoma receiving pembrolizumab. However, the impact of PPIs on immune-related adverse events (irAEs) and the efficacy of pembrolizumab in patients with various solid tumors remain unclear. This study investigated the impact of concomitant PPI use during initial pembrolizumab monotherapy on irAEs and its efficacy in various cancers. Patients and Methods: We retrospectively analyzed the electronic medical records of The University of Osaka Hospital to examine the effect of PPIs on irAE development, OS, and PFS in 177 patients who received pembrolizumab monotherapy. Results: The rate of any irAEs in patients with PPIs (49%, n=33) was significantly higher than that in patients without PPIs (31%, n=34). Multivariate Cox regression analysis revealed that PPI use was an independent risk factor for irAEs hazard ratio (HR)=2.324, p=0.025. Although Kaplan-Meier analysis showed no significant differences in OS and PFS between patients with and without PPIs, multivariate Cox regression analysis revealed that irAE occurrence was an independent factor for prolonged OS (HR=0.479, p=0.002) and PFS (HR=0.522, p=0.002). In contrast, concomitant PPI use was an independent risk factor for shortened OS (HR=1.895, p=0.004). Conclusion: Concomitant PPI use during initial pembrolizumab monotherapy could increase irAE risk and worsen OS. The findings of this study provide important information regarding the safe and effective administration of pembrolizumab therapy.