Meta-analysis For The Impact Of Proton Pump Inhibitors On The Efficacy And Safety Of Immune Checkpoint Inhibitors In Non-small Cell Lung Cancer

Objective: Immune checkpoint inhibitors(ICIs)have significantly improved the overall prognosis of patients with non-small cell lung cancer(NSCLC)by blocking the immune escape mechanism of tumors.However,only 20-40% of tumor patients were found to benefit from ICIs.Accumulating studies have demonstrated concomitant proton pump inhibitor(PPI)use may affect the clinical efficacy and safety of ICIs,but the results were inconsistent.In this study,we aimed to perform a meta-analysis to systematically review the effects of PPI on the clinical efficacy and safety of ICIs in NSCLC.Methods: Eligible literatures were systematically searched using PubMed,Embase,Cochrane Library,CNKI,VIP and Wanfang databases.The search period was from database construction to January 23,2023.Screened literature and extracted data according to inclusion and exclusion criteria.The Newcastle-Ottawa Scale(NOS)was used to evaluate the quality of the included literature.Clinical efficacy was assessed using survival prognosis and efficacy response.Survival prognosis was evaluated using overall survival(OS)and progression-free survival(PFS),with risk ratio(hazard ratios,HR)as the effect size.The efficacy response was evaluated by objective response rate(ORR)and disease control rate(DCR),with odds ratio(OR)as the effect size.Safety was evaluated using immune-related adverse events(irAEs),with OR as the effect size.Meta-analysis was performed using a fixed-effects model for indicators with less heterogeneity between studies,otherwise a random-effects model was used and further subgroup analysis was performed stratified by studuies and patients characteristics.Sensitivity analysis was performed using the method of excluding one literature at a time.Funnel plots and Egger’s test were used to assess literature publication bias.RevMan 5.4 software and Stata 14.0 software were used for data analysis.P < 0.05 indicated that the differences were statistically significant.Results: This Meta-analysis included 25 cohorts from 22 literatures,including18,096 patients with NSCLC treated with ICIs,and 7,214 patients used PPI.Compared with those who did not use PPI,PPI use decreased OS [HR=1.33,95%CI(1.20,1.48),P<0.05] and PFS [HR=1.33,95%CI(1.20,1.50),P<0.05] in NSCLC patients treated with ICIs.However,there had no effect with ORR [OR=0.95,95%CI(0.61,1.47),P=0.80],DCR [OR=0.53,95%CI(0.23,1.25),P=0.15] and irAEs [OR=1.38,95%CI(0.57,3.32),P=0.47].Subgroup analysis of survival prognosis showed that PPI shortened OS and PFS in NSCLC patients in Europe and Asia(P<0.05),but had no effect on OS and PFS in NSCLC patients in Americas and Australia(P>0.05).In the subgroup of ICIs types,PPI decreased OS and PFS in patients treated with PD-1inhibitors and PD-L1 inhibitors(P<0.05),but had no effect in the cohort treated with CTLA-4 inhibitors(P>0.05).In the subgroup of PPI exposure window,PPI use before ICIs decreased OS and PFS in NSCLC patients(P<0.05),but PPI use during ICIs only shortened PFS(P<0.05).In addition,subgroup analyses of treatment regimen,number of lines treated,and sample size suggested that the use of PPI decreased OS and PFS in patients with NSCLC(P<0.05).Subgroup analysis of efficacy response showed that PPI had no effect on ORR and DCR in NSCLC patients in Asia(P>0.05),but decreased ORR in patients in Europe(P<0.05).In the subgroup of ICIs types,ORR was worse in patients using PPI in studies with sample sizes greater than 200(P<0.05),but PPI had no effect on ORR and DCR in studies with sample sizes less than 200(P>0.05).Subgroup analysis for safety showed that the use of PPI increased the incidence of ICIs-related acute kidney injury(P<0.05).Sensitivity analysis suggested that the Meta-analysis results were robust and reliable.Publication bias analysis suggested no publication bias for the indicator PFS,while some publication bias existed for the indicator OS.Conclusions: In NSCLC patients treated with ICIs,PPI exposure had a negative impact on OS and PFS,but no significant impact on ORR and DCR.In addition,PPI use did not increase the overall incidence of irAEs,but increased the risk of ICIs-related acute kidney injury.Clinicians should minimize the concomitant use of PPI and ICIs.