An Up-To-Date Investigation Into the Correlation Between Proton Pump Inhibitor Use and the Clinical Efficacy of Immune Checkpoint Inhibitors in Advanced Solid Cancers: A Systematic Review and Meta-Analysis

Abstract

BackgroundAlthough immune checkpoint inhibitors (ICIs) have revolutionized the current anticancer therapies, a considerable proportion of patients are found to hardly benefit from these drugs. Accumulating studies have demonstrated that concomitant proton pump inhibitor (PPI) use may affect the clinical efficacy of ICIs; however, their results are inconsistent. In this study, based on updated evidence, we aimed to perform a meta-analysis to clarify the prognostic significance of PPI use in advanced solid cancer patients receiving ICI therapy.MethodsEligible literature was searched using PubMed, Cochrane Library, Web of Science, EMBASE, and other network resources before July 2021. Clinical outcome was evaluated using overall survival (OS) and progression-free survival (PFS). The correlation of PPI use with OS or PFS was determined based on hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsA total of 17 studies enrolling 9,978 ICI-treated cancer patients were included in our meta-analysis. The global analysis demonstrated that PPI use was significantly correlated with worse OS [HR = 1.29 (1.10–1.50)] instead of PFS [HR = 1.19 (0.98–1.44)] in solid cancer patients receiving ICI therapy. In a subgroup analysis, the negative correlation of PPI use with ICI efficacy was significant in patients with non-small cell lung cancer [PFS, HR = 1.27 (1.10–1.47)] and urothelial carcinoma [OS, HR = 1.55 (1.31–1.84), PFS, HR = 1.52 (1.13–2.06)] and mixed cohorts containing multiple cancer types [OS, HR = 1.40 (1.16–1.69)], while an opposite result was observed in the PFS of patients with melanoma [HR = 0.48 (0.25–0.90)]. Moreover, the unfavorable prognostic impact of PPI use was also significant in patients over 65 years old [OS, HR = 1.28 (1.05–1.55), PFS, HR = 1.32 (1.12–1.56)] or those receiving anti-PD-1 [OS, HR = 1.37 (1.04–1.79)] or anti-PD-L1 therapies (OS, HR = 1.49 (1.30–1.69), PFS, HR = 1.34 (1.20–1.50). Finally, PPI use was significantly correlated with a worse prognosis in patients receiving PPIs 30 days before and/or after ICI initiation (OS, HR = 1.38 (1.18–1.62), PFS, HR = 1.23 (1.06–1.43)).ConclusionAlthough our global analysis revealed PPI use was not correlated with the PFS of ICI-treated patients, considering the results of our subgroup analysis, PPIs should be still cautiously used shortly before or during ICI therapy. Furthermore, more clinical validations and related mechanism investigations are of great necessity to clarify the clinical correlation of PPI use with ICI efficacy.Systematic Review Registration[https://www.crd.york.ac.uk/prospero/], PROSPERO [No. CRD42021243707].

Association of proton pump inhibitor use with survival outcomes in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis

“…Later, in a more recent meta-analysis, Qin et al 53 using data from seven studies reported that PPI therapy shortened the PFS and OS of cancer patients treated with ICIs. Finally, Liu et al 54 in a meta-analysis including 17 studies, observed that PPI therapy for cancer patients receiving ICI shortens the OS, but not PFS. Therefore, despite these meta-analysis, the impact of PPIs on ICI therapy still remains controversial.…”

A Clinical Outcome of the anti-PD-1 Therapy of Melanoma in Polish Patients Is Mediated by Population-Specific Gut Microbiome Composition

“…Another study also demonstrated that PPI use was significantly correlated with reduced clinical benefits. However, the effect of PPIs differs by cancer type, therapeutic strategy, patient age, sample size, and PPI exposure timeframes [135]. A negative correlation with PPI use was found in NSCLC, urothelial carcinoma, and mixed cohorts with multiple cancer types, whereas prolonged PFS was observed in melanoma patients exposed to PPI.…”

The Association between Baseline Proton Pump Inhibitors, Immune Checkpoint Inhibitors, and Chemotherapy: A Systematic Review with Network Meta-Analysis

“…Six meta-analyses [13][14][15][16][17][18] have investigated the survival impacts of concomitant PPI on the effectiveness of ICI, but their results are contradictory. One [14] demonstrated negligible survival influence of PPI on ICI.…”

“…One [14] demonstrated negligible survival influence of PPI on ICI. Another three [15,17,18] alluded that PPI could negatively affect ICI in advanced cancers, while the remaining two syntheses [13,16] implied melanoma patients may derive survival benefits due to lower disease recurrence. Despite these six meta-analyses, there has been little investigation and discussion on the interaction of PPI against ICI and chemotherapy.…”