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Meta-Analysis
. 2023 Jan 26:14:1070076.
doi: 10.3389/fimmu.2023.1070076. eCollection 2023.

Do proton pump inhibitors alter the response to immune checkpoint inhibitors in cancer patients? A meta-analysis

Sébastien Lopes  1 , Lucile Pabst  2 , Anne Dory  1 , Marion Klotz  2 , Bénédicte Gourieux  1 , Bruno Michel  1 , Céline Mascaux  2   3
Affiliations
Meta-Analysis

Do proton pump inhibitors alter the response to immune checkpoint inhibitors in cancer patients? A meta-analysis

Sébastien Lopes et al. Front Immunol. .

Abstract

Introduction: Gut microbiota can significantly affect the effectiveness of immune checkpoint inhibitors (ICIs) in cancer patients. Recently, antibiotics were shown to decrease survival rate of patients treated by ICIs. Proton pump inhibitors (PPIs) can indeed modulate microbiota's diversity, therefore altering ICIs response. A meta-analysis was performed based on published data to verify this hypothesis.

Methods: In this study, over 41 publications, exploring the impact of concomitant PPI treatment on outcomes of ICI-treated patients, were analyzed. Evaluated endpoints were overall survival (OS) and progression-free survival (PFS). Pooled hazard ratios (HRs) with a 95% confidence interval (CI) were reported in ICIs in PPI users versus non-PPI users. Subgroup analyses were performed to minimize the impact of study heterogeneity and to investigate the influence of PPI on the different groups of interest. There was no evidence of publication bias for OS and PFS analysis in subgroup analysis.

Results: Forty-one studies were included in the meta-analysis, including a total of 20,042 patients. OS of patients receiving ICIs was negatively correlated in patients concomitantly treated with PPI (HR=1.37; 95%CI, 1.23-1.52). PFS of cancer patients receiving ICIs was also negatively correlated with PPI treatment (HR=1.28; 95%CI, 1.15-1.42). PPI and ICI use was associated with worst OS and PFS not only for non-small-cell lung cancer (NSCLC) or urothelial cancer patients but also for patients treated with anti PD-1 (OS) and anti PD-L1 (OS and PFS) immunotherapies when administered in non-first line and when PPI was received as baseline treatment or in 60 days before ICI initiation. PPI and ICI use also showed the worst OS and PFS for patients from Europe and Asia.

Conclusion: This meta-analysis suggests that PPI treatment leads to significantly worse outcomes in advanced cancer patients treated by ICIs in terms of PFS and OS.

Keywords: immune checkpoint inhibitors; meta – analysis; proton pump inhibitors; solid cancer; survival.

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Conflict of interest statement

CM was employed by Roche, AstraZeneca, MSD, Kephren, Janssens, Bristol-Myers Squibb, Pfizer, Takeda, Sanofi, Boehringer Ingelheim, Novartis, and Amgen. BG was employed by MSD, Sobi, and Pfizer. AD was employed by Novartis, Amgen, Takeda, and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) flow diagram of articles identification and selection. PPI, proton pump inhibitor.
Figure 2
Figure 2
Association between PPI use and overall survival (A) and progression-free survival (B) in cancer patients treated with immunotherapy. PPI, proton pump inhibitor; CI, confidence interval.
Figure 3
Figure 3
Begg’s funnel plot of HR ratios of (A) OS and (B) PFS. HR, hazard ratio; SE, standard error.
Figure 4
Figure 4
Subgroup analysis of association between PPI use and overall survival by (A) cancer type, (B) type of immunotherapy, (C) treatment line, (D) PPIs use window, and (E) continents. PPI, proton pump inhibitor; CI, confidence interval; NSCLC, non-small cell lung cancer; ICI, immune checkpoint inhibitor.
Figure 5
Figure 5
Subgroup analysis of association between PPI use and progression-free survival by (A) cancer type, (B) type of immunotherapy, (C) treatment line, (D) PPIs use window, and (E) by continents. PPI, proton pump inhibitor; CI, confidence interval; NSCLC, non-small cell lung cancer; ICI, immune checkpoint inhibitor.
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