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October 18, 2025

Impact of Concomitant Proton Pump Inhibitor Use on the Efficacy of Immune Checkpoint Inhibitors Across Multiple Cancer Types

Key Points

Concomitant PPI use increased mortality rates in cancer patients treated with PD-1 inhibitors.
In melanoma patients, the hazard ratio for mortality with PPI use was significantly high at 1.889.
The study employed a large retrospective cohort design using data from over 35,621 patients across various cancer types.
These findings call for careful prescribing of PPIs in patients undergoing immune checkpoint inhibitor therapy.

Abstract

Background: Proton pump inhibitors (PPIs) are commonly prescribed medications that may influence the gut microbiome and impact the efficacy of immune checkpoint inhibitors (ICIs) in cancer treatment. Patients and Methods: We conducted a large retrospective cohort study using the TriNetX database, encompassing >35,621 patients with cancer treated with ICIs between January 2015 and June 2021. Patients were stratified into 2 cohorts: those receiving ICIs with concurrent PPI use and those without PPI use. Results: Concomitant PPI use was associated with significantly higher mortality rates in patients treated with PD-1 inhibitors across multiple cancer types, including melanoma (hazard ratio HR, 1.889; 95% CI, 1.752–2.037); breast cancer (HR, 1.512; 95% CI, 1.345–1.701); urothelial carcinoma (HR, 1.406; 95% CI, 1.276–1.551); colorectal cancer (HR, 1.310; 95% CI, 1.187–1.445); hepatocellular carcinoma (HR, 1.413; 95% CI, 1.238–1.614); renal cancer (HR, 1.490; 95% CI, 1.375–1.614); Hodgkin lymphoma (HR, 1.646; 95% CI, 1.212–2.236); head and neck cancers (HR, 1.402; 95% CI, 1.259–1.561); and lung cancer (HR, 1.308; 95% CI, 1.184–1.445). Similar trends were observed with PD-L1 inhibitors, where PPI use correlated with increased mortality in melanoma (HR, 1.657; 95% CI, 1.049–2.617); breast cancer (HR, 1.584; 95% CI, 1.297–1.934); renal cancer (HR, 1.380; 95% CI, 1.059–1.799); and urothelial carcinoma. ICU admissions were more frequent among PPI users across different cancer types and ICI treatments. Conclusions: This study underscores the potential risks associated with the concomitant use of PPIs and ICIs in cancer treatment. The findings suggest that careful consideration is necessary when prescribing PPIs to patients undergoing ICI therapy.

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