Five-year survival outcomes in NSCLC patients with concurrent GERD on proton pump inhibitors receiving pembrolizumab or nivolumab: A global study.

Abstract

e20611 Background: Immune checkpoint inhibitors (ICIs) have transformed the treatment of non-small cell lung cancer (NSCLC), though response variability remains a challenge. Emerging evidence suggests that proton pump inhibitors (PPIs) may impair ICI efficacy, potentially through gut microbiome and immune modulation, warranting further investigation. Methods: We conducted a retrospective cohort study utilizing de-identified patient data from the TriNetX platform, a comprehensive electronic health records system consisting of 143 healthcare systems from 18 participating countries and more than 163 million patients' clinical records globally. The efficacy of ICIs was evaluated by comparing NSCLC patients treated with pembrolizumab or nivolumab without PPI use (Cohort A) to those receiving the same therapy with concurrent PPI use (Cohort B). Propensity score matching was utilized to balance baseline characteristics between the cohorts, including age, sex, ethnicity, and comorbidities. Results: Cohort A demonstrated a 5-year survival probability of 37.2% with median survival days for Cohort A was 740 days (N=2,444, deceased=984) while Cohort B exhibited a 5-year survival probability of 28.3% with a median survival days of 526 days (N=2430, deceased 1200). P-value < 0.0001. Conclusions: The gut microbiota plays a crucial role in modulating cancer treatment outcomes, particularly in patients receiving immune checkpoint inhibitors (ICIs). Dysbiosis, or microbial imbalance, is linked to poor ICI responses, while specific bacterial taxa such as Akkermansia muciniphila , Bacteroides fragilis , and Ruminococcus spp. are associated with enhanced antitumor immunity. Akkermansia muciniphila improves ICI efficacy by activating CD8+ T cells, modulating the tumor immune microenvironment, and disrupting PD-L1+ neutrophil and CD8+ T cell interactions. Bacteroides fragilis enhances antitumor responses through polysaccharide A, which induces regulatory T cells and a Th1 immune response. Ruminococcus spp. contribute by producing short-chain fatty acids like butyrate, which support regulatory T cell function and improve immune activation. Proton pump inhibitors (PPIs), commonly used for gastroesophageal reflux disease, significantly alter gut microbiota by suppressing gastric acidity, reducing microbial diversity, and impairing colonization by beneficial taxa. This PPI-induced dysbiosis may undermine immune responses and diminish the efficacy of ICIs, highlighting the need to consider PPI use carefully in cancer patients.