Impact of proton pump inhibitors and antibiotics on survival in immunotherapy treated gastrointestinal cancers.

Abstract

836 Background: Despite significant progress in cancer immunotherapy, a substantial proportion of patients up to 70% experience primary resistance to immune checkpoint inhibitors (ICIs). Recent research has highlighted the gut microbiome (GM) as a critical regulator of immune function, influencing the effectiveness of immunotherapy. Medications that disrupt the GM, such as antibiotics and proton pump inhibitors (PPIs), have been linked to reduced immunotherapy efficacy in certain cancers. However, data on the impact of PPIs in gastrointestinal (GI) cancers remain limited. This study aims to evaluate the association between proton pump inhibitor (PPI) use and survival outcomes in patients with gastrointestinal (GI) cancers undergoing treatment with immune checkpoint inhibitors. Additionally, it investigates the impact of antibiotic exposure on survival in the same patient population. Methods: A retrospective chart review was conducted at The Ottawa Cancer Center, including adult patients treated between July 1, 2019, and May 31, 2024. Collected data included demographics, cancer characteristics, treatment details, and clinical outcomes. PPI exposure was defined as use within 30 days before or after initiating ICIs, sustained for at least four weeks. Overall survival was analyzed using Kaplan–Meier and Cox regression models, with multivariable adjustments for tumor type, stage, age, sex, chemotherapy, and antibiotic/steroid use. Results: Among 286 patients with GI cancers treated with ICIs, 67% were male, and gastroesophageal cancer was the most prevalent (42%), followed by hepatocellular carcinoma (23%). PPI use was common, observed in 69% of patients. Overall, PPI use did not significantly affect immunotherapy efficacy across the general GI cancer population, overall survival (OS) HR 0.98 (95% CI, 0.71-1.35), p=0.906. In contrast, antibiotic use was associated with worse survival outcome (HR 0.85; 95% CI, 0.74–0.99; p=0.045), reinforcing concerns about GM disruption. The occurrence of immune related adverse events (irAEs), including those requiring systemic steroids and therapy interruption, did not correlate with worse survival outcomes HR 1.02 (95% CI, 0.86-1.21), p=0.786. Multivariate analysis identified tumor type, stage, and chemotherapy use as significant predictors of survival. Conclusions: PPI use did not negatively impact immunotherapy outcomes in GI cancers overall. Conversely, antibiotic use was linked to worse outcomes, emphasizing the potential role of GM modulation. These findings suggest that the influence of concomitant medications on ICI efficacy may vary by cancer type and warrant further prospective investigation.