Impact of proton pump inhibitors or antibiotics on immunotherapy efficacy after CRT in locally advanced non-small cell lung cancer

Baseline exposure to antibiotics and proton pump inhibitors (PPIs) has been associated with reduced efficacy of immune check inhibitors (ICIs) in patients with advanced tumors, possibly through gut microbiome disruption. Post-hoc analysis of the PACIFIC trial evaluated the association of baseline antibiotics and PPIs with progression-free survival (PFS) and overall survival (OS) in patients receiving ICIs for unresectable stage III non-small cell lung cancer (NSCLC). In PACIFIC, patients were randomly assigned (2:1) to durvalumab or placebo after chemoradiotherapy (CRT); among the 660 patients includede in the post-hoc analysis, 449 received durvalumab and 211 received placebo. Baseline PPI exposure was recorded in 263 patients (40%) and antibiotic exposure in 69 (10%). Median follow-up in the pooled population was 62.4 months (IQR 61.9-63.2). This figure shows the results of the analysis. In the durvalumab group, baseline exposure to PPIs was associated with shorter PFS (9.4 months versus 17.2 months; p<0.0001) and shorter OS (33.0 months versus 57.9 months; p<0.0001) compared to no exposure to PPIs, while baseline exposure to antibiotics was associated with shorter PFS (9.2 months versus 15.6 months; p=0.016) without significant impact on OS (37.7 months versus 49.2 months; p=0.16). In the placebo group, neither baseline exposure to PPIs nor to antibiotics was associated with PFS and OS. The authors conclude that baseline exposure to PPIs and antibiotics was associated with inferior outcomes with durvalumab but not with placebo.