PPIs may blunt durvalumab benefit in stage III lung cancer

Clinical takeaway: Before starting durvalumab after chemoradiotherapy for unresectable stage III non–small-cell lung cancer (NSCLC), reassess whether proton pump inhibitors and antibiotics are clinically necessary. These findings do not support withholding needed medications, but they reinforce avoiding unnecessary exposure when appropriate.

Durvalumab after concurrent chemoradiotherapy is the standard of care for unresectable stage III NSCLC, yet treatment responses vary. Growing evidence suggests that medications that alter the gut microbiome, including proton pump inhibitors (PPIs) and antibiotics, may reduce the effectiveness of immune checkpoint inhibitors.

A post-hoc analysis of the phase 3 PACIFIC trial found that patients receiving durvalumab who had been exposed to PPIs within 30 days before treatment had significantly shorter progression-free survival (9.4 vs 17.2 months; hazard ratio [HR], 1.57) and overall survival (33.0 vs 57.9 months; HR, 1.66) than patients without PPI exposure. These associations were not seen in the placebo group, suggesting a treatment-specific effect rather than a general marker of poorer prognosis.

Baseline antibiotic exposure was also associated with shorter progression-free survival in the durvalumab group (9.2 vs 15.6 months; HR, 1.50), although no significant difference in overall survival was observed.

Patients exposed to both PPIs and antibiotics had the poorest outcomes, consistent with a possible additive effect.

The findings suggest that this association extends beyond advanced NSCLC to patients receiving curative-intent immunotherapy after chemoradiotherapy.

“Rather than discouraging clinically indicated supportive therapies, future work should focus on pragmatic antibiotic stewardship and on identifying patients in whom alternative management strategies might be reasonable,” the study authors concluded.

Source: Brunetti L, et al. (2026 July 3) Lancet Oncol. Differential impact of proton pump inhibitors and antibiotics on immunotherapy efficacy after chemoradiotherapy in locally advanced non-small-cell lung cancer: a post-hoc analysis of the PACIFIC trial