Proton pump inhibitors and antibiotics linked to reduced durvalumab benefit in unresectable stage III NSCLC

Already linked to weaker immunotherapy response in advanced disease

Durvalumab, a PD-L1 immune checkpoint inhibitor, is given as consolidation treatment after concurrent chemoradiotherapy in unresectable stage III NSCLC, the approach established by the original PACIFIC trial. Earlier work in advanced and metastatic cancers had linked two commonly prescribed classes of medication, proton pump inhibitors and systemic antibiotics, to weaker responses to checkpoint inhibitors, an effect attributed to disruption of the gut microbiome. Whether the same held in earlier-stage disease treated with curative intent had not been established. The investigators examined the question using the completed PACIFIC dataset at its final five-year cutoff.

Worse survival on durvalumab, absent on placebo

Among patients treated with durvalumab, baseline proton pump inhibitor use was associated with shorter progression-free survival, a median of 9.4 months versus 17.2 months without exposure (hazard ratio 1.57; 95% CI 1.28–1.93; p<0.0001), and shorter overall survival, 33.0 months versus 57.9 months (hazard ratio 1.66; 95% CI 1.30–2.13; p<0.0001). Baseline antibiotic use was likewise associated with shorter progression-free survival, 9.2 months versus 15.6 months (hazard ratio 1.50; 95% CI 1.08–2.10; p=0.016), although the difference in overall survival did not reach statistical significance (hazard ratio 1.33; 95% CI 0.90–1.97; p=0.16).

No such associations appeared in the placebo group, where neither medication class was linked to progression-free or overall survival. The interaction between treatment and proton pump inhibitor exposure was statistically significant for both progression-free survival (p=0.023) and overall survival (p<0.0001); the interaction with antibiotics was not. The authors note that the analysis is observational and cannot show that the medications caused the poorer outcomes.

A possible interaction with the drug, not just sicker patients

Because the association was present with durvalumab but not with placebo, the investigators described the medications as potentially attenuating the drug’s benefit rather than simply marking patients with worse prognosis. They set the finding against the curative intent of treatment at this stage of disease:

“Given the curative intent of treatment in this setting, these results underscore the importance of careful evaluation of concomitant medications when clinically appropriate.”Brunetti et al., The Lancet Oncology (2026)

The authors call for prospective studies with standardised exposure definitions and integrated microbiome profiling to test whether the association is causal and to inform antibiotic stewardship in this setting.