TOPLINE

In an analysis of the PACIFIC trial, baseline exposure to proton pump inhibitors (PPI) or antibiotics was associated with poorer survival outcomes in patients with locally advanced non-small cell lung cancer (NSCLC) receiving durvalumab after chemoradiotherapy.

METHODOLOGY

• Studies have tied exposure to antibiotics and PPI to reduced immune checkpoint inhibitor efficacy in patients with metastatic NSCLC, possibly through gut microbiome disruption. Whether the association extends to patients with earlier-stage disease is unclear.
• Researchers conducted a post hoc analysis of the phase 3 PACIFIC trial, which randomly assigned 660 patients with unresectable stage III NSCLC to either durvalumab (every 2 weeks for up to 12 months) or placebo following concurrent chemoradiotherapy.
• Overall, 40% of the patients had baseline exposure to PPI (any oral or intravenous [IV] administration within 30 days before randomization), whereas 10% had baseline antibiotic exposure (oral or IV administration within 30 days before durvalumab/placebo initiation).
• Co-primary endpoints were progression-free survival and overall survival, based on the trial’s final 5-year data cutoff. Median follow-up was just over 62 months.

TAKEAWAY

• In the durvalumab group, baseline PPI exposure was associated with significantly shorter progression-free survival at a median of 9.4 months vs 17.2 months with no PPI exposure (hazard ratio [HR], 1.57; P < .0001). Similarly, median overall survival was shorter, at 33 months vs 58 months (HR, 1.66; P < .0001).
• Baseline antibiotic exposure in the durvalumab group was associated with shorter median progression-free survival, at 9.2 months vs 15.6 months (HR, 1.50; P = .016). There was no significant association with overall survival (median, 37.7 months vs 49.2 months; HR, 1.33; P = .160).
• Exposure to the medications showed no association with survival outcomes in the placebo group. The interaction between treatment and PPI, though not antibiotics, was significant for both progression-free survival (P = .023) and overall survival (P < .0001) — supporting a treatment-dependent pattern.
• In the durvalumab group only, there was a graded pattern across incremental exposure categories: Patients with no exposure had the most favorable outcomes, followed by those exposed to a single drug class; those exposed to both PPI and antibiotics had the shortest progression-free and overall survival.

IN PRACTICE

“Overall, these results contribute to growing evidence that concomitant medications might modulate the efficacy of immune checkpoint inhibitors and provide the first suggestion of such an association in the curative-intent stage III NSCLC setting of a [randomized] trial population,” the study authors wrote. They cautioned, however, that prospective validation is needed before translating the findings into clinical decision-making.

SOURCE

The study, led by Leonardo Brunetti, MD, of Fondazione Policlinico Universitario Campus Bio-Medico in Rome, Italy, was published online in Lancet Oncology.

LIMITATIONS

Indications for PPI and antibiotics, as well as details of timing, duration, and adherence were unavailable, so confounding by indication cannot be excluded. Residual confounding remains possible despite multivariable adjustment. Exposure definitions were restricted to a 30-day window before treatment initiation to minimize reverse causation and misclassification bias.

DISCLOSURES

The study received no direct funding. Several co-authors reported financial relationships with durvalumab maker AstraZeneca and numerous other pharmaceutical companies. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.