Baseline use of proton pump inhibitors (PPIs) and, to a lesser extent, systemic antibiotics appears to lessen the benefit of consolidation durvalumab after chemoradiotherapy in patients with unresectable stage 3 non‑small cell lung cancer (NSCLC), according to a recent post‑hoc analysis of the phase 3 PACIFIC trial.
Study details and main findings
The analysis examined 660 of the 713 participants who were randomly assigned in the PACIFIC trial between May 2014 and April 2016. Of those, 449 received durvalumab and 211 were given placebo.
Median follow‑up across the pooled cohort was 62.4 months. At baseline, 263 patients (40 %) had taken a PPI and 69 (10 %) had been prescribed an antibiotic within 30 days before randomization.
Among patients treated with durvalumab, baseline exposure to PPIs was linked to a shorter progression‑free survival (PFS) with a hazard ratio (HR) of 1.57 (95 % CI 1.28‑1.93, P < .0001) and a shorter overall survival (OS) with an HR of 1.66 (95 % CI 1.30‑2.13, P < .0001) compared with those who had no such exposure. Antibiotic use at baseline was associated with reduced PFS (HR 1.50, 95 % CI 1.08‑2.10, P = .016) but did not significantly affect OS (HR 1.33, 95 % CI 0.90‑1.97, P = .16).
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In the placebo arm, neither PPIs nor antibiotics showed any association with changes in PFS or OS. Interaction tests between treatment and exposure were significant for PPIs (PFS P = .023; OS P < .0001) but not for antibiotics, suggesting a treatment‑dependent effect rather than a purely prognostic one.
Interpretation and clinical implications
Multivariable models that adjusted for baseline characteristics confirmed that the adverse associations with PPIs persisted in the durvalumab group. Antibiotic exposure remained independently linked to shorter PFS but not to OS. These results echo earlier observations in other solid tumors, where PPI use has been tied to poorer outcomes with immune checkpoint inhibitors.
Exposure definitions were specific: any oral or intravenous PPI administered within 30 days before randomization, and any oral or intravenous antibiotic given for any indication within the same 30‑day window. The authors caution that the analysis is retrospective and was not prespecified in the original PACIFIC protocol. Details such as why the medications were prescribed, their exact timing, duration, and patient adherence were not captured, leaving room for potential confounding by indication.
Residual confounding cannot be ruled out despite adjustments. For example, patients who received PPIs had a lower frequency of nonsquamous histology (49 % vs 59 %; P = .014). The authors call for prospective studies with standardized exposure definitions and prespecified timing windows to clarify whether PPIs and antibiotics truly diminish immunotherapy benefit or simply mark higher‑risk patients.
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Given the frequent prescription of PPIs and antibiotics during the peri‑concurrent chemoradiotherapy period, oncology and health‑system pharmacists are in a position to identify baseline exposure through medication reconciliation, assess the necessity of acid suppression, and promote antibiotic stewardship. One perspective suggests that even modest reductions in unnecessary PPI use or more disciplined antibiotic prescribing could translate into a sizable population benefit, especially as immune checkpoint inhibitors become standard for non‑driver‑mutated NSCLC.
The findings may influence prescribing habits.
Quotes from investigators
Alessio Cortellini, MD, PhD, of Imperial College London, and colleagues noted, “These findings suggest that commonly prescribed supportive medications such as proton pump inhibitors and antibiotics could be associated with attenuation of benefit from consolidation immunotherapy in patients with unresectable stage 3 NSCLC.” They added, “Given the curative intent of treatment in this setting, these results highlight the importance of careful evaluation of concomitant medications when clinically appropriate.”
Arthi Sridhar, MD, and John D. Minna, MD, of UT Southwestern Medical Center in Dallas emphasized a “pragmatic shift” toward judicious PPI use, active antibiotic stewardship, and minimizing avoidable polypharmacy, noting that “even modest interventions could yield a large population benefit.”