Oncology · Medical Literature
[Articles] 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
Abstract
Baseline exposure to proton pump inhibitors and antibiotics was associated with inferior outcomes with durvalumab, but not with placebo, consistent with potential attenuation of the benefit of durvalumab with proton pump inhibitors and antibiotics in patients with unresectable stage III NSCLC.
Clinical relevance
Does baseline exposure to proton pump inhibitors (PPIs) or antibiotics within 30 days of treatment initiation attenuate the progression-free survival (PFS) and overall survival (OS) benefit of consolidation durvalumab compared with placebo in patients with unresectable stage III NSCLC who have not progressed after concurrent platinum-based chemoradiotherapy? __SNAPSHOT__ {"studyDesign":"Post-hoc analysis of a completed randomized, double-blind, placebo-controlled phase 3 trial (PACIFIC; NCT02125461), using the final 5-year data cutoff. No formal power calculation was performed for this post-hoc analysis.","setting":"Multinational; international academic and community oncology centers participating in the PACIFIC trial","sampleSize":"n=660 (durvalumab: n=449, placebo: n=211); derived from the 713 originally randomized PACIFIC patients after excluding 49 who had not consented to exploratory analyses and 4 who did not receive assigned treatment","population":"Patients aged ≥18 years with unresectable stage III squamous or non-squamous NSCLC, WHO performance status 0–1, without disease progression after ≥2 cycles of concurrent platinum-based chemoradiotherapy. Majority male (68.6%); race reported as White in 64.2%, Asian in 23.1%, Black/African American in 0.7%. PPI exposure was associated with older age (>65 years), ECOG PS 1, and higher PD-L1 expression.","intervention":"Durvalumab 10 mg/kg IV every 2 weeks for up to 12 months, initiated 1–42 days after chemoradiotherapy completion. Exposure of interest: baseline PPI use (any oral or IV administration within 30 days before randomization) or systemic antibiotic use (any administration within 30 days before treatment initiation).","comparator":"Matched placebo IV every 2 weeks for up to 12 months","primaryOutcome":"Co-primary endpoints: progression-free survival (PFS) and overall survival (OS) according to baseline exposure to PPIs and systemic antibiotics, analyzed separately within each treatment arm using Kaplan–Meier estimation, log-rank tests, and multivariable Cox proportional hazards regression","followUp":"Median follow-up 62.4 months (approximately 5 years); data cutoff January 11, 2021","fundingSource":"None (no direct funding reported). Data accessed via Vivli, Inc. from AstraZeneca. Multiple co-authors reported financial relationships with AstraZeneca and other pharmaceutical companies."}
Key findings
Among 660 included patients, 40% (n=263) had baseline PPI exposure and 10% (n=69) had baseline antibiotic exposure. In the durvalumab arm, baseline PPI exposure was associated with significantly shorter PFS (median 9.4 vs. 17.2 months; HR 1.57, 95% CI 1.28–1.93, p<0.0001) and significantly shorter OS (median 33.0 vs. 57.9 months; HR 1.66, 95% CI 1.30–2.13, p<0.0001) compared with PPI-unexposed patients. In multivariable analysis adjusted for baseline clinicopathological characteristics, PPI exposure remained independently associated with increased risk of disease progression in the durvalumab arm (HR 1.59, 95% CI 1.29–1.97, p<0.0001) but not in the placebo arm. Baseline antibiotic exposure was independently associated with shorter PFS in the durvalumab arm in multivariable analysis (HR 1.47, 95% CI 1.05–2.08, p=0.025) but not in the placebo arm; the OS impact of antibiotic exposure was not statistically significant after multivariable adjustment. The presence of a significant treatment-by-exposure interaction for both PPIs and antibiotics supports a treatment-dependent pattern rather than a generic adverse prognostic effect. NNT/NNH not calculable from available data. Adverse event data specific to this post-hoc analysis were not reported. Toposcore-based microbiome analyses were conducted as exploratory outcomes but detailed results were not available in the abstract or secondary sources reviewed.
Practice implications
This analysis provides, to authors' knowledge, the first randomized-trial-derived evidence that baseline PPI and antibiotic use are associated with attenuated benefit from consolidation durvalumab—not merely with a generically poorer prognosis—in unresectable stage III NSCLC, extending prior observations from the metastatic setting to the curative-intent context. The significant treatment-by-exposure interaction is an important methodological strength distinguishing a drug-specific effect from a prognostic confound. However, critical limitations preclude causal conclusions: indications, timing, duration, and adherence data for PPIs and antibiotics were unavailable, meaning confounding by indication cannot be excluded; residual confounding remains possible despite multivariable adjustment. The analysis was post-hoc and exploratory, with no formal power calculation. The 30-day exposure window, while chosen to minimize reverse causation, may not capture clinically meaningful long-term microbiome disruption. PPI-exposed patients were older, had worse performance status, and higher PD-L1 expression—characteristics partially adjusted for but not fully accountable in observational analyses. The population was predominantly male and White/Asian, limiting generalizability to underrepresented groups. These findings should not prompt withholding clinically necessary PPIs or antibiotics; rather, they signal a need for thoughtful prescribing review before and during consolidation immunotherapy. Practice should not change based on this analysis alone—prospective confirmation is required. Only the abstract and secondary reporting sources were available for this summary; full quantitative data from the manuscript (including interaction p-values, Toposcore results, and complete OS antibiotic analyses) may differ in granularity. __LIMITATIONS__ Post-hoc, exploratory analysis with no formal pre-specified power calculation—hypothesis-generating only,Indications for PPI and antibiotic prescriptions, as well as timing, duration, and adherence data, were unavailable—confounding by indication cannot be excluded,Residual confounding remains possible despite multivariable adjustment for baseline clinicopathological factors,PPI-exposed patients were systematically older, had worse ECOG performance status, and were more likely PD-L1-positive—potentially incompletely corrected imbalances,Exposure definitions restricted to a 30-day pre-randomization window may miss clinically relevant chronic use or underestimate microbiome disruption from prior chemoradiotherapy-related exposures,Only 660 of 713 randomized patients included (consent-based selection), introducing possible selection bias,Antibiotic OS associations were not statistically significant in multivariable analysis, limiting strength of inference for this agent class on mortality,Population skewed toward male sex (68.6%) and White/Asian race (87.3%), limiting generalizability,Toposcore microbiome data represented a subset ancillary cohort; full details not available in secondary reporting,Several co-authors had financial relationships with AstraZeneca (durvalumab manufacturer), representing a potential conflicts-of-interest concern, though the study received no direct funding,Only abstract and secondary reports available for this summary; full manuscript data may contain additional nuance __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This post-hoc analysis of the PACIFIC trial signals that baseline PPI and antibiotic exposure are associated with meaningfully attenuated PFS and OS benefit from consolidation durvalumab—but not placebo—in unresectable stage III NSCLC, with a treatment-by-exposure interaction supporting a drug-specific rather than purely prognostic effect. Causality cannot be established given the observational, post-hoc design, unavailability of prescribing indication data, and residual confounding. Clinicians should critically review the necessity of PPIs and antibiotics around the time of durvalumab initiation, but should not withhold medically necessary agents pending prospective validation.