PPI, Antibiotic Exposure Associated With Attenuated Immunotherapy Benefit in Stage 3 NSCLC

Baseline exposure to proton pump inhibitors (PPIs) and, to a lesser degree, systemic antibiotics was associated with attenuated benefit from consolidation durvalumab (Imfinzi; AstraZeneca) after chemoradiotherapy in patients with unresectable stage 3 non–small cell lung cancer (NSCLC), according to a post-hoc analysis of the phase 3 PACIFIC trial (NCT02125461) published in Lancet Oncology.¹

The analysis included 660 of the 713 patients randomly assigned in PACIFIC between May 2014 and April 2016, of whom 449 received durvalumab and 211 received placebo. Median follow-up in the pooled population was 62.4 months. At baseline, 263 patients (40%) had been exposed to PPIs and 69 (10%) to antibiotics.²

Among durvalumab-treated patients, baseline PPI exposure was associated with shorter progression-free survival (PFS; HR, 1.57 [95% CI 1.28-1.93]; P < .0001) and shorter overall survival (OS; HR, 1.66 [95% CI 1.30-2.13]; P < .0001) compared with no exposure, said Alessio Cortellini, MD, PhD, of Imperial College London, and colleagues. Baseline antibiotic exposure was associated with shorter PFS (HR, 1.50 [95% CI 1.08-2.10]; P = .016), but there was no significant difference in OS (HR, 1.33 [95% CI 0.90-1.97]; P =.16).²

Neither PPI nor antibiotic exposure was associated with changes in PFS or OS among patients treated with placebo. Treatment-by-exposure interaction tests were significant for PPIs (PFS: P = .023; OS: P < .0001) but not for antibiotics, a pattern the authors described as supporting a treatment-dependent rather than a purely prognostic association.¹

Further, in multivariable models adjusted for baseline characteristics, the PPI associations persisted in the durvalumab group, and antibiotic exposure remained independently associated with PFS but not OS. The findings were consistent with prior studies in solid tumors, suggesting that PPI exposure is associated with inferior immune checkpoint inhibitor outcomes.¹

Exposure to PPIs was defined as any oral or intravenous administration within 30 days before randomization and antibiotic exposure as any oral or intravenous antibiotic given for any indication within a prespecified window of 30 days before treatment initiation.

"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," Cortellini and colleagues said. "Given the curative intent of treatment in this setting, these results underscore the importance of careful evaluation of concomitant medications when clinically appropriate."^1,2

Because PPIs and antibiotics are frequently prescribed in the peri-concurrent chemoradiotherapy setting, oncology and health-system pharmacists are positioned to identify baseline exposure through medication reconciliation, evaluate whether acid suppression remains indicated, and support antibiotic stewardship.

Arthi Sridhar, MD, and John D. Minna, MD, both of UT Southwestern Medical Center in Dallas, said that the findings, "…support a pragmatic shift: judicious use of PPIs, active antibiotic stewardship at each decision point, and minimizing avoidable polypharmacy in the absence of robust data on how most drugs affect the gut microbiome." Because immune checkpoint inhibitors are now used in most cases of non–driver-mutated NSCLC, "…even modest interventions could yield a large population benefit," they noted.^2,3

The authors emphasized that the analysis was retrospective and was not prespecified in the original PACIFIC protocol. Reasons for prescribing PPIs and antibiotics—as well as details of their timing, duration, and adherence—were unavailable, "…so confounding by indication cannot be excluded."¹

Residual confounding remained possible despite multivariable adjustment, the authors added, citing baseline imbalances such as the lower frequency of nonsquamous histology among PPI-exposed patients (49% vs 59%; P = .014). Sridhar and Minna called for prospective studies "with standardized exposure definitions and prespecified timing windows" to determine whether the 2 drug classes attenuate the benefit of immunotherapy or instead mark higher-risk patients.^2,3

REFERENCES

1. Brunetti L, Santo V, Pinato DJ, et al. 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. Lancet Oncol. 2026:S1470-2045(26)00191-9. doi:10.1016/S1470-2045(26)00191-9

2. Bassett M. Common Meds Linked to Reduced Immunotherapy Benefit in Lung Cancer Trial. MedPage Today. July 6, 2026. Accessed July 14, 2026. https://www.medpagetoday.com/hematologyoncology/lungcancer/122068

3. Sridhar A, Minna JD. Co-medications and gut microbiome in NSCLC immunotherapy. Lancet Oncol. 2026. doi:10.1016/S1470-2045(26)00289-5