A post-hoc analysis of the PACIFIC trial found an association between baseline exposure to proton pump inhibitors (PPIs) and reduced survival among patients with unresectable stage III non-small cell lung cancer who received durvalumab. Patients treated with durvalumab who had baseline exposure to PPIs experienced shorter progression-free survival (median 9.4 months vs 17.2 months) and shorter overall survival (median 33 months vs 57.9 months) compared to those without PPI exposure.

The analysis also indicated that baseline exposure to antibiotics was associated with shorter progression-free survival (9.2 months vs 15.6 months) in the durvalumab group. However, antibiotic exposure was not associated with a change in overall survival (37.7 months vs 49.2 months). For patients in the placebo group, exposure to PPIs or antibiotics showed no association with changes in progression-free or overall survival. In the post-hoc analysis, 40% of patients received PPIs at baseline, and 10% received antibiotics.

"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 III NSCLC," said Alessio Cortellini, MD, PhD. "Given the curative intent of treatment in this setting, these results underscore the importance of careful evaluation of concomitant medications when clinically appropriate."

"These findings support a pragmatic shift: judicious use of proton pump inhibitors, 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," said Arthi Sridhar, MD. "Even modest interventions could yield a large population benefit." Sridhar added, "Prospective studies with standardized exposure definitions and pre-specified timing windows should validate whether proton pump inhibitors and antibiotics attenuate the benefit of immunotherapy or mark higher-risk patients."

The PACIFIC trial enrolled 713 patients from May 2014 to April 2016, who were randomly assigned in a 2:1 ratio to receive durvalumab or a matched placebo in a double-blind manner. The original trial determined that durvalumab following chemoradiotherapy improved survival for patients with unresectable stage III non-small cell lung cancer, leading it to become the standard of care. The post-hoc analysis included 660 patients, with 449 receiving durvalumab and 211 receiving placebo. Approximately 69% of patients in the analysis were men, 64.2% were white, and 23.1% were Asian. Median follow-up in the pooled population was 62.4 months. Exposure to PPIs was defined as any oral or intravenous administration within 30 days before randomization, while exposure to systemic antibiotics was defined as any oral or intravenous antibiotic administered within a 30-day window before treatment initiation.

Why It Matters

This post-hoc analysis identifies a potential interaction between commonly prescribed supportive medications and cancer immunotherapy, specifically durvalumab, which is the standard of care for unresectable stage III non-small cell lung cancer. The findings suggest that background medication use, particularly PPIs and antibiotics, might influence the effectiveness of immunotherapy. The analytical approach was retrospective and not prespecified in the original trial protocol, meaning it focused on previously collected data without a predefined hypothesis for these specific medication interactions. This limits the ability to draw definitive causal conclusions, as reasons for prescribing these medications, along with timing, duration, and patient adherence details, were unavailable.

A retrospective study from South Korea linked PPI use during palbociclib treatment to higher risks of progression and death among breast cancer patients. The current analysis suggests a need for further prospective studies to confirm these associations and to guide clinical practice regarding concomitant medications during immunotherapy for non-small cell lung cancer.