Key Takeaways
- In the PACIFIC trial, durvalumab following chemoradiotherapy significantly improved survival in patients with unresectable stage III non-small cell lung cancer, and became the standard of care in this setting.
- In a post-hoc analysis of the trial, exposure to proton pump inhibitors was associated with worse survival among patients in the durvalumab group.
- Exposure to antibiotics was also associated with shorter progression-free survival compared with no exposure, but not overall survival.
Exposure to proton pump inhibitors (PPIs) was associated with worse progression-free survival (PFS) and overall survival (OS) in patients with locally advanced non-small cell lung cancer (NSCLC) who were treated with durvalumab (Imfinzi) after chemoradiotherapy, according to a post-hoc analysis of the PACIFIC trial.
Among patients treated with durvalumab, baseline exposure to PPIs was associated with shorter PFS (median 9.4 vs 17.2 months, HR 1.57, 95% CI 1.28-1.93, P<0.0001) and OS (median 33 vs 57.9 months, HR 1.66, 95% CI 1.30-2.13, P<0.0001) compared with no exposure, reported Alessio Cortellini, MD, PhD, of Imperial College London, and colleagues.
Meanwhile, baseline exposure to antibiotics was associated with shorter PFS (9.2 vs 15.6 months, HR 1.50, 95% CI 1.08-2.10, P=0.016) compared with no exposure, but there was no significant change in OS (37.7 vs 49.2 months, HR 1.33, 95% CI 0.90-1.97, P=0.16), they noted in Lancet Oncology.
Exposure to PPIs or antibiotics was not associated with changes in PFS and OS among patients treated with placebo.
"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," wrote Cortellini and colleagues. "Given the curative intent of treatment in this setting, these results underscore the importance of careful evaluation of concomitant medications when clinically appropriate."
The results are in line with prior studies suggesting that exposure to PPIs is associated with inferior outcomes with immune checkpoint inhibitors -- "plausibly through microbiome disruption" -- in patients with solid tumors, they pointed out. For example, a retrospective study from South Korea indicated that using PPIs during treatment with palbociclib (Ibrance) was linked to higher risks of progression and death among breast cancer patients.
In a comment accompanying the study, Arthi Sridhar, MD, and John D. Minna, MD, both of the UT Southwestern Medical Center in Dallas, noted that the 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."
In this analysis, 40% of patients received PPIs and 10% received antibiotics at baseline. Considering that immune checkpoint inhibitors are now used in most cases of non-driver-mutated NSCLC, "even modest interventions could yield a large population benefit," Sridhar and Minna wrote.
"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," they suggested.
In the landmark PACIFIC trial, durvalumab following chemoradiotherapy significantly improved PFS and OS compared with placebo in patients with unresectable stage III NSCLC with squamous and non-squamous histology, and became the standard of care in this setting.
In the phase III trial, eligible patients were randomly assigned 2:1 to durvalumab or matched placebo in a double-blind manner. Of the 713 patients randomly assigned from May 2014 to April 2016, 660 were included in the post-hoc analysis, of whom 449 received durvalumab and 211 received placebo. About 69% 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 of PPIs within 30 days before randomization, while exposure to systemic antibiotics was defined as any oral or intravenous antibiotic administered for any indication within a prespecified time window of 30 days before treatment initiation.
Cortellini and colleagues noted that this was a retrospective analysis and was not prespecified in PACIFIC's original protocol.
"Reasons for prescribing proton pump inhibitors and antibiotics, as well as details of their timing, duration, and adherence were unavailable, so confounding by indication cannot be excluded," they added.