As reported in The Lancet Oncology by Brunetti et al, a post hoc analysis of the phase III PACIFIC trial showed that baseline exposure to proton pump inhibitors and antibiotics was associated with inferior outcomes among patients with unresectable stage III non–small cell lung cancer (NSCLC) treated with durvalumab after chemoradiotherapy, but not among those who received placebo.
Study Details
PACIFIC was a randomized, double-blind, placebo-controlled phase III trial of durvalumab after concurrent chemoradiotherapy in patients with unresectable stage III NSCLC. Eligible patients had no disease progression after at least two cycles of concurrent chemoradiotherapy and were randomly assigned 2:1 to receive durvalumab at 10 mg/kg intravenously every 2 weeks for up to 12 months or placebo.
The current post hoc analysis used the final 5-year data cutoff from the completed trial and included 660 treated patients who had consented to exploratory analyses: 449 in the durvalumab group and 211 in the placebo group. Baseline proton pump inhibitor exposure was defined as any oral or intravenous use within 30 days before randomization; systemic antibiotic exposure was defined as any oral or intravenous antibiotic use within 30 days before treatment initiation.
The coprimary endpoints of the post hoc analysis were progression-free survival and overall survival according to baseline exposure to proton pump inhibitors and systemic antibiotics. Among the 660 patients, 263 (40%) had baseline exposure to proton pump inhibitors and 69 (10%) had baseline exposure to antibiotics. Median follow-up in the pooled population was 62.4 months.
Key Findings
In the durvalumab group, baseline exposure to proton pump inhibitors was associated with significantly shorter progression-free survival compared with no exposure: median progression-free survival was 9.4 months vs 17.2 months (hazard ratio [HR] = 1.57, P < .0001). Overall survival was also shorter among patients with proton pump inhibitor exposure: median overall survival was 33.0 months vs 57.9 months (HR = 1.66, P < .0001).
In contrast, no significant differences in progression-free survival or overall survival were observed according to proton pump inhibitor exposure in the placebo group. Interaction analyses suggested that the association between proton pump inhibitor exposure and outcomes was treatment-dependent.
Baseline antibiotic exposure in the durvalumab group was associated with shorter progression-free survival compared with no exposure: median progression-free survival was 9.2 months vs 15.6 months (HR = 1.50, P = .016). However, antibiotic exposure was not associated with a significant difference in overall survival: median overall survival was 37.7 months vs 49.2 months (HR = 1.33, P = .16).
In the placebo group, antibiotic exposure was not associated with significant differences in progression-free survival or overall survival. A similar treatment-by-exposure interaction was not observed for antibiotic exposure.
In adjusted multivariable analyses, proton pump inhibitor exposure remained associated with increased risks of disease progression and death in the durvalumab group, but not in the placebo group. Antibiotic exposure was independently associated with shorter progression-free survival in the durvalumab group but not with overall survival.
The investigators noted that the findings should be interpreted as treatment-dependent associations rather than proof of causality, because reasons for prescribing proton pump inhibitors and antibiotics, as well as details of timing, duration, and adherence, were unavailable.
The investigators concluded: “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.”
Alessio Cortellini, MD, PhD, of the Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, is the corresponding author for The Lancet Oncology article.
DISCLOSURE: For full disclosures of the study authors, visit thelancet.com.
