Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: pooled post hoc analyses of the OAK and POPLAR trials

Abstract

Background: Preclinical data have shown that proton pump inhibitors (PPI) can modulate the microbiome, and singlearm studies suggested that antibiotics (ATB) may decrease the efficacy of immune checkpoint inhibitors (ICI), but randomized controlled trial data are lacking. This pooled analysis evaluated the effect of ATB and PPI on outcome in patients randomized between ICI and chemotherapy. Patients and methods: This retrospective analysis used pooled data from the phase II POPLAR (NCT01903993) and phase III OAK (NCT02008227) trials, which included 1512 patients with previously treated non-small-cell lung cancer (NSCLC) randomly assigned to receive atezolizumab (n ¼ 757) or docetaxel (n ¼ 755). The main objective of this analysis was to assess the impact of ATB and PPI use on overall survival (OS) and progression-free survival (PFS). Results: A total of 169 (22.3%) patients in the atezolizumab group and 202 (26.8%) in the docetaxel group received ATB, and 234 (30.9%) and 260 (34.4%), respectively, received PPI. Multivariate analysis in all patients revealed that ATB were associated with shorter OS [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.04e1.39], as was PPI (HR 1.26, 95% CI 1.10e1.44). Within the atezolizumab population, OS was significantly shorter in patients who received ATB (8.5 versus 14.1 months, HR 1.32, 95% CI 1.06e1.63, P ¼ 0.01) or PPI (9.6 versus 14.5 months, HR 1.45, 95% CI 1.20e1.75, P ¼ 0.0001). PPI use was associated with shorter PFS in the atezolizumab population (1.9 versus 2.8 months, HR 1.30, 95% CI 1.10À1.53, P ¼ 0.001). There was no association between ATB and PPI use and PFS or OS within the docetaxel population. Conclusion:In this unplanned analysis from two randomized trials, data suggest that ATB or PPI use in patients with metastatic NSCLC is associated with poor outcome and may influence the efficacy of ICI.

<p>Management of Immune Checkpoint Inhibitor Toxicities</p>

“…This observation was not found for the docetaxel arms. 25 Similar data were also observed for other cancer types like renal cell carcinoma. 26 This phenomenon could be explained by the role of the microbiota.…”

Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice

“…6 7 In the case of systemic antibiotics, the evidence for a causative effect seems stronger and more plausible in view of their capacity to perturbate the gut microbiome, a renown determinant of response to ICIs. [8][9][10] Nevertheless, the risk of collinearity with the underlying cause for the antibiotics prescription (eg, infections which might subtend to poorer clinical condition), has yet to be fully discriminated.…”

“…Proton pump inhibitors were associated to decreased progression-free survival (PFS) and overall survival (OS) in non-small-cell-lung-cancer (NSCLC) and melanoma patients receiving programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint inhibitors, 9 11 while some studies investigated the impact of other concomitant medication, such as non-steroidal anti-inflammatory drugs (NSAIDs), metformin, aspirin, β-blockers and statins, without conclusive results. 12 13 …”

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

“…The composition and the diversification of the gut microbiota play an important role in the response to ICI as shown by Frankel et al, who reported that patients who had Bacteroidescaccae in their gut flora had better responses to ICI [ 264 ]. The use of antibiotics 30 to 60 days prior to treatment with ICI and the use of PPI have been shown to have a deleterious effect on ICI efficacy, as reported by Chalabi et al [ 265 ], and this may be due to the decrease in the diversity of bacterial species and an increase gastric pH, which affects gut microbiomes [ 266 , 267 ]. The gut microbiota and its role in ICI resistance is still not clearly understood, and further studies are needed to further clarify its role.…”