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

M Chalabi; A Cardona; D R Nagarkar; A Dhawahir Scala; D R Gandara; A Rittmeyer; M L Albert; T Powles; M Kok; F G Herrera; imCORE working group of early career investigators

doi:10.1016/j.annonc.2020.01.006

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

Ann Oncol. 2020 Apr;31(4):525-531. doi: 10.1016/j.annonc.2020.01.006. Epub 2020 Jan 16.

Authors

Affiliations

¹ Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: m.chalabi@nki.nl.
² PD Biometrics, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
³ Cancer Immunology, Genentech, Inc., South San Francisco, USA.
⁴ Department of Thoracic Oncology, UC Davis Comprehensive Cancer Center, Sacramento, USA.
⁵ Department of Thoracic Oncology, Pulmonary Clinic Immenhausen, Immenhausen, Germany.
⁶ Centre for Experimental Cancer Medicine, Barts Cancer Institute, London, UK.
⁷ Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁸ Immune Oncology Service, Lausanne University Hospital, Ludwig Institute for Cancer Research, Lausanne, Switzerland. Electronic address: Fernanda.Herrera@chuv.ch.

PMID: 32115349
DOI: 10.1016/j.annonc.2020.01.006

Abstract

Background: Preclinical data have shown that proton pump inhibitors (PPI) can modulate the microbiome, and single-arm 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 = 757) or docetaxel (n = 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) 1.04-1.39], as was PPI (HR 1.26, 95% CI 1.10-1.44). Within the atezolizumab population, OS was significantly shorter in patients who received ATB (8.5 versus 14.1 months, HR 1.32, 95% CI 1.06-1.63, P = 0.01) or PPI (9.6 versus 14.5 months, HR 1.45, 95% CI 1.20-1.75, P = 0.0001). PPI use was associated with shorter PFS in the atezolizumab population (1.9 versus 2.8 months, HR 1.30, 95% CI 1.10-1.53, P = 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.

Keywords: antibiotics; immune checkpoint inhibitors; lung cancer; microbiota; proton pump inhibitors.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents
Antibodies, Monoclonal, Humanized
Carcinoma, Non-Small-Cell Lung* / drug therapy
Humans
Lung Neoplasms* / drug therapy
Proton Pump Inhibitors
Retrospective Studies

Substances

Anti-Bacterial Agents
Antibodies, Monoclonal, Humanized
Proton Pump Inhibitors
atezolizumab

Associated data

ClinicalTrials.gov/NCT01903993
ClinicalTrials.gov/NCT02008227