Efficacy of Atezolizumab in Patients With Advanced NSCLC Receiving Concomitant Antibiotic or Proton Pump Inhibitor Treatment: Pooled Analysis of Five Randomized Control Trials

Ashley M Hopkins; Sarah Badaoui; Ganessan Kichenadasse; Christos S Karapetis; Ross A McKinnon; Andrew Rowland; Michael J Sorich

doi:10.1016/j.jtho.2022.02.003

Efficacy of Atezolizumab in Patients With Advanced NSCLC Receiving Concomitant Antibiotic or Proton Pump Inhibitor Treatment: Pooled Analysis of Five Randomized Control Trials

J Thorac Oncol. 2022 Jun;17(6):758-767. doi: 10.1016/j.jtho.2022.02.003. Epub 2022 Feb 17.

Authors

Ashley M Hopkins¹, Sarah Badaoui², Ganessan Kichenadasse³, Christos S Karapetis³, Ross A McKinnon², Andrew Rowland², Michael J Sorich²

Affiliations

¹ College of Medicine and Public Health, Flinders University, Adelaide, Australia. Electronic address: ashley.hopkins@flinders.edu.au.
² College of Medicine and Public Health, Flinders University, Adelaide, Australia.
³ College of Medicine and Public Health, Flinders University, Adelaide, Australia; Department of Medical Oncology, Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Adelaide, Australia.

PMID: 35183773
DOI: 10.1016/j.jtho.2022.02.003

Abstract

Introduction: Gut dysbiosis may reduce immune checkpoint inhibitor (ICI) efficacy. Antibiotics and proton pump inhibitors (PPIs) are commonly used drugs causing gut dysbiosis. There is limited randomized controlled trial (RCT) evidence on whether antibiotics or PPIs impact ICI benefit versus comparator treatments.

Methods: This study pooled five RCTs (IMpower130, IMpower131, IMpower150, OAK, and POPLAR) evaluating atezolizumab in advanced NSCLC. Atezolizumab efficacy (hazard ratio with 95% confidence intervals) was assessed for subgroups on the basis of antibiotic and PPI use at randomization. The association between antibiotic and PPI use with pretreatment peripheral blood immunophenotype was also explored.

Results: Of 4458 participants, 285 received an antibiotic in the 30-day pretreatment and 1225 were using a PPI at treatment initiation. Overall survival efficacy of atezolizumab was similar (p[interaction] = 0.35) for antibiotic users (hazard ratio 95% confidence interval: 0.73 [0.53-0.99]) and antibiotic nonusers (0.82 [0.74-0.91]). Nevertheless, efficacy was reduced (p[interaction] = 0.003) for PPI users (1.00 [0.85-1.17]) compared with PPI nonusers (0.76 [0.69-0.83]). Findings were consistent across RCTs and for progression-free survival. PPI use was associated with 9%, 18%, and 9% lower counts of lymphocytes, CD19+, and CD16+CD56+ immune cells, respectively (p < 0·01).

Conclusions: Reassuringly, atezolizumab efficacy did not differ for antibiotic users. Opposingly, PPI use was consistently associated with decreased atezolizumab efficacy and lower pretreatment counts of lymphocytes, CD19+, and CD16+CD56+ immune cells. Given that approximately 30% of patients with cancer use PPIs, there is an urgent need for evidence on the impacts of PPIs on other ICIs and for the development of guidelines on nonessential PPI use with ICIs.

Keywords: Antibiotics; Atezolizumab; Gut dysbiosis; Non–small cell lung cancer; Proton pump inhibitors; Survival.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / therapeutic use
Antibodies, Monoclonal, Humanized* / therapeutic use
Carcinoma, Non-Small-Cell Lung* / drug therapy
Dysbiosis
Humans
Lung Neoplasms* / drug therapy
Proton Pump Inhibitors / therapeutic use
Randomized Controlled Trials as Topic
Treatment Outcome

Substances

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