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