Concomitant Proton Pump Inhibitor Use and Survival in Urothelial Carcinoma Treated with Atezolizumab

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Abstract

Purpose: Emerging evidence indicates that gut microbiota dysbiosis can reduce the effectiveness of immune checkpoint inhibitors (ICI). Proton pump inhibitors (PPI) are known to induce gut microbiota changes. However, little is known on the effects of PPIs on outcomes with ICI therapy, and it has not been explored in urothelial cancer treatment.

Experimental Design: Individual-participant data from the advanced urothelial cancer trials, IMvigor210 (single-arm atezolizumab trial, n ¼ 429) and IMvigor211 (phase III randomized trial of atezolizumab vs. chemotherapy, n ¼ 931) were pooled in a Cox proportional hazard analysis assessing the association between PPI use and overall survival (OS) and progression-free survival (PFS). PPI use was defined as any PPI administration between 30 days prior and 30 days after treatment initiation.

Results: Of the 1,360 participants, 471 (35%) received a PPI within the 60-day window. PPI use was associated with significantly worse OS [HR (95% confidence interval (CI)) ¼ 1.52 (1.27-1.83), P < 0.001] and PFS [1.38 (1.18-1.62), P < 0.001] with atezolizumab, but not chemotherapy (P > 0.05). In the randomized cohort of IMvigor211, the OS treatment effect [HR (95% CI)] of atezolizumab versus chemotherapy was 1.04 (0.81-1.34) for PPI users, compared with 0.69 (0.56-0.84) for PPI nonusers (Pinteraction ¼ 0.013). Similar associations were noted in the PD-L1 IC2/3 population.

Conclusions: This study indicates PPI use is a negative prognostic marker in advanced urothelial carcinoma treated with ICI therapy, but not chemotherapy. Furthermore, the analysis suggests PPIs influence the magnitude of ICI efficacy, and this warrants further investigation.

Original languageEnglish
Pages (from-to)5487-5493
Number of pages7
JournalClinical Cancer Research
Volume26
Issue number20
DOIs
Publication statusPublished - Oct 2020

Keywords

  • gut microbiota dysbiosis
  • immune checkpoint inhibitors
  • Immune checkpoint inhibitors (ICI)
  • Proton pump inhibitors
  • Proton pump inhibitors (PPI)
  • ICI therapy
  • Urothelial Carcinoma
  • urothelial cancer treatment
  • Atezolizumab

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