Recent evidence indicates that proton pump inhibitors may cause significant changes in the gut microbiota; gut microbiota dysbiosis has been linked to reduced immune checkpoint inhibitor effectiveness. In a retrospective analysis of clinical trials investigating the immune checkpoint inhibitor atezolizumab and atezolizumab vs chemotherapy in patients with urothelial carcinoma, researchers found that proton pump inhibitor use was associated with a significantly higher risk of death in patients treated with atezolizumab. However, the use of proton pump inhibitors did not impact overall or progression-free survival in patients treated with chemotherapy. The study by Hopkins et al was published in Clinical Cancer Research.
Study Methodology
The researchers analyzed patient data from the IMvigor210 (single-arm atezolizumab trial, n = 429) and IMvigor211 (phase III randomized trial of atezolizumab vs chemotherapy, n = 931) clinical trials. The data were pooled in a Cox proportional analysis assessing the association between the use of proton pump inhibitors and overall survival and progression-free survival. Proton pump inhibitor use was defined as any proton pump inhibitor administration between 30 days prior and 30 days after treatment initiation.
KEY POINTS
- Among patients with urothelial cancer treated with atezolizumab, those who used proton pump inhibitors had a 68% greater risk of death, a 47% greater risk of disease progression, and a 54% lower objective response rate those who did not use proton pump inhibitors.
- Among nonusers of proton pump inhibitors, those treated with atezolizumab had a 31% lower risk of death than patients treated with chemotherapy.
- This study suggests that proton pump inhibitor use may alter the magnitude of atezolizumab efficacy compared to chemotherapy.
Study Results
The researchers found that of the 1,360 participants, 471 (35%) received a proton pump inhibitor within the 60-day window. Proton pump inhibitor use was associated with significantly worse overall survival (hazard ratio [HR] = 1.52, 95% confidence interval [CI] = 1.27–1.83, P < .001) and progression-free survival (HR = 1.38, 95% CI = 1.18–1.62, P < .001) in patients treated with atezolizumab, but not in those treated with chemotherapy (P > .05).
In the randomized cohort of IMvigor211, the overall survival treatment effect [HR (95% CI) of atezolizumab vs chemotherapy was 1.04 (0.81–1.34) for proton pump inhibitor users, compared to 0.69 (0.56–0.84) for proton pump inhibitor nonusers (P = .013). Similar associations were noted in the PD-L1 immune checkpoint 2/3 population.
Translational Relevance
Since many patients with cancer use proton pump inhibitors, often for extended periods of time, this study offers important information on how proton pump inhibitor use may alter the magnitude of atezolizumab efficacy compared to chemotherapy.
“Proton pump inhibitors are overused or inappropriately used in patients with cancer by up to 50%, seemingly from a perspective that they will cause no harm,” said lead study author Ashley M. Hopkins, PhD, a research fellow at Flinders University in Australia, in a statement. “The findings from this study suggest that noncritical proton pump inhibitor use needs to be approached very cautiously, particularly when an immune checkpoint inhibitor is being used to treat urothelial cancer.”
Disclosure: For full disclosures of the study authors, visit clincancerres.aacrjournals.org.
