Proton Pump Inhibitor Use May Impact Response to Atezolizumab in Patients with Bladder Cancer

In this study, patients with advanced urothelial carcinoma saw worse outcomes with proton pump inhibitor (PPI) use when treated with atezolizumab, compared with those who were not treated with PPIs.

A study published in Clinical Cancer Research suggested that proton pump inhibitor (PPI) use is a negative prognostic marker in patients with advanced urothelial carcinoma treated with the immune checkpoint inhibitor (ICI) therapy atezolizumab (Tecentriq), but not chemotherapy.1

Additionally, the study results indicated that PPIs affect the extent of ICI efficacy, though this finding requires further investigation.

“There is growing concern that an altered gut microbiome could negatively impact the efficacy of immune checkpoint inhibitors,” first-author Ashley Hopkins, PhD, an early-career research fellow at Flinders University in Australia, said in a press release.2 “Given that approximately 30 percent of cancer patients use PPIs, often for extended time periods, there is an urgent need to determine if PPIs influence the efficacy of immune checkpoint inhibitors.”

Using individual participant data from the IMvigor210 trial, a single-arm trial of atezolizumab in 429 patients, and the IMvigor211 trial, a phase 3 randomized trial of atezolizumab versus chemotherapy in 931 patients, researchers assessed the association between PPI use and overall survival (OS) and progression-free survival (PFS). Notably, PPI use was defined as any PPI administration between 30 days before and 30 days after treatment initiation.

Of the total cohort of 1360 patients with advanced urothelial carcinoma, 471 (35%) received a PPI within the 60-day window. Overall, PPI use was associated with significantly worse OS (HR = 1.52; 95% CI, 1.27-1.83; P < .001) and PFS (HR, 1.38; 95% CI, 1.18-1.62; P < .001) with atezolizumab, but not chemotherapy (P > .05).

Specifically in the randomized cohort of patients in the IMvigor211 study, the treatment effect of atezolizumab on OS versus chemotherapy was 1.04 (95% CI, 0.81-1.34) for PPI users, compared with 0.69 (95% CI, 0.56-0.84) for PPI nonusers (Pinteraction = .013). Moreover, similar associations were observed in a PD-L1 IC2/3 population of patients.

“The findings of the analysis herein demonstrate the potential significance of PPIs, where PPI users had no atezolizumab benefit, while PPI nonusers did gain from atezolizumab in both the PD-L1 IC2/3 population and the total population,” the authors explained. “Albeit there was a trend toward an effect, there was no statistical evidence to indicate PPI use was associated with varying atezolizumab benefit within the PD-L1 IC0/1 population.”

Given that approximately 30% of patients with cancer use PPIs, usually for extended periods of time, the investigators concluded that there is a critical need to conclusively determine if PPIs influence ICI efficacy.

Moving forward, researchers indicated future research should evaluate other ICIs, other cancer types, first-line ICI use, combination ICI use, and combination chemotherapy approaches. Further, they recommended that future research also evaluate the impact of concomitantly using PPIs and antibiotics.

“PPIs are overused, or inappropriately used, in patients with cancer by up to 50 percent, seemingly from a perspective that they will cause no harm,” Hopkins said. “The findings from this study suggest that non-critical PPI use needs to be approached very cautiously, particularly when an immune checkpoint inhibitor is being used to treat urothelial cancer.”


1. Hopkins AM, Kichenadasse G, Karapetis CS, Rowland A, Sorich MJ. Concomitant Proton Pump Inhibitor Use and Survival in Urothelial Carcinoma Treated with Atezolizumab. Clinical Cancer Research. doi: 10.1158/1078-0432.CCR-20-1876

2. Proton Pump Inhibitors May Affect Responses to Atezolizumab in Patients with Urothelial Cancer [news release]. Published September 15, 2020. Accessed September 15, 2020.