PPIs may affect responses to atezolizumab in patients with urothelial cancer

Bottom Line: Proton pump inhibitor (PPI) use was associated with worse outcomes in patients with urothelial cancer treated with the immunotherapeutic atezolizumab (Tecentriq), compared with patients who did not use PPIs.

Journal in Which the Study was Published: Clinical Cancer Research, a journal of the American Association for Cancer Research

Author: Ashley Hopkins, PhD, an early-career research fellow at Flinders University in Australia

Background: PPIs are commonly used medications for acid reflux, heartburn, and ulcers. Recent evidence indicates that PPIs cause significant changes to the gut microbiome, which plays an important role in regulating immune function, explained Hopkins. “There is growing concern that an altered gut microbiome could negatively impact the efficacy of immune checkpoint inhibitors,” he said. “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.” Five immune checkpoint inhibitors are currently approved in the United States for the treatment of urothelial cancer.

How the Study was Conducted: In this study, Hopkins and colleagues evaluated how PPI use impacted survival outcomes in patients with urothelial cancer (commonly referred to as bladder cancer) who were treated with the immune checkpoint inhibitor atezolizumab or with chemotherapy. The researchers examined data from the IMvigor210 and IMvigor211 clinical trials, which evaluated atezolizumab in patients with locally advanced or metastatic urothelial cancer. IMvigor210 was a single-arm study evaluating atezolizumab in previously treated or treatment-naïve patients, while IMvigor211 was a randomized control trial that compared atezolizumab with chemotherapy in previously treated patients.

Results: Of the 429 patients enrolled in IMvigor210 who received atezolizumab treatment, 33 percent had used PPIs within the 30 days before or the 30 days after initiating atezolizumab. In IMvigor211, 31 percent of the 467 patients treated with atezolizumab and 40 percent of the 185 patients treated with chemotherapy had used PPIs within the 60-day window.

Hopkins and colleagues found that among patients treated with atezolizumab, those who used PPIs had a 68 percent greater risk of death, a 47 percent greater risk of disease progression, and a 54 percent lower objective response rate than those who did not use PPIs. PPI use was associated with worse outcomes even after adjusting for several patient and tumor characteristics. In contrast, PPI use did not significantly impact overall survival, progression-free survival, or the objective response rate for patients treated with chemotherapy.

Among PPI non-users, those treated with atezolizumab had a 31 percent lower risk of death than patients treated with chemotherapy. However, among PPI users, there were no significant differences in survival outcomes between patients treated with atezolizumab and chemotherapy, suggesting that PPI use impacted the magnitude of atezolizumab benefit.

Author’s Comments: “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,” said Hopkins. “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.”

Study Limitations: A limitation of the study is that it was a retrospective analysis that evaluated a single immune checkpoint inhibitor in one cancer type. Hopkins suggested that future research should evaluate the impact of PPI use on other immune checkpoint inhibitors, additional cancer types, and different combinations of immune checkpoint inhibitors or chemotherapy regimens.


Funding & Disclosures: The study was supported by funds from the National Breast Cancer Foundation (Australia) and Cancer Council South Australia. Hopkins declares no conflicts of interest.

About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes 47,000?laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 127 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops–the largest of which is the AACR Annual Meeting, with more than 100,000 attendees for the 2020 virtual meetings and more than 22,500 attendees for past in-person meetings. In addition, the AACR publishes nine prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit?http://www.AACR.org.

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