OncoTargets and Therapy (Sep 2018)
PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer
Abstract
David D Stenehjem,1,2 Dao Tran,1 Michael A Nkrumah,1 Shilpa Gupta2,3 1Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, 2Masonic Cancer Center, University of Minnesota, 3Division of Hematology, Oncology and Transplantation, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA Introduction: Until recently, systemic chemotherapy was the only option for treating bladder cancer and outcomes remained dismal. After a long gap of no progress for 40 years, immunotherapy with checkpoint inhibitors (PDL1 and PD1) has revolutionized the treatment paradigm of bladder cancer, with five approved agents to treat platinum-refractory bladder cancer since the first approval of atezolizumab in May 2016. Methods: This review summarizes the most recent data on approved checkpoint inhibitors currently used in management of advanced bladder cancer. Early- and late-phase trials of the five checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab) in advanced bladder cancer are reviewed in detail. This review also describes the potential application of PD1/PDL1 inhibitors in adjuvant and neoadjuvant settings and non-muscle-invasive bladder cancer, as well as with radiation in muscle-invasive bladder cancer treatment. The role of PDL1 and tumor-mutation burden and clinical considerations in choosing a particular immunotherapy are also discussed. Results: The approved checkpoint inhibitors (PD1 and PDL1 inhibitors) have similar efficacy and safety profiles in metastatic platinum-refractory bladder cancer, but they vary in dose and frequency and cost burden. However, only pembrolizumab has shown superiority over standard chemotherapy in a randomized Phase III setting so far. In addition, in the first-line setting for cisplatin-ineligible patients, both pembrolizumab and atezolizumab are US Food and Drug Administration-approved and well tolerated. There is a lack of consensus on the utility of testing for PDL1 as a predictive biomarker, as patients with no PDL1 expression also derive some clinical benefit. Tumor-mutation burden is another predictive biomarker, but needs further validation. Conclusion: Immunotherapy has offered a glimmer of hope to patients with bladder cancer. The current landscape is rapidly evolving, with novel immunotherapy-combination trials to improve outcomes further and evaluate predictive biomarkers to help identify patients most likely to benefit from such therapies. Keywords: pembrolizumab, checkpoint inhibitors, urothelial cancer, tumor-mutation burden, bladder cancer, immunotherapy
