With the advent of platinum-based chemotherapy, survival rates for metastatic urothelial carcinoma have plateaued, giving way to the modern immunotherapy paradigm. Although immunotherapy as an effective treatment dates back to the live, attenuated bacillus Calmette-Guérin vaccine, the recent impact of immune checkpoint inhibitors targeting programmed death/programmed death-ligand 1 (PD-1/PD-L1) coupled with the promise of both anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) antibodies and indoleamine-2, 3-dioxygenase-1 (IDO-1) inhibitors have provided a resurgence. To date, pembrolizumab, a PD-1 inhibitor, has been granted full FDA approval based on its high antitumor activity, tolerability, and efficacy, with notable prolonged durable responses in the second-line setting. Nivolumab (a PD-1 inhibitor) and atezolizumab, durvalumab, and avelumab (PD-L1 inhibitors) have also gained accelerated drug approval in the second-line setting. In addition, atezolizumab and pembrolizumab have been approved for platinum-ineligible patients in the first-line setting. Effective 2-drug combinations reported include nivolumab plus the CTLA-4 antibody ipilimumab and pembrolizumab plus the IDO-1 inhibitor epacadostat. Further expansion of immunotherapy will hinge in part on the ability to define responders versus nonresponders through the use of biomarkers like PD-L1 or mutational load. Clinical trials with immunotherapy for metastatic disease as single agents or in combination are ongoing. This review explores the rise of immunotherapy and presents the current treatments and challenges posed with development of biomarkers, and provides a summary of ongoing phase III clinical trials.
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