Combination therapy with immune checkpoint inhibitors in urothelial carcinoma: Current data and future outlook

Until 5 years ago, systemic therapeutic options for urothelial carcinoma, the most common form of bladder cancer, had been limited to cisplatin-based regimens (methotrexate/vinblastine/doxorubicin/cisplatin; gemcitabine/cisplatin) and taxanes (as single agents or in combinations), which had minimal survival benefit and excessive toxicity. In 2016, systemic options expanded with the advent of immunotherapy oncology (IO) drug approvals. Due to the different and lower toxicity profiles of these IO agents, their approvals in the first-line platinum-ineligible (pembrolizumab [Keytruda]; atezolizumab[Tecentriq]) and second-line metastatic (avelumab [Bavencio]; atezolizumab; durvalumab [Imfinzi]; nivolumab [Opdivo]; pembrolizumab) settings expanded our ability to treat a broader population of patients with metastatic disease. However, this came with the realization that response rates were low and, although there were durable responses, there was also a lack of predictive markers to select which patients would benefit. With several recent approvals—of the first biomarker-targeted therapy to treat urothelial carcinoma, erdafitinib (Balversa), and of the antibody-drug conjugates enfortumab vedotin (EV; Padcev) and sacituzumab govitecan—we are now challenged with sequencing and exploring combination therapies with IOs. This article explores the current and future outlooks for combination therapy with IOs in urothelial carcinoma.