Checkpoint inhibitors: the new treatment paradigm for urothelial bladder cancer

Bladder cancer is the most common malignancy involving the genitourinary system (Siegel et al. in CA Cancer J Clin, 66:7–30, 2016). In the USA, it is the fifth most common cancer and approximately 79,000 new cases will be diagnosed in 2017 (Siegel et al. in CA Cancer J Clin, 66:7–30, 2016). The mortality from bladder cancer is approximately 17,000 deaths each year (Siegel et al. in CA Cancer J Clin, 66:7–30, 2016). The incidence rate for bladder cancer is higher in men compared to women. Risk factors are predominantly related to tobacco smoking, although infection with Schistosoma haematobium is another risk factor in selected populations (Antoni et al. in Eur Urol, 71:96–108, 2017). Cisplatin-based systemic chemotherapy regimens remain the standard of care in both the neoadjuvant and metastatic setting for muscle-invasive bladder cancer (Gupta et al. in Cancer, 9(15):1–14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602–4608, 2005; De Santis et al. in J Clin Oncol, 30:191–199, 2012; Bellmunt et al. in J Clin Oncol, 27: 4454–4461, 2009). There is an estimated overall survival of 9–15 months in metastatic bladder cancer in those who receive the standard of care platinum-based chemotherapy (Von der Maase et al. in J Clin Oncol, 23:4602–4608, 2005; De Santis et al. in J Clin Oncol, 30:191–199, 2012). The median survival, however, is significantly reduced after relapse in patient treated with platinum chemotherapy to less than 7 months (Bellmunt et al. in J Clin Oncol, 27: 4454–4461, 2009). Thus, this approach is preferred for patients who can tolerate this treatment as first-line chemotherapy (Gupta et al. in Cancer, 9(15):1–14, 2017). Until recently, there were few treatment options for those patients with poor performance status who are ineligible to receive cisplatin including renal insufficiency and multiple comorbidities or had disease progression after receiving platinum-based chemotherapy (Gupta et al. in Cancer, 9(15):1–14, 2017). With further understanding of tumor immune evasion, systemic immunotherapy which utilizes the patient’s own immune system directly to eradicate and target neoplastic cells, has now been approved for urothelial bladder cancer. Monoclonal antibodies that target programmed cell death protein 1 (PD-1), including Nivolumab and Pembrolizumab, and its ligand, PD-L1, including Atezolizumab, Durvalumab, Avelumab, have all been investigated and approved in the setting of metastatic refractory urothelial cancer (Gupta et al. in Cancer, 9(15):1–14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602–4608, 2005; Zilchi et al. in BioMed Res Int, 2017, 2017, doi:10.​1155/​2017/​5618174). Atezolizumab and Pembrolizumab have also been approved as first-line therapy in the setting of cisplatin-ineligible metastatic bladder cancer (Gupta et al. in Cancer, 9(15):1–14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi:10.​1155/​2017/​5618174). Those that target cytotoxic T-lymphocyte-associated protein 4, including Ipilimumab and Tremelimumab, have also been investigated and further studies are being performed (Gupta et al. in Cancer, 9(15):1–14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi:10.​1155/​2017/​5618174). This review outlines the systemic immunotherapies that have been approved or are currently being investigated.