Development of immunotherapy in bladder cancer: present and future on targeting PD(L)1 and CTLA-4 pathways

Purpose Over the past 3 decades, no major treatment breakthrough has been reported for advanced bladder cancer. Recent Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors in the management of advanced bladder cancer represent new therapeutic opportunities. This review examines the available data of the clinical trials leading to the approval of ICIs in the management of metastatic bladder cancer and the ongoing trials in advanced and localized settings. Methods A literature search was performed on PubMed and ClinicalTrials.gov combining the MeSH terms: 'urothelial carcinoma' OR 'bladder cancer', and 'immunotherapy' OR 'CTLA-4' OR 'PD-1' OR 'PD-L1' OR 'atezolizumab' OR 'nivolumab' OR 'ipilimumab' OR 'pembrolizumab' OR 'avelumab' OR 'durvalumab' OR 'tremelimumab'. Prospectives studies evaluating anti-PD(L)1 and anti-CTLA-4 monoclonal antibodies were included. Results Evidence-data related to early phase and phase III trials evaluating the 5 ICIs in the advanced urothelial carcinoma are detailed in this review. Anti-tumour activity of the 5 ICIs supporting the FDA approval in the second-line setting are reported. The activity of PD(L)1 inhibitors in the first-line setting in cisplatin-ineligible patients are also presented. Ongoing trials in earlier disease-states including non-muscle-invasive and muscle-invasive bladder cancer are discussed. Conclusions Blocking the PD-1 negative immune receptor or its ligand, PD-L1, results in unprecedented rates of anti-tumour activity in patients with metastatic urothelial cancer. However, a large majority of patients do not respond to anti-PD(L) 1 drugs monotherapy. Investigations exploring the potential value of predictive biomarkers, optimal combination and sequences are ongoing to improve such treatment strategies.