Immunotherapy for advanced urothelial carcinoma (UC): rational and current evidence

Combination platinum-based chemotherapy has been the standard of care for several decades in first-line treatment of advanced urothelial carcinoma (UC) patients. UC is often chemosensitive, though durable responses are quite rare and the development of chemoresistance still leads to poor clinical outcomes. Up until a few years ago, UC patients could not benefit from any valuable alternatives to cytotoxic chemotherapy, but the scenario has been recently transformed by the advent of immunotherapy. Molecular biology of UC is characterised by a relatively high prevalence of alterations in DNA damage response pathway, genomic instability, high tumour burden, and elevated programmed cell death ligand 1 (PD-L1) protein expression, which are established factors predicting favourable response to immune checkpoint inhibitors (ICIs) in several tumour types. To date, various ICIs have been approved as systemic anti-cancer therapy for advanced UC in multiple settings, including first-line, maintenance, and second-line therapy. ICIs are also in development either as monotherapy or in combination with chemotherapy or other targeted agents. Moreover, a number of alternative ICIs, interleukins, and novel immune molecules have been identified as promising agents in advanced UC. Herein, we review rational and current literature evidence supporting the clinical development and current indications of immunotherapy, particularly focusing on ICIs.