**2. Up-to-Date Clinical Benefit of the Current ICI Paradigm**

The five approved ICI mAbs target either programmed cell death protein 1 (PD-1) or programmed death ligand-1 (PD-L1). The rationale for targeting the PD-1/PD-L1 axis with mAbs is multi-fold. First, blocking the interaction of PD-1 and PD-L1 increases the likelihood that the immune system, if active against malignant cells, remains active. Second, levels of PD-L1 expression have been shown to correlate with bladder cancer aggressiveness and outcome. Third, the tumor mutation burden (TMB) is high, which suggests that ICIs could have significant clinical impact because of a greater T-cell-mediated antitumor immune response elicited by invasive bladder cancer [18]. Briefly, the TMB is defined as the total number of somatic mutations per DNA megabase. A thorough review on the evolution of the PD-1/PD-L1 axis in bladder cancer is reviewed in Bellmunt et al. [19].

Approvals were based on key endpoints such as objective response rate (ORR), OS and, duration of response (DOR) for locally advanced or metastatic bladder cancer. We highlight the most up-to-date clinically relevant information. AEs were also important parameters and, closely monitored and are described in a focused subsequent section.

### *2.1. Atezolizumab (Tecentriq; Genentech; South San Francisco, CA, USA)*
