Pembrolizumab is a humanised monoclonal immunoglobulin (Ig) G4 anti-body that blocks the interaction between the transmembrane programmed cell death-1 (PD-1) protein and its ligands PD-L1 and PD-L2. Thereby, pembrolizumab potentiates T-cell responses, including anti-tumour responses and cancer-specific T-cells. Since May 2017, pembrolizumab is approved by the US Food and Drug Administration (FDA) for the treatment of locally advanced or metastatic urothelial cancer (UC) patients. However, pembrolizumab is not approved for the second-line treatment of patients with UC by the European Medicines Agency (EMA).

The FDA approval was based on an open-label, international, randomised phase III study, the KEYNOTE-045 trial. The study was conducted to assess the efficacy and safety of pembrolizumab in 542 patients with UC who have recurred or progressed following platinum-based chemotherapy. Overall survival (OS) was statistically significantly longer in the total as well as in the PD-L1 ≥10% population after the early termination of the trial (second interim analysis). There was no statistically significant difference in the duration of progression-free survival (PFS) between the two study groups. However, the ORR in the total population was statistically significantly higher in the pembrolizumab group compared to the chemotherapy group (+9.7%). In terms of safety, treatment-related adverse events (AEs) of any grade, as well as of grades 3–5, were more common in the chemotherapy group than in the pembrolizumab group. The most frequent treatment-related AEs of any grade in the pembrolizumab arm were pruritus, fatigue and nausea. Patient-reported outcomes, such as quality of life (QoL), were only reported in abstract form.

Overall, the treatment with pembrolizumab offers a statistically significant improvement in OS, independent of the PD-L1 status, with a superior safety profile compared to chemotherapy at high costs. However, due to the early termination of the trial, a systematic overestimation of the treatment effect of pembrolizumab is possible, leading to a need for long-term data. Finally, head-to-head comparison trials comparing pembrolizumab to nivolumab and atezolizumab are essential to investigate which second-line treatment option UC patients benefit the most from.