Until 2023 the standard of care for first-line advanced urothelial cancer treatment was platinum-based chemotherapy and since then we published the EV-302 study which tested enfortumab vedotin plus pembrolizumab versus standard platinum chemotherapy and showed that EV plus pembrolizumab was clearly superior to chemotherapy. As this treatment regimen only contains anti-PD-1 and there’s perhaps still room for improvement on the immunotherapy response, we hypothesised in this study that adding other immune checkpoint inhibitors could increase response or durability of response. So in this study we added combinations of pembrolizumab with either anti-LAG-3 or anti-TIGIT1 to enfortumab vedotin in a signal-finding study.

Can you describe the design of the KEYMAKER-U04 sub-study 04B and the patient population enrolled? What were the results?

KEYMAKER-U04 is a study in which we tested EV plus pembrolizumab, so the standard, and added other immune checkpoint inhibitors to this combination in co-formulations. This was a randomised signal-finding study, each arm having about 40 patients and the idea was to detect any increase in efficacy, especially in response rate, and then potentially expand the study or conduct a large randomised study.

In this study we found that the combinations, so the new combinations with other checkpoint inhibitors did not really add to the efficacy, at least not in objective response rate. So this, in fact, in the end was a negative study where we don’t think it’s justified to continue any of these combinations further in clinical development for advanced urothelial cancer.

We also noted that adding these checkpoints in some cases could potentially increase immune-related adverse events so this is perhaps another reason to not continue this development.