We had transformative results in 2023 in the metastatic bladder cancer space with enfortumab vedotin and pembrolizumab. It really changed the landscape of metastatic urothelial cell carcinoma; it doubled overall survival. We had 30% of them who had a complete response and even a lot of these responders are ongoing after two years – 75% are still in a complete remission if they achieved it. So we entered these products into the muscle-invasive bladder cancer space.

We chose for the KEYNOTE-905 the very bad population, the frail population, a lot of comorbidities. This is an ineligible population. Most of them are cisplatin ineligible based on renal impairment, it can also be based on ECOG performance status, it can be based on cardiovascular disease, it can be based on polyneuropathy, hearing impairment. But we chose this population, we omitted for peripheral neuropathy because enfortumab vedotin is also giving this, because these patients don’t have any options. With muscle-invasive bladder cancer they go straight to surgery, up-front surgery, and then they are followed up but there are not that good data of what is the prognosis of this patient population but we know that it is very bad – up to 70% of them will relapse and most of them, a lot of them, will die within five years.

So this is the population setting and we had the control arm in the MIBC cisplatin-ineligible population and then we added two experimental arms, the pembrolizumab monotherapy arm and the EV-P experimental arm perioperative. So one year of pembrolizumab and three cycles of EV in the neoadjuvant setting and six cycles in the adjuvant setting. All the patients with MIBC cisplatin ineligible could enter the trial. In 2022 based on these promising results in the metastatic setting we stopped the pembrolizumab monotherapy arm and we continued only with the EV-P versus the control arm.

What we presented here at the congress is the first prespecified interim analysis of all patients concurrently randomised to the EV-P arm versus the control. The centrally assessed event free survival is the primary endpoint and key secondary endpoints are overall survival and pathCR. It was a very strong hit for all of them. So the primary endpoint of event free survival showed an early and sustained separation of the Kaplan-Meier curves, translating into a hazard ratio of 0.4 in favour of the EV-P arm. You always want to see that translated into an overall survival benefit and we also had that hit, also with a hazard ratio of 0.5, which was quite good. At two years, for example, you have 63% of patients that are still alive in the control arm and up to 80% in the intervention arm.

Also very important is the endpoint of pathCR, also a key secondary endpoint. We were very fair in that we used the denominator of all the ITT population, so even the patients that have an extremely good clinical response on enfortumab vedotin + pembrolizumab but opted not to go to surgery were also considered non-responders because for the denominator we used also all the patients that did not go to surgery. For the pathCR by this analysis we had 57.1% so you can imagine if you add these good responses it would be even higher. But this is already the highest pathCR rate ever reported in a phase III MIBC trial and maybe that also paves the way for the next generation trials with bladder sparing because you can imagine if you tell your patient we’ve removed your bladder but we see a pT0, N0, then the patient will question you but why did you remove it?

So this is, first of all, a trial that is transformative for the MIBC patients who are cisplatin ineligible and I hope that that will be confirmed in the cis eligible patients with the P15 trial that’s ongoing. But for now I will be very happy to offer this to all of my cisplatin-ineligible MIBC patients. It also paves the way for a lot of beautiful trials to come.