ESMO 2025 | Updates in EV-pembrolizumab MIBC from the KEYNOTE-905/EV-303 trial

Yeah, we know that in muscle-invasive bladder carcinoma, the cystectomy is the mainstay in the non-metastatic situation to treat the patients. And we know that neoadjuvant therapy, which was usually done with gemcitabine, cisplatin, platinum-based chemotherapy, and sometimes then followed by adjuvant therapy, will increase the disease-free survival and the overall survival for the patient. So, in Keynote 905 or EV303, the new perioperative concept of enfortumab vedotin, the antibody drug conjugate in combination with pembrolizumab, was explored in the neoadjuvant and adjuvant settings. So this is why we say perioperative: neoadjuvant, cystectomy, and then the third cornerstone, the adjuvant therapy. And the trial was done in the platinum-ineligible population, so the cisplatin-ineligible population. Why is that important? I mentioned at the early beginning, so neoadjuvant chemotherapy is mainly done and mainly used with gemcitabine plus cisplatin. But patients not being eligible for cisplatin chemotherapy usually do not receive any neoadjuvant strategy, no neoadjuvant chemotherapy. And this gap is now filled by the Keynote 905 trial using and applying the EV pembrolizumab regimen in this patient population. So to make a long story short, three cycles of EV-P were administered in the neoadjuvant, then cystectomy, and then an adjuvant phase followed with EV plus pembrolizumab up to the completeness of one year. The primary endpoint of this trial was the pathological complete response rate. And if you’re talking about primary endpoint, you must know what was the comparator. And as I mentioned, there is no established standard for cisplatin-ineligible patients. Patients in a control arm went directly to cystectomy. It was allowed that these patients received in the adjuvant setting a PD-1 inhibitor like nivolumab, which is approved here in the EMA region for the PD-1 positive patient population. So, going back to the pathological response rate, the pathCR was 58% in patients receiving EV-pembrolizumab compared to patients directly undergoing cystectomy. And I think this is one of the main and remarkable results because we learned and know that pathological response serves as a surrogate for an increased event-free survival or disease-free survival and also for overall survival. And these are the other endpoints of the trial that the DFS and also the overall survival was significantly increased by the treatment of EV-pembrolizumab in this perioperative setting. Well, if you ask me for my personal opinion, I think this is one of the latest data moving the EV-pembrolizumab combination, which is approved in the first-line setting based on the EV-302 data, and is a well-established standard here over platinum-based chemotherapy. Now a little bit more into the frontline setting, into the perioperative setting, more in early, not really early stages, because you’re not in non-muscle-invasive, it’s muscle-invasive bladder carcinoma, even but non-metastatic, and it has the potential to be a new standard of care here.

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