ESMO 2025 – Padcev plus Keytruda sets the perioperative bar

At ESMO two years ago Padcev plus Keytruda impressed in first-line bladder cancer, and now the combo could become a new standard of care in perioperative muscle-invasive bladder cancer, ESMO heard on Saturday.

In the Keynote-905 trial the Pfizer/Astellas/Merck & Co doublet given before and after surgery produced a 60% reduction in the risk of tumour recurrence, progression or death, the primary endpoint, versus surgery alone. The combo also led to a 50% reduction in death, a key secondary endpoint.

Both outcomes were highly statistically significant, and back the companies' claims of a clinically meaningful result when they toplined the data in August. The ESMO discussant, Memorial Sloan Kettering's Dr Jonathan Rosenberg, called the results "remarkable" and said it was "quite clear" that the combo was poised to become the new standard of care in the trial's population, patients refusing or ineligible for cisplatin chemotherapy.

Still, Astellas’s head of oncology development, Moitreyee Chatterjee-Kishore, was more cautious, saying in a pre-ESMO interview with ApexOnco only that she hoped this would be the case, “but this has to go through [regulatory] review". She also declined to discuss filing timelines, saying the process was “in progress”.

Results from Keynote-905 (EV-303) in perioperative MIBC (chemo-ineligible/declined)

Notes: *primary endpoint; cutoff date 6 Jun 2025. Source: ESMO 2025. 

Keynote-905, also known as EV-303, enrolled MIBC patients who were ineligible for, or refused, cisplatin chemo. One question ahead of the readout was how had actually declined cisplatin. Dr Timothée Olivier of University Hospital of Geneva noted that surgery alone might not be the best option for these patients, and speculated that they might drop out of the study to get more appropriate care, leaving frailer patients in the control arm, which could flatter the results.

While results weren't as convincing in chemo refusers, this subgroup made up less than 20% of the trial, so drawing conclusions here is difficult, Rosenberg noted.

Toxicity

Another issue could be toxicity, with the risk/benefit equation likely changing as therapy moves earlier. Padcev carries a black box warning for severe skin reactions, and is linked with peripheral neuropathy and hyperglycaemia.

In Keynote-905, grade 3 or higher adverse events were seen in 71% of patients receiving the combo, versus 46% in the surgery cohort. Chatterjee-Kishore contended that adverse events were “no different from what’s been previously reported” for the Padcev plus Keytruda combo. This stance was echoed by Rosenberg, who said the overall survival benefit suggested that any toxicity was "worthwhile".

There are also questions around the relative contributions of neoadjuvant and adjuvant therapy, an issue that has exercised the FDA recently. According to Rosenberg, this will become increasingly important, while Chatterjee-Kishore said that it was “something we’re looking at in great detail. We’re cognisant of the fact we’ll have to discuss this.”

Meanwhile, Keynote-905 is secondarily testing perioperative Keytruda versus surgery alone. The partners are also carrying out the Keynote-B15 (EV-304) trial, testing perioperative Padcev plus Keytruda, versus neoadjuvant chemo, in cisplatin-eligible patients. Astellas has previously said this would read out in the second half of its 2025 fiscal year, which ends in March 2026.