ASCO-GU: Padcev and Keytruda impress again

Pfizer, Astellas and Merck & Co, fresh from last year’s speedy perioperative bladder cancer nod for Padcev plus Keytruda, will hope to repeat the trick following impressive late-breaking results presented on Friday at the ASCO Genitourinary Cancers symposium.

The recent thumbs up came for cisplatin-ineligible muscle-invasive bladder cancer, while the latest data, from the Keynote-B15 study, could expand the combo into cisplatin-eligible patients. With the market split roughly in half, getting approval in both uses will be important. This doesn’t look in doubt, with an ASCO expert, Dr Brian Rini of the Vanderbilt-Ingram Cancer Center, describing Keynote-B15 as a “slam-dunk home run” during a pre-meeting press briefing. 

The trial, also known as EV-304, compared Padcev plus Keytruda, given before and after cystectomy, versus cisplatin and gemcitabine chemo administered in the neoadjuvant setting. The study found a convincing benefit on its primary endpoint of event-free survival, with a hazard ratio of 0.53 and a p value of less than 0.0001.

There was also a statistically significant improvement in overall survival at the first interim analysis, with a hazard ratio of 0.65, as well as a benefit on another secondary endpoint, pathologic complete response. 

The partners haven’t yet disclosed a filing in this setting, but previous Padcev/Keytruda approvals have come within a month of submission.

Checkmate checked?

One potential stumbling block could be the fact that Keynote-B15’s control arm lacked an adjuvant therapy, as noted by the ASCO-GU discussant, Dr William Kelly of Thomas Jefferson University.

One potential option here is Bristol Myers Squibb’s Opdivo, which was FDA approved in August 2021 for the adjuvant treatment of high-risk urothelial carcinoma, based on the Checkmate-274 trial.

When asked about this, Keynote-B15’s presenter, Mount Sinai’s Dr Matthew Galsky, noted that Checkmate-274 only applied to a subset of patients who had received neoadjuvant cisplatin and gemcitabine, and added that while the Bristol trial found an improvement in disease-free survival with Opdivo it only showed a trend towards an improvement in OS.

Furthermore, Keynote-B15 began in April 2021, before Opdivo was approved.

It had also once been feared that the FDA was cracking down on perioperative trials that couldn’t tease out how much benefit came pre or post-operatively. But that fear hasn't materialised for trials already designed before a 2024 FDA adcom, with AstraZeneca’s Imfinzi getting the thumbs up last year in periadjuvant MIBC, on the back of the Niagara trial.

Competition

Imfinzi could provide competition for Padcev plus Keytruda here, although Galsky pointed to a less convincing result with the Astra drug on pathological complete response; still, he cautioned against relying on cross-trial comparisons.

Meanwhile, Pfizer hopes to take Padcev earlier in bladder cancer, and plans to start a pivotal trial in a bladder-sparing MIBC setting this year, the company disclosed at JP Morgan in January. A company spokesperson said this would again test a Padcev/Keytruda combo, but declined to give more details.

Still, Padcev previously failed in the phase 1 EV-104 trial in high-risk, BCG-unresponsive non-muscle invasive bladder cancer. Pfizer confirmed that it had no plans for further development in NMIBC. 

The Padcev/Keytruda combo is also approved for first-line metastatic bladder cancer.

Cross-trial comparison of Padcev + Keytruda vs Imfinzi in chemo-eligible perioperative MIBC

Note: *Niagara failed on pCR, but Astra claimed a win based on re-analysis including 59 samples initially incorrectly considered non-responders. Source: ASCO-GU 2026 & ESMO 2024.