FDA Approves Keytruda Plus Padcev as First Platinum-Free Regimen for Muscle-Invasive Bladder Cancer

The FDA approved Keytruda plus Padcev as the first platinum-free regimen for muscle-invasive bladder cancer on July 10, 2026, expanding the combination to all patients regardless of cisplatin eligibility. The approval came five weeks ahead of the FDA’s PDUFA date.

Keytruda (pembrolizumab, Merck, MRK) or Keytruda QLEX given with Padcev (enfortumab vedotin-ejfv, Astellas/Pfizer, PFE) can now be used before and after bladder removal surgery for adults with muscle-invasive bladder cancer (MIBC). This extends the prior approval, which covered only patients ineligible for cisplatin chemotherapy, to the full MIBC population. MRK closed at $130.48 and PFE at $25.01 on July 23.

The trial

The approval rests on the Phase 3 KEYNOTE-B15 trial (EV-304, NCT04700124), which randomized 808 patients to perioperative Keytruda plus Padcev or to neoadjuvant gemcitabine plus cisplatin followed by surgery. The results:

• Event-free survival: 47% risk reduction (HR 0.53, 95% CI 0.41-0.70, p<0.0001). Median EFS was not reached in the Keytruda/Padcev arm versus 48.5 months for chemotherapy.
• Overall survival: 35% risk reduction (HR 0.65, 95% CI 0.48-0.89, p=0.0029). Median OS was not reached in either arm.
• Pathologic complete response: 55.8% of patients had no evidence of invasive cancer in the removed tissue, versus 32.5% for chemotherapy (p<0.0001).

The FDA’s approval notice confirmed the review was granted priority review and conducted under Project Orbis, with concurrent reviews in Australia, Canada, Switzerland, the UK, and Israel.

Why platinum-free matters

Cisplatin has been the standard neoadjuvant treatment for MIBC for over 20 years, but it is toxic. Kidney damage, hearing loss, and nerve damage are common side effects, and up to half of patients cannot tolerate it. The Keytruda plus Padcev combination replaces cisplatin with a PD-1 inhibitor and an antibody-drug conjugate (ADC), attacking the tumor through immune activation and direct cell killing without the platinum toxicity.

The prior approval, based on the KEYNOTE-905 trial in cisplatin-ineligible patients, showed a 60% reduction in EFS events and a 50% reduction in mortality versus surgery alone. The KEYNOTE-B15 data now extends the benefit to cisplatin-eligible patients, where the combination beat chemotherapy head-to-head rather than comparing to surgery alone.

What to watch

The pathologic complete response rate of 55.8% is an early signal, not a guarantee of long-term cure. Longer follow-up from KEYNOTE-B15 will show whether the EFS and OS benefits hold at five and ten years. The combination carries real risks: serious adverse reactions occurred in 27% of patients in the neoadjuvant phase, and fatal adverse reactions occurred in 1.7%. Peripheral neuropathy, skin reactions, and pneumonitis are among the labeled warnings. For Merck, every new Keytruda indication extends the franchise before its 2028 patent cliff. For Pfizer and Astellas, Padcev gains a larger addressable population in the curative-intent setting.