FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer

Regulatory approval: On Nov 21, 2025, the FDA approved pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) in combination with enfortumab vedotin-ejfv (Padcev) as neoadjuvant therapy followed by adjuvant therapy after cystectomy for adults with muscle-invasive bladder cancer who are ineligible for cisplatin. Approval was supported by KEYNOTE-905/EV-303, which showed statistically significant improvements in event-free and overall survival versus immediate surgery alone.

FDA approval: pembrolizumab + enfortumab vedotin for cisplatin-ineligible MIBC (perioperative)

Type: Regulatory approval
Date: 2025-11-21
Agency: US FDA

The FDA approved pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) in combination with enfortumab vedotin-ejfv (Padcev) as neoadjuvant treatment followed by adjuvant treatment after cystectomy for adults with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin.

Supporting evidence

Approval was based on KEYNOTE-905/EV-303 (NCT03924895), an open-label, randomized, multicenter, active-controlled trial (n=344) in previously untreated MIBC patients eligible for radical cystectomy with pelvic lymph node dissection but ineligible for or declined cisplatin. Patients were randomized 1:1 to perioperative pembrolizumab + enfortumab vedotin (with adjuvant continuation, then pembrolizumab monotherapy) versus immediate surgery alone.

Primary outcome: event-free survival (EFS; blinded independent central review). Additional outcome: overall survival (OS).

Results showed statistically significant improvements with the combination vs surgery alone:

  • EFS: median not reached (95% CI 37.3, NR) vs 15.7 months (95% CI 10.3, 20.5); HR 0.40 (95% CI 0.28–0.57); p<0.0001
  • OS: median NR vs 41.7 months (95% CI 31.8, NR); HR 0.50 (95% CI 0.33–0.74); p=0.0002

Safety

The safety profile was reported as similar to prior trials in advanced urothelial cancer. Label warnings include pembrolizumab immune-mediated adverse reactions and enfortumab vedotin risks such as skin reactions, hyperglycemia, pneumonitis/ILD, peripheral neuropathy, and ocular disorders.

Review pathway

The review used Project Orbis, received priority review, and was approved 5 months ahead of the FDA goal date.

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