FDA Approves Perioperative Enfortumab Vedotin Plus Pembrolizumab for Cisplatin-Ineligible MIBC

The FDA has approved enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) as neoadjuvant treatment followed by adjuvant treatment after cystectomy for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin.1

The regulatory decision is supported by findings from the phase 3 EV-303/KEYNOTE-905 trial (NCT03924895), which demonstrated that perioperative treatment with enfortumab vedotin plus pembrolizumab significantly improved event-free survival (EFS) vs radical cystectomy plus pelvic lymph node dissection (RC + PLND) alone.

Findings supporting the approval showed that patients treated with the combination experienced a median EFS that was not reached (NR; 95% CI, 37.3-NR) vs 15.7 months (95% CI, 10.3-20.5) for patients who underwent RC + PLND alone (HR, 0.40; 95% CI, 0.28-0.57; P < .0001). The median overall survival (OS) was NR (95% CI, NR-NR) in the combination arm vs 41.7 months (95% CI, 31.8-NR) in the control arm (HR, 0.50; 95% CI, 0.33-0.74; P = .0002).

Data previously presented at the 2025 ESMO Congress also demonstrated that enfortumab vedotin plus pembrolizumab (n = 170) elicited a median EFS that was NR (95% CI, 37.3-NR) compared with 15.7 months (95% CI, 10.3-20.5) for RC + PLND alone (n = 174; HR, 0.40; 95% CI, 0.28-0.57; 1-sided P < .0001).2 Twelve-month EFS rates were 77.8% vs 55.1%, respectively, and the respective 24-month EFS rates were 74.7% vs 39.4%.

Median OS was NR in the combination arm (95% CI, NR-NR) vs 41.7 months (95% CI, 31.8-NR) in the control arm (HR, 0.50; 95% CI, 0.33-0.74; 1-sided P = .0002). The 12-month OS rates were 86.3% vs 75.7%, and the 24-month rates were 79.7% vs 63.1%, respectively.

The combination's perioperative indication follows the December 2023 FDA approval of enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial cancer.3

How was the EV-303 trial designed?

EV-303 was an open-label, randomized, three-arm, controlled phase 3 study evaluating perioperative enfortumab vedotin plus pembrolizumab in patients with cisplatin-ineligible MIBC.2 Eligible patients had clinical stage T2-T4aN0M0 or T1-T4aN1M0 disease, urothelial histology of at least 50%, and ECOG performance status of 0-2.

Enrolled patients were randomly assigned to 1 of 3 arms:

• Arm A: Neoadjuvant and adjuvant pembrolizumab monotherapy plus RC + PLND
• Arm B: RC + PLND
• Arm C: Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab plus RC + PLND

In Arm C, neoadjuvant therapy included enfortumab vedotin given at 1.25 mg/kg on days 1 and 8 once every 3 weeks plus pembrolizumab at 200 mg every 3 weeks for 3 cycles, followed by RC + PLND. Adjuvant therapy continued with enfortumab vedotin on days 1 and 8 every 3 weeks for 6 cycles and pembrolizumab every 3 weeks for 14 cycles.

The primary end point was EFS; secondary end points comprised OS, pCR, and safety.

What safety data were reported for perioperative enfortumab vedotin plus pembrolizumab?

Any-grade treatment-emergent adverse effects (TEAEs) were reported in 100% of patients receiving the combination (n = 167) and 64.8% of those in the surgery-only arm (n = 159).

Grade 3 or higher TEAEs occurred in 71.3% of patients receiving the combination vs 45.9% treated with RC + PLND alone. Serious TEAEs were reported in 58.1% vs 40.9% of patients, respectively. Surgery delays occurred in 4.0% and 0.6% of patients, respectively.

Dose reductions of enfortumab vedotin occurred in 16.8% of patients, and enfortumab vedotin was discontinued in 41.3%; pembrolizumab was discontinued in 34.1%. AEs leading to death occurred in 7.8% of patients in the combination arm vs 5.7% in the control arm.

References

1. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. November 21, 2025. Accessed November 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer
2. Vulsteke C, Kaimakliotis HZ, Danchaivijitr P, et al. Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: phase 3 KEYNOTE-905 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA2.
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed November 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer