FDA Approves Neo/Adjuvant Pembrolizumab/Enfortumab in MIBC

The FDA has approved intravenous pembrolizumab (Keytruda) or subcutaneous pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) with enfortumab vedotin-efjv (Padcev) for neoadjuvant treatment followed by adjuvant treatment preceded by cystectomy in adult patients with muscle-invasive bladder cancer (MIBC) who are not eligible for cisplatin chemotherapy.¹

The approval is supported by data from the open-label, randomized, multicenter, active-controlled phase 3 KEYNOTE-905/EV-303 trial (NCT03924895). Patients receiving the approved combination had significantly better event-free survival (EFS) and overall survival (OS) outcomes, the major and additional efficacy outcomes, respectively.

Those receiving the experimental saw a 60% reduction in the risk of death or cancer event compared with those in the active control arm, who received surgery alone. Median EFS was not reached (NR) for patients in the experimental arm (95% CI, 37.3-NR) vs 15.7 months (95% CI, 10.0-20.5) in the control arm (hazard ratio [HR], 0.40; 95% CI, 0.28-0.57; P <.0001).

Further, the combination resulted in a 50% reduction in the risk of disease progression or death. Median OS was NR (95% CI, NR-NR) in the experimental arm compared with 41.7 months (95% CI, 31.8-NR) in the surgery alone arm (HR, 0.50; 95% CI, 0.33-0.74; P = .0002).

In the trial, 344 patients with treatment-naive MIBC who were candidates for radical cystectomy (RC) who had pelvic lymph node dissection (PLND) but were either not eligible for or declined cisplatin-based chemotherapy were randomized 1:1 to receive either:

1. Neoadjuvant pembrolizumab and enfortumab, then RC with PLND, then adjuvant enfortumab combined with pembrolizumab, then pembrolizumab monotherapy, OR
2. Immediate RC with PLND alone

Pembrolizumab/Enfortumab Safety

According to the FDA’s announcement, the safety profile of pembrolizumab and enfortumab reported in KEYNOTE-905/EV-303 was similar to safety data reported in previous trials observing the combination in advanced urothelial cancer.

Data on the randomized, open-label, phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), upon which the combination of enfortumab with pembrolizumab was approved in locally advanced or metastatic urothelial cancer, reflected that the most common adverse effects that occurred in at least 20% of patients on pembrolizumab/enfortumab vedotin including laboratory abnormalities were increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, and diarrhea.² Alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection, and decreased platelets were also frequently reported.

How is Pembrolizumab/Enfortumab Dosed and Administered?

The FDA recommends a dose of 200 mg of IV pembrolizumab every 3 weeks combined with 1.25 mg/kg of IV enfortumab up to 125 mg in patients weighing at least 100 kg on days 1 and 8 of a 3-week cycle for 3 cycles, totaling 9 weeks, in the neoadjuvant setting.¹

In the adjuvant setting, enfortumab should be continued for 6 more cycles every 3 weeks, combined with pembrolizumab at either 200 mg via IV every 3 weeks for 14 cycles or 400 mg via EV every 6 weeks for 7 cycles.

In the adjuvant setting, the combination of pembrolizumab and enfortumab is 18 weeks, and the total duration of adjuvant therapy, including single-agent pembrolizumab, is 42 weeks. When pembrolizumab and enfortumab are given on the same day, enfortumab should be administered first.

Reference

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. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed November 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer