FDA Grants Approval to Pembrolizumab With Enfortumab Vedotin for Muscle Invasive Bladder Cancer

Key Takeaways:

FDA Approval: The FDA approved pembrolizumab (± berahyaluronidase alfa-pmph) with enfortumab vedotin-ejfv as neoadjuvant and adjuvant therapy for cisplatin-ineligible muscle-invasive bladder cancer (MIBC).

Survival Benefit: In KEYNOTE-905/EV-303 (N=344), perioperative pembrolizumab + enfortumab vedotin significantly improved outcomes versus surgery alone.

Manageable Safety Profile: Adverse events were consistent with prior trials.

On November 21, 2025, the US Food and Drug Administration (FDA) granted approval to pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph with enfortumab vedotin-ejfv as neoadjuvant treatment followed by adjuvant treatment after cystectomy for patients with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin.

For this approval, the efficacy was assessed in KEYNOTE-905/EV-303 (NCT03924895), an open-label, randomized, multi-center, active-controlled trial in 344 patients with previously untreated MIBC who were candidates for radical cystectomy (RC) with pelvic lymph node dissection (PLND) but were ineligible for or declined cisplatin-based chemotherapy. 

In the trial, 344 patients were randomized 1-to-1 to receive neoadjuvant pembrolizumab and enfortumab vedotin-ejfv followed by surgery followed by adjuvant enfortumab vedotin-ejfv in combination with pembrolizumab followed by pembrolizumab as a single agent or to undergo immediate surgery alone.

The major efficacy outcome measure was event-free survival (EFS) assessed by blinded independent central review. Overall survival (OS) was an additional efficacy outcome. The trial demonstrated statistically significant improvements in EFS and OS in patients treated with pembrolizumab and enfortumab vedotin-ejfv before and after RC and PLND compared with surgery alone. 

The median EFS was not reached (NR) (95% Confidence Interval [CI], 37.3 to NR) in the pembrolizumab and enfortumab vedotin arm and was 15.7 months (95% CI, 10.3 to 20.5) in the RC and PLND arm (Hazard Ratio [HR] 0.40 [95% CI, 0.28 to 0.57]; p <0.0001). Median OS was NR (95% CI, NR to NR) and 41.7 months (95% CI, 31.8 to NR) in the respective arms (HR 0.50 [95% CI, 0.33 to 0.74]; p  0.0002).

The overall safety profile of enfortumab vedotin-ejfv with pembrolizumab in KEYNOTE-905/EV-303 was noted to be comparable to that observed in prior trials in advanced urothelial cancer. The pembrolizumab prescribing information includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity. 

As for potential adverse events, the enfortumab vedotin-ejfv prescribing information advises of risks for skin reactions, hyperglycemia, pneumonitis/interstitial lung disease (ILD), peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.

Source:

US Food and Drug Administration. Accessed November 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer