On November 21, 2025, the Food and Drug Administration approved pembrolizumab (Keytruda, Merck) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex, Merck) with enfortumab vedotin-ejfv (Padcev, Astellas Pharma) as neoadjuvant treatment followed by adjuvant treatment after cystectomy for adults with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin.

Full prescribing information for Keytruda, Keytruda Qlex, and Padcev will be posted on Drugs@FDA. 

Efficacy and Safety

Efficacy was evaluated in KEYNOTE-905/EV-303 (NCT03924895), an open-label, randomized, multicenter, 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. Patients were randomized (1:1) 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. Median EFS was not reached (NR) (95% CI: 37.3, NR) in the pembrolizumab and enfortumab vedotin arm and was 15.7 months (95% CI: 10.3, 20.5) in the RC and PLND arm (Hazard Ratio [HR] 0.40 [95% CI: 0.28, 0.57]; p-value <0.0001). Median OS was NR (95% CI: NR, NR) and 41.7 months (95% CI: 31.8, NR) in the respective arms (HR 0.50 [95% CI: 0.33, 0.74]; p-value 0.0002).

The overall safety profile of enfortumab vedotin-ejfv with pembrolizumab in KEYNOTE-905/EV-303 was similar 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. The enfortumab vedotin-ejfv prescribing information includes warnings and precautions for skin reactions, hyperglycemia, pneumonitis/interstitial lung disease (ILD), peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.

Recommended Dosage

The recommended pembrolizumab dose for neoadjuvant treatment is 200 mg IV every 3 weeks administered in combination with enfortumab vedotin-ejfv 1.25 mg/kg (up to a maximum of 125 mg for patients ≥ 100 kg) IV on Days 1 and 8 of a 21-day cycle for 3 cycles for a total duration of 9 weeks of neoadjuvant treatment. In the adjuvant phase, enfortumab vedotin-ejfv is continued for 6 additional cycles every 3 weeks in combination with pembrolizumab, administered either as 200 mg IV every 3 weeks for 14 cycles or 400 mg IV every 6 weeks for 7 cycles. The duration of the combination of pembrolizumab and enfortumab vedotin-ejfv in the adjuvant setting is 18 weeks and the overall duration of adjuvant therapy, including pembrolizumab as a single agent, is 42 weeks. Administer pembrolizumab after enfortumab vedotin when given on the same day.

For dosage and administration information for pembrolizumab and berahyaluronidase alfa-pmph given in combination with enfortumab vedotin-ejfv, refer to the Keytruda Qlex prescribing information.

Expedited Programs

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health Canada (HC), Switzerland’s Swissmedic (SMC), and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 5 months ahead of the FDA goal date.

This application was granted priority review. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.

Follow the Oncology Center of Excellence on X: @FDAOncology.