The U.S. FDA approved the combination of Pembrolizumab and Enfortumab vedotin-ejfv for the treatment

On November 21, 2025, the U.S. Food and Drug Administration (FDA) approved the regimen of pembrolizumab (Keytruda, Merck & Co., Inc.) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex, Merck & Co., Inc.) in combination with enfortumab vedotin-ejfv (Padcev, Astellas Pharma Inc.) for adult patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin. The specific treatment modality consists of neoadjuvant therapy followed by cystectomy, and subsequent adjuvant therapy.

About the KEYNOTE-905/EV-303 Study

The efficacy data of this regimen is based on the KEYNOTE-905/EV-303 study (ClinicalTrials.gov Identifier: NCT03924895). This is an open-label, randomized, multicenter, active-controlled study that enrolled a total of 344 previously untreated patients with muscle-invasive bladder cancer. All these patients were scheduled to receive radical cystectomy combined with pelvic lymph node dissection, but were either ineligible for or declined cisplatin-based chemotherapy.

Patients were randomized 1:1 into two groups:

Experimental group: Patients first received neoadjuvant therapy with pembrolizumab in combination with enfortumab vedotin-ejfv, followed by surgical treatment; after surgery, they continued to receive adjuvant therapy with pembrolizumab plus enfortumab vedotin-ejfv, and subsequently sequential monotherapy with pembrolizumab.

Control group: Patients received immediate surgical treatment alone.

The primary efficacy endpoint of the study was event-free survival (EFS), assessed by a blinded independent central review committee; overall survival (OS) served as the secondary efficacy endpoint.

Study results showed that compared with the surgery-alone group, patients who received pembrolizumab combined with enfortumab vedotin-ejfv both before and after radical cystectomy plus pelvic lymph node dissection achieved statistically significant improvements in EFS and OS:

The median EFS was not reached (NR) in the pembrolizumab plus enfortumab vedotin-ejfv group (95% confidence interval [CI]: 37.3 months – NR); the median EFS in the surgery-alone group was 15.7 months (95% CI: 10.3 – 20.5 months), with a hazard ratio (HR) of 0.40 (95% CI: 0.28 – 0.57) and a p-value < 0.0001.

The median OS was NR (95% CI: NR – NR) in the combination therapy group versus 41.7 months (95% CI: 31.8 months – NR) in the surgery-alone group, with an HR of 0.50 (95% CI: 0.33 – 0.74) and a p-value = 0.0002.

In the KEYNOTE-905/EV-303 study, the overall safety profile of enfortumab vedotin-ejfv in combination with pembrolizumab was consistent with the safety data observed in previous studies for advanced urothelial carcinoma.

Warnings and Precautions

The prescribing information for pembrolizumab includes the following warnings and precautions: immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.

The prescribing information for enfortumab vedotin-ejfv includes the following warnings and precautions: skin reactions, hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.

Recommended Dosage

Neoadjuvant treatment phase: The recommended dose of pembrolizumab is 200 mg administered intravenously every 3 weeks, in combination with enfortumab vedotin-ejfv (administered intravenously at a dose of 1.25 mg/kg; for patients weighing ≥ 100 kg, the maximum dose shall not exceed 125 mg). The treatment cycle is 21 days, with administration on Days 1 and 8 of each cycle. The neoadjuvant treatment lasts for a total of 3 cycles, with an overall treatment duration of 9 weeks.

Adjuvant treatment phase: After surgery, patients continue to receive enfortumab vedotin-ejfv combined with pembrolizumab for an additional 6 cycles (each cycle is 3 weeks). For pembrolizumab, one of the two dosing regimens can be selected: ① 200 mg administered intravenously every 3 weeks for 14 cycles; ② 400 mg administered intravenously every 6 weeks for 7 cycles. In the adjuvant treatment phase, the duration of combination therapy with pembrolizumab and enfortumab vedotin-ejfv is 18 weeks; the total duration of adjuvant therapy, including subsequent monotherapy with pembrolizumab, is 42 weeks. If the two drugs are administered on the same day, enfortumab vedotin-ejfv should be infused first, followed by pembrolizumab.