FDA Approves Perioperative Pembrolizumab Plus Enfortumab Vedotin for MIBC

The FDA has approved pembrolizumab (Keytruda) or subcutaneous pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) each in combination with enfortumab vedotin-ejfv (Padcev) as perioperative treatment for adults with muscle-invasive bladder cancer (MIBC).¹

The approval covers neoadjuvant treatment with pembrolizumab plus enfortumab vedotin followed by radical cystectomy and pelvic lymph node dissection, then adjuvant therapy with the combination followed by pembrolizumab monotherapy. The decision, expedited under priority review, was supported by findings from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124).

About KEYNOTE-B15/EV-304: Key Findings

KEYNOTE-B15/EV-304 was an open-label, randomized, multicenter trial that enrolled 808 patients with previously untreated MIBC who were candidates for radical cystectomy with pelvic lymph node dissection but were eligible for cisplatin-based chemotherapy.²

Patients were randomly assigned in a 1:1 ratio to receive perioperative pembrolizumab plus the antibody-drug conjugate enfortumab vedotin followed by surgery and adjuvant therapy, or neoadjuvant gemcitabine and cisplatin followed by surgery. The primary end point was event-free survival (EFS) as assessed by blinded independent central review, with overall survival (OS) serving as an additional efficacy end point.

Treatment with the perioperative regimen resulted in statistically significant improvements in both EFS and OS compared with surgery alone. Median EFS was not reached (95% CI, not reached [NR]-NR) in the pembrolizumab plus enfortumab vedotin arm vs 48.5 months (95% CI, 43.3-NR) in the surgery-alone arm (HR, 0.53; 95% CI, 0.41-0.70; P <.0001). Median OS was not reached in either arm (HR, 0.65; 95% CI, 0.48- 0.89; P =.0029).

Safety Findings

The safety profile of pembrolizumab plus enfortumab vedotin observed in KEYNOTE-B15/EV-304 was consistent with prior studies evaluating the regimen in advanced urothelial carcinoma, with no new safety signals identified.

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 prescribing information includes warnings for skin reactions, hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, ocular disorders, infusion-site extravasation, and embryo-fetal toxicity.

REFERENCES

1. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. News release. United States Food and Drug Administration. July 10, 2026. Accessed July 10, 2026. https://tinyurl.com/32e9cvv8

2. Perioperative Enfortumab Vedotin (EV) Plus Pembrolizumab (MK-3475) Versus Neoadjuvant Chemotherapy for Cisplatin-Eligible Muscle Invasive Bladder Cancer (MIBC) (MK-3475-B15/​ KEYNOTE-B15 /​ EV-304) (KEYNOTE-B15). ClinicalTrials.gov. Updated June 26, 2026. Accessed July 10, 2026. https://clinicaltrials.gov/study/NCT04700124