July 10, 2026
The U.S. Food and Drug Administration (FDA) has approved pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) in combination with enfortumab vedotin-ejfv (Padcev) as perioperative therapy for adults with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy.
The approval significantly expands the indication for this regimen, extending its use from cisplatin-ineligible patients to all patients with MIBC who are candidates for radical cystectomy, regardless of cisplatin eligibility. It represents another major milestone in bringing immunotherapy and antibody-drug conjugates into earlier stages of bladder cancer treatment.
KEYNOTE-B15: Perioperative Enfortumab Vedotin Plus Pembrolizumab in Muscle-Invasive Bladder Cancer
A New Perioperative Standard
Patients receive the combination as neoadjuvant therapy before surgery, followed by radical cystectomy with pelvic lymph node dissection, and then continue treatment in the adjuvant setting.
This strategy aims not only to shrink the primary tumor before surgery but also to eradicate residual microscopic disease afterward, ultimately reducing recurrence risk and improving long-term survival.
KEYNOTE-B15/EV-304
The approval is supported by the global phase III KEYNOTE-B15/EV-304 trial, which enrolled 808 previously untreated patients with muscle-invasive bladder cancer who were eligible for cisplatin-based chemotherapy and radical cystectomy.
Participants were randomized to receive either:
- perioperative pembrolizumab plus enfortumab vedotin, or
- the previous standard approach of neoadjuvant gemcitabine plus cisplatin followed by surgery.
The primary endpoint was event-free survival (EFS), with overall survival (OS) as a key secondary endpoint.
Superior Event-Free and Overall Survival
The study demonstrated clear superiority of the pembrolizumab–enfortumab vedotin regimen over standard cisplatin-based chemotherapy.
Patients treated with the immunotherapy–ADC combination experienced a 47% reduction in the risk of recurrence, progression, or death compared with gemcitabine plus cisplatin.
Key efficacy results included:
- Median EFS: Not reached vs 48.5 months
- EFS Hazard Ratio: 0.53
- Overall Survival Hazard Ratio: 0.65
Notably, median overall survival had not yet been reached in either treatment arm, indicating durable long-term benefit with ongoing follow-up.
These findings establish perioperative pembrolizumab plus enfortumab vedotin as one of the most effective systemic treatment strategies yet reported for operable muscle-invasive bladder cancer.
Safety Profile
The safety profile was consistent with previous studies evaluating the combination in advanced urothelial carcinoma, with no unexpected toxicities observed.
Clinicians should remain vigilant for the known adverse events associated with each agent.
Pembrolizumab carries risks of immune-mediated adverse events affecting multiple organ systems, infusion-related reactions, complications following allogeneic stem cell transplantation, and embryo-fetal toxicity. Enfortumab vedotin is associated with skin toxicity, peripheral neuropathy, hyperglycemia, pneumonitis or interstitial lung disease, ocular disorders, infusion-site extravasation, and embryo-fetal toxicity.
Overall, the safety findings were considered manageable and aligned with the established profiles of both therapies.
Why This Approval Matters
For nearly two decades, cisplatin-based neoadjuvant chemotherapy has remained the standard systemic treatment for operable muscle-invasive bladder cancer. This approval marks an important shift by introducing a perioperative strategy that combines PD-1 blockade with a Nectin-4–targeted antibody-drug conjugate, improving both event-free and overall survival compared with conventional chemotherapy.
Beyond expanding access to patients regardless of cisplatin eligibility, the approval highlights the growing role of immunotherapy and antibody-drug conjugates in earlier-stage disease, where preventing recurrence offers the greatest opportunity for cure.
Conclusion
The FDA approval of perioperative pembrolizumab (or pembrolizumab and berahyaluronidase alfa-pmph) plus enfortumab vedotin establishes a new treatment option for patients with muscle-invasive bladder cancer undergoing radical cystectomy. Supported by the phase III KEYNOTE-B15/EV-304 trial, the regimen significantly improved event-free and overall survival compared with standard cisplatin-based chemotherapy. This landmark approval further reinforces the expanding role of immunotherapy and antibody-drug conjugates in curative-intent treatment of urothelial cancer.