Mursalin Pathan – Content Writer
Pune, India | November 24, 2025
The U.S. Food and Drug Administration approved pembrolizumab (Keytruda) combined with enfortumab vedotin-ejfv (Padcev) for adults with muscle-invasive bladder cancer (MIBC) who cannot tolerate cisplatin chemotherapy. This combination therapy applies to both preoperative and postoperative treatment, offering patients with limited options new hope for improved outcomes.
The approval primarily relied on results from the KEYNOTE-905/EV-303 trial, a randomized, open-label study including 344 cisplatin-ineligible MIBC patients. Participants received neoadjuvant therapy using pembrolizumab and enfortumab vedotin before radical cystectomy and pelvic lymph node dissection. That is followed by adjuvant therapy post-surgery to reduce the risk of disease recurrence.
The trial revealed significant clinical benefits. Event-free survival (EFS) improved notably for patients receiving the combination therapy compared with those undergoing surgery alone. Median EFS was not reached in the treatment group, whereas the control group achieved 15.7 months, producing a hazard ratio of 0.40. Moreover, overall survival (OS) favored the combination therapy, with median OS not reached, compared with 41.7 months in the surgery-only group, resulting in a hazard ratio of 0.50.
Safety outcomes aligned with previously reported findings. Patients experienced immune-mediated reactions, infusion-related complications, and other adverse effects associated with pembrolizumab. Enfortumab vedotin caused skin reactions, hyperglycemia, pulmonary inflammation, peripheral neuropathy, ocular disorders, and infusion-site complications. Clinicians found these adverse events manageable through careful monitoring and timely dose adjustments.
The recommended treatment regimen specifies precise dosing. During neoadjuvant therapy, patients receive pembrolizumab 200 mg intravenously every three weeks and enfortumab vedotin 1.25 mg/kg (maximum 125 mg) on Days 1 and 8 of each 21-day cycle for three cycles. After surgery, enfortumab vedotin continues every three weeks for six cycles alongside pembrolizumab. Subsequently, pembrolizumab continues as a single agent, either 200 mg every three weeks for 14 cycles or 400 mg every six weeks for seven cycles. On days when both drugs are administered, clinicians should administer pembrolizumab after enfortumab vedotin.
Regulatory support accelerated the approval process. Project Orbis enabled international collaboration among regulatory agencies. While the FDA used its Assessment Aid to streamline evaluation without compromising drug safety or efficacy. Consequently, patients gained faster access to this potentially life-saving treatment.
Experts describe the approval as practice-changing for MIBC patients ineligible for cisplatin therapy. Clinical investigators suggest that combining pembrolizumab with enfortumab vedotin could establish a new standard of care, improving survival outcomes for a high-risk population with historically limited treatment options.
Healthcare professionals must continue reporting serious adverse events associated with either pembrolizumab or enfortumab vedotin through the FDA’s MedWatch system. Vigilant reporting safeguards patient safety and enables continuous monitoring of long-term effects, ensuring that therapy remains effective and manageable.
This approval marks a significant milestone in bladder cancer management. By combining immunotherapy with targeted therapy, clinicians can now address an unmet clinical need, offering patients effective preoperative and postoperative options. Proper administration and monitoring allow physicians to maximize therapeutic benefits while minimizing risks, giving patients renewed hope, longer survival, and better overall outcomes.
