FDA Approves Keytruda–Padcev Combination as First Perioperative Treatment for Bladder Cancer

The FDA has approved pembrolizumab (Keytruda) or pembrolizumab Qlex with enfortumab vedotin (Padcev) as the first perioperative regimen for cisplatin-ineligible muscle-invasive bladder cancer. In the Phase 3 KEYNOTE-905 trial, the combination reduced the risk of EFS events by 60% and death by 50%, achieving a 57% pathologic complete response versus 9% with surgery alone.

The U.S. Food and Drug Administration (FDA) has approved pembrolizumab (Keytruda) and pembrolizumab-berahyaluronidase alfa-pmph (Keytruda Qlex) in combination with enfortumab vedotin-ejfv (Padcev) as neoadjuvant and adjuvant therapy for adults with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. This decision establishes the first perioperative regimen combining a PD-1 inhibitor with an antibody–drug conjugate (ADC) for this patient population.

A New Option for Patients

Until now, patients with MIBC who could not receive cisplatin had limited treatment options beyond radical cystectomy. Up to half of these individuals experience disease recurrence even after bladder removal. The approval of pembrolizumab plus enfortumab vedotin introduces an evidence-based alternative capable of addressing a long-standing therapeutic gap.

“Half of patients with MIBC may experience cancer recurrence even after having their bladder removed, and many of these patients are ineligible to receive cisplatin. These approvals, based on striking event-free and overall survival benefits, may represent an important practice-changing advance for these patients who’ve had no new options in decades,” said Dr. Matthew Galsky, Director of Genitourinary Medical Oncology at Mount Sinai Tisch Cancer Center and investigator of the KEYNOTE-905 study.  

Strong Evidence from the Phase 3 KEYNOTE-905/EV-303 Trial

The FDA approval is supported by data from the Phase 3 KEYNOTE-905 (EV-303) trial, conducted in collaboration with Pfizer and Astellas. The open-label, randomized, multicenter study enrolled 344 patients with previously untreated MIBC who were either ineligible for or declined cisplatin-based chemotherapy. Participants were randomized 1:1 to receive perioperative pembrolizumab plus enfortumab vedotin followed by surgery and continued treatment, or surgery alone.

After a median follow-up of 25.6 months, the combination achieved a 60% reduction in the risk of event-free survival (EFS) events compared with surgery alone (HR 0.40; 95% CI, 0.28–0.57; p<0.0001). Median EFS was not reached in the pembrolizumab plus enfortumab vedotin arm versus 15.7 months in the surgery-only arm. Overall survival (OS) also significantly improved, with a 50% reduction in the risk of death (HR 0.50; 95% CI, 0.33–0.74; p=0.0002). Median OS was not reached in the combination arm and was 41.7 months in the control group.

A notable finding was the pathologic complete response (pCR) rate of 57.1% with pembrolizumab plus enfortumab vedotin, compared with 8.6% after surgery alone. These results underscore the potential of dual immunotherapy and ADC approaches to improve both preoperative and postoperative outcomes in localized bladder cancer.

Treatment Administration and Design

Patients in the experimental arm received pembrolizumab 200 mg intravenously every 3 weeks with enfortumab vedotin 1.25 mg/kg on days 1 and 8 of each 21-day cycle for three cycles before surgery. Postoperatively, adjuvant treatment included pembrolizumab for up to 14 cycles and enfortumab vedotin for up to six cycles, continuing until completion or unacceptable toxicity. The study was not designed to isolate the independent effects of pembrolizumab in the neoadjuvant or adjuvant phases.

Safety Profile

The overall safety of pembrolizumab plus enfortumab vedotin was consistent with prior trials in advanced urothelial cancer. The most common adverse reactions (≥20%) included rash, pruritus, fatigue, peripheral neuropathy, alopecia, dysgeusia, diarrhea, constipation, and decreased appetite. Serious adverse events occurred in approximately one-third of patients, with urinary tract infection and hematuria among the most frequent.

Immune-mediated adverse reactions were consistent with the known profile of pembrolizumab, including potential pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Enfortumab vedotin carries warnings for skin reactions, hyperglycemia, interstitial lung disease, peripheral neuropathy, and ocular toxicity.

“Our company’s ongoing commitment to putting patients at the center of finding new innovations in cancer care has made the introduction of these new options a reality for patients who are truly in need. Moreover, we are honored to provide these patients who previously had only one option — surgery — with a choice to receive their immunotherapy either intravenously or subcutaneously,” said Dr. Marjorie Green, Senior Vice President and Head of Oncology, Global Clinical Development at Merck Research Laboratories.

Expanding Access with KEYTRUDA QLEX

Merck’s new formulation, Keytruda Qlex—a co-formulation of pembrolizumab with berahyaluronidase alfa-pmph—offers a subcutaneous administration option designed to improve patient convenience. Pharmacokinetic and safety data from the MK-3475A-D77 study supported its equivalence to intravenous pembrolizumab, providing clinicians flexibility in the perioperative setting.