A New Era in MIBC: Perioperative Pembrolizumab + Enfortumab Vedotin Approved for Cisplatin-Ineligible Patients

The FDA has approved the combination of pembrolizumab and enfortumab vedotin-ejfv as the first perioperative (neoadjuvant + adjuvant) therapy for adults with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin. Backed by the KEYNOTE-905/EV-303 trial, the regimen demonstrated significant improvements in event-free and overall survival compared with surgery alone. This approval introduces a new treatment pathway that pairs checkpoint inhibition with a nectin-4–directed antibody-drug conjugate, expanding options for patients unable to receive traditional chemotherapy. Clinicians should review updated dosing schedules, safety considerations, and perioperative integration to align practice with this new standard of care.

Drug Profile & Mechanism

• Pembrolizumab: PD-1 checkpoint inhibitor, enhancing anti-tumor immunity.
• Enfortumab vedotin-ejfv: Nectin-4-directed antibody-drug conjugate delivering a cytotoxic payload, shown previously to be effective in advanced urothelial carcinoma.
• Target Population: Adult MIBC patients ineligible for cisplatin.
• Delivery System: intravenous (IV)
• Dosing & Administration:
  • Neoadjuvant
    • Pembrolizumab: 200 mg IV q3w
    • Enfortumab vedotin-ejfv: 1.25 mg/kg IV (max 125 mg) on Days 1 and 8 of each 21-day cycle
      • → 3 cycles (≈ 9 weeks) before surgery.
  • Adjuvant
    • Continue enfortumab vedotin-ejfv + pembrolizumab
    • Pembrolizumab: 200 mg q3w × 14 cycles OR 400 mg q6w × 7 cycles
    • Enfortumab vedotin-ejfv: 6 cycles q3w
      • → Total adjuvant duration ~ 42 weeks, including single-agent pembrolizumab period.

KEYNOTE-905 / EV-303 Study Design (NCT03924895)

• Design: Global, randomized, open-label, multicenter, active-controlled.
• Population: 344 patients with previously untreated MIBC eligible for radical cystectomy/PLND but ineligible for or declining cisplatin.
• Arms:
  • Experimental: Neoadjuvant pembrolizumab + enfortumab vedotin-ejfv → cystectomy → adjuvant enfortumab vedotin-ejfv + pembrolizumab → pembrolizumab alone.
  • Control: Immediate surgery alone.

Primary & Key Endpoints

• Event-Free Survival (EFS):
  • Median not reached in combo arm vs 15.7 months with surgery alone.
  • Hazard Ratio (HR) 0.40 (95% CI: 0.28–0.57); p < 0.0001.
• Overall Survival (OS):
  • Median not reached vs 41.7 months in control.
  • HR 0.50 (95% CI: 0.33–0.74); p = 0.0002.

Regulatory Milestones

• Approval Date: November 21, 2025
• Regulatory Pathway: Application granted priority review and approved roughly 5 months ahead of FDA goal date.
• Approval Review: Project Orbis (facilitates concurrent oncology-drug reviews across multiple international regulatory agencies)

Safety

The safety profile in KEYNOTE-905 was generally consistent with known toxicities of the individual agents.

• Perbrolizumab:
  • Immune-mediated events (e.g., colitis, hepatitis, endocrinopathies)
  • Infusion reactions
  • Embryo-fetal toxicity
• Enfortumab vedotin-ejfv:
  • Skin reactions
  • Hyperglycemia
  • Peripheral neuropathy
  • Pneumonitis/ILD
  • Ocular disorders
  • Infusion site issues
  • Embryo-fetal toxicity

Note: Detailed boxed warnings and precautions are outlined within each respective prescribing information (Perbrolizumab or Enfortumab vedotin-ejfv)

Side Effect Reporting: Healthcare professionals are encouraged to report negative side effects to the FDA

Key Clinical Implications

✔ New perioperative standard for cisplatin-ineligible MIBC: expanding beyond cystectomy alone.

✔ Combines immunotherapy with a targeted ADC approach in the localized disease setting.

✔ Offers meaningful improvements in key outcomes where traditional cisplatin chemotherapies are not feasible.

Sources:

• Center. “FDA Approves Pembrolizumab with Enfortumab Vedotin-Ejfv.” U.S. Food and Drug Administration, 21 Nov. 2025, www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer?utm_source=twitter&utm_medium=social. Accessed 11 Dec. 2025.

• “Perioperative Pembrolizumab (MK-3475) plus Cystectomy or Perioperative Pembrolizumab plus Enfortumab Vedotin plus Cystectomy versus Cystectomy Alone in Participants Who Are Cisplatin-Ineligible or Decline Cisplatin with Muscle-Invasive Bladder Cancer (MK-3475-905/​KEYNOTE-905/​EV-303).” Clinicaltrials.gov, 28 Aug. 2025, clinicaltrials.gov/study/NCT03924895. Accessed 11 Dec. 2025.

• Vulsteke, C., et al. “LBA2 Perioperative (Periop) Enfortumab Vedotin (EV) plus Pembrolizumab (Pembro) in Participants (Pts) with Muscle-Invasive Bladder Cancer (MIBC) Who Are Cisplatin-Ineligible: The Phase III KEYNOTE-905 Study.” Annals of Oncology, vol. 36, Sept. 2025, www.annalsofoncology.org/article/S0923-7534(25)04894-X/fulltext, https://doi.org/10.1016/j.annonc.2025.09.124. Accessed 11 Dec. 2025.

• Galsky, Matthew D, et al. “Perioperative Pembrolizumab Therapy in Muscle-Invasive Bladder Cancer: Phase III KEYNOTE-866 and KEYNOTE-905/EV-303.” Future Oncology, vol. 17, no. 24, Aug. 2021, pp. 3137–3150, https://doi.org/10.2217/fon-2021-0273. Accessed 25 July 2022.