Oncology Drug Approval News Flash: FDA approves perioperative pembrolizumab plus enfortumab vedotin-ejfvfor cisplatin-ineligible muscle invasive bladder cancer (MIBC)

On November 21, 2025, the U.S. FDA approved pembrolizumab (Keytruda / Keytruda Qlex) in combination with enfortumab vedotin-ejfv (Padcev) as neoadjuvant and adjuvant therapy for adults with muscle invasive bladder cancer (MIBC) who are eligible for radical cystectomy with pelvic lymph node dissection (RC + PLND) but are ineligible for or decline cisplatin-based chemotherapy.

Pivotal trial: KEYNOTE-905 / EV-303

The approval is based on the phase 3 KEYNOTE-905/EV-303 trial (NCT03924895), an open-label, randomized, multicenter, active-controlled study in 344 previously untreated MIBC patients.

• Eligible population
  • Candidates for RC + PLND
  • Ineligible for or refusing cisplatin-based chemotherapy
• Study arms
  1. Neoadjuvant pembrolizumab + enfortumab vedotin-ejfv → RC + PLND →
     adjuvant enfortumab vedotin-ejfv + pembrolizumab →
     maintenance pembrolizumab monotherapy
  2. Control arm: immediate RC + PLND alone (no perioperative systemic therapy)
• Endpoints
  • Primary: Event-free survival (EFS) by blinded independent central review
  • Key secondary: Overall survival (OS)

Key efficacy outcomes: significant improvement in EFS and OS

Perioperative pembrolizumab plus enfortumab vedotin-ejfv significantly improved both EFS and OS versus surgery alone.

• Event-free survival (EFS)
  • Combination arm: median not reached (NR) (95% CI: 37.3, NR)
  • Surgery-alone arm: median 15.7 months (95% CI: 10.3, 20.5)
  • Hazard ratio (HR) 0.40 (95% CI: 0.28, 0.57); p < 0.0001
• Overall survival (OS)
  • Combination arm: median NR (95% CI: NR, NR)
  • Surgery-alone arm: median 41.7 months (95% CI: 31.8, NR)
  • HR 0.50 (95% CI: 0.33, 0.74); p = 0.0002

These data indicate a substantial reduction in the risk of EFS and OS events in the perioperative combination arm.

Safety profile and key adverse events

The overall safety profile of enfortumab vedotin-ejfv plus pembrolizumab in KEYNOTE-905/EV-303 was consistent with prior experience in advanced urothelial carcinoma.

• Pembrolizumab
  • Immune-mediated AEs (e.g., pneumonitis, hepatitis, endocrinopathies, dermatologic reactions)
  • Infusion-related reactions
  • Complications of allogeneic HSCT
  • Embryo-fetal toxicity
• Enfortumab vedotin-ejfv
  • Severe skin reactions
  • Hyperglycemia
  • Pneumonitis / interstitial lung disease
  • Peripheral neuropathy
  • Ocular disorders
  • Infusion site extravasation
  • Embryo-fetal toxicity

Clinicians should carefully review the latest U.S. prescribing information for detailed contraindications, warnings, dose modifications, and monitoring recommendations.

Perioperative dosing regimen (summary)

According to the FDA communication, the perioperative regimen is summarized as follows:

• Neoadjuvant phase
  • Pembrolizumab 200 mg IV every 3 weeks
  • Enfortumab vedotin-ejfv 1.25 mg/kg (up to 125 mg for patients ≥100 kg) IV on Days 1 and 8 of a 21-day cycle
  • Total of 3 cycles (approximately 9 weeks)
• Adjuvant phase
  • Enfortumab vedotin-ejfv continued for 6 additional cycles every 3 weeks
  • Pembrolizumab options:
    • 200 mg IV every 3 weeks for 14 cycles, or
    • 400 mg IV every 6 weeks for 7 cycles
  • Duration of combination therapy in the adjuvant setting: ~18 weeks
  • Overall adjuvant duration including pembrolizumab monotherapy: ~42 weeks
  • When given on the same day, enfortumab vedotin-ejfv should be administered before pembrolizumab

For dosing of pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) in combination with enfortumab vedotin-ejfv, prescribers should refer to the Keytruda Qlex prescribing information.

Regulatory aspects: Project Orbis and priority review

This application was reviewed under the FDA Oncology Center of Excellence’s Project Orbis, enabling concurrent review with international partners, including Australia’s TGA, Health Canada, Swissmedic, and the UK MHRA. It was also granted priority review and approved approximately five months ahead of the FDA goal date.

Editorial perspective (Morningglorysciences)

For cisplatin-ineligible MIBC, treatment options around radical cystectomy have historically been limited, and the role of perioperative systemic therapy has been less clearly defined than in cisplatin-eligible disease.

The KEYNOTE-905/EV-303 data now suggest that an IO + ADC combination can meaningfully improve both EFS and OS versus surgery alone in this population, potentially establishing a new perioperative standard of care.

However, real-world implementation will need to balance:

• The intensity and duration of this perioperative regimen
• Management of skin toxicity, hyperglycemia, and neuropathy associated with enfortumab vedotin-ejfv
• Patient age, comorbidities, and performance status
• Healthcare resource use and cost/access issues

As more mature data and real-world evidence accumulate, treatment algorithms for MIBC—particularly in cisplatin-ineligible patients—are likely to be redefined over the coming years.

This article was produced by the Morningglorysciences Editorial Team.

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