The FDA has granted Priority Review to a supplemental Biologics License Application (sBLA) for perioperative PADCEV (enfortumab vedotin) plus Keytruda (pembrolizumab) in patients with muscle-invasive bladder cancer (MIBC) regardless of cisplatin eligibility. The submission is based on Phase 3 EV-304 trial data demonstrating significant improvements in event-free and overall survival compared to standard neoadjuvant chemotherapy, with a PDUFA target action date of August 17, 2026.

Clinical Takeaway

If approved, this would represent the first and only approved perioperative treatment for patients with MIBC regardless of cisplatin eligibility, potentially establishing a new standard of care. The combination is already approved for cisplatin-ineligible MIBC patients as of November 2025, and this expansion could address the significant unmet need in the broader MIBC population where more than 50% of patients experience disease recurrence despite curative-intent surgery.

Drug Profile & Mechanism

  • PADCEV (enfortumab vedotin-ejfv): First-in-class antibody-drug conjugate (ADC) directed against Nectin-4, a protein highly expressed on bladder cancer cells
  • Keytruda (pembrolizumab): PD-1 inhibitor that enhances immune system recognition of cancer cells
  • Combination rationale: Dual targeting through ADC-mediated cytotoxicity and immune checkpoint inhibition

Target Population

  • Current approved indication: Cisplatin-ineligible MIBC patients (perioperative setting)
  • Proposed expanded indication: All MIBC patients regardless of cisplatin eligibility
  • Disease context: MIBC represents approximately 30% of all bladder cancer cases, with bladder cancer being the 9th most common cancer worldwide
  • Current treatment challenge: Standard cisplatin-based neoadjuvant chemotherapy followed by surgery is associated with recurrence in approximately 50% of patients

Study Design

  • Trial name: EV-304/KEYNOTE-B15
  • Design: Open-label, randomized, controlled Phase 3 study
  • Population: MIBC patients eligible for cisplatin-based chemotherapy
  • Treatment arms:
    • Arm A: Perioperative enfortumab vedotin + pembrolizumab (9 cycles EV + 17 cycles pembrolizumab)
    • Arm B: Neoadjuvant gemcitabine + cisplatin (standard of care)
  • Surgery: Curative-intent cystectomy performed in both arms

Endpoints

  • Primary endpoint: Event-free survival (EFS) – time from randomization to disease progression precluding surgery, failure to undergo surgery with residual disease, gross residual disease at surgery, local/distant recurrence, or death
  • Key secondary endpoints:
    • Overall survival (OS)
    • Pathological complete response (pCR) rate

Efficacy Outcomes

  • Event-free survival: 47% reduction in the risk of tumor recurrence, progression, or death versus standard neoadjuvant chemotherapy
  • Overall survival: 35% reduction in the risk of death compared to gemcitabine plus cisplatin
  • Pathological complete response:
    • Combination arm: 55.8% pCR rate
    • Chemotherapy arm: 32.5% pCR rate
  • Data presentation: Results presented at 2026 ASCO Genitourinary Cancers Symposium

Safety

  • Safety profile: Consistent with prior experience with the enfortumab vedotin plus pembrolizumab combination
  • New safety signals: None identified in EV-304 trial
  • Clinical experience: Findings were consistent with the established safety profile observed in prior studies and the currently approved cisplatin-ineligible MIBC indication

Key Clinical Implications

✔ Potential paradigm shift: Could establish first perioperative treatment standard for all MIBC patients regardless of cisplatin eligibility

✔ Improved outcomes: Substantial improvements in EFS (47% risk reduction) and OS (35% risk reduction) compared to current standard of care

✔ Enhanced pathological response: Higher pCR rates (55.8% vs 32.5%) may translate to better long-term outcomes

✔ Broader patient access: Expansion beyond cisplatin-ineligible patients addresses significant unmet medical need

✔ Priority Review status: FDA recognition of potential significant treatment advance with accelerated timeline

Bottom Line

The EV-304 trial data supporting this sBLA demonstrate compelling efficacy for perioperative PADCEV plus pembrolizumab in cisplatin-eligible MIBC patients, with meaningful improvements across multiple endpoints compared to standard neoadjuvant chemotherapy. If approved by the August 17, 2026 PDUFA date, this combination could expand the perioperative treatment landscape for patients with MIBC regardless of cisplatin eligibility. The improvements in event-free survival, overall survival, and pathological complete response observed in EV-304 support the potential for this regimen to become an important treatment option in the perioperative setting.

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