The U.S. Food and Drug Administration has approved pembrolizumab—administered either intravenously or as the subcutaneous formulation pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex)—in combination with enfortumab vedotin-ejfv as neoadjuvant and adjuvant therapy for adults with muscle-invasive bladder cancer who cannot receive cisplatin. The approval, announced November 21, covers use before and after radical cystectomy.
Trial Results
The decision is based on findings from the phase III KEYNOTE-905/EV-303 trial (NCT03924895), an open-label, randomized study enrolling 344 previously untreated patients eligible for radical cystectomy but ineligible for or declining cisplatin-based chemotherapy.
Participants were randomly assigned to receive neoadjuvant pembrolizumab plus enfortumab vedotin followed by surgery and adjuvant therapy with the same combination, then pembrolizumab alone—or to undergo immediate cystectomy.
The trial showed significant improvements in both event-free survival (EFS) and overall survival (OS):
Median EFS: not reached (95% CI = 37.3 months to not reached) with combination therapy vs 15.7 months (95% CI = 10.3–20.5) with surgery alone
Hazard ratio (HR): 0.40 (95% CI = 0.28–0.57; P < .0001)
Median OS: not reached in the combination arm vs 41.7 months (95% CI = 31.8 to not reached) with surgery alone
HR: 0.50 (95% CI = 0.33–0.74; P = .0002)
The safety profile of the pembrolizumab–enfortumab vedotin regimen in this setting was consistent with earlier studies in advanced urothelial cancer.
Key pembrolizumab warnings include immune-mediated toxicities, infusion reactions, transplant-related complications, and embryo-fetal risk.
Enfortumab vedotin carries warnings for severe skin reactions, hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, ocular disorders, infusion-site extravasation, and embryo-fetal toxicity.
Neoadjuvant therapy consists of:
- Pembrolizumab 200 mg IV every 3 weeks
- Enfortumab vedotin 1.25 mg/kg (maximum 125 mg for patients ≥100 kg) IV on days 1 and 8 of each 21-day cycle
- Three cycles total (9 weeks)
Adjuvant therapy includes:
Six additional cycles of enfortumab vedotin every 3 weeks
Pembrolizumab given concurrently for 18 weeks, followed by pembrolizumab monotherapy to complete 42 weeks of total adjuvant treatment
Pembrolizumab should be administered after enfortumab vedotin when both are given on the same day. Keytruda Qlex dosing follows its own prescribing information.
Regulatory Pathway
The approval was conducted under Project Orbis, enabling concurrent international review with regulatory partners in Australia, Canada, Switzerland, and the United Kingdom. The application received Priority Review and was approved five months ahead of the FDA’s target date. The sponsor also used the FDA’s voluntary Assessment Aid to support the evaluation process.
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