FDA Grants Regular Approval to Padcev (enfortumab vedotin-ejfv) + Keytruda (pembrolizumab) for Locally Advanced or Metastatic Urothelial Carcinoma
On Dec. 15, 2023, US FDA granted full approval to Padcev (enfortumab vedotin-ejfv) in combination with Keytruda (pembrolizumab) for patients with locally advanced or metastatic urothelial cancer (la/mUC).
Previously on Apr. 3, 2023, US FDA granted accelerated approval to this combination for la/mUC not eligible for cisplatin-containing chemotherapy.
Of note to Regulatory Affairs:
The FDA approved this application 5 months ahead of the FDA goal date.
This review used:
- Project Orbis - FDA collaborated with the Australian Therapeutic Goods Administration and Health Canada for this review.
- Real-Time Oncology Review (RTOR)
- Assessment Aid
This application was granted priority review and breakthrough designation.
Phase 3 EV-302/KEYNOTE-A39 (NCT04223856) is an open-label, randomized trial of patients with la/mUC and no prior systemic therapy for advanced disease. EV-302 serves as the US confirmatory trial for accelerated approval.
Patients were randomized 1:1 to two arms:
- enfortumab vedotin-ejfv with pembrolizumab
- platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin)
Randomization was stratified by cisplatin eligibility, PD-L1 expression, and presence of liver metastases.
Efficacy was evaluated in 886 patients. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as assessed by blinded independent central review.
Statistically significant improvements in both OS and PFS were demonstrated for enfortumab vedotin-ejfv with pembrolizumab compared with platinum-based chemotherapy.
Median OS was 31.5 months (95% CI: 25.4, not estimable) for patients who received enfortumab vedotin-ejfv with pembrolizumab and 16.1 months (95% CI: 13.9, 18.3) for those who received platinum-based chemotherapy (Hazard ratio [HR] 0.47 [95% CI: 0.38, 0.58]).
Median PFS was 12.5 months (95% CI: 10.4, 16.6) for patients who received enfortumab vedotin-ejfv with pembrolizumab and 6.3 months (95% CI: 6.2, 6.5) for those who received platinum-based chemotherapy (HR 0.45 [95% CI: 0.38, 0.54]).
The most common (≥20%) adverse reactions, including laboratory abnormalities, in patients receiving the combination were increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection, and decreased platelets.