On July 9, 2021, the U.S. Food and Drug Administration (FDA) approved enfortumab vedotin-ejfv (Padcev), a Nectin-4–directed antibody and microtubule inhibitor conjugate, for adults with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy. It also was approved for patients who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
The FDA granted accelerated approval to enfortumab vedotin in December 2019 for patients with locally advanced or metastatic urothelial cancer who have received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.
EV-301 and EV-201
Approval was partially based on the EV-301 trial (NCT03474107), an open-label, randomized, multicenter study required to confirm the clinical benefit of the 2019 accelerated approval. This trial enrolled 608 patients with locally advanced or metastatic urothelial cancer who received a prior PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Patients were randomly assigned 1:1 to receive either enfortu-mab vedotin at 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle or investigator’s choice of single-agent chemotherapy (docetaxel, paclitaxel, or vinflunine).
Median overall survival was 12.9 months (95% confidence interval [CI] = 10.6–15.2 months) for patients receiving enfortumab vedotin vs 9.0 months (95% CI = 8.1–10.7 months) for those receiving chemotherapy (hazard ratio [HR] = 0.70, 95% CI = 0.56–0.89, P = .0014). Median progression-free survival was 5.6 months (95% CI = 5.3–5.8 months) compared with 3.7 months (95% CI = 3.5–3.9 months), respectively (HR = 0.62, 95% CI = 0.51–0.75, P < .0001). The overall response rate was 40.6% (95% CI = 34.9%–46.5%) vs 17.9% (95% CI = 13.7%–22.8%), respectively (P < .0001).
Efficacy for patients ineligible for cisplatin-containing chemotherapy was evaluated in cohort 2 of EV-201 (NCT03219333), a single-arm, multicohort, international trial in 89 patients with locally advanced or metastatic urothelial cancer who received a prior PD-1 or PD-L1 inhibitor and were ineligible for cisplatin-containing chemotherapy. The primary efficacy endpoint was confirmed overall response rate, assessed by blinded independent central review, and the key secondary efficacy endpoint was response duration. The confirmed overall response rate was 51% (95% CI = 39.8%–61.3%), including 22% with complete responses, and the median response duration was 13.8 months (95% CI = 6.4 months to not estimable).
The recommended dose of enfortumab vedotin is 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity.