As reported in The New England Journal of Medicine by Powles et al, a prespecified interim analysis of the phase III EV-301 trial has shown improved overall survival with enfortumab vedotin-ejfv vs investigator choice of chemotherapy in patients with previously treated advanced urothelial carcinoma.

Based on findings of durable objective responses in the phase II EV-201 trial, enfortumab vedotin was granted accelerated approval in December 2019 for the treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.

Study Details

In the open-label trial, 608 patients from sites in 19 countries who had received platinum-containing chemotherapy and had experienced disease progression during or after treatment with a PD-1 or PD-L1 inhibitor were randomly assigned to receive intravenous enfortumab vedotin at 1.25 mg/kg on days 1, 8, and 15 of 28-day cycles (n = 301) or chemotherapy selected by investigators before randomization (n = 307). Chemotherapy options consisted of docetaxel at 75 mg/kg (n = 117), paclitaxel at 175 mg/kg (n = 112), and vinflunine at 320 mg/m² (n = 78) given on day 1 of 21-day cycles. The primary endpoint was overall survival in the intention-to-treat population.

Overall Survival

At interim analysis (July 2020), with a median follow-up of 11.1 months, median overall survival was 12.88 months (95% confidence interval [CI] =10.58–15.21 months) in the enfortumab vedotin group vs 8.97 months (95% CI = 8.05–10.74 months) in the chemotherapy group (hazard ratio [HR] = 0.70, 95% CI = 0.56–0.89, P = .001). Survival rates at 12 months were 51.5% vs 39.2%. Hazard ratios favored enfortumab vedotin in nearly all subgroups examined, including those assessed according to chemotherapy regimen.

Median progression-free survival was 5.55 months (95% CI = 5.32–5.82 months) in the enfortumab vedotin group and 3.71 months (95% CI = 3.52–3.94 months) in the chemotherapy group (HR = 0.62, 95% CI = 0.51–0.75, P < .001). Among 288 vs 296 patients evaluable for response, an objective response was observed in 40.6% vs 17.9% of patients (P < .001), with complete response in 4.9% vs 2.7%. Median durations of response were 7.39 months vs 8.11 months. Disease control rates were 71.9% vs 53.4% (P < .001).

Adverse Events

Treatment-related grade ≥ 3 adverse events occurred in 51.4% of patients in the enfortumab vedotin group vs 49.8% in the chemotherapy group. The most common were maculopapular rash (7.4%), fatigue (6.4%), and decreased neutrophil count (6.1%) in the enfortumab vedotin group and decreased neutrophil count (13.4%), anemia (7.6%), decreased white blood cell count (6.9%), neutropenia (6.2%), and febrile neutropenia (5.5%) in the chemotherapy group.

Treatment-related adverse events resulted in discontinuation of treatment in 13.5% vs 11.3% of patients, with the most common cause in the enfortumab vedotin group being peripheral neuropathy (2.4%). The most common treatment-related adverse events of special interest in the were rash (43.9% any grade, 14.5% grade ≥ 3 in the enfortumab vedotin group; 9.6% any grade, 0.3% grade 3 in chemotherapy group) and peripheral neuropathy (46.3% any grade, 3.7% grade 3 in the enfortumab vedotin group; 30.6% any grade, 2.4% grade 3 in the chemotherapy group).

The investigators concluded: “Enfortumab vedotin significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor.”

Disclosure: The study was funded by Astellas Pharma US and Seagen. For full disclosures of the study authors, visit nejm.org.