EV-301 Trial: Enfortumab Vedotin-ejfv Improves Overall Survival vs Chemotherapy in Previously Treated Advanced Urothelial Carcinoma

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Thomas Powles, MD

Thomas Powles, MD

As reported in The New England Journal of Medicine by Thomas Powles, MD, of Barts Cancer Centre, Queen Mary University of London, and colleagues, a prespecified interim analysis of the phase III EV-301 trial has shown improved overall survival with the antibody-drug conjugate enfortumab vedotin-ejfv vs investigator’s choice of chemotherapy in patients with previously treated advanced urothelial carcinoma.1 Enfortumab vedotin consists of a monoclonal antibody specific for Nectin-4 and the antimicrotubule agent monomethyl auristatin E.

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. Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) performance status score (0 or 1), geographic region (Western Europe, United States, or the rest of the world), and the presence or absence of liver metastasis at baseline. The primary endpoint was overall survival in the intention-to-treat population.

For the enfortumab vedotin vs chemotherapy groups, median patient age was 68 vs 68 years, and 79% vs 76% were male. The region was Western Europe for 42% vs 42%, United States for 14% vs 14%, and the rest of the world for 44% vs 44%. Tobacco use was former for 56% vs 53%, current for 10% vs 10%, and never for 30% vs 33%; and 19% vs 19% had a history of diabetes or hyperglycemia. ECOG performance status was 0 for 40% vs 40% and 1 for 60% vs 60%. Bellmunt risk score was 0 to 1 in 67% vs 68%. The origin site of primary disease was upper urinary tract in 33% vs 35% and bladder or other site in 67% vs 65%. Histology at diagnosis was urothelial or transitional cell carcinoma in 76% vs 75%; 78% vs 82% had visceral metastases; 87% vs 88% had received one to two lines of previous therapy; and response to previous immune checkpoint inhibitor treatment had been observed in 20% of 268 patients vs 16% of 265 patients.

Overall Survival

At interim analysis (July 2020), with a median follow-up of 11.1 months, median overall survival was 12.9 months (95% confidence interval [CI] = 10.6–15.2 months) in the enfortumab vedotin group vs 9.0 months (95% CI = 8.1–10.7 months) in the chemotherapy group (hazard ratio [HR] = 0.70, 95% CI = 0.6–0.9, P = .001); rates at 12 months were 51.5% vs 39.2%.

Hazard ratios favored enfortumab vedotin in nearly all of the subgroups examined. For stratification subgroups, hazard ratios were 0.8 (95% CI = 0.5–1.1), 0.9 (95% CI = 0.5–1.5), and 0.6 (95% CI = 0.5–0.9) for Western Europe, the United States, and the rest of world; 0.8 (95% CI = 0.5–1.2) and 0.7 (95% CI = 0.5–0.9) for an ECOG performance status of 0 and 1; and 0.7 (95% CI = 0.5–1.0) and 0.7 (0.6–1.0) for liver metastases and no liver metastases. Hazard ratios by comparator chemotherapy regimen were 0.7 (95% CI = 0.5–1.0); 0.7 (95% CI = 0.5–1.0); and 0.8 (95% CI = 0.5–1.2) for paclitaxel, docetaxel, and vinflunine.


  • Enfortumab vedotin significantly prolonged overall survival vs chemotherapy in previously treated advanced urothelial carcinoma.
  • Significant improvements in progression-free survival and objective response rate were observed.

Median progression-free survival was 5.6 months (95% CI = 5.3–5.8 months) in the enfortumab vedotin group and 3.7 months (95% CI = 3.5–3.9 months) in the chemotherapy group (HR = 0.6, 95% CI = 0.5–0.8, 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 a complete response in 4.9% vs 2.7%. Median durations of response were 7.4 months (95% CI = 6.0–9.5 months) vs 8.1 months (95% CI = 5.7–9.6 months), with responses maintained for 6 months in 53.8% vs 56.0% and 12 months in 27.7% vs 19.8% of responders. 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, fatigue, and decreased neutrophil count with enfortumab vedotin and decreased neutrophil count, anemia, decreased white cell count, neutropenia, and febrile neutropenia with chemotherapy. Treatment-related adverse events resulted in discontinuation of treatment in 13.5% of patients vs 11.3% of patients, the most common cause being peripheral neuropathy in both groups (2.4% vs 2.1%). Adverse events irrespective of causality attribution led to death in 11 patients (3.7%) and 11 patients (3.8%) in the two groups.

The most common treatment-related adverse events of special interest in the enfortumab vedotin group were rash (43.9% any grade, 14.5% grade ≥ 3; 9.6% any grade, 0.3% grade 3, in the chemotherapy group) and peripheral neuropathy (46.3% any grade, 3.7% grade 3; 30.6% any grade, 2.4% grade 3, in the chemotherapy group). Treatment-related hyperglycemia occurred in 19 patients (6.4%) treated with enfortumab vedotin vs 1 patient (0.3%) treated with chemotherapy. Hyperglycemia was grade 3 in 11 patients in the enfortumab vedotin group and resulted in death in 1 patient.

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. Dr. Powles has received honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; has served as a consultant or advisor to Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; has received research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Ipsen, MSD, Pfizer, and Roche.


1. Powles T, Rosenberg JE, Sonpavde GP, et al: N Engl J Med 384:1125-1135, 2021.

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