Clinical Summary:

• Design/Population: The phase 3 EV-302/KEYNOTE-A39 trial randomized patients with previously untreated locally advanced or metastatic urothelial carcinoma to receive enfortumab vedotin plus pembrolizumab or platinum-based chemotherapy.
• Key Outcomes: After 3.5 years of follow-up, enfortumab vedotin plus pembrolizumab maintained a significant overall survival benefit compared with chemotherapy. Nearly half of responders achieved a complete response, with many complete responses evolving from initial partial responses during continued treatment.
• Clinical Relevance: These findings reinforce enfortumab vedotin plus pembrolizumab as the preferred first-line treatment and suggest that continued therapy may help maximize depth of response and long-term survival outcomes.

Results from the phase 3 EV-302/KEYNOTE-A39 trial demonstrated that enfortumab vedotin plus pembrolizumab continued to improve overall survival (OS) compared with chemotherapy among previously untreated patients with locally advanced or metastatic urothelial carcinoma. 

These results were presented by Thomas Powles, MD, Queen Mary University of London, United Kingdom, at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

In this trial, 886 patients were randomized 1:1 to receive 1.25 mg/kg of enfortumab vedotin intravenously on days 1 and 8 plus 200 mg of pembrolizumab on day 1 (n = 442) or gemcitabine plus cisplatin and carboplatin chemotherapy (n = 444) in 21-day cycles until disease progression, unacceptable toxicity, or completion of planned therapy. The dual primary end points were progression-free survival (PFS) and OS. A key secondary end point was safety. 

At a median follow-up of 42.8 months, median OS was 33.6 months in the enfortumab vedotin plus pembrolizumab arm and 15.9 months in the chemotherapy arm, with 42-month OS rates of 44.0% and 24.6%, respectively. 

Complete responses were achieved in 45.1% of patients treated with enfortumab vedotin plus pembrolizumab compared with 32.8% of patients treated with chemotherapy. Among complete responders in the enfortumab vedotin plus pembrolizumab arm, 66.2% initially achieved a partial response before converting to a complete response. The median time from partial response to complete response was 4.5 months, requiring a median of 5 additional cycles of enfortumab vedotin and 6 additional cycles of pembrolizumab.

Long-term outcomes were particularly favorable among patients who converted from partial response to complete response. Median OS was not reached, and more than 80% of these patients remained alive at 42 months, corresponding to a 42-month OS rate of 82.4%, compared with 83.6% among all patients who achieved a complete response. Patients who converted from partial response to complete response received a median of 15 total cycles of enfortumab vedotin and 31 total cycles of pembrolizumab.

Platinum-based chemotherapy was the most common subsequent therapy after enfortumab vedotin plus pembrolizumab (30.5%), whereas PD-L1 inhibitors were most commonly administered after chemotherapy (59.7%). Among patients who received subsequent platinum-based chemotherapy following enfortumab vedotin plus pembrolizumab, investigator-assessed responses were observed in 20.7%.

No new safety signals emerged with longer follow-up, and extended treatment duration among patients who converted from partial response to complete response did not appear to increase toxicity.

“EV-302 represents the longest follow-up available for [enfortumab vedotin plus pembrolizumab] in a phase 3 trial,” concluded Dr Powles. “After 3.5 years of median follow-up, [enfortumab vedotin plus pembrolizumab] continues to demonstrate superior efficacy vs chemo, with no new safety signals.”

Source:

Powles T, Van der Heijden MS, Bedke J, et al. Enfortumab vedotin plus pembrolizumab (EV+P) vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): 3.5-year follow-up and response analyses from the phase 3 EV-302 study. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract 4507.