As reported in The New England Journal of Medicine by Thomas Powles, MD, and colleagues, the phase III EV-302 trial has shown that the combination of the antibody-drug conjugate enfortumab vedotin-ejfv and the PD-1 inhibitor pembrolizumab improved progression-free and overall survival vs platinum-based chemotherapy in previously untreated patients with locally advanced or metastatic urothelial carcinoma.
Thomas Powles, MD
The trial supported the December 2023 approval of enfortumab vedotin plus pembrolizumab in this setting.
Study Details
In the open-label trial, 886 patients from sites in 25 countries were randomly assigned to receive enfortumab vedotin plus pembrolizumab (n = 442) or platinum-based chemotherapy (n = 444).
Treatments consisted of either:
- 3-week cycles of enfortumab vedotin at 1.25 mg/kg on days 1 and 8 and pembrolizumab at 200 mg on day 1
- 3-week cycles of gemcitabine plus either cisplatin or carboplatin.
Pembrolizumab was given for up to 35 doses, with no set limit for enfortumab vedotin; chemotherapy was given for up to six cycles. The primary endpoints were progression-free survival on blinded independent central review and overall survival.
Efficacy Outcomes
Median progression-free survival was 12.5 months (95% confidence interval [CI] = 10.4–16.6 months) in the enfortumab vedotin/pembrolizumab group vs 6.3 months (95% CI = 6.2–6.5 months) in the chemotherapy group (hazard ratio [HR] = 0.45, 95% CI = 0.38–0.54, P < .001).
Subsequent anticancer therapy was received by 31.7% of patients in the enfortumab vedotin/pembrolizumab group (most commonly platinum-based chemotherapy) and 70.5% of the chemotherapy group (most commonly PD-1 or PD-L1 inhibitor–containing therapy).
Median overall survival was 31.5 months (95% CI = 25.4 months to not reached) in the enfortumab vedotin/pembrolizumab group vs 16.1 months (95% CI = 13.9–18.3 months) in the chemotherapy group (HR = 0.47, 95% CI = 0.38–0.58, P < .001). Rates at 12 months were 78.2% vs 61.4%, respectively.
Adverse Events
Grade ≥ 3 treatment-related adverse events occurred in 55.9% of patients in the enfortumab vedotin/pembrolizumab group and 69.5% of those in the chemotherapy group. The most common were maculopapular rash (7.7%), hyperglycemia (5.0%), and neutropenia (4.8%) in the enfortumab vedotin/pembrolizumab group, and anemia (31.4%), neutropenia (30.0%), and thrombocytopenia (19.4%) in the chemotherapy group. Treatment-related adverse events resulted in discontinuation of any treatment in 35.0% of patents (including enfortumab vedotin in 29.5% and pembrolizumab in 21.4%) vs 18.5% of patients. Treatment-related adverse events led to death in four patients (< 1.0%) in the enfortumab vedotin/pembrolizumab group (due to multiple organ dysfunction syndrome, immune-mediated lung disease, diarrhea, and asthenia in one patient each) and in four patients (< 1.0%) in the chemotherapy group (due to sepsis, febrile neutropenia, neutropenic sepsis, and myocardial infarction in one patient each).
The investigators concluded, “Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports.”
Dr. Powles, of the Barts Cancer Institute Biomedical Research Centre, Queen Mary University of London, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by Astellas Pharma US and others. For full disclosures of the study authors, visit nejm.org.
