As reported in The New England Journal of Medicine by Thomas Powles, MD, Barts Cancer Institute Biomedical Research Centre, Queen Mary University of London, and colleagues, the phase III EV-302 trial has shown that the combination of the antibody–drug conjugate enfortumab vedotin-ejfv, which is directed against nectin-4, and the PD-1 inhibitor pembrolizumab improved progression-free and overall survival vs platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma.1 Histologic subtypes were varied, including subtypes such as adenocarcinoma or squamous cell differentiation.
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 at 1,000 mg/m2 on days 1 and 8 and either cisplatin at 70 mg/m2 or carboplatin (AUC 4.5–5.0) on day 1.
Patients in the chemotherapy group received cisplatin or carboplatin on the basis of their eligibility to receive cisplatin. Of note, 29% of patients in this group received maintenance avelumab as part of first-line therapy. Pembrolizumab was given for up to 35 doses, with no set limit for enfortumab vedotin; chemotherapy was given for up to six cycles. Randomization was stratified according to eligibility to receive cisplatin, PD-L1 expression status (high = combined positive score [CPS] ≥ 10 vs low = CPS < 10), and presence of liver metastases. A total of 95% of patients in both groups had metastatic disease. 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). Rates at 12 and 18 months were 50.7% vs 21.6% and 43.9% vs 11.7%. Hazard ratios for stratification subgroups were 0.48 (95% CI = 0.38–0.62) for 244 vs 234 patients who were eligible for cisplatin and 0.43 (95% CI = 0.33–0.55) for 198 vs 210 patients ineligible for cisplatin, 0.50 (95% CI = 0.38–0.65) for 184 vs 185 patients with low PD-L1 expression and 0.42 (95% CI = 0.33–0.53) for 254 vs 254 patients with high PD-L1 expression, and 0.53 (95% CI = 0.38–0.76) for 100 vs 99 patients with liver metastases and 0.43 (95% CI = 0.35–0.52) for 342 vs 345 patients without liver metastases.
Subsequent anticancer therapy was received by 31.7% of the enfortumab vedotin/pembrolizumab group, most commonly platinum-based chemotherapy (24.9%), and 70.5% of the chemotherapy group, most commonly PD-1 or PD-L1 inhibitor–containing therapy (58.6%).
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 and 18 months were 78.2% vs 61.4% and 69.5% vs 44.7%. Hazard ratios for stratification subgroups were 0.53 (95% CI = 0.39–0.72) for those eligible for cisplatin and 0.43 (95% CI = 0.31–0.59) for those ineligible for cisplatin, 0.44 (95% CI = 0.31–0.61) for those with low PD-L1 expression and 0.49 (95% CI = 0.37–0.66) for those with high PD-L1 expression, and 0.47 (95% CI = 0.32–0.71) for those with liver metastases and 0.47 (95% CI = 0.36–0.61) for those without liver metastases.
Among 437 vs 441 evaluable patients, an objective response was observed in 67.7% of the enfortumab vedotin/pembrolizumab group, with a complete response in 29.1%, vs 44.4% of the chemotherapy group, with a complete response in 12.5%. Median durations of response was not reached (95% CI = 20.2 months to not evaluable) vs 7.0 months (95% CI = 6.2–10.2 months).
Adverse Events
The most common treatment-related adverse events of any grade in the enfortumab vedotin/pembrolizumab group were peripheral sensory neuropathy (50.0%), pruritus (39.8%), alopecia (33.2%), maculopapular rash (32.7%), fatigue (29.3%), and diarrhea (27.5%). The most common in the chemotherapy group included anemia (56.6%), neutropenia (41.6%), nausea (38.8%), fatigue (36.0%), thrombocytopenia (34.2%), and decreased appetite (22.6%). Grade ≥ 3 treatment-related adverse events occurred in 55.9% of the enfortumab vedotin/pembrolizumab group and 69.5% of 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% of patients. Treatment-related adverse events led to death in four patients (< 1%) in the enfortumab vedotin/pembrolizumab group (from multiple organ dysfunction syndrome, immune-mediated lung disease, diarrhea, and asthenia in one patient each) and in four patients (< 1%) in the chemotherapy group (from 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.”
DISCLOSURE: The study was funded by Astellas Pharma US and others. Dr. Powles reported financial relationships with AstraZeneca, Eisai, Merck, Novartis, Pfizer, Roche, Astellas Pharma, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Seattle Genetics, Merck Sharp & Dohme, Merck Serono, Johnson & Johnson, and Mashup. For full disclosures of all study authors, visit nejm.org.
REFERENCE
1. Powles T, Valderrama BP, Gupta S, et al: Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med 390:875-888, 2024.
