ASCO GU 2022: Study EV-302: A Two-Arm, Open-Label, Randomized Controlled Phase 3 Study of Enfortumab Vedotin in Combination With Pembrolizumab Versus Chemotherapy in Previously Untreated Advanced Urothelial Carcinoma

(UroToday.com) On the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 focused on urothelial carcinoma during the Trials in Progress Poster Session B, Dr. Van Der Heijden presented the rationale and design of EV-302 assessing enfortumab vedotin (EV) with pembrolizumab compared to chemotherapy as first-line treatment in advanced urothelial carcinoma (aUC).

For eligible patients with aUC, platinum-based chemotherapy is standard first line therapy. Recently, data has shown that maintenance therapy immune checkpoint inhibition may be offered for patients who do not progress during first-line chemotherapy. However, not all patients are eligible for maintenance therapy and many will progress or succumbing to their disease prior to receiving second-line therapy. Therefore, there is an ongoing unmet need for improved first-line treatment.

Enfortumab vedotin (EV) is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human mAb conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable linker. In patients who have previously received platinum-based therapy and a PD-(L)1 inhibitor, EV has shown an OS benefit compared to chemotherapy. As a result, EV is FDA approved. However, in addition to monotherapy, EV, and other MMAE containing ADCs, have been shownto induce immunogenic cell death and enhance anti-tumor immunity. As a result, the combination of EV with PD-1/PD-L1 inhibitor may show evidence of synergy.

In EV-302/KN-A39 (NCT04223856), the combination of EV and pembrolizumab will be compared to standard first-line chemotherapy (gemcitabine plus either cisplatin or carboplatin) in patients with aUC. This study will enroll patients with measurable disease, an ECOG status of ≤2, who are eligible to receive EV, pembrolizumab, and either cisplatin or carboplatin.

Following enrollment, patients will be randomized in a 1:1 fashion to receive EV and pembrolizumab or standard chemotherapy. Randomization is stratified based on cisplatin eligibility, PD-L1 expression, and liver metastases. In the combination arm, patients will receive EV (1.25 mg/kg) administration on Days 1 and 8 and pembrolizumb (200 mg) on Day 1. In the control arm, patients will receive gemcitabine (1000 mg/m2) on Days 1 and 8; and cisplatin (70 mg/m2) or carboplatin (AUC 4.5 or 5) on Day 1 of every 3-week cycle.

The primary endpoints are overall survival and progression-free survival, per RECIST v1.1 by blinded independent central review. Secondary outcomes include ORR, duration of response, and disease control rate based on both blinded independent central review and investigator assessment; progression-free survival by investigator assessment; adverse events; and patient reported outcomes. The study opened March 2020 with sites actively enrolling globally in North and South America, Europe, Asia, and Australia.