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 (aUC) (trial in progress).

Abstract

TPS589 Background: Platinum-based chemotherapy is standard first line (1L) therapy for aUC. Maintenance therapy may be offered for patients (pts) who do not progress on 1L chemotherapy. However, not all pts are eligible for maintenance therapy, with many succumbing to their disease prior to 2L. Therefore, there is a persistent unmet need for safe and effective drug combinations in the 1L setting. 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. EV has previously shown an OS benefit vs chemotherapy in pts with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based therapy and a PD-(L)1 inhibitor (Powles NEJM 2021). EV is FDA-approved in this and other settings (PADCEV, Seagen Inc., 2021). Preclinical studies showed that MMAE containing ADCs, including EV, induce evidence of immunogenic cell death and can enhance anti-tumor immunity, thereby laying the foundation for EV-PD-1/PD-L1 inhibitor combination (Liu Cancer Res 2020; Cao Can Res 2016). EV-302 will evaluate the efficacy and safety of EV+pembrolizumab (EV+P) combination vs gemcitabine+cisplatin (gem+cis) or carboplatin (carbo) in pts with previously untreated aUC. Methods: EV-302/KN-A39 (NCT04223856) evaluates EV+P combination vs gem+cis or carbo in previously untreated pts with aUC. Eligibility criteria include pts with measurable disease, an ECOG status of ≤2, and eligible to receive EV, P, and cis or carbo. EV+P combination includes EV (1.25 mg/kg) administration on Days 1 and 8 with P (200 mg) on Day 1. Gem+cis or carbo includes: gem (1000 mg/m2) on Days 1 and 8; and cis (70 mg/m2) or carbo (AUC 4.5 or 5) on Day 1 of every 3-wk cycle. Randomization is 1:1 with stratification factors: cis eligibility, PD-L1 expression, and liver metastases. The primary endpoints are PFS and OS for EV+P compared to gem+cis or carbo. Other endpoints include ORR, duration of response, disease control rate, AEs, patient reported outcomes, PK, and biomarkers. The study opened March 2020 with sites actively enrolling globally. Clinical trial information: NCT04223856.