EV-301: An open-label, randomized phase III study to evaluate enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial cancer (la/mUC)

Abstract

Background: Standard first-line treatment for patients (pts)with la/mUC is cisplatinbased chemotherapy or carboplatin-based chemotherapy for pts unfit for cisplatin. Recently, immune checkpoint inhibitors (CPIs) have become standard treatment options for pts who progressed during/after platinum-based chemotherapy or are ineligible for cisplatin. While some pts with la/mUC achieve durable responses with CPIs, only aminority respond. Following failure with CPI, no therapies are approved. Enfortumab vedotin (EV) is a fully humanizedmonoclonal antibody that delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is highly expressed in 97% ofmUC patient samples (Petrylak ASCO2017). In a phase 1 study (EV-101; NCT02091999), single-agent EV at the established recommended phase 2 dose of 1.25mg/ kg was generally well tolerated and demonstrated a confirmed objective response rate of 41%(n=46/112) across the overall population of pts withmUC; in pts with prior CPI therapy, a confirmed ORR of 40% (n=36/89) was observed. Trial design: EV-301 is a global, multicenter, open-label phase 3 trial (NCT03474107) enrolling adult pts with la/mUC and an ECOG score ≤1, who have received one prior platinum-containing chemotherapy, and have experienced disease progression during or following treatment with a CPI. Approximately 550 pts will be randomized 1:1 to receive EV 1.25 mg/kg (Arm A) or chemotherapy (Arm B); randomization will be stratified by ECOG score, regions of the world, and liver metastases at baseline. Patients in Arm A will receive EV on Days 1, 8, and 15 of each 28-day cycle; pts in Arm B will receive either docetaxel, paclitaxel, or vinflunine (determined by investigator) on Day 1 of every 21-day cycle. Patients will continue to receive study treatment until disease progression, intolerance, or other discontinuation criterion is met. The primary endpoint is overall survival; secondary endpoints include progression-free survival, duration of response, and overall response rate, as well as assessment of safety/tolerability, and quality-of-life parameters.