Abstract A23: The EV-103 Trial: Enfortumab vedotin plus pembrolizumab and/or chemotherapy for patients with locally advanced or metastatic urothelial cancer
Authors: Hoimes Christopher J. , Rosenberg Jonathan E. , Petrylak Daniel P. , Carret Anne-Sophie , Melhem-Bertrandt Amal , Flaig Thomas W. 
Published: August 2020

Abstract
Background: PD-(L)1-targeted immune checkpoint inhibitors (CPIs), such as pembrolizumab, are approved for patients with locally advanced or metastatic urothelial cancer (la/mUC) who progress after platinum, are ineligible for first-line (1L) cisplatin (PD-L1 positive), or are ineligible for 1L platinum. However, la/mUC remains a lethal disease, with an ORR of ~25% for all CPI-treated patients, and a combination approach may provide additional benefit. Enfortumab vedotin (EV), an investigational antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which are found in 97% of mUC patient samples (Petrylak, ASCO 2017). In a phase 1 study (NCT02091999), EV (1.25 mg/kg) was generally well tolerated with a confirmed ORR of 43% in 112 mUC patients (Rosenberg, ASCO-GU 2019). These encouraging results, along with the potential for an enhanced immune response, suggest that EV+pembrolizumab may improve response rates and extend response durability.
Trial Design: EV-103, a phase 1b trial for nonresectable la/mUC patients with no prior CPI, added an additional 4 cohorts (Parts 2 and 3) in an Oct. 2018 amendment. Anticipated enrollment is now approximately 159 patients. Dose-escalation patients (EV+pembrolizumab, 1L or 2L) must be ineligible for 1L cisplatin-based chemotherapy or have disease progression during/following treatment with ≥1 platinum-containing regimen. Dose expansion (Part 1) will evaluate EV+pembrolizumab in 1L (Cohort A) and 2L settings (Optional Cohort B). Part 2 will evaluate 1L EV+cisplatin (Cohort D), 1L EV+carboplatin (Cohort E), and 1L or 2L EV+gemcitabine (Optional Cohort F). Part 3 (Cohort G) will evaluate 1L EV+pembrolizumab+cisplatin or carboplatin, depending on patients' cisplatin-eligibility. In all cohorts, patients receive EV on Days 1 and 8 of each 3-week cycle. In combination therapies, patients receive pembrolizumab, cisplatin, and carboplatin on Day 1 or gemcitabine on Days 1 and 8 of each cycle. The primary objective is to assess the safety and tolerability of EV+pembrolizumab and/or chemotherapy. Secondary objectives are establishing the recommended EV dose for combination cohorts, assessing ORR per RECIST for all cohorts and per iRECIST for therapies with pembrolizumab, as well as assessing disease control rate, duration of response, progression-free survival, overall survival, pharmacokinetics, and biomarkers. The study opened in Oct. 2017.
Citation Format: Christopher J. Hoimes, Jonathan E. Rosenberg, Daniel P. Petrylak, Anne-Sophie Carret, Amal Melhem-Bertrandt, Thomas W. Flaig. The EV-103 Trial: Enfortumab vedotin plus pembrolizumab and/or chemotherapy for patients with locally advanced or metastatic urothelial cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A23.