Abstract CT267: ENB-003, an ETBR antagonist, in combination with pembrolizumab for advanced solid tumor: The ENBolden trial

Abstract Programmed cell death 1 (PD-1) inhibitors have minimal effect in ovarian cancer (OC) and pancreatic ductal adenocarcinoma (PDAC). Selective endothelin B receptor (ETBR) blockade stimulates T cell tumor infiltration and synergizes with anti-PD-1 therapy in OC and PDAC mouse models. We are conducting an ongoing Phase Ib, open-label dose escalation study to assess the safety and tolerability of the selective ETBR antagonist ENB-003 (vodudeutentan) in combination with pembrolizumab in metastatic PDAC, OC and other advanced solid tumors (NCT04205227). The primary objectives are safety and tolerability. Secondary objectives include overall survival (OS), progression free survival (PFS), and disease control rate (DCR). Chemotherapy-resistant PDAC and platinum refractory/platinum resistant OC patients were microsatellite stable (MSS). The ENB-003 plus pembrolizumab combination was well tolerated across 6 dosing cohorts with no increase in toxicity above what is typically observed with pembrolizumab as a single agent. Encouraging preliminary efficacy signals have been observed. The DCR across 21 patients is 43% including 8 patients with stable disease (38%) and 1 (5%) with partial response (PR). The DCR for OC is 100% including 3 patients with stable disease (75%) and one MSS, PDL1 negative platinum refractory patient with a 95% PR (25%) of 12-month duration. In the current and final cohort, 3 PAC patients have been treated. One 4th line PDAC patient has exceeded 6-month survival (33%). We also observed a 7-month arrest of disease progression in a tonsillar SCC patient with innate resistance to anti-PD1. These data suggest that ETBR blockade is well tolerated, may expand the benefit of anti-PD1 in drug resistant solid tumors and warrants further study in subsequent trials. Citation Format: Sumayah Jamal, Adnan Nagrial, Matteo Carlino, Rasha Cosman, Anthony Joshua, Richard Eek, Sarina Piha-Paul, Omid Hamid, Jenny Liu. ENB-003, an ETBR antagonist, in combination with pembrolizumab for advanced solid tumor: The ENBolden trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT267.