803 Phase 1/2 study using ENB-003, a first-in-class selective ETBRi, in combination with pembrolizumab in subjects with advanced refractory solid tumors

BackgroundThe endothelin B receptor (ETBR) is upregulated in many types of cancer and is associated with poor overall survival and a paucity of TILs (tumor infiltrating lymphocytes). The ETBR prevents T-cell extravasation and tumor infiltration by a mechanism involving adhesion molecule downregulation in the tumor vasculature. Thus ETBR expression may mediate resistance to immunomodulatory therapy. ENB-003 is a small molecule ETBRi (ETBR inhibitor) which overcomes resistance to anti-PD1 across multiple cancer types in preclinical studies. Part 1 of this study seeks to evaluate the safety and tolerability of ENB-003 in combination with pembrolizumab in refractory advanced ETBR+ solid tumors. Part 2 of the study is an expansion cohort basket trial assessing the efficacy of ENB-003 in combination with pembrolizumab in anti-PD1 refractory melanoma, platinum resistant ovarian cancer and refractory pancreatic cancer.MethodsStudy ENB-003-101 (MK-3475-951) is a multicenter, Phase 1/2, open-label study of ENB-003 in combination with pembrolizumab in adult subjects with advanced solid tumors. The part 1 dose escalation is enrolling subjects with ETBR+ tumors and includes 5 doses of ENB-003 in combination with a fixed dose of pembrolizumab. The primary objective of part 1 is to assess safety and tolerability, the secondary objective is to evaluate anti-tumor effect (RECIST 1.1 and iRECIST). Exploratory objectives are to examine biomarkers/pharmacodynamics.ResultsENB-003, as a single agent and in combination with anti-PD1, was investigated in a variety of syngeneic preclinical models. ENB-003 enhanced the anti-tumor activity of anti-PD1 in anti-PD1 resistant models of melanoma, ovarian cancer, pancreatic cancer, bladder cancer and SCC. For example, the combination of ENB-003 plus anti-PD1 in an anti-PD1-resistant melanoma model resulted in complete tumor eradication in 21 days as well as the formation of TLOs (tertiary lymphoid organs). The combination of ENB-003 plus pembrolizumab was well tolerated in the first 2 cohorts of the ongoing Phase 1 trial in patients with advanced refractory solid tumors that are ETBR+. Best overall responses from the first 2 cohorts (n=6) demonstrates disease stabilization (SD) in 2 patients as well as a partial response (PR) in an ovarian cancer patient with ~60% reduction in target lesions.ConclusionsETBRi is a novel approach to overcoming immunotherapy resistance. The combination of ENB-003 and pembrolizumab is well tolerated thus far and is demonstrating promising early signals of anti-tumor efficacy. Trial updates will be reported.Trial RegistrationNCT04205227Ethics ApprovalThis study was approved by an institutional Review Board at each investigational site.ReferenceKandalaft L, Facciabene A, Buckanovich R, Coukos G. Endothelin B Receptor, a New Target in Cancer Immune Therapy. Clin Cancer Res 2009;15(14):4521-4528.