Background The 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).1 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.
Methods Study 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.
Results ENB-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.
Conclusions ETBRi 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 Registration NCT04205227
Ethics Approval This study was approved by an institutional Review Board at each investigational site.
Kandalaft 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.
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