Abstract 4038: ABM-1310, A novel BRAF Inhibitor, combined with EGFR and MEK inhibitors, inhibits colorectal tumor growth and increases overall survival in vivo

Abstract

Abstract Colorectal cancer (CRC) is a cancer that starts in the colon or the rectum, and the current treatment mainly relies on chemotherapies. For example, ERBITUX® /cetuximab is an FDA approved targetedtherapy drug to treat CRC with wild-type KRAS, the 11% low response rate limits its clinical application. BRAF inhibitors have been widely used clinically for melanoma and lung cancer, however, they have dismally low response rate at only approximately 5% of colorectal cancer patients with BRAFv600 mutation. Here, we report that ABM-1310, a novel small molecule inhibitor of BRAF (specifically inhibit BRAFv600 mutant), has shown good potency in colon cancer xenograft models, when combined with a MEK inhibitor and EGFR antibody. In the HT-29 xenograft subcutaneous model, 10 to 25mg/kg/day oral dose of ABM-1310 combined with cetuximab (0.1mg/dose, twice a week) and 3 mg/kg/day of Binimetinib (MEK inhibitor) significantly inhibited HT-29 tumor growth with TGI of 85% to 92% after 34-days treatment. As a monotherapy or combined with cetuximab alone, ABM-1310 also brought the TGI of 74% and 82% at 25mg/kg/day, which indicates ABM-1310 played a key role in tumor growth inhibition in the combinations. Beside with Binimetinib, we also tested combination of ABM-1310 with other different MEK inhibitors in this model. ABM-1310 is highly water-soluble small molecule with high cell permeability and blood brain barrier penetration. ABM-1310 shown good efficacy in melanoma A375 (luciferase labelled cells) in the subcutaneous/intracranial/intracardiac xenograft models (brain metastasis models). In the HT-29 colon intracranial model, ABM-1310 also demonstrated significant tumor inhibition effect and increased animal overall survival. Compared with vehicle or marketed BRAF inhibitor vemurafenib, the median survival time of ABM-1310 group was >90 days vs 51 days (vemurafenib) and 38 days (vehicle), respectively. In Summary, ABM-1310, as a novel small molecule BRAF inhibitor, combined with EGFR and MEK inhibitors, has shown strong anti-tumor effect in preclinical in vivo models of colon cancer with BRAFv600 mutation, especially with brain metastasis. Citation Format: Yong Hu, Chen Chen, Charles Huang, Min Xu, Youqin Chen, Xiyuan Zhao, Li Zhao. ABM-1310, A novel BRAF Inhibitor, combined with EGFR and MEK inhibitors, inhibits colorectal tumor growth and increases overall survival in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4038.