Abstract 476: ABM-1310 has significant improved BBB-penetration and intracranial tumor growth inhibition compared to FDA approved BRAF inhibitors

Abstract ABM-1310 is a novel small-molecule BRAF inhibitor designed to treat primary CNS tumors or advanced cancer patients with BRAFv600 mutation, with or without brain metastasis. Currently, a Phase I clinical trial of ABM-1310 is actively recruiting patients at multiple clinical centers in US.BRAF mutation takes place in about 8% of all tumors, among which around 90% is V600E amino acid mutation. BRAFv600 mutation causes BRAF’s continuous activation, and results in cancerous cells eventually. Melanoma is the most common cancer type with BRAFv600 mutation, and ~50% of melanoma will develop brain metastasis. Similar situation also occurs in other cancer types like papillary carcinoma of thyroid gland, low-grade serous ovarian carcinoma, colon cancer, and lung cancer with lower rate. A few of primary CNS solid tumors also have significant BRAFv600 mutation rate. Currently, FDA has approved three combination therapy of BRAF inhibitor (i.e., dabrafenib/Tafinlar®, vemurafenib/Zelboraf®, and encorafenib/Braftovi®) to treat patients with unresectable or metastatic melanoma, with metastatic NSCLC, with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation. These combination therapies of BRAF and MEK inhibitors demonstrated clinical benefit, but they all shown poor efficacy on intracranial tumor lesions, which may be due to the limited BBB-penetration of these BRAF/MEK inhibitors. Thus, to treat intracranial tumors with BRAFv600 mutation is still a big unmet medical need currently. Here, we shown preclinical results that ABM-1310 has significantly improved BBB-penetration compared with approved BRAF inhibitors: in mice, B/P ratio and Kp,uu values were 0.2 and 0.2 for Vemurafenib, 0.025 and 0.021 for Dabrafenib, 0.006 and 0.03 for Encorafenib, 0.27 and 1.0 for ABM-1310. Also, in the A375-luc intracranial model, ABM-1310 alone or combo with ABM proprietary, BBB-penetrable MEK inhibitor ABM-168, demonstrated significant improved antitumor activity and animal medial survival time (MST) compared with combination regimens of other BRAF/MEK inhibitors (vemurafenib + cobimetinib, dabrafenib + trametinib, or encorafenib + binimetinib). Either ABM-1310 as a single agent or the combination of ABM-1310 and ABM-168 showed a BLI decrease (%) > 99% on Day 26 and MST of > 69 days, while MST for vehicle was 27 days, and MST for the combo of Dabrafenib and Trametinib was 33 days. In a primary GBM model (DBTGR-05MG, a BRAFv600 mutant GBM cell line), the similar result was demonstrated. Citation Format: Chen Chen, Charles Huang, Min Xu, YouQin Chen, Lanjiao Zhao, Xiaobing Lv, Chen Yang, Yong Hu. ABM-1310 has significant improved BBB-penetration and intracranial tumor growth inhibition compared to FDA approved BRAF inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 476.