Abstract A093: Deep Cyclic Inhibition of the MAPK pathway with IMM-6-415, alone and in combination with encorafenib, demonstrates anti-tumor activity and tolerability in RAF mutant tumors in vivo

Abstract

Abstract Introduction: A significant proportion of cancer patients have tumors addicted to uncontrolled MAPK signaling. Activating mutations in RAS or RAF are often directly responsible and have been observed in over 20% of human tumors1. Because MEK is downstream of RAS and RAF, it is an appealing drug target. However, MEK inhibitors have historically suffered from poor clinical durability, high toxicity and a susceptibility to pathway reactivation that has limited monotherapy activity in the RAS mutant setting. Unlike other MEK inhibitors, IMM-1-104 [NCT05585320] and IMM-6-415 are designed with distinctive features including both (1.) a unique target engagement mechanism that helps resist MAPK pathway reactivation and (2.) a pharmacokinetic (PK) profile that enables fast cadence deep cyclic inhibition (DCI). DCI drives pulsatile targeted inhibition that deprives tumor cells of a critical oncogenic pathway while limiting drug-related toxicities by affording normal cells an adequate PK recovery window between drug doses. To our knowledge, IMM-6-415’s preclinical activity is driven by the shortest drug plasma half-life (0.3-hours in mice) of any MEK inhibitor developed to date. Experimental Procedures: IMM-6-415 has already demonstrated promising activity in RAS-mutant xenograft tumor models (SITC 2022). Here, the antitumor activity of IMM-6-415 was evaluated in over 60 humanized 3D tumor growth assays (3D-TGA), which included 30 BRAF class I-mutant tumor models. Additionally, multiple drug-drug combinations have been explored, including vertical drug combinations with BRAF inhibitors. IMM-6-415, binimetinib and encorafenib were tested head-to-head as single agents and in combination with encorafenib in BRAFV600E melanoma and colorectal subcutaneous tumor xenograft models in female BALB/c nude mice. Summary of New Data: As monotherapy, IMM-6-415 demonstrated antitumor activity in over 50% (34 of 66) of the 3D-TGA models tested, including 30 BRAF-mutant preclinical models in which 19 (63%) showed activity. Therefore, we further explored both monotherapy and combination activity of IMM-6-415 in the A-375 (melanoma) and HT-29 (colorectal) BRAF V600E tumor xenograft models. Monotherapy treatment with encorafenib or IMM-6-415 displayed superior tumor growth inhibition (TGI) when compared to binimetinib. Furthermore, the combination of IMM-6-415 plus encorafenib prompted greater TGI with superior durability of response when tested head-to-head against the combination of binimetinib plus encorafenib in vivo at human equivalent doses for registered drugs. Conclusions: IMM-6-415 demonstrated promising activity and tolerability in preclinical models alone and in combination with encorafenib. In combination with encorafenib, IMM-6-415 achieved a greater TGI in vivo than the combination of encorafenib plus binimetinib in BRAFV600E colorectal cancer and melanoma tumor models, suggesting an opportunity for IMM-6-415 as monotherapy or in combination in BRAF mutant tumors. Citation Format: Anna Travesa, Mai Johnson, Peter King, Praveen Nair, Jason Funt, Sarah Kolitz, Kevin D Fowler, John Brothers II, Amy Axel, Scott Barrett, Benjamin J Zeskind, Brett Hall. Deep Cyclic Inhibition of the MAPK pathway with IMM-6-415, alone and in combination with encorafenib, demonstrates anti-tumor activity and tolerability in RAF mutant tumors in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A093.