Abstract B155: IK-595, a best-in-class MEK-RAF complex inhibitor, drives broad and potent anti-tumor activity in RAS/RAF-driven tumors

Abstract

Abstract Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. Although MEK is a clinically validated cancer target and several MEK inhibitors have been approved by the FDA, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas. We developed IK-595, a potent inhibitor of the MEK-RAF complex, to overcome the limitations of available MEK inhibitors. IK-595 traps MEK in an inactive complex with all RAF isoforms and blocks RAF-dependent MEK phosphorylation, thereby alleviating CRAF-mediated MEK reactivation that hinders the efficacy of approved MEK inhibitors in RAS/RAF-driven tumors. We demonstrate that IK-595 leads to potent and prolonged inhibition of MEK and ERK1/2 phosphorylation, in KRAS-mutant cancer and NRAS-mutant melanoma models. In addition to trapping all three RAF isoforms, IK-595 stabilizes the interaction of MEK with BRAF Class I, II, and III mutant proteins. This delays the onset of known resistance mechanisms to other MAPK pathway targeting agents, such as CRAF-mediated pathway reactivation and receptor tyrosine kinase upregulation and/or activation. Importantly, IK-595 has a much slower off-rate binding to MEK and retains CRAF longer in an inactive complex with MEK than other MEK/RAF inhibitors allowing for more prolonged target engagement and durable pathway inhibition in RAS/RAF mutant cancer cells. Moreover, CRAF-ARAF heterodimerization, which is detected in type II pan-RAF inhibitor-treated KRAS mutant cells as an established resistance mechanism, is not observed upon IK-595 treatment. IK-595 exhibits potent signal agent activity across a wide range of cancer models harboring various RAS/RAF alterations, including lung, pancreatic, colorectal cancer (CRC), melanoma, AML, and others. Strong synergy with inhibitors targeting multiple key mechanisms, both within the RAS/MAPK pathway and across parallel survival pathways, has also been observed in multiple models. Key to the design of IK-595 is its PK profile that enables transient high plasma drug exposure and flexible dosing schedules. Intermittent dosing of IK-595 every other day (QOD) or every three days (Q3D) in KRAS mutant mouse tumor models shows similar efficacy and improved tolerability compared to daily dosing (QD), affording a larger therapeutic window. Preclinical pharmacology studies provide clear guidance to the clinical development plan of IK-595, where flexible dosing schedules and multiple expansion cohorts in RAS/RAF altered patient populations will be explored. IK-595 is a novel MEK-RAF complex inhibitor that prolongs pathway inhibition, minimizing the potential for resistance, while providing an optimal therapeutic window for patients with RAS/RAF-driven cancer. Citation Format: Eric Haines, Rachel Catterall, Victor De Jesus, Bin Li, Sarah R Wessel, Jill Cavanaugh, Michael Burke, Joseph D Manna, Okzana Zavidij, Ao Yang, Lan Xu, Sergio Santillana, Jeffrey Ecsedy, X. Michelle Zhang, Sabine K Ruppel. IK-595, a best-in-class MEK-RAF complex inhibitor, drives broad and potent anti-tumor activity in RAS/RAF-driven tumors [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 B155.