A first-in-human study of IK-595, an oral MEK/RAF molecular glue, in patients with RAS- or RAF-altered advanced solid tumors.

Abstract

TPS3185 Background: Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. MEK is a clinically validated cancer target and despite FDA approval of several MEK inhibitors, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas mostly due to early emergence of resistance and low therapeutic indices. IK-595, a potent novel MEK-RAF molecular glue, is being developed to overcome these limitations. 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, in addition to kinase independent CRAF activity. IK-595 exhibits potent single agent activity in a wide range of in vivo cancer models harboring various RAS/RAF alterations, including, but not limited to, lung, pancreatic, colorectal cancer (CRC), melanoma, and AML. The preclinical pharmacokinetic profile of IK-595 also enables flexible dosing schedules resulting in a broader therapeutic window. Methods: This is a phase 1, first-in-human, open-label, multicenter study to evaluate IK-595 as monotherapy in patients with RAS- or RAF-altered advanced solid tumors for whom there are no other further treatment options known to confer clinical benefit. Dose escalation uses a Bayesian Optimal Interval Design (BOIN) in patients with advanced and unresectable, or metastatic solid tumors with confirmed RAS/RAF gene alterations. Backfilling of cleared dose levels with key target indications will initiate upon achievement of efficacious plasma exposures. Dose expansion will occur in genetically defined cohorts, for example NRAS-mutant CRC and malignant melanoma, as well as BRAF non-V600 and KRAS mutant tumors using a Simon 2-stage adaptive design. IK-595 will initially be administered on an intermittent dosing schedule in 30-day cycles. Additional dosing schedules may be explored. Primary objectives of the study are to evaluate safety and tolerability of IK-595 and to determine the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD). Secondary objectives include evaluation of preliminary antitumor activity by RECIST 1.1, pharmacokinetic (PK) parameters, and pharmacodynamic effects of IK-595 on pERK in paired tumor biopsies. Key exploratory endpoints include changes in pERK in peripheral blood cells, changes in pERK target genes in tumor biopsies, and assessment of candidate baseline response biomarkers. The study began in December 2023 and enrollment in Cohort 1 was completed with no DLTs; dose escalation continues to enroll. Clinical trial information: NCT.