Abstract P226: Design and rationale of a first in human (FIH) phase 1/1b study evaluating KIN-2787, a potent and highly selective pan-RAF inhibitor, in adult patients with BRAF mutation positive solid tumors

Abstract

Abstract Background BRAFV600 mutations (BRAF Class I mutations) encode a highly active monomeric oncogenic kinase that can be targeted by approved RAF kinase inhibitors in patients (pts) with melanoma (MEL), NSCLC, colorectal & anaplastic thyroid cancers. In other discrete patient populations, molecularly distinct BRAF alterations drive dimer-dependent oncogenic signaling including BRAF Class II and III alterations. Class II alterations include single nucleotide variants (SNVs), indels and gene fusions that induce BRAF homodimer formation leading to oncogenic kinase activation. Class III mutations, typically SNVs, are low activity kinase mutations that promote RAF dimerization and oncogenic MAPK pathway signaling that is RAS-dependent. Approved BRAF inhibitors have limited clinical activity in diverse solid tumors driven by BRAF Class II or III alterations, highlighting the urgency to develop effective targeted therapies for these patients. KIN-2787 is a potent, highly selective pan-RAF type II kinase inhibitor designed to target both monomeric & dimeric forms of the mutant BRAF kinase and minimize paradoxical activation, a liability often observed with other RAF inhibitors that can adversely impact tolerability & require addition of a MEK inhibitor to suppress pathway activation. KIN-2787 has favorable pharmaceutical properties, achieves substantial systemic exposures in pre-clinical toxicology studies & induces regressions in human cancer xenograft models driven by BRAF Class I, II or III mutations. Methods This is a FIH, multicenter, non-randomized, open-label, Ph1 study (NCT04913285) of KIN-2787 in adult patients with BRAF mutant advanced & metastatic solid tumors (AMST). KIN-2787 will be given orally bid continuously in 28-day cycles until drug intolerance or disease progression. Planned sample size is approx. 115 pts in two parts: Part A is a dose-escalation to MTD open to pts with AMST driven by BRAF Class I, II or III genomic alterations. Part B will evaluate a selected dose of KIN-2787 in 3 cohorts of pts with MEL, NSCLC, or other AMST, each driven by BRAF Class II or III alterations. Standard Ph1 enrollment criteria are required (ECOG PS ≤ 2, normal organ function, prior receipt of standard treatment or medical judgment that such is not appropriate). Patients may have measurable or evaluable disease per RECIST v1.1. Key exclusion criteria include known active brain metastases from non-brain tumors, prior receipt of BRAF-, MEK-, or MAPK-directed inhibitor therapy (unless for FDA approved indications), HBV & HCV seropositivity. Primary endpoints are safety/tolerability (Part A), and preliminary antitumor activity: objective response rate (ORR), disease control rate (DCR), duration of response (DOR), & duration of stable disease (Part B). Secondary objectives include pharmacokinetic (PK) and pharmacodynamic (PD) assessments including tissue and blood-based measures of MAPK signaling inhibition. This study recently opened for Part A recruitment in the United States (NCT04913285). Citation Format: Meredith McKean, Shumei Kato, Alexander Spira, Yan Xing, Hao Xie, Elizabeth Buchbinder, Ken Kobayashi, Richard Williams. Design and rationale of a first in human (FIH) phase 1/1b study evaluating KIN-2787, a potent and highly selective pan-RAF inhibitor, in adult patients with BRAF mutation positive solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P226.