Abstract 4927: Exarafenib (KIN-2787) is a potent, selective pan-RAF inhibitor with activity in preclinical models of BRAF class II/III mutant and NRAS mutant melanoma
Authors: Wang Tim S. , Lee Catherine , Severson Paul , Pelham Robert J. , Williams Richard , Miller Nichol L. G. 
Published: April 2023

Background: MAPK activating mutations are common in melanoma, with 40% of cases attributed to oncogenic BRAF mutations and 20-25% NRAS mutations. Secondary MAPK activation is a known resistance mechanism to approved BRAF inhibitors in BRAFV600 melanoma. While BRAF inhibitors are approved for Class I BRAFV600 melanomas, patients with dimer-driven BRAF Class II/III and RAF1-dependent NRAS activated melanomas lack approved targeted therapy. Development of next-gen pan-RAF inhibitors targeting all RAF proteins and mutant dimers remains a priority. Emerging clinical data from pan-RAF inhibitors combined with MEK inhibitors suggests increased benefit for MAPK-altered melanoma patients. Exarafenib (KIN-2787) is a clinical stage, novel, highly selective pan-RAF inhibitor designed to be effective in RAF-dependent cancers.Methods: KIN-2787 was evaluated using enzyme assays across the human kinome and activity against oncogenic RAF alterations were validated in BaF3 cells. MAPK pathway suppression and cell growth inhibition were assessed across a panel of human tumor cell lines. Combination dose matrices were performed with KIN-2787 and binimetinib (bini) to evaluate synergistic cell growth inhibition. Extended cell growth studies were performed by Incucyte. In vivo KIN-2787 efficacy was evaluated in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of human BRAF and NRAS mutant cancer.Results: Exarafenib demonstrated exceptional kinome selectivity with minimal off-target kinases significantly inhibited relative to BRAF. Exarafenib potently inhibited a broad panel of oncogenic BRAF mutations in biochemical and BaF3 cell assays. Functional MAPK signaling and viability studies in human tumor cell lines highlighted exarafenib activity in BRAF and NRAS mutant melanoma with minimal activity in normal (BRAF WT) cells. Synergy with the MEK inhibitor bini was determined and the exarafenib + bini combination durably inhibited growth in NRAS mutant melanoma cell lines. In line with cellular studies, treatment with exarafenib demonstrated significant tumor growth inhibition at 30 mg/kg BID in CDX and PDX models of human NRAS mutant melanoma. 10 mg/kg BID exarafenib combined with a clinically relevant dose of bini resulted in combination benefit and durable suppression of the MAPK pathway, relative to either agent alone.Conclusions: The superior kinome selectivity of exarafenib and its activity across multiple RAF-dependent melanoma models position it as a potentially class-leading pan-RAF inhibitor. In addition to efficacy in BRAF mutant tumors, these data support use of exarafenib in combination therapy with MEK inhibitors in NRAS mutant melanoma. A Ph I dose escalation clinical trial evaluating the safety and efficacy of exarafenib in monotherapy and in combination with binimetinib is ongoing (NCT04913285).

Citation Format: Tim S. Wang, Catherine Lee, Paul Severson, Robert J. Pelham, Richard Williams, Nichol L. G. Miller. Exarafenib (KIN-2787) is a potent, selective pan-RAF inhibitor with activity in preclinical models of BRAF class II/III mutant and NRAS mutant melanoma. [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 4927.