On April 9, 2024 FORE Biotherapeutics reported new nonclinical data related to plixorafenib (FORE8394; formerly PLX8394), the company’s novel, investigational, small-molecule, next-generation, orally available selective inhibitor of BRAF alterations, will be presented at the AACR (Free AACR Whitepaper) Annual Meeting 2024, taking place April 5-10, 2024, in San Diego and virtually (Press release, Fore Biotherapeutics, APR 9, 2024, View Source [SID1234641931]). The data show nonclinical synergistic activity of plixorafenib when combined with MEK inhibition across all BRAF alterations tested. In cells with BRAF V600 or non-V600 mutations or BRAF fusions, the combination of plixorafenib and binimetinib is most potent of the BRAF and pan-RAF inhibitors tested. In plixorafenib resistant cells, these cells can be resensitized with the addition of binimetinib. To date, plixorafenib has demonstrated encouraging efficacy and safety data from the phase 1/2a study; these nonclinical data help build the foundation for potential future development of plixorafenib in combination with a MEK inhibitor.
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Poster
Abstract number: 4609
Poster Title: The paradox-breaker BRAF inhibitor plixorafenib (PLX8394; FORE8394) synergizes with MEK inhibitors (MEKi) in BRAF V600 and non-V600 alterations, with higher potency compared to early generation BRAFi and pan-RAFi
Presentation Session Date/Time: April 9, 2024, 9:00 AM – 12:30 PM Poster Session
About Plixorafenib
Plixorafenib is an investigational, novel, small-molecule, next-generation, orally available selective inhibitor of mutated BRAF. It was designed to target a wide range of BRAF alterations while sparing wild-type forms of RAF. Nonclinical and clinical studies have shown that its unique mechanism of action effectively inhibits not only the constitutively active BRAF V600 monomers targeted by first- and second-generation RAF inhibitors but also disrupts constitutively active dimeric BRAF class 2 mutants, fusions, splice variants and others. Unlike earlier-generation BRAF inhibitors, plixorafenib does not induce paradoxical activation of the RAF/MEK/ERK pathway. As a "paradox breaker", plixorafenib could therefore address acquired resistance to current RAF inhibitors and, additionally, may yield improved safety and more durable efficacy than first-generation RAF inhibitors.
Plixorafenib is currently being evaluated in two clinical trials in patients with advanced solid tumors with activating BRAF alterations. Interim clinical data from a Phase 1/2a trial presented at ESMO (Free ESMO Whitepaper) 2022, ASCO (Free ASCO Whitepaper) 2023 and SNO 2023 provided evidence of durable anti-tumor activity in patients with BRAF-mutated cancers with a 42% overall response rate and a median duration of response of 17.8 months in MAPK inhibitor-naïve participants with V600-mutated advanced solid tumors. Of the 9 patients with primary central nervous system tumors, 6 had confirmed response (ORR 67%) with a median duration of response of 13.9 months. In addition to the Phase 1/2a trial, plixorafenib is currently being investigated in the ongoing, potentially registrational Phase 2 FORTE study.