Abstract CT247: FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers

Abstract BACKGROUND: Type I RAF inhibitors in combination with MEK inhibitors demonstrate durable responses but high toxicity rates in BRAF V600-mutated tumors including pyrexia and cardiovascular, hepatic, gastrointestinal, and ocular toxicities. A type II RAF inhibitor shows benefit in low-grade glioma with BRAF fusions or V600 mutations but confers the risk of major hemorrhage, skin toxicities, reductions in growth velocity, and viral and upper respiratory infections. There remains an unmet need for tolerable and efficacious targeted therapies for the treatment of BRAF-altered tumors. Plixorafenib (FORE8394; PLX8394) is a novel, oral, small-molecule BRAF inhibitor highly selective for BRAF V600 monomers and BRAF-containing dimers. Plixorafenib binding disrupts RAF dimerization and prevents paradoxical activation, targeting both Class I V600 mutations and Class II fusions and avoiding the need for combination with a MEK inhibitor. In a phase 1/2a study, plixorafenib demonstrated promising safety and clinical activity across a range of doses tested in tumors with BRAF V600 mutations and BRAF fusions. The most common adverse events included predominantly grade 1-2 liver function test changes and grade 1 fatigue, nausea, diarrhea, and vomiting. METHODS: The FORTE Phase 2 basket study is currently enrolling patients ≥10 years of age into 4 sub-protocols. Study details are shown in the Table. Eligible patients have received prior therapy for advanced disease, have measurable disease, and have a Karnofsky (≥16 years) or Lansky (<16 years) Performance Score of ≥60 at study entry. All patients receive plixorafenib continuous dosing, in some cohorts coadministered with cobicistat, a pharmacokinetic booster. Prior MAPK inhibitor therapy is excluded unless otherwise specified below. As of January 2025, the trial is recruiting participants in 9 countries globally, with 54 sites currently activated. Clinical trial registry number: NCT05503797. Citation Format: Karisa C. Schreck, Macarena I. de la Fuente, Jessica Rine, Irina Kline, Stacie Peacock Shepherd, Jordi Rodon, Rona Yaeger, Eric Sherman. FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT247.