Abstract CT273: FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers

Abstract BACKGROUND: Plixorafenib (FORE8394; PLX8394) is a novel, oral, small-molecule BRAF inhibitor and paradox breaker highly selective for BRAF V600 monomers and BRAF-containing dimers, including fusions. Plixorafenib binding disrupts RAF dimerization and prevents paradoxical MAPK pathway activation, avoiding the need for combination with a MEK inhibitor. Plixorafenib demonstrated in vitro activity against V600 and non-V600 mutant BRAF proteins, and anti-tumor activity has been demonstrated in BRAF V600 and non-V600 nonclinical models.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.The ongoing FORTE basket study is assessing the safety and efficacy of plixorafenib as monotherapy in participants with BRAF-altered advanced solid tumors. METHODS: The FORTE study is currently enrolling participants ≥10 years of age (to be expanded to ≥8 years upon N=6 pediatric patients and IDMC approval) into 4 baskets. Study details are shown in the Table. Eligible participants have received available therapies for advanced disease, have measurable disease, and have a Karnofsky (≥16 years) or Lansky (<16 years) Performance Score of ≥60 at study entry. All participants receive plixorafenib continuous dosing once daily within 30 minutes following a meal. Prior MAPK inhibitor therapy is excluded unless otherwise specified below.As of January 2026, the trial is recruiting participants in 11 countries globally, with 64 sites currently activated. To date, over 100 patients are enrolled. Clinical trial registry number: NCT05503797. Citation Format: Elisa Fontana, Macarena I. de la Fuente, Eric Sherman, Rona Yaeger, Malaka Ameratunga, Valentina Gambardella, Jessica Rine, Shubin Shahab, Morgan Winkler, Manish Monga, Dominik Modest, Jeffrey Yachnin, Mehdi Touat, Guillermo de Velasco, Jordi Rodon, Karisa C. Schreck. FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT273.