FORE Biotherapeutics Advances Plixorafenib in BRAF-Driven Tumors, Eyes Potential FDA Submission
核心洞察
FORE Biotherapeutics (搜索) is advancing plixorafenib in clinical trials targeting BRAF (搜索) V600-mutated recurrent CNS tumors, rare solid tumors (搜索), and solid tumors with BRAF fusions.
Interim efficacy analyses for plixorafenib in these monotherapy indications are expected throughout 2025, potentially leading to an FDA submission under the accelerated approval pathway.
Plixorafenib's unique mechanism targets both BRAFV600 monomers and dimeric BRAF (搜索) mutants, differentiating it from current BRAF inhibitors and offering a potential new standard of care.
FORE Biotherapeutics (搜索) is making strides in the development of plixorafenib, a targeted therapy aimed at treating patients with various BRAF (搜索)-driven tumors. The company anticipates multiple value-creating catalysts in 2025, with a focus on advancing plixorafenib as a monotherapy and exploring its potential in combination regimens. William Hinshaw, CEO of Fore Biotherapeutics, highlighted these advancements at the 43rd Annual JP Morgan Healthcare Conference on January 14, 2025.
Plixorafenib's Novel Mechanism of Action
Plixorafenib is designed to inhibit both constitutively active BRAFV600 monomers and disrupt constitutively active dimeric BRAF (搜索) class II mutants, fusions, splice variants, and others. This mechanism differentiates it from current approved therapies, potentially addressing the limitations of first-generation RAF inhibitors. The company believes plixorafenib has the potential to reset the standard of care for patients with BRAF-driven tumors.
FORTE Master Protocol and Clinical Trials
FORE Biotherapeutics (搜索) is currently executing the FORTE Master Protocol, a global clinical trial evaluating plixorafenib in distinct patient populations. The three monotherapy indications under evaluation are:
- BRAF V600 Recurrent Primary Central Nervous System (CNS) Tumors
- Rare BRAF V600 Mutated Solid Tumors
- Solid Tumors with BRAF Fusions
BRAF V600 Recurrent Primary CNS Tumors
The company is continuing enrollment in a registration-intended basket trial with up to 50 patients with BRAF V600-mutated recurrent primary CNS tumors (搜索). This trial (BOP2 design) enrolls patients who are naïve to MAPK pathway inhibitor (MAPKi) treatment. Major efficacy endpoints include overall response rate (ORR) and duration of response (DOR). Previous clinical trials of plixorafenib showed that 67% (6 out of 9) of MAPKi-naïve adults with recurrent BRAF (搜索) V600-mutated primary CNS tumors demonstrated a partial response (PR) with a median DOR (mDOR) of 13.9 months.
An interim efficacy analysis from the first 25 evaluable patients is anticipated in the third quarter of 2025, with topline data expected in the second half of 2026, pending a positive recommendation from the data monitoring committee. The company anticipates that this trial, with sufficient demonstration of safety and efficacy, would enable the submission of an NDA to the US Food and Drug Administration under the accelerated approval pathway.
Rare BRAF V600 Mutated Solid Tumors
Enrollment has commenced in a registration-intended basket trial with up to 75 patients with rare BRAF (搜索) V600-mutated solid tumors (搜索). This BOP2 design trial enrolls patients who are naïve to MAPKi treatment, with ORR and DOR as major efficacy endpoints. Prior trials showed a 42% PR rate with a mDOR of 17.8 months in MAPKi-naïve adults with BRAF V600-mutated solid tumors.
An interim efficacy analysis from the first 25 evaluable patients is anticipated in the fourth quarter of 2025.
Solid Tumors with BRAF Fusions
Enrollment is ongoing in a registration-intended basket trial with up to 75 patients with BRAF (搜索) fusion advanced solid tumors (搜索). This trial (BOP2 design) enrolls patients with tumors harboring BRAF fusions, excluding those with prior MAPK inhibitor treatment and patients with colorectal or pancreatic ductal adenocarcinoma. The primary endpoint is ORR, as determined by RANO criteria or RECIST v1.1. Previous trials demonstrated promising single-agent activity, including one complete response with a DOR of 66.7+ months and one PR with a DOR of 9.2+ months.
An interim efficacy analysis from the first 25 evaluable patients is anticipated in the fourth quarter of 2025.
AACR and ISPNO Data
At the American Association for Cancer Research (AACR) 2024, FORE Biotherapeutics (搜索) reported nonclinical data demonstrating that plixorafenib in combination with binimetinib, a MEK inhibitor, is more potent than other BRAF (搜索) and pan-RAF inhibitors combined with binimetinib. The data also highlighted the synergistic activity of plixorafenib with MEK inhibition across all BRAF alterations tested.
Additionally, safety and efficacy data presented at the International Symposium on Pediatric Neuro-Oncology (ISPNO 2024) built on existing evidence of plixorafenib in children and adults with BRAF (搜索)-altered recurrent primary CNS tumors. Data presented at the Ovarian Cancer (搜索) Research Symposium (OCRS) showed durable partial responses in three heavily pre-treated patients with BRAF V600-mutated ovarian cancer.