The clinical-stage oncology company FORE Biotherapeutics has successfully raised $38 million in Series D-2 financing to support the continued development of its lead asset plixorafenib, a novel BRAF inhibitor designed to target both V600 and non-V600 BRAF mutations.
The newly secured funds will primarily advance the company's registration-intended FORTE Master Protocol, a global Phase 2 clinical trial evaluating plixorafenib across four distinct patient populations. The trial currently focuses on three monotherapy indications: BRAF V600 Recurrent Primary Central Nervous System (CNS) Tumors, Rare BRAF V600 Mutated Solid Tumors, and Solid Tumors with BRAF Fusions.
2025 Clinical Development Roadmap
FORE Biotherapeutics has outlined an ambitious clinical development plan for 2025, with interim analyses expected across all three monotherapy indications in the FORTE Master Protocol.
For the BRAF V600 Primary Recurrent CNS Tumors cohort, the company plans to enroll approximately 50 patients, with primary endpoints of overall response rate (ORR) and median duration of response (mDOR). An interim efficacy analysis from the first 25 evaluable patients is anticipated in Q3 2025. Pending positive results, the company expects this trial could support a New Drug Application (NDA) submission to the FDA under the Accelerated Approval pathway.
"The early data for plixorafenib in CNS tumors is particularly encouraging," said a company spokesperson. "In our previous Phase 1/2 study of MAPK inhibitor naïve patients with BRAF V600 primary recurrent CNS tumors, plixorafenib demonstrated a 67% overall response rate and a median duration of response of 13.9 months, along with a favorable tolerability profile."
For the Rare BRAF V600 Mutated Solid Tumors cohort, approximately 75 patients will be treated with plixorafenib, with an interim analysis of the first 25 evaluable patients expected in Q4 2025. Previous Phase 1/2 data in this population showed a 42% ORR and an impressive mDOR of 17.8 months.
The third cohort, focusing on Advanced Solid Tumors with BRAF Fusions, will also enroll approximately 75 patients, with interim analysis planned for Q4 2025. Earlier clinical work in this population demonstrated promising activity, including one complete response with a duration of response exceeding 67 months.
Scientific Advances and Mechanism of Action
Plixorafenib (FORE8394, formerly PLX8394) represents a significant advance in BRAF inhibitor technology. Unlike first and second-generation BRAF inhibitors, plixorafenib was rationally designed with a "dimer-breaker" property that addresses key resistance mechanisms.
At the recent American Association for Cancer Research (AACR) Annual Meeting 2025, FORE presented new circulating tumor DNA (ctDNA) results from a previously completed plixorafenib clinical trial. The analysis of over 70 plixorafenib-treated patients demonstrated high concordance between changes in ctDNA and tissue biopsy across several BRAF mutations.
Importantly, the data revealed no new mutations in MAPK pathway genes following plixorafenib treatment, supporting the drug's novel mechanism of action compared to earlier generation BRAF inhibitors that often face acquired resistance.
"The ctDNA findings are particularly significant," noted a clinical investigator familiar with the program. "The correspondence between changes in ctDNA and tumor size across tumor types suggests that ctDNA may serve as a viable surrogate marker for monitoring disease response, potentially allowing for less invasive patient monitoring."
Upcoming Scientific Presentations
FORE Biotherapeutics will continue to build scientific momentum with an upcoming presentation at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 30 - June 3 in Chicago. The company will present the master protocol design of the ongoing global Phase 2 FORTE clinical trial, providing the oncology community with deeper insights into this potentially registration-enabling study.
About Plixorafenib and BRAF Mutations
BRAF mutations occur in approximately 8% of all cancers and play a critical role in tumor growth and survival. While first-generation BRAF inhibitors have shown efficacy in certain cancers like melanoma, resistance often develops, and these agents have limited activity against non-V600 BRAF mutations.
Plixorafenib represents a potential breakthrough as a pan-BRAF inhibitor capable of targeting both V600 and non-V600 BRAF mutations. The drug has demonstrated single-agent efficacy signals across multiple tumor types with a manageable safety profile in a Phase 1/2a clinical trial involving over 100 patients.
The FORTE Master Protocol is designed to support potential registration for three distinct indications, potentially offering new treatment options for patients with limited therapeutic alternatives. If successful, plixorafenib could address significant unmet needs in BRAF-mutated cancers, particularly in rare and difficult-to-treat tumor types.
