FORE Biotherapeutics Presents New Plixorafenib Results at AACR 2025 Demonstrating Pharmacodynamic Effect in Clinical Tumor Biopsies and Decreased V600E Mutant Allele Frequency in ctDNA of 85% of Patients

PHILADELPHIA–(BUSINESS WIRE)–FORE Biotherapeutics, a registration stage biotherapeutics company dedicated to developing targeted therapies to treat patients with cancer, today presented new plixorafenib results from the Phase 1/2a clinical trial that demonstrate that circulating tumor DNA (ctDNA) accurately detects BRAF mutations in tumor biopsies and change in variant allele frequency (VAF) of BRAF mutation in ctDNA may be a surrogate marker for monitoring disease. The data is being presented at the American Association for Cancer Research (AACR) Annual Meeting 2025, taking place April 25-30 in Chicago.

“Plixorafenib was designed to inhibit mutated oncogenic BRAF V600, without causing paradoxical MAPK pathway activation, and also confers dimer–breaking properties and activity against non-V600 BRAF alterations,” said Rona Yaeger, M.D., Gastrointestinal Medical Oncologist and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center. “The data from this clinical study, demonstrating molecular response and durable clinical responses (including when given without a MEK inhibitor) and the absence of emergent MAPK pathway alterations on treatment, further support the unique mechanism of action and the potential to benefit patients with BRAF-altered malignancies.”

“These results are important because they show additional evidence of the strong clinical activity of plixorafenib, in both BRAF V600 mutations and BRAF fusions,” said Stacie Peacock Shepherd, M.D., Ph.D., Chief Medical Officer of Fore. “In addition, this analysis also demonstrated high concordance of ctDNA BRAF mutations with biopsy tissue and changes in ctDNA corresponded closely to tumor size across tumor types; thus, liquid biopsies with widely used next-generation sequencing methodologies may provide a straightforward approach to identify appropriate patients for plixorafenib treatment, monitor disease status, and response. We are excited to share this data, along with the study design for our ongoing registrational FORTE study in BRAF altered advanced solid tumors, as we develop plixorafenib to help patients with BRAF driven tumors and generate further data to inform treatment.”

The ctDNA results are from over 70 plixorafenib-treated patients and were an exploratory endpoint from a previously completed Phase 1/2a study. Utilizing next-generation sequencing (NGS), the plasma ctDNA results demonstrated high concordance with tissue biopsy at baseline across tumor types and mutations. Declines of V600 VAF% were observed in 85% of study participants after one cycle of plixorafenib treatment. Declines of class 2 and class 3 BRAF alterations in ctDNA were also observed. In participants with available paired tumor biopsies, decreases in pERK validated ctDNA results and demonstrated the suppression of the MAPK pathway at clinically relevant exposures. In addition, participants with V600E-mutated advanced solid tumors, early changes in V600E VAF% may predict response to plixorafenib, as responders had larger decreases in VAF% from baseline to cycle 2. In longitudinal samples, changes in ctDNA corresponded to tumor size across tumor types, suggesting that ctDNA may be a surrogate marker for monitoring disease. Compared to acquired mutations driving resistance to early generation BRAF inhibitors, no new mutations in MAPK pathway genes were found following plixorafenib treatment, supporting the dimer–breaker property and novel mechanism of action of plixorafenib from the early generation BRAF inhibitors. In participants without response, co-occurrent drivers at baseline included RAS, MAPK-associated or NF1 mutation, including melanoma patients who all received prior MAPKi therapies.

Also being presented at AACR 2025 is a trial in progress poster showcasing the global FORTE master protocol with a basket design, including three monotherapy sub-protocols in patients with BRAF fusions, rare BRAF V600-mutated tumors, and BRAF V600 primary recurrent central nervous system tumors. An interim analysis is planned for each of the monotherapy baskets during 2025. A fourth, exploratory sub-protocol will assess preliminary activity of plixorafenib in BRAF V600-mutated select solid tumors. Alongside primary and key secondary endpoints of overall response rate, duration of response, safety, progression-free survival, overall survival, and pharmacokinetics, key exploratory endpoint of each of the four sub-protocols is a longitudinal ctDNA assessment.

Poster Presentation Details:

Title: Circulating tumor DNA analysis of patients with BRAF-mutated advanced unresectable solid tumors treated with plixorafenib (FORE8394/PLX8394) in Phase 1/2a study
Poster Session: Liquid Biopsy Circulating Nucleic Acids 1
Date and Time: Monday, April 28, 2025, 2:00 – 5:00 p.m. CT
Abstract Number: 3248
Presenter: Jessica C. Jang, Fore Biotherapeutics

Title: FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers
Poster Session: Late Breaking and Clinical Trials – Phase II and Phase III Clinical Trials in Progress
Date and Time: Tuesday, April 29, 2025, 2:00 – 5:00 p.m. CT
Abstract Number: CT247
Presenter: Macarena I. de la Fuente, M.D., Sylvester Comprehensive Cancer Center

About FORE Biotherapeutics

Fore is a registration stage targeted oncology company dedicated to developing innovative treatments that provide better outcomes for patients with the hardest-to-treat cancers. The Company’s lead asset plixorafenib (FORE8394; formerly PLX8394) is a V600 and non-V600 BRAF inhibitor rationally designed with a first-in-class mechanism to address treatment gaps from 1^st and 2^nd generation BRAF inhibitors. Plixorafenib has demonstrated single-agent efficacy signals across a variety of tumor types with a manageable safety profile in a Phase 1/2a clinical trial of over 100 patients and is currently enrolling patients in FORTE, a global registrational basket trial to support three distinct indications. For more information, please visit www.fore.bio or follow us on X and LinkedIn.