Investigators are assessing FORE8394, which received orphan drug designation from the FDA, in primary brain and central nervous system malignancies in the phase 2 FORTE trial.
The FDA has granted orphan drug designation to FORE8394, an investigational, next-generation, orally available BRAF inhibitor for the management of primary brain and central nervous system (CNS) malignancies, according to a press release from FORE Biotherapeutics.1
FORE8394 is currently under investigation as therapy for adult and pediatric patients with advanced unresectable solid or primary CNS tumors with BRAF alterations in the phase 2 FORTE trial (NCT05503797).
“The receipt of orphan drug designation is another important regulatory achievement that reinforces the FDA's recognition of the potential of FORE8394 to improve clinical outcomes in patients with BRAF-altered brain tumors,” Stacie Shepard, MD, PhD, chief medical officer of Fore Biotherapeutics, said in the press release. “This designation will help us continue to expedite the development of our novel BRAF inhibitor, and we look forward to working closely with the global investigator community supporting FORTE and to advancing the development of FORE8394 for patients in need.”
Preclinical studies and clinical trials have demonstrated the agent’s capability for effectively inhibiting active BRAF V600E monomers as well as disrupting dimeric BRAF class 2 mutations fusions, and splice variants. As the agent does not paradoxically activate the RAF/MEK/ERK pathway, it may serve as a “paradox breaker” that can overcome acquired resistance to current RAF inhibitors while yielding improvements in safety and efficacy.
In the phase 2 FORTE trial, patients who had unresectable locally advanced or metastatic solid tumors or primary CNS tumors with BRAF fusions received 900 mg of FORE8394 orally plus 150 mg of oral cobicistat (Tybost) once a day in continuous 3-week cycles until disease progression or unacceptable toxicity.
The primary end point of the trial was objective response rate per blinded independent central review. Secondary end points included duration of response, time to response, progression-free survival, overall survival, and disease control rate.
Patients 10 years or older with a histologic diagnosis of a solid or primary CNS tumor and documentation of a BRAF gene fusions were eligible to enroll on the trial. Additional inclusion criteria included having archival tissue sample available for central next generation sequencing testing and biomarker analyses, receiving available standard therapy, and having all adverse effects associated with previous therapy resolved to grade 1 or baseline.
Patients with known NF1 alterations or RAS-related mutations were not eligible for enrollment on the trial. Patients were also unsuitable for enrollment if they had received prior treatment with a MEK inhibitor, malignancies with co-occurring activating RAS mutations at any time, or uncontrolled intercurrent illness that would limit compliance with study requirements.
The FDA previously granted fast track designation to FORE8394 as therapy for tumors harboring class 1 or 2 BRAF alterations in September 2022.2 The fast track designation was supported by data from a phase 1/2a trial (NCT02428712) read out at the 2022 European Society for Medical Oncology (ESMO) Congress, in which investigators evaluated the agent in patients with solid and CNS tumors harboring activating BRAF V600 mutations.