Plixorafenib Receives FDA BTD for BRAF V600E-Mutated High-Grade Glioma

Plixorafenib has received breakthrough therapy designation from the FDA for the treatment of patients with BRAF V600E-mutated recurrent or progressive high-grade glioma, according to a press release from the drug developer, Fore Biotherapeutics.¹ The agency’s decision is supported by clinical evidence from the completed phase 1/2a trial (NCT02428712) and the ongoing phase 2 FORTE basket study (NCT05503797), which is evaluating the next-generation BRAF inhibitor in patients with BRAF V600E-mutated central nervous system (CNS) malignancies.

Plixorafenib, also known as FORE8394, is a small-molecule, orally available inhibitor designed to target both V600 and non-V600 mutations. Previously known as FORE8394, plixorafenib was granted fast track designation by the FDA for patients with tumors harboring class 1/2 BRAF alterations for whom all previous therapies have been exhausted.²

“High-grade gliomas are aggressive primary brain tumors associated with poor outcomes despite multimodality treatment approaches,” stated Macarena da la Fuente MD, chief of the Neuro-Oncology Division in the Department of Neurology at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine.¹ “In addition to their limited prognosis, patients experience substantial morbidity related to both the disease itself and the toxicities of current therapies. Therefore, there remains a critical need for novel treatments that are not only effective but also better tolerated.”

What is the clinical efficacy of plixorafenib in BRAF-mutated glioma?

Previously shared at the 2023 American Society of Clinical Oncology Annual Meeting, data from the phase 1/2a study demonstrated significant antitumor activity in patients with BRAF V600-mutated primary CNS tumors who were naive to MAPK inhibitors. In a prespecified subgroup of 9 patients with refractory MAPK inhibitor-naïve, BRAF V600E-mutated primary CNS tumors, plixorafenib monotherapy achieved an overall response rate (ORR) of 67% and a clinical benefit rate (CBR) exceeding 75%. Among patients with various BRAF V600-mutated solid tumors, the agent produced an ORR of 42%, a median duration of response (DOR) of 17.8 months, and a CBR greater than 70%.

Plixorafenib demonstrated a favorable safety and tolerability profile across disease types in the phase 1/2 trial. Treatment-related adverse events led to treatment discontinuation in less than 2% of patients.

In the FORTE trial, the most recent readout demonstrated that the BRAF V600E primary CNS basket met the pre-specified interim analysis. The independent data monitoring committee (IDMC) supported that the study may continue as planned based on responses assessed by blinded independent central review. The IDMC has also continued oversight of safety.

How is the FORTE clinical trial for plixorafenib structured?

The phase 2 FORTE study is a multi-institutional, open-label basket trial designed to evaluate the safety and efficacy of plixorafenib in patients with BRAF-altered malignancies.³ Participants were sorted into cohorts based on tumor type and genetic alteration: Group A included patients with advanced solid tumors or primary CNS tumors harboring BRAF fusions; Group B focused on patients with recurrent primary CNS tumors specifically carrying the BRAF V600E mutation; Group C included patients with advanced, rare, non-CNS solid tumors harboring BRAF V600E mutations; and Group D included patients with BRAF V600E-mutated advanced solid tumors.

Patients in groups A, B, and C received plixorafenib at increasing doses as tolerated, continuously in 2-week cycles until progression, unacceptable toxicity, or withdrawal.

Eligibility criteria varied by group, but in groups A, B, and C all patients were required to be 10 years of age or older with histologically confirmed disease.

The primary end point was ORR in groups A, B, and C, as well as pharmacokinetics in group D.

“The granting of breakthrough therapy designation is a significant development milestone for plixorafenib and reinforces our conviction in its unique mechanism of action which, further supported by the tolerability and efficacy profile seen in BRAF-altered tumors, underscores the potential of plixorafenib as a treatment option for patients living with difficult to treat cancers,” added Stacie Peacock Shepherd, MD, PhD, chief medical officer of Fore.¹ “BRAF alterations are an important actionable driver in the molecularly integrated clinical decision paradigm for the treatment of high-grade gliomas, and plixorafenib has demonstrated a differentiated profile in patients with primary CNS tumors, including glioblastoma and other high-grade gliomas. The maturation of the data from FORTE may help validate these findings, with [breakthrough therapy designation] status further accelerating the delivery of this promising therapy to patients.”

References

1. Fore Biotherapeutics receives breakthrough therapy designation for plixorafenib. News release. Fore Biotherapeutics. April 1, 2026. Accessed April 2, 2026. https://tinyurl.com/4edwcywn
2. Fore Biotherapeutics announces fast track designation granted by FDA to FORE8394 for the treatment of cancers harboring BRAF class 1 and class 2 alterations. News release. Fore Biotherapeutics. September 28, 2022. Accessed April 2, 2026. https://bwnews.pr/3CfWtHb
3. A study to assess the efficacy and safety of FORE8394 in participants with cancer harboring BRAF alterations. ClinicalTrials.gov. Updated March 10, 2026. Accessed April 2, 2026. https://tinyurl.com/msbxkex7