FDA Grants Breakthrough Therapy Designation to Plixorafenib for BRAF V600E Glioma

The FDA has granted breakthrough therapy designation (BTD) to plixorafenib (FORE8394) for the treatment of adult patients with BRAF V600E–mutated high-grade glioma (HGG).¹ The designation was based on data from approximately 25 patients enrolled in a completed phase 1/2a trial (NCT02428712)² and the ongoing phase 2 FORTE basket study (NCT05503797)³ evaluating plixorafenib in BRAF V600E–mutated central nervous system (CNS) tumors.

Plixorafenib is an investigational, oral BRAF inhibitor with a mechanism of action that functions as both a dimer breaker and a paradox breaker, distinguishing it from earlier-generation BRAF inhibitors. The agent has demonstrated selectivity for BRAF alterations across both class 1 (V600) and class 2 (including fusions) mutations.

BTD is intended to expedite the development and regulatory review of investigational therapies for serious or life-threatening conditions that demonstrate substantial improvement over available therapies on one or more clinically significant endpoints. The designation provides FORE Biotherapeutics, the sponsor, with more frequent and intensive FDA guidance, involvement of senior reviewers, and eligibility for rolling and priority review of the marketing application.

Clinical Evidence Supporting the Designation

The FDA's decision was informed by efficacy and safety data from the phase 1/2a trial and interim data from the FORTE study. In a prespecified subgroup of patients with refractory, MAPK inhibitor–naive BRAF V600–mutated primary CNS tumors (n = 9) enrolled in the phase 1/2a trial, plixorafenib monotherapy demonstrated an overall response rate (ORR) of 67% and a clinical benefit rate (CBR) greater than 75%. Among patients with BRAF V600 alterations who were MAPK inhibitor–naive across tumor types, the agent achieved a 42% response rate with a median duration of response (mDOR) of 17.8 months and a CBR exceeding 70%. The drug-related adverse event discontinuation rate was less than 2%.

Data from the phase 1/2a trial were previously presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2023 and the Society for Neuro-Oncology (SNO) Annual Meeting in 2023. In the FORTE study, the BRAF V600E primary CNS basket met its prespecified interim analysis, with the independent data monitoring committee (IDMC) supporting continuation of the study based on responses assessed by blinded independent central review (BICR).

About the FORTE Basket Study

The FORTE Master Protocol (NCT05503797) is a global, registration-intended phase 2 clinical trial employing a Bayesian adaptive design.³ The study includes 4 subprotocol baskets evaluating plixorafenib in distinct patient populations. The 3 monotherapy indications currently under evaluation are: recurrent or progressive BRAF V600 primary CNS tumors; solid tumors with BRAF fusions; and rare BRAF V600–mutated solid tumors. Topline results from the CNS basket evaluating plixorafenib monotherapy for recurrent or progressive BRAF V600 primary CNS tumors are anticipated by the end of 2026. If positive, FORE Biotherapeutics intends to submit a new drug application to the FDA under the accelerated approval pathway.¹

Disease Context and Unmet Need

HGG encompasses aggressive primary brain tumors, including glioblastoma and anaplastic astrocytoma, that are associated with poor prognoses despite multimodality treatment approaches. BRAF alterations represent an actionable molecular driver in the treatment paradigm for HGG, yet currently approved therapies carry significant limitations in efficacy, tolerability, and safety.

"In addition to their limited prognosis, patients experience substantial morbidity related to both the disease itself and the toxicities of current therapies," said Macarena de la Fuente, MD, chief of the Neuro-Oncology Division, Department of Neurology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, in a news release. "Therefore, there remains a critical need for novel treatments that are not only effective but also better tolerated."

Regulatory Context

Plixorafenib previously received fast track designation for patients with cancers harboring BRAF class 1 (V600) and class 2 (including fusions) alterations who have exhausted prior therapies, as well as orphan drug designation for the treatment of primary brain and CNS malignancies. The BTD is the first granted to a targeted therapy for HGG, according to FORE Biotherapeutics. Together, these designations are intended to support the development of plixorafenib for BRAF-altered primary CNS tumors in both adult and pediatric patients.

"BRAF alterations are an important actionable driver in the molecularly integrated clinical decision paradigm for the treatment of [HGGs], and plixorafenib has demonstrated a differentiated profile in patients with primary CNS tumors, including glioblastoma and other high-grade gliomas," said Stacie Peacock Shepherd, MD, PhD, chief medical officer of FORE Biotherapeutics, in a news release. "The maturation of the data from FORTE may help validate these findings, with BTD status further accelerating the delivery of this promising therapy to patients."

REFRENCES

1. FORE Biotherapeutics receives Breakthrough Therapy Designation for plixorafenib. News release. FORE Biotherapeutics. April 1, 2026. Accessed April 2, 2026. https://tinyurl.com/3h783nyk
2. A phase 1/2a study to assess the safety, pharmacokinetics, and pharmacodynamics of FORE8394 in patients with advanced unresectable solid tumors. ClinicalTrials.gov. NCT02428712. Updated July 29, 2025. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT02428712
3. A phase 2 master protocol to assess the efficacy and safety of FORE8394, an inhibitor of BRAF Class 1 and Class 2 alterations, in participants with cancer harboring BRAF alterations (FORTE). ClinicalTrials.gov. NCT05503797. Updated March 10, 2026. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT05503797