Plixorafenib Elicits Durable Responses in BRAF-Altered CNS Tumors

Treatment with plixorafenib (PLX8394/ FORE8394) led to durable responses in patients with BRAF V600E–mutated primary central nervous system tumors and showed no evidence of cumulative adverse effects (AEs) with prolonged treatment, according to long-term follow-up data from the phase 1/2a PLX120-03 trial (NCT02428712) presented at the 2026 Society for Neuro-Oncology Annual Meeting.¹

Among patients with BRAF V600E–mutated, MAPK inhibitor–naive primary central nervous system (CNS) tumors in the prespecified efficacy subgroup (N = 9), the objective response rate was 67%, and all 6 responses were partial responses. The objective response rate (ORR) was 80% among patients with high-grade glioma (n = 5) and 50% among those with low-grade glioma or glioneuronal tumor (n = 4). The respective progression-free survival rates were 56% at a minimum of 12 months and 33% at a minimum of 24 months, and the median treatment duration was 13.8 months (range, 2.8-61.8+).

“Additionally, we saw that at the time of progression on [plixorafenib], some of these patients in the high-grade glioma [HGG] and in the low-grade glioma [LGG] cohorts were treated with other [MAPK] inhibitors, achieving again, prolonged responses,” Macarena I. de la Fuente, MD, of the University of Miami in Florida, stated in a presentation of the data. “Some of these patients stayed on drug for a longer period, both in the CNS group and the solid tumor groups, some patients almost up to [approximately] 10 years, with some having remarkable clinical improvement,” de la Fuente said.

How was the phase 1/2a PLX120-03 trial of plixorafenib in BRAF-altered primary CNS tumors analyzed?

Plixorafenib is designed to inhibit BRAF V600 monomers and break up mutant BRAF dimers, including class 2 alterations, while avoiding paradoxical MAPK pathway activation, and it is intended for use as a single agent. PLX120-03 evaluated plixorafenib alone in adult and pediatric patients with advanced unresectable solid tumors, enrolled 113 patients, and reached completion in July 2024.² The current analysis presented focused on patients with primary CNS tumors.¹ The safety cohort included 22 patients (HGG, n = 12; LGG/ glioneuronal tumor [GNT], n = 10) with a median age of 41.5 years (range, 4-80). Of these, 13 patients with BRAF V600–mutated tumors had post-baseline efficacy assessments, and 9 patients with no prior MAPK inhibitor exposure formed the prespecified efficacy subgroup.

The subgroup included 5 patients with HGG (glioblastoma, n = 4; anaplastic astrocytoma, n = 1) and 4 patients with LGG/GNT (neuroepithelial glioneuronal tumor, ganglioglioma glioneuronal tumor, pilocytic astrocytoma, and pleomorphic xanthoastrocytoma, n = 1 each). Responses were assessed per RECIST 1.1 or Response Assessment in Neuro-Oncology criteria, depending on the protocol version. Patients still receiving plixorafenib when the study closed were permitted to roll over to a compassionate-use program through a single-patient investigational new drug application.

What did earlier phase 1/2a results show for plixorafenib in BRAF V600–mutated tumors?

Earlier results from the trial were presented at the 2023 Society for Neuro-Oncology Annual Meeting.³ At that time, plixorafenib generated an ORR of 30.2% (95% CI, 17.2%-46.1%) in patients with BRAF V600–mutated tumors (n = 43), which was 41.2% among those who were MAPK inhibitor naive (n = 24), and the median duration of response was 17.8 months (95% CI, 3.7-59.2). Grade 4 treatment-related adverse effects were uncommon and limited to asymptomatic laboratory abnormalities, and no treatment-related adverse effects (TRAEs) were fatal. The investigators found no acquired MAPK pathway mutations after progression on plixorafenib.

What was the long-term safety profile of plixorafenib in BRAF-altered primary CNS tumors?

In the current analysis, among patients in the CNS safety cohort, the most common TRAEs of any grade were nausea, fatigue, vomiting, and diarrhea.¹ These TRAEs began mainly within the first 3 months of treatment, were mostly low grade, and typically lasted 3 to 5 days, and no late-onset or cumulative AEs emerged with prolonged exposure. Class-relevant TRAEs were all grade 1 or 2, and almost all occurred early, with no grade 3 or 4 class-relevant TRAEs; grade 1 rash only (n = 1); no clinically significant ocular effects; no hair or nail effects; no hemorrhagic, cardiovascular, or thromboembolic effects; no secondary malignancies; and no reduction in growth velocity among the 5 pediatric patients enrolled.

The investigators monitored for class-relevant ocular and cardiovascular AEs, hair and nail effects, hemorrhage (including intracranial hemorrhage), and reduced growth velocity in pediatric patients.

“We did not observe any of those expected [AEs],” de la Fuente said.

Increases in alanine aminotransferase levels (68%; n = 15) and aspartate aminotransferase levels (64%; n = 14) were the most common laboratory TRAEs, and grade 3 or higher alanine aminotransferase increases occurred in 18% of patients (n = 4). Grade 3 or higher laboratory TRAEs were limited to liver enzyme level elevations, most occurred with cobicistat (Tybost; a pharmacokinetic booster used early in the study), and most resolved within 1 to 2 weeks. Regardless of causality, the only grade 3 or higher AEs reported in more than 1 patient were ALT increases (n = 4) and headache (n = 2); anemia occurred in 18% of patients (n = 4) and was grade 1 or 2 only.

How long did patients with CNS tumors remain on plixorafenib through compassionate use?

Seven patients from the trial rolled over to receive the agent through compassionate use, 6 patients remained on treatment, and total treatment exposure ranged from 4.3 to 9.8 years. The rollover patients included 3 with CNS-relevant tumors (pilocytic astrocytoma, ganglioglioma, and neurodegenerative Langerhans cell histiocytosis) and 4 with other tumor types (papillary thyroid cancer, n = 3; melanoma, n = 1). In patients receiving ongoing treatment, clinical benefit was maintained for several months after they transitioned to dosing with food. In the CNS population, this benefit was observed for up to 5 years.

What are the next steps for investigating plixorafenib in BRAF-altered CNS tumors?

The phase 2 FORTE master protocol (NCT05503797) is evaluating plixorafenib in patients with BRAF-altered solid tumors and recurrent or progressive primary CNS tumors, is recruiting, and has an estimated enrollment of 254 patients.⁴ The PLX120-03 trial investigators anticipate CNS results from FORTE in 2027 and expect that giving plixorafenib with food rather than a pharmacokinetic booster will improve tolerability.¹

Notably, plixorafenib also received breakthrough therapy designation from the FDA in April 2026 for the treatment of patients with BRAF V600E–mutant HGG.

References

1. de la Fuente MI, Allen CE, Butowski N, et al. Long-term safety and efficacy of plixorafenib in patients with BRAF-altered CNS neoplasms from the phase 1/2a PLX120-03 study. Presented at: 2026 Society for Neuro-Oncology Annual Meeting; November 12-15, 2026; Philadelphia, PA. Abstract CTNI-09.
2. A phase 1/2a study to assess the safety, pharmacokinetics, and pharmacodynamics of FORE8394 in patients with advanced unresectable solid tumors (PLX120-03). ClinicalTrials.gov. Accessed November 13, 2026. https://clinicaltrials.gov/study/NCT02428712
3. de la Fuente MI, et al. Efficacy of BRAF inhibitor plixorafenib (FORE8394) in recurrent, primary central nervous system tumors (PCNST). Paper presented at: 2023 Society for Neuro-Oncology Annual Meeting; November 15-19, 2023; Vancouver, Canada
4. A study to assess the efficacy and safety of FORE8394 in participants with cancer harboring BRAF alterations. ClinicalTrials.gov. Updated July 27, 2026. Accessed November 13, 2026. https://clinicaltrials.gov/study/NCT05503797