Plixorafenib Delivers Promising Outcomes in CNS Tumors

3d illustration of human body organ(brain anatomy): © PIC4U - stock.adobe.com

Plixorafenib (FORE8394, PLX8394), a novel small-molecule BRAF inhibitor, demonstrated favorable efficacy and tolerability in the treatment of patients with BRAF V600-mutated tumors, according to findings from a phase 1/2a trial (NCT02428712).¹

According to findings presented at the Society for Neuro-Oncology (SNO) 2023 Annual Meeting held November 15-19,1 out of 9 patients with BRAF V600 primary central nervous system tumors (PCNSTs) who were naïve to treatment with a mitogen-activated protein kinase inhibitor (MAPKi), 6 achieved a response when treated with plixorafenib, making for an overall response rate (ORR) of 66.7% (95% CI, 29.9%-92.5%). Of the 24 MAPKi-naïve patients with other BRAF V600-mutated advanced solid tumors, 10 achieved a response with the study treatment for an ORR of 41.7%.

The median duration of response (mDOR) of patients with PCNSTs was 13.9 months (range, 3.7-32.3) with treatment, and 4 of 6 patients (67%) had a DOR of 6 months or longer. The mDOR among patients with other advanced solid tumors was 17.8 months (range, 3.7-59.2) with plixorafenib. The median time to response for all patients with BRAF V600-mutated solid tumors was 3.5 months.

“The updated data from our phase 1/2a study continues to reinforce plixorafenib’s differentiated clinical profile in patients harboring BRAF V600 mutations,” said Stacie Shepherd, MD, PhD, and chief medical officer of Fore Biotherapeutics, in a press release. “The data presented today at SNO 2023 demonstrate deep and durable confirmed responses in MAPK inhibitor-naive patients, including a 67% overall response rate in patients with primary central nervous system tumors.”

For progression-free survival (PFS), median PFS was not reached in patients with low-grade glioma or glioneuronal tumors (range, 1.6-27.8+). The median PFS was 6.7 months (range, 2.8-34.1). in patients with high-grade gliomas.

There has been a relatively low incidence of treatment-emergent adverse events (TEAEs) compared with approved BRAF or MEK inhibitors, according to Fore Biotherapeutics, plixorafenib’s manufacturer. At the recommended phase 2 dose of 900 mg, there were no dose-limiting toxicities, symptomatic TEAEs were almost all grade 1, and the most common laboratory abnormality TEAEs were primarily grade 1-2. In patients with PCNSTs, headache was the only symptomatic grade 3 or higher TEAE and this occurred in less than 5% of patients.

About the Phase 1/2a Trial of Plixorafenib

Plixorafenib was granted an FDA orphan drug designation for the treatment of PCNST and a fast track designation for patients with BRAF V600 mutations who have exhausted prior lines of therapy.²

This phase 1/2a trial of plixorafenib consists of a dose-escalation part and a dose-extension part. The trial has an enrollment of 113 patients across locations in Arizona, California, Florida, Indiana, Massachusetts, Michigan, New York, Missouri, Tennessee, Texas, and Utah.³

The primary end points of the trial are area under the curve, maximum concentration, time to peak concentration, half-life, incidence of TEAEs, recommended phase 2 dose, and ORR. The secondary end points are DOR, PFS, and clinical benefit rate after 24 weeks.

Patients were considered eligible if they were at least 10 years old, weighed at least 30 kg, had a solid tumor with an activating BRAF V600 mutation, had measurable disease per RECIST v1.1, had an ECOG performance status of 0-1, and had completed previous anti-cancer therapy at least 2 weeks before trial initiation. Patients were excluded if they had a known RAS-related mutation or RTK activation, uncontrolled intercurrent illness, colorectal or pancreatic cancer, an active secondary malignancy, clinically significant cardiac disease, or a known HIV, HBC, or HCV infection.

REFERENCES:

1. Fore Biotherapeutics announces oral presentation at SNO 2023 reporting updated phase 1/2a results for plixorafenib in BRAF V600 advanced solid tumors, including novel data for patients with BRAF V600 primary CNS tumors. News release. Fore Biotherapeutics. November 17, 2023. Accessed November 20, 2023. https://tinyurl.com/mavak6cb

2. Plixorafenib program. Fore Biotherapeutics. Accessed November 20, 2023. https://tinyurl.com/4sbrj432

3. A study of FORE8394 as a single agent in patients with advanced unresectable solid tumors. ClinicalTrials.gov. Updated March 27, 2023. Accessed November 20, 2023. https://clinicaltrials.gov/study/NCT02428712