In an early-phase study, the novel BRAF inhibitor FORE8394 shows impressive efficacy in brain tumors and other cancers with a benign safety profile.

Sylvester Comprehensive Cancer Center neuro-oncologist Macarena de la Fuente, M.D., will be presenting early-phase clinical trial results on FORE8394, a new and promising BRAF inhibitor therapy, at the American Society of Clinical Oncology (ASCO) annual meeting. The Phase 1/2a study found FORE8394 is safe and shows encouraging signs of efficacy in a variety of solid tumors including glioblastoma.

“We have seen responses across the board from ovarian cancer to thyroid cancer to high-grade gliomas, including glioblastomas, and low-grade gliomas, which are less aggressive than glioblastoma but still incurable brain tumors,” said Dr. de la Fuente, who is associate professor of neurology and chief of neuro-oncology. “We are particularly excited by the durable responses we are seeing in these tumors.”

Novel BRAF Inhibitor

FORE8394 targets BRAF, an enzyme that plays a major role in cell growth and division and other functions. However, molecular alterations in the BRAF gene can lead to cancer development.

While available BRAF inhibitors target V600 mutations, they do not target the much less common non-V600 mutations. Additionally, treatments with current BRAF inhibitors may result in the activation of the MAPK pathway. On top of the ability of FORE8394 to target V600 and non-V600 mutations, its use does not result in the paradoxical activation of the MAPK pathway.

“FORE8394 can hit BRAF alterations that are not targetable by the drugs that are currently on the market,” said Dr. de la Fuente. “In addition, because it does not cause paradoxical MAPK activation, patients don’t have to take a second drug, called an MEK inhibitor.”

The Study

The multi-site study enrolled 113 patients to test FORE8394 for safety and efficacy. The drug was very well tolerated, with relatively mild side effects. Overall, the drug showed better tolerability than existing BRAF/MEK combinations.

Because BRAF variations are found in several cancers, the trial enrolled patients with glioma, melanoma, ovarian and thyroid cancers within other solid tumors. Though the patient samples are quite small, the results have been highly encouraging in some tumor types as glioblastoma, which have a median survival of 16 months.

“The clinical data we present is quite strong,” said Dr. de la Fuente. “Patients tolerated the drug well, and we are seeing durable responses. There are patients that have been on the drug for over six years.”

Phase 2 Started

Dr. de la Fuente, who specializes in treating primary brain tumors, cautions that only about 3% of glioblastomas have a BRAF alteration. However, for that patient subset, FORE8394 could show significant value.

In March 2023, the U.S. Food and Drug Administration gave FORE8394 Orphan Drug Designation for central nervous system tumors. This key regulatory move could accelerate the drug’s development and get it to patients sooner.

“At ASCO, we will discuss the drug’s safety, long-term tolerability and preliminary efficacy,” said Dr. de la Fuente. “Based on these results, we are already running a Phase 2 study (NCT05503797) to further confirm these promising results.”