FORE Biotherapeutics presented compelling Phase 1/2a clinical data at the American Thyroid Association 2025 Annual Meeting demonstrating that plixorafenib, a novel BRAF inhibitor, achieved durable disease control in patients with BRAF-altered thyroid cancers. The data showed a median progression-free survival of 63.9 months and clinical benefit rate of 85.7% in MAPK inhibitor-naïve patients with BRAF V600-mutated papillary thyroid cancer.
Exceptional Duration of Response in Treatment-Naïve Patients
The Phase 1/2a study evaluated 21 patients with thyroid cancer, including 16 with papillary thyroid cancer (PTC) and 5 with anaplastic thyroid cancer (ATC). In MAPK inhibitor-naïve patients with BRAF V600 mutations, plixorafenib demonstrated remarkable durability, with four PTC patients remaining on treatment for over five years. One patient achieved a partial response lasting 59.2 months with a treatment duration of 7.6 years, while another maintained a partial response for 30.9 months with 8.3 years of treatment duration.
"These results presented at ATA 2025 demonstrate durable clinical benefit in both V600 mutated and BRAF fusion thyroid tumors, and durable disease control in patients with stable disease," said Eric J. Sherman, M.D., Head and Neck Cancer Medical Oncologist at Memorial Sloan Kettering Cancer Center and Principal Investigator for the ongoing FORTE Phase 2 study.
Activity Across Multiple Thyroid Cancer Subtypes
In anaplastic thyroid cancer patients with BRAF V600 mutations, all of whom were MAPK inhibitor-naïve, plixorafenib achieved a median progression-free survival of 16.1 months. One patient experienced a confirmed partial response lasting 17.8 months, while two patients achieved stable disease. Clinical benefit was also observed in patients with BRAF fusion PTC, with one of three patients achieving a partial response lasting 12.9 months.
Even in previously treated patients, plixorafenib showed activity. Among three PTC patients who had received prior MAPK inhibition therapy and at least one prior BRAF inhibition therapy, all three achieved stable disease, resulting in a clinical benefit rate of 33.3%.
Differentiated Mechanism Avoids Combination Requirements
Plixorafenib's novel mechanism of action distinguishes it from earlier generation BRAF inhibitors by avoiding paradoxical activation of the MAPK pathway. This characteristic eliminates the need for combination with MEK inhibitors, potentially improving safety, efficacy, and durability compared to treatments containing prior generation RAF inhibitors.
"The data also demonstrate a high duration of response in MAPKi-naïve patients, highlighting the unique mechanism of action of plixorafenib that avoids paradoxical MAPK pathway activation and delivers differentiated results as a single therapeutic agent in BRAF altered cancers," said Stacie Peacock Shepherd, M.D., Ph.D., Chief Medical Officer of FORE Biotherapeutics.
Addressing Significant Unmet Medical Need
The clinical results address a substantial unmet need in thyroid cancer treatment. Papillary thyroid cancers account for approximately 80% of all thyroid cancers, with BRAF V600E alterations occurring in approximately 60% of these cases. In anaplastic thyroid cancer, BRAF V600E alterations occur in 45% of cases.
"Patients with differentiated thyroid cancer, including papillary thyroid cancers which account for about 80% of all thyroid cancers, are in dire need of new treatment options," Sherman noted. "BRAF V600E alterations occur in approximately 60% of papillary thyroid cancers, underscoring the need for development of a targeted therapy such as plixorafenib."
Advancing Toward Registration
FORE Biotherapeutics is currently advancing the registration-intended FORTE Master Protocol, a global Phase 2 clinical trial featuring four sub-protocol baskets evaluating plixorafenib in distinct patient populations. The three monotherapy indications under evaluation include BRAF V600 progressive or recurrent primary CNS tumors, rare BRAF V600 mutated advanced solid tumors including ATC, and solid tumors with BRAF fusions including PTC and ATC.
The safety profile of plixorafenib in thyroid cancer patients was consistent with previously reported results from the Phase 1/2a study, which enrolled 113 patients with advanced, unresectable solid tumors. All 21 thyroid cancer patients had received prior radiation therapy, nearly all underwent prior surgery, and the majority had received prior systemic anticancer therapies.
