BRAF-Mutant Thyroid Cancer Treatment Yields 63.9-Month PFS

Plixorafenib (FORE8394) yielded durable clinical efficacy that appeared favorable compared with historical data, and an encouraging safety profile, in patients with BRAF-altered papillary thyroid cancer and anaplastic thyroid cancers in a phase 1/2a clinical trial (NCT02428712), according to a press release from the developer, FORE Biotherapeutics.1

In 21 patients with thyroid cancer, the median progression-free survival was 63.9 months, and the clinical benefit rate, defined as patients who had a response or stable disease for at least 24 weeks, was 85.7% (n = 6/7).

Of the patients who were naïve to MAPK inhibitors, 4 remained on treatment for over 5 years, including 1 patient who had a partial response of 59.2 months and a second partial response of 30.9 months. Of the patients with anaplastic thyroid cancers harboring a BRAF V600 mutation who were naïve to MAPK inhibitors, the median PFS was 16.1 months; 1 patient had a confirmed partial response lasting 17.8 months, and 2 patients had stable disease. In the 3 patients with papillary thyroid cancer who received prior MAPK inhibitor therapy and at least 1 prior BRAF inhibitor therapy, all 3 achieved stable disease and had a clinical benefit rate of 33.3%.

Additionally, patients with BRAF fusion papillary thyroid cancer also had clinical benefit with the therapy, as 1 of 3 patients achieved a partial response lasting 12.9 months, and 1 patient with anaplastic thyroid cancer had stable disease.

Results from this trial were shared at the American Thyroid Association (ATA) 2025 Annual Meeting.2

Previously, in September 2022, plixorafenib was granted fast track designation by the FDA for the treatment of those with tumors harboring Class 1/2 BRAF alterations for whom all previous therapies have been exhausted.3

“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. These new findings continue to support the strong clinical profile of plixorafenib as well as the potential to benefit patients with BRAF-altered thyroid cancers,” stated Eric J. Sherman, MD, head and neck cancer medical oncologist at the Memorial Sloan Kettering Cancer Center, and principal investigator of the ongoing phase 2 FORTE study (NCT05503797), in the press release.1

This trial was split into 2 parts: part 1, the dose-escalation phase, which evaluated the safety, pharmacokinetics, pharmacodynamics, and the recommended phase 2 dose of plixorafenib in adult and pediatric patients with BRAF-mutated tumors; and part 2, the dose-extension phase, which assessed the objective tumor response to treatment in adult and adolescent patients with advanced BRAF-mutated tumors.4

A total of 113 patients were enrolled in the trial and received at least 1 dose of plixorafenib, of whom 21 patients had thyroid cancers, 16 of which were papillary thyroid cancers and 5 were anaplastic thyroid cancers.

Oral plixorafenib was administered between 900 and 3600 mg per day with or without cobicistat in adult or pediatric patients with BRAF-mutated, histologically confirmed, advanced, unresectable solid tumors who also had measurable disease and were intolerant to standard therapy or had no standard therapy available.

Regarding safety, the most common any-grade plixorafenib-related treatment-emergent adverse events (TEAEs) were increased alanine transferase (38.1%), increased aspartate transferase (34.5%), fatigue (20.4%), and nausea (19.5%); grade 3 events included increased aspartate transferase (1.8%), increased blood bilirubin (1.8%), diarrhea (1.8%), hyperbilirubinemia (0.9%), and increased alanine transferase (0.9%). A single grade 4 event was reported, which was hyperbilirubinemia (0.9%).

Notably, 1 patient with papillary thyroid cancer discontinued plixorafenib due to a grade 1 blood bilirubin increase.

“The data also demonstrate a high duration of response in MAPK [inhibitor]-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, MD, PhD, chief medical officer of FORE Biotherapeutics.1 “We continue to advance our ongoing registrational FORTE basket study, which includes BRAF V600-altered thyroid cancers, as we aim to generate further data to inform treatment and help patients with BRAF-driven tumors.”