Plixorafenib Demonstrates Clinical Benefit in Thyroid Cancer

Plixorafenib (FORE 8394; PLX8394) with or without cobicistat (Tybost) demonstrated a clinical benefit and differentiated duration of response in patients with MAPK inhibitor-naive thyroid cancer harboring a BRAF V600 mutation.¹

The findings of the phase 1/2a study (NCT05503797), presented at the American Thyroid Association (ATA) 2025 Annual Meeting last week, showed a median progression-free survival (PFS) of 63.9 months and a clinical benefit rate (CBR) of 85.7%. Four of 13 patients with papillary thyroid cancer (PTC) who were naïve to MAPK inhibitors remained on treatment for over 5 years, with 1 partial response (PR) of 59.2 months (treatment duration, 7.6 years) and a second PR of 30.9 months (treatment duration, 8.3 years).

In 3 patients with PTC who received prior MAPK inhibitor therapy as well as at least 1 prior BRAF inhibitor, all reached stable disease with a CBR of 33.3%.

In 4 patients with advanced thyroid cancer who were MAPK inhibitor-naive, the median PFS was 16.1 months with 1 confirmed PR lasting 17.8 months and 2 patients achieving stable disease.

A clinical benefit was also observed in patients with BRAF fusion PTC: 1 of 3 patients achieved a PR of 12.9 months (treatment duration, 25 months). One patient with ATC reached stable disease.

The safety profile of the regimen was consistent with what has been previously observed, and no new safety signals were noted.

“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,” said Eric J. Sherman, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, and principal investigator for the ongoing phase 2 plixorafenib study, in a press release.

“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. BRAF V600E alterations occur in approximately 60% of papillary thyroid cancers, underscoring the need for development of a targeted therapy such as plixorafenib that addresses the mechanistic drivers of these tumors along with the compelling clinical efficacy and safety profile demonstrated by treatment with plixorafenib,” Sherman added.

What is the Phase 2 Study of Plixorafenib Investigating?

Plixorafenib, an orally available BRAF protein inhibitor, is being assessed for safety and efficacy in patients with locally advanced or metastatic solid tumors or recurrent/progressive primary central nervous system (CNS) tumors harboring BRAF fusions, or in patients with rare BRAF V600-mutant solid tumors, melanoma, thyroid, or recurrent primary CNS tumors.² The study’s primary end points are objective response rate and pharmacokinetics, and secondary end points include duration of response, time to response, PFS, overall survival, and disease control rate.

The study’s design consists of 4 subprotocols:

• Subprotocol A: Patients with unresectable, locally advanced or metastatic tumors or primary CNS tumors harboring BRAF fusions will receive plixorafenib, increased as tolerated, in 3-week cycles.
• Subprotocol B: Patients with recurrent primary CNS tumors with BRAF V600E mutations will receive plixorafenib plus cobicistat continuously in 3-week cycles.
• Subprotocol C: Patients with advanced, rare, non-CNS tumors with BRAF V600E mutations will receive plixorafenib with cobicistat continuously in 3-week cycles.
• Subprotocol D: Patients with BRAF V600E-mutated cutaneous melanoma and MAPK inhibitor-naïve thyroid cancer will be randomized to receive plixorafenib with or without cobicistat.

REFERENCES:

1. FORE Biotherapeutics Presents Phase 1/2a Plixorafenib Data Demonstrating Prolonged Duration of Effect in BRAF Altered Thyroid Cancers at American Thyroid Association® 2025 Annual Meeting. News release. FORE Biotherapeutics. September 12, 2025. Accessed September 18, 2025. https://tinyurl.com/2edu6yhs

2. A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations. ClinicalTrials.gov. Updated July 24, 2025. Accessed September 18, 2025. https://clinicaltrials.gov/study/NCT05503797