How strong were the ATA 2025 thyroid cancer results for FORE Biotherapeutics’ plixorafenib?
FORE Biotherapeutics presented new data at the 2025 Annual Meeting of the American Thyroid Association (ATA), demonstrating prolonged clinical benefit and disease control with its lead BRAF inhibitor plixorafenib in patients with BRAF-altered papillary and anaplastic thyroid cancers. The data, which stem from a previously completed Phase 1/2a trial, suggested a median progression-free survival (mPFS) of up to 64 months in MAPK-inhibitor-naïve patients, raising the possibility of a differentiated therapeutic profile in treatment-refractory or mutation-driven thyroid cancers.
The data included 21 patients with advanced thyroid cancer, treated as part of a broader 113-patient solid tumor study. Among them, 16 had papillary thyroid cancer (PTC) and five had anaplastic thyroid cancer (ATC)—two disease subtypes with particularly limited treatment options once standard therapies fail.
FORE Biotherapeutics, which is currently in a registration-stage development phase, said that the findings support continued development of plixorafenib within its global FORTE Phase 2 program, especially in BRAF V600-mutated and BRAF fusion thyroid cancers.
What makes plixorafenib different from earlier BRAF-targeted therapies in thyroid cancer?
Plixorafenib (also known as FORE8394 or PLX8394) is a next-generation, “paradox breaker” BRAF inhibitor. Unlike traditional BRAF-targeted drugs, it does not activate the MAPK pathway in non-mutant cells, eliminating the need for combination therapy with MEK inhibitors—a frequent requirement with earlier BRAF therapies like vemurafenib or dabrafenib. This may lead to improved safety profiles and greater therapeutic durability.
Data presented at ATA 2025 showed that among seven MAPK-inhibitor-naïve PTC patients with BRAF V600 mutations, plixorafenib achieved a clinical benefit rate (CBR) of 85.7%. Notably, four of these patients remained on treatment for over five years, with one patient sustaining a partial response for more than 59 months and receiving treatment for 7.6 years. Another patient maintained a 30.9-month response and remained on therapy for 8.3 years.
In ATC patients, where disease progression is typically rapid and survival rates are poor, the mPFS was 16.1 months among four MAPK-inhibitor-naïve individuals. One patient achieved a 17.8-month partial response, while two others maintained stable disease.
Even among heavily pre-treated patients—those who had already failed MAPK and BRAF inhibitors—clinical benefit was observed, albeit at a lower rate (CBR of 33.3%).
How do these new data position plixorafenib in the broader thyroid cancer treatment landscape?
The thyroid cancer therapy market has lacked targeted precision tools for patients with specific oncogenic drivers, especially BRAF V600 mutations and fusions. Papillary thyroid cancer (PTC), the most common subtype, accounts for roughly 80% of all thyroid malignancies, and BRAF V600 mutations are found in approximately 60% of these cases. In anaplastic thyroid cancer (ATC), one of the most aggressive forms of cancer with limited survival expectancy, BRAF V600 mutations occur in up to 45% of patients.
Current approved options such as dabrafenib-trametinib combinations carry toxicity risks and require complex regimens. The durable, single-agent performance of plixorafenib—especially in patients who are naïve to prior MAPK inhibition—could signal a shift toward simpler and more tolerable treatment strategies.
The data also add to a growing narrative around “basket trials” and precision oncology, where drugs like plixorafenib are evaluated across multiple tumor types defined by specific genetic mutations rather than organ site.
What does the ongoing FORTE trial aim to establish across multiple BRAF-driven tumors?
Plixorafenib is currently being evaluated under the FORTE (FORE Trials of Efficacy) Master Protocol, a global Phase 2 basket trial designed to support registration across multiple BRAF-altered tumor types. This trial features four sub-protocols, targeting specific patient populations defined by the presence of BRAF alterations. These include progressive or recurrent primary central nervous system (CNS) tumors harboring BRAF V600 mutations, rare advanced solid tumors with BRAF V600 mutations such as anaplastic thyroid cancer (ATC), and solid tumors with BRAF fusions including papillary thyroid cancer (PTC) and ATC.
The FORTE trial employs an adaptive basket design, which allows FORE Biotherapeutics to evaluate plixorafenib’s efficacy across genetically similar tumor types, irrespective of their tissue of origin. This approach streamlines the regulatory development path by generating clinical data relevant to multiple indications under a single protocol framework. According to the American oncology biotech firm, the study is also structured to inform future new drug application (NDA) submissions, subject to continued data robustness.
Although no direct head-to-head comparisons were made between plixorafenib and existing BRAF-targeted therapies during the ATA 2025 presentation, institutional observers noted that the durability and safety outcomes observed thus far appear to exceed those typically associated with earlier-generation BRAF inhibitors. These signals, coupled with a differentiated safety profile, could enable plixorafenib to expand its potential utility beyond thyroid cancer into challenging indications such as BRAF-driven CNS tumors and other rare malignancies with fusion alterations.
What is the expert and institutional sentiment around FORE Biotherapeutics and its lead asset?
While FORE Biotherapeutics has not disclosed updated financial guidance in relation to plixorafenib’s development timeline, the clinical narrative is generating renewed attention from the oncology research and biotech investor communities. Experts at the ATA conference noted that the therapy’s “paradox breaker” mechanism offers a structurally differentiated solution to a known problem with legacy BRAF agents, reducing the risk of secondary malignancies or off-target effects due to unintended MAPK pathway activation.
Analysts tracking the oncology pipeline have highlighted FORE Biotherapeutics as part of a new generation of targeted oncology firms moving into registrational trials with selective, mutation-specific drugs. Plixorafenib’s progress is being watched closely, especially given its clean safety profile and early efficacy durability signals.
Institutional sentiment appears cautiously optimistic, with potential milestones in the FORTE trial seen as pivotal for value inflection. If data in additional cohorts (e.g., CNS tumors or BRAF fusion-driven cancers) continues to impress, plixorafenib could be positioned as a potential best-in-class agent within its niche.
What’s next for plixorafenib in the BRAF-targeted oncology space?
The clinical community and potential investors will be closely watching the FORTE trial’s readouts across different tumor baskets over the next 12–18 months. FORE Biotherapeutics has stated its intention to use the data for global registration efforts, positioning plixorafenib not just as an add-on, but as a potential first-line therapy in BRAF-altered cancers where treatment options are constrained.
Given the strong clinical benefit rate observed in thyroid cancer, particularly among naïve patients, future regulatory filings may include applications for breakthrough designation or accelerated approval pathways, especially in subtypes like ATC, where survival outcomes remain poor.
With the ATA 2025 data, FORE Biotherapeutics has added momentum to its pitch for plixorafenib as a versatile, next-generation BRAF inhibitor—one that avoids the pitfalls of older therapies and addresses high-unmet-need populations.
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