Dabrafenib and trametinib combination as a neoadjuvant strategy in BRAF- positive anaplastic thyroid cancer (ANAPLAST-NEO)

Anaplastic thyroid cancer (ATC) has a poor prognosis, with median overall survival (OS) duration in the range of 5–12 months. ATC have high proliferative activity and are prone to numerous somatic mutations, BRAF V600 mutations are a common driver of the ATC and are present in up to 50% of ATCs. Dabrafenib (BRAF inhibitor) and Trametinib (MEK inhibitor) may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Presented here is a trial-in-progress that will evaluate whether dabrafenib and trametinib may help to control BRAF V600-mutated ATC when given before surgery and improve the response rate. This is a single-center, phase II, open-label, single-arm, non-randomized study to determine the efficacy of Dabrafenib and Trametinib in subjects with BRAF-mutated ATC in neoadjuvant settings. Patients will receive dabrafenib 150 mg orally (PO) twice daily, trametinib 2 mg PO once daily for 3 months. Key eligibility criteria include BRAF - positive anaplastic thyroid cancer, measurable disease based on RECIST v1.1, an ECOG PS 0-2, and absence of metastases in the brain. Key exclusion criteria include taking any type of low molecular weight kinase inhibitor for 2 weeks or 5 half-lives of the agent or receiving any type of anticancer drugs or systemic chemotherapy within 2 weeks before starting treatment in the present trial. Primary outcome measures are overall response rate (ORR) in neoadjuvant mode and number of R0 resections after 3 months of neoadjuvant combination therapy with anti-BRAF and MEK inhibitors (comparison of the proportion of surgical resections with historical controls of 5 percent). The secondary endpoints include OS, progression-free survival, safety profile, and health-related quality of life (using the EQ-5D). Calculations of the required sample size are based on the primary ORR endpoint using Fleming's one-step design (Fleming, 1982). It is necessary to include N = 18 patients in order to achieve a power of 90% for the binomial testing procedure in case the true ORR is 35% or higher. Phase II enrollment began in January 2021. NCT04739566. The authors. Has not received any funding.