EA3231: A randomized phase III study of BRAF-targeted therapy vs cabozantinib in RAI-refractory differentiated thyroid cancer with <i>BRAF</i> V600Em.

TPS6140 Background: About half of patients with RAIR advanced differentiated thyroid cancer (DTC) harbor a mutation in BRAF V600E. Although multiple systemic therapies are now approved, optimal treatment sequencing remains undefined for patients with BRAF V600Em RAIR DTC. Given the indolent natural history of this disease and often prolonged exposure to oral therapies with significant toxicity, comparative data on efficacy and tolerability of second-line therapy is a clear unmet need. Methods: EA3231 (NCT06475989) is a NCTN cooperative group randomized phase III study in patients with BRAF V600Em RAIR DTC who have progressed on prior multikinase inhibitor therapy such as lenvatinib or sorafenib. Patients will be randomized 1:1 to BRAF-targeted therapy (dabrafenib and trametinib) or cabozantinib, all of which are FDA-approved agents in this setting. The primary objective is to compare progression-free survival (PFS) between dabrafenib/trametinib vs cabozantinib, with secondary objectives including overall response rate, overall survival, PFS2, and safety and tolerability. We hypothesize that BRAF-directed therapy will be associated with improved PFS and tolerability compared to cabozantinib. Our target accrual is 120 patients; this sample size will provide 83% power to detect a HR of 0.60 (corresponding to a median PFS of 12 months) compared to an estimated median PFS of 7.2 months in the cabozantinib arm. This study was activated in late 2024, and has enrolled 8/120 patients as of 1/2026. Clinical trial information: NCT06475989 .