A Randomized Phase III Study of BRAF-Targeted Therapy vs Cabozantinib in RAI-Refractory Differentiated Thyroid Cancer with BRAF V600E

By Lova Sun, MD, MSCE

@LovaSunMD

Identifying the optimal sequence of therapies for patients with progressive radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) is a question commonly encountered in practice, posing a challenge for clinicians. Approximately half of these patients harbor a mutation in BRAF V600E, yet there is considerable variation in real-world clinical practice on the most effective treatment approach once multikinase inhibitor (MKI) therapy (e.g., lenvatinib, sorafenib) stops working. Patients are often on these oral treatments for extended periods of time, and can experience significant toxicity.

In June 2022, the FDA issued a tumor-agnostic approval for the BRAF-targeted combination of dabrafenib and trametinib for patients whose advanced solid tumors harbor a BRAF V600E mutation. The goal of the EA3231 phase 3 trial, which opened in August 2024, is to determine whether this combination is more effective than second-line MKI therapy with cabozantinib in BRAF V600E mutant RAI-refractory DTC, after progression on a frontline MKI such as lenvatinib. We hypothesize that the BRAF-targeted therapy will be associated with improved progression-free survival and tolerability compared with cabozantinib.

The trial will randomize patients 1:1 as follows:

• Dabrafenib 150 mg PO BID plus trametinib 2 mg PO QD
• Cabozantinib 60 mg PO QD

Patients are stratified according to baseline tumor burden (sum of all target lesions <4 cm or ≥4 cm). Eligible patients must have documented radiographic progressive disease with a BRAF V600E mutation as determined by local testing. These patients may be enrolled over any time interval after treatment with one to two MKIs, including, but not limited to, lenvatinib and sorafenib. Treatment will continue until disease progression or intolerable toxicity.

To further encourage enrollment, the trial was amended in June 2025. The amendment allows prior treatment with a checkpoint inhibitor, e.g., pembrolizumab, as long as it is noted on the case report form. Patients with anaplastic histology on recurrence remain ineligible, but this amendment removed the eligibility requirement that patients must not have any lesions with a ≥ 2 cm growth within 3 months or ≥ 1.5 cm growth within 2 months of randomization. A proposed amendment will further broaden inclusion criteria, including allowing non-RECIST measurable/progressive disease.

Sites that have not yet opened EA3231 are encouraged to do so. Although participants to date have been predominantly from academic sites, EA3231 is a community site–friendly study. Sites may also want to consult with other specialists within their health system, e.g., endocrinologists, to make sure that they are aware of this clinical trial opportunity.

To date, there have been no studies comparing BRAF-targeting therapy to MKIs for RAI-refractory DTC. A better understanding of the relative efficacy, response durability, and long-term tolerability of these agents and how to sequence them has the potential to improve the quality of life for this patient population, thus helping providers to counsel patients planning for these treatments in the future.

Learn more about the EA3231 trial at ecog-acrin.org.

Dr. Sun (University of Pennsylvania/Abramson Cancer Center) is the study chair for this trial. The study co-chair is Nabil F. Saba, MD (Emory University/Winship Cancer Institute), and the community co-chair is Mei Tang, MD (Greater Baltimore Medical Center).

The NCTN group study champions are Cristina Rodriguez, MD (University of Washington/UW Medicine Fred Hutchinson Cancer Center) for NRG Oncology, Paul Loren Swiecicki, MD (University of Michigan/UM Health Rogel Cancer Center) for SWOG, and Ari Rosenberg, MD (University of Chicago/UChicago Medicine Comprehensive Cancer Center) for Alliance.