EA3231 – A Randomized Phase III Study of BRAF-Targeted Therapy vs Cabozantinib in RAI-Refractory Differentiated Thyroid Cancer with BRAF V600E

The study chair for this trial is Lova Sun, MD (University of Pennsylvania/Abramson Cancer Center). The study co-chairs are Nabil F. Saba, MD (Emory University/Winship Cancer Institute), Laila Gharzai, MD (Northwestern University/Robert H. Lurie Comprehensive Cancer Center), and Mei Tang, MD (Greater Baltimore Medical Center).

Approximately 15-20% of patients with differentiated thyroid cancer (DTC) experience disease progression after standard treatment with radioactive iodine (RAI). The usual treatment for RAI-refractory patients is tyrosine kinase inhibitors (TKIs) that target vascular endothelial growth factor receptors (VEGFR). The US Food and Drug Administration (FDA) has approved several VEGFR-targeting TKIs for these patients, such as sorafenib, lenvatinib, and cabozantinib. These are oral medications, and patients may take them sequentially over several years to control this cancer, which is often slow-growing.

Nearly half of patients with this type of thyroid cancer harbor a mutation in BRAF V600E—and several studies have shown that BRAF-targeted therapies are effective for these patients. In June 2022, the FDA approved the combination of dabrafenib and trametinib for treating people with most types of advanced solid tumors with a BRAF V600E mutation.

To date, there have been no studies comparing BRAF-targeted therapy to MKIs for RAI-refractory DTC. How to optimally sequence these agents is an unanswered question that doctors commonly encounter in clinical practice. Further, patients with RAI-refractory DTC can be on treatment for years with oral therapies that cause significant toxicities. A better understanding of the relative efficacy, response durability, and long-term tolerability of these medicines is essential to improving quality of life and outcomes.

The EA3231 trial is a phase 3 study for patients with BRAF-mutant RAI-refractory DTC whose cancer has progressed on VEGFR-targeting TKI therapy. Patients will be randomized to receive either dabrafenib–trametinib or cabozantinib, both of which are FDA-approved. Treatment will continue until disease progression or intolerable toxicity. Crossover is allowed at the time of progression.

The study’s primary objective is to compare progression-free survival between the two groups. Secondary objectives are to compare the objective response rate, duration of response, overall survival, time to second disease progression, as well as safety and tolerability.

To be eligible for the study, patients must have differentiated thyroid cancer with a BRAF V600E mutation as determined by local testing. They must have been previously treated with—or deemed ineligible for treatment with—Iodine-131 and must be receiving thyroxine suppression therapy. Additionally, patients must have had prior treatment with at least one VEGFR-targeting TKI. Up to two prior VEGFR-targeting TKIs are allowed, including but not limited to lenvatinib and sorafenib.

Learn more about EA3231 at ecog-acrin.org.