Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Previously Treated Patients With Metastatic, Radio-active Iodine Refractory BRAF V600E Mutation Positive Differentiated Thyroid Cancer

This is a global, multicenter, randomized, double-blind, placebo-controlled Phase III study designed to evaluate the efficacy and safety of dabrafenib plus trametinib in adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC) that is positive for the BRAF V600E mutation, refractory to radioactive iodine (RAI), and has progressed following prior vascular endothelial growth factor receptor (VEGFR) targeted therapy.

After eligibility assessment, patients will be randomized in a 2:1 ratio to receive either dabrafenib plus trametinib or placebo. Patients will be stratified by the number of prior VEGFR targeted therapies (one versus two) and prior lenvatinib treatment (yes versus no).

The scientific objective guiding the primary estimand is based on progression-free survival (PFS) as per blinded independent review committee (BIRC) assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

This study will enroll approximately 150 patients.

Patients randomized to the placebo arm who experience disease progression as per RECIST 1.1 confirmed by BIRC and meet eligibility criteria will have the option to cross over to the open-label combination of dabrafenib plus trametinib.

Treatment may continue beyond RECIST 1.1 disease progression (confirmed by BIRC) if, in the investigator's judgment, there is evidence of clinical benefit and the patient wishes to remain on study treatment. In cases where there is a discrepancy between local site determination and BIRC (for example, disease progression determined locally but not by BIRC), the patient should not be discontinued from study treatment until progression is confirmed by BIRC or, at a minimum, until one additional tumor assessment has been completed, provided this is clinically acceptable.

After treatment discontinuation, all patients will be followed for safety and efficacy evaluations during the post-treatment follow-up period. Subsequently, patient status will be collected every 12 weeks as part of survival follow-up.

This study is ongoing, and enrollment was completed on 09-May-2024. The primary analysis was performed after all patients had either completed at least 16 weeks of treatment or discontinued early, and after approximately 95 PFS events had occurred.

Key Inclusion Criteria:

• Signed informed consent
• Male or female ≥ 18 years of age at time of informed consent
• Histologically or cytologically confirmed diagnosis of advanced/metastatic differentiated thyroid carcinoma
• Radioactive-iodine refractory disease
• BRAF V600E mutation-positive tumor sample as per central laboratory result
• Has progressed on at least 1 but not more than 2 prior VEGFR targeted therapies
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• At least one measurable lesion as defined by RECIST v1.1.

Key Exclusion Criteria:

• Anaplastic or medullary carcinoma of the thyroid
• Previous treatment with a BRAF inhibitor and/or a MEK inhibitor
• Concomitant RET Fusion-Positive Thyroid Cancer
• Treatment with any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before randomization
• Treatment with any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 4 weeks before randomization
• Treatment with radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before randomization
• A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy

Other inclusion/exclusion criteria may apply.