Kinetics of Re-differentiation with Short-Course Dabrafenib and Trametinib in Patients with Radioiodine-Refractory Thyroid Cancer

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Abstract
Purpose: MAPK pathway activation suppresses iodine-handling genes, including sodium-iodide symporter (NIS), contributing to loss of iodine avidity in radioiodine-refractory thyroid cancer. Prior BRAF/ MEK inhibitor re-differentiation trials improved iodine uptake but used empiric 4–6 week treatment. The timing of maximal NIS re-expression remains undefined. We evaluated whether short course dabrafenib plus trametinib restores iodine uptake and provides clinical benefit. Patients and Methods: In this multicentre phase II trial, patients with progressive metastatic radioiodine-refractory thyroid carcinoma harbouring BRAFV600E or RAS mutations received dabrafenib and trametinib. I-124 PET/CT dosimetry was performed at baseline and after 2 weeks, with repeat imaging at week 4 post therapy if dosimetry criteria was not met. Radioiodine was administered once criteria was met. The primary endpoint was attainment of predicted lesional absorbed dose ≥20 Gy with I-131 activity ≤300 mCi. Secondary endpoints included RECIST response, progression-free survival (PFS), thyroglobulin response, and safety. Results: Nine of 14 patients (64%) met the dosimetry criteria and received radioiodine; 6 out of 9 (67%) restored iodine uptake within 2 weeks. Among radioiodine-treated patients, best objective response rate within 6 months was 75% by RECIST. Median PFS was 10.8 months. RAS-mutant tumours demonstrated greater lesion regression than BRAFV600E-mutant tumours. Early reduction in stimulated thyroglobulin and preserved FOXE1 nuclear localisation, and higher tumour-to-normal GLIS3 nuclear expression were associated with re-differentiation response. Conclusions: Short-course dabrafenib/ trametinib can induce rapid re-differentiation within 2 weeks in a subset of patients with MAPK-driven radioiodine-refractory thyroid cancer, supporting individualized BRAF/MEK inhibition duration rather than empiric prolonged treatment.