Short-Course Dabrafenib With Trametinib Restores Radioiodine Uptake in Thyroid Cancer

In a multicentre phase II trial, investigators evaluated whether short-course dabrafenib plus trametinib could restore iodine avidity and deliver clinical benefit in patients with progressive metastatic radioiodine-refractory thyroid carcinoma carrying BRAFV600E or RAS mutations. MAPK pathway activation suppresses sodium-iodide symporter (NIS) and other iodine-handling genes, and prior trials relied on empiric 4- to 6-week treatment durations because the optimal timing of maximal NIS re-expression remained undefined.

Patients underwent I-124 PET/CT dosimetry at baseline and at 2 weeks, with repeat imaging at 4 weeks if criteria were not met. Radioiodine was administered once patients met the primary endpoint of a predicted lesional absorbed dose of ≥20 Gy with an I-131 activity of ≤300 mCi.

Overall, 9 of 14 patients (64%) met dosimetry criteria and received radioiodine, with 6 out of 9 (67%) restoring iodine uptake within 2 weeks. For those treated with radioiodine, the best objective response rate within 6 months was 75% according to RECIST, and median progression-free survival was 10.8 months. RAS-mutant tumours demonstrated greater lesion regression than BRAFV600E-mutant tumours. Additionally, early reduction in stimulated thyroglobulin, preserved FOXE1 nuclear localisation, and higher tumour-to-normal GLIS3 nuclear expression were associated with re-differentiation response. The authors conclude that short-course dabrafenib and trametinib can induce rapid re-differentiation within 2 weeks in a subset of patients, supporting an individualized duration of BRAF/MEK inhibition rather than empiric prolonged therapy.