Background: Patients with papillary and follicular thyroid cancer (PTC and FTC) who are refractory to radioactive iodine treatment (RAIR) have poor prognosis. Frequently these patients are found to have BRAF V600E and NRAS Q61R mutations, which can be targeted using BRAF and MEK inhibitors to promote redifferentiation of thyroid cancer (TC) cells to take up RAI. The aim of this study is to define clinical, pathological, and molecular characteristics associated with response to redifferentiation therapy. Methods: NGS was performed to identify targetable mutations. The protocol consisted of 6 weeks of either dual therapy Trametinib and Dabrafenib (BRAF V600E) or Trametinib alone (NRAS Q61R) followed by dosimetry and therapeutic RAI administration. Interim imaging and biochemical analysis were performed at 3 months and 6 months. Statistical analysis was performed using the Kaplan-Meier survival analysis to estimate the mean time to progression from the protocol finish date. Patients who did not progress were censored at the last date of their clinic visit or at 192 days. Exploratory analysis was conducted to look at the change in trends in thyroglobulin (TG) values. Results: 16 patients met eligibility criteria. Previous RAI dosage ranged from 83mCi to 700mCi of Iodine 131 (I-131). 5 patients were African American, and 1 was Hispanic. Upon molecular analysis, 11 patients were found to have BRAF V600E mutation, 4 patients had NRAS Q61R mutation, and 1 was not identified. All but one patient had RAI uptake and received a dosage of 140 – 357 mCi of I-131 after dosimetry scan calculation. Upon interim analysis, 3 patients progressed at 3 months and an additional 3 patients progressed at 192 days. At 192 days, the mean time to progression from protocol finish date was 170 days (SD=9.7). Interim TG level analysis and images analysis are reflected in the table. There were other mutations identified: 11 patients were PDL1 negative, 5 PDL1 positive with range of 1-50%, 8 with TERT mutation, 4 with TP53, 2 with CHEK 2, other mutations were DNMT3A, FGFR3, BLM, EGFR, GNAS, ARID1, PDGFRA, NFE2L2, ARID2, Exon 17, POT1 Exon 14, and NTRK, were only present in one patient each. Conclusions: All but one patient with RAIR TC with BRAF V600E or NRASQ61R mutation who have undergone redifferentiation protocol have increased uptake of RAI after 6 weeks of targeted therapy with excellent response on interim analysis. Our study is ongoing to further define clinical, pathological, and molecular characteristics that help select patients with advanced TC who benefit most from redifferentiation treatment. Clinical trial information: 00005381.