Durable Response to Redifferentiation in a Patient With Metastatic <i>NCOA4::RET</i> Fusion-driven Papillary Thyroid Cancer

Redifferentiation therapy (RDT) is a promising strategy for follicular cell-derived thyroid cancer (TC) in the era of personalized oncology. Limited data are available on long-term clinical outcomes of RDT in patients with fusion-driven TC. A 22-year-old female with recurrent radioactive iodine (RAI)-refractory metastatic progressive, <i>NCOA4::RET</i> fusion-driven papillary TC was treated with selective <i>RET</i> inhibitor, selpercatinib, for 3 months before a therapeutic dose of RAI 146 mCi (5402 MBq). The posttherapy scan showed enhancement of RAI avidity of previously mildly avid pulmonary metastases. After RDT, the thyroglobulin levels significantly declined, and pulmonary nodules completely resolved on chest computed tomography scan. At 24 months of follow-up, the patient did not have evidence of progression. Moreover, thyroglobulin levels continued to decline. RDT with selpercatinib enhanced RAI uptake in the lungs, with a persistent structural and biochemical response sustained 24 months after RAI therapy and discontinuation of selpercatinib. Clinical trials are warranted further to investigate RDT with selective inhibitors in oncogene fusion-driven TC.