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Standard treatment for unresectable papillary thyroid carcinoma (PTC) is a multi-kinase inhibitor, including lenvatinib and sorafenib. Rearranged during transfection ( RET ) fusions are found in approximately 10% of PTC. Here, we present a case of metastatic RET fusion-positive PTC with long-term disease control by selective RET inhibition. A 72-year-old woman with PTC and multiple lymph nodes and lung metastases progressed after initial lenvatinib and subsequent sorafenib treatment. Reintroduction of lenvatinib led to marked tumour shrinkage. During the rechallenge with lenvatinib, molecular screening of the tumour specimen revealed a CCDC6-RET gene fusion. The patient was enrolled in a phase 1/2 trial of the potent and specific RET inhibitor selpercatinib. All target and non-target lesions responded to selpercatinib in parallel with a remarkable decrease in serum thyroglobulin levels. Although a new lesion appeared in the right adrenal gland 14 months after the initiation of selpercatinib, ongoing stable disease was observed in all lesions over 28 months, including the new adrenal lesion. Adverse events included grade 3 fatigue, grade 2 anorexia, and grade 4 thrombocytopaenia but were easily manageable by suspension and dose reduction of selpercatinib. Selective kinase inhibition with selpercatinib provides RET fusion-positive PTC with clinical benefits, even in patients heavily pre-treated with multi-kinase inhibitors. This case supports the importance of routine molecular profiling in patients with PTC to identify uncommon but actionable gene alterations, such as RET gene fusions.

Durable Disease Control by RET Inhibitor Selpercatinib in a Heavily Pre-Treated RET Fusion-Positive Papillary Thyroid Cancer