Response to RET-Specific Therapy in RET Fusion-Positive Anaplastic Thyroid Carcinoma

Background: Anaplastic thyroid carcinoma (ATC) remains one of the most challenging malignancies to treat in the modern era. Most patients present with or develop recurrent/metastatic incurable disease with poor response rates to conventional chemotherapy, and life expectancy is short. Next-generation sequencing (NGS) can be leveraged in ATC to identify oncogenic alterations that can be targeted with molecularly specific therapy, offering new effective treatment options to a subset of patients. Patient Findings: A 73-year-old man presenting with locally advanced papillary thyroid carcinoma containing a minor component of ATC was treated with surgery and iodine-131. He developed biopsy-confirmed ATC distant metastases that progressed on cytotoxic chemotherapy. NGS revealed several alterations, including a CCDC6-RET gene fusion. The patient enrolled in LIBRETTO-001, a phase I/II trial of the potent and specific RET inhibitor, LOXO-292. The patient tolerated LOXO-292 well and experienced a deep and durable partial response, ongoing beyond 19 months. Conclusion: This clinically significant response achieved with LOXO-292 in a patient with a CCDC6-RET fusion-positive ATC who had exhausted conventional treatment options highlights the importance of conducting tumor genomic profiling in patients with ATC to identify uncommon but actionable genomic alterations, such as RET gene fusions.