Real-world clinical responses to selpercatinib in RET M918T-mutant medullary thyroid carcinoma.

BACKGROUND: RET alterations, especially the M918T mutation, contribute to the development of aggressive medullary thyroid carcinoma (MTC). Selective RET inhibition has shown greater efficacy compared to VEGFR-targeting multikinase inhibitors (MKIs). Nevertheless, evidence from real-world settings, particularly involving patients with extensive metastatic burden, concurrent genomic alterations, or disease progression despite MKI therapy, remains scarce. This case series details three patients with metastatic RET-mutant medullary thyroid carcinoma (MTC), all of whom were treated with selpercatinib, including one patient who experienced disease progression on cabozantinib prior to transitioning to selective RET inhibition. RESULTS: All three patients possessed pathogenic RET M918T mutations. Case 1 also harbored a pathogenic MUTYH variant, whereas Case 3 demonstrated additional alterations, including ARID1A truncation, as well as deletions in MLH1 and CDKN2A. Two patients were treated with selpercatinib as first-line targeted therapy and experienced swift biochemical improvements accompanied by partial radiologic regression of metastases in the liver, lung, and bones. Case 2 exhibited radiologic progression at month 3 while on cabozantinib, subsequently followed by a significant biochemical and radiologic response after transitioning to selpercatinib. Selpercatinib was well tolerated across all cases, with only moderate and transient adverse events. CONCLUSION: Selpercatinib produced rapid, durable biochemical and radiologic responses in metastatic RET-mutant MTC, including in a patient with clear progression on VEGFR-directed therapy. These findings support selective RET inhibition as an effective and well-tolerated treatment strategy and emphasize the importance of routine genomic profiling to guide precision therapy in advanced MTC.