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

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. 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. 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.