Selective RET Inhibitor Selpercatinib Demonstrated Favorable Clinical Outcome over Cabozantinib or Vandetanib in RET-mutant Medullary Thyroid Cancer

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Medullary thyroid cancer (MTC) is a rare neuroendocrine malignancy originating from parafollicular C cells that secrete calcitonin, constituting 2-4% of all thyroid malignancies. MTCs are categorized as either sporadic (75%) or hereditary (25%). Germline RET mutations are the cause and are detected in 100% of hereditary MTC cases. Sporadic MTC exhibit RET mutations in 25%-50% of cases, rising to nearly 90% in advanced and metastatic MTC. Selpercatinib is a selective RET tyrosine kinase inhibitor (TKI) that was approved by US FDA in 2020 for treating advanced or metastatic RET-mutant MTC in adults and pediatric patients aged ≥12. As alternative options for treating RET-mutant MTC, multikinase inhibitors cabozantinib and vandetanib were established as first-line therapy for advanced MTC based on results from two phase 3 studies, EXAM and ZETA, respectively. The LIBRETTO-531 trial aimed to determine the optimal first-line regimen for RET-mutant MTC. The trial enrolled RET-mutant MTC identified through NGS or PCR  randomizing them 2:1 into the selpercatinib arm and physician’s choice arm (cabozantinib or vandetanib) for a head-to-head comparison. LIBRETTO-531 successfully achieved its primary endpoint, demonstrating a statistically significant improvement in progression-free survival (PFS) assessed by BICR. The median PFS (mPFS) was not estimable (NE) in the selpercatinib arm and 16.8 month in the control arm, yielding a hazard ratio (HR) of 0.280, p < 0.001. Consistently favorable PFS benefits with selpercatinib were observed across all subgroups. The overall response rate (ORR) favored selpercatinib at 69.4% compared to 38.8%. In conclusion, selpercatinib, a selective RET inhibitor, has demonstrated superiority to multikinase inhibitors in the first-line setting for RET-mutant MTC.

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Citation: Julien Hadoux presented at 2023 ESMO, LBA3. Gild et al. Endocr Rev. 2023 Sep 15;44(5):934-946. Dabelić et al., Acta Clin Croat. 2020 Jun;59(Suppl 1):50-59.

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