Selpercatinib – a new option for a precision approach to the treatment of medullary thyroid cancer

Introduction. Multikinase inhibitors are used to treat nonresectable locally advanced and/or metastatic medullary thyroid cancer (MTC). However  they are characterized by high toxicity associated with kinase inhibition. Selective RET inhibitor selpercatinib demonstrates high selectivity and tolerance which makes it a promising agent for MTC treatment.

Aim. To evaluate selpercatinib effectiveness and tolerance in patients with metastatic MTC associated with a mutation in the RET gene.

Materials and methods. The study included 9 patients with metastatic MTC and mutation in the RET gene who received treatment with selpercatinib 160 mg 2 times a day. The drug effectiveness was evaluated every 2–3 months based on the results of multispiral computed tomography of the whole body and tumor marker (calcitonin and carcinoembryonic antigen) levels.

Results. Median duration of therapy was 29 months  overall response rate was 78 %; complete response was observed in 56 % of patients. After 12 months of therapy  progression-free survival was 100 %; after 24 months  it was 89 %. Persistent decrease in calcitonin level (by more than 90 %) was achieved in all patients. The most common adverse events were arterial hypertension and insignificant creatinine increase.

Conclusion. The results of therapy show significant improvement in the rate of objective response and progression[1]free survival which makes selpercatinib a preferential treatment choice in this category of patients.

1. Wells S.A., Asa S.L., Dralle H. et al. American Thyroid Association guidelines task force on medullary thyroid carcinoma. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015;25(6):567–610. DOI: 10.1089/thy.2014.0335

2. Elisei R., Cosci B., Romei C. et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab 2008;93(3):682–7. DOI: 10.1210/jc.2007-1714

3. Mulligan L.M. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer 2014;14(3):173–86. DOI: 10.1038/nrc3680

4. Ciampi R., Romei C., Ramone T. et al. Genetic landscape of somatic mutations in a large cohort of sporadic medullary thyroid carcinomas studied by next-generation targeted sequencing. iScience 2019;20:324–36. DOI: 10.1016/j.isci.2019.09.030

5. Romei C., Casella F., Tacito A. et al. New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with double RET mutations. J Med Genet 2016;53(11):729–34. DOI: 10.1136/jmedgenet-2016-103833

6. Wells S.A., Robinson B.G., Gagel R.F. et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012;30(2):134–41. DOI: 10.1200/JCO.2011.35.5040

7. Elisei R., Schlumberger M.J., Müller S.P. et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 2013;31(29):3639–46. DOI: 10.1200/ JCO.2012.48.4659

8. Северская Н.В., Чойнзонов Е.Л., Решетов И.В. и др. Проект клинических рекомендаций по диагностике и лечению медуллярного рака щитовидной железы. Эндокринная хирургия 2022;16(3):5–23. DOI: 10.14341/serg12794

9. Brose M.S., Bible K.C., Chow L.Q.M. et al. Treatment of toxic side effects in patients with advanced medullary thyroid cancer. Opukholi golovy i shei = Head and Neck Tumors 2019;9(1):51–67. (In Russ.). DOI: 10.17650/2222-1468-2019-9-1-51-67

10. Liu X., Shen T., Mooers B.H.M. et al. Drug resistance profiles of mutations in the RET kinase domain. Br J Pharmacol 2018;175(17):3504–15. DOI: 10.1111/bph.14395

11. Hadoux J., Elisei R., M.S. Brose et al. Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer. New En J Med 2023;389(20):1851–61. DOI: 10.1056/NEJMoa2309719

12. Schlumberger M., Elisei R., Müller S. et al. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol 2017;28(11):2813–9. DOI: 10.1093/annonc/mdx479

13. Chougnet C.N., Borget I., Leboulleux S. et al. Vandetanib for the treatment of advanced medullary thyroid cancer outside a clinical trial: results from a French cohort. Thyroid 2015;25(4):386–91. DOI: 10.1089/thy.2014.0361

14. Wirth L.J., Sherman E., Robinson B. et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med 2020;383(9):825–35. DOI: 10.1056/NEJMoa2005651