Targeted Molecular Therapy

  • Arabella Hunt
  • Kate L. NewboldEmail author


The treatment of advanced thyroid cancer has developed with increased understanding of the molecular basis of the disease. Alongside this targeted therapies have been developed, and there is evidence of efficacy for multikinase inhibitors in improving progression-free survival in this population of patients. An impact on overall survival, however, has yet to be proven. The design and results of the four published phase III randomised controlled trials leading to the licensing of vandetanib, cabozantinib, sorafenib and lenvatinib in advanced thyroid cancer are discussed. Identification of predictive biomarkers including histopathological, molecular and demographic factors may guide the most effective treatment selection for individual patients in the future and remains an area of active research. Continued enrolment of patients into clinical trials is therefore strongly encouraged to further improve the outcomes for patients with advanced thyroid cancer.


Advanced thyroid cancer Kinase inhibitors Vandetanib Cabozantinib Sorafenib Lenvatinib 


  1. 1.
    Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13(3):184–99.CrossRefPubMedCentralGoogle Scholar
  2. 2.
    Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005;12(2):245–62.CrossRefPubMedCentralGoogle Scholar
  3. 3.
    Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, et al. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab. 2008;93(8):3106–16.CrossRefPubMedCentralGoogle Scholar
  4. 4.
    Liu Z, Liu D, Bojdani E, El-Naggar AK, Vasko V, Xing M. IQGAP1 plays an important role in the invasiveness of thyroid cancer. Clin Cancer. 2010;16(24):6009–18.CrossRefGoogle Scholar
  5. 5.
    Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science (New York). 2000;289(5483):1357–60.CrossRefGoogle Scholar
  6. 6.
    Spitzweg C, Morris JC, Bible KC. New drugs for medullary thyroid cancer: new promises? Endocr Relat Cancer. 2016;23(6):R287–97.CrossRefPubMedCentralGoogle Scholar
  7. 7.
    Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567–610.CrossRefPubMedCentralGoogle Scholar
  8. 8.
    Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Chester R, Jackson JA, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 2002;62(16):4645–55.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, 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.CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Leboulleux S, Bastholt L, Krause T, de la Fouchardiere C, Tennvall J, Awada A, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13(9):897–905.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–308.CrossRefPubMedCentralGoogle Scholar
  12. 12.
    Elisei R, Schlumberger MJ, Muller SP, Schoffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639–46.CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–109.CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384(9940):319–28.CrossRefPubMedCentralGoogle Scholar
  15. 15.
    Yamamoto Y, Matsui J, Matsushima T, Obaishi H, Miyazaki K, Nakamura K, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vascular Cell. 2014;6:18.CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621–30.CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Haddad RI, Schlumberger M, Wirth LJ, Sherman EJ, Shah MH, Robinson B, et al. Incidence and timing of common adverse events in Lenvatinib-treated patients from the SELECT trial and their association with survival outcomes. Endocrine. 2017.Google Scholar
  18. 18.
    Schlumberger M, Jarzab B, Cabanillas ME, Robinson B, Pacini F, Ball DW, et al. A phase II trial of the multitargeted tyrosine kinase inhibitor Lenvatinib (E7080) in advanced medullary thyroid cancer. Clin Cancer Res. 2016;22(1):44–53.CrossRefPubMedCentralGoogle Scholar
  19. 19.
    Tahara M, Kiyota N, Yamazaki T, Chayahara N, Nakano K, Inagaki L, et al. Lenvatinib for anaplastic thyroid cancer. Front Oncol. 2017;7:25.CrossRefPubMedCentralGoogle Scholar
  20. 20.
    Valerio L, Pieruzzi L, Giani C, Agate L, Bottici V, Lorusso L, et al. Targeted therapy in thyroid cancer: state of the art. Clin Oncol (R Coll Radiol). 2017;29(5):316–24.CrossRefGoogle Scholar
  21. 21.
    Schmidt A, Iglesias L, Klain M, Pitoia F, Schlumberger MJ. Radioactive iodine-refractory differentiated thyroid cancer: an uncommon but challenging situation. Arch Endocrinol Metab. 2017;61(1):81–9.CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Grande E, Kreissl MC, Filetti S, Newbold K, Reinisch W, Robert C, et al. Vandetanib in advanced medullary thyroid cancer: review of adverse event management strategies. Adv Ther. 2013;30(11):945–66.CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Hayes DN, Lucas AS, Tanvetyanon T, Krzyzanowska MK, Chung CH, Murphy BA, et al. Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res. 2012;18(7):2056–65.CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Chakravarty D, Santos E, Ryder M, Knauf JA, Liao XH, West BL, et al. Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. J Clin Invest. 2011;121(12):4700–11.CrossRefPubMedCentralGoogle Scholar
  25. 25.
    Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368(7):623–32.CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Thyroid UnitThe Royal Marsden NHS Foundation TrustSurreyUK

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