Advances in Therapy

, Volume 29, Issue 11, pp 925–934

Cabozantinib for the Treatment of Advanced Medullary Thyroid Cancer

  • Madhavi Nagilla
  • Rebecca L. Brown
  • Ezra E. W. Cohen
Review

Abstract

Introduction

Patients with advanced medullary thyroid cancer (MTC) have poor prognoses and limited treatment options. Improved knowledge about molecular aberrations associated with MTC and the availability of novel targeted tyrosine kinase inhibitors (TKIs) have led to new potential treatment modalities. Cabozantinib is an oral multitargeted TKI with activity against multiple receptors including RET, vascular endothelial growth factor receptor type 2 (VEGFR2), and MET that has been evaluated in MTC in the preclinical and clinical arenas.

Methods

This article reviews unmet clinical needs in advanced MTC. The authors consider novel agents that have been studied in MTC, with a focus on the investigational agent cabozantinib. Up-to-date clinical data of cabozantinib in MTC are discussed.

Results

Recent clinical evaluation suggests that cabozantinib is the first agent to prolong progression-free survival in patients with progressive MTC. These findings indicate that cabozantinib may be an effective therapy in advanced MTC. No improvement in overall survival has been demonstrated but data are not mature.

Conclusion

Cabozantinib may be an effective treatment option for patients with advanced MTC and is worthy of further evaluation.

Keywords

Cabozantinib Endocrinology Medullary thyroid cancer Oncology Targeted therapy Tyrosine kinase inhibitors 

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References

  1. 1.
    Schlumberger M, Carlomagno F, Baudin E, Bidart JM, Santoro M. New therapeutic approaches to treat medullary thyroid carcinoma. Nat Clin Pract Endocrinol Metab. 2008;4:22–32.PubMedCrossRefGoogle Scholar
  2. 2.
    Fugazzola L, Muzza M, Mian C, et al. RET genotypes in sporadic medullary thyroid cancer: studies in a large Italian series. Clin Endocrinol (Oxf). 2008;69:418–425.CrossRefGoogle Scholar
  3. 3.
    Mian C, Pennelli G, Barollo S, et al. Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: a useful tool for patient risk stratification. Eur J Endocrinol. 2011;164:971–976.PubMedCrossRefGoogle Scholar
  4. 4.
    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;93:682–687.PubMedCrossRefGoogle Scholar
  5. 5.
    Moura MM, Cavaco BM, Pinto AE, Leite V. High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab. 2011;96:E863–E868.PubMedCrossRefGoogle Scholar
  6. 6.
    Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29:2660–2666.PubMedCrossRefGoogle Scholar
  7. 7.
    Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer. 2006;107:2134–2142.PubMedCrossRefGoogle Scholar
  8. 8.
    Brierley J, Sherman E. The role of external beam radiation and targeted therapy in thyroid cancer. Semin Radiat Oncol. 2012;22:254–262.PubMedCrossRefGoogle Scholar
  9. 9.
    Brierley J, Tsang R, Simpson WJ, Gospodarowicz M, Sutcliffe S, Panzarella T. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid. 1996;6:305–310.PubMedCrossRefGoogle Scholar
  10. 10.
    Fife KM, Bower M, Harmer CL. Medullary thyroid cancer: The role of radiotherapy in local control. Eur J Surg Oncol. 1996;22:588–591.PubMedCrossRefGoogle Scholar
  11. 11.
    Martinez SR, Beal SH, Chen A, Chen SL, Schneider PD. Adjuvant external beam radiation for medullary thyroid carcinoma. J Surg Oncol. 2010;102:175–178.PubMedCrossRefGoogle Scholar
  12. 12.
    Lessin LS. Medullary carcinoma of the thyroid; chemotherapy. In: Wartofsky L, Van Nostrand D, eds. Thyroid Cancer: A Comprehensive Guide to Clinical Management. Totowa, NJ: Humana Press; 2006:609–611.Google Scholar
  13. 13.
    Mahler C, Verhelst J, de Longueville M, Harris A. Long-term treatment of metastatic medullary thyroid carcinoma with the somatostatin analogue octreotide. Clin Endocrinol (Oxf). 1990;33:261–269.CrossRefGoogle Scholar
  14. 14.
    Vitale G, Tagliaferri P, Caraglia M, et al. Slow release lanreotide in combination with interferon-alpha2b in the treatment of symptomatic advanced medullary thyroid carcinoma. J Clin Endocrinol Metab. 2000;85:983–988.PubMedCrossRefGoogle Scholar
  15. 15.
    Frank-Raue K, Fabel M, Delorme S, Haberkorn U, Raue F. Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma. Eur J Endocrinol. 2007;157:215–220.PubMedCrossRefGoogle Scholar
  16. 16.
    de Groot JW, Zonnenberg BA, van Ufford-Mannesse PQ, et al. A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92:3466–3469.PubMedCrossRefGoogle Scholar
  17. 17.
    Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009;27:3794–3801.PubMedCrossRefGoogle Scholar
  18. 18.
    Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol. 2010;28:2323–2330.PubMedCrossRefGoogle Scholar
  19. 19.
    De Souza JA, Busaidy N, Zimrin A, et al. Phase II trial of sunitinib in medullary thyroid cancer (MTC) [abstract]. J Clin Oncol. 2010;28(Suppl.). Abstract 5504.Google Scholar
  20. 20.
    Cohen EE, Rosen LS, Vokes EE, et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol. 2008;26:4708–4713.PubMedCrossRefGoogle Scholar
  21. 21.
    Wells SA, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010;28:767–772.PubMedCrossRefGoogle Scholar
  22. 22.
    Wells SA, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, doubleblind phase III trial. J Clin Oncol. 2012;30:134–141.PubMedCrossRefGoogle Scholar
  23. 23.
    Robinson BG, Paz-Ares L, Krebs A, Vasselli J, Haddad R. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2010;95:2664–2671.PubMedCrossRefGoogle Scholar
  24. 24.
    Schoffski P, Elisei R, Müller S, et al.; EXAM Study Group. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline [abstract]. J Clin Oncol. 2012;30:(Suppl.). Abstract 5508.Google Scholar
  25. 25.
    de Groot JW, Zonnenberg BA, Plukker JT, van Der Graaf WT, Links TP. Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther. 2005;78:433–438.PubMedCrossRefGoogle Scholar
  26. 26.
    Wells SA, Gosnell JE, Gagel RF, et al. Vandetanib in metastatic hereditary medullary thyroid cancer: Follow-up results of an open-label phase II trial [abstract]. J Clin Oncol. 2007;25:(Suppl.). Abstract 6018.Google Scholar
  27. 27.
    Vandetanib REMS Program. AstraZeneca Pharmaceuticals LP, 2001.Google Scholar
  28. 28.
    Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298–2308.PubMedCrossRefGoogle Scholar
  29. 29.
    Runeberg-Roos P, Saarma M. Neurotrophic factor receptor RET: structure, cell biology, and inherited diseases. Ann Med. 2007;39:572–580.PubMedCrossRefGoogle Scholar
  30. 30.
    Capp C, Wajner SM, Siqueira DR, Brasil BA, Meurer L, Maia AL. Increased expression of vascular endothelial growth factor and its receptors, VEGFR-1 and VEGFR-2, in medullary thyroid carcinoma. Thyroid. 2010;20:863–871.PubMedCrossRefGoogle Scholar
  31. 31.
    Bunone G, Vigneri P, Mariani L, et al. Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. Am J Pathol. 1999;155:1967–1976.PubMedCrossRefGoogle Scholar
  32. 32.
    de la Torre NG, Buley I, Wass JA, Turner HE. Angiogenesis and lymphangiogenesis in thyroid proliferative lesions: relationship to type and tumour behaviour. Endocr Relat Cancer. 2006;13:931–944.PubMedCrossRefGoogle Scholar
  33. 33.
    Joao Bugalho M, Madureira D, Espadinha C, Paula Font A, Sobrinho LG. Serum vascular endothelial growth factor levels in patients with medullary thyroid carcinoma. Eur J Endocrinol. 2008;159:167–169.PubMedCrossRefGoogle Scholar
  34. 34.
    Feng Y, Thiagarajan PS, Ma PC. MET signaling: novel targeted inhibition and its clinical development in lung cancer. J Thorac Oncol. 2012;7:459–467.PubMedCrossRefGoogle Scholar
  35. 35.
    Papotti M, Olivero M, Volante M, et al. Expression of hepatocyte growth factor (HGF) and its receptor (MET) in medullary carcinoma of the thyroid. Endocr Pathol. 2000;11:19–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Joly AH. Simultaneous blockade of VEGF and HGF receptors results in potent anti-angiogenic and anti-tumor effects. Eur J Cancer Supplements. 2006;4:35.CrossRefGoogle Scholar
  37. 37.
    Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012;2:270–287.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Healthcare 2012

Authors and Affiliations

  • Madhavi Nagilla
    • 1
  • Rebecca L. Brown
    • 1
  • Ezra E. W. Cohen
    • 1
  1. 1.Section of Endocrinology, Diabetes and Metabolism, Department of MedicineUniversity of ChicagoChicagoUSA

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