Skip to main content
SpringerLink
Log in

Vandetanib

In Medullary Thyroid Cancer

  • Adis Drug Profile
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Vandetanib, an orally active, small-molecule, multi-targeted tyrosine kinase inhibitor, demonstrates potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR)-2 and -3, epidermal growth factor receptor (EGFR) and the rearranged during transfection (RET) tyrosine kinase receptor.

The large (n= 331), randomized, double-blind, multinational ZETA trial compared vandetanib at a dosage of 300 mg once daily with placebo in patients with un-resectable, locally advanced or metastatic, hereditary or sporadic, medullary thyroid cancer. During a median follow-up period of 2 years, vandetanib demonstrated statistically significant clinical benefits over placebo with respect to the primary endpoint, namely progression-free survival (PFS), and a range of secondary endpoints, which included objective response rate, disease control rate, time to worsening of pain and calcitonin biochemical response rate. The PFS benefit with vandetanib was mostly consistent across patient subgroups based on baseline characteristics and disease status.

Although the correlation between RET mutation status and clinical outcome could not be clearly evaluated in this trial, it is notable that, among patients with sporadic disease, vandetanib not only demonstrated a PFS benefit in the subgroup confirmed as having a RET mutation, but also in the subgroup for whom the RET mutation status was unknown.

Vandetanib was generally well tolerated in the ZETA trial; the majority of adverse events were manageable according to standard clinical practice alone or in combination with vandetanib dose reductions. The adverse event of most concern is corrected QT interval prolongation, particularly in view of the long terminal elimination half-life of the drug.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV
Table V
Table VI
Fig. 1
Table VII

Similar content being viewed by others

References

  1. Sharma PK. Thyroid cancer [online]. Available from URL: http://emedicine.medscape.com/article/851965-overview [Accessed 2012 Feb 23]

  2. Cancer Research UK. Thyroid cancer: UK incidence statistics [online]. Available from URL: http://info.cancerresearchuk.org/cancerstats/types/thyroid/incidence/uk-thyroid-cancer-incidence-statistics [Accessed 2012 Feb 22]

  3. Pitt SC, Moley JF. Medullary, anaplastic, and metastatic cancers of the thyroid. Semin Oncol 2010 Dec; 37 (6): 567–79

    Article  PubMed  Google Scholar 

  4. Houvras Y. Completing the arc: targeted inhibition of RET in medullary thyroid cancer. J Clin Oncol 2012 Jan 10; 30 (2): 200–2

    Article  PubMed  CAS  Google Scholar 

  5. Ball DW. Medullary thyroid cancer: therapeutic targets and molecular markers. Curr Opin Oncol 2007 Jan; 19 (1): 18–23

    Article  PubMed  CAS  Google Scholar 

  6. Quale FJ, Moley JF. Medullary thyroid carcinoma: management of lymph node metastases. Curr Treat Options Oncol 2005; 6 (4): 347–54

    Article  Google Scholar 

  7. Gomez K, Varghese J, Jimenez C, et al. MTC: molecular signaling pathways and emerging therapies. J Thyroid Res 2011; 815-26

  8. Moley J. Medullary thyroid carcinoma: management of lymph node metastases. J Natl Compr Canc Netw 2010; 8: 549–56

    PubMed  Google Scholar 

  9. Sippel RS, Kunnimalaiyaan M, Chen H. Current management of medullary thyroid cancer. Oncologist 2008; 13: 539–47

    Article  PubMed  Google Scholar 

  10. Rodríquez-Antona C, Pallares J, Montero-Conde C, et al. Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis. Endocr Relat Cancer 2010; 17: 7–16

    Article  Google Scholar 

  11. Hu MI. Updates in the management of medullary thyroid cancer. Clin Adv Hematol Oncol 2011 May; 9 (5): 391–4

    PubMed  Google Scholar 

  12. Wu LS, Roman SA, Sosa JA. Medullary thyroid cancer: an update of new guidelines and recent developments. Curr Opin Oncol 2011 Jan; 23 (1): 22–7

    Article  PubMed  Google Scholar 

  13. Schlumberger M, Carlomagno F, Baudin E, et al. New therapeutic approaches to treat medullary thyroid cancer. Nat Clin Pract Endocrinol Metab 2007; 4 (1): 22–32

    Article  Google Scholar 

  14. Orlandi F, Caraci P, Mussa A, et al. Treatment of medullary thyroid carcinoma: an update. Endocr Relat Cancer 2001; 8: 135–47

    Article  PubMed  CAS  Google Scholar 

  15. American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Assocation. Thyroid 2009 Jun; 19 (6): 565–612

    Article  PubMed  Google Scholar 

  16. Gild ML, Bullock M, Robinson BG, et al. Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nat Rev Endocrinol 2011 Oct; 7 (10): 617–24

    Article  PubMed  CAS  Google Scholar 

  17. Antonelli A, Fallahi P, Ferrari SM, et al. RET TKI: potential role in thyroid cancers. Curr Oncol Rep 2012 Jan 28

  18. Commander H, Whiteside G, Perry C. Vandetanib: first global approval. Drugs 2011; 71 (10): 1355–65

    Article  PubMed  CAS  Google Scholar 

  19. AstraZeneca AB. Caprelsa 100mg and 300mg film-coated tablets: summary of product characteristics [online]. Available from URL: http://www.medicines.org.uk [Accessed 2012 Mar 22]

  20. Caprelsa ® (vandetanib) tablets: US prescribing information [online]. Available from URL: http://www1.astrazeneca-us.com/pi/vandetanib.pdf [Accessed 2012 Feb 27]

  21. Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 2002 Aug 15; 62 (16): 4645–55

    PubMed  CAS  Google Scholar 

  22. Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 2002; 62 (24): 7284–90

    PubMed  CAS  Google Scholar 

  23. Carlomagno F, Guida T, Anaganti S, et al. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene 2004; 23 (36): 6056–63

    Article  PubMed  CAS  Google Scholar 

  24. Carlomagno F, Guida T, Anaganti S, et al. Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474. Endocr Relat Cancer 2009; 16: 233–41

    Article  PubMed  CAS  Google Scholar 

  25. Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 2003 Oct 16; 349 (16): 1517–25

    Article  PubMed  CAS  Google Scholar 

  26. Broutin S, Dupuy C, Caillou B, et al. In vitro and in vivo activity of vandetanib in a human medullary thyroid carcinoma model bearing a RET(C634W) activating mutation (abstract no. 1788). 100th Annual Meeting of the American Association for Cancer Research; 2009 Apr 18–22; Denver (CO)

  27. Vitagliano D, De Falco V, Tamburrino A, et al. The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells. Endocr Relat Cancer 2011 Feb; 18 (1): 1–11

    Article  PubMed  CAS  Google Scholar 

  28. Wu W, Isobe T, Onn A, et al. Targeted therapy against VEGF and EGF receptor signalling with ZD6474 blocks angiogenesis and inhibits the growth and dissemination of orthotopic human lung cancer in mice. Clin Cancer Res 2003; 9 (Pt. 2): 6143s

    Google Scholar 

  29. Drevs J, Konerding MA, Wolloscheck T, et al. The VEGF receptor tyrosine kinase inhibitor, ZD6474, inhibits angiogenesis and affects microvascular architecture within an orthotopically implanted renal cell carcinoma. Angiogenesis 2004; 7 (4): 347–54

    Article  PubMed  CAS  Google Scholar 

  30. McCarty MF, Whey J, Stoeltzing O, et al. ZD6474, a dual tyrosine kinase inhibitor with activity against VEGF-R and EGF-R, inhibits orthotopic growth and angiogenesis of gastric cancer. Clin Cancer Res 2003; 9 (Pt 2): 6140s

  31. Bruns CJ, Köhl G, Guba M, et al. Anti-angiogenic and antitumour activity of a novel VEGFR-2 tyrosine kinase inhibitor ZD6474 in a metastatic human pancreatic tumour model. Proc Am Soc Cancer Res (2nd ed) 2003; 44: 604

    Google Scholar 

  32. Wu W, Isobe T, Itasaka S, et al. ZD6474, a small molecule targetting VEGF and EGF receptor signaling, inhibits lung angiogenesis and metastasis and improves survival in an orthotopic model of non-small cell lung cancer. Proc Am Assoc Cancer Res 2004; 45: 1051

    Google Scholar 

  33. Arao T, Fukumoto H, Takeda M, et al. Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474. Cancer Res 2004 Dec 15; 64: 9101–4

    Article  PubMed  CAS  Google Scholar 

  34. Taguchi F, Koh Y, Koizumi F, et al. Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib (“Iressa”)-sensitive and resistant xenograft models. Cancer Sci 2004 Dec; 95 (12): 984–9

    Article  PubMed  CAS  Google Scholar 

  35. Gule MK, Chen Y, Sano D, et al. Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model. Clin Cancer Res 2011 Apr 15; 17 (8): 2281–91

    Article  PubMed  CAS  Google Scholar 

  36. Ryan AJ, Wedge SR. ZD6474: a novel inhibitor of VEGFR and EGFR tyrosine kinase activity. Br J Cancer 2005; 92 Suppl. 1: S6–13

    Article  PubMed  CAS  Google Scholar 

  37. Brassard M, Neraud B, Trabado S, et al. Endocrine effects of the tyrosine kinase inhibitor vandetanib in patients treated for thyroid cancer. J Clin Endocrinol Metab 2011; 96 (9): 2741–9

    Article  PubMed  CAS  Google Scholar 

  38. Center for Drug Evaluation and Research. Application number: 022405Orig1s000. Pharmacology review(s) [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022405Orig1s000PharmR.pdf [Accessed 2012 Feb 29]

  39. European Medicines Agency. Assessment report. Caprelsa. Vandetanib. Procedure no. EMEA/H/C/002315//0000 [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002315/WC500123603.pdf [Accessed 2012 Feb 29]

  40. Wells SA, Robinson BG, Gagel RF. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012 Jan 10; 30 (2): 134–41

    Article  PubMed  CAS  Google Scholar 

  41. Center for Drug Evaluation and Research. Application number: 022405Orig1s000. Clinical pharmacology and biopharmaceutics review(s) [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022405Orig1s000ClinPharmR.pdf [Accessed 2012 Feb 29]

  42. Martin P, Oliver S, Kennedy S-J, et al. Pharmacokinetics of vandetanib: three phase I studies in healthy subjects. Clin Ther 2012 Jan; 34 (1): 221–37

    Article  PubMed  CAS  Google Scholar 

  43. Weil A, Martin P, Smith R, et al. Pharmacokinetics of vandetanib in subjects with renal or hepatic impairment. Clin Pharmacokinet 2010 Sep 1; 49 (9): 607–18

    Article  PubMed  CAS  Google Scholar 

  44. Holden SN, Eckhardt SG, Basser R, et al. Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol 2005 Aug; 16 (8): 1391–7

    Article  PubMed  CAS  Google Scholar 

  45. Zhang L, Li S, Zhang Y, et al. Pharmacokinetics and tolerability of vandetanib in Chinese patients with solid, malignant tumors: an open-label, phase I, rising multiple-dose study. Clin Ther 2011; 33 (3): 315–27

    Article  PubMed  CAS  Google Scholar 

  46. Matin P, Oliver S, Robertson J, et al. Pharmacokinetic drug interactions with vandetanib during coadministration with rifampicin or intraconazole. Drugs R D 2011; 11 (1): 37–51

    Article  Google Scholar 

  47. Robinson BG, Paz-Ares L, Krebs A, et al. Vandetanib (100mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab 2010; 95 (6): 2664–71

    Article  PubMed  CAS  Google Scholar 

  48. Wells Jr 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 Feb 10; 28 (5): 767–72

    Article  PubMed  CAS  Google Scholar 

  49. Langmuir PB, Yver A. Vandetanib for the treatment of thyroid cancer. Clin Pharmacol Ther 2012; 91 (1): 71–80

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements and Disclosures

The manuscript was reviewed by: A. Antonelli, Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy; H. Deshpande, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit.

Author information

Authors and Affiliations

  1. Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand

    James E. Frampton

Authors
  1. James E. Frampton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James E. Frampton.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Frampton, J.E. Vandetanib. Drugs 72, 1423–1436 (2012). https://doi.org/10.2165/11209300-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11209300-000000000-00000

Keywords

Search

Navigation