Skip to main content
SpringerLink
Log in

Sorafenib: a review of its use in patients with radioactive iodine-refractory, metastatic differentiated thyroid carcinoma

  • Adis Drug Evaluation
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Sorafenib (Nexavar®) is the first tyrosine kinase inhibitor to be approved for the treatment of radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC). In the pivotal phase III DECISION trial in patients with RAI-refractory, locally advanced or metastatic DTC, oral sorafenib 400 mg twice daily significantly prolonged median progression-free survival (PFS) relative to placebo. The PFS benefit of sorafenib over placebo was evident in all pre-specified clinical and genetic biomarker subgroups, and neither BRAF nor RAS mutation status was predictive of sorafenib benefit for PFS. The objective response rate was significantly higher in patients receiving sorafenib than in those receiving placebo; all objective responses were partial responses. The overall survival benefit of sorafenib is as yet unclear, with no significant benefit observed at the time of primary analysis or at 9 months following the primary analysis. Overall survival was possibly confounded by the crossover of patients in the placebo group to sorafenib upon disease progression. The adverse events associated with sorafenib in the DECISION trial were consistent with the known tolerability profile of the drug, with hand-foot skin reaction, diarrhea, and alopecia reported most commonly. Most treatment-emergent adverse events were grade 1 or 2 in severity and occurred early in treatment. However, a high proportion of patients discontinued sorafenib therapy or required dose reductions or interruptions because of toxicity. Although final overall survival data are awaited, current evidence suggests that sorafenib is a promising new treatment option for patients with RAI-refractory, metastatic DTC.

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

Fig. 1

Similar content being viewed by others

References

  1. Pacini F, Schlumberger M, Dralle H et al (2006) European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 154:787–803

    Article  CAS  PubMed  Google Scholar 

  2. National Comprehensive Cancer Network (2014) NCCN clinical practice guidelines in oncology: thyroid carcinoma v2.2014. http://www.nccn.org. Accessed 4 Feb 2015

  3. Seigel R, Ma J, Zou Z et al (2014) Cancer statistics, 2014. CA Cancer J Clin 64(1):9–29

    Article  Google Scholar 

  4. Cancer Research UK (2014) Thyroid cancer incidence statistics. http://www.cancerresearchuk.org. Accessed 4 Feb 2015

  5. International Agency for Research on Cancer (2012) GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr. Accessed 4 Feb 2015

  6. Cooper DS, Doherty GM, Haugen BR et al (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19(11):1167–1214

    Article  PubMed  Google Scholar 

  7. Capdevila J, Argiles G, Rodriguez-Frexinos V et al (2010) New approaches in the management of radioiodine-refractory thyroid cancer: the molecular targeted therapy era. Discov Med 9(45):153–162

    PubMed  Google Scholar 

  8. Pitoia F (2014) Response to sorafenib treatment in advanced metastatic thyroid cancer. Arq Bras Endocrinol Metabol 58(1):37–41

    Article  PubMed  Google Scholar 

  9. Durante C, Haddy N, Baudin E et al (2006) Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 91:2892–2899

    Article  CAS  PubMed  Google Scholar 

  10. Sacks W, Braunstein GD (2014) Evolving approaches in managing radioactive iodine-refractory differentiated thyroid cancer. Endocr Pract 20(3):263–275

    Article  PubMed  Google Scholar 

  11. Busaidy NL, Cabanillas ME (2012) Differentiated thyroid cancer: management of patients with radioiodine nonresponsive disease. J Thyroid Res. doi:10.1155/2012/618985

    PubMed Central  PubMed  Google Scholar 

  12. McCubrey JA, Steelman LS, Chappell WH et al (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 1773(8):1263–1284

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Xing M (2005) BRAF mutation in thyroid cancer. Endocr Relat Cancer 12(2):245–262

    Article  CAS  PubMed  Google Scholar 

  14. Wilhelm S, Carter C, Lynch M et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5(10):835–844

    Article  CAS  PubMed  Google Scholar 

  15. Adnane L, Trail PA, Taylor I et al (2006) Sorafenib (BAY 43-9006, Nexavar®), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol 407:597–612

    Article  CAS  PubMed  Google Scholar 

  16. Nixon IJ, Shaha AR, Tuttle MR (2013) Targeted therapy in thyroid cancer. Curr Opin Otolaryngol Head Neck Surg 21(2):130–134

    Article  PubMed  Google Scholar 

  17. Fallahi P, Ferrari SM, Santini F et al (2013) Sorafenib and thyroid cancer. BioDrugs 27(6):615–628

    Article  CAS  PubMed  Google Scholar 

  18. Wilhelm SM, Carter C, Tang L et al (2004) 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 64(19):7099–7109

    Article  CAS  PubMed  Google Scholar 

  19. Bayer (2013) Prescribing information for sorafenib. http://www.accessdata.fda.gov. Accessed 4 Feb 2015

  20. European Medicines Agency (2014) Nexavar (sorafenib): summary of product characteristics. http://www.ema.europa.eu. Accessed 4 Feb 2015

  21. Awada A, Hendlisz A, Gil T et al (2005) Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer 92(10):1855–1861

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Clark JW, Eder JP, Ryan D et al (2005) Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 11(15):5472–5480

    Article  CAS  PubMed  Google Scholar 

  23. Moore M, Hirte HW, Siu L et al (2005) Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 16(10):1688–1694

    Article  CAS  PubMed  Google Scholar 

  24. Strumberg D, Richly H, Hilger RA et al (2005) Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 23(5):965–972

    Article  CAS  PubMed  Google Scholar 

  25. Minami H, Kawada K, Ebi H et al (2008) Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors. Cancer Sci 99(7):1492–1498

    Article  CAS  PubMed  Google Scholar 

  26. Yarchoan M, Cohen AB, Stopenski SJ et al. (2014) Molecular predictors of response to sorafenib in patients with radioactive iodine-resistant advanced thyroid cancer [abstract no. 6088]. In: Annual Meeting of the American Society of Clinical Oncology

  27. European Medicines Agency (2014) CHMP extension of indication variation assessment report. http://www.ema.europa.eu. Accessed 4 Feb 2015

  28. Lathia C, Lettieri J, Cihon F et al (2006) Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol 57(5):685–692

    Article  CAS  PubMed  Google Scholar 

  29. Lettieri J, Lathia C, Rotolo C (2011) Effect of neomycin on the pharmacokinetics (PK) of sorafenib (S) [abstract no. PII-54]. In: American Society for Clinical Pharmacology and Therapeutics Annual Meeting

  30. Brose MS, Nutting CM, Jarzab B et al (2014) Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 384(9940):319–328

    Article  CAS  PubMed  Google Scholar 

  31. Brose MS, Nutting CM, Sherman SI et al (2011) Rationale and design of decision: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer. BMC Cancer 11:349

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Ahmed M, Barbachano Y, Riddell AM et al (2011) Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur J Endocrinol 165(2):315–322

    Article  CAS  PubMed  Google Scholar 

  33. Gupta-Abramson V, Troxel AB, Nellore A et al (2008) Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 26(29):4714–4719

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Hoftijzer H, Heemstra KA, Morreau H et al (2009) Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur J Endocrinol 161(6):923–931

    Article  CAS  PubMed  Google Scholar 

  35. Kloos RT, Ringel MD, Knopp MV et al (2009) Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 27(10):1675–1684

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Schneider TC, Abdulrahman RM, Corssmit EP et al (2012) Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial. Eur J Endocrinol 167(5):643–650

    Article  CAS  PubMed  Google Scholar 

  37. Brose MS, Troxel AB, Harlacker K et al. (2009) Completion of a phase II study of sorafenib for advanced thyroid cancer [abstract no. 51LBA]. In: Joint 15th European Cancer Organisation and 34th European Society for Medical Oncology

  38. Keefe SM, Troxel AB, Rhee S, et al. (2011) Phase II trial of sorafenib in patients with advanced thyroid cancer [abstract no. 5562]. In: Annual Meeting of the American Society of Clinical Oncology

  39. Brose MS, Nutting C, Shong YK, et al. (2013) Association between tumor BRAF and RAS mutation status and clinical outcomes in patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) randomized to sorafenib or placebo: sub-analysis of the phase III DECISION trial [abstract no. 3155]. In: European Cancer Congress

  40. Schlumberger M, Elisei R, Pacini F, et al. (2014) Prognostic and predictive factors correlated with treatment outcomes for radioactive iodine-refractory differentiated thyroid cancer (RAI-rDTC) patients receiving sorafenib or placebo on the phase III DECISION trial [abstract no. 13 plus oral presentation]. In: 84th Annual Meeting of the American Thyroid Association

  41. Brose MS, Jarzab B, Elisei R, et al. (2014) Updated overall survival analysis of patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer (RAI-rDTC) treated with sorafenib on the phase 3 DECISION trial [abstract no. 6060 plus poster]. In: Annual Meeting of the American Society of Clinical Oncology

  42. Schlumberger M, Jarzab B, Elisei R, et al. (2013) Phase III randomized, double-blinded, placebo-controlled trial of sorafenib in locally advanced or metastatic patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC)—exploratory analyses of patient-reported outcomes [abstract no. 100]. In: 83rd Annual Meeting of the American Thyroid Association

  43. Worden FP, Fassnacht M, Shi Y, et al. (2014) Safety and tolerability of sorafenib for treatment of locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer (RAI-rDTC): detailed analyses from the phase III DECISION trial [abstract no. 6062 plus poster]. In: Annual Meeting of the American Society of Clinical Oncology

  44. McFarland DC, Misiukiewicz KJ (2014) Sorafenib in radioactive iodine-refractory well-differentiated metastatic thyroid cancer. Onco Targets Ther 7:1291–1299

    Article  PubMed Central  PubMed  Google Scholar 

  45. Dadu R, Waguespack SG, Sherman SI et al (2014) Efficacy and tolerability of different starting doses of sorafenib in patients with differentiated thyroid cancer. Oncologist 19(5):477–482

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Chu D, Lacouture ME, Fillos T et al (2008) Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol 47(2):176–186

    Article  CAS  PubMed  Google Scholar 

  47. Azad NS, Aragon-Ching JB, Dahut WL et al (2009) Hand-foot skin reaction increases with cumulative sorafenib dose and with combination anti-vascular endothelial growth factor therapy. Clin Cancer Res 15(4):1411–1416

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Ren Z, Zhu K, Kang H, et al. (2012) A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma [abstract no. 4008]. In: Annual Meeting of the American Society of Clinical Oncology

  49. Thomas L, Lai SY, Dong W et al (2014) Sorafenib in metastatic thyroid cancer: a systematic review. Oncologist 19(3):251–258

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Shen C-T, Qiu Z-L, Luo Q-Y (2014) Sorafenib in the treatment of radioiodine-refractory differentiated thyroid cancer: a meta-analysis. Endocr Relat Cancer 21(2):253–261

    Article  CAS  PubMed  Google Scholar 

  51. Haraldsdottir S, Shah MH (2014) An update on clinical trials of targeted therapies in thyroid cancer. Curr Opin Oncol 26(1):36–44

    Article  CAS  PubMed  Google Scholar 

  52. Bayer (2014) Prospective, non-interventional, post-authorization safety study that includes all patients diagnosed as unresectable differentiated thyroid carcinoma and treated with sorafenib (JPMS-DTC) [ClinicalTrials.gov identifier NCT02185560] US National Institutes of Health, ClinicalTrials.gov. https://www.clinicaltrials.gov/show/NCT02185560. Accessed 4 Feb 2015.

Download references

Data selection sources

Relevant medical literature (including published and unpublished data) on sorafenib was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 4 February 2015], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug.

Search terms

Sorafenib, Nexavar, BAY 43-9006, thyroid cancer

Study selection

Studies in patients with thyroid cancer who received sorafenib. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included

Disclosure

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 authors on the basis of scientific and editorial merit. Hannah Blair and Greg Plosker are salaried employees of Adis/Springer.

Author information

Authors and Affiliations

  1. Springer, Private Bag 65901, Mairangi Bay, 0754, Auckland, New Zealand

    Hannah A. Blair & Greg L. Plosker

Authors
  1. Hannah A. Blair
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Greg L. Plosker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hannah A. Blair.

Additional information

The manuscript was reviewed by A. Awada, Medical Oncology Clinic, Jules Bordet Institute, Brussels, Belgium and M. Xing, Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blair, H.A., Plosker, G.L. Sorafenib: a review of its use in patients with radioactive iodine-refractory, metastatic differentiated thyroid carcinoma. Targ Oncol 10, 171–178 (2015). https://doi.org/10.1007/s11523-015-0363-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-015-0363-z

Keywords

Search

Navigation