Skip to main content
Log in

Sorafenib

A Review of its Use in Advanced Hepatocellular Carcinoma

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

Summary

Abstract

Sorafenib (Nexavar®) is an orally active multikinase inhibitor that is approved in the EU for the treatment of hepatocellular carcinoma. Monotherapy with sorafenib prolongs overall survival and delays the time to progression in patients with advanced hepatocellular carcinoma who are not candidates for potentially curative treatment or transarterial chemoembolization. Sorafenib is generally well tolerated in patients with advanced hepatocellular carcinoma. Thus, sorafenib represents an important advance in the treatment of advanced hepatocellular carcinoma and is the new standard of care for this condition.

Pharmacological Properties

The bi-aryl urea sorafenib is an oral multikinase inhibitor that inhibits cell surface tyrosine kinase receptors (e.g. vascular endothelial growth factor receptors and platelet-derived growth factor receptor-β) and downstream intracellular serine/threonine kinases (e.g. Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in tumour cell proliferation and tumour angiogenesis. In vitro, dose-dependent inhibition of cell proliferation and induction of apoptosis was seen with sorafenib in human hepatocellular carcinoma cells lines. Sorafenib demonstrated dose-dependent antitumour activity in a murine xenograft model of human hepatocellular carcinoma.

Steady-state plasma concentrations were reached within 7 days in patients with advanced, refractory solid tumours who received twice-daily oral sorafenib. Metabolism of sorafenib occurs primarily in the liver and is mediated via cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase 1A9. In advanced hepatocellular carcinoma, differences in sorafenib pharmacokinetics between Child-Pugh A and B patients were not considered clinically significant. Sorafenib may be associated with drug interactions. For example, sorafenib exposure was reduced by an average 37% with concomitant administration of the CYP3A4 inducer rifampicin (rifampin); sorafenib concentrations may also be decreased by other CYP3A4 inducers.

Therapeutic Efficacy

Monotherapy with oral sorafenib 400 mg twice daily prolonged median overall survival and delayed the median time to progression in patients with advanced hepatocellular carcinoma, according to the results of two randomized, double-blind, placebo-controlled, multicentre, phase III trials (the SHARP trial and the Asia-Pacific trial). There was no significant difference between sorafenib and placebo recipients in the median time to symptomatic progression in either trial. The vast majority of patients included in these trials were Child-Pugh A.

Combination therapy with sorafenib plus doxorubicin did not delay the median time to progression to a significant extent compared with doxorubicin alone in patients with advanced hepatocellular carcinoma, according to the results of a randomized, double-blind, phase II trial. However, the median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone. Combination therapy with sorafenib plus tegafur/uracil or mitomycin also showed potential in advanced hepatocellular carcinoma, according to the results of noncomparative trials.

Tolerability

Monotherapy with oral sorafenib was generally well tolerated in patients with advanced hepatocellular carcinoma, with a manageable adverse effect profile; diarrhoea and hand-foot skin reaction were consistently the most commonly occurring drug-related adverse events in clinical trials. In the SHARP trial, drug-related adverse events of any grade occurring in significantly more sorafenib than placebo recipients included diarrhoea, hand-foot skin reaction, anorexia, alopecia, weight loss, dry skin, abdominal pain, voice changes and ‘other’ dermatological events. A similar tolerability profile was seen in the Asia-Pacific trial.

As expected given the addition of a chemotherapy agent, the adverse event profile in patients with advanced hepatocellular carcinoma who received combination therapy with sorafenib plus doxorubicin differed somewhat to that seen with sorafenib monotherapy in the SHARP trial. In patients receiving sorafenib plus doxorubicin, the most commonly occurring all-cause adverse events (all grades) included fatigue, neutropenia, diarrhoea, elevated bilirubin levels, abdominal pain, hand-foot skin reaction, left ventricular dysfunction, hypertension and febrile neutropenia.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Table II
Fig. 2
Table III
Table IV
Fig. 3

Similar content being viewed by others

References

  1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastro-enterology 2007 Jun; 132(7): 2557–76

    Article  CAS  Google Scholar 

  2. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006 Dec 15; 66(24): 11851–8

    Article  PubMed  CAS  Google Scholar 

  3. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008 Oct; 48(4): 1312–27

    Article  PubMed  CAS  Google Scholar 

  4. Méndez-Sánchez N, Vásquez-Fernández F, Zamora-Valdés D, et al. Sorafenib, a systemic therapy for hepatocellular carcinoma. Ann Hepatol 2008 Jan-Mar; 7(1): 46–51

    PubMed  Google Scholar 

  5. Adnane L, Trail PA, Taylor I, et al. 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 2005; 407: 597–612

    Article  Google Scholar 

  6. Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006 Oct; 5(10): 835–44

    Article  PubMed  CAS  Google Scholar 

  7. Chaparro M, Gonzalez Moreno L, Trapero-Marugan M, et al. Review article: pharmacological therapy of hepatocellular carcinoma with sorafenib and other oral agents. Aliment Pharmacol Ther 2008 Dec 1; 28(11–12): 1269–77

    Article  PubMed  CAS  Google Scholar 

  8. European Medicines Agency. Sorafenib (Nexavar): summary of product characteristics [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/nexavar/H-690-PI-en.pdf [Accessed 2008 Oct 15]

  9. Wilhelm SM, Carter C, Tang LY, 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 Oct 1; 64(19): 7099–109

    Article  PubMed  CAS  Google Scholar 

  10. Wang Z, Zhou J, Fan J, et al. Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res 2008 Aug 15; 14(16): 5124–30

    Article  PubMed  CAS  Google Scholar 

  11. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006 Sep 10; 24(26): 4293–300

    Article  PubMed  CAS  Google Scholar 

  12. Furuse J, Ishii H, Nakachi K, et al. Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma. Cancer Sci 2008 Jan; 99(1): 159–65

    PubMed  CAS  Google Scholar 

  13. Lathia C, Lettieri J, Cihon F, et al. Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol 2006 May 1; 57(5): 685–92

    Article  PubMed  CAS  Google Scholar 

  14. Awada A, Hendlisz A, Gil T, et al. 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 2005; 92(10): 1855–61

    Article  PubMed  CAS  Google Scholar 

  15. Richly H, Henning BF, Kupsch P, et al. Results of a phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. Ann Oncol 2006 May; 17(5): 866–73

    Article  PubMed  CAS  Google Scholar 

  16. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008 Jul 24; 359(4): 378–90

    Article  PubMed  CAS  Google Scholar 

  17. Cheng A-L, Kang Y-K, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009 Jan; 10(1): 25–34

    Article  PubMed  CAS  Google Scholar 

  18. Craxi A, Porta C, Sangiovanni A, et al. Efficacy and safety of sorafenib in patients with alcohol-related hepatocellular carcinoma: a subanalysis from the SHARP trial [abstract no. 15591]. 44th Annual Meeting of the American Society of Clinical Oncology; 2008 May 30–Jun 3; Chicago (IL)

  19. Galle P, Blanc J, Van Laethem J-L, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and prior anti-tumor therapy: a subanalysis from the SHARP trial [abstract no. 994]. 43rd Annual Meeting of the European Association for the Study of the Liver; 2008 Apr 23–27; Milan

  20. Bolondi L, Caspary W, Bennouna J, et al. Clinical benefit of sorafenib in hepatitis C patients with hepatocellular carcinoma (HCC): subgroup analysis of the SHARP trial [abstract no. 129]. 2008 Gastrointestinal Cancers Symposium; 2008 Jan 25–27; Orlando (FL)

  21. Raoul J, Santoro A, Beaugrand M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to ECOG performance status: a subanalysis from the SHARP trial [abstract no. 4587]. 44th Annual Meeting of the American Society of Clinical Oncology; 2008 May 30–Jun 3; Chicago (IL)

  22. Llovet J, Peña C, Shan M, et al. Biomarkers predicting ouctome of patients with hepatocellular carcinoma: results from the randomized phase III SHARP trial [abstract no. 149]. Hepatology 2008 Oct; 48 (4 Suppl.): 372A

    Article  Google Scholar 

  23. Guan Z, Kang Y, Chen Z, et al. Sorafenib is effective in hepatitis B-positive patients with hepatocellular carcinoma (HCC): subgroup analysis of a randomized, double-blind, phase III trial performed in the Asia-Pacific region [abstract no. 512PD]. Ann Oncol 2008 Sep; 19 Suppl. 8: 68–9

    Google Scholar 

  24. Abou-Alfa GK, Amadori D, Santoro A, et al. Is sorafenib (S) safe and effective in patients (pts) with hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis? [abstract no. 4518]. American Society of Clinical Oncology 44th Annual Meeting; 2008 May 30–Jun 3; Chicago (IL)

  25. Weinmann A, Schrabback P, Schulze-Bergkamen H, et al. Alpha-feto-protein levels during treatment with sorafenib in patients with advanced hepatocellular carcinoma [abstract no. 417]. 43rd Annual Meeting of the European Association for the Study of the Liver; 2008 Apr 23–27; Milan

  26. Siemerink E, Mulder NH, Brouwers AH, et al. Early prediction of response to sorafenib treatment in patients with hepatocellular carcinoma (HCC) with 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) [abstract no. 15600]. 44th Annual Meeting of the American Society of Clinical Oncology; 2008 May 30–Jun 3; Chicago (IL)

  27. Abou-Alfa G, Johnson P, Knox J, et al. Final results from a phase II (PhII), randomized, double-blind study of sorafenib plus doxorubicin (S + D) vesrus placebo plus doxorubicin (P + D) in patients (pts) with advanced hepa-tocellular carcinoma (AHCC) [abstract plus slide presentation]. 14th European Cancer Conference; 2007 Sep 23–27; Barcelona

  28. Dima G, Lucia M, LaGattuta G, et al. Perspective phase II study of combination sorafenib plus mitomycin-c in the treatment of advanced hepatocellular carcinoma (HCC) [abstract no. P-081]. Ann Oncol 2008 Jun; 19 Suppl. 6: 149

    Google Scholar 

  29. Shen Y, Shao Y, Hsu C, et al. Phase II study of sorafenib plus tegafur/uracil (UFT) in patients with advanced hepatocellular carcinoma (HCC) [abstract no. 15664]. American Society of Clinical Oncology 44th Annual Meeting; 2008 May 30–Jun 3; Chicago (IL)

  30. Wu S, Chen JJ, Kudelka A, et al. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol 2008 Feb; 9(2): 117–23

    Article  PubMed  CAS  Google Scholar 

  31. Greten T, Scherübl J, Scheulen M, et al. Baseline transaminase levels and efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma (HCC): a subgroup analysis of SHARP [abstract no. 197]. 2008 Gastrointestinal Cancers Symposium; 2008 Jan 25–27; Orlando (FL)

  32. Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol 2008; 48 Suppl. 1: S20–37

    Article  PubMed  CAS  Google Scholar 

  33. El-Serag HB, Marrero JA, Rudolph L, et al. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008 May; 134(6): 1752–63

    Article  PubMed  Google Scholar 

  34. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008 May 21; 100(10): 698–711

    Article  PubMed  Google Scholar 

  35. Skelton MR, O'Neil B. Targeted therapies for hepatocellular carcinoma. Clin Adv Hematol Oncol 2008 Mar; 6(3): 209–18

    PubMed  Google Scholar 

  36. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: hepatobiliary cancers. V.2.2008 [online]. Available from URL: http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf [Accessed 2008 Oct 17]

  37. Galle PR. Sorafenib in advanced hepatocellular carcinoma: we have won a battle not the war. J Hepatol 2008; 49: 871–3

    Article  PubMed  CAS  Google Scholar 

  38. Muszbek N, Shah S, Carroll S, et al. Economic evaluation of sorafenib in the treatment of hepatocellular carcinoma in Canda. Curr Med Res Opin 2008; 24(12): 3559–69

    Article  PubMed  Google Scholar 

  39. Roberts LR. Sorafenib in liver cancer: just the beginning. N Engl J Med 2008 Jul 24; 359(4): 420–2

    Article  PubMed  CAS  Google Scholar 

  40. Data on file, Bayer S.p.A., 2009

  41. Italian Trial in Medical Oncology. Phase II study of sorafenib and infusional 5-fluorouracil in advanced hepatocellular carcinoma (HCC) [ClinicalTrials.gov identifier NCT00619541]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from http://www.clinicaltrials.gov [Accessed 2008 Oct 23]

  42. Mahidol University. Efficacy and safety of sorafenib (Nex-avar) in combination with gemcitabine in advanced hepatocellular carcinoma (HCC) [ClinicalTrials.gov identifier NCT00703365]. US National Institutes of Health, Clinical Trials.gov [online]. Available from http://www.clinicaltrials.gov [Accessed 2008 Oct 23]

  43. The University of Hong Kong. Sorafenib with capecitabine and oxaliplatin for advanced or metastatic hepatocellular carcinoma (SECOX) [ClinicalTrials.gov identifier NCT00752063]. US National Institutes of Health, Clinical Trials.gov [online]. Available from http://www.clinicaltrials.gov [Accessed 2008 Oct 23]

  44. Radboud University. Phase I study with sorafenib and sirolimus [ClinicalTrials.gov identifier NCT00509613]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from http://www.clinicaltrials.gov [Accessed 2008 Oct 23]

  45. Bayer HealthCare AG. Sorafenib as adjuvant treatment in the prevention of recurrence of hepatocellular carcinoma (STORM) [ClinicalTrials.gov identifier NCT00692770]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from http://www.clinicaltrials.gov [Accessed 2008 Oct 23]

  46. Heinrich-Heine University. TACE and sorafenib for advanced hepatocellular carcinoma (HCC) (SOCRATES) [ClinicalTrials.gov identifier NCT00618384]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from http://www.clinicaltrials.gov [Accessed 2008 Oct 23]

  47. University of Bern. Sorafenib with TACE to treat hepatocellular carcinoma (S-TACE) [ClinicalTrials.gov identifier NCT00478374]. US National Institutes of Health, Clinical Trials.gov [online]. Available from http://www.clinicaltrials.gov [Accessed 2008 Oct 23]

  48. Medical University of Vienna. Sorafenib and transarterial chemoembolization for hepatocellular carcinoma [Clinical Trials.gov identifier NCT00768937]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from http://www.clinicaltrials.gov [Accessed 2008 Oct 23]

  49. University of Pittsburgh. Effectiveness and safety study of TACE plus oral sorafenib for unresectable HCC [Clinical Trials.gov identifier NCT00576056]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from http://www.clinicaltrials.gov [Accessed 2008 Oct 23]

  50. Autier J, Escudier B, Wechsler J, et al. Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor. Arch Dermatol 2008 Jul; 144(7): 886–92

    Article  PubMed  CAS  Google Scholar 

  51. Chu D, Lacouture ME, Fillos T, et al. Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol 2008; 47(2): 176–86

    Article  PubMed  CAS  Google Scholar 

  52. Roberts LR. Sorafenib in advanced hepatocellular carcinoma [letter]. N Engl J Med 2008 Dec 4; 359(23): 2499

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gillian M. Keating.

Additional information

Various sections of the manuscript reviewed by: P.R. Galle, Department of Internal Medicine, University of Mainz, Mainz, Germany; T.F. Greten, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany; N. Méndez-Sánchez, Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico; C. Porta, Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy; J.-L. Raoul, Department of Medical Oncology, Centre Eugene Marquis, Rennes, France.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘sorafenib’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘sorafenib’ and (‘liver cancer’ or ‘liver neoplasms’ or ‘liver cell carcinoma’ or ‘hepatocellular cancer’). Searches were last updated 21 January 2009.

Selection: Studies in patients with advanced hepatocellular carcinoma who received sorafenib. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Sorafenib, hepatocellular carcinoma, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keating, G.M., Santoro, A. Sorafenib. Drugs 69, 223–240 (2009). https://doi.org/10.2165/00003495-200969020-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200969020-00006

Keywords

Navigation