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Sorafenib: A Review in Hepatocellular Carcinoma

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Abstract

Sorafenib (Nexavar®) is currently the only systemic agent approved for use in hepatocellular carcinoma (HCC). Its approval was based on the results of the pivotal SHARP and Sorafenib Asia-Pacific (AP) trials in Child-Pugh (CP) class A patients with advanced HCC, which showed significantly longer median overall survival (OS) and time to radiological progression (TTP) with sorafenib 400 mg twice daily than with placebo, with no significant between-group difference in the median time to symptomatic progression (TTSP). Subsequent results from real-world studies such as GIDEON also support the use of sorafenib in HCC, including in carefully selected CP class B patients, although the median OS achieved in these patients appears relatively short. Sorafenib has a well characterized tolerability and safety profile, with strategies available to prevent and manage adverse effects such as hand-foot skin reactions. In conclusion, sorafenib remains an important option for the treatment of HCC.

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References

  1. D’Angelo S, Secondulfo M, De Cristofano R, et al. Selection and management of hepatocellular carcinoma patients with sorafenib: recommendations and opinions from an Italian liver unit. Future Oncol. 2013;9(4):485–91.

    Article  PubMed  Google Scholar 

  2. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.

  3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): hepatobiliary cancers (version 2.2016). 2016. http://www.nccn.org/. Accessed 16 Jan 2017.

  4. Bayer HealthCare Pharmaceuticals Inc. Nexavar (sorafenib) tablets, oral: US prescribing information. 2013. http://labeling.bayerhealthcare.com/html/products/pi/Nexavar_PI.pdf. Accessed 16 Jan 2017

  5. European Medicines Agency. Nexavar (sorafenib): EU summary of product characteristics. 2016. http://www.ema.europa.eu/. Accessed 7 Feb 2017.

  6. 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. 2006;407:597–612.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Wilhelm SM, Carter C, Tang L, 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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;66(24):11851–8.

    Article  CAS  PubMed  Google Scholar 

  10. Cheng A-L, Kang Y-K, Lin D-Y, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31(32):4067–75.

    Article  CAS  PubMed  Google Scholar 

  11. Johnson PJ, Qin S, Park J-W, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31(28):3517–24.

    Article  CAS  PubMed  Google Scholar 

  12. Cainap C, Qin S, Huang W-T, et al. Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33(2):172–9.

    Article  CAS  PubMed  Google Scholar 

  13. Cheng A-L, Thongprasert S, Lim HY, et al. Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma. Hepatology. 2016;64(3):774–84.

    Article  CAS  PubMed  Google Scholar 

  14. Zhu AX, Rosmorduc O, Evans TRJ, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33(6):559–66.

    Article  CAS  PubMed  Google Scholar 

  15. Hsu C-H, Shen Y-C, Shao Y-Y, et al. Sorafenib in advanced hepatocellular carcinoma: current status and future perspectives. J Hepatocell Carcinoma. 2014;1:85–99.

    PubMed  PubMed Central  Google Scholar 

  16. Chen K-F, Tai W-T, Liu T-H, et al. Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res. 2010;16(21):5189–99.

    Article  CAS  PubMed  Google Scholar 

  17. Tai W-T, Cheng A-L, Shiau C-W, et al. Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma. J Hepatol. 2011;55(5):1041–8.

    Article  CAS  PubMed  Google Scholar 

  18. Swamy SG, Kameshwar VH, Shubha PB, et al. Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma. Target Oncol. 2017;12(1):1–10.

    Article  PubMed  Google Scholar 

  19. Sonntag R, Gassler N, Bangen J-M, et al. Pro-apoptotic sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo. Cell Death Dis. 2014;5, e1030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen M-L, Yan B-S, Lu W-C, et al. Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. Int J Cancer. 2014;134(2):319–31.

    Article  PubMed  Google Scholar 

  21. Cao M, Xu Y, Youn J-I, et al. Kinase inhibitor sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. Lab Investig. 2011;91(4):598–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen J, Jin R, Zhao J, et al. Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma. Cancer Lett. 2015;367(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  23. Nishida N, Kitano M, Sakurai T, et al. Molecular mechanism and prediction of sorafenib chemoresistance in human hepatocellular carcinoma. Dig Dis. 2015;33(6):771–9.

    Article  PubMed  Google Scholar 

  24. Strumberg D, Richly H, Hilger RA, et al. 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. 2005;23(5):965–72.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Lettieri JT, Mazzu AL, Huang L, et al. Effect of hepatic impairment on sorafenib pharmacokinetics: results of a multicenter, open-label, single-dose, phase I trial [abstract no. 2580]. J Clin Oncol. 2014;29(Suppl).

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. 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;10(1):25–34.

    Article  CAS  PubMed  Google Scholar 

  30. Bruix J, Raoul J-L, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012;57(4):821–9.

    Article  CAS  PubMed  Google Scholar 

  31. Cheng A-L, Guan Z, Chen Z, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer. 2012;48(10):1452–65.

    Article  CAS  PubMed  Google Scholar 

  32. Bruix J, Cheng A-L, Meinhardt G, et al. Prognostic factors and predictors of response to sorafenib in patients with advanced hepatocellular carcinoma (HCC): pooled analysis of randomized clinical trials [abstract no. O-140 plus slide presentation]. Hepatol Int. 2016;10 Suppl 1:S57–8.

    Google Scholar 

  33. Raoul J-L, Bruix J, Greten TF, et al. Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses. J Hepatol. 2012;56(5):1080–8.

    Article  CAS  PubMed  Google Scholar 

  34. Pressiani T, Boni C, Rimassa L, et al. Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis. Ann Oncol. 2013;24(2):406–11.

    Article  CAS  PubMed  Google Scholar 

  35. Nakano M, Tanaka M, Kuromatsu R, et al. Sorafenib for the treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a prospective multicenter cohort study. Cancer Med. 2015;4(12):1836–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Marrero JA, Kudo M, Venook AP, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study. J Hepatol. 2016;65(6):1140–7.

    Article  CAS  PubMed  Google Scholar 

  37. Lencioni R, Kudo M, Ye S-L, et al. First interim analysis of the GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) non-interventional study. Int J Clin Pract. 2012;66(7):675–83.

    Article  CAS  PubMed  Google Scholar 

  38. Lencioni R, Kudo M, Ye S-L, et al. GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis. Int J Clin Pract. 2014;68(5):609–17.

    Article  CAS  PubMed  Google Scholar 

  39. Kudo M, Lencioni R, Marrero JA, et al. Regional differences in sorafenib-treated patients with hepatocellular carcinoma: GIDEON observational study. Liver Int. 2016;36(8):1196–205.

    Article  CAS  PubMed  Google Scholar 

  40. Geschwind J-F, Kudo M, Marrero JA, et al. TACE treatment in patients with sorafenib-treated unresectable hepatocellular carcinoma in clinical practice: final analysis of GIDEON. Radiology. 2016;279(2):630–40.

    Article  PubMed  Google Scholar 

  41. Geschwind J-FH, Gholam PM, Goldenberg A, et al. Use of transarterial chemoembolization (TACE) and sorafenib in patients with unresectable hepatocellular carcinoma: US regional analysis of the GIDEON registry. Liver Cancer. 2016;5(1):37–46.

    Article  CAS  PubMed  Google Scholar 

  42. Daniele B, Croitoru A, Papandreou C, et al. Impact of sorafenib dosing on outcome from the European patient subset of the GIDEON study. Future Oncol. 2015;11(18):2553–62.

    Article  CAS  PubMed  Google Scholar 

  43. D’Angelo S, Germano D, Zolfino T, et al. Therapeutic decisions and treatment with sorafenib in hepatocellular carcinoma: final analysis of GIDEON study in Italy [in Italian]. Recenti Prog Med. 2015;106(5):217–26.

    PubMed  Google Scholar 

  44. Turnes J, Díaz R, Hernandez-Guerra M, et al. Therapeutic decisions in the treatment of hepatocellular carcinoma and patterns of sorafenib use: results of the international observational GIDEON trial in Spain [in Spanish]. Gastroenterol Hepatol. 2015;38(4):263–73.

    Article  PubMed  Google Scholar 

  45. Kudo M, Ikeda M, Takayama T, et al. Safety and efficacy of sorafenib in Japanese patients with hepatocellular carcinoma in clinical practice: a subgroup analysis of GIDEON. J Gastroenterol. 2016;51(12):1150–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ye S-L, Chen X, Yang J, et al. Safety and efficacy of sorafenib therapy in patients with hepatocellular carcinoma: final outcome from the Chinese patient subset of the GIDEON study. Oncotarget. 2016;7(6):6639–48.

    PubMed  Google Scholar 

  47. Kim DY, Kim HJ, Han K-H, et al. Real-life experience of sorafenib treatment for hepatocellular carcinoma in Korea: from GIDEON data. Cancer Res Treat. 2016;48(4):1243–52.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Di Costanzo GG, Sacco R, de Stefano G, et al. Safety and efficacy of sorafenib in STELLA study, a multicenter, observational, phase IV study in Italian centers [abstract no. L17]. Ann Oncol. 2015;26(Suppl 6).

  49. Iavarone M, Cabibbo G, Piscaglia F, et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology. 2011;54(6):2055–63.

    Article  CAS  PubMed  Google Scholar 

  50. Ganten TM, Stauber R, Schott E, et al. Final analysis of overall survival per subgroups of HCC patients in the prospective, non-interventional INSIGHT study treated with sorafenib [abstract no. 728P]. Ann Oncol. 2014;25(Suppl 4).

  51. Hollebecque A, Cattan S, Romano O, et al. Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score. Aliment Pharmacol Ther. 2011;34(10):1193–201.

    Article  CAS  PubMed  Google Scholar 

  52. Di Costanzo GG, Tortora R, Morisco F, et al. Impact of diabetes on outcomes of sorafenib therapy for hepatocellular carcinoma. Target Oncol. 2017;12(1):61–7.

    Article  PubMed  Google Scholar 

  53. Kaneko S, Ikeda K, Matsuzaki Y, et al. Safety and effectiveness of sorafenib in Japanese patients with hepatocellular carcinoma in daily medical practice: interim analysis of a prospective postmarketing all-patient surveillance study. J Gastroenterol. 2016;51(10):1011–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ji Y-X, Zhang Z-F, Lan K-T, et al. Sorafenib in liver function impaired advanced hepatocellular carcinoma. Chin Med Sci J. 2014;29(1):7–14.

    Article  CAS  PubMed  Google Scholar 

  55. Verslype C, Rosmorduc O, Rougier P. Hepatocellular carcinoma: ESMO-ESDO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 Suppl 7:vii41–8.

    Article  PubMed  Google Scholar 

  56. Faivre S, de Gramont A, Raymond E. Learning from 7 years of experience with sorafenib in advanced HCC: sorafenib better than sorafenib? Target Oncol. 2016;11(4):565–7.

    Article  PubMed  Google Scholar 

  57. Lencioni R, Llovet JM, Han G, et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J Hepatol. 2016;64(5):1090–8.

    Article  CAS  PubMed  Google Scholar 

  58. Sansonno D, Lauletta G, Russi S, et al. Transarterial chemoembolization plus sorafenib: a sequential therapeutic scheme for HCV-related intermediate-stage hepatocellular carcinoma: a randomized clinical trial. Oncologist. 2012;17(3):359–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kudo M, Imanaka K, Chida N, et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer. 2011;47(14):2117–27.

    Article  CAS  PubMed  Google Scholar 

  60. Peck-Radosavljevic M, Raoul J-L, Lee HC, et al. An international observational study to assess the use of sorafenib after transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC): OPTIMIS [abstract no. P1338]. J Hepatol. 2015;62(Suppl 2):S858.

  61. Ren Z, Zhu K, Kang H, et al. Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33(8):894–900.

    Article  CAS  PubMed  Google Scholar 

  62. Kim JE, Ryoo B-Y, Ryu M-H, et al. Sorafenib dose escalation in the treatment of advanced hepatocellular carcinoma. Oncology. 2012;82(2):119–25.

    Article  CAS  PubMed  Google Scholar 

  63. Abou-Alfa GK, Niedzwieski D, Knox JJ, et al. Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance) [abstract no. 4003]. J Clin Oncol. 2016;34(Suppl).

  64. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66.

    Article  CAS  PubMed  Google Scholar 

  65. Colagrande S, Inghilesi AL, Aburas S, et al. Challenges of advanced hepatocellular carcinoma. World J Gastroenterol. 2016;22(34):7645–59.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin Cancer Res. 2014;20(8):2072–9.

    Article  CAS  PubMed  Google Scholar 

  67. Llovet JM, Peña CEA, Lathia CD, et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18(8):2290–300.

    Article  CAS  PubMed  Google Scholar 

  68. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 2015;33(6):550–8.

    Article  PubMed  Google Scholar 

  69. Ogasawara S, Chiba T, Ooka Y, et al. Liver function assessment according to the albumin-bilirubin (ALBI) grade in sorafenib-treated patients with advanced hepatocellular carcinoma. Investig New Drugs. 2015;33(6):1257–62.

    Article  CAS  Google Scholar 

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Acknowledgements

During the peer review process, the manufacturer of sorafenib was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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    Gillian M. Keating

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Correspondence to Gillian M. Keating.

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The preparation of this review was not supported by any external funding.

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Gillian Keating is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

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The manuscript was reviewed by: G. G. Di Costanzo, Department of Transplantation - Liver Unit, Cardarelli Hospital, Naples, Italy; M. Nakano, Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan; J.-L. Raoul, Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France; L. Rimassa, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.

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Keating, G.M. Sorafenib: A Review in Hepatocellular Carcinoma. Targ Oncol 12, 243–253 (2017). https://doi.org/10.1007/s11523-017-0484-7

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