Beyond sorafenib: Novel targeted therapies for advanced hepatocellular carcinoma

Expert Opinion on Investigational Drugs

Volumn 19, Issue 5, 2010, Pages 663-672

  Zhu, Andrew X ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Bevacizumab; Brivanib; EGFR inhibitors; Everolimus; Hepatocellular carcinoma; Sorafenib; Sunitinib; Targeted agents

Indexed keywords

1 [4 (3 AMINO 1H INDAZOL 4 YL)PHENYL] 3 (2 FLUORO 5 METHYLPHENYL)UREA; 5 (4 BROMO 2 CHLOROANILINO) 4 FLUORO 1 METHYL 1H BENZIMIDAZOLE 6 CARBOHYDROXAMIC ACID 2 HYDROXYETHYL ESTER; BEVACIZUMAB; BRIVANIB ALANINATE; CAPECITABINE; CEDIRANIB; CETUXIMAB; CISPLATIN; DOXORUBICIN; EPIDERMAL GROWTH FACTOR RECEPTOR; ERLOTINIB; EVEROLIMUS; GEFITINIB; GEMCITABINE; LAPATINIB; MAMMALIAN TARGET OF RAPAMYCIN; OXALIPLATIN; PAZOPANIB; PLACEBO; RAPAMYCIN; SORAFENIB; SUNITINIB; TEMSIROLIMUS; VATALANIB;

ADVANCED CANCER; ALANINE AMINOTRANSFERASE BLOOD LEVEL; AMINOTRANSFERASE BLOOD LEVEL; ANGIOGENESIS; ANOREXIA; ANTINEOPLASTIC ACTIVITY; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BILIRUBIN BLOOD LEVEL; CANCER COMBINATION CHEMOTHERAPY; CLINICAL TRIAL; COUGHING; DIARRHEA; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; ELECTROLYTE DISTURBANCE; FATIGUE; HAND FOOT SYNDROME; HEADACHE; HEART LEFT VENTRICLE FAILURE; HEART MUSCLE ISCHEMIA; HEMATOLOGIC DISEASE; HUMAN; HYPERBILIRUBINEMIA; HYPERTENSION; HYPOCALCEMIA; HYPOMAGNESEMIA; HYPONATREMIA; INFECTION; LIVER CELL CARCINOMA; LIVER DYSFUNCTION; MULTIPLE CYCLE TREATMENT; NEUTROPENIA; PERIPHERAL EDEMA; PROGRESSION FREE SURVIVAL; PROTEINURIA; RASH; REVIEW; SIDE EFFECT; SURVIVAL RATE; THROMBOCYTOPENIA; TREATMENT DURATION; TREATMENT INDICATION; TREATMENT RESPONSE; VOMITING;

ANTINEOPLASTIC AGENTS; BENZENESULFONATES; CARCINOMA, HEPATOCELLULAR; CLINICAL TRIALS, PHASE III AS TOPIC; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; LIVER NEOPLASMS; PYRIDINES;

EID: 77951465662     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543781003767426     Document Type: Review

References (66)

1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55(2):74-108
2. Zhu AX. Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be? Oncologist 2006;11(7):790-800 (Pubitemid 44157567)
3. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378-390
4. Cheng AL, Kang YK, 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
5. 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):7099-7109 (Pubitemid 39331023)
6. 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):11851-11858 (Pubitemid 46094197)
7. 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):4293-4300 (Pubitemid 46630787)
8. Pinter M, Sieghart W, Graziadei I, et al. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist 2009;14(1):70-76
9. 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? J Clin Oncol 2008;26(20 Suppl):abstract 4518
10. Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 2009;27(11):1800-1805
11. Zhu AX, Clark JW. Commentary: sorafenib use in patients with advanced hepatocellular carcinoma and underlying Child-Pugh B cirrhosis: evidence and controversy. Oncologist 2009;14(1):67-69
12. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100(10):698-711
13. Abou-Alfa GK, Johnson P, Knox J, et al. Final results from a phase II (PhII), randomized, double-blind study of sorafenib plus doxorubicin (S+D) versus placebo plus doxorubicin (P+D) in patients (pts) with advanced hepatocellular carcinoma (AHCC). [abstract 128]. 2008 Gastrointestinal Cancers Symposium; Orlando, FL, USA
14. Martinelli E, Troiani T, Laus G, et al. Synergistic antitumor activity of the combination of the multitargeted tyrosine kinase inhibitor sorafenib and of EGFR inhibitors in human colon and lung cancer cell lines. Eur J Cancer 2006;4:123
15. Duran I, Hotte SJ, Hirte H, et al. Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors. Clin Cancer Res 2007;13(16):4849-4857 (Pubitemid 47294792)
16. Ciardiello F, Troiani T, Bianco R, et al. Interaction between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways: a rational approach for multi-target anticancer therapy. Ann Oncol 2006;17(Suppl 7):vii109-14
17. Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005;23(27):6657-6663
18. Messerini L, Novelli L, Comin CE. Microvessel density and clinicopathological characteristics in hepatitis C virus and hepatitis B virus related hepatocellular carcinoma. J Clin Pathol 2004;57(8):867-871
19. Miura H, Miyazaki T, Kuroda M, et al. Increased expression of vascular endothelial growth factor in human hepatocellular carcinoma. J Hepatol 1997;27(5):854-861 (Pubitemid 27454829)
20. Yamaguchi R, Yano H, Iemura A, et al. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 1998;28(1):68-77
21. Yamaguchi R, Yano H, Nakashima Y, et al. Expression and localization of vascular endothelial growth factor receptors in human hepatocellular carcinoma and non-HCC tissues. Oncol Rep 2000;7(4):725-729
22. Chao Y, Li CP, Chau GY, et al. Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol 2003;10(4):355-362
23. Jeng KS, Sheen IS, Wang YC, et al. Prognostic significance of preoperative circulating vascular endothelial growth factor messenger RNA expression in resectable hepatocellular carcinoma: a prospective study. World J Gastroenterol 2004;10(5):643-648
24. Poon RT, Ho JW, Tong CS, et al. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma. Br J Surg 2004;91(10):1354-1360
25. Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther 2005;315(3):971-979
26. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9(1):327-337
27. Pawson T. Regulation and targets of receptor tyrosine kinases. Eur J Cancer 2002;38(Suppl 5):S3-10
28. Faivre S, Raymond E, Boucher E, et al. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study. Lancet Oncol 2009;10(8):794-800
29. Hoda D, Catherine C, Strosberg J, et al. Phase II study of sunitinib malate in adult pts (pts) with metastatic or surgically unresectable hepatocellular carcinoma (HCC) [abstract 128]. 2008 Gastrointestinal Cancers Symposium; Orlando, FL, USA
30. Koeberle D, Montemurro M, Samaras P, et al. Continuous sunitinib treatment in patients with unresectable hepatocellular carcinoma (HCC): a multicenter phase II trial (SAKK 77/06 and SASL 23). J Clin Oncol 2009;27(15S):abstract 4591
31. Zhu AX, Sahani DV, Duda DG, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 2009;27(18):3027-3035
32. Huynh H, Ngo VC, Fargnoli J, et al. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res 2008;14(19):6146-6153
33. Raoul JL, Finn RS, Kang YK, et al. An open-label phase II study of first-and second-line treatment with brivanib in patients with hepatocellular carcinoma (HCC). J Clin Oncol 2009;27(15S):abstract 4577
34. Toh H, Chen P, Carr BI, et al. A phase II study of ABT-869 in hepatocellular carcinoma (HCC): Interim analysis. J Clin Oncol 2009;27(15s):abstract 4581
35. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001;7(9):987-989
36. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10(2):145-147
37. Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008;26(18):2992-2998
38. Malka D, Dromain C, Farace F, et al. Bevacizumab in patients (pts) with advanced hepatocellular carcinoma (HCC): preliminary results of a phase II study with circulating endothelial cell (CEC) monitoring. 2007 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;25(18S):4570
39. Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24(12):1898-1903
40. Sun W, Haller DG, Mykulowycz K, et al. Combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): a phase II study. 2007 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;25(18S):4574
41. Hsu C, Yang T, Hsu C, et al. Modified-dose capecitabine + bevacizumab for the treatment of advanced/metastatic hepatocellular carcinoma (HCC): a phase II, single-arm study. 2007 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;25(18S):15190
42. Thomas MB, Morris JS, Chadha R, et al. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol 2009;27(6):843-850
43. Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 2005;65(10):4389-4400
44. Alberts SR, Morlan BW, Kim GP, et al. NCCTG phase II trial (N044J) of AZD2171 for patients with hepatocellular carcinoma (HCC)-Interim review of toxicity [abstract No: 186]. 2007 Gastrointestinal Cancers Symposium; Orlando, FL, USA
45. Wood JM. Inhibition of vascular endothelial growth factor (VEGF) as a novel approach for cancer therapy. Medicina 2000;60(Suppl 2):41-47
46. Drevs J, Muller-Driver R, Wittig C, et al. PTK787/ZK 222584, a specific vascular endothelial growth factor-receptor tyrosine kinase inhibitor, affects the anatomy of the tumor vascular bed and the functional vascular properties as detected by dynamic enhanced magnetic resonance imaging. Cancer Res 2002;62(14):4015-4022
47. Koch I, Baron A, Roberts S, et al. Influence of hepatic dysfunction on safety, tolerability, and pharmacokinetics (PK) of PTK787/ZK 222584 in patients (Pts) with unresectable hepatocellular carcinoma (HCC). 2005 ASCO Annual Meeting Proceedings Part I of II. J Clin Oncol 2005;23(16S):4134
48. Yau CC, Chen PJ, Curtis CM, et al. A phase I study of pazopanib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2009;27(15S):abstract 3561
49. Carlin CR, Simon D, Mattison J, Knowles BB. Expression and biosynthetic variation of the epidermal growth factor receptor in human hepatocellular carcinoma-derived cell lines. Mol Cell Biol 1988;8(1):25-34
50. Harada K, Shiota G, Kawasaki H. Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma. Liver 1999;19(4):318-325
51. Ito Y, Takeda T, Higashiyama S, et al. Expression of heparin binding epidermal growth factor-like growth factor in hepatocellular carcinoma: an immunohistochemical study. Oncol Rep 2001;8(4):903-907
52. Kira S, Nakanishi T, Suemori S, et al. Expression of transforming growth factor alpha and epidermal growth factor receptor in human hepatocellular carcinoma. Liver 1997;17(4):177-182
53. Kiss A, Wang NJ, Xie JP, Thorgeirsson SS. Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth Factor/c-met, TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res 1997;3(7):1059-1066
54. Yeh YC, Tsai JF, Chuang LY, et al. Elevation of transforming growth factor alpha and its relationship to the epidermal growth factor and alpha-fetoprotein levels in patients with hepatocellular carcinoma. Cancer Res 1987;47(3):896-901
55. Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 2007;110(5):1059- 1067
56. O'Dwyer PJ, Giantonio BJ, Levy DE, et al. Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Group's Study E1203. 2006 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2006;24(18S):4143
57. Ramanathan RK, Belani CP, Singh DA, et al. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 2009;64(4):777-783
58. Bekaii-Saab T, Markowitz J, Prescott N, et al. A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas. Clin Cancer Res 2009;15(18):5895-5901
59. Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 2007;110(3):581-589
60. Gruenwald V, Wilkens L, Gebel M, et al. A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma: final results. 2007 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;25(18S):4598
61. Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer 2007;109(7):1384-1390
62. O'Neil BH, Bernard SA, Goldberg RM, et al. Phase II study of oxaliplatin, capecitabine, and cetuximab in advanced hepatocellular carcinoma. J Clin Oncol 2008;26(20 Suppl):abstract 4604
63. Villanueva A, Chiang DY, Newell P, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008;135(6):1972-1983, 83 e1-11
64. Chen L, Shiah HS, Chen CY, et al. Randomized, phase I, and pharmacokinetic (PK) study of RAD001, an mTOR inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2009;27(15S):abstract 4587
65. Huynh H, Nguyen TT, Chow KH, et al. Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterol 2003;3:19
66. O'Neil BH, Williams-Goff LW, Kauh J, et al. A phase II study of AZD6244 in advanced or metastatic hepatocellular carcinoma. J Clin Oncol 2009;27(Suppl):abstract 15574