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Ramucirumab as a second line therapy for advanced HCC: a significant achievement or a wasted opportunity for personalised therapy?

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Summary

The second line treatment of hepatocellular carcinoma (HCC) has recently become an exciting area of interest since new emerging options have demonstrated survival benefits versus placebo. Unfortunately, predictive biomarkers are unavailable for these treatments. Ramucirumab, a monoclonal antibody against VEGFR-2, has demonstrated overall survival superiority against placebo as a second line therapy for patients with AFP > 400 ng/ml in the recent REACH-2 trial. This review will provide the current updated knowledge regarding the HCC cancerogenesis and angiogenic VEGF/VEGFR-2 pathways and the clinical development of ramucirumab in advanced HCC. This study will also critically assess the gaps in a previous negative phase III trial that tested other potentially useful treatments and suggest ways to modernise clinical trials and personalise therapy for advanced HCC.

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References

  1. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis M, Roberts LR, Zhu AX, Murad MH M, and Marrero J. AASLD Guidelines for the Treatment of Hepatocellular Carcinoma. Hepatology, Vol 67, No.1, 2018

  2. AACR Cancer Progress Writing Committee (2013) AACR Cancer Progress report 2013. Clin Cancer Res 19:S4–S98

    Google Scholar 

  3. European Association for the Study of the Liver (2018) EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 69:182–236

    Article  Google Scholar 

  4. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, Robles-Aviña J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T, Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng AL (2013) 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 31(28):3517–3524

    Article  CAS  PubMed  Google Scholar 

  5. Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, Kudo M, Kang YK, Chen PJ, Toh HC, Gorbunova V, Eskens FA, Qian J, McKee MD, Ricker JL, Carlson DM, El-Nowiem S (2015 Jan 10) Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 33(2):172–179

    Article  CAS  PubMed  Google Scholar 

  6. Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, Chung HC, Song X, Xu J, Poggi G, Omata M, Pitman Lowenthal S, Lanzalone S, Yang L, Lechuga MJ, Raymond E (2013) Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 31:4067–4075

    Article  CAS  PubMed  Google Scholar 

  7. Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, Bruix J, Qin S, Thuluvath PJ, Llovet JM, Leberre MA, Jensen M, Meinhardt G, Kang YK (2015 Feb 20) SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 33(6):559–566

    Article  CAS  PubMed  Google Scholar 

  8. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V, Mathurin P, Fartoux L, Lin DY, Bruix J, Poon RT, Sherman M, Blanc JF, Finn RS, Tak WY, Chao Y, Ezzeddine R, Liu D, Walters I, Park JW (2013 Oct 1) Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 31(28):3509–3516

    Article  CAS  PubMed  Google Scholar 

  9. Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, Poon RTP, Blanc JF, Vogel A, Chen CL, Dorval E, Peck-Radosavljevic M, Santoro A, Daniele B, Furuse J, Jappe A, Perraud K, Anak O, Sellami DB, Chen LT (2014) Effect of everolimus on survival in advanced hepatocellular carci- Noma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 312(1):57–67

    Article  PubMed  CAS  Google Scholar 

  10. Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, Rota Caremoli E, Porta C, Daniele B, Bolondi L, Mazzaferro V, Harris W, Damjanov N, Pastorelli D, Reig M, Knox J, Negri F, Trojan J, López López C, Personeni N, Decaens T, Dupuy M, Sieghart W, Abbadessa G, Schwartz B, Lamar M, Goldberg T, Shuster D, Santoro A, Bruix J (2018 May) Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol 19(5):682–693

    Article  CAS  PubMed  Google Scholar 

  11. Abou-Alfa G, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Park JW, Blanc JF, Bolondi L, Klümpen HJ, Chan L, Dadduzio V, Hessel C, Borgman-Hagey A, Schwab G, Kelley RK (2018) Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial. J Clin Oncol 36(suppl 4S; abstr 207)

    Article  Google Scholar 

  12. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL (2018) Lenvatinib versus sorafenib in first- line treatment of patients with unresectable hepatocellular carci- Noma: a randomised phase 3 non-inferiority trial. Lancet 391:1163–1173

    Article  CAS  PubMed  Google Scholar 

  13. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Rd WTH, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I (2017 Jun 24) Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389(10088):2492–2502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB (2019 Feb) Kudo M; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20(2):282–296

    Article  CAS  PubMed  Google Scholar 

  15. Forner A, Llovet JM, Bruix J (2012) Hepatocellular carcinoma. Lancet. 379:1245–1255

    Article  PubMed  Google Scholar 

  16. Villanueva A, Llovet JM (2014) Mutational landscape of HCC – the end of the beginning. Nat Rev Clin Oncol 11:73–74

    Article  CAS  PubMed  Google Scholar 

  17. Llovet JM, Villanueva A, Lachenmayer A, Finn R (2015) Advances in target therapies for hepatocellular carcinoma in genomic era. Nat Rev Clin Oncol 12:408–424

    Article  CAS  PubMed  Google Scholar 

  18. Sawey E, Chanrion M, Cai C, Wu G, Zhang J, Zender L, Zhao A, Busuttil RW, Yee H, Stein L, French DM, Finn RS, Lowe SW, Powers S (2011 Mar 8) Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening. Cancer Cell 19(3):347–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zucman-Rossi J, Villeneuve A, Nault JC, Llovet J (2015) Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 149:1226–1239

    Article  CAS  PubMed  Google Scholar 

  20. Chuma M, Terashita K, Sakamoto N (2015) New molecularly targeted therapies against advanced hepatocellular carcinoma: from molecular pathogenesis to clinical trials and future directions. Hepatol Res 45:E1–E11

    Article  CAS  PubMed  Google Scholar 

  21. Hoshida Y, Moeini A, Alsinet C, Kojima K, Villanueva A (2012) Gene signatures in management of hepatocellular carcinoma. Semin Oncol 4:473–485

    Article  CAS  Google Scholar 

  22. Nault JC, De Reyniès A, Villanueva A, Calderaro J, Rebouissou S, Couchy G, Decaens T, Franco D, Imbeaud S, Rousseau F, Azoulay D, Saric J, Blanc JF, Balabaud C, Bioulac-Sage P, Laurent A, Laurent-Puig P, Llovet JM, Zucman-Rossi J (2013 Jul) A hepatocellular carcinoma 5-gene score associated with survival of patients after liver resection. Gastroenterology. 145(1):176–187

    Article  CAS  PubMed  Google Scholar 

  23. Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, Durnez A, Demetris AJ, Thorgeirsson SS (2004 Sep) Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 40(3):667–676

    Article  CAS  PubMed  Google Scholar 

  24. Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, Villanueva A, Newell P, Ikeda K, Hashimoto M, Watanabe G, Gabriel S, Friedman SL, Kumada H, Llovet JM, Golub TR (2009 Sep 15) Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 69(18):7385–7392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Muto J, Shirabe K, Sugimachi K, Maehara Y (2015) Review of angiogenesis in hepatocellular carcinoma. Hepatol Res 45:1–9

    Article  PubMed  Google Scholar 

  26. Choi BI (2004) The current status of imaging diagnosis of hepatocellular carcinoma. Liver Transpl 10:S20–S25

    Article  PubMed  Google Scholar 

  27. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature. 473:298–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhu A, Duda DG, Sahani DV, Jain R (2011) HCC and angiogenesis: possible targets and future directions. Nat Rev Clin Oncol 8:292–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zetter BR (1998) Angiogenesis and tumor metastasis. Annu Rev Med 49:407–424

    Article  CAS  PubMed  Google Scholar 

  30. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  CAS  PubMed  Google Scholar 

  31. Tsunoda S, Nakamura T, Sakurai H et al (2007) Fibroblast growth factor 2- induced host stroma reaction during initial tumor growth promotes progression of mouse melanoma via vascular endothelial growth factor A-dependent neovascularization. Cancer Sci 98:541–548

    Article  CAS  PubMed  Google Scholar 

  32. Ghouri YA, Mian I, Rowe JH (2017) Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis. J Carcinog 16:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N, Selig M, Nielsen G, Taksir T, Jain RK, Seed B (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell. 94:715–725

    Article  CAS  PubMed  Google Scholar 

  34. Lichtenberger BM, Tan PK, Niederleithner H, Ferrara N, Petzelbauer P, Sibilia M (2010) Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell. 140:268–279

    Article  CAS  PubMed  Google Scholar 

  35. Masood R, Cai J, Zheng T, Smith DL, Hinton DR, Gill PS (2001) Vascular endothelial growth factos (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors. Blood 98:1904–1913

    Article  CAS  PubMed  Google Scholar 

  36. Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK (2001) Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res 61:6020–6024

    CAS  PubMed  Google Scholar 

  37. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Huang Y, Goel S, Duda DG, Fukumura D, Jain RK (2013) Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 73:2943–2948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, Dubreuil O, Carpentier AF, Tartour E, Taieb J (2013) VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 73:539–549

    Article  CAS  PubMed  Google Scholar 

  40. Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312:549–560

    Article  CAS  PubMed  Google Scholar 

  41. El-Assal ON et al (1998) Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology 27:1554–1562

    Article  CAS  PubMed  Google Scholar 

  42. Poon RT-P, Lau CP-Y, Cheung S-T, Yu W-C, Fan S-T (2003) Quantitative correlation of serum levels and tumor expression of vascular endothelial growth factor in patients with hepatocellular carcinoma. Cancer Res 63:3121–3126

    CAS  PubMed  Google Scholar 

  43. Yao DF, Wu XH, Zhu Y, Shi GS, Dong ZZ, Yao DB, Wu W, Qiu LW, Meng XY (2005) Quantitative analysis of vascular endothelial growth factor, microvascular density and their clinicopathologic features in human hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 4:220–226

    CAS  PubMed  Google Scholar 

  44. Zhou J, FanZhi-Quan T, Xiao-Ming W, Yin-Kun L, Fei L, Hui-Chuan L, Ye S-l (2000) Expression of platelet-derived endothelial cell growth factor and vascular endothelial growth factor in hepatocellular carcinoma and portal vein tumor thrombus. J Cancer Res Clin Oncol 126:57–61

    Article  CAS  PubMed  Google Scholar 

  45. Schoenleber SJ, Kurtz DM, Talwalkar JA, Roberts LR, Gores GJ (2009) Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br J Cancer 100:1385–1392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhan P, Qian Q, Yu L (2013) Prognostic significance of vascular endothelial growth factor expression in hepatocellular carcinoma tissue: a meta-analysis. Hepatobiliary Surg Nutr 2(3):148–155

    PubMed  PubMed Central  Google Scholar 

  47. Guangchao C, Xiaoyun L, Chao Q, Jie L (2015) Prognostic value of VEGF in hepatocellular carcinoma patients treated with Sorafenib: a meta-analysis. Med Sci Monit 21:3144–3151

    Article  Google Scholar 

  48. Poor RT et al (2002) Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: a comparison with angiopoietin/tie pathway. Anticancer Res 22:379–386

    Google Scholar 

  49. Huang J, Zhang X, Tang Q, Zhang F, Li Y, Feng Z, Zhu J (2011) Prognostic significance and potential therapeutic target of VEGFR2 in hepatocellular carcinoma. J Clin Pathol 64:343e348

    Google Scholar 

  50. Llovet JM, Pena CE, Lathia CD, Shan M, Meinhardt G, Bruix J (2012) Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res 18:2290–2300

    Article  CAS  PubMed  Google Scholar 

  51. Lu D, Shen J, Vil MD, Zhang H et al (2003) Tailoring in vitro selection for a picomolar affinity human antibody directed against vascular endothelial growth factor receptor 2 for enhanced neutralizing activity. J Biol Chem 278:43496–43507

    Article  CAS  PubMed  Google Scholar 

  52. Zhu AX, Finn RS, Mulcahy M, Gurtler J, Sun W, Schwartz JD, Dalal RP, Joshi A, Hozak RR, Xu Y, Ancukiewicz M, Jain RK, Nugent FW, Duda DG, Stuart K (2013) A phase II and biomarker study of Ramucirumab, a human monoclonal antibody targeting the VEGF Receptor-2, as first-line monotherapy in patients with advanced hepatocellular Cancer. Clin Cancer Res 19:6614–6623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tangkijvanich P et al (2000) Clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels. J Clin Gastroenterol 31:302–308

    Article  CAS  PubMed  Google Scholar 

  54. Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, Nakanishi K, Fujimoto I, Inoue A, Yamazaki H, Kawashima T (1993) Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328:1797–1801

    Article  CAS  PubMed  Google Scholar 

  55. Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O'Bryant C, Chow LQM, Serkova NJ et al (2010) Phase I pharmacologic and biologic study of Ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor Receptor-2. J Clin Oncol 28:780–787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chiorean EG, Hurwitz HI, Cohen RB, Schwartz JD, Dalal RP, Fox FE, Gao L, Sweeney CJ (2015) Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth fac- tor receptor-2 in patients with advanced solid tumors. Ann Oncol 26(6):1230–1237

    Article  CAS  PubMed  Google Scholar 

  57. Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Pfiffer TE, Okusaka T, Kubackova K, Trojan J, Sastre J, Chau I, Chang SC, Abada PB, Yang L, Schwartz JD (2015 Jul) Kudo M; REACH trial investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 16(7):859–870

    Article  CAS  PubMed  Google Scholar 

  58. Zhu A, Finn R, Galle P, Llovet J, Blanc JF, Okusaka T, Chau I, Abada P, Hsu Y, Kudo M (2018) Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: Pooled efficacy and safety across two global randomized Phase 3 studies (REACH-2 and REACH). Ann Oncol 29(Supplement 5):v122–v123

    Article  Google Scholar 

  59. Tangkijvanich P et al (2000) Clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels. J Clin Gastroenterol 31:302–308

    Article  CAS  PubMed  Google Scholar 

  60. Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, Nakanishi K, Fujimoto I, Inoue A, Yamazaki H, Kawashima T (1993) Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328:1797–1801

    Article  CAS  PubMed  Google Scholar 

  61. Biselli M, Conti F, Gramenzi A, Frigerio M, Cucchetti A, Fatti G, D'Angelo M, Dall'Agata M, Giannini EG, Farinati F, Ciccarese F, Andreone P, Bernardi M, Trevisani F (2015) A new approach to the use of a-fetoprotein as surveillance test for hepatocellular carcinoma in patients with cirrhosis. Br J Cancer 112:69–76

    Article  CAS  PubMed  Google Scholar 

  62. Di Bisceglie AM, Sterling RK, Chung RT, Everhart JE, Dienstag JL, Bonkovsky HL et al (2005) Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C trial. J Hepatol 43:434–441

    Article  PubMed  CAS  Google Scholar 

  63. Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, Budhu A, Zanetti KA, Chen Y, Qin LX, Tang ZY, Wang XW (2008) EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 68:1451–1461

    Article  CAS  PubMed  Google Scholar 

  64. Pons F, Varela M, Llovet JM (2005) Staging systems in hepatocellular carcinoma. HPB (Oxford) 7:35–41

    Article  Google Scholar 

  65. Huang J, Zhang X, Tang Q, Zhang F, Li Y, Feng Z, Zhu J (2011) Prognostic significance and potential therapeutic target of VEGFR2 in hepatocellular carcinoma. J Clin Pathol 64:343–348

    Article  CAS  PubMed  Google Scholar 

  66. Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, Budhu A, Zanetti KA, Chen Y, Qin LX, Tang ZY, Wang XW (2008) EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 68:1451–1461

    Article  CAS  PubMed  Google Scholar 

  67. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clément B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouzé E, Calvo F, Zucman-Rossi J (2012) Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 44:694–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Thillai K, Ross P, Sarker D (2016) Molecularly targeted therapy for advanced hepatocellular carcinoma - a drug development crisis? WJGO 8(2):173–185

    Article  PubMed  PubMed Central  Google Scholar 

  69. Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, Sindhwani V, Blaszkowsky LS, Yoon SS, Lahdenranta J, Bhargava P, Meyerhardt J, Clark JW, Kwak EL, Hezel AF, Miksad R, Abrams TA, Enzinger PC, Fuchs CS, Ryan DP, Jain RK (2009) Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 27:3027–3035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, Van Vlierberghe H, Trojan J, Kolligs FT, Weiss A, Miles S, Gasbarrini A, Lencioni M, Cicalese L, Sherman M, Gridelli C, Buggisch P, Gerken G, Schmid RM, Boni C, Personeni N, Hassoun Z, Abbadessa G, Schwartz B, Von Roemeling R, Lamar ME, Chen Y, Porta C (2013) Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebocontrolled phase 2 study. Lancet Oncol 14:55–63

    Article  CAS  PubMed  Google Scholar 

  71. McNamara MG, Le LW, Horgan AM, Aspinall A, Burak KW, Dhani N, Chen E, Sinaei M, Lo G, Kim TK, Rogalla P, Bathe OF, Knox JJ (2015 May 15) A phase II trial of second-line axitinib following prior antiangiogenic therapy in advanced hepatocellular carcinoma. Cancer. 121(10):1620–1627

    Article  CAS  PubMed  Google Scholar 

  72. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G (2017) Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blin d, placebo-c ontrolle d, phase 3 trial. Lancet 389:56–66

    Article  CAS  PubMed  Google Scholar 

  73. Lin J, Liangcai W, Bai X, Wang A, Zhang H, Xiaobo Y, Wan X, Lu X, Sang X, Zhao H (2016) Combination treatment including targeted therapy for advanced hepatocellular carcinoma. Oncotarget 25:71036–71051

    Article  Google Scholar 

  74. Finn R, Zhu A, Farah W, Almasri J, Zaiem F, Prokop F (2018) Therapies for advanced stage hepatocellular carcinoma with macrovascular invasion or metastatic disease: a systematic review and meta-analysis. Hepatology 67:422–435

    Article  CAS  PubMed  Google Scholar 

  75. Allain C, Angenard G, Clement B, Coulouarn C (2016) Integrative genomic analysis identifies the core transcriptional hallamarks of human hepatocellular carcinoma. Cancer Res 21:OF1–OF8

    Google Scholar 

  76. Roviello G, Zanotti L, Cappelletti MR, Gobbi A, Borsella G, Pacifico C, Multari AG, Generali D (2016 Dec) New molecular therapies in patients with advanced hepatocellular Cancer in second line of treatment: is a real defeat?: results from a literature based meta-analysis of randomized trials. Crit Rev Oncol Hematol 108:62–68

    Article  PubMed  Google Scholar 

  77. Allen Chan KC (2013) Scanning for Cancer genomic changes in plasma: toward an era of personalized blood-based tumor markers. Clin Chem 59:1553–1555

    Article  CAS  Google Scholar 

  78. Chau I, Peck-Radosavljevic M, Borg C, Malfertheiner P, Seitz JF, Park JO, Ryoo BY, Yen CJ, Kudo M, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Okusaka T, Bowman L, Cui ZL, Girvan AC, Abada PB, Yang L, Zhu AX (2017 Aug) Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: patient-focused outcome results from the randomised phase III REACH study. Eur J Cancer 81:17–25

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Health Sciences, University of Florence, viale Pieraccini, 6, 50139, Florence, Italy

    Giandomenico Roviello

  2. Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129, Trieste, Italy

    Navid Sohbani

  3. Medical Oncology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy

    Roberto Petrioli

  4. Division of Medical Oncology, Department of Onco-Hematology, IRCCS-CROB, Referral Cancer Center of Basilicata, via Padre Pio 1, 85028, Rionero, Vulture, PZ, Italy

    Maria Grazia Rodriquenz

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Rodriquenz MG declares that she has no conflict of interest. Sohbani N declares that he has no conflict of interest. Petrioli R declares that he has no conflict of interest. Roviello G declares that he has no conflict of interest.

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Roviello, G., Sohbani, N., Petrioli, R. et al. Ramucirumab as a second line therapy for advanced HCC: a significant achievement or a wasted opportunity for personalised therapy?. Invest New Drugs 37, 1274–1288 (2019). https://doi.org/10.1007/s10637-019-00760-0

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  • DOI: https://doi.org/10.1007/s10637-019-00760-0

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