Systemic therapies for hepatocellular carcinoma: a recap of the current status

Abstract

After decades of frustrating nihilism due to lack of innovative therapeutic solutions, the onco-hepatological community is facing up to important novelties for the treatment of intermediate and advanced stages of liver cancer. Four new drugs have been investigated and resulted in positive data: lenvatinib resulted not inferior to the standard of care sorafenib in first line, regorafenib and cabozantinib demonstrated prolonging survival in patients progressed to sorafenib and nivolumab approved by FDA as option after first-line. Contemporary, the knowledge acquired after ten years’ experience of sorafenib in patient selection and adverse events management revealed an increase of the outcomes. Physicians dedicated to treat advanced and intermediated liver cancer are close to live a new era where systemic treatments could have a huge impact on the disease. The aim of this review is to anticipate this new approach at the disease, summarizing data currently available for these therapies to identify therapeutic strategies of sequences and choosing drugs according to the patient profile.

Keywords

Hepatocellular carcinoma / liver cancer / sorafenib / regorafenib / lenvatinib / cabozantinib / nivolumab

References

[1] Fischer S,Rothermundt C.Sequence of treatment in locally advanced and metastatic renal cell carcinoma..Transl Androl Urol2015;4:310-25 PMCID:PMC4708238

[2] Siegel RL,Jemal A.Cancer statistics, 2017..CA Cancer J Clin2017;67:7-30

[3] Zhu AX.Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be?.Oncologist2006;11:790-800

[4] Pinter M,Peck-Radosavljevic M.Cancer and liver cirrhosis: implications on prognosis and management..ESMO Open2016;1:e000042 PMCID:PMC5070280

[5] Llovet JM,Mazzaferro V,Gane E,de Oliveira AC,Raoul JL,Schwartz M,Zeuzem S,Greten TF,Seitz JF,Haussinger D,Shan M,Voliotis D,Group SIS.Sorafenib in advanced hepatocellular carcinoma..N Engl J Med2008;359:378-90

[6] Forner A,Bruix J.Hepatocellular carcinoma..Lancet2018;391:1301-14

[7] Kudo M,Qin S,Ikeda K,Baron A,Han G,Blanc JF,Komov D,Lopez C,Guo M,Kraljevic S,Ren M.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial..Lancet2018;391:1163-73

[8] Bruix J,Merle P,Huang YH,Pracht M,Rosmorduc O,Gerolami R,Ross PJ,Bronowicki JP,Kudo M,Llovet JM,LeBerre MA,Meinhardt G,Investigators R.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial..Lancet2017;389:56-66

[9] IPSEN Press Release. Ipsen announces that phase 3 CELESTIAL trial of cabozantinib meets primary endpoint of overall survival in patients with advanced hepatocellular carcinoma. Available from: https://www.ipsen.com/websites/IPSENCOM-PROD/wp-content/uploads/2017/10/16115941/16-10-2017-IPSEN-CELESTIAL-OS-EN-FINAL-FINAL.pdf [Last accessed on 18 Apr 2017].

[10] BMS Press Release. Bristol-Myers Squibb's Opdivo^® (nivolumab) receives FDA approval for the treatment of hepatocellular carcinoma patients previously treated with sorafenib. Available from: https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibbs-opdivo-nivolumab-receives-fda-approval-t [Last accessed on 18 Apr 2017].

[11] Faivre S,Raymond E.Learning from 7 years of experience with sorafenib in advanced HCC: sorafenib better than sorafenib?.Target Oncol2016;11:565-7

[12] Bolondi L,Trevisani F,Di Costanzo GG,Camma C,Danesi R,Boni C,Colombo M.Refining sorafenib therapy: lessons from clinical practice..Future Oncol2015;11:449-65

[13] Lin S,Schemmer P.Treatment of hepatocellular carcinoma: a systematic review..Liver Cancer2012;1:144-58 PMCID:PMC3760458

[14] European Association For The Study Of The Liver..EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma..J Hepatol2012;56:908-43

[15] Salhab M.An overview of evidence-based management of hepatocellular carcinoma: a meta-analysis..J Cancer Res Ther2011;7:463-75

[16] Raoul JL,Forner A,Piscaglia F,Lencioni R.Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization..Cancer Treat Rev2011;37:212-20

[17] Bolondi L,Dufour JF,Mazzaferro V,Raoul JL.Heterogeneity of patients with intermediate (BCLC-B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions..Semin Liver Dis2012;32:348-59

[18] Verslype C,Rougier P.Hepatocellular carcinoma: ESMO–ESDO clinical practice guidelines for diagnosis, treatment and follow-up..Ann Oncol2012;23:vii41-8

[19] Sieghart W,Peck-Radosavljevic M.Transarterial chemoembolization: modalities, indication, and patient selection..J Hepatol2015;62:1187-95

[20] Raoul JL,Piana G.How to define transarterial chemoembolization failure or refractoriness: a European perspective..Liver Cancer2014;3:119-24 PMCID:PMC4057788

[21] Sieghart W,Pinter M,Vogel W,Heinzl H,Peck-Radosavljevic M.The ART of decision making: retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma..Hepatology2013;57:2261-73

[22] Hucke F,Pinter M,Vogel W,Heinzl H,Trauner M.The ART-strategy: sequential assessment of the ART score predicts outcome of patients with hepatocellular carcinoma re-treated with TACE..J Hepatol2014;60:118-26

[23] Llovet JM.Negative phase 3 study of (90)Y microspheres versus sorafenib in HCC..Lancet Oncol2018;19:e69

[24] Vilgrain V,Assenat E,Ilonca AD,Sibert A,Lebtahi R,Barraud H,Mathias E,Tasu JP,Silvain C,Mundler O,Vidal V,Oberti F,Brenot-Rossi I,Sarran A,Itti E,Adam R,Samuel D,Dinut A,Chatellier G.Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial..Lancet Oncol2017;18:1624-36

[25] Chow PK,Gebski V.The SIRveNIB and SARAH trials and the role of SIR-Spheres(R) Y-90 resin microspheres in the management of hepatocellular carcinoma..Future Oncol2017;13:2213-6

[26] Cheng AL,Chen Z,Qin S,Luo R,Ye S,Xu J,Liang H,Wang J,Pan H,Zou J,Guan Z.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 Oncol2009;10:25-34

[27] Forner A,Bruix J.Hepatocellular carcinoma..Lancet2012;379:1245-55

[28] Bruix J,Meinhardt G,De Sanctis Y.Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies..J Hepatol2017;67:999-1008

[29] Kudo M,Marrero JA,Bronowicki JP,Dagher L,Geschwind JF,Papandreou C,Takayama T,Nakajima K,Heldner S.Regional differences in sorafenib-treated patients with hepatocellular carcinoma: GIDEON observational study..Liver Int2016;36:1196-205

[30] Iavarone M,Piscaglia F,Grieco A,Camma C.Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy..Hepatology2011;54:2055-63

[31] Ponziani FR,Germini A,Flores M,Facciorusso A,Mazzaferro V.Inducing tolerability of adverse events increases sorafenib exposure and optimizes patient's outcome in advanced hepatocellular carcinoma..Liver Int2016;36:1033-42

[32] Reig M,Rodriguez-Lope C,NLL,Darnell A,Ayuso C.Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib..J Hepatol2014;61:318-24

[33] Bettinger D,Knuppel E,Blum HE.Diarrhea predicts a positive response to sorafenib in patients with advanced hepatocellular carcinoma..Hepatology2012;56:789-90

[34] Otsuka T,Kawazoe S,Ario K,Kawasoe H,Mizuta T.Skin toxicities and survival in advanced hepatocellular carcinoma patients treated with sorafenib..Hepatol Res2012;42:879-86

[35] Estfan B,Kim R.Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy..Am J Clin Oncol2013;36:319-24

[36] Vincenzi B,Russo A,Giuliani F,Rizzo S,Frezza AM,Colucci G,Tonini G.Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib..Oncologist2010;15:85-92 PMCID:PMC3227883

[37] Kudo M.Locoregional therapy for hepatocellular carcinoma..Liver Cancer2015;4:163-4 PMCID:PMC4608615

[38] Lencioni R,Han G,Yang J,Paik SW,Kim DY,Luca A,Leberre MA,Nicholson K,Bruix J.Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial..J Hepatol2016;64:1090-8

[39] Bruix J,Mazzaferro V,Yang J,Cai J,Han KH,Lee HC,Roayaie S,Lee KS,Souza F,Meinhardt G.Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial..Lancet Oncol2015;16:1344-54

[40] Zhong JH,Xiang BD.Adjuvant sorafenib in hepatocellular carcinoma: a cautionary comment of STORM trial..World J Hepatol2016;8:957-60 PMCID:PMC4990759

[41] Geschwind JH.Sorafenib in combination with transarterial chemoembolization for the treatment of hepatocellular carcinoma..Gastroenterol Hepatol2016;12:504-6

[42] NCT02529761. TACE With or Without Sorafenib in Intermediate Stage Hepatocellular Carcinoma. Available from: https://clinicaltrials.gov/ct2/show/NCT02529761 [Last accessed on 18 Apr 2018].

[43] NCT03097848. Efficacy and Safety of Sorafenib as Adjuvant and Latter Radiofrequency Ablation for Recurrent Hepatocellular Carcinoma (ESCALATOR). Available from: https://clinicaltrials.gov/ct2/show/NCT03097848 [Last accessed on 18 Apr 2018].

[44] NCT02436902. Adjuvant Therapies for Patients With HCC and MVI (A-TACE/S-HCC). Available from: https://clinicaltrials.gov/ct2/show/NCT02436902 [Last accessed on 18 Apr 2018].

[45] Zhu AX,Evans TR,Santoro A,Bruix J,Thuluvath PJ,Leberre MA,Meinhardt G.Search: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma..J Clin Oncol2015;33:559-66

[46] Abou-Alfa GK,Knox JJ,Davidenko I,Leung T,Saltz LB.Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial..JAMA2010;304:2154-60

[47] Treating Advanced Hepatocellular Carcinoma in 2018. Available from: https://gicasym.org/daily-news/treating-advanced-hepatocellular-carcinoma-2018 [Last accessed on 18 Apr 2018].

[48] Abou-Elkacem L,Brix G,Zopf D,Lederle W.Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model..Mol Cancer Ther2013;12:1322-31

[49] Bruix J,Gasbarrini A,Colombo M,Mazzaferro V,Reig M,Bolondi L.Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study..Eur J Cancer2013;49:3412-9

[50] Bruix J,Merle P,Huang YH,Pracht M,Rosmorduc O,Gerolami R,Ross PJ,Bronowicki JP,Kudo M,Llovet JM,LeBerre MA,Meinhardt G.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial..Lancet2016;6736:32453-9

[51] Finn RS,Granito A,Bodoky G,Yokosuka O,Gerolami R,Cabrera R,Sun W,Le Berre MA,Meinhardt G.Outcomes with sorafenib (SOR) followed by regorafenib (REG) or placebo (PBO) for hepatocellular carcinoma (HCC): results of the international, randomized phase 3 RESORCE trial..J Clin Oncol2017;35 suppl 4:abstr344

[52] Lorusso L,Biagini A,Valerio L,Passannanti P,Battaglia V,Molinaro E.Lenvatinib and other tyrosine kinase inhibitors for the treatment of radioiodine refractory, advanced, and progressive thyroid cancer..Onco Targets Ther2016;9:6467-77 PMCID:PMC5079697

[53] Motzer RJ,Ren M,Larkin J.Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma..Lancet Oncol2016;17:e4-5

[54] Ikeda K,Kawazoe S,Ikeda M,Tamai T,Hisai T,Okita K.Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma..J Gastroenterol2017;52:512-9 PMCID:PMC5357473

[55] Kudo M,Qin S,Ikeda K,Baron A,Han G,Blanc JF,Komov D,Lopez C,Guo M,Kraljevic S,Ren M.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase III non-inferiority trial..Lancet2018;391:1163-73

[56] Markowitz JN.Cabozantinib: a multitargeted oral tyrosine kinase inhibitor..Pharmacotherapy2018;38:357-69

[57] Kelley RK,Cohn AL,Su WC,Braiteh F,Spira A,Lee Y.Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study..Ann Oncol2017;28:528-34 PMCID:PMC5391701

[58] Abou-Alfa GKMT.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 Oncol2018;36:207

[59] El-Khoueiry AB,Yau T,Kudo M,Kim TY,Trojan J,Meyer T,Yeo W,Anderson J,Lang L,Tang H,Melero I.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial..Lancet2017;389:2492-502

[60] NCT02576509. An Investigational Immuno-therapy Study of Nivolumab Compared to Sorafenib as a First Treatment in Patients With Advanced Hepatocellular Carcinoma. Available from: https://clinicaltrials.gov/ct2/show/NCT02576509 [Last accessed on 18 Apr 2018].

[61] Yoon SM,Lee SJ,Shin JH,Lee HC.Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: a randomised clinical trial..JAMA Oncol2018;;

[62] Kudo M,Kokudo N,Sakamoto M,Kojiro M.Management of hepatocellular carcinoma in Japan: consensus-based clinical practice guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version..Dig Dis2011;29:339-63

[63] Yamanaka K,Kitamura K,Ishii T,Taura K,Isoda H,Uemoto S.Early evaluation of transcatheter arterial chemoembolization-refractory hepatocellular carcinoma..J Gastroenterol2012;47:343-6

[64] Italian Association for the Study of the Liver (AISF), AISF Expert Panel, AISF Coordinating Committee..Position paper of the Italian Association for the Study of the Liver (AISF): the multidisciplinary clinical approach to hepatocellular carcinoma..Dig Liver Dis2013;45:712-23

[65] Verslype C,Rougier P.Hepatocellular carcinoma: ESMO-ESDO clinical practice guidelines..Ann Oncol2012;23:vii41-8

[66] Bruix J.AASLD PRACTICE GUIDELINE management of hepatocellular carcinoma: an update..Hepatology2011;53:1020-2 PMCID:PMC3084991

[67] PR Newswire Release. Lilly Announces CYRAMZA^® (ramucirumab) Phase 3 REACH-2 Study in Second-Line Hepatocellular Carcinoma Patients Met Overall Survival Endpoint. Available from: https://www.prnewswire.com/news-releases/lilly-announces-cyramza-ramucirumab-phase-3-reach-2-study-in-second-line-hepatocellular-carcinoma-patients-met-overall-survival-endpoint-300624113.html [Last accessed on 19 Apr 2018]