Immunotherapy and immunotherapy biomarkers for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is increasing in prevalence and has the potential to be a highly lethal malignancy. Patients with early-stage HCC have potentially curative therapeutic options, but treatments for more advanced HCC were limited until recently. Historically, tyrosine kinase inhibitors have been used in both the first- and second-line treatment of patients with advanced HCC; however, given HCC’s highly immune-responsive origins, immunotherapy is proving to be a promising systemic therapy in the frontline as well as later lines of treatment. Notably, recent studies of the novel antibody therapy combination atezolizumab (anti-PD-L1) and bevacizumab demonstrated unprecedented, practice-changing efficacy in the advanced HCC setting and led to its Food and Drug Administration approval. Although such landmark studies offer new treatment options for patients with HCC, the role of potential biomarkers to monitor immunotherapy response is largely unknown and undergoing exploration.

Keywords

Hepatocellular carcinoma / immunotherapy / checkpoint inhibitor / biomarkers

References

[1] Ferlay J,Soerjomataram I.Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods..Int J Cancer2019;144:1941-53

[2] Siegel RL,Jemal A.Cancer statistics, 2020..CA Cancer J Clin2020;70:7-30

[3] Fattovich G,Zagni I.Hepatocellular carcinoma in cirrhosis: incidence and risk factors..Gastroenterology2004;127:S35-50

[4] Mittal S.Epidemiology of hepatocellular carcinoma: consider the population..J Clin Gastroenterol.2013;47 Suppl:S2-6 PMCID:PMC3683119

[5] Fitzmorris P.Surveillance and Diagnosis of Hepatocellular Carcinoma..Gastroenterol Hepatol (N Y)2015;11:38-46 PMCID:PMC4836577

[6] Kudo M.Japan’s Successful Model of Nationwide Hepatocellular Carcinoma Surveillance Highlighting the Urgent Need for Global Surveillance..Liver Cancer2012;1:141-3 PMCID:PMC3760465

[7] Vitale A,Giannini EG.Personalized treatment of patients with very early hepatocellular carcinoma..J Hepatol2017;66:412-23

[8] Santambrogio R,Costa M.Hepatic resection for hepatocellular carcinoma in patients with Child-Pugh’s A cirrhosis: is clinical evidence of portal hypertension a contraindication?.HPB (Oxford)2013;15:78-84 PMCID:PMC3533715

[9] Xu DW,Xia Q.Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: A review..World J Gastroenterol2016;22:3325-34 PMCID:PMC4806190

[10] Ye SL,Geschwind J,Bronowicki JP.Current approaches to the treatment of early hepatocellular carcinoma..Oncologist.2010;15 Suppl 4:34-41

[11] Burak KW.Prognosis in the early stages of hepatocellular carcinoma: Predicting outcomes and properly selecting patients for curative options..Can J Gastroenterol2011;25:482-4 PMCID:PMC3202354

[12] Byam J,Millis JM.Liver transplantation for hepatocellular carcinoma. Hepatobiliary surgery and nutrition 2013;2:22-30..Hepatobiliary Surg Nutr2013;2:22-30 PMCID:PMC3924634

[13] Mazzaferro V,Doci R.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis..N Engl J Med1996;334:693-9

[14] Lencioni R,Crocetti L.Chemoembolization of hepatocellular carcinoma..Semin Intervent Radiol2013;30:3-11 PMCID:PMC3700789

[15] Yamakado K,Nakatsuka A.Radiofrequency ablation for hepatocellular carcinoma..Gastrointest Interv2014;3:35-39

[16] Llovet JM,Mazzaferro V.Sorafenib in advanced hepatocellular carcinoma..N Engl J Med2008;359:378-90

[17] Cheng A,Chen 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 Oncology2009;10:25-34

[18] Abou-Alfa GK,Cheng AL.Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma..N Engl J Med2018;379:54-63 PMCID:PMC7523244

[19] Bruix J,Merle P.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

[20] Finn RS,Ikeda M.Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma..N Engl J Med2020;382:1894-905

[21] Kudo M,Qin S.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial..Lancet2018;391:1163-73

[22] Yau T,Kim T.Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040..JCO2019;37:4012

[23] Zhu AX,Edeline J.Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial..The Lancet Oncology2018;19:940-52

[24] Zhu AX,Ryoo B.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..The Lancet Oncology2015;16:859-70

[25] Iwanaga T.Studies on cases of spontaneous regression of cancer in Japan in 2011, and of hepatic carcinoma, lung cancer and pulmonary metastases in the world between 2006 and 2011..Gan To Kagaku Ryoho2013;40:1475-87

[26] Kumar A.Hepatocellular Carcinoma Regression After Cessation of Immunosuppressive Therapy..J Clin Oncol2016;34:e90-2 PMCID:PMC4886225

[27] Parks AL,Evason K.Cases of spontaneous tumor regression in hepatobiliary cancers: implications for immunotherapy?.J Gastrointest Cancer2015;46:161-5 PMCID:PMC5321609

[28] Chen DS.Elements of cancer immunity and the cancer-immune set point..Nature2017;541:321-30

[29] Kim JY,Eisenhut M.Tumor Mutational Burden and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis..Cancers (Basel)2019;11:1798 PMCID:PMC6895916

[30] Marabelle A,Ascierto PA.Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study..J Clin Oncol2020;38:1-10

[31] Stenzinger A,Maas J.Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions..Genes Chromosomes Cancer2019;58:578-88 PMCID:PMC6618007

[32] Subrahmanyam PB,Gusenleitner D.Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients..J Immunother Cancer2018;6:18 PMCID:PMC5840795

[33] Farkona S,Blasutig IM.Cancer immunotherapy: the beginning of the end of cancer?.BMC Med2016;14:73 PMCID:PMC4858828

[34] Vinay DS,Pawelec G.Immune evasion in cancer: Mechanistic basis and therapeutic strategies..Semin Cancer Biol.2015;35 Suppl:S185-98

[35] Yang Y.Cancer immunotherapy: harnessing the immune system to battle cancer..J Clin Invest2015;125:3335-7 PMCID:PMC4588312

[36] Breous E.Potential of immunotherapy for hepatocellular carcinoma..J Hepatol2011;54:830-4

[37] Hato T,Greten TF,Zhu AX.Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions..Hepatology2014;60:1776-82 PMCID:PMC4211962

[38] Hong YP,Prasoon P.Immunotherapy for hepatocellular carcinoma: From basic research to clinical use..World J Hepatol2015;7:980-92 PMCID:PMC4419101

[39] Pinato DJ,Fessas P.Immune-based therapies for hepatocellular carcinoma..Oncogene2020;39:3620-37 PMCID:PMC7190571

[40] Johnston MP.Immunotherapy for hepatocellular carcinoma: Current and future..World J Gastroenterol2019;25:2977-89 PMCID:PMC6603808

[41] Kudo M.Pembrolizumab for the Treatment of Hepatocellular Carcinoma..Liver Cancer2019;8:143-54 PMCID:PMC6547263

[42] Xu W,Chen M.Immunotherapy for hepatocellular carcinoma: recent advances and future perspectives..Ther Adv Med Oncol2019;11:1758835919862692 PMCID:PMC6651675

[43] Melero I,Riezu-Boj JI.Abstract 4387: Antiviral and antitumoral effects of the anti-CTLA4 agent tremelimumab in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection: Results from a phase II clinical trial..Cancer Research2012;72:4387

[44] Sangro B,de la Mata M.A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C..J Hepatol2013;59:81-8

[45] El-khoueiry AB,Yau T.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 PMCID:PMC7539326

[46] Zhu AX,Kudo M.KEYNOTE-224: Phase II study of pembrolizumab in patients with previously treated advanced hepatocellular carcinoma..J Clin Oncol2017;35:TPS504

[47] Finn RS,Merle P.Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC)..J Clin Oncol2019;37:4004

[48] Yau T,Finn R.CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC)..Ann Oncol2019;30:v874-5

[49] Lee MS,Hsu C.Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study..The Lancet Oncology2020;21:808-20

[50] Zhu AX,Ikeda M.A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC)..J Clin Oncol2020;38:4519

[51] Jiao SC,Dong J.Clinical activity and safety of penpulimab (Anti-PD-1) with anlotinib as first-line therapy for advanced hepatocellular carcinoma (HCC)..J Clin Oncol2020;38:4592

[52] Pal SK,Castellano DE.Phase Ib (COSMIC-021) trial of cabozantinib (C) in urothelial carcinoma (UC) or C in combination with atezolizumab (A) in patients (pts) with UC, castrate resistant prostate cancer (CRPC) or renal cell carcinoma (RCC)..J Clin Oncol2019;37:TPS683-TPS683

[53] Kelley RK,Hazra S.Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 Phase III study design..Future Oncol2020;16:1525-36

[54] Yau T,Kim TY.Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial..JAMA Oncol2020;e204564 PMCID:PMC7530824

[55] Kelley RK,Harris WP.Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC)..J Clin Oncol2020;38:4508-4508

[56] Abou-Alfa GK,Furuse J.A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study..J Clin Oncol2018;36:TPS4144-TPS4144

[57] Benson AB3rd,Abbott DE.NCCN Guidelines Insights: Hepatobiliary Cancers, Version 1.2017..J Natl Compr Canc Netw2017;15:563-73 PMCID:PMC5557008

[58] FDA. FDA expands approved use of Stivarga to treat liver cancer. Available from: https://www.fda.gov/news-events/press-announcements/fda-expands-approved-use-stivarga-treat-liver-cancer 2017;Content Current as of: 04/27/2017. [Last accessed on 16 Dec 2020]

[59] FDA. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-hcc-previously-treated-sorafenib 2017;Content current as of: 09/25/2017. [Last accessed on 16 Dec 2020]

[60] FDA. FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma. Available from: https://www.fda.gov/drugs/fda-grants-accelerated-approval-pembrolizumab-hepatocellular-carcinoma 2018;Content current as of: 12/14/2018. [Last accessed on 16 Dec 2020]

[61] FDA. FDA approves lenvatinib for unresectable hepatocellular carcinoma. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenvatinib-unresectable-hepatocellular-carcinoma 2018;Content current as of: 08/16/2018. [Last accessed on 16 Dec 2020]

[62] FDA. FDA approves ramucirumab for hepatocellular carcinoma. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ramucirumab-hepatocellular-carcinoma 2019;Content current as of: 05/10/2019. [Last accessed on 16 Dec 2020]

[63] FDA. FDA approves cabozantinib for hepatocellular carcinoma. Available from: https://www.fda.gov/drugs/fda-approves-cabozantinib-hepatocellular-carcinoma 2019;Content current as of: 03/12/2019. [Last accessed on 16 Dec 2020]

[64] FDA. FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-plus-bevacizumab-unresectable-hepatocellular-carcinoma 2020;Content current as of: 06/01/2020. [Last accessed on 16 Dec 2020]

[65] FDA. FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma 2020;Content current as of: 03/11/2020. [Last accessed on 16 Dec 2020]

[66] Lang L.FDA approves sorafenib for patients with inoperable liver cancer..Gastroenterology2008;134:379

[67] Sasaki A,Iwashita Y,Ohta M.Microsatellite distribution and indication for locoregional therapy in small hepatocellular carcinoma..Cancer2005;103:299-306

[68] Shi M,Zhang YQ,Li JQ.Micrometastases of solitary hepatocellular carcinoma and appropriate resection margin..World J Surg2004;28:376-81

[69] Suh SW.Predictors of Micrometastases in Patients with Barcelona Clinic Liver Cancer Classification B Hepatocellular Carcinoma..Yonsei Med J2017;58:737-42 PMCID:PMC5447103

[70] Ali MY,Ritter M.Activation of dendritic cells by local ablation of hepatocellular carcinoma..J Hepatol2005;43:817-22

[71] Dromi SA,Herby S.Radiofrequency ablation induces antigen-presenting cell infiltration and amplification of weak tumor-induced immunity..Radiology2009;251:58-66 PMCID:PMC2663580

[72] Dagoglu N,Caglar HB.Abscopal Effect of Radiotherapy in the Immunotherapy Era: Systematic Review of Reported Cases..Cureus2019;11:e4103 PMCID:PMC6476623

[73] Liu Y,Kong L,Zhu H.Abscopal effect of radiotherapy combined with immune checkpoint inhibitors..J Hematol Oncol2018;11:104 PMCID:PMC6097415

[74] Aerts M,Van Vlierberghe H,Reynaert H.Current status and perspectives of immune-based therapies for hepatocellular carcinoma..World J Gastroenterol2016;22:253-61 PMCID:PMC4698490

[75] Tai WMD,Gogna A.A phase II open-label, single-center, nonrandomized trial of Y90-radioembolization in combination with nivolumab in Asian patients with advanced hepatocellular carcinoma: CA 209-678..J Clin Oncol2020;38:4590-4590

[76] Kaseb AO,Mohamed YI.Final results of a randomized, open label, perioperative phase II study evaluating nivolumab alone or nivolumab plus ipilimumab in patients with resectable HCC..J Clin Oncol2020;38:4599-4599

[77] Flecken T,Hild S.Immunodominance and functional alterations of tumor-associated antigen-specific CD8 + T-cell responses in hepatocellular carcinoma..Hepatology2014;59:1415-26 PMCID:PMC4139003

[78] Gao Q,Fan J.Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection..J Clin Oncol2007;25:2586-93

[79] Liang J,Guo ZW.Expression pattern of tumour-associated antigens in hepatocellular carcinoma: association with immune infiltration and disease progression..Br J Cancer2013;109:1031-9 PMCID:PMC3749565

[80] Unitt E,Gelson W.Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation..J Hepatol2006;45:246-53

[81] Hsu CH,Abbas A.Longitudinal and personalized detection of circulating tumor DNA (ctDNA) for monitoring efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma (HCC)..J Clin Oncol2020;38:3531-3531

[82] Zhu AX,Abbas AR.Abstract CT044: Genomic correlates of clinical benefits from atezolizumab combined with bevacizumab vs. atezolizumab alone in patients with advanced hepatocellular carcinoma (HCC)..Cancer Research2020;80:CT044-CT044

[83] Alexandrov LB,Wedge DC.Signatures of mutational processes in human cancer..Nature2013;500:415-21 PMCID:PMC3776390

[84] Lawrence MS,Polak P.Mutational heterogeneity in cancer and the search for new cancer-associated genes..Nature2013;499:214-8 PMCID:PMC3919509

[85] Shrestha R,Anaka M.Monitoring Immune Checkpoint Regulators as Predictive Biomarkers in Hepatocellular Carcinoma..Front Oncol2018;8:269 PMCID:PMC6053505