Vol 71, No 6 (2021)
Review paper
Published online: 2021-12-06

open access

Page views 5826
Article views/downloads 361
Get Citation

Connect on Social Media

Connect on Social Media

Management of hepatocellular carcinoma with novel immunotherapeutic agents and prospects for the future

Katarzyna Szklener1, Michał Piwoński2, Klaudia Żak2, Julita Szarpak2, Sylwiusz Niedobylski2, Paweł Stanicki3, Sebastian Szklener4, Sławomir Mańdziuk1
Nowotwory. Journal of Oncology 2021;71(6):391-400.


The most frequent type of primary liver cancer is hepatocellular carcinoma (HCC). Although HCC is not the most frequent cancer, it is characterized by high mortality – the 5-year survival rate is 6,9%. In recent decades there was only one molecule available in treatment (sorafenib). However, in the past few years there have been advances in treatment. Nowadays, new generation tyrosine kinase inhibitors, check point inhibitors and anti-angiogenesis drugs are available. All those studies were analyzed outcome in context of monotherapy or combined therapies. In this review we made an attempt to com­pare results from different studies. Even though, many studies are undergoing final stages of clinical trials, it seems that combined therapies should be the next step in treatment advances.

Article available in PDF format

View PDF Download PDF file


  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011; 61(2): 69–90.
  2. Ozakyol A. Global Epidemiology of Hepatocellular Carcinoma (HCC Epidemiology). J Gastrointest Cancer. 2017; 48(3): 238–240.
  3. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007; 132(7): 2557–2576.
  4. Petruzziello A. Epidemiology of Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) Related Hepatocellular Carcinoma. Open Virol J. 2018; 12: 26–32.
  5. Perz JF, Armstrong GL, Farrington LA, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006; 45(4): 529–538.
  6. Margini C, Dufour JF. The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. Liver Int. 2016; 36(3): 317–324.
  7. Bruix J, Reig M, Sherman M. Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma. Gastroenterology. 2016; 150(4): 835–853.
  8. Escudier B, Worden F, Kudo M. Sorafenib: key lessons from over 10 years of experience. Expert Rev Anticancer Ther. 2019; 19(2): 177–189.
  9. Abdelgalil AA, Alkahtani HM, Al-Jenoobi FI. Sorafenib. Profiles Drug Subst Excip Relat Methodol. 2019; 44: 239–266.
  10. Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359(4): 378–390.
  11. Bruix J, Raoul JL, 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): 821–829.
  12. Kondo M, Morimoto M, Kobayashi S, et al. Randomized, phase II trial of sequential hepatic arterial infusion chemotherapy and sorafenib versus sorafenib alone as initial therapy for advanced hepatocellular carcinoma: SCOOP-2 trial. BMC Cancer. 2019; 19(1): 954.
  13. Al-Salama ZT, Syed YY, Scott LJ. Lenvatinib: A Review in Hepatocellular Carcinoma. Drugs. 2019; 79(6): 665–674.
  14. Rimassa L, Wörns MA. Navigating the new landscape of second-line treatment in advanced hepatocellular carcinoma. Liver Int. 2020; 40(8): 1800–1811.
  15. Fung A, Tam V, Meyers D, et al. Real world eligibility for cabozantinib (C), regorafenib (Reg), and ramucirumab (Ram) in hepatocellular carcinoma (HCC) patients after sorafenib (S). J Clin Oncol. 2019; 37(4_suppl): 422–422.
  16. Rimassa L, Assenat E, Peck-Radosavljevic M, et al. 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. 2018; 19(5): 682–693.
  17. Llovet JM, Decaens T, Raoul JL, et al. 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. 2013; 31(28): 3509–3516.
  18. Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014; 312(1): 57–67.
  19. 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. The Lancet. 2017; 389(10064): 56–66.
  20. Grothey A, Blay JY, Pavlakis N, et al. Evolving role of regorafenib for the treatment of advanced cancers. Cancer Treat Rev. 2020; 86: 101993.
  21. Abou-Elkacem L, Arns S, Brix G, et al. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther. 2013; 12(7): 1322–1331.
  22. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011; 10(12): 2298–2308.
  23. Birchmeier C, Birchmeier W, Gherardi E, et al. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003; 4(12): 915–925.
  24. Michieli P, Mazzone M, Basilico C, et al. Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell. 2004; 6(1): 61–73.
  25. Abounader R, Lal B, Luddy C, et al. In vivo targeting of SF/HGF and c-met expression via U1snRNA/ribozymes inhibits glioma growth and angiogenesis and promotes apoptosis. FASEB J. 2002; 16(1): 108–110.
  26. Firtina Karagonlar Z, Koc D, Iscan E, et al. Elevated hepatocyte growth factor expression as an autocrine c-Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells. Cancer Sci. 2016; 107(4): 407–416.
  27. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018; 379(1): 54–63.
  28. Spratlin JL, Cohen RB, Eadens M, et al. 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. 2010; 28(5): 780–787.
  29. Zhu AX, Park JOh, Ryoo BY, et al. 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. 2015; 16(7): 859–870.
  30. Zhu A, Ryoo BY, Yen CJ, et al. Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): Analysis of patients with elevated α-fetoprotein (AFP) from the randomized phase III REACH study. J Clin Oncol. 2015; 33(3_suppl): 232–232.
  31. Zhu AX, Kang YK, Yen CJ, et al. 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. 2019; 20(2): 282–296.
  32. Johnston MP, Khakoo SI. Immunotherapy for hepatocellular carcinoma: Current and future. World J Gastroenterol. 2019; 25(24): 2977–2989.
  33. Ishiguro T, Sano Y, Komatsu SI, et al. An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors. Sci Transl Med. 2017; 9(410).
  34. Takahashi Y, Ohta T, Mai M. Angiogenesis of AFP producing gastric carcinoma: correlation with frequent liver metastasis and its inhibition by anti-AFP antibody. Oncol Rep. 2004; 11(4): 809–813.
  35. Ghassemi S, Milone MC. Manufacturing Chimeric Antigen Receptor (CAR) T Cells for Adoptive Immunotherapy. J Vis Exp. 2019(154).
  36. Mata-Molanes JJ, Sureda González M, Valenzuela Jiménez B, et al. Cancer Immunotherapy with Cytokine-Induced Killer Cells. Target Oncol. 2017; 12(3): 289–299.
  37. Bagheri Y, Barati A, Aghebati-Maleki A, et al. Current progress in cancer immunotherapy based on natural killer cells. Cell Biol Int. 2021; 45(1): 2–17.
  38. Calmeiro J, Carrascal MA, Tavares AR, et al. Dendritic Cell Vaccines for Cancer Immunotherapy: The Role of Human Conventional Type 1 Dendritic Cells. Pharmaceutics. 2020; 12(2).
  39. Slingluff C. The Present and Future of Peptide Vaccines for Cancer. The Cancer Journal. 2011; 17(5): 343–350.
  40. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3--potential mechanisms of action. Nat Rev Immunol. 2015; 15(1): 45–56.
  41. Hato T, Goyal L, Greten TF, et al. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology. 2014; 60(5): 1776–1782.
  42. Fife BT, Pauken KE. The role of the PD-1 pathway in autoimmunity and peripheral tolerance. Ann N Y Acad Sci. 2011; 1217: 45–59.
  43. Hui E, Cheung J, Zhu J, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017; 355(6332): 1428–1433.
  44. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020; 10(3): 727–742.
  45. El-Khoueiry A, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. The Lancet. 2017; 389(10088): 2492–2502.
  46. Bristol-Myers Squibb. A Randomized, Multi-center Phase III Study of Nivolumab Versus Sorafenib as First-Line Treatment in Patients With Advanced Hepatocellular Carcinoma (CheckMate 459: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 459). Report No.: NCT02576509. https://clinicaltrials.gov/ct2/show/NCT02576509 (10.05.2021).
  47. Mo H, Huang J, Xu J, et al. Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in advanced solid tumours: a dose-escalation, phase 1 study. Br J Cancer. 2018; 119(5): 538–545.
  48. Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020; 21(4): 571–580.
  49. Jiangsu HengRui Medicine Co., Ltd. A Phase III, Multicentered, Randomized, Double-blinded, Parallel Controlled Study to Evaluate Camrelizumab (PD-1 Antibody) in Combination With FOLFOX4 Regimen Versus Placebo in Combination With FOLFOX4 Regime in First-Line Therapy in Subjects With Advanced Hepatocellular Carcinoma (HCC). Report No.: NCT03605706. https://clinicaltrials.gov/ct2/show/NCT03605706 (10.05.2021).
  50. Finn RS, Ryoo BY, Merle P, et al. KEYNOTE-240 investigators. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020; 38(3): 193–202.
  51. Zhu AX, Finn RS, Edeline J, et al. KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018; 19(7): 940–952.
  52. Innovent Biologics (Suzhou) Co. Ltd. A Randomized, Open-label,Multi-center Study to Evaluate the Efficacy and Safety of the Combination of Sintilimab and IBI305 Compared to Sorafenib in the First-Line Treatment of Patients With Advanced Hepatocellular Carcinoma. (ORIENT-32). Report No.: NCT03794440. https://clinicaltrials.gov/ct2/show/NCT03794440 (10.05.2021).
  53. BeiGene. RATIONALE-301: A Randomized, Open-label, Multicenter Phase 3 Study to Compare the Efficacy and Safety of BGB-A317 Versus Sorafenib as First-Line Treatment in Patients With Unresectable Hepatocellular Carcinoma. Report No.: NCT03412773. https://clinicaltrials.gov/ct2/show/NCT03412773 (10.05.2021).
  54. Voutsadakis IA. PD-1 inhibitors monotherapy in hepatocellular carcinoma: Meta-analysis and systematic review. Hepatobiliary Pancreat Dis Int. 2019; 18(6): 505–510.
  55. Wainberg Z, Segal N, Jaeger D, et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J Clin Oncol. 2017; 35(15_suppl): 4071–4071.
  56. Kroemer G, Zitvogel L, Krummel MF, et al. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995; 182(2): 459–465.
  57. Chen J, Ganguly A, Mucsi AD, et al. Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy. J Exp Med. 2017; 214(2): 327–338.
  58. Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013; 59(1): 81–88.
  59. AstraZeneca. A Randomized, Open-label, Multi-center Phase III Study of Durvalumab and Tremelimumab as First-line Treatment in Patients With Advanced Hepatocellular Carcinoma [Internet]. Report No.: NCT03298451. https://clinicaltrials.gov/ct2/show/NCT03298451 (10.05.2021).
  60. Novartis Pharmaceuticals. A Phase I/Ib, Open-label, Multi-center Dose Escalation Study of NIS793 in Combination With PDR001 in Adult Patients With Advanced Malignancies. Report No.: NCT02947165. https://clinicaltrials.gov/ct2/show/NCT02947165 (10.05.2021).
  61. University of Hawaii. Phase II Study of TSR-022 in Combination With TSR-042 for the Treatment of Advanced Hepatocellular Carcinoma. Report No.: NCT03680508. https://clinicaltrials.gov/ct2/show/NCT03680508 (10.05.2021).
  62. Bristol-Myers Squibb. A Phase I/2a Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and Efficacy of Anti-LAG-3 Monoclonal Antibody (BMS-986016) Administered Alone and in Combination With Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in Advanced Solid Tumors. Report No.: NCT01968109. https://clinicaltrials.gov/ct2/show/NCT01968109 (10.05.2021).
  63. Nobuoka D, Motomura Y, Shirakawa H, et al. Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes. Int J Oncol. 2012; 40(1): 63–70.
  64. Zerbini A, Pilli M, Laccabue D, et al. Radiofrequency thermal ablation for hepatocellular carcinoma stimulates autologous NK-cell response. Gastroenterology. 2010; 138(5): 1931–1942.
  65. Hansler J, Wissniowski TT, Schuppan D, et al. Activation and dramatically increased cytolytic activity of tumor specific T lymphocytes after radio-frequency ablation in patients with hepatocellular carcinoma and colorectal liver metastases. World J Gastroenterol. 2006; 12(23): 3716–3721.
  66. Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017; 66(3): 545–551.
  67. Lee MS, Ryoo BY, Hsu CH, et al. GO30140 investigators. Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. Lancet Oncol. 2020; 21(6): 808–820.
  68. Hack SP, Spahn J, Chen M, et al. IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncol. 2020; 16(15): 975–989.
  69. Yau T, Kang YK, Kim TY, et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020; 6(11): e204564.
  70. Imfinzi plus tremelimumab demonstrated promising clinical activity and tolerability in patients with advanced liver cancer. https://www.astrazeneca.com/media-centre/press-releases/2020/imfinzi-plus-tremelimumab-demonstrated-promising-clinical-activity-and-tolerability-in-patients-with-advanced-liver-cancer.html (01.03.2021).
  71. Bang YJ, Golan T, Dahan L, et al. Ramucirumab and durvalumab for previously treated, advanced non-small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: An open-label, phase Ia/b study (JVDJ). Eur J Cancer. 2020; 137: 272–284.
  72. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2020; 38(26): 2960–2970.
  73. Schulte N, Li M, Zhan T, et al. Response of advanced HCC to pembrolizumab and lenvatinib combination therapy despite monotherapy failure. Z Gastroenterol. 2020; 58(8): 773–777.
  74. Liu Z, Li X, He X, et al. Complete response to the combination of Lenvatinib and Pembrolizumab in an advanced hepatocellular carcinoma patient: a case report. BMC Cancer. 2019; 19(1): 1062.
  75. Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer. J Clin Oncol. 2020; 38(26): 2981–2992.
  76. Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019; 20(5): 711–718.
  77. Kawazoe A, Fukuoka S, Nakamura Y, et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Lancet Oncol. 2020; 21(8): 1057–1065.
  78. Motzer R, Alekseev B, Rha SY, et al. CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021; 384(14): 1289–1300.
  79. Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020; 31(8): 1030–1039.
  80. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019; 380(12): 1103–1115.
  81. Kudo M, Motomura K, Wada Y, et al. First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100). J Clin Oncol. 2019; 37(15_suppl): 4072–4072.
  82. Thomas MB, Garrett-Mayer E, Anis M, et al. A Randomized Phase II Open-Label Multi-Institution Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients with Advanced Hepatocellular Carcinoma. Oncology. 2018; 94(6): 329–339.
  83. He L, Deng H, Lei J, et al. Efficacy of bevacizumab combined with erlotinib for advanced hepatocellular carcinoma: a single-arm meta-analysis based on prospective studies. BMC Cancer. 2019; 19(1): 276.
  84. Kaseb AO, Morris JS, Iwasaki M, et al. Phase II trial of bevacizumab and erlotinib as a second-line therapy for advanced hepatocellular carcinoma. Onco Targets Ther. 2016; 9: 773–780.
  85. Yau T, Wong H, Chan P, et al. Phase II study of bevacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease. Invest New Drugs. 2012; 30(6): 2384–2390.

Nowotwory. Journal of Oncology