Immune Efficacy of Immunotherapeutic Agents for Hepatocellular Carcinoma

Murat BARDAKÇIa , Mehmet Ali Nahit ŞENDURa,b
aAnkara Bilkent City Hospital, Clinic of Medical Oncology, Ankara, Türkiye
bAnkara Yıldırım Beyazıt University Faculty of Medicine, Department of Medical Oncology, Ankara, Türkiye

Bardakçı M, Şendur MAN. Immune efficacy of immunotherapeutic agents for hepatocellular carcinoma. In: Şendur MAN, ed. Current Immunotherapy Landscape for Solid Tumors. 1st ed. Ankara: Türkiye Klinikleri; 2024. p.82-6.

ABSTRACT
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide and up to 90% of HCC cases are caused by underlying cirrhosis. Clinically approved tyrosine kinase inhibitors (TKIs) for the treatment of patients with HCC who are unresectable and ineligible for curative therapies have shown limited improvement in survival rates. Immune checkpoint inhibitors (ICIs) are landmark drugs used in the treatment of many solid tumors, including HCC. While single-agent immunotherapy drugs have shown limited efficacy in the treatment of HCC, the combination of anti-programmed cell death ligand-1 (PD-L1) atezolizumab and anti-vascular endothelial growth factor (VEGF) bevacizumab showed a significant improvement in survival rates compared with sorafenib as first-line treatment. Furthermore, durvalumab-tremelimumab was shown to be superior to sorafenib, making this treatment a new first-line option. These results further encourage the preclinical and clinical development of immunotherapeutic treatment. In contrast, inconsistent results have been obtained with combinations of ICIs and tyrosine kinase inhibitors, with only one phase-III trial showing OS benefit. In conclusion, the combination of ICIs with other therapies such as anti-VEGF, anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), and TKIs has been shown to improve the overall response rate and survival of monoclonal antibodies.

Keywords: Immune checkpoint inhibitors; hepatocellular carcinoma; sorafenib; atezolizumab; bevacizumab

Referanslar

  1. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma. Hepatology. 2021;73 Suppl 1(Suppl 1):4-13. [Crossref]  [PubMed]  [PMC]
  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-49. [Crossref]  [PubMed]
  3. Stoian M, Stoica V. Risk Factors for Hepatocellular Carcinoma. Int Med. 2018;15(6):7-20. [Crossref]
  4. Global Burden of Disease Liver Cancer Collaboration; Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, et al. The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015. JAMA Oncol. 2017;3(12):1683-91. [Crossref]  [PubMed]  [PMC]
  5. Patel P, Schutzer SE, Pyrsopoulos N. Immunobiology of hepatocarcinogenesis: Ways to go or almost there? World J Gastrointest Pathophysiol. 2016;7(3):242-55. [Crossref]  [PubMed]  [PMC]
  6. Hassanipour S, Vali M, Gaffari-Fam S, Nikbakht HA, Abdzadeh E, Joukar F, et al. The survival rate of hepatocellular carcinoma in Asian countries: a systematic review and meta-analysis. EXCLI J. 2020;19:108-30. [Crossref]
  7. Terashima T, Yamashita T, Takata N, Toyama T, Shimakami T, Takatori H, et al. Comparative analysis of liver functional reserve during lenvatinib and sorafenib for advanced hepatocellular carcinoma. Hepatol Res. 2020;50(7):871-84. [Crossref]  [PubMed]
  8. Casadei-Gardini A, Scartozzi M, Tada T, Yoo C, Shimose S, Masi G, et al. Lenvatinib versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: An inverse probability of treatment weighting analysis. Liver Int. 2021;41(6):1389-97. [Crossref]  [PubMed]
  9. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23-34. Erratum in: N Engl J Med. 2018;379(22):2185. [Crossref]  [PubMed]  [PMC]
  10. Flynn MJ, Sayed AA, Sharma R, Siddique A, Pinato DJ. Challenges and Opportunities in the Clinical Development of Immune Checkpoint Inhibitors for Hepatocellular Carcinoma. Hepatology. 2019;69(5):2258-70. [Crossref]  [PubMed]
  11. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, 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 Jul;19(7):940-952. Erratum in: Lancet Oncol. 2018;19(9):e440. [Crossref]  [PubMed]
  12. Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862-73. [Crossref]  [PubMed]
  13. Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070. [Crossref]  [PubMed]
  14. Qin S, Chan L, Gu S, Bai Y, Ren Z, Lin X, et al. LBA35 Camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): A randomized, phase III trial. Ann Oncol. 2022;33(Suppl_7):S808-S69. [Crossref]
  15. Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23(1):77-90. [Crossref]  [PubMed]
  16. Schenker M, Burotto M, Richardet M, Ciuleanu T, Goncalves A, Steeghs N, et al. Abstract CT022: CheckMate 848: a randomized, open-label, phase 2 study of nivolumab in combination with ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden. Cancer Res. 2022;82(12_Suppl):CT022-CT. [Crossref]
  17. Qin S, Finn RS, Kudo M, Meyer T, Vogel A, Ducreux M, et al. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Future Oncol. 2019;15(16):1811-22. [Crossref]  [PubMed]
  18. Kelley RK, Rimassa L, Cheng AL, Kaseb A, Qin S, Zhu AX, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(8):995-1008. [Crossref]  [PubMed]
  19. Finn R, Kudo M, Merle P, Meyer T, Qin S, Ikeda M, et al. LBA34 Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2022;33(Suppl_7):S808-69. 10.1016/annonc/annonc1089. [Crossref]
  20. Merle P, Kudo M, Edeline J, Bouattour M, Cheng AL, Chan SL, et al. Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer Term Follow-Up from the Phase 3 KEYNOTE-240 Trial. Liver Cancer. 2023;12(4):309-20. [Crossref]  [PubMed]  [PMC]
  21. Qin S, Chen Z, Fang W, Ren Z, Xu R, Ryoo BY, et al. Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2023;41(7):1434-43. [Crossref]  [PubMed]  [PMC]
  22. Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, 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. Erratum in: JAMA Oncol. 2021;7(1):140. [Crossref]  [PubMed]  [PMC]