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Digestive Disease Interventions 2021; 05(03): 277-282
DOI: 10.1055/s-0041-1722932
Special Communication

Emerging Role of Immune Therapy in HCC

Stacey M. Stein 
1   Department of Medicine, Yale School of Medicine, New Haven, Connecticut
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Abstract

Hepatocellular carcinoma (HCC) remains a prevalent cancer diagnosis with an expected increase in incidence in the next decade. Treatment options for advanced disease have expanded significantly in the last decade since sorafenib was first approved in 2007. There have been approvals for multiple tyrosine kinase inhibitors (TKIs) with modest improvements in survival. Single-agent PD-1 inhibition has shown responses in ∼15% of patients, with a tail of the curve that is very beneficial to a small subset of patients. Most recently, studies of combination therapy with immune therapy drugs are showing more durable responses in a larger number of patients with unprecedented response rates over 30%. Different strategies have been pursued, including PD-1 and PD-L1 combinations with vascular endothelial growth factor inhibition, TKIs, and anti-CTLA-4 antibodies. This article provides a review of studies both completed and ongoing with immune therapy in advanced HCC.

Keywords

advanced HCC - immune therapy combinations


Publication History

Received: 09 August 2020

Accepted: 01 December 2020

Article published online:
16 March 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Petrick JL, Kelly SP, Altekruse SF, McGlynn KA, Rosenberg PS. Future of hepatocellular carcinoma incidence in the United States Forecast through 2030. J Clin Oncol 2016; 34 (15) 1787-1794
    CrossrefPubMedGoogle Scholar
  • 2 Llovet JM, Ricci S, Mazzaferro V. et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359 (04) 378-390
    CrossrefPubMedGoogle Scholar
  • 3 Bruix J, Qin S, Merle P. et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389 (10064): 56-66
    CrossrefPubMedGoogle Scholar
  • 4 Abou-Alfa GK, Meyer T, Cheng AL. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018; 379 (01) 54-63
    CrossrefPubMedGoogle Scholar
  • 5 Kudo M, Finn RS, Qin S. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomized phase 3 non- inferiority trial. Lancet DOI: 10.1016/SO140-6736(18)30207-1.
    CrossrefPubMedGoogle Scholar
  • 6 Zhu AX, Park JO, 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 (07) 859-870
    CrossrefPubMedGoogle Scholar
  • 7 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 (02) 282-296
    CrossrefPubMedGoogle Scholar
  • 8 Siegel AB, Cohen EI, Ocean A. et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008; 26 (18) 2992-2998
    CrossrefPubMedGoogle Scholar
  • 9 O'Rourke JM, Sagar VM, Shah T, Shetty S. Carcinogenesis on the background of liver fibrosis: implications for the management of hepatocellular cancer. World J Gastroenterol 2018; 24 (39) 4436-4447
    CrossrefPubMedGoogle Scholar
  • 10 Yarchoan M, Xing D, Luan L. et al. Characterization of the immune microenvironment in hepatocellular carcinoma. Clin Cancer Res 2017; 23 (23) 7333-7339
    CrossrefPubMedGoogle Scholar
  • 11 El-Khoueiry AB, 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. Lancet 2017; 389 (10088): 2492-2502
    CrossrefPubMedGoogle Scholar
  • 12 Yau T, Park JW, Finn RS. et al. 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 Oncol 2019; 30: V874-V875
    CrossrefPubMedGoogle Scholar
  • 13 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 (07) 940-952
    CrossrefPubMedGoogle Scholar
  • 14 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 (03) 193-202
    CrossrefPubMedGoogle Scholar
  • 15 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 (06) 808-820
    CrossrefPubMedGoogle Scholar
  • 16 Finn RS, Qin S, Ikeda M. et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020; 382 (20) 1894-1905
    CrossrefPubMedGoogle Scholar
  • 17 Galle PR, Finn RS, Qin S. et al. Patient-reported outcomes (PROs) from the phase III IMbrave 150 trial of atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann Oncol 2019; 30 (09) AbstractLBA3
    PubMedGoogle Scholar
  • 18 Zhu AX, Finn RS, Ikeda M. et al. A phase 1b study of lenvatinib plus pembrolizumab in unresectable hepatocellular carcinoma. Presented at: ASCO Virtual Scientific Program. J Clin Oncol 2020; 38: 4519
    CrossrefPubMedGoogle Scholar
  • 19 Lovet JM, Kudo M, Chang AL. et al. Lenvatinib (Len) plus pembrolizumab (Pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 3 LEAP-002 study. J Clin Oncol 2019; 37 (15) TPS4152-TPS4152
    CrossrefPubMedGoogle Scholar
  • 20 Merck and Eisai Receive Complete Response Letter for KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) Combination as First-Line Treatment for Unresectable Hepatocellular Carcinoma, News release. Merck and Eisai. July 8, 2020 https://bwnews.pr/2Z89nmX
    PubMedGoogle Scholar
  • 21 Kelley RK, Oliver JW, Hazra S. et al. Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 phase III study design. Future Oncol 2020; 16 (21) 1525-1536
    CrossrefPubMedGoogle Scholar
  • 22 Kudo M. Scientific rationale for combination immunotherapy of hepatocellular carcinoma with anti-PD-1/PD-L1 and anti-CTLA-4 antibodies. Liver Cancer 2019; 8 (06) 413-426
    CrossrefPubMedGoogle Scholar
  • 23 Wolchok JD, Chiarion-Sileni V, Gonzalez R. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017; 377 (14) 1345-1356
    CrossrefPubMedGoogle Scholar
  • 24 Yau T, Kang Y-K, Kim T-Y. et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. J Clin Oncol 2019; 37 (Suppl. 15) 4012 DOI: 10.1200/JCO.2019.37.15_suppl.4012.
    CrossrefPubMedGoogle Scholar
  • 25 Yau T, Zagonel V, Santoro A. et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol 2020; 38 (04) 478-478
    CrossrefPubMedGoogle Scholar
  • 26 Kelley RK, Sangro B, Harris WP. et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab in combination with durvalumab for patients with advanced hepatoceullar carcinoma. J Clin Oncol 2020; 38 (15) 4508-4508
    CrossrefPubMedGoogle Scholar
  • 27 Kelley RK, Kudo M, Harris W. et al. The novel regimen of tremelimumab in combination with durvalumab provides a favorable safety profile and clinical activity for patients with advanced hepatocellular carcinoma (aHCC). Presented at: ESMO World Congress on Gastrointestinal Cancer 2020. July 1–4, 2020; Virtual. Abstract O-6
    PubMedGoogle Scholar