Efficacy Comparison of Immune Combination Therapies in Subgroups for Advanced Hepatocellular Carcinoma Patients: Systematic Review and Network Meta-analysis

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2024 Jul 22

PMID 39038010

Authors

Yani Wang

Wanyee Lau

Yafei Li

Yichen Tian

Yongrong Lei

Feng Xia

Jianhua Wang

Affiliations

Soon will be listed here.

Abstract

Background: There is a lack of precision in the immunotherapy strategy tailored for patients exhibiting diverse clinical characteristics. This study aims to employ a rigorous network meta-analysis (NMA) approach to systematically evaluate the effectiveness of immune-combination therapies among patients with advanced hepatocellular carcinoma, taking into account their varying clinico-characteristics.

Methods: Studies were retrieved from PubMed, Embase, Cochrane Library, and Web of Science databases. The included first-line phase III studies were categorized into three types: immunotherapy combined with anti-angiogenetic agents, immunotherapy combined with tyrosine kinase inhibitors, and dual immunotherapy, with sorafenib serving as the control group. The primary endpoint used to assess efficacy was overall survival (OS), facilitating a comparative analysis among the three treatment modalities. Furthermore, subgroup analyses were conducted to evaluate the varying effectiveness for patients with diverse clinico-characteristics. Secondary outcome measures included progression-free survival, objective response rate, and toxicity assessment.

Results: A total of 6 studies were included in the NMA, encompassing a cohort of 3840 patients. The results revealed that immunotherapy combined with anti-angiogenetic agents exhibited a significantly enhanced therapeutic effect in terms of improving OS compared to sorafenib (HR = 0.61, 95% CrI, 0.42-0.90). Furthermore, based on various clinicopathological features, this combination therapy demonstrated superior OS responses in specific patient subgroups: BCLC C (HR = 0.63, 95% CrI, 0.42-0.93), ECOG 1 (HR = 0.57, 95% CrI, 0.36-0.91), with extrahepatic spread (EHS) (HR = 0.59, 95% CrI, 0.37-0.92), alpha fetoprotein (AFP)<400ng/ml (HR = 0.56, 95% CrI, 0.33-0.94) and viral hepatitis positivity (HR = 0.56, 95% CrI, 0.39-0.77) (especially HBV (HR = 0.58, 95% CrI, 0.40-0.85)). Importantly, the advantage of this combination therapy was even more pronounced in patients with viral hepatitis positivity. Also, the adverse events associated with immunotherapy combined with antiangiogenic drugs were moderate.

Conclusions: Immunotherapy combined with anti-angiogenetic agents could represent the most effective first-line intervention for achieving improved OS, particularly in patients with viral hepatitis positivity.

References

Fukumura D, Kloepper J, Amoozgar Z, Duda D, Jain R . Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018; 15(5):325-340. PMC: 5921900. DOI: 10.1038/nrclinonc.2018.29. View

Dudek M, Pfister D, Donakonda S, Filpe P, Schneider A, Laschinger M . Auto-aggressive CXCR6 CD8 T cells cause liver immune pathology in NASH. Nature. 2021; 592(7854):444-449. DOI: 10.1038/s41586-021-03233-8. View

Cheng A, Qin S, Ikeda M, Galle P, Ducreux M, Kim T . Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2021; 76(4):862-873. DOI: 10.1016/j.jhep.2021.11.030. View

Chi X, Jiang L, Yuan Y, Huang X, Yang X, Hochwald S . A comparison of clinical pathologic characteristics between alpha-fetoprotein negative and positive hepatocellular carcinoma patients from Eastern and Southern China. BMC Gastroenterol. 2022; 22(1):202. PMC: 9034573. DOI: 10.1186/s12876-022-02279-w. View

Rooney M, Shukla S, Wu C, Getz G, Hacohen N . Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015; 160(1-2):48-61. PMC: 4856474. DOI: 10.1016/j.cell.2014.12.033. View

Ringelhan M, Pfister D, OConnor T, Pikarsky E, Heikenwalder M . The immunology of hepatocellular carcinoma. Nat Immunol. 2018; 19(3):222-232. DOI: 10.1038/s41590-018-0044-z. View

Georganaki M, van Hooren L, Dimberg A . Vascular Targeting to Increase the Efficiency of Immune Checkpoint Blockade in Cancer. Front Immunol. 2019; 9:3081. PMC: 6309238. DOI: 10.3389/fimmu.2018.03081. View

Pfister D, Gonzalo Nunez N, Pinyol R, Govaere O, Pinter M, Szydlowska M . NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021; 592(7854):450-456. PMC: 8046670. DOI: 10.1038/s41586-021-03362-0. View

Foerster F, Gairing S, Ilyas S, Galle P . Emerging immunotherapy for HCC: A guide for hepatologists. Hepatology. 2022; 75(6):1604-1626. PMC: 9117522. DOI: 10.1002/hep.32447. View

10.

Pinter M, Jain R, Duda D . The Current Landscape of Immune Checkpoint Blockade in Hepatocellular Carcinoma: A Review. JAMA Oncol. 2020; 7(1):113-123. PMC: 8265820. DOI: 10.1001/jamaoncol.2020.3381. View

11.

Scott L . Apatinib: A Review in Advanced Gastric Cancer and Other Advanced Cancers. Drugs. 2018; 78(7):747-758. DOI: 10.1007/s40265-018-0903-9. View

12.

Han C, Tian B, Yan L, Ding Z, Liu H, Mao X . Efficacy and safety of immune checkpoint inhibitors for hepatocellular carcinoma patients with macrovascular invasion or extrahepatic spread: a systematic review and meta-analysis of 54 studies with 6187 hepatocellular carcinoma patients. Cancer Immunol Immunother. 2023; 72(7):1957-1969. PMC: 10991272. DOI: 10.1007/s00262-023-03390-x. View

13.

Zhu A, Abbas A, Ruiz de Galarreta M, Guan Y, Lu S, Koeppen H . Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat Med. 2022; 28(8):1599-1611. DOI: 10.1038/s41591-022-01868-2. View

14.

Xia Y, Tang W, Qian X, Li X, Cheng F, Wang K . Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial. J Immunother Cancer. 2022; 10(4). PMC: 8981365. DOI: 10.1136/jitc-2022-004656. View

15.

Llovet J, De Baere T, Kulik L, Haber P, Greten T, Meyer T . Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021; 18(5):293-313. DOI: 10.1038/s41575-020-00395-0. View

16.

Zhang H, Dai Z, Wu W, Wang Z, Zhang N, Zhang L . Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer. J Exp Clin Cancer Res. 2021; 40(1):184. PMC: 8178863. DOI: 10.1186/s13046-021-01987-7. View

17.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

18.

Llovet J, Kudo M, Merle P, Meyer T, Qin S, Ikeda M . Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023; 24(12):1399-1410. DOI: 10.1016/S1470-2045(23)00469-2. View

19.

Abou-Alfa G, Lau G, Kudo M, Chan S, Kelley R, Furuse J . Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2024; 1(8):EVIDoa2100070. DOI: 10.1056/EVIDoa2100070. View

20.

Shea B, Reeves B, Wells G, Thuku M, Hamel C, Moran J . AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017; 358:j4008. PMC: 5833365. DOI: 10.1136/bmj.j4008. View