肝细胞癌系统治疗进展与展望

黄勇; 黄声稀; 刘秀峰

doi:10.12449/JCH250803

肝细胞癌系统治疗进展与展望

DOI: 10.12449/JCH250803

黄勇¹,
黄声稀²,
刘秀峰^1, , ,

1.
东部战区总医院全军肿瘤中心肿瘤内科，南京 210002
2.
东部战区总医院全军肿瘤中心特诊科，南京 210002

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：刘秀峰负责拟定文章思路，研究数据的获取分析，并起草和修改文章关键内容；黄勇负责起草和修改文章关键内容；黄声稀对研究的思路和设计有关键贡献。

详细信息

通信作者:
刘秀峰， liuxiufeng@csco.org.cn （ORCID： 0000-0002-1599-2474）

计量
- 文章访问数: 607
- HTML全文浏览量: 181
- PDF下载量: 200
- 被引次数: 0
出版历程
- 收稿日期: 2025-06-26
- 录用日期: 2025-07-23
- 出版日期: 2025-08-25

Advances and prospects of systemic therapy for hepatocellular carcinoma

1.
Department of Medical Oncology PLA Cancer Center General Hospital of Eastern Theater Command，Nanjing 210002，China
2.
Department of Special Diagnosis and Treatment, PLA Cancer Center General Hospital of Eastern Theater Command，Nanjing 210002，China

More Information

Corresponding author: LIU Xiufeng， liuxiufeng@csco.org.cn （ORCID： 0000-0002-1599-2474）

摘要

摘要: 肝细胞癌系统治疗近年来取得突破性进展，显著改善了中晚期患者的临床预后。本文系统梳理了当前肝细胞癌系统治疗领域的关键进展与临床挑战。随着多种新型靶免联合和双免联合方案的应用，临床治疗选择日益丰富，但也面临方案优化、耐药处理和特殊人群治疗等关键挑战。当前研究正探索基于多组学特征的精准分型和新型联合治疗策略，特别是三联治疗方案展现出突破现有疗效瓶颈的潜力。未来需要构建更加个体化和精细化的全程管理体系，通过优化免疫微环境调控和转化治疗模式，进一步提升患者的长期生存获益。这一领域的发展将推动肝癌治疗从传统模式向精准医学时代的转变。
- 癌，肝细胞 /
- 系统治疗 /
- 药物疗法，联合
Abstract: Ground-breaking advances have been made in systemic therapy for hepatocellular carcinoma （HCC）， which have significantly improved the clinical prognosis of patients with advanced HCC. This article summarizes the key advances and clinical challenges in systemic therapy for HCC. With the combination of various novel targeted therapy and immunotherapy regimens and the application of dual immunotherapy regimens， there has been an increasing number of clinical treatment options， while there are still key challenges such as optimization of treatment regimens， management of drug resistance， and treatment of special populations. Current studies are exploring precise classification based on multi-omics characteristics and the strategies for novel combined therapies， and in particular， triple-combination regimens have the potential to break through the bottleneck in efficacy. In the future， it is necessary to establish a more individualized and refined whole-course management system and further improve the long-term survival benefits of patients by optimizing immune microenvironment modulation and transforming therapeutic paradigms. Advances in this field will promote the transition from traditional paradigm to precision medicine in the treatment of HCC.
- Carcinoma，Hepatocellular /
- Systemic Therapy /
- Durg Therapy， Combination

HTML全文

表 1 HCC一线免疫联合治疗Ⅲ期RCT结果比较

Table 1. Comparison of phase Ⅲ RCT results on first-line immunotherapy combinations for HCC

项目	IMbrave 150^［5］	ORIENT- 32^［6］	HIMALAYA^［7］	CARES- 310^［8］	CheckMate- 9DW^［9］	SCT-I10A+ SCT510^［10］	APOLLO^［11］	HEPATORCH^［12］
试验组例数（例）	329	380	393	272	335	230	433	162
病因学
乙型肝炎占比（%）	49	94	31	76	34	90.4	84.3	90.7
丙型肝炎占比（%）	21	2	28	8	27	NE	3.5	4.3
非乙、丙型肝炎占比（%）	30	4	41	15	37	NE	12.2	5.0
中位年龄（岁）	64	53	65	58	65	57	57	58
性别（男/女，%）	82/18	88/12	83.2/16.8	83/17	81/19	85.7/14.3	85.7/14.3	82.7/17.3
亚洲人群占比（%）	40	100	39	83	40	100	100	100
BCLC B/C期（%）	15/82	15/85	19.6/80.4	14/86	27/73	20/80	18.5/81.33	20.4/79.6
Child-Pugh A/B级（%）	100/0	96/4	100/0	100/0	100/0	93.1/6.9	92.2/7.6	100/0
ORR（%）	27.3	21.0	20.1	25.4	36.0	32.8	21.0	25.3
DoR（月）	NE	NE	22.3	14.8	30.4	NE	16.2	NE
PD率（%）	19.6	27.0	39.9	16.2	20.0	17.9	19.0	25.3
mPFS（月）	6.8	4.6	3.8	5.6	9.1	7.1	6.9	5.8
mOS（月）	19.2	NR	16.4	23.8	23.7	22.1	16.5	20.0
≥G3级 AE发生率（%）	56.5	56	50.5	82	41.0	84.8	48.2	45.7
注：BCLC，巴塞罗那肝癌分期；NE，未评估；mPFS，中位无进展生存期。

下载: 导出CSV

参考文献(38)

[1]	RUMGAY H, ARNOLD M, FERLAY J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040[J]. J Hepatol, 2022, 77( 6): 1598- 1606. DOI: 10.1016/j.jhep.2022.08.021.
[2]	National Health Commission of the People’s Republic of China. Standard for diagnosis and treatment of primary liver cancer(2024 edition)[J]. J Clin Hepatol, 2024, 40( 5): 893- 918. DOI: 10.12449/JCH240508. 中华人民共和国国家卫生健康委员会. 原发性肝癌诊疗指南(2024年版)[J]. 临床肝胆病杂志, 2024, 40( 5): 893- 918. DOI: 10.12449/JCH240508.
[3]	National Comprehensive Cancer Network(NCCN). NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. Version 1.2025[C]. Plymouth Meeting, PA: NCCN; 2025.
[4]	Guidelines Working Committee of the Chinese Society of Clinical Oncology. Guidelines of Chinese society of clinical oncology(CSCO) hepatocellular carcinoma[M]. Beijing: People’s Medical Publishing House, 2024. 中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)原发性肝癌诊疗指南-2024[M]. 北京: 人民卫生出版社, 2024.
[5]	FINN RS, QIN SK, IKEDA M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma[J]. N Engl J Med, 2020, 382( 20): 1894- 1905. DOI: 10.1056/NEJMoa1915745.
[6]	REN ZG, XU JM, BAI YX, et al. Sintilimab plus a bevacizumab biosimilar(IBI₃05) versus sorafenib in unresectable hepatocellular carcinoma(ORIENT-32): A randomised, open-label, phase 2-3 study[J]. Lancet Oncol, 2021, 22( 7): 977- 990. DOI: 10.1016/S1470-2045(21)00252-7.
[7]	ABOU-ALFA GK, LAU G, KUDO M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma[J]. NEJM Evid, 2022, 1( 8): EVIDoa2100070. DOI: 10.1056/EVIDoa2100070.
[8]	QIN SK, CHAN SL, GU SZ, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma(CARES-310): A randomised, open-label, international phase 3 study[J]. Lancet, 2023, 402( 10408): 1133- 1146. DOI: 10.1016/S0140-6736(23)00961-3.
[9]	YAU T, GALLE PR, DECAENS T, et al. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma(CheckMate 9DW): An open-label, randomised, phase 3 trial[J]. Lancet, 2025, 405( 10492): 1851- 1864. DOI: 10.1016/S0140-6736(25)00403-9.
[10]	XU JM, ZHANG YQ, WANG G, et al. SCT-I10A combined with a bevacizumab biosimilar(SCT510) versus sorafenib in the first-line treatment of advanced hepatocellular carcinoma: A randomized phase 3 trial[J]. J Clin Oncol, 2024, 42( 16_suppl): 4092. DOI: 10.1200/jco.2024.42.16_suppl.4092.
[11]	ZHOU J, BAI L, LUO J, et al. Anlotinib plus penpulimab versus sorafenib in the first-line treatment of unresectable hepatocellular carcinoma(APOLLO): A randomised, controlled, phase 3 trial[J]. Lancet Oncol, 2025, 26( 6): 719- 731. DOI: 10.1016/S1470-2045(25)00190-1.
[12]	SHI YH, HAN GH, ZHOU J, et al. Toripalimab plus bevacizumab versus sorafenib as first-line treatment for advanced hepatocellular carcinoma(HEPATORCH): A randomised, open-label, phase 3 trial[J]. Lancet Gastroenterol Hepatol, 2025, 10( 7): 658- 670. DOI: 10.1016/S2468-1253(25)00059-7.
[13]	Alliance of Liver Cancer Conversion Therapy, Committee of Liver Cancer, China Anti-Cancer Association. Chinese expert consensus on conversion and perioperative therapy of primary liver cancer(2024 edition)[J]. Chin J Dig Surg, 2024, 23( 4): 492- 513. DOI: 10.3760/cma.j.cn115-610-20240228-00135. 中国抗癌协会肝癌专业委员会转化治疗协作组. 原发性肝癌转化及围手术期治疗中国专家共识(2024版)[J]. 中华消化外科杂志, 2024, 23( 4): 492- 513. DOI: 10.3760/cma.j.cn115610-20240228-00135.
[14]	Alliance of Chinese Expert Consensus on Neoadjuvant Therapy for Hepatocellular Carcinoma, Committee of Digestive Surgery of Chinese Research Hospital Association. Committee of Liver Cancer, Chinese Anti-Cancer Association Chinese expert consensus on neoadjuvant therapy for hepatocellular carcinoma(2023 edition)[J]. Chin J Surg, 2023, 61( 12): 1035- 1045. DOI: 10.3760/cma.j.cn112139-20230914-00121. 肝癌新辅助治疗中国专家共识协作组, 中国研究型医院学会消化外科专业委员会, 中国抗癌协会肝癌专业委员会. 肝癌新辅助治疗中国专家共识(2023版)[J]. 中华外科杂志, 2023, 61( 12): 1035- 1045. DOI: 10.3760/cma.j.cn112139-20230914-00121.
[15]	LIU XF, XIA F, CHEN Y, et al. Chinese expert consensus on refined diagnosis, treatment, and management of advanced primary liver cancer(2023 edition)[J]. Liver Res, 2024, 8( 2): 61- 71. DOI: 10.1016/j.livres.2024.05.001.
[16]	KUDO M, YAU T, DECAENS T, et al. Nivolumab(NIVO) plus ipilimumab(IPI) vs lenvatinib(LEN) or sorafenib(SOR) as first-line(1L) therapy for unresectable hepatocellular carcinoma(uHCC): CheckMate 9DW expanded analyses[J]. J Clin Oncol, 2025, 43( 4_suppl): 520. DOI: 10.1200/jco.2025.43.4_suppl.520.
[17]	SHROFF RT, SHI W, WU XZ, et al. Clinical outcomes of camrelizumab + rivoceranib vs sorafenib(CARES-310) as first-line treatment for patients with unresectable hepatocellular carcinoma(uHCC) of non-viral and viral etiology[J]. J Clin Oncol, 2025, 43( 4_suppl): 578. DOI: 10.1200/jco.2025.43.4_suppl.578.
[18]	HAN JW, LEE SK, KWON JH, et al. A machine learning algorithm facilitates prognosis prediction and treatment selection for Barcelona clinic liver cancer stage C hepatocellular carcinoma[J]. Clin Cancer Res, 2024, 30( 13): 2812- 2821. DOI: 10.1158/1078-0432.CCR-23-3978.
[19]	LLOVET JM, KUDO M, MERLE P, et al. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma(LEAP-002): A randomised, double-blind, phase 3 trial[J]. Lancet Oncol, 2023, 24( 12): 1399- 1410. DOI: 10.1016/S1470-2045(23)00469-2.
[20]	FINN RS, RYOO BY, HSU CH, et al. Tiragolumab in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma(MORPHEUS-Liver): A randomised, open-label, phase 1b-2, study[J]. Lancet Oncol, 2025, 26( 2): 214- 226. DOI: 10.1016/S1470-2045(24)00679-X.
[21]	QIN S, FAN J, YANG F, et al. LBA38 Iparomlimab and tuvonralimab(QL1706) with bevacizumab and/or chemotherapy in first-line(1L) treatment of advanced hepatocellular carcinoma(aHCC): A randomized, open-label, phase II/III study(DUBHE-H-308)[J]. Ann Oncol, 2024, 35: S1229- S1230. DOI: 10.1016/j.annonc.2024.08.2278.
[22]	LIU LX, WANG JB, ZHENG TS, et al. SHR-8068 plus adebrelimab and bevacizumab for advanced hepatocellular carcinoma(aHCC): A phase 1b/2 study[J]. J Clin Oncol, 2025, 43( 16_suppl): 4093. DOI: 10.1200/jco.2025.43.16_suppl.4093.
[23]	KHALED N BEN, EHMER U, KUBISCH I, et al. Sequential or up-front triple combination with durvalumab, tremelimumab, and bevacizumab for patients with unresectable hepatocellular carcinoma(AIO-MONTBL‑ANC): Safety interim analysis[J]. J Clin Oncol, 2025, 43( 16_suppl): 4122. DOI: 10.1200/jco.2025.43.16_suppl.4122.
[24]	LE MH, LE DM, BAEZ TC, et al. Global incidence of adverse clinical events in non-alcoholic fatty liver disease: A systematic review and meta-analysis[J]. Clin Mol Hepatol, 2024, 30( 2): 235- 246. DOI: 10.3350/cmh.2023.0485.
[25]	ARAB JP, LA DÍAZ, REHM J, et al. Metabolic dysfunction and alcohol-related liver disease(MetALD): Position statement by an expert panel on alcohol-related liver disease[J]. J Hepatol, 2025, 82( 4): 744- 756. DOI: 10.1016/j.jhep.2024.11.028.
[26]	CAO LQ, XIE YH, FLEISHMAN JS, et al. Hepatocellular carcinoma and lipid metabolism: Novel targets and therapeutic strategies[J]. Cancer Lett, 2024, 597: 217061. DOI: 10.1016/j.canlet.2024.217061.
[27]	EL-KHOUEIRY AB, KIM TY, BLANC JF, et al. International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma(HCC) previously treated with immune checkpoint inhibitors(ICI)[J]. J Clin Oncol, 2024, 42( 16_suppl): 4007. DOI: 10.1200/jco.2024.42.16_suppl.4007.
[28]	MA WH, CHENG JM, YU HL, et al. Efficacy and safety of regorafenib combination with PD-1 inhibitors vs. regorafenib monotherapy in second-line treatment for patients with unresectable hepatocellular carcinoma after failure of different first-line treatments: A multicenter retrospective real-world study[J]. J Clin Oncol, 2025, 43( 16_suppl): 4088. DOI: 10.1200/jco.2025.43.16_suppl.4088.
[29]	DUCREUX M, ABOU-ALFA GK, BEKAII-SAAB T, et al. The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 24th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2022[J]. ESMO Open, 2023, 8( 3): 101567. DOI: 10.1016/j.esmoop.2023.101567.
[30]	YOO C, KIM JH, RYU MH, et al. Clinical outcomes with multikinase inhibitors after progression on first-line atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: A multinational multicenter retrospective study[J]. Liver Cancer, 2021, 10( 2): 107- 114. DOI: 10.1159/000512781.
[31]	WONG JSL, KWOK GGW, TANG V, et al. Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors[J]. J Immunother Cancer, 2021, 9( 2): e001945. DOI: 10.1136/jitc-2020-001945.
[32]	HWANG SY, LEE SL, LIU HQ, et al. Second-line treatment after failure of immune checkpoint inhibitors in hepatocellular carcinoma: Tyrosine kinase inhibitor, retrial of immunotherapy, or locoregional therapy?[J]. Liver Cancer, 2023, 13( 3): 246- 255. DOI: 10.1159/000534303.
[33]	YANG CX, PAN YX, YE F, et al. The pattern of tumor progression on first-line immune checkpoint inhibitor-based systemic therapy for Chinese advanced hepatocellular carcinoma-CLEAP 004 study[J]. Front Immunol, 2024, 15: 1310239. DOI: 10.3389/fimmu.2024.1310239.
[34]	CABIBBO G, CELSA C, ALIMENTI E, et al. Evaluating the risk-benefit ratio of immunotherapy according to liver-functional reserve in advanced HCC: The dark side of the moon[J]. Hepatology, 2023, 77( 4): 1074- 1077. DOI: 10.1097/HEP.0000000000000205.
[35]	D’AVOLA D, GRANITO A, DE LA TORRE-ALÁEZ M, et al. The importance of liver functional reserve in the non-surgical treatment of hepatocellular carcinoma[J]. J Hepatol, 2022, 76( 5): 1185- 1198. DOI: 10.1016/j.jhep.2021.11.013.
[36]	CABIBBO G, AGHEMO A, LAI Q, et al. Optimizing systemic therapy for advanced hepatocellular carcinoma: The key role of liver function[J]. Dig Liver Dis, 2022, 54( 4): 452- 460. DOI: 10.1016/j.dld.2022.01.122.
[37]	KULKARNI AV, TEVETHIA H, KUMAR K, et al. Effectiveness and safety of atezolizumab-bevacizumab in patients with unresectable hepatocellular carcinoma: A systematic review and meta-analysis[J]. EClinicalMedicine, 2023, 63: 102179. DOI: 10.1016/j.eclinm.2023.102179.
[38]	FULGENZI CAM, SCHEINER B, D’ALESSIO A, et al. Immunotherapy vs best supportive care for patients with hepatocellular cancer with child-pugh B dysfunction[J]. JAMA Oncol, 2024, 10( 9): 1253- 1258. DOI: 10.1001/jamaoncol.2024.2166.