Research advances in second-line therapies for hepatocellular carcinoma after resistance to targeted therapy combined with immunotherapy

Tianqi ZHANG; Yuzhe CAO; Mengxuan ZUO; Yangkui GU

doi:10.12449/JCH240227

Volume 40 Issue 2

Feb. 2024

Turn off MathJax

Article Contents

Abstract

References

Article Navigation > Journal of Clinical Hepatology > 2024 > 40(2): 386-390

PDF( 552 KB)

Research advances in second-line therapies for hepatocellular carcinoma after resistance to targeted therapy combined with immunotherapy

DOI: 10.12449/JCH240227

Tianqi ZHANG^{1, 2},
Yuzhe CAO^{1, 2},
Mengxuan ZUO^{1, 2},
Yangkui GU^{1, 2
,
,
,}

1.
Department of Minimally Invasive Interventional Therapy，Sun Yat-sen University Cancer Center，Guangzhou 510060，China
2.
State Key Laboratory of Oncology in South China，Guangzhou 510060，China

Research funding:

Guangzhou Science and Technology Program Civic Technology Research Plan (2024A04J4245);

Natural Science Foundation of Guangdong Province (2020A1515011539)

More Information

Corresponding author: GU Yangkui， guyk@sysucc.org.cn （ORCID： 0000-0002-6689-7338）
Received Date: 2023-03-20
Accepted Date: 2023-05-18
Published Date: 2024-02-19

Abstract

Abstract

In recent years， clinical studies on targeted therapy and immunotherapy for advanced hepatocellular carcinoma used alone or in combination have provided abundant evidence on efficacy and safety for the selection of first-line therapies. However， no consensus has been reached on the selection of second-line therapies in various clinical guidelines for hepatocellular carcinoma， which is caused by the fact that existing evidence is limited to the options after failure of sorafenib and that there is still a lack of high-level evidence for new first-line therapies such as second-line therapies after resistance to targeted therapy and immunotherapy for hepatocellular carcinoma. This article reviews the results of current clinical trials and summarizes the studies on second-line therapies for hepatocellular carcinoma after resistance to first-line targeted therapy and immunotherapy for hepatocellular carcinoma based on the different mechanisms of action of drugs， as well as the research advances in recent years. For hepatocellular carcinoma patients with resistance to first-line targeted therapy and immunotherapy， targeted combination therapy and dual-immune therapy are expected to improve treatment outcome and survival， and more prospective clinical studies are needed in the future to provide effective and safe treatment regimens for hepatocellular carcinoma patients with resistance to targeted therapy and immunotherapy.
- Carcinoma， Hepatocellular,
- Drug Therapy,
- Drug Resistance， Neoplasm

FullText(HTML)

References(40)

References

[1]	SUNG H, FERLAY J, SIEGEL RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71( 3): 209- 249. DOI: 10.3322/caac.21660.
[2]	CAO W, CHEN HD, YU YW, et al. Changing profiles of cancer burden worldwide and in China: A secondary analysis of the global cancer statistics 2020[J]. Chin Med J, 2021, 134( 7): 783- 791. DOI: 10.1097/CM9.0000000000001474.
[3]	THOMAS MB, JAFFE D, CHOTI MM, et al. Hepatocellular carcinoma: Consensus recommendations of the National Cancer Institute Clinical Trials Planning Meeting[J]. J Clin Oncol, 2010, 28( 25): 3994- 4005. DOI: 10.1200/JCO.2010.28.7805.
[4]	VILLANUEVA A. Hepatocellular carcinoma[J]. N Engl J Med, 2019, 380( 15): 1450- 1462. DOI: 10.1056/nejmra1713263.
[5]	REIG M, FORNER A, RIMOLA J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update[J]. J Hepatol, 2022, 76( 3): 681- 693. DOI: 10.1016/j.jhep.2021.11.018.
[6]	LLOVET JM, RICCI S, MAZZAFERRO V, et al. Sorafenib in advanced hepatocellular carcinoma[J]. N Engl J Med, 2008, 359( 4): 378- 390. DOI: 10.1056/nejmoa0708857.
[7]	CHENG AL, KANG YK, CHEN ZD, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial[J]. Lancet Oncol, 2009, 10( 1): 25- 34. DOI: 10.1016/S1470-2045(08)70285-7.
[8]	KUDO M, FINN RS, QIN SK, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial[J]. Lancet, 2018, 391( 10126): 1163- 1173. DOI: 10.1016/S0140-6736(18)30207-1.
[9]	QIN SK, BI F, GU SZ, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: A randomized, open-label, parallel-controlled phase II-III trial[J]. J Clin Oncol, 2021, 39( 27): 3002- 3011. DOI: 10.1200/JCO.21.00163.
[10]	QIN SK, FINN RS, KUDO M, et al. RATIONALE 301 study: Tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma[J]. Future Oncol, 2019, 15( 16): 1811- 1822. DOI: 10.2217/fon-2019-0097.
[11]	QIN S, KUDO M, MEYER T, et al. LBA36 Final analysis of RATIONALE-301: Randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma[J]. Ann Oncol, 2022, 33: S1402- S1403. DOI: 10.1016/j.annonc.2022.08.033.
[12]	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.
[13]	CHENG AL, QIN SK, IKEDA M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma[J]. J Hepatol, 2022, 76( 4): 862- 873. DOI: 10.1016/j.jhep.2021.11.030.
[14]	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.
[15]	QIN S, CHAN L, GU S, 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[R]. ESMO, 2022.
[16]	BRUIX J, QIN SK, 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[J]. Lancet, 2017, 389( 10064): 56- 66. DOI: 10.1016/S0140-6736(16)32453-9.
[17]	ZHU AX, KANG YK, YEN CJ, et al. 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[J]. Lancet Oncol, 2019, 20( 2): 282- 296. DOI: 10.1016/S1470-2045(18)30937-9.
[18]	ABOU-ALFA GK, MEYER T, CHENG AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma[J]. N Engl J Med, 2018, 379( 1): 54- 63. DOI: 10.1056/NEJMoa1717002.
[19]	QIN SK, LI Q, GU SZ, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma(AHELP): A multicentre, double-blind, randomised, placebo-controlled, phase 3 trial[J]. Lancet Gastroenterol Hepatol, 2021, 6( 7): 559- 568. DOI: 10.1016/S2468-1253(21)00109-6.
[20]	JIN HJ, SHI YP, LV YY, et al. EGFR activation limits the response of liver cancer to lenvatinib[J]. Nature, 2021, 595( 7869): 730- 734. DOI: 10.1038/s41586-021-03741-7.
[21]	HUANG JJ, GUO YJ, HUANG WS, et al. Regorafenib combined with PD-1 blockade immunotherapy versus regorafenib as second-line treatment for advanced hepatocellular carcinoma: A multicenter retrospective study[J]. J Hepatocell Carcinoma, 2022, 9: 157- 170. DOI: 10.2147/JHC.S353956.
[22]	GUAN RG, YU CY, LI SH, et al. A preliminary study on drug switching strategy for second-line therapy after combination treatment of tyrosine kinase inhibitors and immune checkpoint inhibitors for unresectable hepatocellular carcinoma[J]. Front Pharmacol, 2022, 13: 998534. DOI: 10.3389/fphar.2022.998534.
[23]	LEE MS, RYOO BY, HSU CH, et al. Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma(GO30140): An open-label, multicentre, phase 1b study[J]. Lancet Oncol, 2020, 21( 6): 808- 820. DOI: 10.1016/S1470-2045(20)30156-X.
[24]	FINN RS, KUDO M, KLÜMPEN H, et al. Regorafenib in patients with unresectable hepatocellular carcinoma(uHCC) in routine clinical practice: Exploratory analysis of overall survival(OS) in the prospective, observational REFINE study[J]. J Clin Oncol, 2022, 40( 4_suppl): 433. DOI: 10.1200/JCO.2022.40.4_suppl.433.
[25]	AL-BATRAN S. Pembrolizumab and lenvatinib in patients with advanced HCC who are refractory to atezolizumab and bevacizumab therapy[EB/OL]. 2022. https://www.clinicaltrials.gov/ct2/show/NCT05101629. https://www.clinicaltrials.gov/ct2/show/NCT05101629
[26]	BAYER. Regorafenib plus pembrolizumab in patients with advanced or spreading liver cancer who have been previously treated with PD-1/PD-L1 immune checkpoint inhibitors[EB/OL]. 2022. https://clinicaltrials.gov/ct2/show/NCT04696055. https://clinicaltrials.gov/ct2/show/NCT04696055
[27]	CROCENZI T, EL-KHOUEIRY A, YAU T, et al. Nivolumab(nivo) in sorafenib(sor)-naive and-experienced pts with advanced hepatocellular carcinoma(HCC): CheckMate 040 study[J]. J Clin Oncol, 2017, 35: 4013. DOI: 10.1200/JCO.2017.35.15_suppl.4013.
[28]	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[J]. JAMA Oncol, 2020, 6( 11): e204564. DOI: 10.1001/jamaoncol.2020.4564.
[29]	ZHU AX, FINN RS, EDELINE J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib(KEYNOTE-224): A non-randomised, open-label phase 2 trial[J]. Lancet Oncol, 2018, 19( 7): 940- 952. DOI: 10.1016/S1470-2045(18)30351-6.
[30]	FINN RS, RYOO BY, MERLE P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: A randomized, double-blind, phase III trial[J]. J Clin Oncol, 2020, 38( 3): 193- 202. DOI: 10.1200/JCO.19.01307.
[31]	QIN SK, CHEN ZD, FANG WJ, 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]. J Clin Oncol, 2023, 41( 7): 1434- 1443. DOI: 10.1200/JCO.22.00620.
[32]	QIN SK, REN ZG, MENG ZQ, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: A multicentre, open-label, parallel-group, randomised, phase 2 trial[J]. Lancet Oncol, 2020, 21( 4): 571- 580. DOI: 10.1016/S1470-2045(20)30011-5.
[33]	DUCREUX M, ABOU-ALFA G, REN Z, et al. Results from a global phase 2 study of tislelizumab, an investigational PD-1 antibody, in patients with unresectable hepatocellular carcinoma[J]. Ann Oncol, 2021, 32: S217. DOI: 10.1016/j.annonc.2021.05.005.
[34]	MELERO I, YAU T, KANG Y, et al. SO-12 Nivolumab(NIVO) plus ipilimumab(IPI) combination therapy in patients with advanced hepatocellular carcinoma(aHCC): 5-year results from CheckMate 040[J]. Ann Oncol, 2022, 33: S361. DOI: 10.1016/j.annonc.2022.04.411.
[35]	FELIP E, DOGER B, MAJEM M, et al. Initial results from a phase II study(TACTI-002) in metastatic non-small cell lung or head and neck carcinoma patients receiving eftilagimod alpha(soluble LAG-3 protein) and pembrolizumab[J]. J Clin Oncol, 2020, 38: 3100. DOI: 10.1200/jco.2020.38.15_suppl.3100.
[36]	FELIP E, MAJEM M, DOGER B, et al. A phase II study(TACTI-002) in first-line metastatic non-small cell lung carcinoma investigating eftilagimod alpha(soluble LAG-3 protein) and pembrolizumab: Updated results from a PD-L1 unselected population[J]. J Clin Oncol, 2022, 40( 16_suppl): 9003. DOI: 10.1200/JCO.2022.40.16_suppl.9003.
[37]	SILVA IP DA, AHMED T, REIJERS ILM, et al. Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: A multicentre, retrospective, cohort study[J]. Lancet Oncol, 2021, 22( 6): 836- 847. DOI: 10.1016/S1470-2045(21)00097-8.
[38]	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.
[39]	ROESSLER D, ÖCAL O, PHILIPP AB, et al. Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: A multicenter retrospective study[J]. J Cancer Res Clin Oncol, 2023, 149( 7): 3065- 3073. DOI: 10.1007/s00432-022-04206-8.
[40]	BAI L, SUN M, XU A, et al. Phase 2 study of AK104(PD-1/CTLA-4 bispecific antibody) plus lenvatinib as first-line treatment of unresectable hepatocellular carcinoma[J]. J Clin Oncol, 2021, 39( 15_suppl): 4101. DOI: 10.1200/JCO.2021.39.15_suppl.4101.

Relative Articles

[1]	Jiarui YANG, Jianxin JIANG. An excerpt of EASL clinical practice guidelines on the management of hepatocellular carcinoma（2024 edition）[J]. Journal of Clinical Hepatology, 2025, 41(2): 234-239. doi: 10.12449/JCH250207
[2]	Lijuan LONG, Zongyu WANG, Yali ZHAO, Chuanfu QIN, Hua QIU. Research advances in traditional Chinese medicine for the treatment of hepatocellular carcinoma by regulating immune cells[J]. Journal of Clinical Hepatology, 2025, 41(2): 349-358. doi: 10.12449/JCH250223
[3]	Yue YANG, Siyu XU, Jue WANG, Shilin DU, Chunlei ZHANG, Haiyan SONG. Mechanism of action of cinobufotalin in inhibiting lung metastasis of hepatocellular carcinoma by regulating AKT-mediated epithelial-mesenchymal transition in a nude mouse model[J]. Journal of Clinical Hepatology, 2024, 40(9): 1840-1847. doi: 10.12449/JCH240919
[4]	Yuan DUAN, Ting ZHANG, Jing ZHANG, Guiwen GUAN, Jingzhou WANG, Xiangmei CHEN. Expression of AU-rich element RNA-binding factor 1 in hepatocellular carcinoma and its value in prognostic evaluation[J]. Journal of Clinical Hepatology, 2024, 40(9): 1833-1839. doi: 10.12449/JCH240918
[5]	Zheng SONG, Wei LUO, Xiujuan CHANG, Yongping YANG. Construction of a novel disulfidptosis-related prognostic model for patients with hepatocellular carcinoma based on bioinformatics analysis[J]. Journal of Clinical Hepatology, 2024, 40(9): 1822-1832. doi: 10.12449/JCH240917
[6]	Changwang ZHANG, Ninghan WU, Cong WANG, Zheng ZHENG, Siming GAO, Changpeng ZOU, Sujing ZHANG, Na LI. Efficacy and safety of cryoablation combined with Camrelizumab monoclonal antibody in treatment of hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2024, 40(6): 1169-1174. doi: 10.12449/JCH240616
[7]	Xiaohua ZHANG, Ying FENG, Xianbo WANG. Role of the Hedgehog signaling pathway in hepatocellular carcinoma and its tumor microenvironment[J]. Journal of Clinical Hepatology, 2024, 40(4): 822-827. doi: 10.12449/JCH240429
[8]	Tingting SHI, Runbing ZHANG, Yang WU, Yani ZHANG, Lingling ZHU, Chun GAO, Jingjing JIANG, Xiaofeng ZHENG, Jiucong ZHANG. Role of extracellular vesicles of different origins in the development and progression of hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2024, 40(6): 1264-1268. doi: 10.12449/JCH240630
[9]	Shichun LU. Challenges and reflections on conversion therapy for advanced hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2024, 40(9): 1738-1740. doi: 10.12449/JCH240904
[10]	Chi MA, Guang TAN. Strategies and practice of conversion therapy for hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2024, 40(9): 1725-1731. doi: 10.12449/JCH240902
[11]	Runbing ZHANG, Tingting SHI, Yang WU, Jiucong ZHANG, Xiaofeng ZHENG. The mechanism of autophagy inducing drug resistance of hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2024, 40(11): 2315-2319. doi: 10.12449/JCH241128
[12]	Xiaomeng YAO, Keke SUN, Yunkai LIN, Hui WANG, Liwei DONG, Lei CHEN, Heping HU. Molecular mechanism of lenvatinib resistance in hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2024, 40(12): 2524-2530. doi: 10.12449/JCH241225
[13]	Hongxia LI, Yimeng SUN, Hongtao ZHANG, Shuwang HAN, Delin ZHANG, Haitao SHANG, Wu GUO, Junjian LIU, Zhonglian LI. Role of HBV DNA polymerase in mediating the immune escape of tumor cells in HBV-related hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2023, 39(12): 2858-2866. doi: 10.3969/j.issn.1001-5256.2023.12.017
[14]	Chun GAO, Jingjing JIANG, Yuchun CHEN, Xiaohui YU, Jiucong ZHANG, . Mechanism of action of N7-methylguanosine in hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2023, 39(12): 2946-2951. doi: 10.3969/j.issn.1001-5256.2023.12.029
[15]	Liver Oncology Branch, China Association for the Promotion of International Exchange in Healthcare, Immunology Branch. Chinese expert consensus on targeted immunotherapy combined with local therapy for advanced hepatocellular cancer[J]. Journal of Clinical Hepatology, 2023, 39(12): 2782-2792. doi: 10.3969/j.issn.1001-5256.2023.12.006
[16]	Quan ZHOU, Chunlin CAI, Jinqiang LI. Gut-liver axis： Intestinal microbial homeostasis and hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2023, 39(11): 2710-2717. doi: 10.3969/j.issn.1001-5256.2023.11.029
[17]	Zhisong NI, Junhan WEN, Weiwei ZHAO, Shoujun YU, Liang HAO, Yu CHENG, Xin LIU. Neoadjuvant therapy for hepatocellular carcinoma： Current situation and prospects[J]. Journal of Clinical Hepatology, 2023, 39(11): 2697-2704. doi: 10.3969/j.issn.1001-5256.2023.11.027
[18]	Pengwei REN, Ying HAN, Xinmin ZHOU. Predictive indicators for the efficacy of targeted therapy/immunotherapy for hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2023, 39(11): 2705-2709. doi: 10.3969/j.issn.1001-5256.2023.11.028
[19]	Shisi LI, Zhitang GUO, Zhangbin CHEN, Yishan TENG. Research advances in systemic therapy for advanced hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2021, 37(12): 2943-2946. doi: 10.3969/j.issn.1001-5256.2021.12.044
[20]	Liang Yuan, Wang ShiMing, Shi ZhenMing. Research advances in application of molecular- targeted therapy for hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2016, 32(3): 601-604. doi: 10.3969/j.issn.1001-5256.2016.02.03.045

Supplements(0)

Cited By

Cited by

Periodical cited type(4)

1.	吴慧娴，刘诗云，罗维劼，蒋艳，叶涛. 基于网络药理学和分子对接探究龙胆泻肝汤治疗肝癌发热的作用机制. 中华养生保健. 2025(02): 16-21 .
2.	杨新，刘志新，刘娇，杨卓，安娜. 甲状旁腺激素样激素与肝细胞癌免疫浸润相关性及其对患者预后预测价值. 临床军医杂志. 2024(04): 425-429 .
3.	刘新宇，丁泽邦，吴焕，马俊杰，陆进. 肝细胞癌组织核孔蛋白85(NUP85)高表达与免疫细胞浸润及预后相关性分析. 细胞与分子免疫学杂志. 2024(06): 508-519 .
4.	姚鹏，柴嘉穗，潘登，陈彦，王旭，张宏杰，李小争. 改良二步肝切除联合免疫靶向治疗临界可切除肝癌的临床疗效. 中华消化外科杂志. 2024(07): 984-988 .

Other cited types(0)

Proportional views

Proportional views

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

Get Citation

PDF

XML

Article Metrics

Article views (1033) PDF downloads(141)