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

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

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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

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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.

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

DOI: 10.12449/JCH240227

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

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