国际肿瘤学杂志››2023,Vol. 50››Issue (11): 688-695.doi:10.3760/cma.j.cn371439-20230605-00130
收稿日期:
2023-06-05修回日期:
2023-06-25出版日期:
2023-11-08发布日期:
2024-01-11通讯作者:
徐细明 E-mail:doctorxu120@aliyun.comReceived:
2023-06-05Revised:
2023-06-25Online:
2023-11-08Published:
2024-01-11Contact:
Xu Ximing E-mail:doctorxu120@aliyun.com摘要:
肝细胞癌(HCC)是世界上最常见的恶性肿瘤之一,在我国的发病率及病死率居高不下。自从索拉非尼开辟了HCC靶向治疗的新时代,全球的药物研发人员在HCC系统治疗上的探索做出了许多的努力与贡献。近年来,新型分子靶向药物、免疫检查点抑制剂及其联合治疗方案在晚期HCC中进行了许多大样本、国际多中心临床试验。结果显示,免疫联合靶向以及双免疫联合的治疗效果相较于靶向或免疫单药具有显著的优势,在延长生存期、改善患者生命质量的同时也具有令人满意的安全性。
江山, 徐细明. 肝细胞癌的靶向及免疫治疗新进展[J]. 国际肿瘤学杂志, 2023, 50(11): 688-695.
Jiang Shan, Xu Ximing. Recent progresses of targeted therapy and immunotherapy of hepatocellular carcinoma[J]. Journal of International Oncology, 2023, 50(11): 688-695.
[1] | Toh MR, Wong EYT, Wong SH, et al. Global epidemiology and genetics of hepatocellular carcinoma[J].Gastroenterology,2023,164(5): 766-782. DOI:10.1053/j.gastro.2023.01.033. pmid:36738977 |
[2] | Vogel A, Meyer T, Sapisochin G, et al. Hepatocellular carcinoma[J].Lancet,2022,400(10360): 1345-1362. DOI:10.1016/S0140-6736(22)01200-4. pmid:36084663 |
[3] | Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma[J].Nat Rev Dis Primers,2021,7(1): 6. DOI:10.1038/s41572-020-00240-3. pmid:33479224 |
[4] | Da Fonseca LG, Reig M, Bruix J. Tyrosine kinase inhibitors and hepatocellular carcinoma[J].Clin Liver Dis,2020,24(4): 719-737. DOI:10.1016/j.cld.2020.07.012. pmid:33012455 |
[5] | Tang W, Chen Z, Zhang W, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects[J].Signal Transduct Target Ther,2020,5(1): 87. DOI:10.1038/s41392-020-0187-x. |
[6] | Llovet JM, Montal R, Sia D, et al. Molecular therapies and precision medicine for hepatocellular carcinoma[J].Nat Rev Clin Oncol,2018,15(10): 599-616. DOI:10.1038/s41571-018-0073-4. pmid:30061739 |
[7] | 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. |
[8] | Cheng AL, Kang YK, Chen Z, 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. |
[9] | Xia S, Pan Y, Liang Y, et al. The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma[J].EBioMedicine,2020,51: 102610. DOI:10.1016/j.ebiom.2019.102610. |
[10] | Zhao Y, Zhang YN, Wang KT, et al. Lenvatinib for hepatocellular carcinoma: from preclinical mechanisms to anti-cancer therapy[J].Biochim Biophys Acta Rev Cancer,2020,1874(1):188391. DOI:10.1016/j.bbcan.2020.188391. |
[11] | Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model[J].Cancer Sci,2018,109(12): 3993-4002. DOI:10.1111/cas.13806. |
[12] | Kudo M, Finn RS, Qin S, 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. pmid:29433850 |
[13] | Nair A, Reece K, Donoghue MB, et al. FDA supplemental approval summary: lenvatinib for the treatment of unresectable hepatocellular carcinoma[J].Oncologist,2021,26(3): e484-e491. DOI:10.1002/onco.13566. pmid:33044793 |
[14] | Esteban-Fabró R, Willoughby CE, Piqué-Gili M, et al. Cabozantinib enhances anti-PD1 activity and elicits a neutrophil-based immune response in hepatocellular carcinoma[J].Clin Cancer Res,2022,28(11): 2449-2460. DOI:10.1158/1078-0432.CCR-21-2517. pmid:35302601 |
[15] | 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. |
[16] | Shang R, Song X, Wang P, et al. Cabozantinib-based combination therapy for the treatment of hepatocellular carcinoma[J].Gut,2021,70(9): 1746-1757. DOI:10.1136/gutjnl-2020-320716. |
[17] | Ou DL, Chen CW, Hsu CL, et al. Regorafenib enhances antitumor immunity via inhibition of p38 kinase/Creb1/Klf4 axis in tumor-associated macrophages[J].J Immunother Cancer,2021,9(3): e001657. DOI:10.1136/jitc-2020-001657. |
[18] | Bruix J, Qin S, 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. pmid:27932229 |
[19] | Heo YA, Syed YY. Regorafenib: a review in hepatocellular carcinoma[J].Drugs,2018,78(9): 951-958. DOI:10.1007/s40265-018-0932-4. |
[20] | Keam SJ, Duggan S. Donafenib: first approval[J].Drugs,2021,81(16): 1915-1920. DOI:10.1007/s40265-021-01603-0. pmid:34591285 |
[21] | Qin S, Bi F, Gu S, 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. |
[22] | Sammarco G, Varricchi G, Ferraro V, et al. Mast cells, angioge-nesis and lymphangiogenesis in human gastric cancer[J].Int J Mol Sci,2019,20(9): 2106. DOI:10.3390/ijms20092106. |
[23] | Qin S, Li Q, Gu S, 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. |
[24] | Llovet JM, Singal AG, Villanueva A, et al. Prognostic and predictive factors in patients with advanced HCC and elevated alpha-fetoprotein treated with ramucirumab in two randomized phase Ⅲtrials[J].Clin Cancer Res,2022,28(11): 2297-2305. DOI:10.1158/1078-0432.Ccr-21-4000. pmid:35247922 |
[25] | Zhu AX, Park JO, Ryoo BY, et al. 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[J].Lancet Oncol,2015,16(7): 859-870. DOI:10.1016/S1470-2045(15)00050-9. pmid:26095784 |
[26] | 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. pmid:30665869 |
[27] | Syed YY. Ramucirumab: a review in hepatocellular carcinoma[J].Drugs,2020,80(3): 315-322. DOI:10.1007/s40265-020-01263-6. pmid:32034692 |
[28] | Sangro B, Sarobe P, Hervás-Stubbs S, et al. Advances in immunotherapy for hepatocellular carcinoma[J].Nat Rev Gastroenterol Hepatol,2021,18(8): 525-543. DOI:10.1038/s41575-021-00438-0. pmid:33850328 |
[29] | Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade[J].Science,2018,359(6382): 1350-1355. DOI:10. 1126/science.aar4060. pmid:29567705 |
[30] | Kudo M. Pembrolizumab for the treatment of hepatocellular carcinoma[J].Liver Cancer,2019,8(3): 143-154. DOI:10.1159/000500143. pmid:31192152 |
[31] | 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. |
[32] | Qin S, Chen Z, Fang W, et al. Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): phase 3 KEYNOTE-394 study[J].J Clin Oncol,2022,40(4_suppl): 383. DOI:10.1200/JCO.2022.40.4_suppl.383. |
[33] | 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[J].Lancet,2017,389(10088): 2492-2502. DOI:10.1016/S0140-6736(17)31046-2. pmid:28434648 |
[34] | Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a rando-mised, multicentre, open-label, phase 3 trial[J].Lancet Oncol,2022,23(1): 77-90. DOI:10.1016/S1470-2045(21)00604-5. |
[35] | Ren Z, Xu J, Bai Y, 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. |
[36] | Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with pre-viously 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. |
[37] | Deva S, Lee JS, Lin CC, et al. A phase Ⅰa/Ⅰb trial of tislelizumab, an anti-PD-1 antibody (ab), in patients (pts) with advanced solid tumors[J].Ann Oncol,2018, 29 Supplement 10: X24-X25. DOI:10.1093/annonc/mdy487.042. |
[38] | 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 Supplement 7: S1402-S1403. DOI:10.1016/j.annonc.2022.08.033. |
[39] | Wainberg ZA, Segal NH, Jaeger D, et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC)[J].J Clin Oncol,2017,35(15_suppl): 4071. DOI:10.1200/JCO.2017.35.15_suppl.4071. |
[40] | Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C[J].J Hepatol,2013,59(1): 81-88. DOI:10.1016/j.jhep.2013.02.022. pmid:23466307 |
[41] | Raybould AL, Sanoff H. Combination antiangiogenic and immunotherapy for advanced hepatocellular carcinoma: evidence to date[J].J Hepatocell Carcinoma,2020,7: 133-142. DOI:10.2147/JHC.S224938. pmid:32984090 |
[42] | Zhu AX, Abbas AR, de Galarreta MR, et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma[J].Nat Med,2022,28(8): 1599-1611. DOI:10.1038/s41591-022-01868-2. pmid:35739268 |
[43] | Liu X, Lu Y, Qin S. Atezolizumab and bevacizumab for hepatocellular carcinoma: mechanism, pharmacokinetics and future treatment strategies[J].Future Oncol,2021,17(17): 2243-2256. DOI:10.2217/fon-2020-1290. |
[44] | Finn RS, Qin S, 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. |
[45] | Ducreux M, Zhu AX, Cheng AL, et al. IMbrave150: exploratory analysis to examine the association between treatment response and overall survival (OS) in patients (pts) with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor)[J].J Clin Oncol,2021,39(15_suppl): 4071. DOI:10.1200/JCO.2021.39.15_suppl.4071. |
[46] | Qin S, Ren Z, Feng YH, et al. Atezolizumab plus bevacizumab versus sorafenib in the chinese subpopulation with unresectable hepatocellular carcinoma: phase 3 randomized, open-label IMbrave 150 study[J].Liver Cancer,2021,10(4): 296-308. DOI:10.1159/000513486. |
[47] | Finn RS, Kudo M, Merle P, et al. LBA34 Primary results from the phase Ⅲ LEAP-002 study: lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC)[J].Ann Oncol,2022, 33, Supplement7: S1401. DOI:10.1016/j.annonc.2022.08.031. |
[48] | Qin S, Chan LS, 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[J].Ann Oncol,2022,33 Supplement 7: S1401-S1402. DOI:10.1016/j.annonc.2022.08.032. |
[49] | Kelley RK, Yau T, Cheng AL, et al. VP10-2021: Cabozantinib (C) plus atezolizumab (A) versus sorafenib (S) as first-line systemic treatment for advanced hepatocellular carcinoma (aHCC): results from the randomized phase Ⅲ COSMIC-312 trial[J].Ann Oncol,2022,33(1): 114-116. DOI:10.1016/j.annonc.2021.10.008. |
[50] | 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: the CheckMate 040 randomized clinical trial[J].JAMA Oncol,2020,6(11): e204564. DOI:10.1001/jamaoncol.2020.4564. |
[51] | Saung MT, Pelosof L, Casak S, et al. FDA approval summary: nivolumab plus ipilimumab for the treatment of patients with hepatocellular carcinoma previously treated with sorafenib[J].Oncologist,2021,26(9): 797-806. DOI:10.1002/onco.13819. pmid:33973307 |
[52] | Kelley RK, Abou-Alfa GK, Bendell JC, et al. Phase Ⅰ/Ⅱ study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase Ⅰ safety and efficacy analyses[J].J Clin Oncol,2017,35(15_suppl): 4073. DOI:10.1200/JCO.2017.35.15_suppl.4073. |
[53] | Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA[J].J Clin Oncol,2022,40(4_suppl): 379. DOI:10.1200/JCO.2022.40.4_suppl.379. |
[54] | De Castria TB, Khalil DN, Harding JJ, et al. Tremelimumab and durvalumab in the treatment of unresectable, advanced hepatocellular carcinoma[J].Future Oncol,2022,18(33): 3769-3782. DOI:10.2217/fon-2022-0652. pmid:36399155 |
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