PDF下载 ( 2049 KB)
程序性细胞死亡受体1及其配体抑制剂在肝细胞癌治疗中的应用进展
DOI: 10.3969/j.issn.1001-5256.2021.02.040
作者贡献声明：王昭月负责资料分析、撰写论文；魏来负责指导写作思路、修改论文；黄缘负责指导撰写文章、最后定稿。
Advances in the application of programmed death-1/programmed death-ligand 1 inhibitors in the treatment of hepatocellular carcinoma
-
摘要: 肝细胞癌(HCC)是我国最常见的恶性肿瘤之一，由于缺乏特异性表现，超过一半的患者在初诊时已处于进展期。靶向治疗和系统化疗是进展期HCC的主要治疗方法，疗效有限。近年来，免疫治疗迅速发展。介绍了免疫检查点抑制剂——程序性细胞死亡受体1及其配体(PD-1/PD-L1)抑制剂在HCC治疗中的现状，归纳了多项临床试验的数据结果，分析了单药治疗及联合治疗的安全性及有效性。通过分析表明，免疫治疗已成为全身系统治疗的重要方法之一，尤其是联合治疗可显著提高HCC的疗效，其安全性亦在可控范围内，是未来发展的重要方向。
-
关键词:
- 癌, 肝细胞 /
- 免疫疗法 /
- 免疫检查点抑制剂 /
- 程序性细胞死亡受体1
Abstract: Hepatocellular carcinoma (HCC) is one of the most common malignancies in China, and due to the lack of specific symptoms, more than half of these patients are in the advanced stage at the time of initial diagnosis. Targeted therapy and systemic chemotherapies are the main treatment methods for advanced HCC with limited efficacy. In recent years, immunotherapy has been developed rapidly. This article introduces the current status of the immune checkpoint inhibitors, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, in the treatment of HCC, summarizes the latest data of several clinical trials, and analyzes the safety and efficacy of monotherapy and combination therapy. The analysis shows that immunotherapy has become one of the important methods for systemic treatment, and combination therapy can significantly improve the outcome of HCC with a manageable safety profile, which is an important direction for future development. -
表 1 PD-1/PD-L1抑制剂单药治疗在aHCC中的临床试验
药物 临床试验 分期 治疗线数 入组例数 ORR(%) CR(%) DCR(%) mDOR(月) mOS(月) mPFS(月) TRAEs(%) 任何级别 3~4级 Nivolumab CheckMate 040 Ⅰ/Ⅱ - 48 15 6 58 17 15.0 - 83 25 - 214 20 1 64 9.9 NR 4.0 74 19 一线 80 20 1 54 17.15 28.6 - 78 29 二线 ESC组，n=37 19 3 54 19.35 15.0 - 77 18 EXP组，n=145 14 1 55 16.59 15.6 - - 85(亚洲队列) 15 4 49 9.7 14.9 - 74 16 - 49(Child-Pugh B) 10.2 - 55.1 9.9 7.6 - 51 24.5 Nivolumabvs Sorafenib CheckMate 459 Ⅲ 一线 743(NIVO，n=371；SOR，n=372) 15 vs 7 4 vs 1 55 vs 58 23.3 vs 23.4 16.4 vs 14.7 3.7 vs 3.8 - 22 vs 49 Pembrolizumab KEYNOTE-224 Ⅱ 二线 104 17 1 62 NR 12.9 4.9 73 25 Pembrolizumabvs安慰剂 KEYNOTE-240 Ⅲ 二线 413(PEM，n=278；安慰剂，n=135) 18.3 vs 4.4 2.2 vs 0 62.2 vs 53.3 13.8 vs NR 13.9 vs 10.6 3.0 vs 2.8 60.9 vs 48.5 18.3 vs 7.5 Camrelizumab(SHR-1210) - Ⅱ 二线 217 14.7 0 44.2 NR 13.8 2.1 - 22 Durvalumab - Ⅰ/Ⅱ 二线 40(可评估，n=39) 10.3 (n=39) 0 33.3 (n=39) - 13.2 - 80 20 注：“-”，未提供数据；ORR，客观缓解率；CR，完全缓解；DCR，疾病控制率；mDOR，中位缓解持续时间；mOS，中位总生存期；mPFS，中位无进展生存期；TRAEs，治疗相关不良事件；NR，未达到；ESC，剂量爬坡；EXP，剂量扩展；表格中所列数据均根据实体瘤疗效评价标准1.1版(RECIST v1.1)评估所得。 
下载: 导出CSV
表 2 PD-1/PD-L1抑制剂联合治疗在aHCC中的临床试验
药物 临床试验 分期 治疗线数 入组例数 ORR(%) CR(%) DCR(%) mDOR(月) mOS(月) mPFS(月) TRAEs(%) 任何级别 3~4级 Pembrolizumab+Lenvatinib KEYNOTE-524/Study 116 Ⅰb 一线 100 36 1 88 12.6 22.0 8.6 95 67 Nivolumab+Lenvatinib Study 117 Ⅰb 一线 30 76.7 13.3 96.7 - - - 100 - Camrelizumab(SHR-1210)+Apatinib - Ⅰ 二线 16(可评估) 50 0 93.8 NR NR 7.2 - - Avelumab+Axitinib VEGF Liver 100 Ⅰb 一线 22 13.6 - - - - 5.5 - - Atezolizumab+Bevacizumab GO30140 Ⅰb 一线 队列A，n=104 36 12 71 NE 17.1 7.3 88 39 队列F，n=119
Atezo+Bev，n=60；
Atezo，n=5920 vs 17 2 vs 5 67 vs 49 NE vs NE - 5.6 vs 3.4 68 vs 41 20 vs 5 Atezolizumab+Bevacizumabvs Sorafenib IMBrave 150 Ⅲ 一线 501Atezo+Bev，n=336；
SOR，n=16527.3 vs 11.9 5.5 vs 0 73.6 vs 55.3 NE vs 6.3 NE vs 13.2 6.8 vs 4.3 84 vs 94 36 vs 46 194(中国人群)
Atezo+Bev，n=133；
SOR，n=6125 vs 7 - - - NE vs 11.4 5.7 vs 3.2 - - Nivolumab+Ipilimumab CheckMate 040 Ⅰ/Ⅱ 二线 148 31 4.7 49 17.5 - - - 37 A组，n=50 32 8 54 17.5 22.8 B组，n=49 31 6 43 22.2 12.5 C组，n=49 31 0 49 16.6 12.7 Durvalumab+Tremelimumab - Ⅱ - T300+D，n=75 22.7 - - NR 18.7 - - 35.1 T75+D，n=84 9.5 - - 13.2 11.3 - - 24.4 Camrelizumab+FOLFOX4 - Ⅱ 一线 34 26.5 - 79.4 NR NR 5.5 - 85.3 Nivolumab+Cabozantinib±Ipilimumab CheckMate 040 Ⅰ/Ⅱ - 71二联，n=36三联，n=35 17 vs 26 0 vs 0 81 vs 83 - NR vs NR 5.5 vs 6.8 - 42 vs 71 注：NE，无法评估；表格中所列数据均根据RECIST v1.1评估所得；Atezo, Atezolizumab; Bev, Bevacizumab; SOR, Sorafenib。
下载: 导出CSV
-
[1] Bureau of Medical Administration, National Health Commission of the People's Republic of China. Guidelines for diagnosis and treatment of primary liver cancer in China (2019 edition)[J]. J Clin Hepatol, 2020, 36(2): 277-292. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2020.02.007中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019年版)[J]. 临床肝胆病杂志, 2020, 36(2): 277-292. DOI: 10.3969/j.issn.1001-5256.2020.02.007 [2] PARDOLL DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer, 2012, 12(4): 252-264. DOI: 10.1038/nrc3239 [3] 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 [4] CROCENZI TS, EL-KHOUEIRY AB, YAU T, et al. Nivolumab in sorafenib-naive and-experienced patients with advanced hepatocellular carcinoma: CheckMate 040 study[J]. J Clin Oncol, 2017, 35(15 Suppl): 4013. [5] YAU T, HSU C, KIM TY, et al. Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis[J]. J Hepatol, 2019, 71(3): 543-552. DOI: 10.1016/j.jhep.2019.05.014 [6] KUDO M, MATILLA A, SANTORO A, et al. Checkmate-040: Nivolumab (NIVO) in patients (pts) with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) status[J]. J Clin Oncol, 2019, 37(4 Suppl): 327. [7] KAMBHAMPATI S, BAUER KE, BRACCI PM, et al. Nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis: Safety and clinical outcomes in a retrospective case series[J]. Cancer, 2019, 125(18): 3234-3241. DOI: 10.1002/cncr.32206 [8] YAU T, PARK JW, FINN RS, et al. CheckMate 459: A randomized, multi-center phase Ⅲ study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC)[J]. Ann Oncol, 2019, 30(Suppl 5): v874-v875. [9] SUN YK. Interpretation of CSCO guidelines for the diagnosis and treatment of primary liver cancer: Systemic treatment[J/CD]. Electronic J Liver Tumor, 2018, 5(3): 11-14. (in Chinese)孙永琨. 2018《CSCO原发性肝癌诊疗指南》解读——全身治疗部分[J/CD]. 肝癌电子杂志, 2018, 5(3): 11-14. [10] National Comprehensive Cancer Network(NCCN). Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers, Version 1.2020.[EB/OL]. (2020-03-23)[2020-06-20]. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. [11] 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 [12] KUDO M, FINN RS, EDELINE J, et al. Updated efficacy and safety of KEYNOTE-224: A phase Ⅱ study of pembrolizumab (pembro) in patients with advanced hepatocellular carcinoma (HCC)[J]. J Clin Oncol, 2020, 38(4 Suppl): 518. [13] 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 [14] BENSON AB, D'ANGELICA MI, ABBOTT DE, et al. Guidelines insights: Hepatobiliary cancers, Version 2.2019[J]. J Natl Compr Canc Netw, 2019, 17(4): 302-310. DOI: 10.6004/jnccn.2019.0019 [15] QIN S, REN Z, MENG Z, 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 [16] 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. [17] FENG Z, RONG P, WANG W. Meta-analysis of the efficacy and safety of PD-1/PD-L1 inhibitors administered alone or in combination with anti-VEGF agents in advanced hepatocellular carcinoma[J]. Gut, 2020, 69(10): 1904-1906. DOI: 10.1136/gutjnl-2019-320116 [18] KUDO M. Immuno-oncology therapy for hepatocellular carcinoma: Current status and ongoing trials[J]. Liver Cancer, 2019, 8(4): 221-238. DOI: 10.1159/000501501 [19] ZHU AX, FINN RS, IKEDA M, et al. A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC)[J]. J Clin Oncol, 2020, 38(15 Suppl): 4519. [20] LLOVET JM, KUDO M, CHENG AL, et al. Lenvatinib (len) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 3 LEAP-002 study[J]. J Clini Oncol, 2019, 37(15 Suppl): TPS4152. [21] KUDO M, IKEDA M, MOTOMURA K, et al. A phase Ib study of lenvatinib (LEN) plus nivolumab (NIV) in patients (pts) with unresectable hepatocellular carcinoma (uHCC): Study 117[J]. J Clin Oncol, 2020, 38(4 Suppl): 513. [22] XU J, ZHANG Y, JIA R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: An open-label, dose escalation and expansion study[J]. Clin Cancer Res, 2019, 25(2): 515-523. DOI: 10.1158/1078-0432.CCR-18-2484 [23] KUDO M, MOTOMURA K, WADA Y, et al. First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100)[J]. J Clin Oncol, 2019, 37(15 Suppl): 4072. [24] RIMASSA L, CHENG AL, BRAITEH F, et al. Phase Ⅲ (COSMIC-312) study of cabozantinib (C) in combination with atezolizumab (A) vs sorafenib (S) in patients (pts) with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy[J]. Ann Oncol, 2019, 30(Suppl 5): v320. [25] LEE M, RYOO BY, HSU CH, et al. Randomised efficacy and safety results for atezolizumab (Atezo) + bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC)[J]. Ann Oncol, 2019, 30(Suppl 5): v875. [26] 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 [27] CHENG AL, QIN S, IKEDA M, et al. IMbrave150: Efficacy and safety results from a ph Ⅲ study evaluating atezolizumab (atezo)+bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC)[J]. Ann Oncol, 2019, 30(Suppl 9): ix186-ix187. [28] QIN SK, REN ZG, FENG YS, et al. OP02-03 efficacy and safety of atezolizumab + bevacizumab vs sorafenib in Chinese patients with unresectable HCC in the phase Ⅲ IMbrave150 study.[EB/OL]. (2020-02-06)[2020-06-20]. https://easl.eu/livercancersummit2020/wp-content/uploads/2020/01/Liver-Cancer-Summit-2020-Abstract-book.pdf. [29] YAU T, KANG YK, KIM TY, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040[J]. J Clin Oncol, 2019, 37(15 Suppl): 4012. [30] HE AR, YAU T, HSU C, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Subgroup analyses from CheckMate 040[J]. J Clin Oncol, 2020, 38(4 Suppl): 512. [31] KELLEY RK, SANGRO B, HARRIS WP, et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC)[J]. J Clin Oncol, 2020, 38(15 Suppl): 4508. [32] ABOU-ALFA GK, CHAN SL, FURUSE J, et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study[J]. J Clin Oncol, 2018, 36(15 Suppl): TPS4144. [33] QIN S, CHEN Z, LIU Y, et al. A phase Ⅱ study of anti-PD-1 antibody camrelizumab plus FOLFOX4 or GEMOX systemic chemotherapy as first-line therapy for advanced hepatocellular carcinoma or biliary tract cancer[J]. J Clin Oncol, 2019, 37(15 Suppl): 4074. [34] YAU T, ZAGONEL V, SANTORO A, et al. Nivolumab (NIVO)+ipilimumab (IPI)+cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040[J]. J Clin Oncol, 2020, 38(4 Suppl): 478. -
本文二维码
图(1) / 表(2)
计量
- 文章访问数: 541
- HTML全文浏览量: 178
- PDF下载量: 64
- 被引次数: 0
