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晚期肝细胞癌的系统治疗
DOI: 10.12449/JCH241127
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：徐家豪、尹东旭负责查阅文献，撰写论文；李宇辰、陈富杰负责收集数据，查阅文献；王明达、杨田负责指导论文写作，审校定稿。徐家豪和尹东旭对本文贡献等同，同为第一作者。
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摘要: 肝细胞癌是全球范围内发病率和死亡率前列的恶性肿瘤。随着分子生物学和肿瘤免疫学的进步，以酪氨酸激酶抑制剂（如索拉非尼、仑伐替尼等）为代表的分子靶向药物和以程序性死亡受体-1/程序性死亡配体-1单抗为代表的免疫治疗为晚期肝细胞癌患者带来福音。免疫治疗联合抗血管生成治疗可进一步提高疗效。此外，立体定向放疗、局部治疗与系统治疗的优化整合有望使得患者获益最大化。未来，深入理解肝细胞癌异质性，发展精准分子分型和个体化治疗，建立多学科协作诊疗体系，系统治疗有望实现晚期肝细胞癌的长期管理。本文就晚期肝细胞癌系统治疗的研究现状和进展作一综述。Abstract: Hepatocellular carcinoma （HCC） is one of the most common malignancies with high morbidity and mortality rates worldwide. With the advances in molecular biology and tumor immunology， molecular-targeted agents represented by tyrosine kinase inhibitors （such as sorafenib and lenvatinib） and immunotherapy represented by PD-1/PD-L1 monoclonal antibodies have brought hope for patients with advanced HCC. The combination of immunotherapy and anti-angiogenic therapy can further improve the treatment outcome of patients. In addition， the optimization and integration of stereotactic body radiotherapy， local treatment， and systemic treatment may maximize the benefits of patients. In the future， through a deep understanding of the heterogeneity of HCC， the development of precision molecular subtyping and individualized treatment， and the establishment of a multidisciplinary collaborative diagnosis and treatment system， systemic therapy is expected to achieve long-term management of advanced HCC. This article reviews the current status and advances in systemic therapy for advanced HCC.
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Key words:
- Carcinoma， Hepatocellular /
- Precision Medicine /
- Therapeutics
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图 1 晚期HCC系统治疗代表性临床研究
Figure 1. Representative clinical studies of systemic therapy for advanced hepatocellular carcinoma
表 1 ICI联合治疗在晚期HCC一线治疗中的Ⅲ期临床研究结果汇总
Table 1. Summary of phase Ⅲ clinical trial results of ICI-combined regimen in advanced HCC first-line treatment
类别 IO+大分子单抗 IO+小分子TKI IO+IO IMbrave 150［24］ ORIENT-32［29］ SHR-1210-Ⅲ-310［30］ LEAP-002［31］ COSMIC-312［33］ HIMALAYA［36］ ICI药物种类 PD-L1抑制剂 PD-1抑制剂 PD-1抑制剂 PD-1抑制剂 PD-L1抑制剂 PD-L1、CTLA-4
抑制剂
药物 阿替利珠单抗+贝伐珠单抗 vs
索拉非尼
信迪利单抗+ IBI305 vs 索拉非尼 卡瑞利珠单抗+阿帕替尼 vs 索拉非尼 帕博利珠单抗+仑伐替尼 vs 仑伐替尼 阿替利珠单抗+卡博替尼 vs 索拉非尼 度伐利尤单抗+替西木单抗 vs 索拉非尼 研究设计 全球、多中心、开放标签、随机对照，Ⅲ期 多中心、开放标签、随机对照、Ⅱ/Ⅲ期 全球、随机、开放标签、Ⅲ期 全球、随机、双盲、安慰剂对照、Ⅲ期 全球多中心、开放标签、随机、Ⅲ期 全球、多中心、开放标签、随机对照，Ⅲ期 入组人数（例） 501 571 543 794 837 782 特有入组标准 内镜检查，排除出血或高出血风险 Child-Pugh评分≤7分 随机化后3个月内的内静检查；无门静脉主干侵犯（Vp4） 无门静脉主干
侵犯（Vp4）
中位OS（月） 19.2 vs 13.4
HR=0.66
NR vs 10.4
HR=0.57
22.1 vs 15.2
HR=0.62
21.2 vs 19.0
HR=0.840
15.4 vs 15.5
HR=0.90
16.4 vs 13.8
HR=0.78
中位PFS（月） 6.9 vs 4.3
HR=0.65
4.6 vs 2.8
HR=0.56
5.6 vs 3.7
HR=0.52
8.2 vs 8.1
HR=0.834
6.8 vs 4.2
HR=0.63
3.78 vs 4.07
HR=0.90
ORR 30% vs 11% 21% vs 4% 25.4% vs 5.9% 26.1% vs 17.5% 11% vs 4% 20.1% vs 5.1% DCR 74% vs 55% 72% vs 64% 78.3% vs 53.9% 81.3% vs 78.4% 78% vs 65% 60.1% vs 60.7% PD 19% vs 25% 27% vs 33% 16.2% vs 36.5% 12.2% vs 15.0% 14% vs 20% 20.6% vs 6.7% 任何级别AE发生率 86% vs 95% 89% vs 94% 96.5% vs 95.7% 93% vs 90% 76% vs 85% ≥3级AE发生率 45% vs 47% 34% vs 36% 81% vs 52% 63% vs 58% 55% vs 33% 26% vs 37% 所有级别出血发生率 25% vs17.3% 4.7% vs 4.9% 1% vs 1% 1.8% vs 4.8% G3/4出血发生率 6.3% vs 5.8% 3.4% vs 2.7% 0.5% vs 1% 0.5% vs 1.6% 注：IO，肿瘤免疫疗法；PD，疾病发展；NR，未达到。
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表 2 正在进行的局部联合系统治疗不可切除HCC的Ⅲ期临床研究
Table 2. Ongoing phase Ⅲ clinical trials of locoreginal therapy combined with systemic therapy in patients with unresectable HCC
研究编码 研究状态 研究类型 入组人数（例） 干预措施 主要终点 入组条件 NCT03778957
（EMERALD-1）
活跃，未招募 Ⅲ期 RCT 600 TACE+度伐利尤单抗+安慰剂；
TACE+度伐利尤单抗+贝伐珠单抗；
TACE+安慰剂+安慰剂
PFS 适用于TACE，Child-Pugh≤7分，PS 0/1分 NCT05301842
（EMERALD-3）
招募中 Ⅲ期 RCT 725 TACE+曲美木单抗+度伐利尤单抗+仑伐替尼；
TACE+曲美木单抗+度伐利尤单抗；
TACE
PFS 适用于TACE，Child-Pugh A级，
PS 0/1分
NCT04246177
（LEAP-012）
活跃，未招募 Ⅲ期 RCT 450 TACE+仑伐替尼+帕博利珠单抗；
TACE
OS和PFS 不适用于根治性治疗 NCT04268888 招募中 Ⅱ/Ⅲ期 RCT 522 TACE+纳武利尤单抗；
TACE/TAE
OS和TTTP 不适用于外科切除或肝移植，
Child-Pugh≤6分
NCT04712643 活跃，未招募 Ⅲ期 RCT 342 TACE+阿替利珠单抗+贝伐珠单抗；
TACE
OS和PFS 适用于TACE，Child-Pugh A级，
PS 0/1分，无PVTT
NCT05738616 招募中 Ⅲ期 RCT 168 TACE+卡瑞利珠单抗+仑伐替尼；
TACE
CRR和OS BCLC C，Child-Pugh A/B级，
PS 0/1分，初治
NCT05320692 招募中 Ⅲ期RCT 360 TACE+卡瑞利珠单抗+阿帕替尼；
TACE
PFS Child-Pugh A级，PS 0/1分 NCT05608213 招募中 Ⅲ期RCT 183 仑伐替尼+I-125放射性粒子植入；
仑伐替尼
OS 由JSH判定TACE 抵抗，Child-Pugh A/B级，PS 0/1分，无PVTT NCT05608200 招募中 Ⅲ期 RCT 427 仑伐替尼+信迪利单抗+TACE；
仑伐替尼+TACE
OS BCLC C，或CNL C Ⅲa and Ⅲb，Child-Pugh A级，PS 0/1分，初治，无PVTT NCT05985798 招募中 Ⅲ期 RCT 258 信迪利单抗+贝伐珠单抗+TACE；
仑伐替尼+TACE
OS BCLC C，Child-Pugh A级，
PS 0/1分，初治，无PVTT
NCT04387695 招募中 Ⅲ期 RCT 54 序贯SBRT+TACE+索拉非尼；
索拉非尼
PFS BCLC C，合并PVTT，
Child-Pugh≤7分，PS≤2分，初治
NCT05313282 招募中 Ⅲ期 RCT 140 mFOLFOX7-HAIC+阿帕替尼+卡瑞利珠单抗；阿帕替尼+卡瑞利珠单抗 PFS BCLC C，Child-Pugh A级，
PS 0/1分，初治
NCT05198609 招募中 Ⅲ期 RCT 214 mFOLFOX7-HAIC+阿帕替尼+卡瑞利珠单抗；阿帕替尼+卡瑞利珠单抗 OS 合并PVTT，初治
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