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酪氨酸激酶抑制剂联合免疫检查点抑制剂在中晚期肝细胞癌二线治疗中的效果及安全性分析
DOI: 10.12449/JCH240818
伦理学声明：本研究于2023年11月经苏州大学附属第一医院医学伦理委员会审查并获批，批号：2023伦研批第461号。
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：聂宏负责实施研究，收集与分析资料，撰写论文；沈健、仲斌演参与课题设计、指导及论文修改；朱晓黎负责指导撰写文章并最后定稿。
Efficacy and safety of tyrosine kinase inhibitor combined with immune checkpoint inhibitor as the second-line therapy for advanced hepatocellular carcinoma
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摘要:
目的 评估酪氨酸激酶抑制剂（TKI）联合免疫检查点抑制剂在中晚期肝细胞癌（HCC）二线治疗中的效果及安全性。 方法 收集2018年1月—2022年12月苏州大学附属第一医院介入科收治的经过经肝动脉化疗栓塞术（TACE）联合一线TKI治疗后进展/不耐受，换用二线TKI联合或者不联合免疫检查点抑制剂的63例中晚期HCC患者的临床资料。其中使用二线TKI联合免疫检查点抑制剂共32例（联合组），使用二线TKI共31例（单纯组）。依据改良实体瘤疗效评价标准（mRECIST）评估肿瘤反应，根据通用不良事件术语5.0标准（CTCAE 5.0）评估不良事件。使用Kaplan-Meier法计算两组的中位生存期（mOS）、中位无进展生存期（mPFS）。比较两组的客观缓解率（ORR）和疾病控制率（DCR）。基线资料及随访结果的组间比较采用χ2检验。 结果 63例患者中位随访时间为16.5（3.2～53.4）个月。联合组mOS、mPFS 分别为24.3个月（95%CI：20.0～28.6）和9.8个月（95%CI：7.5～12.1），15.8个月（95%CI：11.4～20.1）和4.1个月（95%CI：3.2～4.9），两组mOS、mPFS之间差异均有统计学意义（P值分别为0.029、0.038）。联合组ORR和DCR分别为47%和84%，单纯组为19%和65%，两组之间ORR差异有统计学意义（P=0.021），DCR差异无统计学意义（P=0.070）。联合组中4例（12.5%）、单纯组中3例（10.0%）发生Ⅲ～Ⅳ级严重不良事件，两组均无药物不良反应致死事件，两组患者不良事件的发生率比较，差异无统计学意义（P=0.783）。 结论 与单用TKI治疗相比，TKI联合免疫检查点抑制剂作为中晚期HCC二线治疗的疗效更显著，且不会增加严重不良反应。 Abstract:Objective To investigate the efficacy and safety of tyrosine kinase inhibitor （TKI） combined with immune checkpoint inhibitor as the second-line therapy for advanced hepatocellular carcinoma （HCC）. Methods A retrospective analysis was performed for the clinical data of 63 patients with advanced HCC who were admitted to Department of Interventional Radiology， The First Affiliated Hospital of Soochow University， from January 2018 to December 2022， and all patients experienced progression/intolerance after transcatheter arterial chemoembolization combined with first-line TKI and were switched to second-line TKI with or without immune checkpoint inhibitor. The 32 patients receiving second-line TKI with immune checkpoint inhibitor were enrolled as combination group， and the 31 patients receiving second-line TKI alone were enrolled as single treatment group. Modified Response Evaluation Criteria in Solid Tumors was used to evaluate tumor response， and Common Terminology Criteria for Adverse Events 5.0 was used to evaluate adverse events. The Kaplan-Meier method was used to calculate median overall survival （mOS） and median progression-free survival （mPFS） for the two groups， and the two groups were compared in terms of objective response rate （ORR） and disease control rate （DCR）. The chi-square test was used for comparison of baseline data and follow-up results between groups. Results The median follow-up time was 16.5 （3.2 — 53.4） months for the 63 patients. The combination group had an mOS of 24.3 （95% confidence interval ［CI］： 20.0 — 28.6） months and an mPFS of 9.8 （95%CI： 7.5 — 12.1） months， while the single treatment group had an mOS of 15.8 （95%CI： 11.4 — 20.1） months and an mPFS of 4.1 （95%CI： 3.2 — 4.9） months， and there were significant differences in mOS and mPFS between the two groups （P=0.029 and 0.038）. The combination group had an ORR of 47% and a DCR of 84%， while the single treatment group had an ORR of 19% and a DCR of 65%； there was a significant difference in ORR between the two groups （P=0.021）， but with no significant difference in DCR between the two groups （P=0.070）. As for adverse events， 4 patients （12.5%） in the combination group and 3 （10.0%） in the single treatment group experienced grade Ⅲ — Ⅳ serious adverse events， with no fatal drug reactions in either group， and there was no significant difference in the incidence rate of adverse events between the two groups （P=0.783）. Conclusion Compared with TKI alone， TKI combined with immune checkpoint inhibitor has a more significant therapeutic effect as the second-line therapy for advanced HCC， without increasing serious adverse reactions. -
图 2 联合组与单纯组OS曲线
Figure 2. Kaplan-Meier curves for OS of combination group and control group
图 3 联合组与单纯组PFS曲线
Figure 3. Kaplan-Meier curves for PFS of combination group and control group
表 1 两组患者基线资料比较
Table 1. Baseline characteristics of two groups
指标 单纯组 （n=31） 联合组 （n=32） P值 年龄［例（%）］ 0.513 ≤60岁 12（38.7） 15（46.9） >60岁 19（61.3） 17（53.1） 性别［例（%）］ 0.143 男 29（93.5） 26（81.3） 女 2（6.5） 6（18.7） 病因［例（%）］ 0.179 乙型肝炎 23（74.2） 28（87.5） 其他 8（25.8） 4（12.5） 病灶个数［例（%）］ 0.373 ≤3个 12（38.7） 9（28.1） >3个 19（61.3） 23（71.9） 血管侵犯［例（%）］ 0.898 无 16（51.6） 16（50.0） 有 15（48.4） 16（50.0） 病灶大小［例（%）］ 0.513 ≤5 cm 12（38.7） 15（46.9） >5 cm 19（61.3） 17（53.1） 肝外转移［例（%）］ 0.338 无 22（71.0） 26（81.3） 有 9（29.0） 6（18.7） Child-Pugh分级［例（%）］ 0.910 A级 17（54.8） 18（56.2） B级 14（45.2） 14（43.8） ALBI评分［例（%）］ 0.563 Ⅰ 6（19.4） 7（21.9） Ⅱ 24（77.4） 22（68.7） Ⅲ 1（3.2） 3（9.4） ECOG评分［例（%）］ 0.649 0 9（29.0） 11（34.4） 1 22（71.0） 21（65.6） AFP［例（%）］ 0.932 ≤400 ng/mL 10（32.3） 10（31.2） >400 ng/mL 21（67.7） 22（68.8） 外科切除史［例（%）］ 0.153 无 10（32.3） 16（50.0） 有 21（67.7） 16（50.0） 二线是否有过TACE［例（%）］ 0.722 无 11（35.5） 10（31.3） 有 20（64.5） 22（68.7） 一线治疗方案［例（%）］ 0.261 TACE+仑伐替尼 18（58.1） 14（43.8） TACE+索拉非尼 12（38.7） 18（56.2） TACE+多纳非尼 1（3.2） 0（0.0） 
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表 2 两组疗效对比
Table 2. Treatment responses in combination group and control group
指标 单纯组（n=31） 联合组（n=32） CR（例） 1 3 PR（例） 5 12 SD（例） 14 12 PD（例） 11 5 ORR（%） 19 47 DCR（%） 65 84
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表 3 两组不良事件发生情况对比
Table 3. Adverse events in the two groups
不良反应 单纯组（n=31） 联合组（n=32） Ⅰ~Ⅱ级 Ⅲ~Ⅳ级 Ⅰ~Ⅱ级 Ⅲ~Ⅳ级 肝功能损伤（例） 27 1 26 1 手足反应（例） 25 1 26 0 高血压（例） 23 0 19 0 发热（例） 13 0 17 0 蛋白尿（例） 7 1 5 0 消化道症状（例） 22 0 24 0 腹痛（例） 11 0 16 0 免疫相关性肺炎（例） 0 0 2 0 免疫相关性心肌炎（例） 0 0 1 1 免疫相关性肠炎（例） 0 0 1 1 免疫相关性甲减（例） 0 0 1 1
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