Tang Peng, Zhou Fei
Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
Department of Obstetrics and Gynaecology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
Front Pharmacol. 2025 Mar 24;16:1535444. doi: 10.3389/fphar.2025.1535444. eCollection 2025.
The use of immune checkpoint inhibitors (ICIs) in treating hepatocellular carcinoma (HCC) has grown significantly. However, the therapeutic benefits of ICIs alone are notably modest. This meta-analysis assesses the efficacy and safety of using PD-1/PD-L1 inhibitors in conjunction with tyrosine kinase inhibitors (TKIs) for patients with advanced or unresectable HCC.
An extensive search of the literature was performed using databases such as PubMed, Web of Science, Embase, and the Cochrane Library, capturing randomized controlled trials (RCTs) until 16 October 2024. Efficacy was measured by progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Safety was gauged through the occurrence of treatment-related adverse events (TRAEs). Hazard ratios (HRs) for PFS and OS, along with risk ratios (RRs) for ORR, DCR, and TRAEs, were calculated, each with 95% confidence intervals (CIs). Heterogeneity among studies was quantified using Cochran's Q test, I statistics, and 95% prediction intervals (PIs).
This analysis incorporated 4 studies with a total of 2,174 patients. Treatment regimens combining PD-1/PD-L1 inhibitors with TKIs significantly improved PFS (HR = 0.694, 95% CI: 0.527-0.914; 95% PI: 0.228-2.114) and ORR (RR = 2.303, 95% CI: 1.360-3.902; 95% PI: 0.408-12.991) compared with first-line monotherapy or TKI monotherapy in the overall population. Subgroup analysis indicated that the improvements in PFS and OS were particularly significant among patients of Asian descent or those with hepatitis B virus (HBV) infection (all < 0.05). While the occurrence of any grade TRAEs did not differ significantly between the two groups (RR = 1.016, 95% CI: 0.996-1.036; 95% PI: 0.941-1.097), the incidence of serious (RR = 2.068, 95% CI: 1.328-3.222; 95% PI: 0.487-8.776) and grade ≥3 TRAEs (RR = 1.287, 95% CI: 1.020-1.624; 95% PI: 0.574-2.883) increased in patients treated with the combination of PD-1/PD-L1 inhibitors and TKIs.
This study revealed that combining PD-1/PD-L1 inhibitors with TKIs in the treatment of advanced or unresectable HCC leads to superior clinical outcomes compared to first-line monotherapy or TKIs alone, particularly in patients with HBV infection and those of Asian descent. Clinicians are advised to be vigilant regarding the potential for TRAEs in clinical settings.
免疫检查点抑制剂（ICI）在肝细胞癌（HCC）治疗中的应用显著增加。然而，单纯使用ICI的治疗效果明显有限。本荟萃分析评估了PD-1/PD-L1抑制剂联合酪氨酸激酶抑制剂（TKI）用于晚期或不可切除HCC患者的疗效和安全性。
使用PubMed、Web of Science、Embase和Cochrane图书馆等数据库对文献进行广泛检索，纳入截至2024年10月16日的随机对照试验（RCT）。疗效通过无进展生存期（PFS）、总生存期（OS）、客观缓解率（ORR）和疾病控制率（DCR）来衡量。安全性通过治疗相关不良事件（TRAE）的发生情况来评估。计算PFS和OS的风险比（HR）以及ORR、DCR和TRAE的风险比（RR），并给出95%置信区间（CI）。使用Cochran's Q检验、I统计量和95%预测区间（PI）对研究间的异质性进行量化。
本分析纳入了4项研究，共2174例患者。与一线单药治疗或TKI单药治疗相比，PD-1/PD-L1抑制剂联合TKI的治疗方案显著改善了总体人群的PFS（HR = 0.694，95% CI：0.527 - 0.914；95% PI：0.228 - 2.114）和ORR（RR = 2.303，95% CI：1.360 - 3.902；95% PI：0.408 - 12.991）。亚组分析表明，在亚裔患者或乙型肝炎病毒（HBV）感染患者中，PFS和OS的改善尤为显著（均P < 0.05）。虽然两组间任何级别的TRAE发生率无显著差异（RR = 1.016，95% CI：0.996 - 1.036；95% PI：0.941 - 1.097），但PD-1/PD-L1抑制剂联合TKI治疗的患者中，严重TRAE（RR = 2.068，95% CI：1.328 - 3.222；95% PI：0.487 - 8.776）和≥3级TRAE的发生率增加（RR = 1.287，95% CI：1.020 - 1.624；95% PI：0.574 - 2.883）。
本研究表明，与一线单药治疗或单独使用TKI相比，PD-1/PD-L1抑制剂联合TKI治疗晚期或不可切除HCC可带来更好的临床疗效，尤其是在HBV感染患者和亚裔患者中。建议临床医生在临床环境中警惕TRAE的可能性。
