PD-1 inhibitors improve the efficacy of tyrosine kinase inhibitors combined with transcatheter arterial chemoembolization in advanced hepatocellular carcinoma: a meta-analysis and trial sequential analysis

This meta-analysis and trial sequential analysis (TSA) aimed to evaluate the efficacy and safety of triple therapy with tyrosine kinase inhibitors (TKIs) combined with transcatheter arterial chemoembolization (TACE) plus programmed death 1 (PD-1) inhibitors (T-T-P) and dual therapy with TKIs combined with TACE (T-T) for the treatment of advanced unresectable hepatocellular carcinoma (uHCC). Literature related to the efficacy of TKIs combined with TACE plus PD-1 inhibitors in uHCC was searched using the Embase, PubMed, and Cocrane libraries. TSA was used to reduce false positive results due to random error. Seventeen articles were included in this meta-analysis, including 2,561 patients. In the T-T-P group, OS [HR 0.45, 95% confidence interval (CI) 0.39–0.52; <i>p</i> = 0.000], PFS [HR 0.43, 95% CI 0.38 − 0.48; <i>p</i> = 0.000], were significantly prolonged compared to those in the T-T group; ORR (RR 1.59 [95% CI 1.39–1.81]; <i>p</i> = 0.000) and DCR (RR 1.26 [95% CI 1.15–1.37]; <i>p</i> = 0.000) were significantly higher. TSA analysis showed early results without further testing. Prognostic factor analysis demonstrated that portal vein tumor thrombus (PVTT) and extrahepatic metastasis were common independent risk factors for OS and PFS. Regarding grade 3/4 adverse events results showed no statistically significant differences in any of them. Compared with T-T treatment group, the T-T-P treatment group exhibited a notable improvement in OS and PFS, particularly in cases of PVTT and extrahepatic metastasis. Furthermore, it can markedly enhance the ORR and DCR in patients with uHCC.

本研究采用荟萃分析（meta-analysis）与试验序贯分析（trial sequential analysis, TSA），旨在评估酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs）联合经导管动脉化疗栓塞术（transcatheter arterial chemoembolization, TACE）及程序性死亡受体1（programmed death 1, PD-1）抑制剂的三联疗法（T-T-P），与TKIs联合TACE的双联疗法（T-T）治疗不可切除晚期肝细胞癌（unresectable hepatocellular carcinoma, uHCC）的有效性与安全性。本研究通过Embase、PubMed及科克伦（Cochrane）图书馆检索了关于TKIs联合TACE及PD-1抑制剂治疗uHCC有效性的相关文献，并采用TSA以降低随机误差导致的假阳性结果。本次荟萃分析共纳入17篇文献，涉及2561例患者。与T-T组相比，T-T-P组的总生存期（overall survival, OS）[风险比（hazard ratio, HR）0.45，95%置信区间（confidence interval, CI）0.39~0.52；P=0.000]、无进展生存期（progression-free survival, PFS）[HR 0.43，95%CI 0.38~0.48；P=0.000]均显著延长；客观缓解率（objective response rate, ORR）[相对风险（relative risk, RR）1.59，95%CI 1.39~1.81；P=0.000]与疾病控制率（disease control rate, DCR）[RR 1.26，95%CI 1.15~1.37；P=0.000]均显著升高。TSA分析结果显示本研究已获得早期结论，无需进一步开展试验。预后因素分析表明，门静脉癌栓（portal vein tumor thrombus, PVTT）与肝外转移是影响OS与PFS的常见独立危险因素。针对3/4级不良事件的分析结果显示，两组间各项不良事件发生率均无统计学显著差异。与T-T治疗组相比，T-T-P治疗组可显著改善uHCC患者的OS与PFS，尤其在合并PVTT或肝外转移的患者中效果更为突出，同时可显著提升患者的ORR与DCR。