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抗体偶联药物治疗HER2阴性局部晚期/转移性乳腺癌的疗效和安全性：一项针对III期随机对照试验的Meta分析

Efficacy and safety of antibody-drug conjugates in HER2-negative locally advanced/metastatic breast cancer:A Meta-analysis of Phase III Randomized Controlled Trials

    摘要
  • 摘要: 目的 探索抗体偶联药物（antibody drug conjugates， ADCs）治疗人表皮生长因子受体2（human epidermal growth factor receptor-2， HER2）阴性局部晚期/转移性乳腺癌（advanced/metastatic breast cancer， LABC/MBC）的疗效及其安全性，并进行亚组分析，以确定ADCs的最佳受益人群。方法 系统检索PubMed、Embase、Cochrane Library和Web of Science数据库，获取从建库至2025年6月发表的ADCs治疗HER2阴性LABC/MBC的III期随机对照试验。采用Review Manager 5.4软件中的Cochrane偏倚风险工具评估纳入研究的质量；采用Stata 18.0软件进行Meta分析，主要结局指标为无进展生存期（progression-free survival， PFS）、总生存期（overall survival， OS）和不良事件（adverse event， AE）；采用Stata 18.0软件的Egger检验评估发表偏倚。结果 共纳入7项III期随机对照试验，涉及3821例LABC/MBC患者。纳入研究整体偏倚风险以低风险为主，Egger检验提示无明显发表偏倚。累积效应模型显示，与TPC相比，ADCs可显著改善HER2阴性LABC/MBC的PFS（HR=0.53， 95%CI:0.45～0.64， P<0.001）、OS （HR=0.67， 95%CI:0.57～0.78， P<0.001）。亚组分析显示，相较于TPC，ADCs可使三阴性乳腺癌（triple-negative breast cancer，TNBC）患者（PFS:HR=0.38， 95%CI：0.32～0.45， P<0.001；OS:HR=0.51， 95%CI：0.43～0.61， P<0.001）和激素受体（hormone receptor， HR）+/HER2-乳腺癌患者（PFS: HR=0.62， 95%CI：0.57～0.68， P< 0.001；OS: HR=0.76， 95%CI：0.68～0.85， P< 0.001）获得具有统计学意义上的生存获益，且TNBC患者的生存获益更为显著。安全性方面，在≥3级AE中，仅观察到ADCs组贫血发生率更高（OR=2.27， 95%CI:1.41～3.64， P=0.001）。结论 ADCs可显著改善HER2阴性LABC/MBC患者的生存期，且安全性整体可控。其中，ADCs对TNBC患者的临床获益尤为显著；而对于内分泌抵抗的HR+/HER2-患者，ADCs亦显示出优于TPC的疗效，但获益程度略低于TNBC。

     

    Abstract: Objective To investigate the efficacy and safety of antibody-drug conjugates (ADCs) in the treatment of human epidermal growth factor receptor-2 (HER2)-negative locally advanced/metastatic breast cancer (LABC/MBC), and to perform subgroup analyses to identify the optimal beneficiary population for ADCs. Methods A systematic search was conducted in PubMed, Embase, Cochrane Library, and Web of Science databases to retrieve phase III randomized controlled trials (RCTs) of ADCs for HER2-negative LABC/MBC published from database inception to June 2025. The Cochrane risk of bias tool in Review Manager 5.4 software was used to assess the quality of included studies. Meta-analysis was performed using Stata 18.0 software, with the primary outcome measures being progression-free survival (PFS), overall survival (OS), and adverse events (AEs). The Egger's test in Stata 18.0 software was used to evaluate publication bias. Results A total of 7 phase III RCTs involving 3821 patients with LABC/MBC were included. The overall risk of bias of the included studies was predominantly low, and Egger's test indicated no significant publication bias. The cumulative effect model showed that compared with TPC, ADCs significantly improved PFS (HR=0.53, 95%CI:0.45-0.64, P<0.001) and OS (HR=0.67, 95%CI:0.57-0.78, P<0.001) in HER2-negative LABC/MBC. Subgroup analysis revealed that compared with TPC, ADCs conferred statistically significant survival benefits in patients with triple-negative breast cancer (TNBC) (PFS:HR=0.38, 95%CI:0.32-0.45, P<0.001; OS:HR=0.51, 95%CI:0.43-0.61, P<0.001) and hormone receptor (HR)+/HER2- breast cancer (PFS:HR=0.62, 95%CI:0.57-0.68, P<0.001; OS:HR=0.76, 95%CI:0.68-0.85, P<0.001), with the survival benefit being more pronounced in TNBC patients. In terms of safety, among grade ≥ 3 AEs, only a higher incidence of anemia was observed in the ADCs group (OR=2.27, 95%CI:1.41-3.64, P=0.001). Conclusion ADCs significantly improve survival in patients with HER2-negative LABC/MBC, with an overall manageable safety profile. Among them, the clinical benefit of ADCs is particularly significant in TNBC patients; for endocrine-resistant HR+/HER2- patients, ADCs also demonstrate superior efficacy to TPC, albeit with a slightly lesser degree of benefit than in TNBC.

     

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