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

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.