Safety and efficacy of TROP2-directed ADCs in HER2-negative breast cancer: A systematic review and network meta-analysis
Xiaoning Wu, Qin Li, Bin Shao, Zhihao He, Wei Zhang, Jichun Song, Baichuan Cao, Junzhou Wang, Li LiBackground
Trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugates (ADCs), including sacituzumab govitecan (SG), sacituzumab tirumotecan (SKB264), and datopotamab deruxtecan (Dato-DXd), are active in advanced HER2-negative breast cancer, but direct comparative evidence is lacking.
Objectives
To compare the efficacy and safety of SG, SKB264, and Dato-DXd.
Design
Systematic review with network meta-analysis (NMA).
Data sources and methods
PubMed, Embase, and the Cochrane Library were searched through October 2026. A random-effects frequentist NMA estimated hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs); P-scores were supplementary ranking measures. Safety was summarized descriptively.
Results
Eight phase III randomized controlled trials comprising 3,999 patients were included. In the overall population, indirect estimates suggested a potential progression-free survival (PFS) advantage for SKB264 compared with SG (HR = 1.73, 95% CI: 1.22–2.44) and Dato-DXd (HR = 1.79, 95% CI: 1.23–2.62). For overall survival (OS), the Dato-DXd-versus-SKB264 estimate was statistically significant (HR = 2.02, 95% CI: 1.13–3.62), whereas the SG-versus-SKB264 estimate was not. Objective response rate (ORR) did not differ significantly among ADCs. In hormone receptor-positive/HER2-negative breast cancer, statistically significant indirect differences were observed between SKB264 and both SG and Dato-DXd for PFS and OS, as well as between SG and Dato-DXd for OS. In metastatic triple-negative breast cancer, no significant between-ADC differences were observed for PFS and OS. Safety profiles differed: SG was mainly characterized by neutropenia and gastrointestinal toxicity, SKB264 by broader hematologic toxicity and hepatic laboratory abnormalities, and Dato-DXd by stomatitis and ocular surface events with less severe hematologic toxicity.
Conclusion
Indirect estimates suggested a potential PFS advantage for SKB264 in selected HER2-negative breast cancer populations. However, these cross-trial comparisons did not establish definitive clinical superiority. Given distinct toxicities and no head-to-head trials, therapy should be individualized to clinical features and toxicity tolerance.