Efficacy and safety of antibody-drug conjugates in pretreated HER2-positive advanced breast cancer: a network meta-analysis of randomized controlled trials

BACKGROUND: Antibody-drug conjugates (ADCs) have become the standard treatment for HER2-positive(HER2+)advanced breast cancer following the failure of trastuzumab or taxane. Nevertheless, there are no direct head-to-head trials comparing different ADCs. METHODS: We searched PubMed, Embase, the Cochrane Library and abstracts from major oncology conferences, and included phase III randomized controlled trials (RCTs) investigating HER2-targeting ADCs. We conducted a frequentist random-effects NMA, and utilized the P-score to rank the efficacy of included treatments. The outcome indicators include progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). RESULTS: Seven RCTs involving 3,160 patients and seven ADCs (T-DM1, ARX788, A166, SHR-A1811, RC48, DP303c and T-DXd) were included in our research. All ADCs showed a significant PFS benefit versus chemotherapy plus tyrosine kinase inhibitor (Chem + TKI). T-DXd showed the most favorable PFS (HR = 0.18, 95%CI: 0.13-0.25), followed by SHR-A1811 (HR = 0.22, 95%CI: 0.15-0.33) compared with Chem + TKI. SHR-A1811 showed a promising OS signal(HR = 0.31, 95% CI: 0.14-0.69), followed by T-DXd (HR = 0.41, 95% CI: 0.26-0.66) compared with Chem + TKI. For safety, T-DXd exhibited the highest odds for all-grade TRAEs relative to all included control treatments, with statistically significant differences identified when compared with T-DM1 and Chem + TKI., T-DM1 demonstrated better safety characteristics for grade ≥3 TRAEs, with a significantly lower odds of occurrence than SHR-A1811, ARX788, DP303c, and Chem + TKI. CONCLUSION: Included anti-HER2 ADCs significantly improve PFS over Chem + TKI, among which T-DXd and SHR-A1811 deliver notable survival benefits. Although T-DXd is associated with a higher odd of all-grade TRAEs and T-DM1 exhibits favourable grade ≥3 safety. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251234345, identifier CRD420251234345.