Incidence of HER2-targeted antibody-drug conjugates-related cardiac events: a meta-analysis

Background: Human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) has emerged as a hotspot for research and brought breakthroughs in the treatment of breast cancer and other solid tumors. While the occurrence of cardiac events (CEs) has yet not been systematically reported. Methods: The prospective clinical trials of marketed HER2-targeted ADCs were systematically searched in PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception to May 2023. Two investigators independently extracted data with priority given to ClinicalTrials.gov, followed by peer-reviewed articles. Stata 15.0 software was used to perform the meta-analysis. The effect statistics were estimated as pooled incidence with 95% confidence intervals (CI). The primary objectives were to assess the incidence of all-grade and ≥3 /serious grades CEs related to HER2-targeted ADC. Our study strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and has been registered on PROSPERO (NO. CRD42023440448). Results: After conducting a comprehensive literature search, initially 7000 relevant studies were identified, and eventually a total of 47 trials involving 10594 patients were included for analysis. The pooled incidence of all-grade and ≥3/serious grades CEs respectively were 4.7% [95% CI, 3.7-5.8%] and 0.6% (95% CI, 0.5-0.8%). The pooled incidence of CEs leading to dosage discontinuation was 0.8% (95% CI, 0.4-1.3%). Subgroup analysis revealed a significantly higher incidence of all-grade CEs in T-DXd treatment compared to T-DM1 treatment (7.7% versus 3.6%; p=0.017), as well as in phase I/II trials compared to phase III trials (6.9% versus 3.2%; p=0.002) and combination therapy compared to monotherapy (7.6% versus 3.9%; p=0.013). The electrocardiogram QT corrected interval prolonged was identified as the CE with the highest pooled incidence, occurring at a rate of 5.9% (95% CI, 3.3-8.5%). Conclusions: The incidence of CEs associated with HER2-targeted ADC is relatively low. However, it is crucial to enhance surveillance measures, particularly for T-DXd treatment and combination therapy.