Multicenter phase 2 trial of trastuzumab deruxtecan for metastatic breast cancer with variable HER2 expression

The mechanisms of action of and resistance to trastuzumab deruxtecan (T-DXd), an anti-HER2 antibody-drug conjugate for breast cancer treatment, remain unclear. The multicenter phase 2 DAIY trial in France evaluated T-DXd for HER2-overexpressing (cohort 1), HER2-low (cohort 2), and HER2 non-expressing (cohort 3) metastatic breast cancer (mBC). The primary end point was confirmed objective response rate. The primary end point was met in cohorts 1 and 2. No new safety signals were observed. During treatment, HER2-expressing tumors showed strong T-DXd staining. Conversely, HER2 immunohistochemistry (IHC) 0 samples presented no or very weak T-DXd staining. Among patients with HER2 IHC 0 mBC, 35.7% with ERBB2 expression below the median and 30.0% with ERBB2 expression above the median had confirmed objective response. The authors conclude that although HER2 expression is a determinant of T-DXd efficacy, additional mechanisms may also be involved.