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The phase 2 DAISY trial suggests that HER2 expression is determinant of trastuzumab deruxtecan efficacy, but additional mechanisms may be involved
Several questions still remain regarding mechanisms of action and resistance of trastuzumab deruxtecan (T-DXd) in patients with metastatic breast cancer, including the impact of HER2 expression and its spatial distribution on drug efficacy, the distribution of T-DXd in the tumor, the potential impact on the tumor microenvironment and the molecular mechanisms of resistance. The DAISY trial, recently published in Nature Medicine was deigned to evaluate T-DXd efficacy in patients with metastatic breast cancer according to HER2 expression levels and to explore treatment response and resistance through biomarker analyses of tumor samples at different timepoints.
In total, 186 patients were enrolled into the DAISY trial and assigned to a specific cohort according to HER2 status defined based on the baseline biopsy performed at study entry: cohort 1 included 72 patients with HER2-overexpressing tumors; cohort 2 included 74 patients with HER2-low metastatic breast cancer; 40 patients with non-expressing metastatic breast cancer were assigned to cohort 3. The confirmed objective response rate was 70.6% in cohort 1, 37.5% in cohort 2 and 29.7% in cohort 3. No new safety signals were observed and during treatment HER2-expressing tumors presented strong T-DXd staining, conversely HER2 non-expressing samples presented no or very few T-DXd staining. Among patients with HER2 non-expressing metastatic breast cancer, 35.7% with ERBB2 expression below the median presented a confirmed objective response as compared to 30% in patients with ERBB2 expression above the median. Taken together, these results suggest that HER2 is a determinant of sensitivity to T-DXd, although modest anti-tumor activity can be also observed in a small subset of patients whose cancer did not express HER2, suggesting other mechanisms of action. «Resistance to T-DXd may occur at different levels, potentially involving decrease of HER2 expression, alterations of the cytotoxic effect of DXd and the tumor microenvironment. These data indicate that precision medicine approaches based on molecular analyses will be necessary to optimize treatment after resistance to T-Dxd», authors conclude.