Mechanism of action and resistance to Trastuzumab Deruxtecan in patients with metastatic breast cancer: the DAISY trial

Trastuzumab deruxtecan (T-DXd) is an anti-HER2 (human epidermal growth factor receptor 2) antibody-drug conjugate which has previously shown a meaningful high efficacy in HER2-positive and HER2-low metastatic breast cancer (mBC). However, the mechanism of action of this drug remains partially unknown. DAISY (NCT04132960) is a phase II, open-label study that included patients with mBC whose disease progressed after at least one line of chemotherapy in the metastatic setting. Patients were enrolled in three cohorts according to HER2 expression determined by immunohistochemistry: HER2-overexpressing (n=68), HER2-low (n=72), and HER2-non expressing mBC (n=37). Patients were treated with T-DXd 5.4 mg/kg every 3 weeks until progression disease or unacceptable toxicity. In the per cohort analysis, the objective response rate was of 70.6% (95% CI: 58.3-81) in cohort 1, 37.5% (95% CI: 26.4-49.7) in cohort 2, and 29.7% (95% CI: 16-47) in cohort 3 (p <0.0001). The median progression-free survival was 11.1 months (95% CI: 8.5-14.4; HR: 0.53, 95% IC: 0.34-0.84, p=0.007) in cohort 1, 6.7 months (95% CI: 4.4-8.3; HR: 1) in cohort 2, and 4.2 months (95% CI: 2-5.7; HR: 1.96, 95% IC: 1.21-3.15, p=0.006) in cohort 3. Exploratory analyses showed a lower T-DXd distribution in HER2-non expressing BC. A deep-learning histologic approach identified an association between a cluster of IHC0 cells and non-response to T-DXd. No quantitative modulation of tumor microenvironment was observed after 6 to 8 weeks of cycle 1. Finally, recurrent mutations on SLX4 were identified in 20% of samples at resistance (n=4/20) as compared to 2% in baseline samples (2/88). In conclusion, HER2 expression is a key determinant of T-DXd antitumor activity but several other biomarkers are still unknown.