Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer

**Background:** Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate comprising an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, most patients with advanced HER2-positive breast cancer responded to trastuzumab deruxtecan, with a median response duration of 20.7 months. The effectiveness of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer who have previously been treated with trastuzumab emtansine needs further validation.

**Methods:** This open-label, single-group, multicenter, phase 2 study was conducted in two parts to evaluate trastuzumab deruxtecan in adults with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab emtansine. The first part assessed three different doses of trastuzumab deruxtecan to determine the recommended dose, while the second part evaluated the efficacy and safety of this recommended dose. The primary endpoint was the objective response as determined by independent central review. Key secondary endpoints included the disease-control rate, clinical-benefit rate, duration of response, progression-free survival, and safety.

**Results:** A total of 184 patients, who had undergone a median of six prior treatments, received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0) showed a response to therapy. The median follow-up duration was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median progression-free survival was 16.4 months (95% CI, 12.7 to not reached). The most common grade 3 or higher adverse events were decreased neutrophil count (20.7% of patients), anemia (8.7%), and nausea (7.6%). Independent adjudication linked the trial drug to interstitial lung disease in 13.6% of patients (grade 1 or 2: 10.9%; grade 3 or 4: 0.5%; grade 5: 2.2%).

**Conclusions:** Trastuzumab deruxtecan demonstrated sustained antitumor activity in patients with HER2-positive metastatic breast cancer who had been heavily pretreated. In addition to nausea and myelosuppression, interstitial lung disease was noted in a subset of patients, necessitating attention to pulmonary symptoms and careful monitoring.