We conducted a randomized, two-group, open-label, phase 3 trial involving patients with HER2-low, unresectable or metastatic breast cancer. Trial enrollment was planned for 480 patients with hormone receptor–positive disease (immunoreactive for estrogen or progesterone receptor in ≥1% of tumor-cell nuclei according to local testing) and 60 patients with hormone receptor–negative disease, approximating the proportions of receptor subtype observed in HER2-low breast cancer.1 (link) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician’s choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel. Randomization was stratified according to HER2-low status (IHC1+ vs. IHC 2+ and ISH-negative), the number of previous lines of chemotherapy for metastatic disease (one vs. two), and hormone-receptor status (positive [with vs. without previous CDK4/6 inhibitor therapy] vs. negative).
IHC scores for HER2 expression were determined through central testing of adequate archived or recent tumor-biopsy specimens with the use of an investigational IHC assay, the VENTANA HER2/neu (4B5) IUO (investigational use only) Assay system, according to an algorithm adapted from the 2018 American Society of Clinical Oncology/College of American Pathologists testing guidelines (Table S1 in the Supplementary Appendix , available with the full text of this article at NEJM.org ).22 (link) Specimens that yielded central HER2 IHC scores of 2+ were reflexed to ISH testing with the use of the investigational INFORM HER2 Dual ISH DNA Probe Cocktail IUO Assay system.
Eligible patients must have received chemotherapy for metastatic disease or have had disease recurrence during or within 6 months after completing adjuvant chemotherapy; patients with hormone receptor–positive disease must have received at least one line of endocrine therapy. Patients with treated, stable brain metastases were eligible; patients were ineligible if they had a history of noninfectious interstitial lung disease requiring treatment with glucocorticoids or had suspected interstitial lung disease on imaging at screening.
Trastuzumab deruxtecan was administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight, and the physician’s choice of chemotherapy was administered in accordance with local label or the National Comprehensive Cancer Network guidelines.6 More details are provided in theSupplementary Appendix .
IHC scores for HER2 expression were determined through central testing of adequate archived or recent tumor-biopsy specimens with the use of an investigational IHC assay, the VENTANA HER2/neu (4B5) IUO (investigational use only) Assay system, according to an algorithm adapted from the 2018 American Society of Clinical Oncology/College of American Pathologists testing guidelines (
Eligible patients must have received chemotherapy for metastatic disease or have had disease recurrence during or within 6 months after completing adjuvant chemotherapy; patients with hormone receptor–positive disease must have received at least one line of endocrine therapy. Patients with treated, stable brain metastases were eligible; patients were ineligible if they had a history of noninfectious interstitial lung disease requiring treatment with glucocorticoids or had suspected interstitial lung disease on imaging at screening.
Trastuzumab deruxtecan was administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight, and the physician’s choice of chemotherapy was administered in accordance with local label or the National Comprehensive Cancer Network guidelines.6 More details are provided in the
