A clinical trial comparing trastuzumab deruxtecan as first-line therapy with anti-hormonal therapy in patients with advanced breast cancer with low HER2 expression

Breast cancer (mammary carcinoma) is a malignant disease of the breast gland tissue characterized by the uncontrolled proliferation of breast gland cells. Treatment of the disease depends on numerous factors, such as the patient’s overall health, the stage of the disease, the presence of detectable hormone receptors on the surface of the cancer cells (estrogen receptor- or progesterone receptor-positive) and the presence of the HER2 receptor on the tumor cells. In tumors with low HER2 expression (HER2-low or HER2-ultralow), the HER2 receptor is present on the cell surface, but only in small quantities. Newer drugs such as trastuzumab deruxtecan can still bind specifically to the tumor cells even at this low level of HER2 expression. Trastuzumab deruxtecan is an antibody-drug conjugate in which an antibody that recognizes the HER2 receptor is linked to a chemotherapeutic agent, allowing the active ingredient to be delivered specifically into the cancer cells where it can take effect. The drug is administered as an intravenous infusion. Trastuzumab deruxtecan is not yet approved as a first-line therapy for hormone receptor-positive, low-HER2-expressing breast cancer and is being evaluated in this treatment setting in this study. The goal of this Phase 2 study is to investigate whether the drug trastuzumab deruxtecan is more effective as a first-line therapy than the current standard of care—a CDK4/6 inhibitor plus anti-hormone therapy—in patients whose tumors are classified as non--luminal. A specialized genetic analysis (PAM50) is used to determine whether the tumor corresponds to a so-called non-luminal subtype. Patients with this subtype may respond less well to anti-hormone therapy alone. The study is therefore investigating whether they would benefit from targeted therapy with trastuzumab deruxtecan. In this study, patients are randomly assigned to one of two treatment groups. In study arm A, patients receive trastuzumab deruxtecan as an intravenous infusion. In the control arm (Arm B), patients receive treatment with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) in combination with anti-hormonal therapy (fulvestrant or an aromatase inhibitor). The study is open-label, meaning that both the patients and the study physicians know which treatment is being administered. The primary objective of the study is to investigate whether trastuzumab deruxtecan can prolong progression-free survival (the time during which the disease does not progress) compared to standard therapy. In addition, overall survival, response to therapy, and quality of life, among other factors, will be assessed. Women and men aged 18 years and older with advanced or metastatic (spread) hormone receptor-positive and HER2-low breast cancer are eligible to participate in this study. The cancer must be a non-luminal subtype, and patients must not have received any prior treatment for the advanced disease and must be in sufficient general health (e.g., good heart, liver, and kidney function).