First-line treatment with trastuzumab deruxtecan and pertuzumab for HER2-positive metastatic breast cancer with digital side effect management (TOP-REAL)

Breast cancer (mammary carcinoma) is a malignant disease of the breast tissue characterized by the uncontrolled proliferation of breast cells. In some breast cancer patients, the HER2 receptor (Human Epidermal Growth Factor Receptor 2) is present in increased numbers on the surface of the cancer cells. This is referred to as HER2-positive breast cancer, a particularly aggressive form in which the cancer cells multiply rapidly and can spread to other parts of the body (metastasize). The HER2 receptor serves as a target for modern cancer therapies. Trastuzumab deruxtecan is what is known as an antibody-drug conjugate: The antibody trastuzumab specifically recognizes HER2-positive cancer cells, binds to them, and delivers a cytotoxic agent (deruxtecan) directly into the cancer cell, where it destroys the cell from within. Pertuzumab is another antibody that binds to a different site on the HER2 receptor, thereby further inhibiting its signal transduction. By combining both active ingredients, the cancer cells are attacked in two different ways.

The goal of the Phase 2 study is to evaluate the efficacy and safety of first-line treatment with trastuzumab deruxtecan (T-DXd) and pertuzumab in HER2-positive metastatic breast cancer, as well as to assess the benefits of proactive digital side-effect management for the early detection and management of treatment-related side effects. The study is single-arm, meaning that all patients receive the same treatment with trastuzumab deruxtecan and pertuzumab. Both drugs are administered as an intravenous infusion. A unique feature of the study is the use of digital health tools: Patients receive an app (CANKADO/Resilience) and two devices—a pulse oximeter and a smartwatch—to regularly monitor vital signs such as oxygen saturation and heart rate. The goal is to detect potential side effects, such as inflammatory lung disease (pneumonitis), at an early stage. Before treatment begins, imaging studies are performed to identify measurable tumor lesions. Tumor monitoring takes place every 9 weeks during the first 12 months and every 12 weeks thereafter until the disease progresses, participation is terminated, or the study ends. In addition, a suitable tumor tissue sample is required before treatment begins. This sample is used to confirm HER2 status and to analyze other biomarkers. If the disease progresses, another tumor biopsy will be performed. In addition, blood samples will be collected at specific time points, among other things to examine biomarkers and genetic characteristics that could influence response to treatment. Patients will also complete questionnaires to evaluate the treatment from their own perspective, for example with regard to symptoms and quality of life. In addition, patients are required to take prophylactic medication to prevent nausea and vomiting. Eligible participants include women and men aged 18 and older with HER2-positive breast cancer at an advanced or metastatic stage. The disease must be HER2-positive and may be either hormone receptor-positive (HR+) or hormone receptor-negative (HR−). Patients must not have previously received chemotherapy or HER2-targeted therapy for advanced or metastatic disease. Prior anti-hormone therapy for metastatic breast cancer is permitted to a limited extent. Previous treatments administered during the early stages of the disease are allowed. The disease must be assessable via imaging studies, and suitable tumor tissue for testing must be available.