Combination therapy with disitamab vedotin and tucatinib for HER2-expressing breast cancer and stomach cancer

Breast cancer (mammary carcinoma) results from the uncontrolled growth of cells in the breast tissue, while stomach cancer (gastric carcinoma) and cancer at the junction of the esophagus and the stomach (gastroesophageal adenocarcinoma) are malignant diseases of the digestive tract. In some of these tumors, the HER2 receptor is detectable on the surface of the cancer cells, either in high quantities (HER2-positive) or in lower quantities (HER2-low). HER2 stimulates the cancer cells to grow more rapidly and spread faster. In advanced or metastatic stages, a cure is usually no longer possible, so the goal of treatment is to control the progression of the disease for as long as possible. Disitamab vedotin is an antibody-drug conjugate consisting of an antibody against HER2 and a cytotoxin attached to it. The antibody specifically recognizes HER2 on the surface of cancer cells, binds to it, and delivers the cytotoxic agent directly into the tumor cell, where it inhibits cell division and triggers cell death. The drug is administered as an intravenous infusion and has not yet been approved in Europe. Tucatinib is an active ingredient taken as a tablet that blocks signal transduction via HER2 within the cancer cell, which is intended to further inhibit tumor growth. In Europe, tucatinib is currently approved in combination with other active ingredients for the treatment of previously treated HER2-positive advanced or metastatic breast cancer, but not for HER2-low breast cancer or stomach cancer.

The goal of this Phase 1b/2 study is to investigate the safety and efficacy of the combination of the antibody-drug conjugate disitamab vedotin and the HER2 inhibitor tucatinib. The study will investigate whether the combination of these two drugs could be a new treatment option for these diseases, for which there are currently few treatment options available. The study is open-label (unblinded), meaning that both the patients and the study physicians know which treatment is being administered. The study will first determine the optimal dosage and tolerability of the combination therapy. During the dose-optimization phase, patients will be randomly assigned to one of two dose levels. Subsequently, in the extension phase, patients will be divided into four cohorts based on their disease and HER2 status: patients with HER2-low breast cancer, HER2-positive breast cancer, HER2-low stomach cancer, and HER2-positive stomach cancer. All patients will receive disitamab vedotin as an intravenous infusion in combination with tucatinib as a tablet. The primary objective of the study is to evaluate the efficacy of the treatment as well as the safety and tolerability of the combination. The study is expected to run for approximately 5 years (2024 to 2029).

Patients aged 18 and older who have locally advanced or metastatic breast cancer or stomach cancer and whose tumors express HER2 to varying degrees are eligible to participate in the study. Patients must have already received standard therapies and either experienced disease progression while on those therapies or been unable to tolerate them. In addition, patients must be in sufficient general health.