A study of the new drug zongertinib, both as a single agent and in combination with other therapies, in various advanced HER2-positive cancers

Breast cancer (mammary carcinoma), stomach cancer (gastric carcinoma), esophageal cancer (esophageal carcinoma), and colorectal cancer (colorectal carcinoma) are malignant diseases in which, in advanced or metastatic stages, the tumor can spread to other parts of the body. In some of these tumors, there is overexpression or alteration of the HER2 receptor on the cell surface, which promotes the growth of cancer cells. Depending on the type of cancer, there are already approved medications available for HER2-positive tumors, such as trastuzumab or the antibody-drug conjugates trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1), which are administered as intravenous infusions. However, if the disease progresses despite these therapies, new treatment options are needed. Zongertinib is a selective HER2 tyrosine kinase inhibitor taken orally as a tablet that binds to the HER2 receptor and is designed to specifically block the growth signal of cancer cells. The drug has not yet been approved for the treatment of the conditions being studied in this trial. The goal of this Phase 1b/2 study is to determine an appropriate dosage for the new active ingredient zongertinib and to investigate whether it can shrink tumors on its own or in combination with other medications. The study is open-label (not blinded), meaning that study physicians and patients know which drug is being administered. In Phase 1b (dose escalation), the study will determine which dose of zongertinib, in combination with various other drugs, is well tolerated. In Phase 2 (dose optimization), patients will be randomly assigned to different groups to compare various dosages. There are several study arms in which zongertinib is being evaluated either alone or in combination with trastuzumab deruxtecan, trastuzumab emtansine, trastuzumab (alone or in combination with capecitabine, taken as a tablet), zanidatamab, or the mFOLFOX6 chemotherapy regimen (administered as an infusion, with or without trastuzumab). Patients aged 18 and older with metastatic, HER2-positive breast cancer, stomach or esophageal cancer (adenocarcinoma), or colorectal cancer are eligible to participate in this study. Eligibility criteria include, among other things, that the disease has progressed following prior treatment (for breast, stomach, and esophageal cancer, following treatment targeting HER2) and that patients are in sufficiently good general health.