This clinical trial is focused on studying a type of breast cancer known as HER2-positive breast cancer, which is a form of cancer that has high levels of a protein called HER2. The study is specifically for patients with breast cancer that cannot be surgically removed or has spread to other parts of the body, known as unresectable locally-advanced or metastatic HER2-positive breast cancer. The trial is testing a combination of treatments to see if they can help control the cancer. The treatments being studied include a medication called TUKYSA (tucatinib), which is taken as a tablet, and Kadcyla (ado-trastuzumab emtansine), which is given through an infusion into a vein. Some participants will receive a placebo instead of TUKYSA to compare the effects.

The purpose of the study is to see if the combination of TUKYSA and Kadcyla can help patients live longer without their cancer getting worse. Participants in the study will be randomly assigned to receive either the combination of TUKYSA and Kadcyla or Kadcyla with a placebo. The study is designed to be “double-blind,” meaning neither the participants nor the researchers will know who is receiving the actual medication or the placebo, to ensure unbiased results. The study will last for a period of time, during which participants will receive regular treatments and have their health monitored closely by the research team.

Throughout the study, participants will undergo various assessments to track the progress of their cancer. These assessments may include imaging tests like MRI (magnetic resonance imaging) to check for any changes in the cancer, especially in the brain if there are concerns about cancer spreading there. The main goal is to compare how long patients can live without their cancer worsening, using a standard set of criteria known as RECIST (Response Evaluation Criteria in Solid Tumors). The study will also look at other outcomes, such as overall survival and response rates to the treatment.