Enhertu Compared with Kadcyla in Patients with HER2-Positive, Residual Invasive Early Breast Cancer After Neoadjuvant Therapy

For patients with human epidermal growth factor receptor 2 (HER2)-positive, invasive, early breast cancer, receiving chemotherapy combined with Herceptin (trastuzumab) and Perjeta (pertuzumab) before breast surgery is the preferred treatment course. However, some patients who receive such treatment still have cancer cells that remain after attempts to remove the cancer have been made. This is called “residual invasive disease.” If it occurs, it is generally in the breast or lymph nodes and this is challenging because it puts patients at greater risk for disease recurrence or death, than if cancer is in a state of pathologic complete response, meaning it lacks all signs of cancer in tissue samples removed during surgery or biopsy after treatment with radiation or chemotherapy. Understanding if the cancer is in pathologic complete response can help show how well treatment is working or if the cancer will come back, and whether additional medications should be prescribed to fight the cancer.

Kadcyla (trastuzumab emtansine), an antibody–drug conjugate, was recently approved by the US Food and Drug Administration for the treatment of breast cancer in patients with residual invasive disease after receiving neoadjuvant chemotherapy and Herceptin (or Herceptin with Perjeta) in the breast and the axillary lymph nodes that are located in the armpit area. Neoadjuvant chemotherapy is used as a first step to shrink a tumor before the main treatment, which is surgery.

Antibody–drug conjugates are a class of powerful biological drugs that are built by connecting a tiny molecule of anticancer drug to an antibody, with linker, that easily breaks down. Because the antibody targets only a specific antigen or protein found on the specific targeted cells, it can bind to the cell, and work jointly with the drug. This way, the drug is delivered as best as possible, only to the diseased cells, maximizing their effectiveness and minimizing negative impact around the body. This reduces the risk for side effects caused by the drug.

Enhertu is a powerful HER2-targeted antibody–drug conjugate that has a HER2 antibody attached to medication that can penetrate the remaining breast cancer cells. Eight medication molecules attach to every HER2 antibody. It has been approved for the treatment of adult patients with HER2-positive cancer that is not capable of being entirely surgically removed or metastatic breast cancer that has spread into other areas of the body. In the United States, Enhertu has been approved for patients who have received ≥2 previous anti-HER2–based treatments in the metastatic setting or had previous chemotherapy and the cancer did not respond.

These approvals were based on a phase 2 study in which Enhertu improved the objective response rate, which is defined as the percentage of patients who have a partial or complete response to treatment. In the study, 60.9% of patients responded to treatment and they had a duration of response that was 14.8 months.

Charles E. Geyer, Jr, MD, FACP, Deputy Director, Houston Methodist Cancer Center, Houston, described the latest clinical trial that evaluated how effective and safe Enhertu is, when compared with Kadcyla as postneoadjuvant treatment for high-risk patients who have residual breast cancer cells remaining after neoadjuvant therapy. This trial is call DESTINY-Breast05, and it is a being conducted around the world at approximately 400 centers, and they are currently enrolling patients.

Approximately 1600 participants will be included in the study, and they will be randomly assigned to receive Enhertu or Kadcyla. Either treatment will be administered intravenously every 3 weeks for 14 cycles. Over the course of the study, the researchers will keep track of how well the medication is working, and if there are any side effects by conducting physical examinations, taking vital signs, blood work, and x-rays of the chest if necessary. They will also try to understand how the medication makes patients feel and affect their quality of life by giving questionnaires and taking blood to understand how much medication is in their body over time and how it is impacting the body over time.