This phase III clinical trial showed that people with HER2-low scores, whose cancers previously were categorized as HER2-negative, may benefit from the anti-HER2 therapy TDX-d. The study showed a significant improvement in both overall survival and progression-free survival for the primary group studied, people with hormone receptor-positive, HER2-negative metastatic breast cancer, as well as a smaller group of people with triple-negative disease.
Results of DESTINY-Breast04 were presented as a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology June 5 and simultaneously published in the New England Journal of Medicine. At the conclusion of her talk, presenter Shanu Modi, MD, of the Memorial Sloan-Kettering Cancer Center, received a standing ovation, a rare response from the thousands of doctors gathered in the huge hall at McCormick Place in Chicago.
Until now, breast cancers were classified as either HER2-positive or HER2-negative. Tumor tissue tested in a lab, using a test called immunohistochemistry or IHC, tests for the HER2 protein and results in a numerical score. A HER2 score of 3 or higher is HER2-positive. Breast cancers with scores of 0 through 2 are considered HER2-negative.
Numerous drugs are FDA approved to treat HER2+ breast cancer. Previously, none have shown benefit in breast cancers with HER2 scores in the 1+ to 2+ range. TDX-d (Enhertu) is a newer drug in this category. It received accelerated FDA approval in 2019, breakthrough approval in 2021, and full approval in 2022. Enhertu is currently FDA approved as a first and second treatment for HER2+ metastatic breast cancer.
Trastuzumab deruxtecan is an antibody-drug conjugate, or ADC. This type of treatment uses a targeted therapy, in this case trastuzumab, to direct the treatment to cancer cells, and pairs it with a chemotherapy medicine to kill the cancer cells, using a linking agent. There are many ADCs under study for breast and other cancers.
Led by researchers at Memorial-Sloan Kettering Cancer Center, the DESTINY-Breast04 trial compared TDX-d (Enhertu) to chemotherapy of the doctor’s choice in people with metastatic breast cancer. The study participants had cancers with HER2 scores in the 1+ to 2+ range – what is now known as HER2-low. Participants had received one or two lines of chemotherapy treatment, and their disease was considered resistant to hormonal therapy.
The research team randomized 557 people to two groups: one that received TDX-d, and the other group that received chemotherapy chosen by the physician. The most common chemotherapy given was eribulin (Halaven) but capecitabine (Xeloda), nab-paclitaxel (Abraxane), gemcitabine (Gemzar), and paclitaxel (Taxol) were given, too. The trial was conducted on three continents; most study participants were white or Asian.
The primary goal of the study was to measure disease progression, whether the cancer grew, and a secondary goal was to measure overall survival, how long people lived after starting on the trial. The primary focus was on people with hormone receptor-positive disease, but people with triple-negative breast cancer were included as well. On both measures, TDX-d was more effective. Overall survival was on average 23.4 months for the group on the study drug, versus 16.8 months for the group on chemotherapy. Similar results were seen in people with hormone-receptor positive and hormone-receptor negative breast cancers, though most of the participants had hormone receptor-positive disease. Those who experienced an effect included some with metastatic triple-negative breast cancer.
This trial is the first to show that an anti-HER2 drug can work against breast cancers with low HER2. In doing so, it defines HER2-low as a new marker in treatment choice. This finding could affect approximately half of all people with metastatic breast cancer.
These are dramatic results that will have a significant positive impact for a large percentage of patients with metastatic breast cancer.
What these findings mean for you
This is exciting research that changes the standard of care for metastatic breast cancer by creating a new treatment marker – HER2-low. If you have metastatic breast cancer that was previous identified as HER2-negative, or you know your IHC results were 0, 1, or 2, it’s reasonable for you to talk with your doctor about your options. Ask about the score and whether TDX-d is an option for you.
It is important to note that the side effects of TDX-d can generally be managed, but there is a risk of serious lung side effects, a side effect called Interstitial Lung Disease, or ILD. People with ILD may have cough, fever, trouble breathing, and other respiratory symptoms that should be promptly reported to your provider. ILD can be prevented and treated with careful monitoring. The safety of this drug was confirmed in another study presented on June 4.
During the panel discussion following the presentation, questions were raised about lab tests used to score HER2. Currently, eligibility for any HER2-targeting treatment is determined by an immunohistochemistry, or IHC test, which delivers the 0-3+ scores used to determine whether a cancer is HER2-positive or -negative, or by a FISH (Fluorescence in situ hybridization) test. Some facilities only offer the FISH. FISH test results are only positive or negative, so they would not give the information needed to determine whether a cancer is HER2-low. If you previously had a FISH test, find out if it’s possible to have the tissue tested by IHC. If the HER2 score still does not qualify for this treatment, keep an eye on the research. Look for new, more sensitive tests to become available in the future.
Living Beyond Breast Cancer will continue to share information about these findings in the coming months.