Antibody-Drug Conjugate Advancements for Breast Cancer Treatment: Updates from SABCS 2022 by Leif Ellisen MD
By Leif Ellisen, MD
So antibody drug conjugates, or as I’ll refer to them, ADCs are a really important new class of drugs. They’re very complicated structure in that they have three distinct components. One is an antibody that binds to a target on the surface of the tumor cell. That antibody is linked or conjugated to what we call a “cytotoxic payload,” typically a chemotherapy like drug, and when it’s linked to the antibody, that chemotherapy drug is carried into the cell. When the antibody binds to the tumor cell surface, that cytotoxic payload (cytotoxic drugs) is then released to kill the tumor cell (target cell).
So they have a complex mechanism of action, and why they appear to be so important. Is that now there are multiple antibody drug conjugates, FDA approved for all breast cancer subtypes. And what has been found is that they can be remarkably effective, particularly against metastatic disease, where they have been shown to cause improvements in overall survival across breast cancer subtypes. So in many ways, these are paradigm changing drugs in breast cancer. There are many differences between the different ADCs (antibody drug conjugates) differences, for example, in exactly what target on the cell surface they attach to. Two good examples are T-DM1 and Kadcyla and T-DXd Trastuzumab deruxtecan or in HER2, they both bind to the HER2 molecule on the breast cancer cell surface. Another one named Sacituzumab govitecan or TRODELVY binds to a different molecule, Trop-2, so they have different targets on the cell surface. Nonetheless, these drugs can be effective across breast cancer subtypes. Currently, Sacituzumab or TRODELVY is approved for triple-negative breast cancer, whereas, Enhertu is approved for both HER2 amplified Enhertu in low breast cancer and T-DM1 or Kadcyla approved for HER2 amplified breast cancer.
Those are the things that we know that they can be effective in the right setting. What we really don’t know is about. Whether we can select more patients effectively through biomarkers to determine who will benefit the most. And secondly, many of the tumors ultimately become resistant to these ADCs (antibody drug conjugates), and we know very little about how tumors ultimately become resistant and progress.
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What is the latest data released at SABCS on antibody drug conjugates?
One of the most important questions about the ADCs (antibody drug conjugates) is whether we can use them in sequence, meaning if we use one ADC for a patient and then the tumor progresses. Is it possible that another ADC will then be effective? Yesterday, we heard data from the Destiny Breast Cancer clinical trial, which specifically enrolled patients who had previously progressed on Kadcyla and then gave them in HER2 subsequently. And what was found compared to regular treatment of physician’s choice was that the in HER2 was dramatically more effective, even though the patients had already progressed on another ADC. So that tells us very importantly, that in the right context, we can use ADCs (antibody drug conjugates) in sequence, but clearly, we’re going to have to choose the ADCs carefully so we use the right ADC one after another.
Well, there’s no doubt that antibody drug conjugates are going to continue to be important for breast cancer for a long time to come. They’re now changing the landscape of therapy, particularly for metastatic disease, but there are many unanswered questions. In particular, because most patients ultimately progress on these drugs, we need to understand the mechanisms of resistance. Some of the work that we and others have done is trying to understand that, for example, we’ve shown that in some cases the tumors, when they become resistant to these drugs, do so by acquiring a mutation in actually the target of the ADC (antibody drug conjugates or monoclonal antibodies) on the tumor cell. In other cases, tumors can become resistant through a mutation that affects how the cytotoxic payload works and is delivered to the tumor cell. And these different mechanisms of resistance are quite important because they have important implications for what a ADC we might use next. For example, if the tumor became resistant because of a mutation of a specific target cells, we would clearly not want to use subsequently, an ADC that targeted that same molecule on the tumor cell surface.
We would want to choose a different ADC that targeted a different molecule. Unfortunately, we have a very limited understanding of how common these different mechanisms of resistance are and what it’s going to take to understand that is a lot of translational research looking at patient specimens, patient circulating tumor DNA. To understand the acquisition of mutations, the acquisition of clonal evolution, and resistance, and secondly, to conduct research in the laboratory to understand systematically what are all the various ways that tumor cells can become resistant.
So to summarize, we have a long way to go to understand exactly how ADCs (antibody drug conjugates or monoclonal antibodies) are working and exactly how to use them most effectively to overcome resistance, either through using them in sequence or through using them in combinations with other drugs. But the research in the years ahead is likely to provide new light on this and make these drugs even more powerful for our breast cancer patients.
What are Antibody-Drug Conjugate Advancements for Breast Cancer Treatment?
Antibody-drug conjugates (ADCs or monoclonal antibody) are a promising approach to treating breast cancer. These therapies consist of monoclonal antibodies that is designed to target a specific antigen on cancer cells, coupled with a toxic payload that is released upon internalization of the ADC by the cancer cell.
Recent advancements in ADC technology have led to the development of more potent and stable ADCs that have improved efficacy and reduced toxicity. In addition, new targets have been identified that can be exploited for the development of ADCs for breast cancer, including HER2, Trop-2, and MUC1.
Clinical trials of ADCs in breast cancer have shown promising results, with several ADCs showing significant anti-tumor activity and improved progression-free survival compared to standard of care treatments. However, there are still challenges that need to be addressed in the development of ADCs, including optimization of the therapeutic index and identification of patient populations most likely to benefit from these treatments.
Overall, ADCs (antibody drug conjugates or monoclonal antibodies) represent an exciting and rapidly evolving area of breast cancer therapy that has the potential to significantly improve patient outcomes.
Leif Ellisen, MD, PhD – About The Author, Credentials, and Affiliations
Dr. Ellisen is a Harvard Medical School Professor of Medicine and the Program Director for Breast Medical Oncology at the Mass General Cancer Center. He is also co-Director of the Dana-Farber/Harvard Cancer Center’s Breast Cancer Program. He obtained his undergraduate degree from Harvard, his MD and PhD from Stanford, and he did residency, oncology fellowship, and postdoctoral research training at Brigham and Women’s Hospital, the Dana-Farber Cancer Institute, and Mass General, in that order. Dr. Ellisen has authored numerous publications in the disciplines of cancer biology, treatment, and genetics. Dr. Ellisen’s clinical practice at Mass General is focused on cancer risk assessment, prevention, and early detection as the Director of Breast and Ovarian Cancer Genetics. Dr. Ellisen’s research is at the forefront of changing cancer treatment through tailored cancer medicines. Dr. Ellisen is well renowned for his research on triple-negative breast cancer (TNBC), one of the disease’s most aggressive types.