Antibody drug conjugates (ADCs), which use a targeted monoclonal antibody to deliver a cytotoxic payload, are among the most effective breast cancer therapies yet developed. The first Food and Drug Administration approval of an ADC in breast cancer, ado-trastuzumab emtansine, better known as T-DM1, sparked development of numerous new and promising ADCs for breast cancer.
“T-DM1 was the absolute confirmation of the original premise of these agents,” said Ian Krop, MD, PhD, Associate Director for Clinical Research and Chief Clinical Research Officer, Yale Cancer Center, Yale School of Medicine. “Linking a chemotherapy agent to an antibody can transform a nontargeted, nonspecific drug into one that is very highly targeted to decrease its toxicity and increase its efficacy. It took decades to develop the technology, the monoclonal antibodies, the linkage between chemotherapy and antibody, the molecular targets, improved cytotoxic payloads. We’re not even close to tapping the full potential of this field.”
Dr. Krop will moderate Antibody Drug Conjugates: Future Directions and Opportunities on Wednesday, December 7, from 3:00 pm – 5:00 pm CT in Stars at Night Ballroom 1&2. The entire spectrum of cancer research and clinical practice has ADCs in its sights.
Puja Sapra, PhD, Senior Vice President, Biologics Engineering & Oncology Targeted Delivery, AstraZeneca, will detail the bioengineering and mechanism of action that makes ADCs possible. The concept, linking a toxic biologic payload to a highly targeted antibody delivery vehicle, has been around since monoclonal antibodies were developed in the 1970s. It wasn’t until 2013 that T-DM1 was approved for HER2+ metastatic breast cancer.
“T-DM1 gave us very high efficacy and an almost unprecedented level of safety for a cytotoxic-based molecule,” Dr. Krop said. “What made it such a breakthrough was not just its effectiveness for patients whose cancers had survived many prior therapies, but that the experience from the patient’s perspective was much more like a monoclonal antibody than a chemotherapy. T-DM1 made an even bigger impact when it was proven to substantially reduce the risk of recurrence in early stage HER2+ disease.”
T-DM1 was just the first step. Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, will focus on new ADCs in breast oncology, from trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG)to other agents still in development. SG is the first ADC to show activity in triple negative breast cancer. Recent data shows activity in hormone receptor-positive breast cancer and overlap with HER2-low breast cancers.
T-DXd is a successor to T-DM1, Dr. Krop noted. It offers greater anticancer activity from a more potent payload that is readily transported from HER2+ tumor cells to surrounding tumor cells that may not express the target surface protein.
“This bystander effect is particularly important in cancers that are somewhat heterogeneous in terms of how much they express the target,” Dr. Krop said. “The bystander effect may play a role in making T-DXd effective against HER2-low tumors that are not at all sensitive to other anti-HER2 therapies. We are now in the fortunate, and complicated, situation of figuring out how to sequence these conjugates because there are so many promising ones.”
Leif Ellison, MD, PhD, Program Director, Breast Medical Oncology and Professor of Medicine and Clinical Director, Breast and Ovarian Cancer Genetics, Harvard Medical School, will discuss the latest data on mechanisms of resistance to ADCs. ADCs are not effective in a subset of patients from the outset and metastatic disease eventually develops resistance.
“ADCs have immediate clinical implications that are changing very rapidly,” Dr. Krop said. “We are going to see continued evolution that will be impacting the clinic in the future, perhaps more than any other therapeutic area in breast cancer.”