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Following up on the 2012 annual meeting of the American Society of Clinical Oncology (ASCO), CancerNetwork speaks with Dr. Sara Hurvitz, director of the breast cancer program at the University of California in Los Angeles. Dr. Hurvitz is actively involved in translational phase I/II breast cancer clinical trials as well as in research to better define distinct types of breast tumors to better design novel targeted therapies.
CancerNetwork: Dr. Hurvitz, you were involved in the phase II program for trastuzumab(Drug information on trastuzumab) emtansine (T-DM1) and presented the phase II efficacy results of treatment-naive patients at the European Multidisciplinary Cancer Congress held last year. T-DM1 is a next-generation trastuzumab compound. Can you explain what is unique about this compound?
Dr. Hurvitz: This is a novel molecule called an antibody–drug conjugate and what makes it unique is that it is stably linked to a very cytotoxic chemotherapy. So the trastuzumab, which is a HER2-targeted monoclonal antibody that is relatively nontoxic on its own, is linked to a derivative of a drug called mertansine.
Mertansine is a therapy that was developed in the 1980s and was so toxic they had to shelve it in terms of a regulatory pathway. What has been done is scientists have figured out how to link the trastuzumab to the chemotherapy so that the chemotherapy is not released until it is inside the cancer cell that bears the HER2 on the outside of the cell. The trastuzumab portion of the molecule will bind to the HER2 extracellular domain and the entire T-DM1 molecule is taken up inside the tumor cell and once inside the tumor cell the linker releases the emtansine or derivative of mertansine chemotherapy, which is then activated so that the cell is killed. So it is a beautiful targeted delivery of the toxic payload to cancer cells.
There have been other antibody–drug conjugates that have been developed in the past that have not been nearly as successful and that is because the linker released the chemotherapy prior to getting inside the tumor cell. So that is probably what makes this compound so unique for breast cancer, and the technology of the linker is being exploited for other molecules that are in development for both breast cancer as well as other tumors.
CancerNetwork: The results of the phase III EMILIA trial with T-DM1 in patients that were previously treated were presented at the plenary session at this year’s ASCO. The data showed that T-DM1 improves progression-free survival as compared to lapatinib plus capecitabine(Drug information on capecitabine) and has fewer side effects. There is also a phase III trial called the MARIANNE trial assessing T-DM1 as a first line of treatment that is still ongoing. If the MARIANNE trial results are positive, what do you envision to be the main role for T-DM1? As a first- or second-line agent?
Dr. Hurvitz: The MARIANNE study is actually comparing T-DM1 alone vs T-DM1 plus pertuzumab vs standard of care trastuzumab plus a taxane. If the combination of T-DM1 and pertuzumab is the winner I think that there is going to be a lot of enthusiasm among oncologists to use the two together in the front-line setting to give patients the highest chance of a good response and durable remission. We do see durable remissions especially in HER2-positive disease in the front-line setting. I think most oncologists have a handful of patients that treated in the front-line setting with aggressive upfront therapy achieve a complete response and have years in remission with that therapy, so I think there is a sense that if we treat a little more aggressively upfront, patients may have a chance at a longer time of disease control by doing so.
I think though that there would still be a role for a second-line setting, which was studied in the EMILIA clinical trial. There would still be a role for T-DM1, because for many patients who are treated in the adjuvant setting and have a relapse in a relatively short period of time, or have already had front-line therapy and their disease progresses, T-DM1 offers them a relatively nontoxic approach that’s able to improve progression-free survival. So I think realistically speaking that oncologists would be eager to use it in both types of settings.