Comprehensive insight on therapeutic classes and agents approved in the setting of HER2+ metastatic breast cancer, with a specific focus on how these therapies fit into current treatment strategies.
Neil Iyengar, MD: Hello everyone. My name is Dr Neil Iyengar. I’m a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. I’m joined by Dr Milana Dolezal, who is also a medical oncologist. Today we’ll be discussing recent updates in the management and treatment of HER2-positive advanced and metastatic breast cancer. I’d like to start by providing a general overview in terms of the many new advances we’ve seen within the past few years. This has been a really exciting area for clinical advances.
We’ll start by reviewing some of the newer agents that have become available to us in the clinic. I think we’re all very familiar with the classical antibodies trastuzumab and pertuzumab, which bind the extracellular domain of HER2 and thereby block HER2 dimerization, association with HER3,and subsequent signaling. We’re also seeing the development of bispecific antibodies, which target multiple domains. Ultimately this kind of binding of the extracellular domains inhibits ligand-independent HER2/HER3 association, thereby halting the cell cycle and cancer cell proliferation. Another area of exciting development is antibody-drug conjugates. This is what we’ll spend some time discussing today. Here we see the combination of protein targeting with a cytotoxic payload, which results in both halting of the cell cycle, as well as a direct cytotoxic effect. We also now have novel HER2-targeted immunomodulatory approaches, such as margetuximab, which is of course an anti-HER2 antibody that also stimulates an immune response.
If we move into the cell, we have small-molecule tyrosine kinase inhibitors [TKIs], which have recently been improved and are showing exciting activity for advanced metastatic HER2-positive breast cancer, including patients with CNS [central nervous system] involvement. The TKIs target the intercellular domain of the HER family. I think we’re all familiar with lapatinib, which is a reversible inhibitor of HER2 and HER1, or EGFR. We now have neratinib, which is an irreversible pan-HER inhibitor, as well as tucatinib, which is a reversible inhibitor that is highly specific to HER2. Each of these have distinct toxicity profiles based on their receptor specificity or lack thereof and have helped us to improve the toxicity profile of these agents when treating our patients.
If we think about the overview or the timeline of FDA approvals for HER2-positive breast cancer, we’ve really come a long way since the approval of trastuzumab in the early 1990s for metastatic disease. We had a bit of a dry spell until lapatinib in 2007, followed by pertuzumab and T-DM1 [trastuzumab emtansine]. It was really in 2013 that we started seeing approvals in the earlier stage setting, including pertuzumab, neratinib, and T-DM1. Very recently we’ve seen the approvals of 4 new agents in the metastatic setting. This includes trastuzumab-deruxtecan, tucatinib, neratinib, and margetuximab.
Transcript edited for clarity.