Mark Pegram, MD, provides a historical perspective on recent advancements made in the treatment landscape for patients with HER2-positive breast cancer.
Mark Pegram, MD: The history of HER2 [human epidermal growth factor receptor 2] targeted therapy dates back to the late 1990s when trastuzumab was first approved in 1998 based on a pivotal trial in metastatic disease in combination with chemotherapy in the first line. Trastuzumab was shown to improve both progression-free survival as well as overall survival in that study and also increased response rates significantly. After that, there were the small molecule kinase inhibitors that came a long, the first being lapatinib and more recently tucatinib . These drugs have the advantage of being orally bioavailable.They come in pill form instead of needing a parenteral administration, which is an advantage in some circumstances. The cabozantinib plus lapatinib combination was the first drug registration by the FDA [Food and Drug Administration] for that class of agents in HER2-positive metastatic breast cancer.
After that we had the advent of the antibody-drug conjugates. The first in class was trastuzumab emtansine, or T-DM1. T-DM1 has an emtansine derivative payload, which unfortunately is not soluble, so it does not have a bystander effect. The drug-to-antibody ratio in the case of T-DM1 is low, around 3½ compared to some other more new antibody-drug conjugates. Nevertheless, that had a survival benefit compared to trastuzumab plus capecitabine in a randomized phase III trial, improving overall survival and progression-free survival and the long-term final analysis of survival was positive in that study. Next, we had that advent of engineered antibodies, for example Fc [fragment crystallizable] domain engineered antibodies like margetuximab that can engage activating Fc receptors. That has recently been approved within the past year for the treatment of advanced HER2-positive disease that’s heavily being treated in the salvage setting.
Currently, the first-line recommended regimen is a CLEOPATRA-linked regimen that is taxane with pertuzumab, and trastuzumab in combination. Second line, prior to this ESMO [European Society for Medical Oncology meeting] in 2021, has been T-DM1 firmly entranced in the second-line space. Third line has been equipoised between trastuzumab deruxtecan, which we’ll talk about during this session, and tucatinib-based regimens based on the HER2CLIMB data, which is tucatinib in combination with capecitabine and trastuzumab.
Transcript edited for clarity.