Novel HER2–targeted therapies for HER2–positive metastatic breast cancer

Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of all breast cancers. Before the development of HER2-directed monoclonal antibodies, HER2–positive breast cancer was associated with a rather poor prognosis. With the advent of monoclonal HER2–targeting antibodies (trastuzumab and pertuzumab) and antibody-drug conjugates (trastuzumab emtansine [T-DM1] and trastuzumab deruxtecan), clinical outcomes for HER2–positive breast cancer have dramatically changed, and a greater proportion of patients in the nonmetastatic setting are cured. However, in the metastatic setting, resistance to anti-HER2 treatments still remains a major therapeutic challenge, underscoring the importance of developing novel HER2-directed therapies. Over the last year, there has been a dramatic shift in the current treatment paradigms for HER2–positive metastatic breast cancer, with recent U.S. Food and Drug Administration approvals of trastuzumab deruxtecan (DS-8201), neratinib, and tucatinib in combination with trastuzumab and capecitabine. The authors summarize recent phase 3 data with novel HER2–targeted therapies as well as phase 1 and 2 data with other novel HER2–targeting agents.