HER2-targeted agents are the central component of HER2-positive metastatic breast cancer (MBC) treatment. The combination of trastuzumab, pertuzumab and a taxane is the preferred first-line regimen in most settings. For patients with disease relapse after adjuvant therapy, treatment decisions in the first-line are influenced by the treatment-free interval and the regimens used in the (neo)adjuvant setting. T-DXd has been recently established as the preferred second-line therapy. T-DM1, or the combination of tucatinib, trastuzumab and capecitabine, are reasonable third-line options, although efficacy and safety data of these regimens after prior exposure to T-DXd are lacking. In fourth and later lines, trastuzumab duocarmazine, neratinib plus capecitabine, margetuximab plus chemotherapy, lapatinib-based combinations or the continuation of trastuzumab with different chemotherapy partners are valid alternatives.

(BELG J MED ONCOL 2022;16(6): 287–92)