The role of tyrosine kinase inhibitors in the treatment of HER2+ metastatic breast cancer.

The introduction of trastuzumab and other subsequent human epidermal growth factor receptor 2 (HER2)-targeted therapies dramatically shifted the treatment landscape of HER2+ breast cancer, changing the natural history of the disease. There is no standard-of-care for patients with HER2+ metastatic breast cancer (MBC) in third and later lines of treatment; however, continued use of anti-HER2 therapies is recommended. Small-molecule tyrosine kinase inhibitors (TKIs) that target HER2 and other HER family receptors play a central role in this setting. TKIs have demonstrated various degrees of efficacy against central nervous system (CNS) metastases, which are a major clinical challenge for patients with HER2+ MBC. The TKIs lapatinib, neratinib, and tucatinib have received regulatory approval for the treatment of HER2+ MBC, while pyrotinib and afatinib have been evaluated in this setting. These TKIs vary by molecular weight, HER protein specificity and reversibility of binding and in turn have unique safety profiles. Toxicities reported in clinical trials of TKIs in HER2+ MBC that may require specific management strategies include diarrhoea, palmar-plantar erythrodysesthesia syndrome and rash. Here, we review the efficacy data, including CNS activity, and the safety profiles of the TKIs, and we provide guidance on adverse event management. Finally, we discuss how to incorporate the TKIs into the HER2+ MBC treatment algorithm.