Beyond Trastuzumab: Small Molecule Tyrosine Kinase Inhibitors in HER-2–Positive Breast Cancer

Abstract Learning Objectives After completing this course, the reader will be able to: Describe the potential therapeutic advantages of tyrosine kinase inhibitors (TKIs) over antibody mediated inhibition with trastuzumab, such as oral bioavailability and ability to cross the blood–brain barrier.Explain the ability of TKIs to overcome resistance to and synergize with trastuzumab.Discuss the multiple tyrosine kinase inhibitors currently in development and their spectrum of targets and toxicities. This article is available for continuing medical education credit at CME.TheOncologist.com. HER-2 is a transmembrane, tyrosine kinase (TK) receptor whose overexpression is associated with adverse prognosis in breast cancer. The biological effects of HER-2 are mediated by kinase activity causing phosphorylation of tyrosine residues in the cytoplasmic domain of the receptor molecule, leading to activation of downstream growth-promoting pathways. Antibody-mediated inhibition by trastuzumab as well as TK inhibition are clinically effective anti–HER-2 strategies. Kinase inhibitors offer some potential therapeutic advantages over antibody-based therapies. Being small molecules, TK inhibitors (TKIs) have oral bioavailability and ability to cross the blood–brain barrier. Because of their different mode of action, TKIs may be able to overcome some of the mechanisms of trastuzumab resistance. Preclinical, and limited clinical data also suggest that TKIs and trastuzumab have synergistic activity. Lapatinib is the only TKI available for clinical use at present, but several molecules with anti–HER-2 activity have been identified and are undergoing evaluation. These differ in the spectrum of kinases that they inhibit, potency of HER-2 inhibition, pharmacokinetic properties, and toxicity profiles, and are at various stages of clinical development. In this article we summarize selected HER-2 TKIs approved for clinical use or in development for which clinical data are available.