Abstract
An estimated 15–20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2/ERBB2/neu). Two small-molecule tyrosine kinase inhibitors (TKIs), lapatinib and neratinib, have been approved for the treatment of HER2-positive (HER2+) breast cancer. Lapatinib, a reversible epidermal growth factor receptor (EGFR/ERBB1/HER1) and HER2 TKI, is used for the treatment of advanced HER2+ breast cancer in combination with capecitabine, in combination with trastuzumab in patients with hormone receptor-negative metastatic breast cancer, and in combination with an aromatase inhibitor for the first-line treatment of HER2+ breast cancer. Neratinib, a next-generation, irreversible pan-HER TKI, is used in the US for extended adjuvant treatment of adult patients with early-stage HER2+ breast cancer following 1 year of trastuzumab. In Europe, neratinib is used in the extended adjuvant treatment of adult patients with early-stage hormone receptor-positive HER2+ breast cancer who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy. Preclinical studies have shown that these agents have distinct properties that may impact their clinical activity. This review describes the preclinical characterization of lapatinib and neratinib, with a focus on the differences between these two agents that may have implications for patient management.
Highlights
Five human epidermal growth factor receptor 2 (HER2/ERBB2/neu)-targeted therapies are currently approved by the Food and Drug Administration (FDA) for the treatment of HER2-positive (HER2+)breast cancers: trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1), lapatinib, and neratinib [1].These can be divided into three categories: anti-HER2 monoclonal antibodies, antibody–drug conjugate (T-DM1), and small-molecule pan-HER tyrosine kinase inhibitors (TKIs; lapatinib and neratinib)
This review focuses on preclinical findings regarding lapatinib and neratinib, the two approved small-molecule pan-HER TKIs, in order to provide an in-depth and comprehensive review of preclinical data
Three key properties differentiate the preclinical activities of neratinib and lapatinib: the breadth of targets for neratinib in the HER family of receptors; the greater potency of neratinib versus lapatinib; and the ability of neratinib to irreversibly inhibit EGFR and HER2/4
Summary
Five human epidermal growth factor receptor 2 (HER2/ERBB2/neu)-targeted therapies are currently approved by the Food and Drug Administration (FDA) for the treatment of HER2-positive (HER2+). Breast cancers: trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1), lapatinib, and neratinib [1] These can be divided into three categories: anti-HER2 monoclonal antibodies (trastuzumab and pertuzumab), antibody–drug conjugate (T-DM1), and small-molecule pan-HER tyrosine kinase inhibitors (TKIs; lapatinib and neratinib). This review focuses on preclinical findings regarding lapatinib and neratinib, the two approved small-molecule pan-HER TKIs, in order to provide an in-depth and comprehensive review of preclinical data. Clinical trials involving lapatinib and neratinib have been reviewed elsewhere [5,6] and are not covered in this review. The two most striking are (1) the nature of target binding: lapatinib binds reversibly whereas neratinib binds irreversibly, and (2) differential affinities for epidermal growth factor receptor (EGFR/HER1/ERBB1), HER2, and HER4 (ERBB4).
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