Frontiers in Anti-Cancer Drug Discovery

Volume: 4

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Frontiers in Anti-Cancer Drug Discovery is an Ebook series devoted to publishing the latest and the most important advances in Anti-Cancer drug design and discovery. Eminent scientists write ...
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HER2 Targeted Monoclonal Antibodies and Tyrosine Kinase Inhibitors

Pp. 293-382 (90)

Neil A. O`Brien, Alexandra Canonici, Karen Howe, Martina S.J. McDermott, Denis M. Collins, Brigid C. Browne, John Crown and Norma O`Donovan

Abstract

HER2 is overexpressed in approximately 20-25% of breast cancers and defines an aggressive sub-type of the disease. Fortunately for patients with HER2 positive breast cancer, the prognosis has improved in the last 10 years due to the development of HER2 targeted therapies, in particular trastuzumab, the HER2-directed monoclonal antibody. Recent data show that approximately 9.5% of patients with HER2 positive metastatic breast cancer achieve a durable complete response (> 5 years) following trastuzumab-based therapy. However, 90% of these patients still continue to develop progressive disease. These data highlight the need to develop novel therapeutic strategies to overcome both innate and acquired resistance to HER2 directed therapeutics.

Lapatinib, a small molecule tyrosine kinase inhibitor of HER2 and EGFR, has efficacy in trastuzumab resistant breast cancer and is approved for the treatment of patients with trastuzumab-refractory HER2 positive metastatic breast cancer. However, in metastatic disease, therapeutic action is often short-lived with most patients developing progressive disease. Thus, HER2 positive tumors can be innately resistant, or acquire resistance, to both trastuzumab and lapatinib.

Over the past 2 years, two new HER2 targeted therapies, pertuzumab and T-DM1 have received approval for the treatment of HER2 positive metastatic breast cancer. The pertuzumab monoclonal antibody blocks dimerization of HER2 with other members of the HER family and clinically has been shown to improve overall survival when used in combination with trastuzumab and docetaxel. The novel antibody drug conjugate, T-DM1, which links trastuzumab to the cytotoxic agent emtansine, improves the response of patients with trastuzumab-refractory metastatic breast cancer, compared to the standard of care lapatinib plus capecitabine regimen. A number of second generation irreversible pan-HER tyrosine kinase inhibitors are currently in clinical development, including neratinib, afatinib and dacomitinib.

More recently, the utility of HER2-directly therapeutics has been expanded into nonbreast tumors such as gastric cancers that carry the HER2-alteration. Data from ongoing clinical trials will determine if targeting HER2 can also improve the prognosis of these cancer patients.

Keywords:

Afatinib, antibody-drug conjugate, dacomitinib, lapatinib, neratinib, pertuzumab, T-DMI, trastuzumab, tyrosine kinase inhibitor.

Affiliation:

National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.