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Mentions: Lapatinib (GW572016) is a unique, orally bioavailable, small-molecule dual tyrosine kinase inhibitor developed by GlaxoSmithKline that targets tumor cells overexpressing both human epidermal growth factor receptor (EGFR; ErbB1) and ErbB2 tyrosine kinases (5). Lapatinib inhibition of ErbB1 and ErbB2 kinase activity prevents the activation of downstream cellular signals that promote tumor cell survival and proliferation (6–8) (Fig. 1). Using a rational drug design approach, more than 3200 quinazoline and quinazoline-like compounds with potential tyrosine kinase activity were screened and assayed. Lapatinib was eventually selected from these compounds as it was a selective and potent inhibitor of ErbB1 and ErbB2 that had predictable oral bioavailability and acceptable in vivo toxicity in the targeted patient population (9). First-in-human studies with lapatinib were initiated in 2001; in 2007 lapatinib was approved in the USA for use in combination with capecitabine for the treatment of ErbB2+ advanced or metastatic breast cancer in patients who had received previous treatment including an anthracycline, a taxane and trastuzumab (10) (Fig. 2). Additional approvals for this indication have been granted in 90 more countries, including Japan. The clinical development of lapatinib is continuing with attention focused on ErbB2+ breast cancer as well as other cancers that overexpress ErbB2.Figure 1.
Management of ErbB2-positive Breast Cancer: Insights from Preclinical and Clinical Studies with Lapatinib
Bottom Line: Lapatinib, in combination with chemotherapeutic agents, such as capecitabine, provides clinical benefits to patients with ErbB2+ breast cancer, including patients who develop progressive disease on trastuzumab.Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer.Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer.
Affiliation: Sylvester Comprehensive Cancer Center at Deerfield Beach, University of Miami Miller School of Medicine, 1192 East Newport Center Drive, Deerfield Beach, FL 33442, USA. firstname.lastname@example.org
The management of human epidermal growth factor receptor 2-positive (ErbB2+) breast cancer is challenging; patients with ErbB2+ breast tumors have more aggressive disease and a poor prognosis. The increasing incidence of breast cancer in Asia and the limitations of existing treatments pose additional challenges. In this review, we summarize the preclinical and clinical evidence that indicates how lapatinib, a novel inhibitor that targets the human epidermal growth factor receptor (ErbB1) and ErbB2 may help clinicians address four particularly challenging issues in the management of ErbB2+ breast cancer. These issues are: (i) trastuzumab therapy failure, (ii) development of central nervous system metastases, (iii) minimizing toxicity and (iv) selecting the most appropriate partners (chemotherapy and non-chemotherapy) for combination therapy with lapatinib. Lapatinib, in combination with chemotherapeutic agents, such as capecitabine, provides clinical benefits to patients with ErbB2+ breast cancer, including patients who develop progressive disease on trastuzumab. Lapatinib, in combination with non-chemotherapeutic agents, such as letrozole, may also provide a chemotherapy-free treatment option for postmenopausal patients with estrogen receptor-positive/ErbB2+ metastatic breast cancer. Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer. Promising findings have also been reported for the use of lapatinib to prevent and treat central nervous system metastases. Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer.
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