Lapatinib
Lapatinib, used in the form of lapatinib ditosylate is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2.
Status
In March 2007, the U.S. Food and Drug Administration approved lapatinib in combination therapy for breast cancer patients already using capecitabine. In January 2010, Tykerb received accelerated approval for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor and for whom hormonal therapy is indicated.Pharmaceutical company GlaxoSmithKline markets the drug under the proprietary names Tykerb and Tyverb. The drug currently has approval for sale and clinical use in the US, Australia, Bahrain, Kuwait, Venezuela, Brazil, New Zealand, South Korea, Switzerland, Japan, Jordan, the European Union, Lebanon, India and Pakistan.
In August 2013, India's Intellectual Property Appellate Board revoked the patent for Glaxo's Tykerb citing its derivative status, while upholding at the same time the original patent granted for lapatinib.
The drug lapatinib ditosylate is classified as S/NM that is naturally derived or inspired substrate.
Mode of action
Biochemistry
Lapatinib inhibits the tyrosine kinase activity associated with two oncogenes, EGFR and HER2/neu. Over expression of HER2/neu can be responsible for certain types of high-risk breast cancers in women.Like sorafenib, lapatinib is a protein kinase inhibitor shown to decrease tumor-causing breast cancer stem cells.
Lapatinib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFR/HER2 protein kinase domain, preventing self-phosphorylation and subsequent activation of the signal mechanism.
Clinical application
Breast cancer
Lapatinib is used as a treatment for women's breast cancer in treatment-naïve, ER+/EGFR+/HER2+ breast cancer patients and in patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents, such as anthracycline, taxane-derived drugs, or trastuzumab.A 2006 GSK-supported randomized clinical trial on female breast cancer previously being treated with those agents demonstrated that administrating lapatinib in combination with capecitabine delayed the time of further cancer growth compared to regimens that use capecitabine alone. The study also reported that risk of disease progression was reduced by 51%, and that the combination therapy was not associated with increases in toxic side effects. The outcome of this study resulted in a somewhat complex and rather specific initial indication for lapatinib—use only in combination with capecitabine for HER2-positive breast cancer in women whose cancer have progressed following previous chemotherapy with anthracycline, taxanes and trastuzumab.
Early clinical trials have been performed suggesting that high dose intermittent lapatinib might have better efficacy with manageable toxicities in the treatment of HER2-overexpressing breast cancers.