Lapatinib

Lapatinib (INN), used in the form of lapatinib ditosylate, (USAN) (Tykerb/Tyverb, GSK) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2 growth receptor pathway. It is used in combination therapy for HER2-positive breast cancer. It has been approved as front-line therapy in triple positive breast cancer and as an adjuvant therapy when patients have progressed on Herceptin.

Status
On March 13, 2007, the U.S. Food and Drug Administration (FDA) approved lapatinib in combination therapy for breast cancer patients already using capecitabine (Xeloda, Roche). In February 2010, Tykerb received accelerated approval as front-line therapy in triple positive breast cancer.

Pharmaceutical company GlaxoSmithKline (GSK) markets the drug under the propriety names Tykerb (mostly US) and Tyverb (mostly Europe). The drug currently has approval for sale and clinical use in the US, Australia, Bahrain, Israel, Kuwait, Venezuela, Brazil, New Zealand, South Korea, Switzerland, Japan, the European Union, India and Pakistan.

The drug lapatinib ditosylate is classified as S/NM (a synthetic compound showing competitive inhibition of the natural product) that is naturally derived or inspired substrate (Gordon M. Cragg, Paul G. Grothaus, and David J. Newman, Impact of Natural Products on Developing New Anti-Cancer Agents, Chem. Rev. 2009, 109, 3012–3043)

Biochemistry
Lapatinib inhibits the tyrosine kinase activity associated with two oncogenes, EGFR (epidermal growth factor receptor) and HER2/neu (Human EGFR type 2). 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 (see Receptor tyrosine kinase).

Breast cancer
Lapatinib is used as a treatment for women's breast cancer in treatment naive, ER+/EGFR+/HER2+ breast cancer patients (now often called "triple positive") 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 (Herceptin, Genentech).

A 2006 GSK-supported randomized clinical trial on female breast cancer previously being treated with those agents (anthracycline, a taxane and trastuzumab) demonstrated that administrating lapatinib in combination with capecitabine delayed the time of further cancer growth compared to regime 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.

In February 2010, based on recent studies, GSK issued a press release announcing the approval of lapatinib in first-line therapy in triple positive (hormone receptor, EGFR, HER2) breast cancer patients.

Adverse effects
Like many small molecule tyrosine kinase inhibitors, lapatinib is regarded as well tolerated. The most common side effects reported are diarrhea, fatigue, nausea and rashes. In ongoing studies the drug have shown to provoke toxic hepatitis, the toxicity is reversible when the treatment is stopped.