Lapatinib

Lapatinib (INN) or lapatinib ditosylate (USAN) (Tykerb/Tyverb, GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer.^[1] During development it was known as small molecule GW572016. Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer.^[2] Pharmacologically, lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals.

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).^[2][3]
Pharmaceutical company GlaxoSmithKline (GSK) markets the drug under the propriety names Tykerb (mostly US) and Tyverb (mostly Europe).^[4] The drug currently has approval for sale and clinical use in the US,^[3][4] Australia,^[3] Bahrain,^[3] Israel, Kuwait,^[3] Venezuela,^[3] Brazil,^[5] New Zealand,^[5][6] South Korea,^[5] Switzerland,^[4] and the European Union.^[4]

Mode of action

[edit] 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.^[3] Like Sorafenib, lapatinib is a protein kinase inhibitor shown to decrease tumor-causing breast cancer stem cells. ^[7] 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#Signal transduction).^[8]

Clinical application

Lapatinib is used as a treatment for women's breast cancer 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.^[9]
The results from studies like these leave lapatinib with its somewhat complex and rather specific indication—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.
A number of studies are underway attempting to evaluate the efficacy of lapatinib as a first-line therapy for HER2-positive cancer. As of 2007^[update] they have only progressed to Phase II trials.^[3]

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.^[3][10] In ongoing studies the drug have shown to provoke toxic hepatitis, the toxicity is reversible when the treatment is stopped.