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.

Side Effects by Body System

Side Effects by Body System

General

All clinical trial data were from trials of lapatinib in combination with capecitabine.

To report suspected adverse reactions, contact GlaxoSmithKline at 1-888-825-5249 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Gastrointestinal

Gastrointestinal side effects including diarrhea (65%), nausea (44%), vomiting (26%), stomatitis (14%), and dyspepsia (11%) have been reported.

Diarrhea was the most common adverse reaction resulting in discontinuation of study medication.

Hematologic

Hematologic side effects have included laboratory abnormalities in hemoglobin (56%), neutrophils (22%), and platelets (18%).

Dermatologic

Dermatologic side effects including palmar plantar erythrodysesthesia (53%) (also called hand-foot syndrome or acral erythema), rash (28%), and dry skin (10%) have been reported.

Hepatic

Hepatic side effects have included laboratory abnormalities in AST (49%), total bilirubin (45%), and ALT (37%).

Cardiovascular

Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, left ventricular ejection fraction (LVEF) was monitored in clinical trials at approximately eight-week intervals. LVEF decreases were defined as signs or symptoms of deterioration in left ventricular cardiac function that are grade 3 (NCI CTCAE), or a 20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution's lower limit of normal. Among 198 patients who received lapatinib/capecitabine combination treatment, three experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTC 3.0).

The QT prolongation potential of lapatinib was assessed as part of an uncontrolled, open-label dose escalation study in advanced cancer patients. Eighty-one patients received daily doses of lapatinib ranging from 175 mg/day to 1800 mg/day. Serial ECGs were collected on day 1 and day 14 to evaluate the effect of lapatinib on QT intervals. Thirteen of the 81 subjects were found to have either QTcF (corrected QT by the Friedericia method) greater than 480 msec or an increase in QTcF greater than 60 msec by automated machine-read evaluation of ECG. Analysis of the data suggested a relationship between lapatinib concentration and the QTc interval.

Cardiovascular side effects including decreases in left ventricular ejection fraction and QT prolongation have been reported.

Other

Other side effects including mucosal inflammation (15%), pain in the extremity (12%), dyspnea (12%), back pain (11%), and insomnia (10%) have been reported.

Oncologic

Oncologic side effects including genotoxicity have been reported. An impurity in the drug product was genotoxic when tested alone in both in vitro and in vivo assays.

Respiratory

It is recommended that patients be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. Lapatinib should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis which are greater than or equal to grade 3 (NCI CTCAE).

Respiratory side effects have been reported including interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies

Side Effects of Lapatinib - for the Consumer

Lapatinib

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Lapatinib:

Back pain; diarrhea; dry skin; indigestion; mouth sores; nausea; redness and tingling of the hands and feet; tiredness; trouble sleeping; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Lapatinib:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); dark urine; fast or irregular heartbeat; loss of appetite; pale stools; severe or persistent cough; severe pain, redness, or swelling of hands or feet; severe stomach pain or diarrhea; severe tiredness or weakness; shortness of breath; unusual bruising or bleeding; unusual itching; yellowing of the eyes or skin.