Lapatinib Tablets (Tykerb®)
April 30, 2007 3 minutes read
Pharmacology Update
Lapatinib Tablets (Tykerb®)
By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.
The FDA has approved a new oral tyrosine kinase inhibitor with potent, reversible, selective dual inhibition of epidermal growth factor receptor (EGFR) and ErbB2 kinases. Lapatinib is approved for certain advanced or metastatic breast cancers and is marketed by GlaxoSmithKline as Tykerb®.
Indications
Lapatinib is indicated in combination with capecitabine for the treatment of advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, taxane, and trastuzumab.1
Dosage
The recommended dose is 1250 mg (5 x 250 mg tablets) taken once daily on Days 1-21 in combination with capecitabine (2,000 mg/m2/day in 2 doses 12 hours apart). Capecitabine is taken on days 1-14 of each 21-day cycle. Lapatinib should be taken one hour before or one hour after a meal. Capecitabine is taken with food or within 30 minutes after eating. Dose modification is needed in patients with severe hepatic dysfunction, occurrence of toxicity or concomitant administration of interacting drugs. Treatment should be continued until disease progression or development of toxicity.1
Lapatinib is available as 250 mg tablets.
Potential Advantages
The combination of lapatinib and capecitabine is more effective than capecitabine alone in the treatment of HER2 positive advance breast cancer that has progressed after regimes that include an anthracycline, taxane, and trastumumab.1,2
Potential Disadvantages
The most common adverse effects (> 20%) are diarrhea, palmar-plantar erythrodysesthesia and rash (hand-foot syndrome), nausea, rash, vomiting and fatigue. Other adverse effects include decreased left ventricular ejection fraction and prolongation of the QT interval.1,2 Lapatinib is metabolized by CYP 3A4, therefore strong enzyme inhibitors or inducer can significantly affect lapatinib levels. Inhibitors of P-glyco-protein can increase lapatinib levels. Lapatinib is not an irreversible inhibitor and does not permanently inhibit kinase activity.3
Comments
Lapatinib is an orally active, small molecule, with dual reversible inhibition of the ErbB1 (EGFR, HER1) and ErbB2 (HER2/neu) receptors. The efficacy of lapa- tinib was shown in patients who had overexpression of ErbB2, locally advanced or metastatic breast cancer and had progressed after prior treatment that included anthracyclines, taxanes, and trastuzumab.1,2 Ninety-seven percent had stage IV disease and 48% were estrogen or progesterone positive. Patients were randomized to receive capecitabine alone (2,500 mg/m2/day) on days 1-14 of a 21-day cycle (n = 201) or capecitabine (2000 mg/m2/day) plus lapatinib (1250 mg/day) (n = 198) continuously. The time to progression (primary endpoint) was 18.3 weeks compared to 23.9 weeks with a hazard ratio of 0.72 (95% CI, 0.56-0.92). The response rates were 17.4% and 31.4% respectively. With the exception of diarrhea, rash, dyspepsia, pain in extremity, back pain, and insomnia, adverse events were generally similar to capecitabine alone. The monthly wholesale cost for lapatinib is $2900.
Clinical Implications
A majority of breast cancer patients who have responded to trastuzumab tend to show disease progression within 1 year.4 Cancers that overexpress EGFR and HER2 have a worse outcome than those that overexpress either receptor alone.5 Lapatinib provides an orally active drug with dual inhibition of the EGRF and ErbB2 receptors. Targeting more than one receptor increases the chance of achieving target inhibition and clinical response.
References
1. Tykerb Product Information. GlaxoSmithKline. March 2007.
2. Geyer CE, et al. N Engl J Med. 2006;355:2733-2743.
3. Reid A, et al. Eur J Cancer. 2007;43(3):481-489.
4. Nahta R, et al. Mol Cancer Ther. 2007;6:667-764.
5. Xia W, et al. Clin Cancer Res. 1999;5(12):4164-4174.
The FDA has approved a new oral tyrosine kinase inhibitor with potent, reversible, selective dual inhibition of epidermal growth factor receptor (EGFR) and ErbB2 kinases.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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