In March 2007, the FDA approved lapatinib (Tykerb), in combination with capecitabine (Xeloda), for the treatment of advanced (Stage IIIB) or metastatic (Stage IV) breast cancer. Lapatinib is indicated for patients whose tumors overexpress human epidermal receptor type 2 (HER2) and who have received previous therapy including an anthracycline, a taxane, and trastuzumab (Herceptin).1,2 Lapatinib is the first and only once-daily oral treatment option of its kind for this patient population. It offers additional convenience for patients because it is an oral therapy.1
Lapatinib is a dual tyrosine kinase inhibitor of both epidermal growth factor receptors and HER2 receptors. Some breast tumors overexpress HER2.3 HER2 is involved in the regulation of tumor cell growth, proliferation, metastasis, and transformation.3 Lapatinib reversibly binds to the cytoplasmic adenosine triphosphate-binding site of tyrosine kinase and causes inhibition of receptor phosphorylation.3,4 This action leads to the blockage of the downstream signaling pathway involved in cell proliferation, survival, and invasion.3,4
Serum concentrations of lapatinib peak 4 hours after dosing. The drug is highly bound (>99%) to albumin and alpha-1 acid glycoprotein.4 It is metabolized primarily by CYP3A4 and CYP3A5, with minor involvement from CYP2C19 and CYP2C8.4 Dose adjustment of lapatinib is recommended when it is administered with strong CYP3A4 inducers or inhibitors.
The elimination half-life of lapatinib is 24 hours following repeated dosing, and steady-state concentrations are achieved in 6 to 7 days. Divided daily doses produce a nearly 2-fold higher steady-state area under the curve, when compared with once-daily administration.4 Systemic exposure also is increased by coadministration with food.4 Dose reductions should be considered for patients with severe hepatic impairment. Renal impairment is unlikely to affect the pharmacokinetics of lapatinib because <2% is eliminated by the kidneys.4
A phase 2, open-label, single-group, multicenter study enrolled patients with advanced or metastatic breast cancer who progressed while receiving trastuzumab-containing regimens.5 Patients began treatment at 1250 mg of lapatinib once daily, and a dose increase to 1500 mg was implemented based on the findings of a phase 1 study. The drug resulted in a 5% tumor partial response rate among the 78 patients. No single serious adverse event was reported by more than 1 participant except diarrhea and dehydration. No fatal serious adverse events were reported.5
The efficacy and safety of lapatinib in combination with capecitabine in breast cancer were evaluated in a phase 3, randomized, open-label, multicenter study.6 The study enrolled women with progressive, HER2-positive, locally advanced or metastatic breast cancer who had previously been treated with a minimum of an anthracycline, a taxane, and trastuzumab. The participants were randomized to receive lapatinib 1250 mg daily plus capecitabine 2000 mg/m2/day on days 1 to 14 every 21 days or capecitabine alone at a dose of 2500 mg/m2/day on days 1 to 14 every 21 days.6 The median time to progression for the capecitabine-plus-lapatinib combination therapy was 8.4 months, as compared with 4.4 months for capecitabine monotherapy.6 The results were so convincing that an independent committee decided to end the trial prematurely and offer patients in the capecitabine-only group the option to switch to the combination therapy.6
The recommended dose of lapatinib is 1250 mg (5 tablets) taken orally once daily on days 1 to 21 continuously, in combination with capecitabine 2000 mg/m2/day on days 1 to 14 in a repeating 21-day cycle. Lapatinib should be taken at least 1 hour before or after a meal.4
The drug has been associated with reports of decreases in left ventricular ejection fraction (LVEF). Caution should be taken if the drug is to be administered to patients with preexisting cardiac conditions. Continuous LVEF monitoring is recommended during treatment. In addition, lapatinib prolongs the QT interval in some patients.4 The most common adverse events with the lapatinib plus capecitabine are diarrhea, hand-foot syndrome, nausea, rash, vomiting, and fatigue.4