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FDA Approves Tykerb (lapatinib tablets) for Advanced Metastatic Breast Cancer Patients

On March 13, 2007, the Food and Drug Administration (FDA) granted approval to lapatinib tablets (Tykerb, GlaxoSmithKline) for use in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2) and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.

The efficacy and safety of Tykerb in combination with capecitabine in breast cancer were evaluated in a randomized trial. Patients eligible for enrollment had HER2 (ErbB2) over-expressing tumors (95% were ErbB2 IHC 3+ or IHC 2+ with FISH confirmation), had locally advanced or metastatic breast cancer, and had disease progression after treatment that included taxanes, anthracyclines, and trastuzumab. Patients were randomized to receive either Tykerb 1,250 mg once daily on days 1-21 plus capecitabine 2,000 mg/m2/day on days 1-14 every 21 days, or to receive capecitabine alone at 2,500 mg/m2/day on days 1-14 every 21 days.

The primary endpoint of time-to-progression (TTP) was defined as time from randomization to tumor progression or death related to breast cancer. After the results of a pre-specified interim analysis of 324 patients were made available, further enrollment was discontinued after enrolling 399 patients of a planned 528 patients.

An updated efficacy analysis (399 patients) occurring 4 months after the interim analysis includes both independent and investigator assessments. The median TTP based on the independent review assessment was 27.1 vs 18.6 weeks (HR 0.57, p=0.00013) for the Tykerb combination and capecitabine alone arms, respectively. The median TTP based on the investigator assessment was 23.9 vs 18.3 weeks (HR 0.72, p=0.00762) for the Tykerb combination and capecitabine alone arms, respectively. The response rates were 23.7% vs 13.9% (independent assessment) and 31.8% vs 17.4% (investigator assessment) for the Tykerb combination and the capecitabine alone arms, respectively. At the time of this update, survival data was not mature.

Although the toxicities observed in the Tykerb combination arm were similar to those in the capecitabine alone arm, an increased incidence of diarrhea and rash was noted with the combination. The most frequent adverse reactions during treatment with combination were diarrhea (65%), palmar-plantar erythrodysesthesia (PPE, 53%), nausea (44%), rash (28%), vomiting (26%), and fatigue (23%). Grade 3 or 4 adverse events that occurred with a frequency greater than 5% in patients on the combination arm were diarrhea (13%) and PPE (12%). A 2% incidence of generally reversible decreased left ventricular function in the combination arm was noted. QT prolongation has been observed with Tykerb use. Torsade de Pointes has not been reported.

The recommended dose of Tykerb is 1,250 mg (5 tablets) administered orally once daily for 21 days in combination with capecitabine 2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on days 1-14 in a 21 day cycle. Tykerb should be taken at least one hour before or one hour after meals. Capecitabine should be taken with food or within 30 minutes after food. Tykerb should be taken once daily; dividing the daily dose is not recommended. Treatment should be continued until disease progression or unacceptable toxicity occurs.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available in Drugs@FDA


Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting Program via an online form, by faxing (1-800-FDA-0178) or mailing the postage-paid Form 3500 available at MedWatch, or by telephone (1-800-FDA-1088).

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Created March 16, 2007


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