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Cancer Drug Information

  • Reviewed: 01/14/2011

FDA Approval for Lapatinib Ditosylate

Brand name: Tykerb®

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

Approved for hormone-positive and HER2-positive advanced breast cancer

On January 29, 2010, the U.S. Food and Drug Administration (FDA) granted accelerated approval to lapatinib tablets (Tykerb®, made by GlaxoSmithKline) for use in combination with letrozole (Femara®, made by Novartis Pharmaceuticals Corp.) for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor and for whom hormonal therapy is indicated. Lapatinib, in combination with an aromatase inhibitor, has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer. The approval was based on a clinically meaningful increase in progression-free survival (PFS) observed in a single trial, known as EGF30008 (see the trial's protocol summary).

As a condition of accelerated approval, subsequent randomized trials are required to verify and describe the clinical benefit of lapatinib in patients with metastatic breast cancer who have received prior treatment with trastuzumab.

EGF30008 was a multinational randomized placebo-controlled trial of lapatinib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive metastatic breast cancer who had not received prior therapy for metastatic disease. Patients were randomly assigned to receive lapatinib (1,500 mg once daily) plus letrozole (2.5 mg once daily) or to receive placebo plus letrozole (2.5 mg once daily). The 1286 patients in the study included 219 patients (17 percent) who were HER2-positive, 952 (74 percent) patients who were HER2-negative, and 115 (9 percent) patients who did not have their HER2-receptor status confirmed.

Accelerated approval was based on the results from the group of postmenopausal women with metastatic breast cancer that overexpressed the HER2 receptor. The primary efficacy endpoint was PFS, defined as the time interval between the randomization date and the date of either first documented disease progression or death due to any cause. The lapatinib plus letrozole combination had a median PFS of 35.4 weeks, compared to 13.0 weeks for the placebo plus letrozole arm (HR = 0.71, p = 0.019). The overall survival data are not mature at this time.

Safety data was evaluated in 1278 postmenopausal women with hormone receptor-positive metastatic breast cancer. The safety profile of lapatinib in this trial population was consistent with previous safety data. The most common adverse reactions (at least 10 percent) in the lapatinib plus letrozole arm were diarrhea, rash, nausea, and fatigue. Among patients receiving lapatinib, elevated liver enzymes were reported in 53 percent of patients and elevated bilirubin was reported in 22 percent of the patients. Among 654 patients who received lapatinib plus letrozole, 26 patients experienced Grade 1 or 2 decreases in left ventricular ejection fraction, and 6 patients experienced Grade 3 or 4 decreases in left ventricular ejection fraction.

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Approved for HER2-overexpressing breast cancer

On March 13, 2007, the U. S. Food and Drug Administration granted approval to lapatinib ditosylate tablets (Tykerb®, made by GlaxoSmithKline) for use in combination with capecitabine (Xeloda®) 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 (Herceptin®).

The efficacy and safety of lapatinib ditosylate in combination with capecitabine in breast cancer were evaluated in a randomized trial (see the trial's protocol summary). Patients eligible for enrollment had HER2 (ErbB2) over-expressing tumors (95 percent 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 randomly assigned to receive either lapatinib ditosylate 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 four 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 lapatinib ditosylate 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 lapatinib ditosylate combination and capecitabine alone arms, respectively. The response rates were 23.7 percent vs. 13.9 percent (independent assessment) and 31.8 percent vs. 17.4 percent (investigator assessment) for the lapatinib ditosylate combination and the capecitabine-alone arms, respectively. At the time of this update, survival data was not mature.

Although the toxicities observed in the lapatinib ditosylate 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 percent), palmar-plantar erythrodysesthesia (PPE, 53 percent), nausea (44 percent), rash (28 percent), vomiting (26 percent), and fatigue (23 percent).

Grade 3 or 4 adverse events that occurred with a frequency greater than 5 percent in patients on the combination arm were diarrhea (13 percent) and PPE (12 percent). A 2 percent incidence of generally reversible decreased left ventricular function in the combination arm was noted. QT prolongation has been observed with lapatinib ditosylate use. Torsade de Pointes has not been reported.

The recommended dose of lapatinib ditosylate is 1,250 mg (five tablets) administered orally once daily for 21 days in combination with capecitabine 2,000 mg/m2/day (administered orally in two doses approximately 12 hours apart) on days 1-14 in a 21-day cycle. Lapatinib ditosylate 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. Lapatinib ditosylate should be taken once daily; dividing the daily dose is not recommended. Treatment should be continued until disease progression or unacceptable toxicity occurs.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.

 

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.