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Regulatory Issues: FDA

FDA Drug Approval Summary: Lapatinib in Combination with Capecitabine for Previously Treated Metastatic Breast Cancer That Overexpresses HER-2

Division of Drug Oncology Products, Office of Oncology Drug Products, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

Key Words. FDA summary • Metastatic breast cancer • Multidrug resistant • Lapatinib • Capecitabine

Correspondence: Qin Ryan, M.D., Ph.D., Division of Oncology Drug Products, U.S. Food and Drug Administration, Silver Spring, Maryland 20993, USA. Telephone: 301-796-1449; Fax: 301-796-9845; e-mail: qin.ryan{at}fda.hhs.gov

Received January 23, 2008; accepted for publication August 6, 2008; first published online in THE ONCOLOGIST Express on October 10, 2008.

Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.

On March 13, 2007, the U.S. Food and Drug Administration approved lapatinib (Tykerb® tablets; GlaxoSmithKline, Philadelphia), an oral, small molecule, dual tyrosine kinase inhibitor of ErbB-2 and ErbB-1, for use in combination with capecitabine for the treatment of patients with human epidermal growth factor receptor (HER)-2–overexpressing metastatic breast cancer who had received prior therapy including an anthracycline, a taxane, and trastuzumab.

One multicenter, open-label, randomized trial was submitted. Eligible patients had stage IIIb or IV breast cancer, ErbB-2 overexpression (immunohistochemistry 3+ or 2+ with fluorescence in situ hybridization confirmation), measurable disease, a 0 or 1 Eastern Cooperative Oncology Group performance status score, a cardiac ejection fraction within the institutional normal range, and adequate laboratory function.

Patients received either lapatinib (1,250 mg once daily on days 1–21) plus capecitabine (1,000 mg/m² every 12 hours on days 1–14) every 21 days or capecitabine alone (1,250 mg/m² every 12 hours on days 1–14) every 21 days.

The primary endpoint was time to progression (TTP) determined by a blinded independent review panel. After TTP results of a prespecified interim analysis were made available, study enrollment was discontinued (399 patients enrolled).

The median TTP was 27.1 versus 18.6 weeks (hazard ratio, 0.57; p = .00013) favoring the lapatinib plus capecitabine arm. Response rates were 23.7% (lapatinib plus capecitabine) versus 13.9% (capecitabine alone). Survival data were not mature.

Although the toxicities observed in the lapatinib and capecitabine combination arm were generally similar to those in the capecitabine alone arm, a higher incidence of diarrhea and rash was noted with the combination. Grade 3 or 4 adverse reactions that occurred with a frequency of >5% in patients on the combination arm were diarrhea (13%) and palmar–plantar erythrodysesthesia (12%). There was a 2% incidence of reversible decreased left ventricular function in the combination arm.

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