Women with breast cancer that overexpresses human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) are at greater risk for disease progression and death than women whose tumors do not overexpress HER2.  Therapeutic strategies have been developed to block HER2 signaling pathways in order to improve the treatment of this cancer. Trastuzumab (Herceptin, Genentech), a recombinant, humanized, monoclonal antibody that binds to the extracellular domain of the HER2 protein, is a key component in the treatment of metastatic and early-stage HER2-positive breast cancer.

Metastatic breast cancer eventually develops resistance to trastuzumab,  and in some women, the cancer recurs after adjuvant therapy. For these reasons, there is a need for alternatives to block HER2 signaling. Lapatinib (Tykerb, GlaxoSmithKline) is an orally active small molecule that inhibits the tyrosine kinases of HER2 and epidermal growth factor receptor type 1 (EGFR). In preclinical studies, lapatinib was not cross-resistant with trastuzumab.  The clinical activity of lapatinib in combination with capecitabine (Xeloda)  has been shown in women with HER2-positive breast cancer that progressed while they were receiving trastuzumab.

Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients.

Methods Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions.

Results The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events.

Conclusions Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.