Lapatinib for HER2-Positive Breast Cancer Patients

Summary and Comment |
January 22, 2007

Lapatinib for HER2-Positive Breast Cancer Patients

  1. William J. Gradishar, MD

Lapatinib enhances the effects of chemotherapy after disease progression with trastuzumab and does not significantly increase toxicity.

  1. William J. Gradishar, MD

The epidermal growth factor receptor HER2 is overexpressed in 20% to 25% of all breast cancers. Trastuzumab (Herceptin), a humanized monoclonal antibody that targets the extracellular domain of HER2, has significantly improved outcomes among patients with HER2-positive early-stage breast cancer and advanced disease. Lapatinib is a new orally administered, small-molecule tyrosine kinase inhibitor of HER1 and HER2 that has antitumor activity when used as a single agent in patients with HER2-positive metastatic breast cancer, including inflammatory breast cancer.

Researchers conducted an industry-sponsored, international, randomized, open-label trial in which 324 patients with HER2-positive metastatic breast cancer (that had progressed during treatment with an anthracycline, a taxane, and trastuzumab) received either the FDA-approved dose of capecitabine (Xeloda; 2500 mg/m2 for 14 of 21 days) or a combination regimen of capecitabine (2000 mg/m2 for 14 of 21 days) plus lapatinib (Tykerb; 1250 mg/day continuously). A prespecified interim analysis showed that patients who received the combination had a longer median time to disease progression than did those who received capecitabine alone (8.4 vs. 4.4 months; hazard ratio, 0.49; 95% confidence interval, 0.34–0.71). The response rate with the combination was somewhat higher than the rate with capecitabine alone (22% vs. 14%; P=0.09). Adverse events (including cardiac events) were similar between the groups, with only modest increases in grade I/II diarrhea, dyspepsia, and rash among those who received lapatinib.

Comment

In a population of patients who developed progressive disease following treatment with trastuzumab, the clinical benefit observed when lapatinib was added to capecitabine supports the hypothesis that lapatinib’s mechanism of action is distinct from trastuzumab’s. In clinical practice, patients whose disease progresses while they are receiving chemotherapy plus trastuzumab often continue receiving trastuzumab but start a new chemotherapy regimen. Because clinical trials that were designed to assess this practice failed to accrue enough patients, the validity of this course of action probably will never be determined. Lapatinib clearly enhances the effects of chemotherapy following disease progression with trastuzumab and does not significantly increase toxicity. Cardiac toxicity also seems to be less common with lapatinib treatment than with trastuzumab — an observation with implications for adjuvant-therapy trials designed to define relative benefits of lapatinib and trastuzumab in early-stage breast cancer patients. Lapatinib also appears to cross the blood-brain barrier. Some groups have suggested that fewer brain metastases develop during lapatinib therapy and that existing brain metastases respond to lapatinib treatment (Oncologist 2006; 11:1047). Additional data will be required to support these claims.

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