Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer.

BACKGROUND: Lapatinib is an oral, small-molecule, reversible inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) tyrosine kinases. In March 2007, the US Food and Drug Administration approved lapatinib for use in combination with capecitabine in the treatment of advanced breast cancer overexpressing HER2 (HER2+).

OBJECTIVES: The goals of this review were to summarize the pharmacology, pharmacokinetics, efficacy, and tolerability of lapatinib, and to review studies of the approved and investigational uses of lapatinib.

METHODS: English-language reports of clinical trials of lapatinib in patients with cancer were identified through searches of PubMed/MEDLINE (1990-October 2009) and the American Society of Clinical Oncology abstracts database (2003-2008). Search terms included lapatinib, Tykerb, HER2, EGFR, breast cancer, dual tyrosine kinase inhibitor, and GW572016.

RESULTS: Lapatinib was well tolerated in a Phase II monotherapy trial in patients with advanced breast cancer; however, the response was minimal in HER2+ patients, and no HER2- patients achieved an objective tumor response. A Phase II trial of lapatinib monotherapy in 39 HER2+ patients with breast cancer and brain metastases yielded 1 partial response, although 15.4% of patients had stable disease for > or =16 weeks. In a Phase III trial comparing lapatinib plus capecitabine with capecitabine alone in HER2+ patients with advanced breast cancer that had progressed after trastuzumab therapy, the median time to progression was 8.4 months with combination therapy, compared with 4.4 months with capecitabine alone (P < 0.001). There were no significant differences between combination therapy and capecitabine alone in terms of the overall response rate (22% and 14%, respectively) or overall survival.

CONCLUSIONS: Lapatinib monotherapy was well tolerated, although the response rate was low in patients with advanced breast cancer. Lapatinib combined with capecitabine was associated with significant improvements in the time to progression and response rate compared with capecitabine alone. The available evidence suggests that clinical efficacy in breast cancer is limited to HER2+ disease.