Abstract
Targeting the human epidermal growth factor receptor type 2 (HER2) in breast cancer patients whose tumors overexpress HER2 has been clearly demonstrated to be effective in clinical trials with the monoclonal antibody trastuzumab. Not all patients, however, respond to trastuzumab therapy. Lapatinib is an oral receptor tyrosine kinase inhibitor that targets HER2 and the EGFR. Preclinical data reveal that lapatinib has activity in trastuzumab-resistant cell lines as well as synergistic activity with trastuzumab. In a pivotal phase III trial, a combination of lapatinib and capecitabine significantly decreased the risk of disease progression relative to capecitabine alone in women with HER2-positive advanced or metastatic breast cancer previously treated with anthracyclines, taxanes, and trastuzumab. Other trials are evaluating lapatinib in inflammatory breast cancer—for which encouraging data have been reported—in combination with hormone therapy, in combination with trastuzumab, and as an adjunct to adjuvant therapy for early-stage disease. Notably, lapatinib has not been associated with serious or symptomatic cardiotoxicity in clinical trials. It can cross the blood–brain barrier and might therefore have a role in preventing central-nervous-system progression. These features make lapatinib an ideal agent to evaluate more fully in HER2-positive metastatic and early-stage breast cancer.
Key Points
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Lapatinib is a novel small molecule inhibitor of EGFR and HER2 with proven efficacy in HER2-positive breast cancer
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Randomized phase III trial data showed that in women with advanced or metastatic breast cancer who received prior therapy with an anthracycline, a taxane, and trastuzumab in the metastatic setting, a combination of lapatinib plus capecitabine produced a 43% reduction in risk of disease progression compared with capecitabine alone
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The efficacy of lapatinib in trastuzumab-resistant disease might be due to its different mechanism of action; lapatinib targets the internal tyrosine kinase domain of both EGFR and HER2 whereas trastuzumab targets the extracellular domain of HER2
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These divergent mechanisms of action may also be responsible for the synergy demonstrated by the agents in preclinical studies
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Lapatinib seems to have a favorable cardiac tolerability profile; the incidence of cardiac events was relatively low in the pivotal trial, and all decreases in LVEF were reversible and asymptomatic
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Lapatinib is an ideal agent to study as an adjunct to adjuvant therapy for HER2-positive breast cancer because of its demonstrated activity in HER2-positive advanced breast cancer, its reasonable safety profile, ease of administration, and its ability to cross the blood–brain barrier
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David A Cameron is on the speaker's bureau for GlaxoSmithKline and Roche, and receives grant/research support from GlaxoSmithKline. Steven Stein receives stock and is an employee of GlaxoSmithKline.
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Cameron, D., Stein, S. Drug Insight: intracellular inhibitors of HER2—clinical development of lapatinib in breast cancer. Nat Rev Clin Oncol 5, 512–520 (2008). https://doi.org/10.1038/ncponc1156
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DOI: https://doi.org/10.1038/ncponc1156
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