Abstract
Lapatinib plus capecitabine is active in brain metastases from HER2-positive breast cancer.
Major finding: Lapatinib plus capecitabine is active in brain metastases from HER2-positive breast cancer.
Clinical relevance: Patients with brain metastases are often excluded from breast cancer clinical trials.
Impact: Combined use of lapatinib and capecitabine could delay the need for whole-brain radiotherapy.
Trastuzumab treatment has been associated with an increased risk of brain metastases in patients with HER2-positive breast cancer, although it is unclear whether this finding is attributable to the inability of trastuzumab to cross the blood-brain barrier, improved diagnostic methods, or the increased life expectancy of trastuzumab-treated patients. Whole-brain radiotherapy (WBRT) is the standard of care for patients with metastatic breast cancer involving multiple central nervous system (CNS) lesions, but this approach has a poor clinical outcome and causes neurocognitive toxicity. Lapatinib, a small-molecule HER2 inhibitor presumed to be capable of crossing the blood-brain barrier, has been approved in combination with the chemotherapeutic agent capecitabine for trastuzumab-refractory metastatic HER2-positive breast cancers. An unplanned post-hoc analysis of a phase III trial comparing capecitabine and lapatinib with capecitabine alone suggested that brain metastases were less frequent in the combination group. These findings prompted Bachelot and colleagues to conduct a single-arm phase II, open-label, multicenter trial of lapatinib plus capecitabine in patients with untreated brain metastases from HER2-positive breast cancer in which the trial's primary endpoint was an objective CNS response. This study design was particularly notable because clinical trials of targeted agents in breast cancer routinely exclude patients with known brain metastases. Of 44 evaluable patients, 29 (66%) experienced a 50% or greater volumetric reduction in CNS lesions, and the median time to WBRT was 8.3 months. Half of the patients had at least one grade 3 or 4 adverse event, but no treatment-related deaths were reported. Although drug concentration in cerebrospinal fluid was not assessed to formally determine whether lapatinib or capecitabine penetrates the blood-brain barrier, these results suggest that the combined use of lapatinib and capecitabine could delay WBRT and be an active first-line treatment for brain metastases arising from HER2-positive metastatic breast cancer.
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