Purpose: One third of women with advanced human epidermal growth factor receptor 2 (HER-2)–positive
breast cancer develop brain metastases; a subset progress in the CNS despite standard
approaches. Medical therapies for refractory brain metastases are neither well-studied nor
established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth
factor receptor (EGFR) and HER-2, in patients with HER-2–positive brain metastases.
Patients and Methods: Patients had HER-2–positive breast cancer, progressive brain metastases, prior trastuzumab
treatment, and at least one measurable metastatic brain lesion. Patients received lapatinib 750 mg
orally twice a day. Tumor response was assessed by magnetic resonance imaging every 8 weeks.
The primary end point was objective response (complete response [CR] plus partial response [PR])
in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points
included objective response in non-CNS sites, time to progression, overall survival, and toxicity.
Results: Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving
trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by
RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%)
were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified
additional patients with some degree of volumetric reduction in brain tumor burden. The most
common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%).
Conclusion: The study did not meet the predefined criteria for antitumor activity in highly refractory patients
with HER-2–positive brain metastases. Because of the volumetric changes observed in our
exploratory analysis, further studies are underway utilizing volumetric changes as a primary end
point