Abstract
Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as >or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20% volumetric reduction in their CNS lesions. This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.
Highlights
Brain metastases develop in one third of patients with advanced HER2+ breast cancer
This study enrolled more than 240 patients with progressive HER2+ brain metastases after cranial radiotherapy and trastuzumab.To our knowledge, it is the largest prospective study conducted to date evaluating systemic therapy for patients with brain metastases from breast cancer, which underscores the feasibility of conducting medical oncology treatment trials in this population
Multicenter study, 6% of patients experienced a central nervous system (CNS) objective response with single-agent lapatinib according to stringent composite criteria, including central radiology review
Summary
Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Experimental Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy.The primary end point was CNS objective response, defined as z50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a z20% volumetric reduction in their CNS lesions. Additional responses were documented in patients who joined an optional extension phase of the study and who were treated with lapatinib plus capecitabine after progression on lapatinib alone. Based on these data, further studies of targeted therapy for brain metastases are warranted and ongoing
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