Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer

Abstract

Purpose: 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. 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. Results: 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 z20% 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 z20% volumetric reduction in their CNS lesions. Conclusions: 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.Brain metastases are diagnosed in approximately one third of women treated with trastuzumab for advanced HER2+ breast cancer (1 -5). The high incidence of HER2+ central nervous system (CNS) disease likely results from the inability of trastuzumab to cross the blood-brain barrier, in combination with a predilection of breast cancers that overexpress HER2 to metastasize to visceral sites, including the brain (6 -9). Despite initial therapy with whole-brain radiotherapy or stereotactic

Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases – the UK experience

“…More recently, there have been further reports of responses to lapatinib-based therapy. After an initial singlecentre phase II study of lapatinib monotherapy in patients with HER2-positive breast cancer who developed progressive CNS metastases after prior loco-regional therapy (Lin et al, 2008), a larger multicentre phase II study involving 242 patients reported a 6% CNS ORR to lapatinib alone (Lin et al, 2009). In an exploratory analysis, a further 21% patients experienced a X20% volumetric reduction in CNS lesions, with many having significant improvement in neurological symptoms.…”

“…A phase II study with single agent lapatinib 750 mg bid was undertaken in patients with HER2-positive CNS metastases who had shown progression in their brain after earlier whole-brain radiotherapy (WBRT), and clinical and radiological responses were observed (Lin et al, 2008). Subsequently, a larger multicentre phase 2 study involving 242 patients recently reported a 6% CNS objective response rate to lapatinib alone (defined as X50% volumetric reduction of CNS lesion(s) (Lin et al, 2009). In addition, a further 21% patients experienced a X20% volumetric reduction in their CNS lesions, of whom many had significant improvement in neurological symptoms.…”

Lapatinib, a TKI Dual Inhibitor of Her1 and Her2 Receptors: Review of the Literature

“…In an exploratory analysis, 21% of patients achieved at least a 20% reduction in the volume of 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 [43]. On the basis of the results of this study, prospective studies of lapatinib in combination with other chemotherapeutic agents, novel targeted agents and cranial radiotherapy are ongoing.…”

Role of targeted therapy in the treatment of HER-2-positive breast cancer brain metastases

“…При оценке частоты ответа метастазов в ГМ у ранее леченных больных лапатиниб в монотерапии показал эффективность в пределах от 2,6 до 6,0 % [31,32]. При добавлении капецитабина частота ответа воз-растала до 20-33 % [33][34][35][36].…”