Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER 2-Positive Breast Cancer

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 az20%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 Cancer Therapy: Clinical Authors’Affiliations: Dana-Farber Cancer Institute, Boston Massachusetts, Institut Curie, Paris, France, Rocky Mountain Cancer Centers and U.S. Oncology, Denver, Colorado, Institut Jules Bordet, Brussels, Belgium, Metropolitan Hospital, Athens, Greece, Klinikum der Universita« t Mu« nchen, Munich, Germany, Institut Claudius Regaud, Toulouse, France, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, Private Medical University Hospital Salzburg, Salzburg, Austria, Hospital 12 De Octubre, Madrid, Spain, Klinikum der J.W. Goethe-Universitaet , Frankfurt, Germany, Azienda Opsedaliera di Perugia, Perugia, Italy, Christie Hospital NHS FoundationTrust, Manchester, United Kingdom, Sarah Cannon Cancer Center, Nashville, Tennessee, University of Pittsburgh, Magee Women’s Hospital, Pittsburgh, Pennsylvania, Baylor-Sammons Cancer Center,Texas Oncology, U.S. Oncology Research, Dallas,Texas, GlaxoSmithKline, Upper Providence, Pennsylvania, and GlaxoSmithKline, Stockley Park, United Kingdom Received 5/7/08; revised10/9/08; accepted10/10/08. Grant support: GlaxoSmithKline, Breast Cancer Research Foundation (N.U. Lin and E.P. Winer), and American Society of Clinical Oncology Young Investigator Award and Career Development Award (N.U. Lin). The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). This study was designed by both the academic investigators and employees of the sponsor. Data collection and analysis were supervised by an employee of the sponsor and reviewed along with the raw data by both academic investigators and employees of the sponsor. Interpretationof the datawasperformedby the academic investigators in conjunction with employees of the sponsor. The authors reviewed the results of the analyses, contributed to the writing of the manuscript, and were involved in the decision to submit the manuscript for publication. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL and at the 30th Annual San Antonio Breast Cancer Symposium, December13-16, 2007, San Antonio,TX. Requests for reprints: Eric P.Winer, Dana-Farber Cancer Institute, 44 Binney Street, Boston,MA02115.Phone:617-632-3800;Fax:617-632-1930;E-mail:ewiner@partners.org. F2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-1080 www.aacrjournals.org Clin Cancer Res 2009;15(4) February15, 2009 1452 Research. on May 3, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from radiosurgery, a substantial proportion of patients die of neurologic causes rather than of progressive extracranial disease (1). The development of effective systemic therapy for recurrent brain metastases remains a major challenge and an urgent medical need. Lapatinib is a small-molecule tyrosine kinase inhibitor that inhibits the epidermal growth factor receptor and HER2. In a BALB/c nude mouse model, lapatinib inhibits the colonization of a brain-seeking derivative of the human MDA-MB-231 (231BR) cell line overexpressing both epidermal growth factor receptor and HER2 (10). In mice with established brain metastases, treatment with lapatinib also results in a statistically significant decrease in phosphorylated HER2, suggesting that pharmacologically relevant levels are achieved in CNS metastatic lesions (10). Modest single-agent activity with lapatinib was observed in a pilot study of 39 women with progressive brain metastases from HER2+ breast cancer (11). Lapatinib combined with capecitabine increased the response rate and resulted in a statistically significant improvement in time to progression as compared with single-agent capecitabine in a phase III study of patients with refractory HER2+ metastatic breast cancer (12). In an exploratory analysis of this study, fewer CNS-progression events were observed in patients treated with lapatinib plus capecitabine compared with those treated with capecitabine alone. The current study, EGF105084, was conducted to evaluate the activity of lapatinib in patients with progressive brain metastases from HER2+ breast cancer following prior trastuzumab and cranial radiotherapy. After release of the results of the phase III capecitabine plus lapatinib trial described above, EGF105084 was amended to allow patients, whose disease progressed on single-agent lapatinib, the option to receive the combination of lapatinib plus capecitabine. Materials andMethods Patients. Patients were enrolled from 63 centers between December 2005 and January 2007 and assigned to one of two cohorts: cohort A— Eastern Cooperative Group performance status (PS) 0 to 1 and 1 or 2 prior trastuzumab regimens; cohort B—Eastern Cooperative Group PS 2 and/or >2 prior trastuzumab regimens. Patients were eligible if they had HER2+ breast cancer (defined as 3+ immunohistochemistry or evidence of gene amplification by fluorescence in situ hybridization) and unequivocal evidence of new and/or progressive brain metastases after completion of whole-brain radiotherapy or stereotactic radiosurgery. At least one brain lesion needed to be measurable (z10 mm on T1-weighted, gadolinium-enhanced magnetic resonance imaging). Prior treatment with trastuzumab was also required. Additional inclusion criteria included age, z18 years, life expectancy of z12 weeks, left ventricular ejection fraction within the institution’s reference range, and adequate hematologic, renal, and hepatic function. All radiotherapy, chemotherapy, and/or hormonal therapy had to be completed at least 2 weeks before protocol treatment. Concurrent administration of other antineoplastic agents, radiotherapy, or inducers or inhibitors of CYP3A4 were not permitted. Concomitant treatment with corticosteroids was permitted. Patients with leptomeningeal metastases as the only site of CNS involvement were excluded. The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, in accordance with the Declaration of Helsinki. The institutional review board for each participating institution approved the study protocol. All patients gave written informed consent. The trial was registered at the ClinicalTrials.gov web site (no. NCT00263588). Study design. This was an open-label, phase II study. The primary end point was CNS objective response. Secondary end points included safety and tolerability, neurologic signs and symptoms (NSS), progression-free survival (PFS), and overall survival. Administration of study treatment. The starting dose of single-agent lapatinib was 750 mg twice daily (b.i.d.). Dose delays of up to 2 weeks and two dose reductions, first to 1,500 mg once daily (q.d.) and second to 1,250 mg q.d., were allowed for treatment-related toxicities. When the study first opened, patients with extra-CNS progression but stable or responsive CNS disease were given the option of enrolling into the extension phase and to receive lapatinib in combination with other systemic therapy until disease progression or withdrawal. In June 2006, the study was later amended to allow patients with radiographically documented CNS progression the option to continue to receive lapatinib in combination with capecitabine. During the extension phase, capecitabine was administered at 1,000 mg/m b.i.d. for 14 days in each 21-day cycle in combination with lapatinib 1,250 mg q.d. One dose r