Study of the Biologic Effects of Lapatinib, a Reversible Inhibitor of ErbB1 and ErbB2 Tyrosine Kinases, on Tumor Growth and Survival Pathways in Patients With Advanced Malignancies

作者：Neil L. Spector, Wenle Xia, Howard A. Burris, Herbert I. Hurwitz, E. Claire Dees, Afshin Dowlati, Bert H. O’Neil, Beth A. Overmoyer, Paul Kelly Marcom, Kimberly Blackwell, Deborah Ann Smith, Kevin M. Koch, Andrew G. Stead, Steve Mangum, Matthew J. Ellis, Lei-Hua Liu, Albert K. Man, Troy M. Bremer, Jennifer L. Harris, Sarah S. Bacus · 发表于：Journal of Clinical Oncology · 年份：2005 · DOI：10.1200/jco.2005.12.157 · 被引用次数：367 · 研究领域：HER2/EGFR in Cancer Research、Lung Cancer Treatments and Mutations、Fibroblast Growth Factor Research

PURPOSE: This was a pilot study to assess the biologic effects of lapatinib on various tumor growth/survival pathways in patients with advanced ErbB1 and/or ErbB2-overexpressing solid malignancies. PATIENTS AND METHODS: Heavily pretreated patients with metastatic cancers overexpressing ErbB2 and/or expressing ErbB1 were randomly assigned to one of five dose cohorts of lapatinib (GW572016) administered orally once daily continuously. The biologic effects of lapatinib on tumor growth and survival pathways were assessed in tumor biopsies obtained before and after 21 days of therapy. Clinical response was determined at 8 weeks. RESULTS: Sequential tumor biopsies from 33 patients were examined. Partial responses occurred in four patients with breast cancer, and disease stabilization occurred in 11 others with various malignancies. Responders exhibited variable levels of inhibition of p-ErbB1, p-ErbB2, p-Erk1/2, p-Akt, cyclin D1, and transforming growth factor alpha. Even some nonresponders demonstrated varying degrees of biomarker inhibition. Increased tumor cell apoptosis (TUNEL) occurred in patients with evidence of tumor regression but not in nonresponders (progressive disease). Clinical response was associated with a pretreatment TUNEL score > 0 and increased pretreatment expression of ErbB2, p-ErbB2, Erk1/2, p-Erk1/2, insulin-like growth factor receptor-1, p70 S6 kinase, and transforming growth factor alpha compared with nonresponders. CONCLUSION: Lapatinib exhibited prelimin...