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Originally published as JCO Early Release 10.1200/JCO.2005.12.157 on January 31 2005

Journal of Clinical Oncology, Vol 23, No 11 (April 10), 2005: pp. 2502-2512
© 2005 American Society of Clinical Oncology.
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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

Neil L. Spector, Wenle Xia, Howard Burris, III, Herbert Hurwitz, E. Claire Dees, Afshin Dowlati, Bert O'Neil, Beth Overmoyer, Paul K. Marcom, Kimberly L. Blackwell, Deborah A. Smith, Kevin M. Koch, Andrew Stead, Steven Mangum, Matthew J. Ellis, Leihua Liu, Albert K. Man, Troy M. Bremer, Jennifer Harris, Sarah Bacus

From the Department of Discovery Medicine and Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park; Division of Hematology-Oncology, Duke University Medical Center, Durham; Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC; Tennessee Oncology Associates, Sarah Cannon Cancer Center, Nashville, TN; Division of Hematology-Oncology, Case Western Reserve Medical School, Cleveland, OH; Prediction Sciences, San Diego, CA; Quantitative Diagnostics Laboratory, Westmont, IL

Address reprint requests to Neil L. Spector, MD, Discovery Medicine and Clinical Pharmacology, GlaxoSmithKline, Five Moore Dr, Research Triangle Park, NC 27709-3398; e-mail: Neil.L.Spector{at}gsk.com.

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 preliminary evidence of biologic and clinical activity in ErbB1 and/or ErbB2-overexpressing tumors. However, the limited sample size of this study and the variability of the biologic endpoints suggest that further work is needed to prioritize biomarkers for disease-directed studies, and underscores the need for improved trial design strategies in early clinical studies of targeted agents.

Results from this study were presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, June 5-8, 2004.

Funding for this study was provided by GlaxoSmithKline.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


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