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

被引:288
作者
Spector, NL
Xia, WL
Burris, H
Hurwitz, H
Dees, EC
Dowlati, A
O'Neil, B
Overmoyer, B
Marcom, PK
Blackwell, KL
Smith, DA
Koch, KM
Stead, A
Mangum, S
Ellis, MJ
Liu, LH
Man, AK
Bremer, TM
Harris, J
Bacus, S
机构
[1] GlaxoSmithKline, Dept Discovery Med & Clin Pharmacol, Res Triangle Pk, NC 27709 USA
[2] Duke Univ, Med Ctr, Div Hematol Oncol, Durham, NC USA
[3] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[4] Tennessee Oncol Associates, Sarah Cannon Canc Ctr, Nashville, TN USA
[5] Case Western Reserve Univ, Sch Med, Div Hematol Oncol, Cleveland, OH USA
[6] Predict Sci, San Diego, CA USA
[7] Quantitat Diagnost Lab, Westmont, IL USA
关键词
D O I
10.1200/JCO.2005.12.157
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 and disease stabilization occurred in 11 others with various four patients with breast cancer, malignancies. Responders exhibited variable levels of inhibition of p-ErbB1, p-ErbB2, p-Erk1/2, cyclin D1, and transforming growth factor alpha. Even some nonresponders demon-p-Akt, strated 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.
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页码:2502 / 2512
页数:11
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