can patients tolerate a larger dose and get more benefit giving tykerb intermittently

[Lani]

from ASCO Abstracts:

A phase I dose-escalation study of 5-day intermittent oral lapatinib therapy with biomarker analysis in patients with HER-2-overexpressing breast cancer.

Sub-category: Tyrosine Kinase Inhibitors

Category: Developmental Therapeutics: Molecular Therapeutics

Meeting: 2009 ASCO Annual Meeting


Citation: J Clin Oncol 27, 2009 (suppl; abstr e14530)

Abstract No: e14530




Author(s): A. J. Chien, G. Auerback, H. S. Rugo, M. Melisko, P. N. Munster, E. Khanafshar, K. G. Ordovas, E. F. Petricoin, K. M. Koch, M. M. Moasser; University of California, San Francisco, San Francisco, CA; George Mason University, Manassas, VA; GlaxoSmithKline, Research Triangle Park, NC


Abstract:

Background: Although current HER2 targeting agents have made measurable impact on the treatment of HER2overexpressing breast cancer, their effects have been modest. Recent evidence has redefined the target of interest as the HER2-HER3 signaling dimer and identified inherent signal buffering capacity that protects it against partial inhibitors of HER2 function. In preclinical studies, HER2 catalytic function and HER2-HER3 signaling can be suppressed, but this requires higher fully inactivating doses of HER- family tyrosine kinase inhibitors (TKIs) leading to apoptotic tumor cell death. We hypothesize that TKIs may be much more clinically effective if used at much higher and fully inactivating doses. Such high dosing may only be tolerable if given intermittently rather than continuously. Methods: To test this hypothesis clinically, we conducted a phase 1 dose-escalation study of a 5-day course of lapatinib (Lp) in women with advanced HER2-overexpressing breast cancer. Lp was administered on days 1-5 of a 14 day cycle. Starting Lp dose was 1750 mg/day and was escalated in cohorts of 3 until the maximum tolerated dose (MTD) was defined. The first cycle of Lp therapy was bracketed by tumor fine needle aspirations and serologic studies, performed at baseline and on day 5. Functional signaling pathway biomarker analysis was performed on tumor lysates using Reverse Phase Protein Microarrays to assay the inactivation of HER2-HER3 signaling. Plasma Lp concentration was assayed at all dose levels and cardiac function was rigorously monitored. Tumor core biopsies were performed on a subset of patients at the MTD to determine tissue Lp levels. Results: 17 patients have been treated to date. No grade 4 or serious adverse events (AEs) attributable to Lp have been noted. 1 patient experienced dose-limiting toxicity at dose level 6 (7000 mg/day) consisting of grade 3 diarrhea despite maximal anti-diarrheal support. There have been no cardiac AEs. The most common AEs include grade 2 diarrhea, nausea, vomiting, acne. Conclusions: The MTD and systemic exposure of Lp can be considerably increased throsugh intermittent dosing.