Originally published as JCO Early Release 10.1200/JCO.2007.13.5202 on May 19 2008

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Phase I Dose Escalation and Pharmacokinetic Study of Lapatinib in Combination With Trastuzumab in Patients With Advanced ErbB2-Positive Breast Cancer

Anna Maria Storniolo, Mark D. Pegram, Beth Overmoyer, Paula Silverman, Nancy W. Peacock, Suzanne F. Jones, Jill Loftiss, Nikita Arya, Kevin M. Koch, Elaine Paul, Lini Pandite, Ronald A. Fleming, Peter F. Lebowitz, Peter T.C. Ho, Howard A. Burris, III

From the Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Sarah Cannon Research Institute, Nashville, TN; UCLA Center for the Health Sciences, Los Angeles, CA; Northwestern CT Oncology/Hematology Associates, Torrington, CT; Ireland Cancer Center, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH; and GlaxoSmithKline, Research Triangle Park, NC

Corresponding author: Anna Maria Storniolo, MD, Indiana University Melvin and Bren Simon Cancer Center, 535 Barnhill Dr, Room 473, Indianapolis, IN 46202; e-mail: astornio{at}iupui.edu

Purpose The combination of lapatinib and trastuzumab has been observed to have a synergistic, antiproliferative effect against ErbB2-positive breast cancer cells in vitro. This phase I study assessed the safety, clinical feasibility, optimally tolerated regimen (OTR), pharmacokinetics (PK), and preliminary clinical activity of this combination in patients with ErbB2-positive advanced breast cancer.

Patients and Methods Cohorts of three patients with ErbB2-positive advanced breast cancer were treated with escalating doses of lapatinib (750 to 1,500 mg) administered once daily (continuous) in combination with trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) to determine the OTR. Once the OTR was determined, additional patients were enrolled to provide the PK profile of both agents alone and in combination.

Results A total of 54 patients were treated: 27 in the dose-escalation group and 27 in the PK group. Overall, adverse events were mild to moderate in severity, with no drug-related grade 4 events. The most frequent drug-related grade 3 events included diarrhea (17%), fatigue (11%), and rash (6%). The OTR was 1,000 mg lapatinib with standard weekly trastuzumab. One patient had a complete response and seven patients had partial responses. The PK parameters (maximum concentration in plasma and area under the curve) of lapatinib and trastuzumab in combination were not significantly different than when either was administered alone.

Conclusion The OTR of the lapatinib/trastuzumab combination was lapatinib 1,000 mg per day with standard weekly trastuzumab. At these doses, the regimen was well tolerated and clinically active in this heavily pretreated ErbB2-positive breast cancer population.

published online ahead of print at www.jco.org on May 19, 2008.

Supported by a grant from GlaxoSmithKline.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005; European Cancer Organization 13 Meeting, Paris, France, October 30 to November 3, 2005; and the 28th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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