Originally published as JCO Early Release 10.1200/JCO.2008.16.2578 on October 27 2008

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Phase III, Double-Blind, Randomized Study Comparing Lapatinib Plus Paclitaxel With Placebo Plus Paclitaxel As First-Line Treatment for Metastatic Breast Cancer

Angelo Di Leo, Henry L. Gomez, Zeba Aziz, Zanete Zvirbule, Jose Bines, Michael C. Arbushites, Stephanie F. Guerrera, Maria Koehler, Cristina Oliva, Steven H. Stein, Lisa S. Williams, Judy Dering, Richard S. Finn, Michael F. Press

From the ^"Sandro Pitigliani" Medical Oncology Unit, Prato, Italy; Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Allama Iqbal Medical College, Lahore, Pakistan; Riga Eastern University Hospital Latvian Oncology Centre, Rga, Latvia; National Cancer Institute, Rio De Janeiro, Brazil; Medicine Development Center Oncology, GlaxoSmithKline, Collegeville, PA; Geffen School of Medicine at University of California, Los Angeles; and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA

Corresponding author: Angelo Di Leo, MD, "Sandro Pitigliani" Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy 59100; e-mail: adileo{at}usl4.toscana.it

Purpose Lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER-2/ErbB2), is effective against HER-2–positive locally advanced or metastatic breast cancer (MBC). This phase III trial evaluated the efficacy of lapatinib in HER-2–negative and HER-2–uncharacterized MBC.

Patients and Methods Women with MBC were randomly assigned to first-line therapy with paclitaxel 175 mg/m² every 3 weeks plus lapatinib 1,500 mg/d or placebo. A preplanned retrospective evaluation of HER-2 status was performed using fluorescence in situ hybridization and immunohistochemistry. The primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), clinical benefit rate (CBR), event-free survival (EFS), and overall survival (OS).

Results In the intent-to-treat population (n = 579), there were no significant differences in TTP, EFS, or OS between treatment arms, although differences in ORR and CBR were noted. In 86 HER-2–positive patients (15%), treatment with paclitaxel-lapatinib resulted in statistically significant improvements in TTP, EFS, ORR, and CBR compared with paclitaxel-placebo. No differences between treatment groups were observed for any end point in HER-2–negative patients. The most common adverse events were alopecia, rash, and diarrhea. The incidence of diarrhea and rash was significantly higher in the paclitaxel-lapatinib arm. The rate of cardiac events was low, and no difference was observed between treatment arms.

Conclusion Patients with HER-2–negative or HER-2–untested MBC did not benefit from the addition of lapatinib to paclitaxel. However, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in HER-2–positive patients. Prospective evaluation of the efficacy and safety of this combination is ongoing in early and metastatic HER-2–positive breast cancer patients.

published online ahead of print at www.jco.org on October 27, 2008.

Supported by GlaxoSmithKline. R.S.F. is a recipient of a National Institutes of Health Loan Repayment Program award.

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

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

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