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Phase II Trial of Lapatinib for Brain Metastases in Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

Nancy U. Lin, Lisa A. Carey, Minetta C. Liu, Jerry Younger, Steven E. Come, Matthew Ewend, Gordon J. Harris, Elizabeth Bullitt, Annick D. Van den Abbeele, John W. Henson, Xiaochun Li, Rebecca Gelman, Harold J. Burstein, Elizabeth Kasparian, David G. Kirsch, Ann Crawford, Fred Hochberg, Eric P. Winer

From the Dana-Farber Cancer Institute; Massachusetts General Hospital; Beth Israel Deaconess Medical Center, Boston, MA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC; and the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC

Corresponding author: Eric P. Winer, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: ewiner{at}partners.org

Purpose One third of women with advanced human epidermal growth factor receptor 2 (HER-2)–positive breast cancer develop brain metastases; a subset progress in the CNS despite standard approaches. Medical therapies for refractory brain metastases are neither well-studied nor established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth factor receptor (EGFR) and HER-2, in patients with HER-2–positive brain metastases.

Patients and Methods Patients had HER-2–positive breast cancer, progressive brain metastases, prior trastuzumab treatment, and at least one measurable metastatic brain lesion. Patients received lapatinib 750 mg orally twice a day. Tumor response was assessed by magnetic resonance imaging every 8 weeks. The primary end point was objective response (complete response [CR] plus partial response [PR]) in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included objective response in non-CNS sites, time to progression, overall survival, and toxicity.

Results Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%) were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified additional patients with some degree of volumetric reduction in brain tumor burden. The most common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%).

Conclusion The study did not meet the predefined criteria for antitumor activity in highly refractory patients with HER-2–positive brain metastases. Because of the volumetric changes observed in our exploratory analysis, further studies are underway utilizing volumetric changes as a primary end point.

Supported by an AVON Partners for Progress Award CA89393-AV-55P, National Cancer Institute Specialized Program in Research Excellence in Breast Cancer at Dana-Farber Cancer Institute/Harvard Cancer Center (DF/HCC; Grant No. CA89393) and the University of North Carolina (Grant No. CA58223); American Society of Clinical Oncology Young Investigator Award (N.U.L.); Breast Cancer Research Foundation (E.P.W. and N.U.L.); Leaf Fund (D.G.K.); National Institutes of Health (NIH) Grant No. R01EB000219-NIBIB (E.B.); Tumor Imaging Metrics Core (G.J.H and A.V.D.A.) under DF/HCC National Cancer Institute Comprehensive Cancer Cenger Grant No. P30 CA006516; and NIH Grant No. M01RR00046 (L.A.C).

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006.

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

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