Dual Kinase Inhibition in the Treatment of Breast Cancer: Initial Experience with the EGFR/ErbB-2 Inhibitor Lapatinib

Abstract

Learning Objectives: After completing this course, the reader will be able to: Identify the rationale for the development of dual ErbB receptor inhibitors. Describe safety data from early-phase clinical trials of the dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib. Describe evidence of biologic and clinical activity from early-phase clinical trials of the dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com Dual inhibition of ErbB-1 (EGFR) and ErbB-2 (HER-2) tyrosine kinases has been found to exert greater biologic effects in the inhibition of signaling pathways promoting cancer cell proliferation and survival than inhibition of either receptor alone. The novel dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib (GlaxoSmithKline; Research Triangle Park, NC) has been shown to inhibit tumor cell growth in vitro and in xenograft models for a variety of human tumors. Preliminary findings in a phase I study of lapatinib in patients with solid tumors indicate doses up to 1,800 mg per day are well tolerated. No grade 4 toxicities were observed and only two of 43 patients had grade 3 toxicity (diarrhea). Clinical activity of lapatinib was observed in these patients; nine patients with a variety of tumors remained on study for ≥4 months, one with a complete response (head and neck cancer). In a phase IB study in pretreated metastatic cancer patients with disease that could be biopsied, grade 1 or 2 diarrhea and rash were the most common adverse events. Three patients with breast cancer refractory to trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) had partial responses and 12 patients with a variety of tumors had stable disease. Assessment of biologic correlates in these patients indicates that increased tumor cell apoptosis on the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay correlates with clinical response. Lapatinib currently is being evaluated in phase II and phase III trials in patients with metastatic breast cancer.