A phase I, open-label study of lapatinib (GW572016) plus trastuzumab; a clinically active regimen

559 Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases leading to cell growth arrest and/or apoptosis in ErbB1 and ErbB2 dependent tumor cell lines and xenografts. Combining two ErbB2-targeted therapies, e.g., anti-ErbB2 antibody with small molecule tyrosine kinase inhibitor, that act at different sites of the receptor with distinct mechanisms of action, may enhance the efficacy of both drugs. Methods: Patients (pts) with metastatic breast cancer that overexpress the ErbB2 protein 2+ or 3+ were enrolled at escalating dose levels of lapatinib (750 - 1500 mg/d) in combination with weekly, standard dosing of trastuzumab (4 mg/kg loading dose followed by weekly 2 mg/kg infusions). Three pts were treated at each dose level, with expansion to 6 in the event of dose-limiting toxicity (DLT). Gr 1 - 3 diarrhea, anorexia, fatigue and rash were the common toxicities. Assessments of clinical response per RECIST criteria were performed every 8 weeks. ...