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

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Abstract
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. Cardiac assessments included left ventricular ejection fraction, and 12-lead electrocardiogram at week 4, 8 and then every 8 weeks. Results: 48 pts were treated (750 mg -3; 1000 mg - 32 expanded cohort of 10 + 22 PK pts; 1250 mg - 10 expanded cohort, 1500 mg - 3). Median age was 54 years (28 - 81). Total of 152 treatment periods (4 weeks = 1 treatment period) were completed: median 2. Twenty-seven pts were evaluable for response: (1 CR, duration 8 mo.; 5 PR, duration 2 - 7 months; 10 SD, duration 1 - 5 mo. and 11 PD). Conclusions: 1000 mg lapatinib + standard dose trastuzumab was chosen as the optimally tolerated regimen due to a favorable tolerability profile with chronic dosing and evidence of clinical activity. The combination demonstrated encouraging clinical activity in this heavily pretreated population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline

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