Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings.
Vol 23, No 16S (June 1 Supplement), 2005: 559
© 2005 American Society of Clinical Oncology

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Abstract

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

Indiana Univ Cancer Ctr, Indianapolis, IN; Sarah Cannon Research Institute, Nashville, TN; UCLA Ctr for the Health Sciences, Los Angeles, CA; Ireland Cancer Ctr, Cleveland, OH; GlaxoSmithKline, Durham, NC

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

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Abstract presentation from the 2005 ASCO Annual Meeting