RESUMEN
BACKGROUND: Recent data support the hypothesis that combining lapatinib and trastuzumab with taxane chemotherapy may offer added clinical benefit to patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). This study examined the safety of the triplet combination in first-line HER2-positive MBC. PATIENTS AND METHODS: Patients were enrolled into three sequential cohorts; the last two cohorts were added by protocol amendment following review of safety data from cohort 1. Patients in cohort 1 received lapatinib (1000 mg/day) plus paclitaxel (80 mg/m(2) per week, 3 of every 4 weeks); cohort 2 received lapatinib (1000 mg/day) plus paclitaxel (70 mg/m(2) per week, 3 of every 4 weeks); and cohort 3 received lapatinib (750 mg/day) plus paclitaxel (80 mg/m(2) per week, 3 of every 4 weeks). All received standard trastuzumab dosing. The primary objective was assessment of dose-limiting toxicities, safety, and tolerability of this combination. RESULTS: The most frequent adverse events (AEs) for all cohorts were diarrhea (89%), rash (79%), fatigue (73%), alopecia (63%), nausea (63%), and vomiting (40%). In cohorts 1 and 2, the incidence of grade 3 diarrhea was 62% and 50%, respectively; in cohort 3, the incidence was 25% (with prophylactic loperamide). Dehydration was the most frequent serious AE (10%). Across cohorts, overall response rate was 75%. CONCLUSIONS: The dose-limiting toxicity of paclitaxel, trastuzumab, and lapatinib in first-line HER2-positive MBC was diarrhea. Of the triplet combinations tested, the cohort receiving 750 mg/day dose of lapatinib had the lowest incidence of diarrhea; therefore, this dose should be used in further studies on the treatment of MBC.