Optimally tolerated dose of lapatinib in combinationwith docetaxel plus trastuzumab in first-line treatmentof HER2-positive metastatic breast cancer

Abstract

Background: This phase IB, open-label, dose-escalation study evaluated the safety, tolerability, and optimallytolerated regimen (OTR) of lapatinib in combination with docetaxel and trastuzumab in patients with previouslyuntreated stage IV metastatic breast cancer (MBC) tumors overexpressing human epidermal growth factor receptor 2(HER2).Patients and methods: Evaluated dose regimens included lapatinib (500-1500 mg/day), docetaxel (triweekly; 60-100 mg/m2), and trastuzumab (weekly; 2 mg/kg fixed dose); prophylactic granulocyte colony-stimulating factor wasincluded with regimens with ≥750 mg/day lapatinib. End points included OTR and safety/tolerability (primary), overallresponse rate (ORR), and pharmacokinetics (secondary).Results: None of the patients (N = 53) experienced dose-limiting toxic effects (DLTs) at the highest dose level; thus, theOTR of lapatinib with 100 mg/m2 docetaxel was not determined. Common adverse events included diarrhea, nausea,alopecia, fatigue, and rash; grade 3/4 (≥2 patients) were neutropenia, diarrhea, leukopenia, peripheral neuropathy, andrash. Seven patients had DLTs (cycle 1). In 45 patients with measurable disease confirmed by bone scan, investigatorassessedORR was 31%; without bone scan, confirmation was 64%; 8 patients without measurable disease wereevaluated as stable. Lapatinib/docetaxel plasma concentrations were positively associated with complete response.Conclusions: Lapatinib/docetaxel/trastuzumab is a feasible and well-tolerated treatment of untreated HER2-positivestage IV MBC. Two lapatinib/docetaxel OTR doses were recommended (1250 mg/75 mg/m2; 1000 mg/100 mg/m2). Clinical trial number: NCT00251433. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.