Optimally tolerated dose of lapatinib in combination with docetaxel plus trastuzumab in first-line treatment of HER2-positive metastatic breast cancer.

This phase IB, open-label, dose-escalation study evaluated the safety, tolerability, and optimally tolerated regimen (OTR) of lapatinib in combination with docetaxel and trastuzumab in patients with previously untreated stage IV metastatic breast cancer (MBC) tumors overexpressing human epidermal growth factor receptor 2 (HER2). Evaluated dose regimens included lapatinib (500-1500 mg/day), docetaxel (triweekly; 60-100 mg/m superset of), and trastuzumab (weekly; 2 mg/kg fixed dose); prophylactic granulocyte colony-stimulating factor was included with regimens with >= 750 mg/day lapatinib. End points included OTR and safety/tolerability (primary), overall response rate (ORR), and pharmacokinetics (secondary). None of the patients (N = 53) experienced dose-limiting toxic effects (DLTs) at the highest dose level; thus, the OTR of lapatinib with 100 mg/m(2) 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, and rash. Seven patients had DLTs (cycle 1). In 45 patients with measurable disease confirmed by bone scan, investigator-assessed ORR was 31%; without bone scan, confirmation was 64%; 8 patients without measurable disease were evaluated as stable. Lapatinib/docetaxel plasma concentrations were positively associated with complete response. Lapatinib/docetaxel/trastuzumab is a feasible and well-tolerated treatment of untreated HER2-positive stage IV MBC. Two lapatinib/docetaxel OTR doses were recommended (1250 mg/75 mg/m superset of; 1000 mg/100 mg/m superset of). NCT00251433.