men at definitive DFS analysis for 1-year intravenous trastuzumab treatment versus observation, and a fourthrandomized, open-label clinical trial with a total of 3222 patients (Study BCIRG006).
Studies NSABP B31 and NCCTG N9831
In Studies NSABP B31 and NCCTG N9831, breast tumor specimens were required to show HER2overexpression (3+ by IHC) or gene amplification (by FISH). HER2 testing was verified by a central laboratoryprior to randomization (Study NCCTG N9831) or was required to be performed at a reference laboratory(Study NSABP B31). Patients with a history of active cardiac disease based on symptoms, abnormalelectrocardiographic, radiologic, or left ventricular ejection fraction findings or uncontrolled hypertension(diastolic > 100 mm Hg or systolic > 200 mm Hg) were not eligible.Patients were randomized (1:1) to receive doxorubicin and cyclophosphamide followed by paclitaxel(AC→paclitaxel) alone or paclitaxel plus intravenous trastuzumab (AC→paclitaxel + intravenous trastuzumab). In both trials, patients received four 21-day cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2.
Paclitaxel was administered either weekly (80 mg/m2
) or every 3 weeks (175 mg/m2
) for a total of 12 weeks in
Study NSABP B31; paclitaxel was administered only by the weekly schedule in Study NCCTG N9831.
Intravenous trastuzumab was administered at 4 mg/kg on the day of initiation of paclitaxel and then at a dose of2 mg/kg weekly for a total of 52 weeks. Intravenous trastuzumab treatment was permanently discontinued inpatients who developed congestive heart failure, or persistent/recurrent LVEF decline [see Dosage and
Administration (2.3)]. Radiation therapy, if administered, was initiated after the completion of chemotherapy.
Patients with ER+ and/or PR+ tumors received hormonal therapy. The primary endpoint of the combinedefficacy analysis was DFS, defined as the time from randomization to recurrence, occurrence of contralateralbreast cancer, other second primary cancer, or death. The secondary endpoint was OS.
A total of 3752 patients were included in the joint efficacy analysis of the primary endpoint of DFS following amedian follow-up of 2.0 years in the AC→paclitaxel + intravenous trastuzumab arm. The pre-planned final OSanalysis from the joint analysis included 4063 patients and was performed when 707 deaths had occurred after a
median follow-up of 8.3 years in the AC→paclitaxel + intravenous trastuzumab arm. The data from both armsin Study NSABP B31 and two of the three study arms in Study NCCTG N9831 were pooled for efficacyanalyses. The patients included in the primary DFS analysis had a median age of 49 years (range, 22−80 years;
6% > 65 years), 84% were white, 7% black, 4% Hispanic, and 4% Asian/Pacific Islander. Diseasecharacteristics included 90% infiltrating ductal histology, 38% T1, 91% nodal involvement, 27% intermediateand 66% high grade pathology, and 53% ER+ and/or PR+ tumors. Similar demographic and baselinecharacteristics were reported for the efficacy eva luable population, after 8.3 years of median follow-up in theAC→paclitaxel + intravenous trastuzumab arm.
HERA Study
In the HERA Study, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or geneamplification (by FISH) as determined at a central laboratory. Patients with node-negative disease wererequired to have ≥ T1c primary tumor. Patients with a history of congest |
