rmanently discontinued in patients who developedcongestive 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 combined efficacy analysiswas Disease-Free Survival (DFS), defined as the time from randomization to recurrence, occurrence ofcontralateral breast cancer, other second primary cancer, or death. The secondary endpoint was overallsurvival (OS).
A total of 3752 patients were included in the joint efficacy analysis of the primary endpoint of DFSfollowing a median follow-up of 2.0 years in the AC→paclitaxel + trastuzumab arm. The pre-plannedfinal OS analysis from the joint analysis included 4063 patients and was performed when 707 deaths hadoccurred after a median follow-up of 8.3 years in the AC→paclitaxel + trastuzumab arm. The data fromboth arms in Study 1 and two of the three study arms in Study 2 were pooled for efficacy analyses. Thepatients included in the primary DFS analysis had a median age of 49 years (range, 22–80 years; 6% > 65years), 84% were white, 7% black, 4% Hispanic, and 4% Asian/Pacific Islander. Disease characteristicsincluded 90% infiltrating ductal histology, 38% T1, 91% nodal involvement, 27% intermediate and 66%high grade pathology, and 53% ER+ and/or PR+ tumors. Similar demographic and baseline characteristicswere reported for the efficacy eva luable population, after 8.3 years of median follow-up in theAC→paclitaxel + trastuzumab arm.
Study 3
In Study 3, 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 congestive heart failure or LVEF <55%, uncontrolled arrhythmias, angina requiring medication, clinically significant valvular heart disease,evidence of transmural infarction on ECG, poorly controlled hypertension (systolic > 180 mm Hg ordiastolic > 100 mm Hg) were not eligible.
Study 3 was designed to compare one and two years of three-weekly trastuzumab treatment versusobservation in patients with HER2 positive EBC following surgery, established chemotherapy andradiotherapy (if applicable). Patients were randomized (1:1:1) upon completion of definitive surgery, andat least four cycles of chemotherapy to receive no additional treatment, or one year of trastuzumabtreatment or two years of trastuzumab treatment. Patients undergoing a lumpectomy had also completedstandard radiotherapy. Patients with ER+ and/or PgR+ disease received systemic adjuvant hormonaltherapy at investigator discretion. Trastuzumab was administered with an initial dose of 8 mg/kg followedby subsequent doses of 6 mg/kg once every three weeks. The main outcome measure was Disease-Free Survival (DFS), defined as in Studies 1 and 2.
A protocol specified interim efficacy analysis comparing one-year trastuzumab treatment to observation wasperformed at a median follow-up duration of 12.6 months in the trastuzumab arm and formed the basis for thedefinitive DFS results from this study. Among the 3386 patients randomized to the observation (n = 1693)and trastuzumab one-year (n = 1693) treatment arms, the median age was 49 years (range 21–80), 83%were Caucasian, and 13% |
