roup, whichconstituted 81% of those with data. Definitive conclusions cannot be drawn regarding efficacy within othersubgroups due to the small number of events. The number of events in Study 3 was adequate to demonstrate
significant effects on DFS in the IHC 3+/FISH unknown and the FISH +/IHC unknown subgroups.
Table 10
Treatment Outcomes in Studies 2 and 3 as a Function of HER2 Overexpression or Amplification
Study 2 Study 3c
HER2 Assay Resulta Number of
Patients
Hazard Ratio DFS
(95% CI)
Number of
Patients
Hazard Ratio DFS
(95% CI)
IHC 3+
FISH (+) 1170 0.42
(0.27, 0.64)
91 0.56
(0.13, 2.50)
FISH (−) 51 0.71
(0.04, 11.79)
8 —
FISH Unknown 51 0.69
(0.09, 5.14)
2258 0.53
(0.41, 0.69)
IHC < 3+ /
FISH (+)
174 1.01
(0.18, 5.65)
299b 0.53
(0.20, 1.42)
IHC unknown /
FISH (+)
— — 724 0.59
(0.38, 0.93) a IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio ≥ 2.0) as performed at a central laboratory.
b All cases in this category in Study 3 were IHC 2+.
c Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
14.2 Metastatic Breast Cancer
The safety and efficacy of trastuzumab in treatment of women with metastatic breast cancer were studied in arandomized, controlled clinical trial in combination with chemotherapy (Study 5, n = 469 patients) and an openlabelsingle agent clinical trial (Study 6, n = 222 patients). Both trials studied patients with metastatic breast
cancer whose tumors overexpress the HER2 protein. Patients were eligible if they had 2 or 3 levels ofoverexpression (based on a 0 to 3 scale) by immunohistochemicalassessment of tumor tissue performed by acentral testing lab.
Previously Untreated Metastatic Breast Cancer (Study 5)
Study 5 was a multicenter, randomized, open-label clinical trial conducted in 469 women with metastatic breastcancer who had not been previously treated with chemotherapy for metastatic disease. Tumor specimens weretested by IHC (Clinical Trial Assay, CTA) and scored as 0, 1+, 2+, or 3+, with 3+ indicating the strongest
positivity. Only patients with 2+ or 3+ positive tumors were eligible (about 33% of those screened). Patientswere randomized to receive chemotherapy alone or in combination with trastuzumab given intravenously as a4 mg/kg loading dose followed by weekly doses of trastuzumab at 2 mg/kg. For those who had received prior
anthracycline therapy in the adjuvant setting, chemotherapy consisted of paclitaxel (175 mg/m2 over 3 hoursevery 21 days for at least six cycles); for all other patients, chemotherapy consisted of anthracycline pluscyclophosphamide (AC: doxorubicin 60 mg/m2 or epirubicin 75 mg/m2 plus 600 mg/m2 cyclophosphamide
every 21 days for six cycles). Sixty-five percent of patients randomized to receive chemotherapy alone in thisstudy received trastuzumab at the time of disease progression as part of a separate extension study.
Based upon the determination by an independent response eva luation committee, the patients randomized totrastuzumab and chemotherapy experienced a significantly longer median time to disease progression, a higheroverall response rate (ORR), and a longer median duration of response as compared with patients randomized tochemotherapy alone. Patients randomized to trastuzumab and chemotherapy also had a longer median survival(see Table 11). These treatment effects were observed both in patients |
