ancy in the overall sample size due to a small number of patients who were randomised after the cut-off date for the 12-month median follow-up analysis
The efficacy results from the interim efficacy analysis crossed the protocol pre-specified statistical boundary for the comparison of 1-year of trastuzumab versus observation. After a median follow-up of 12 months, the hazard ratio (HR) for disease-free survival (DFS) was 0.54 (95% CI 0.44, 0.67) which translates into an absolute benefit, in terms of a 2-year disease-free survival rate, of 7.6 percentage points (85.8% versus 78.2%) in favour of the trastuzumab arm.
A final analysis was performed after a median follow-up of 8 years, which showed that 1 year trastuzumab treatment is associated with a 24% risk reduction compared to observation only (HR = 0.76, 95% CI 0.67, 0.86). This translates into an absolute benefit in terms of an 8 year disease-free survival rate of 6.4 percentage points in favour of 1 year trastuzumab treatment.
In this final analysis, extending trastuzumab treatment for a duration of two years did not show additional benefit over treatment for 1 year [DFS HR in the intent to treat (ITT) population of 2 years versus 1 year = 0.99 (95% CI 0.87, 1.13), p-value = 0.90 and OS HR = 0.98 (0.83, 1.15); p-value = 0.78]. The rate of asymptomatic cardiac dysfunction was increased in the 2-year treatment arm (8.1% versus 4.6% in the 1-year treatment arm). More patients experienced at least one grade 3 or 4 adverse reaction in the 2-year treatment arm (20.4%) compared with the 1-year treatment arm (16.3%).
In the NSABP B-31 and NCCTG N9831 studies trastuzumab was administered in combination with paclitaxel, following AC chemotherapy.
Doxorubicin and cyclophosphamide were administered concurrently as follows:
- intravenous push doxorubicin, at 60 mg/m2, given every 3 weeks for 4 cycles.
- intravenous cyclophosphamide, at 600 mg/m2 over 30 minutes, given every 3 weeks for 4 cycles.
Paclitaxel, in combination with trastuzumab, was administered as follows:
- intravenous paclitaxel – 80 mg/m2 as a continuous intravenous infusion, given every week for 12 weeks.
or
- intravenous paclitaxel – 175 mg/m2 as a continuous intravenous infusion, given every 3 weeks for 4 cycles (day 1 of each cycle).
The efficacy results from the joint analysis of the NSABP B-31 and NCCTG N9831 trials at the time of the definitive analysis of DFS* are summarised in Table 7. The median duration of follow-up was 1.8 years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm.
Table 7 Summary of efficacy results from the joint analysis of the NSABP B-31 and NCCTG N9831 trials at the time of the definitive DFS analysis*
Parameter
AC→P
(n = 1679)
AC→PH
(n = 1672)
Hazard Ratio vs AC→P
(95% CI)
p-value
Disease-free survival
No. patients with event (%)
Distant recurrence
No. patients with event
Death (OS event)
No. patients with event
261 (15.5)
193 (11.5)
92 (5.5)
133 (8.0)
96 (5.7)
62 (3.7)
0.48 (0.39, 0.59)
p < 0.0001
0.47 (0.37, 0.60)
p < 0.000
0.67 (0.48, 0.92)
p = 0.014**
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab
* At median duration of follow-up of 1.8 years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm
** p value for OS did not cross the pre-specified statistical boundary for comparison of AC→PH vs AC→P
For the primary endpoint, DFS, the addition of trastuzu |
