The evidence supporting this protocol is provided by a phase III multicentre international double-blind randomised trial (CLEOPATRA) involving 808 patients comparing pertuzumab, trastuzumab, and docetaxel with trastuzumab and docetaxel in patients with HER2-positive first-line metastatic breast cancer.r
Between February 2008 and July 2010, 402 patients were randomised to receive pertuzumab 840 mg (loading dose) followed by 420 mg (subsequent doses), trastuzumab 8 mg/kg (loading dose) followed by 6 mg/kg (subsequent doses), and docetaxel 75 mg/m2 and 406 patients were randomised to receive placebo, trastuzumab 8 mg/kg (loading dose) followed by 6 mg/kg (subsequent doses), and docetaxel 75 mg/m2. The dose of docetaxel in both arms could be increased to 100 mg/m2 if the side effect profile was acceptable. Treatment was repeated every 3 weeks until disease progression or unacceptable toxicity.r
The primary end point was progression-free survival (independent review) and secondary end points included overall survival, progression-free survival (investigator assessed), objective response rate, and safety.r
The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2- positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects.r
Efficacy
After a median follow-up of 50 months, the median overall survival was 56.5 months in the group receiving the pertuzumab combination, as compared with 40.8 months in the group receiving the placebo combination (hazard ratio 0.68, 95% CI 0.56-0.84; p<0.001). This analysis was not adjusted for crossover to the pertuzumab group and is therefore conservative. Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed.r
Kaplan-Meier estimates of overall survival in patients in the intention-to-treat population r
© New England Journal of Medicine 2015
Kaplan-Meier estimates of progression-free survival (investigator assessed) r
© New England Journal of Medicine 2015
Overall responses (independently assessed) - Interim analysis r
© New England Journal of Medicine 2015
As exploratory analyses of the incidence and time to development of CNS metastases showed that the addition of pertuzumab to docetaxel and trastuzumab delayed the onset of CNS disease in patients.r
Toxicity
Serious adverse events were reported in 29% of patients who received placebo, trastuzumab, and docetaxel and 36% of patients who received pertuzumab, trastuzumab, and docetaxel, and included febrile neutropenia, neutropenia, diarrhoea, pneumonia, and cellulitis.r
There were no differences between treatment arms in terms of health-related quality of life were reported.
Adverse events r
© Lancet Oncology 2013
The rate of left ventricular dysfunction was lower in the pertuzumab group than in the control group (6.6% vs 8.6%). Reductions in LVEF of 10% or more from baseline to an absolute value of less than 50% occurred in 6.1% patients in the pertuzumab group and 7.4% in the control group. Declines were reversed in 87.5% in the pertuzumab group and 78.6% in the control group.r