In the phase II EORTC 75111-10114 trial reported in The Lancet Oncology, Wildiers et al found that the addition of metronomic oral cyclophosphamide to pertuzumab (Perjeta) and trastuzumab (Herceptin) improved progression-free survival in elderly or frail women with HER2-positive metastatic breast cancer.
In the open-label trial, 80 patients aged ≥ 70 years or ≥ 60 years with functional restrictions from 30 sites in eight European countries were randomized between July 2013 and May 2016 to receive trastuzumab and pertuzumab without (n = 39) or with (n = 41) metronomic oral cyclophosphamide. Patients had received no prior chemotherapy for metastatic disease. Metronomic oral cyclophosphamide was given at 50 mg per day; trastuzumab was given at a loading dose of 8 mg/kg followed by 6 mg/kg every 3 weeks; and pertuzumab was given at a loading dose of 840 mg followed by 420 mg every 3 weeks. The primary endpoint was investigator-assessed progression-free survival at 6 months, with a difference of ≥ 10% between groups being sought. Patients had a median age of 76–77 years.
Progression-free survival at 6 months was 73.4% in the metronomic chemotherapy group vs 46.2% in the control group (hazard ratio [HR] = 0.65, P = .12); although the difference did not achieve statistical significance, the study design was not powered for direct treatment comparison. At median follow-up of 20.7 months, median progression-free survival was 12.7 months vs 5.6 months. Overall, 36% of patients (15 in the chemotherapy group and 14 in the control group) received trastuzumab emtansine as second-line therapy; among these patients, progression-free survival at 6 months was 49.5% and median progression-free survival was 5.0 months.
The most common grade 3 or 4 adverse events in the chemotherapy group vs control group were hypertension (12% vs 15%), diarrhea (12% vs 10%), dyspnea (10% vs 5%), thromboembolic event (10% vs 0%), fatigue (5% vs 8%), and pain (5% vs 5%). In the chemotherapy group, one patient died from heart failure. In the control group, four patients died without progression due to cardiac arrest during treatment (n = 1), peritoneal infection (n = 1), respiratory failure (n = 1), and sudden death without a specified cause (n = 1). Additional cardiac events included grade 3 heart failure in two patients in the chemotherapy group, grade 3 left ventricular systolic dysfunction in one patient in each group, grade 3 atrial fibrillation in two patients in the chemotherapy group, and 10% or greater asymptomatic left ventricular ejection fraction decrease to < 50% in one patient in each group.
The investigators concluded, “Addition of metronomic oral cyclophosphamide to trastuzumab plus pertuzumab in older and frail patients with HER2-positive metastatic breast cancer increased median progression-free survival by 7 months compared with dual HER2 blockade alone, with an acceptable safety profile. Trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, followed by trastuzumab emtansine after disease progression, might delay or supersede the need for taxane chemotherapy in this population.”
The study was funded by F. Hoffmann-La Roche.
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