Wildiers H, et al. - The intent of the researchers was to examine the efficacy of dual anti-HER2 treatment with or without metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer. A rise was noted in the median progression-free survival by 7 months due to the addition of metronomic oral cyclophosphamide to trastuzumab plus pertuzumab in older and frail patients with HER2-positive metastatic breast cancer when compared with dual HER2 blockade alone. This combination displayed an acceptable safety profile. Findings indicated that delay or superseding could occur in the need for taxane chemotherapy in this cohort via trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, followed by trastuzumab emtansine after disease progression.

Methods

• This multicentre, open-label, randomized, phase 2 trial was performed in 30 centres across 8 countries in Europe.
• The eligible candidates included patients with histologically proven, HER2-positive metastatic breast cancer, without previous chemotherapy for metastatic disease, who were 70 years or older, or 60 years or older with confirmed functional restrictions defined by protocol, and had a life expectancy of more than 12 weeks and a performance status according to WHO scale of 0-3.
• They were randomly allocated (1:1) to receive metronomic oral cyclophosphamide 50 mg per day plus trastuzumab and pertuzumab, or trastuzumab and pertuzumab alone via an online randomisation system based on the minimisation method.
• Herein, trastuzumab was given intravenously with a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks and pertuzumab was given intravenously with a loading dose of 840 mg, followed by 420 mg every 3 weeks.
• During this research, enrollees were stratified by hormone receptor positivity, previous HER2 treatment, and baseline geriatric screening.
• The investigator-assessed progression-free survival at 6 months as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 served as the primary endpoint.
• Between both groups, a variation of 10% or greater was sought.
• Efficacy analyses were by intention to treat, wherein safety was gauged among all patients who received at least one dose of study treatment.
• All patients were offered trastuzumab emtansine, in case of progression.

Results

• A total of 80 patients, of whom 56 (70%) had a potential frailty profile according to the geriatric screening G8 score (≤14), were randomly allocated to receive trastuzumab and pertuzumab (n=39) or trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (n=41) between July 2, 2013, and May 10, 2016.
• Data exhibited that the estimated progression-free survival at 6 months was 46·2% (95% CI 30·2-60·7) with trastuzumab and pertuzumab vs 73·4% (56·6-84·6) with trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (hazard ratio [HR] 0·65 [95% CI 0·37-1·12], p=0·12).
• As per the outcomes, at a median follow-up of 20·7 months (IQR 12·5-30·4), the median progression-free survival was 5·6 months (95% CI 3·6-16·8) with trastuzumab and pertuzumab vs 12·7 months (6·7-24·8) with the addition of metronomic oral cyclophosphamide.
• Hypertension (in 6 [15%] of 39 patients in the trastuzumab and pertuzumab group vs 5 [12%] of 41 in the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group), diarrhoea (4 [10%] vs 5 [12%]), dyspnoea (2 [5%] vs 4 [10%]), fatigue (3 [8%] vs 2 [5%]), pain (2 [5%] vs 2 [5%]), and a thromboembolic event (0 [0%] vs 4 [10%]) were revealed to be the most frequent grade 3-4 adverse events.
• In both groups, severe cardiac toxicities were noted occasionally.
• Death was reported in 4 patients 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) in the trastuzumab and pertuzumab group.
• It was determined that 1 patient died from heart failure in the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group.