Dual HER2 Blockade and Metronomic Chemotherapy Active and Safe for Elderly Patients With HER2-Positive, Metastatic Breast Cancer

Although elderly patients account for more than one-third of advanced breast cancer cases, data about optimal treatment options for these patients are limited, as these patients are largely underrepresented in clinical trials. For younger patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, dual HER2 blockade with the antibodies pertuzumab and trastuzumab in combination with docetaxel chemotherapy is the first-line standard of care. However, docetaxel is associated with clinically relevant toxicity that might impact tolerance and quality of life in older or more frail patients. Metronomic chemotherapy with oral cyclophosphamide was found to be active and a well-tolerated chemotherapy in this patient population. There is unmet need for less toxic regimens for elderly/frail patients with HER2-positive, metastatic breast cancer.

A randomized, open-label, phase II trial (N = 80) evaluated the combination of pertuzumab plus trastuzumab, with or without metronomic chemotherapy (oral cyclophosphamide 50 mg/day), for elderly patients with HER2-positive, metastatic breast cancer, who had not previously received chemotherapy for metastatic disease. Patients were 70 years or older, or 60 years or older with confirmed functional restrictions. The majority of patients (70%) were identified as potentially frail by the G8 geriatric screening assessment (G8 score ≤14).

At a median follow-up of 20.7 months, the median, progression-free survival (PFS) was 5.6 months for dual HER2 blockade alone, compared to 12.7 months for HER2 blockade plus chemotherapy. Estimated 6-month PFS was 46.2% for the anti-HER2 antibodies alone, and 73.4% with the addition of metronomic chemotherapy (hazard ratio [HR] 0.65; P = .12). The difference of 27.2% between the two treatment arms met the 10% difference threshold required by the protocol primary hypothesis. This study was not powered for statistical comparison of the two treatment arms. Overall survival (OS) at 1 year was 67.3% for the antibodies alone and 83.3% with the addition of chemotherapy (HR 0.92; P = .83). Similar response rates were observed in each group, 44% and 53%, respectively. Instrumental Activities of Daily Living (IADL) score, lymph node involvement, and skeletal involvement were identified by multivariate analysis as prognostic for PFS, while social situation, G8 score, IADL score, and visceral involvement were prognostic for OS. Overall survival at 1 year was 100% for patients with G8 score >14 vs 67% with G8 score ≤14 (HR 0.12; P = .01). Of note, subsequent treatment with trastuzumab emtansine in 29 patients (36%) who progressed during the study was active and well tolerated, with 6-month PFS of 49.5% and median PFS of 5 months after starting trastuzumab emtansine.

Similar rates of adverse events (AEs) were observed in both treatment arms. Treatment-related grade 3 to 5 AEs occurred in 54% of patients receiving trastuzumab plus pertuzumab and 56% of patients receiving the antibodies plus metronomic chemotherapy. The most frequent grade 3/4 AEs were hypertension (15% vs 12%), diarrhea (10% vs 12%), dyspnea (5% vs 10%), fatigue (8% vs 5%), pain (5% each), and thromboembolic event (0% vs 10%). Severe cardiac toxicities were occasionally observed in both groups. Unsurprisingly, nine (31%) of 29 observed deaths were not caused by breast cancer. This may be due to the fact that 41% of patients had severe comorbidity.

The investigators concluded that the addition of metronomic oral cyclophosphamide to dual HER2 blockade with trastuzumab and pertuzumab is an effective treatment option with acceptable safety profile for older, frail patients with HER2-positive, metastatic breast cancer and ‘’might delay or even supersede the need for subsequent use of taxanes in a substantial proportion of older patients.’’ However, they highlighted this was a selection, phase II study and further evaluation in a phase III study is needed to justify use of this regimen in clinical practice. In an accompanying commentary, the author agreed, highlighting the unmet need for effective treatment options in the elderly population and the paucity of clinical trials that include these higher risk patients.

Lancet Oncol. 2018 February 9. [Epub ahead of print]. [article]

Lancet Oncol. 2018 February 9. [Epub ahead of print]. [commentary]
elderly-HER2-positive breast-cancer-treatment