Patients with HER2-positive metastatic breast cancer have a high risk of developing brain metastases. Unfortunately, efficacious treatment options are scarce. PERMEATE is the first prospective study demonstrating promising antitumour activity and safety of pyrotinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases, especially in those with radiotherapy-naïve brain metastases.
After treatment with trastuzumab, approximately 30–50% of patients with HER2-positive metastatic breast cancer develop brain metastases, leading to poor outcomes. Although local therapy remains the mainstay treatment for brain metastases, recurrences are common within six to twelve months with a risk for neurocognitive impairment. Standard monoclonal antibodies (trastuzumab and pertuzumab) yield unsatisfactory outcomes against brain metastases. Pyrotinib is an oral irreversible pan-HER receptor tyrosine kinase inhibitor targeting HER1, HER2, and HER4, that previously demonstrated to be effective in patients with HER2-positive metastatic breast cancer. The phase II PERMEATE trial is the first prospective study to investigate the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases.
PERMEATE was designed as a multicentre, single-arm, two-cohort, phase II trial conducted in eight tertiary hospitals in China. Eligible breast cancer patients were adults (≥ 18 years) who had radiotherapy-naive HER2-positive brain metastases (cohort A) or progressive disease after radiotherapy (cohort B), with an Eastern Cooperative Oncology Group performance status of 0-2. All patients received pyrotinib 400 mg orally once daily and capecitabine 1,000 mg/m2 orally twice daily for fourteen days, followed by seven days off every three weeks until disease progression or unacceptable toxicity. The primary endpoint was CNS objective response rate, defined as the proportion of patients with the best intracranial response of confirmed complete or partial response according to RECIST 1.1. Activity and safety were analysed in all patients who received at least one dose of study treatment. The study is ongoing, but recruitment is complete.
Between January 2019 and July 2020, 78 women were enrolled (59 in cohort A and 19 in cohort B). Of these patients, respectively 86% and 95% had previous exposure to trastuzumab. Extracranial metastases were present in 88% and 68% of the patients in each cohort. After a median follow-up of 15.7 months, the CNS objective response rate (ORR) was 74.6% in cohort A, with 12% of the patients having a complete response. The overall CNS ORR in cohort B was 42.1%, with 5% of the patients showing complete response. These results suggest the promising activity of pyrotinib plus capecitabine against brain metastases, especially for the radiotherapy-naive population. Median duration of response was 12.5 months in cohort A and 7.7 months in cohort B. In a post-hoc analysis, the median time to CNS response was 1.3 months in cohort A and 1.5 months in cohort B. Additionally, median progression-free survival was 11.3 and 5.6 months in cohorts A and B, respectively. Fourteen (24%) and two (11%) deaths were registered in cohorts A and B, respectively. Median overall survival was not reached in either of the arms. Furthermore, 58% of the patients in cohort A and 63% of the patients in cohort B came off study due to CNS progression, and seven in cohort A also had simultaneous extracranial progression. Extracranial (non-CNS) objective response rate was 70.4% and 50% among patients with measurable extracranial disease in cohorts A and B, respectively. The most common grade 3 treatment-emergent adverse events (TEAEs) in cohort A were diarrhoea (24%), decreased white blood cell count (14%), and decreased neutrophil count (14%). One grade 4 anaemia was deemed treatment-related by the investigator. For cohort B, the most common grade 3 TEAEs were diarrhoea (21%), decreased white blood cell count (16%), and hypokalaemia (16%). No grade 4 events were reported in cohort B. Two (3%) patients in cohort A and three (16%) in cohort B had treatment-related serious adverse events, leading to hospitalisation. No treatment-related deaths occurred.
PERMEATE is the first prospective study to report the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases. Pyrotinib plus capecitabine was well tolerated and active for both intracranial and extracranial lesions in patients with HER2-positive metastatic breast cancer and brain metastases, especially for those with radiotherapy-naive brain metastases. This combination might delay radiotherapy and provide survival benefits for the patients. Further validation in a large-scale, randomised, controlled trial is warranted.
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