In the Chinese phase II PERMEATE trial reported in The Lancet Oncology, Yan et al found that the combination of the pan-HER receptor tyrosine kinase inhibitor pyrotinib plus capecitabine produced high intracranial response rates in women with HER2-positive breast cancer and brain metastases, particularly among those who had not received prior radiotherapy for brain metastases.
Study Details
In the multicenter trial, 78 women were enrolled between January 2019 and July 2020 into two cohorts consisting of patients with radiotherapy-naive HER2-positive brain metastases (cohort A, n = 59) or progressive disease after radiotherapy (cohort B, n = 19). Totals of 51 patients (86%) in cohort A and 18 (95%) in cohort B had received prior trastuzumab treatment in the adjuvant, neoadjuvant, or advanced setting.
Patients received pyrotinib at 400 mg once daily and capecitabine at 1,000 mg/m2 twice daily for 14 days followed by 7 days off every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed intracranial objective response rate.
Responses
Median follow-up was 15.7 months (interquartile range [IQR] = 9.7–19.0 months). Intracranial objective response was observed in 44 (74.6%, 95% confidence interval [CI] = 61.6%–85.0%) of 59 patients in cohort A, with complete response in 7 (12%), and in 8 (42.1%, 95% CI = 20.3%–66.5%) of 19 in cohort B, with complete response in 1 (5%). Stable disease was observed in an additional 19% and 21% of patients.
The median duration of response was 12.5 months (95% CI = 8.3–14.6 months) in cohort A and 7.7 months (95% CI = 2.8 months to not reached) in cohort B. Median times to response were 1.3 months (IQR =1.2–1.4 months) and 1.5 months (IQR = 1.3–3.4 months), respectively.
An extracranial objective response was observed in 19 (70.4%, 95% CI = 49.8%–86.2%) of 27 patients with measurable disease in cohort A and in 2 (50.0%, 95% CI = 6.8%–93.2%) of 4 in cohort B. Median progression-free survival was 11.3 months (95% CI = 7.7–14.6 months) in cohort A and 5.6 months (95% CI = 3.4–10.0 months) in cohort B. Death occurred in 14 patients (24%) in cohort A and 2 (11%) in cohort B.
Adverse Events
The most common grade ≥ 3 adverse events were diarrhea (24%), decreased white blood cell (WBC) count (14%), and decreased neutrophil count (14%) in cohort A and diarrhea (21%), decreased WBC count (16%), and hypokalemia (16%) in cohort B. Grade 4 adverse events occurred in four patients in cohort A and in none in cohort B.
Treatment-related serious adverse events occurred in two patients (3%) in cohort A (grade 4 anemia and grade 3 abdominal distension) and in three patients (16%) in cohort B (grade 3 anemia, grade 3 increased alanine aminotransferase, and grade 2 vomiting). No treatment-related deaths occurred.
KEY POINTS
- Intracranial objective response was observed in 75% of radiotherapy-naive patients and 42% of patients with prior radiotherapy.
- Median response durations were 12.5 months and 7.7 months, respectively.
The investigators concluded: “To our knowledge, this is the first prospective study showing the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases, especially in radiotherapy-naive population. This combination deserves further validation in a randomised, controlled trial.”
Min Yan, MD, of the Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the National Cancer Centre Climbing Foundation Key Project of China and Jiangsu Hengrui Pharmaceuticals. For full disclosures of the study authors visit www.thelancet.com.
