Pyrotinib/Capecitabine Shows Activity in HER2-Positive Breast Cancer with Brain Metastases

Pyrotinib combined with apecitabine demonstrated promising activity in patients with HER2-positive breast cancer that have brain metastases, according to findings from the prospective phase 2 PERMEATE study.

The combination of pyrotinib (Irene) plus capecitabine (Xeloda) showed promising activity in patients with HER2-positive breast cancer that have brain metastases, according to findings from the prospective phase 2 PERMEATE study (NCT03691051).1

At the median follow-up of 15.7 months, the intracranial objective response rate (ORR) was 74.6% (95% CI, 61.6%-85.0%) in cohort A which consisted of patients with radiotherapy-naïve HER2-positive brain metastases, and 42.1% (95% CI, 20.3%-66.5%) in patients with progressive disease after radiotherapy which made up cohort B.

The study enrolled 78 patients in total among the 2 cohorts. Of the women enrolled, 51 (86%) of 59 patients in cohort A and 18 (95%) of 19 patients in cohort B had previous exposure to trastuzumab (Herceptin).

Eligibility was open to patients aged 18 and older with HER2-positive breast cancer and confirmed brain metastases. Other requirements included an ECOG performance status of ≤ 2,adequate organ function, and previous treatment which could include a history of trastuzumab and other anti-HER2 macromolecular antibodies and any lines of previous chemotherapy.1,2

The primary end point for the study is ORR of intracranial lesions. Secondary end points include progression-free survival (PFS), ORR of extracranial lesion, duration of response (DOR), and overall survival (OS).

Patients received 400 mg of pyrotinib orally once a day and 1000 mg/m2 of capecitabine orally twice a day for 14 days in both cohorts. There were subsequently 7 days off for each 28-day cycle. Patients continued with treatment until either disease progression, intolerable toxicity, or withdrawal of consent.

As stated prior, intracranial ORR was observed in 44 of 59 patients (74.6%) in cohort A, with complete response (CR) in 7 (12%). In cohort B, intracranial ORR was shown in 42.1% of patients (95% CI, 20.3%–66.5%) of 19 patients, with CR in 1 (5%). Stable disease was also observed in 19% and 21% of patients.1

The median DOR in cohort A was 12.5 months (95% CI, 8.3-14.6 months) 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).

In cohort A, an extracranial ORR was observed in 70.4% of patients (95% CI, 49.8%-86.2%) of 27 patients with measurable disease and 50.0% of patients (95% CI, 6.8%-93.2%) of 4 in cohort B. The median PFS 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. Overall survival data was not yet mature, however, investigators reported that death occurred in 14 patients (24%) in cohort A as well as 2 (11%) in cohort B.

Thirty-four patients in cohort A as well as 12 patients in cohort B discontinued treatment as a result of central nervous system (CNS) progression. Seven patients in cohort A experienced simultaneous extracranial progression and 6 in patients in cohort A left the study due to extracranial progression without simultaneous CNS progression. In cohort A, the extracranial ORR was 70.4% (95% CI, 49.8%-86.2%) and 2 included had a CR. Cohort B had an extracranial ORR of 50.0%, with 2 patients having a PR.

In regard to safety, some grade 3 treatment-emergent adverse effects (TRAEs) within cohort A included diarrhea (n = 14), decreased white blood cell count (n = 8), and decreased neutrophil count (n = 8). Only 1 grade 4 event of anemia was found to be treatment related, but blurred vision (n = 1), ventricular fibrillation (n = 1), and acute kidney injury (n = 1) were not. In cohort B, the most common TRAEs were diarrhea (n = 4), decreased white blood cell count (n = 3), and hypokalemia (n = 3). There were no grade 4 events reported in this cohort.

In cohort A, treatment-related serious events that led to hospitalization included grade 4 anemia and grade 3 abdominal distension. In cohort B, these events included grade 3 increased alanine aminotransferase and 1 grade 2 vomiting. No treatment-related deaths occurred during the study.

For 10 patients within cohort A and 2 in cohort B, dose reductions of pyrotinib were necessary. Two patients in cohort B required a reduction of 320 mg, and 1 patient in cohort A required an additional reduction of 240 mg. In regard to capecitabine, reduction occurred in 12 patients in cohort A and 4 in cohort B. Additionally, 1 patient discontinued treatment in cohort B due to grade 2 oral mucositis potentially related to the study drugs.


1. Yan M, Ouyang Q, Sun T, et al. Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single-arm, two-cohort, phase 2 trial. Lancet Oncol. 2022;23(3):353-361. doi:10.1016/S1470-2045(21)00716-6

2. A study of pyrotinib plus capecitabine in patients with brain metastases from HER2-positive metastatic breast cancer. Accessed March 9, 2022.