Pyrotinib/capecitabine shows activity in HER2-positive breast cancer with brain metastases

Pyrotinib plus apecitabine has shown promising activity in patients with HER2-positive breast cancer with brain metastases, according to results from the prospective phase 2 PERMEATE study.

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

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

The study recruited a total of 78 patients from the 2 cohorts. Among the women enrolled, 51 (86%) of the 59 patients in cohort A and 18 (95%) of the 19 patients in cohort B had previously been exposed to trastuzumab (Herceptin).

Eligibility was open to patients aged 18 and over with HER2-positive breast cancer and confirmed brain metastases. Other requirements included ECOG performance status ≤ 2, adequate organ function, and prior therapy that may include a history of trastuzumab and other anti-HER2 macromolecular antibodies and any prior line of chemotherapy.1.2

The primary endpoint of the study is the ORR of intracranial lesions. Secondary endpoints include progression-free survival (PFS), ORR of extracranial injury, duration of response (DOR), and overall survival (OS).

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

As previously reported, 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% (95% CI, 20.3% to 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 not reached) in the cohort B. The 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, 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. 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 were not yet mature, however, investigators report that death occurred in 14 patients (24%) in cohort A and 2 (11%) in cohort B.

Thirty-four patients from Cohort A and 12 patients from Cohort B discontinued treatment due to central nervous system (CNS) progression. Seven Cohort A patients experienced concurrent extracranial progression and 6 Cohort A patients left the study due to extracranial progression without concurrent 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 PR.

With respect to safety, some Grade 3 treatment-emergent adverse reactions (EMTR) in Cohort A included diarrhea (n=14), decreased white blood cell count (n=8), and decreased neutrophil count (n = 8). A single event of grade 4 anemia was found to be treatment-related, but not blurred vision (n=1), ventricular fibrillation (n=1), and acute renal failure (n=1). In Cohort B, the most common AETRs were diarrhea (n=4), decreased white blood cell count (n=3), and hypokalemia (n=3). No grade 4 events were reported in this cohort.

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

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

The references:

1. Yan M, Ouyang Q, Sun T, et al. Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor (PERMEATE)-positive breast cancer and brain metastases: a multicenter, 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. Clinicaltrials.gov. Accessed March 9, 2022. https://bit.ly/3KhBoxf

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