The phase 2 PERMEATE trial yielded positive results in the combination of pyrotinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases.
Pyrotinib (Irene) plus capecitabine demonstrated promising activity in patients with HER2-positive breast cancer and brain metastases, and warrants further validation through randomized and controlled clinical research, according to findings from the prospective phase 2 PERMEATE study (NCT03691051), published in The Lancet Oncology.
The median follow-up was 15.7 months, and the intracranial objective response rate (ORR) was 74.6% (95% CI, 61.6%-85.0%) in those with radiotherapy-naïve HER2-positive brain metastases (cohort A) and 42.1% (95% CI, 20.3%-66.5%) in those with progressive disease after radiotherapy (cohort B).
A total of 59 patients were enrolled in cohort A and 19 were enrolled into cohort B. Sixty-nine patients had underwent prior treatment with trastuzumab (Herceptin), and 65 patients had extracranial metastases. At the median follow-up, 88% of patients in cohort A and 68% in cohort B were still on treatment. The median number of pyrotinib treatment cycles in cohort A was 16.0 and 8.1 in cohort B, and for capecitabine it was 15.5 and 8.5, respectively.
In both cohorts, patients received 400 mg of pyrotinib orally once daily and 1000 mg/m2 of capecitabine orally twice daily for 14 days, and subsequently 7 days off, for each 28-day cycle. Patients continued treatment until disease progression, intolerable toxicity, or withdrawal of consent.
A central nervous system (CNS) objective response was observed in 13 patients in cohort A with 2 having a complete response (CR) and 11 having a partial response (PR). Those who achieved an ORR in cohort A had a CR with 7 patients. In cohort B, 6 patients had a CNS ORR, with 1 patient achieving a CR and 5 having a PR. Patients had a median duration of response of 12.5 months in cohort A and 7.7 months in cohort B. The post-hoc analysis indicated that the median time to CNS response was 1.3 months in cohort A and 1.5 months in cohort B.
Forty-six patients in cohort A and 13 in cohort B experienced disease progression or death as of April 16, 2021, with a median progression-free survival of 11.3 months (95% CI, 7.7-14.6) vs 5.6 months (95% CI, 3.4-10.0) in each cohort, respectively. The overall survival data was not yet mature, with investigators reporting 14 deaths in cohort A and 2 in cohort B.
Thirty-four patients in cohort A and 12 in cohort B discontinued treatment because of CNS progression, with 7 patients in cohort A experiencing simultaneous extracranial progression. Additionally, 6 in patients in cohort A left the study because of extracranial progression without simultaneous CNS progression. The extracranial ORR was 70.4% (95% CI, 49.8%-86.2%) in cohort A, with 2 patients having a CR. In cohort B, the extracranial ORR was 50.0%, with 2 patients having a PR.
Grade 3 treatment-emergent adverse effects (TRAEs) included diarrhea (n = 14), decreased white blood cell count (n = 8), and decreased neutrophil count (n = 8) in cohort A. One grade 4 event of anemia was found to be treatment related, but others such as 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). No grade 4 events were reported in this cohort.
Treatment-related serious events that led to hospitalization included grade 4 anemia and grade 3 abdominal distension in cohort A, and grade 3 increased alanine aminotransferase and 1 grade 2 vomiting in cohort B. There were no treatment-related deaths during the study.
Dose reductions of pyrotinib were necessary for 10 patients in cohort A and 2 in cohort B, with 2 patients in cohort B requiring a reduction of 320 mg, and 1 patient in cohort A requiring an additional reduction of 240 mg. Capecitabine reduction occurred in 12 patients in cohort A and 4 in cohort B. One patient discontinued treatment in cohort B because of grade 2 oral mucositis which was potentially related to the study drugs.
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. Published Online January 24, 2022. doi:10.1016/S1470-2045(21)00716-6