Oral Combo Shows Activity in HER2-Positive Breast Cancer With Brain Metastases

Pyrotinib plus capecitabine showed encouraging antitumor activity in patients with HER2-positive metastatic breast cancer and brain metastases, according to results from the phase II PERMEATE trial.

At a median follow-up of 15.7 months, the combination achieved an intracranial objective response rate (ORR) of 74.6% (95% CI 61.6-85.0) in a cohort of patients who were radiotherapy-naive (cohort A), reported Min Yan, MD, of the Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital in China, and colleagues.

In a cohort of patients who had progressive disease after radiotherapy (cohort B), the intracranial ORR with pyrotinib plus capecitabine was 42.1% (95% CI 20.3-66.5), they noted in Lancet Oncology.

Of the 44 patients in cohort A who achieved the primary endpoint of intracranial objective response, 37 had a partial response and seven had a complete response. Of the eight patients in cohort B who had an objective response, one had a complete response.

“The results of this phase 2 study provide evidence of promising antitumor activity and safety of pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases, especially in those with radiotherapy-naive brain metastases,” Yan and team wrote.

Median duration of response was 12.5 months in cohort A and 7.7 months in cohort B. Median time to central nervous system response was 1.3 months and 1.5 months, respectively, while the disease control rates were 93.2% and 63.2%. Median progression-free survival was 11.3 months in cohort A and 5.6 months in cohort B, they reported.

In a commentary accompanying the study, Caroline Bailleux, MD, of Centre Antoine Lacassagne in Nice, France, and Thomas Bachelot, MD, PhD, of Centre Léon Bérard in Lyon, France, noted that current recommendations rely on surgery and radiotherapy to control brain metastases, “with medical treatment mostly considered after failure of such interventions.”

However, the results from PERMEATE are consistent with previously published data on HER2 tyrosine kinase inhibitor (TKI) combinations, they added, “and confirm the clinical activity of a medical approach for treatment of active brain metastases, either before or after radiotherapy.”

“Future treatment strategies for patients with HER2-positive metastatic breast cancer and active brain metastases will have to take into account medical treatment options,” Bailleux and Bachelot wrote. “As a consequence, precise clinical activity data produced by prospective studies are of utmost importance.”

In explaining the rationale behind the trial, Yan and colleagues noted that standard monoclonal antibodies such as trastuzumab (Herceptin) and pertuzumab (Perjeta) result in disappointing outcomes for brain metastases. However, they observed that results from the HER2CLIMB trial, which evaluated the addition of tucatinib (Tukysa) to trastuzumab and capecitabine-pretreated patients with HER2-positive metastatic breast cancer, “suggest[ed] a pivotal role for small-molecule tyrosine kinase inhibitors to treat brain metastases.”

They also said that results from the phase III PHOEBE and PHENIX studies demonstrated the efficacy of pyrotinib in patients with HER2-positive metastatic breast cancer, while two real-world studies showed activity with pyrotinib against brain metastases.

PERMEATE included 78 women, 59 in cohort A (mean age 49) and 19 in cohort B (mean age 47), with an Eastern Cooperative Oncology Group performance status of 0 to 2.

Patients received pyrotinib 400 mg orally once daily and capecitabine 1,000 mg/m² orally twice daily for 14 days, followed by 7 days off every 3 weeks until disease progression or unacceptable toxicity.

The most common grade 3 treatment-related adverse event was diarrhea (24% of cohort A and 21% of cohort B), and a substantial proportion of patients in both cohorts had grade 1 or 2 diarrhea (68% and 74%, respectively).