Safety and Efficacy of a Tucatinib-Trastuzumab-Capecitabine Combination Treatment for Leptomeningeal Metastases in HER2-Positive Breast Cancer

Patients with leptomeningeal metastases have few treatment options and a poor prognosis. The median overall survival (OS) for these patients is approximately 4 to 5 months.1 Tucatinib is an HER2-targeted tyrosine kinase inhibitor, approved in the United States in combination with trastuzumab and capecitabine, for use in patients with metastatic HER2-positive breast cancer (including brain metastases) who have received ≥1 prior HER2-based metastatic regimens.1 The primary outcome of the study was to assess the safety and efficacy of tucatinib, trastuzumab, and capecitabine in patients with HER2-positive breast cancer with recently diagnosed leptomeningeal metastases.1 Previous studies in patients on tucatinib treatment found therapeutic levels of tucatinib in the cerebrospinal fluid of patients with HER2-positive leptomeningeal metastases.1

Adults with HER2-positive metastatic breast cancer, a Karnofsky performance level of ≥50, and newly diagnosed untreated leptomeningeal metastases were eligible for the study.1 Patients with treated brain metastases and patients with newly diagnosed untreated brain metastases were permitted in the study.1 Patients were given tucatinib 300 mg orally twice daily; capecitabine 1000 mg/m2 orally twice daily on days 1 to 14 of a 21-day cycle; and a trastuzumab loading dosage of 8 mg/kg intravenously on day 1, followed by 6 mg/kg intravenously once every 21 days.1 OS was the major end point.1 The trial was scheduled to enroll 30 patients, but due to a lack of accrual since the FDA approved tucatinib in 2020, it was closed after just 17 patients were enrolled.1

Cerebrospinal fluid cytology was abnormal in 8 (47%) patients.1 All of the patients exhibited MRI evidence of leptomeningeal metastases in the brain, and 82% of them had brain metastases, with 65% of patients having previously had therapy for brain metastases.1 At the start of the trial, the median age was 53 years.1 The average number of treatment cycles was 5.1 The median OS was 11.9 months. At data cutoff, 41% of participants were still alive, with a median follow-up of 17 months (8-26 months). The median time before central nervous system progression was 6.9 months.1

The median OS was just under a year in patients with leptomeningeal disease from HER2-positive metastatic breast cancer who were treated with tucatinib, trastuzumab, and capecitabine.1 This is the first study to show that a systemic regimen can benefit patients with HER2-positive breast cancer with leptomeningeal metastases.1 Further research on the effects of oral medicines and their ability to cross the blood–brain barrier in this patient population is required.1


  1. Murthy R, O’Brien B, Berry D, et al. Safety and efficacy of a tucatinib-trastuzumab-capecitabine regimen for treatment of leptomeningeal metastasis (LM) in HER2-positive breast cancer: results from TBCRC049, a phase 2 non-randomized study. 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. PD4-02.

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