TBCRC 049: A Phase 2 Study to Assess the Safety and Efficacy of Tucatinib and Trastuzumab + Capecitabine for Treatment of Leptomeningeal Metastases in HER2+ Breast Cancer

Treatment options for patients with leptomeningeal disease (LMD) from HER2+ breast cancer are limited, and the prognosis is poor. Tucatinib is an oral, potent, HER2-specific tyrosine kinase inhibitor with good tolerability and notable early combinatory anti-tumor activity, including partial responses in heavily treated patients and those with parenchymal brain metastases.

At SABCS 2019, the trial design was described of an ongoing phase 2 single-arm study to evaluate the efficacy of the combination of tucatinib plus trastuzumab and capecitabine in patients with HER2+ breast cancer and newly diagnosed LMD.1 The target accrual for this study is 30 patients. Central nervous system (CNS) disease will be evaluated at screening and every 6 weeks by magnetic resonance imaging, cerebrospinal fluid (CSF) cytology, and neurologic assessments according to RANO-LMD (adapted) and RANO-BM criteria. Computed tomography (CT) scans/positron emission tomography–CT will evaluate extracranial disease according to RECIST criteria at screening and every 12 weeks. All patients will be followed for survival from the date of the last dose until death, lost to follow-up, or consent withdrawal. Symptom burden and quality-of-life assessments will be conducted throughout the study. Eligible patients are adults with HER2+ breast cancer, ECOG status ≤3, and newly diagnosed untreated LMD (defined as positive CSF cytology and/or radiographic evidence of LMD, plus clinical signs/symptoms). Patients with a history of treated brain metastases or concurrent/new brain metastases are allowed. Patients previously treated with tucatinib or capecitabine (within the past 12 months) are excluded.

The primary end point for the study is overall survival, with secondary end points that include safety, CNS progression-free survival (PFS) at 12 weeks, overall response rate and chemical-biologic-radiologic response in CNS and extra-CNS disease, and symptom burden/quality of life. For the interim analysis, the authors will define success to be CNS PFS for 12 weeks. Enrollment will be stopped if there are <2 successes in the first 15 patients. If the trial continues to completion, the regimen will be considered worthy of future study if the median overall survival is ≥4.4 months. The study is currently active at The University of Alabama at Birmingham and MD Anderson Cancer Center, and additional Translational Breast Cancer Research Consortium sites throughout the country will be activated this year.


  1. Murthy RK, et al. SABCS 2019. Abstract OT2-01-02.

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