The small-molecule tyrosine kinase inhibitor tucatinib outperformed placebo against brain metastases.

  • Major Finding: The small-molecule tyrosine kinase inhibitor tucatinib outperformed placebo against brain metastases.

  • Concept: Adding tucatinib to trastuzumab plus capecitabine extended overall survival by more than six months.

  • Impact: Although exploratory, this work shows the promise of tucatinib for brain-metastatic HER2+ disease.

Brain metastases, which arise in half of patients with metastatic HER2-positive breast cancer, are difficult to treat and a major cause of mortality. Lin and colleagues conducted exploratory analyses on a subset of data from the randomized, controlled, double-blinded HER2CLIMB trial, specifically focusing their investigation on the utility of the small-molecule oral tyrosine kinase inhibitor tucatinib in patients with brain-metastatic HER2-positive breast cancer. Among the 612 patients enrolled in the HER2CLIMB trial, 291 (48%) had brain metastases or a history of brain metastases; these 291 patients were the subject of this work. Most of these patients (87.3%) had undergone prior treatment for their brain metastases, including surgery and/or whole-brain or targeted radiation therapy. With regard to overall survival (OS), the results in the tucatinib arm (tucatinib plus the HER2 antibody trastuzumab and the cytotoxic chemotherapy drug capecitabine) were superior to those in the control arm (placebo plus trastuzumab and capecitabine), with median OS values of 18.1 months in the tucatinib group and 12.0 months in the control group. Importantly, the survival benefit of tucatinib was mostly seen in the 174 patients with active brain metastases, in whom the median OS was 20.7 months with tucatinib versus 11.6 months with placebo; in the 117 patients with stable brain metastases, the median OS was 15.7 months with tucatinib versus 13.6 months with placebo. However, tucatinib showed signs of central nervous system (CNS) activity in both groups, with CNS progression-free survival being 9.9 months with tucatinib versus 4.2 months with placebo among all patients, 9.5 months versus 4.1 months among patients with active brain metastases, and 13.9 months versus 5.6 months in patients with stable brain metastases. Although limited by its exploratory nature, this analysis supports the notion that tucatinib is an agent of interest in specifically treating brain metastases in patients with HER2-positive breast cancer, a topic worth investigating prospectively in future trials.

Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. Jour Clin Oncol 2020 May 29 [Epub ahead of print].

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