A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor-Positive Breast Cancer

The primary objective was to evaluate intracranial objective response rate (iORR) in patients receiving abemaciclib with brain or leptomeningeal metastases (LM) secondary to hormone receptor-positive (HR ) metastatic breast cancer (MBC). Secondary objectives evaluated extracranial response, abemaciclib pharmacokinetics, brain metastases tissue exposure, and safety. This nonrandomized, phase II study (NCT02308020) enrolled patients in tumor subtype-specific cohorts A-D: A (HR , HER2 MBC), B (HR , HER2 MBC), C (HR MBC LM), and D (brain metastases surgical resection). Abemaciclib 200 mg was administered twice daily as monotherapy or with endocrine therapy, or 150 mg twice daily with trastuzumab. Cohorts A and B used a Simon two-stage design. In cohort A ( = 58), 3 patients were confirmed responders resulting in an iORR of 5.2% [95% confidence interval (CI), 0.0-10.9], and the intracranial clinical benefit rate (iCBR) was 24% (95% CI, 13.1-35.2). Median overall survival (OS) was 12.5 months (95% CI, 9.3-16.4). A volumetric decrease in target intracranial lesions was experienced by 38% of patients. In cohort B ( = 27), there were no confirmed intracranial responses. An iCBR of 11% (95% CI, 0.0-23.0) was observed. Median OS was 10.1 months (95% CI, 4.2-14.3). A volumetric decrease in target intracranial lesions was experienced by 22% of patients. In cohort C ( = 10), one confirmed complete parenchymal response was observed. In cohort D ( = 9), unbound brain metastases concentrations of total active abemaciclib analytes were 96- [cyclin-dependent kinase 4 (CDK4)] and 19-fold (CDK6) above IC . Safety was consistent with prior studies. This study did not meet its primary endpoint. Abemaciclib was associated with an iCBR of 24% in patients with heavily pretreated HR , HER2 MBC. Abemaciclib achieved therapeutic concentrations in brain metastases tissue, far exceeding those necessary for CDK4 and CDK6 inhibition. Further studies are warranted, including assessing novel abemaciclib-based combinations.