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.