Assessment of concentrations of abemaciclib and its major active metabolites in plasma, CSF, and brain tumor tissue in patients with brain metastases secondary to hormone receptor positive (HR+) breast cancer.

Abstract

526 Background: Abemaciclib, an oral drug administered twice daily on a continuous schedule, is an inhibitor of both cyclin-dependent kinases (CDKs) 4 and 6. A Phase 1 study of abemaciclib showed evidence of single-agent activity in a cohort of patients with heavily pre-treated HR+ metastatic breast cancer (MBC). These findings, coupled with preclinical data demonstrating that abemaciclib crosses the blood-brain barrier, have led to investigation of abemaciclib in the current trial which includes patients with brain metastases secondary to HR+ MBC. Methods: Study JPBO (NCT02308020) is an open-label, Phase 2 trial evaluating the safety and efficacy of doses of abemaciclib up to 200 mg administered orally every 12 hours on Days 1 to 21 of a 21-day cycle in patients with brain metastases secondary to HR+ MBC, NSCLC, or melanoma. An exploratory objective of this study is to assess approximately 8 patients with brain metastases secondary to HR+ MBC, NSCLC, or melanoma for whom surgical resection is clinically indicated, and who agree to provide post-treatment (5 to 14 days after initiating abemaciclib) brain tumor tissue, with the goal of determining concentrations of abemaciclib and its metabolites in plasma, CSF, and brain metastases. These patients may resume treatment with abemaciclib post-operatively. Results: To date, a total of 3 patients (all with HR+, HER2- MBC) have provided post-treatment brain tumor tissue for analysis. All 3 patients were treated for > 5 days with abemaciclib prior to tumor resection; thus, it is anticipated that abemaciclib was at steady state at the time of surgical resection. Measurable levels of abemaciclib and active metabolites were detected in brain tumor tissue for all 3 patients. Unbound concentrations of abemaciclib in the plasma and tumor tissue were comparable and generally consistent with the CSF concentration for each of the patients. Conclusions: These early data suggest that abemaciclib penetrates human breast cancer brain metastases. Further data, related to safety and efficacy, from this ongoing study are necessary to determine the clinical relevance of these findings. Clinical trial information: NCT02308020.