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

Abstract

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 þ) metastatic breast cancer (MBC). Secondary objectives evaluated extracranial response, abemaciclib pharmacokinetics, brain metastases tissue exposure, and safety. Patients and Methods: This nonrandomized, phase II study (NCT02308020) enrolled patients in tumor subtype-specific cohorts AD: A (HR þ , HER2 À MBC), B (HR þ , HER2 þ MBC), C (HR þ 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. Results: In cohort A (n ¼ 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 (n ¼ 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 (n ¼ 10), one confirmed complete parenchymal response was observed. In cohort D (n ¼ 9), unbound brain metastases concentrations of total active abemaciclib analytes were 96-[cyclindependent kinase 4 (CDK4)] and 19-fold (CDK6) above in vitro IC 50. Safety was consistent with prior studies. Conclusions: This study did not meet its primary endpoint. Abemaciclib was associated with an iCBR of 24% in patients with heavily pretreated HR þ , HER2 À 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 abemaciclibbased combinations.

Endocrine therapy for the treatment of leptomeningeal carcinomatosis in luminal breast cancer: a comprehensive review

“…Also, in the setting of ABC, metastatic CNS disease has historically been excluded from most clinical trials. This reality is changing, and in recent years trials have been designed to specifically approach CNS metastasis [55,65], some of them, in particular those in HER2+ disease [66,67], with promising results. Despite this, LMD continues to be understudied, and evidence for optimal treatment in BC-LMD is still limited [67].…”

Treatment strategies for breast cancer brain metastases

“…A subgroup of 8 patients in this study had surgical resection of BM while undergoing treatment, and it was shown in the resected samples that therapeutic levels of abemaciclib were reached in BM, demonstrating abemaciclib and its active metabolites penetrated the BBB. 89 For patients with triple-negative BCBM, two chemotherapy regimens seem to show specific CNS activity: the anti-vascular endothelial growth factor agent bevacizumab plus paclitaxel in a small Phase 2 study (70% ORR but only 6 patients with triplenegative MBC) 90 and the microtubule inhibitor eribulin in case reports. 91 A Phase 2 trial presented at ASCO 2013 highlighted a combination of bevacizumab plus carboplatin in the treatment of BCBM.…”

The Underlying Biology and Therapeutic Vulnerabilities of Leptomeningeal Metastases in Adult Solid Cancers

“…To date, a small number of clinical trials have been reported specifically studying systemic treatments for breast cancer, lung cancer, and melanoma LM [ 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ], a small subset of which were randomized studies [ 71 , 72 , 73 , 75 , 89 , 90 ]. Several of these studies employ an intrathecal administration of chemotherapy, meaning that the agents are injected directly into the CSF.…”

“…A systemic treatment with small-molecule targeted agents also plays an important role in the management of LM. These therapies include the standard targeted agents used for a particular tumor type defined by specific molecular features, such as abemaciclib (ER+) and trastuzumab (HER2+) for breast cancer LM, EGFR inhibitors in EGFR mutant lung cancer LM, and BRAF + MEK inhibition in BRAF mutant melanoma LM [ 51 , 83 ]. Most recently, the third-generation mutant EGFR inhibitor, osimertinib, has shown substantial activity in controlling LM from the EGFR mutant lung cancer [ 78 ].…”