Although a lower percentage of patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) develop brain metastases when compared with patients with triple-negative and HER2-positive MBC, no systemic agents are approved for the treatment of brain metastases in patients with HR-positive breast cancer, and this remains an unmet medical need. Standard local treatment options include surgery, stereotactic radiosurgery, and/or whole-brain radiation therapy.
Abemaciclib, an oral selective CDK4/6 inhibitor administered on a continuous dosing schedule, has demonstrated clinical activity and an acceptable safety profile in heavily pretreated patients with HR-positive MBC.1 Preclinically, abemaciclib crosses the blood‒brain barrier, which is further supported clinically by detectable levels of abemaciclib similar to plasma levels in resected brain metastases in a subset of patients with HR-positive/HER2-negative MBC, as previously reported.2 These data provided a rationale for evaluating abemaciclib in patients with brain metastases.
The current study was an open-label, phase 2, Simon’s 2-stage trial evaluating the safety and efficacy of abemaciclib up to 200 mg twice daily in 4 cohorts of patients with brain metastases secondary to HR-positive MBC, non–small-cell lung cancer, or melanoma.3 Regarding HR-positive MBC, one cohort included HR-positive/HER2-negative patients, and another included HR-positive/HER2-positive patients. All HR-positive MBC patients enrolled to 1 of these 2 cohorts were required to have ≥1 measurable brain lesions. The primary objective was objective intracranial response rate as defined by Response Assessment in Neuro-Oncology Brain Metastases response criteria. Stage 1 was to enroll 23 evaluable patients per study part; if <2 responded, accrual was to be stopped. If ≥2 responded to abemaciclib, 33 additional evaluable patients were to be enrolled to stage 2. In stage 2, a response in 6 patients is required to warrant further investigation of abemaciclib in this patient population.
For stage 1 efficacy, in patients with HR-positive/HER2-positive MBC, futility was met. However, for HR-positive/HER2-negative patients, 2 confirmed, durable partial responses were observed, and enrollment to stage 2 is ongoing.
Previously, this study provided evidence that abemaciclib penetrates brain metastases in patients with HR-positive/HER2-negative MBC. The current results provided sufficient evidence of antitumor activity on brain metastases in patients with HR-positive/HER2-negative MBC, with an overall response rate of 8.7% and clinical benefit rate of 17.4%, to merit further exploration, but not for patients with HR-positive/HER2-positive disease. Safety and tolerability results were similar to those previously reported for abemaciclib, with the majority of adverse events being gastrointestinal (82.6% of patients with HR-positive/HER2-negative MBC and 65.2% of patients with HR-positive/HER2-positive MBC experienced diarrhea).
1. Dickler MN, et al. Clin Cancer Res. 2017;23:5218-5224.
2. Torres-Guzmán R, et al. Oncotarget. 2017;8:69493-69507.
3. Bachelot T, et al. SABCS 2017. Abstract P1-17-03.