On October 12, 2021, the FDA approved abemaciclib (Verzenio) in combination with endocrine therapy (ET) (i.e., tamoxifen or an aromatase inhibitor [AI]]) for the adjuvant treatment of adult patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-), node-positive, early breast cancer (EBC) with a high risk of recurrence and a Ki-67 score >20%.

Abemaciclib is an oral, continuously dosed, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. This drug approval was based on the monarchE study, which was an open-label, global, phase III, randomized trial comparing adjuvant ET for at least 5 years with or without abemaciclib given for 2 years in patients with EBC who met the above receptor and nodal status criteria.

The study consisted of two patient groups: Cohort 1, which included those with either >4 positive axilliary lymph nodes (ALNs) or one to three positive ALNs and tumor size >5 cm and/or histologic grade 3; and Cohort 2, which consisted of patients with one to three ALNs, tumor size <5 cm, grade <3, and a high Ki-67 index defined as >20%. Ki-67 is a biomarker that is associated with tumor proliferation and growth. Cohort 2 was enrolled 1 year after Cohort 1.

Patients were randomized to either adjuvant abemaciclib 150 mg orally twice daily plus ET (i.e., tamoxifen or an AI based on prescriber preference with or without a gonadotropin-releasing hormone) or ET alone for 2 years (treatment period), with ET prescribed for at least 5 years. Patients were further grouped based on prior use of chemotherapy, menopausal status at the time of BC diagnosis, and region.
The primary objective of the study was invasive disease-free survival (IDFS), as defined by the STEEP criteria. monarchE met its primary endpoint when abemaciclib plus ET produced statistically significant improvement in IDFS compared with ET alone in the previous preplanned interim analysis.  

Secondary endpoints included distant relapse-free survival (DRFS), overall survival (OS), IDFS in the Ki-67-high population, and safety. This paper provides updated results from two timepoints, which include the prespecified primary outcome (PO) analysis and an additional follow-up analysis that was requested by regulatory. Most patients had discontinued or completed the study at the time of this extra follow up. A secondary objective was to test the superiority of the combination regimen compared with ET alone in patients with a high Ki-67 index.

A total of 5,637 patients were randomized to receive abemaciclib + ET (n =  2,808) or ET alone (n = 2,829). Of these, 5,120 patients were enrolled in Cohort 1 and 39.1% had tumors with a high Ki-67 index. Investigators found that in Cohort 1, the frequency of grade 3 tumors was higher in patients with high Ki-67 tumor expression. Patients with low Ki-67 index scores had >4 ALNs.

Over 70.0% of patients completed the 2-year treatment period. After a median follow-up period of 19 months, there was a 29% reduction in the risk of developing an IDFS event (hazard ratio [HR] = 0.71, P = .0009). At the additional follow-up analysis, which occurred after a median of 27 months, there was a 30% decrease in the risk of having an IDFS event (HR = 0.70, P <.0001) and a 31% lower risk of having DRFS (HR = 0.69, P <.0001) despite 90% of patients having been off treatment. The absolute improvement at 3 years in IDFS and DRFS rates was 5.4% and 4.3%, respectively.

Abemaciclib's benefit was seen regardless of Ki-67 index score. Although the biomarker was a prognostic factor, it was not predictive of treatment effect from abemaciclib since benefit was seen regardless of Ki-67 status. There was a higher incidence of grade 3 or higher adverse events in the abemaciclib+ ET group versus the ET monotherapy group. These adverse events included diarrhea, neutropenia, and fatigue in the dual-therapy group.

Pharmacists should be aware of this new treatment option for EBC who are at high risk for recurrence.

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