On March 3, 2023, the FDA approved abemaciclib (Verzenio; Eli Lilly and Company), a CDK4/6 inhibitor, with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence. High risk is defined as having either ≥4 pathological axillary lymph nodes (pALNs) or 1 to 3 pALNs and either tumor grade 3 or a tumor size ≥50 mm. The FDA granted this application priority review.
Abemaciclib was previously approved for this high-risk population but only for patients with a Ki-67 score ≥20%, and this approval removes the Ki-67 testing requirement.
This expanded eligibility of abemaciclib also included the treatment of patients with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based treatment; abemaciclib in combination with fulvestrant for disease that progressed after endocrine therapy; and abemaciclib as monotherapy for disease that progressed after endocrine therapy and previous chemotherapy in the metastatic setting.
“The initial Verzenio FDA approval in early breast cancer was practice-changing and now, through this indication expansion, we have the potential to reduce the risk of breast cancer recurrence for many more patients, relying solely on commonly utilized clinicopathologic features to identify them,” said trial investigator Erika P. Hamilton, MD, Director of Breast and Gynecologic Cancer Research at Sarah Cannon Research Institute, Nashville, TN.
This FDA approval was based on results of the phase 3 monarchE clinical trial (NCT03155997), a randomized (1:1), open-label, 2-cohort, multicenter study including adult women and men with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathological features associated with a high risk of recurrence.
Inclusion in cohort 1 required having either ≥4 pALNs or 1 to 3 pALNs and either tumor grade 3 or a tumor size ≥50 mm; for cohort 2, patients could not be eligible for cohort 1 and must have had 1 to 3 pALNs and tumor Ki-67 score ≥20%. Patients were randomly assigned to receive either 2 years of either abemaciclib plus standard endocrine therapy with tamoxifen or an aromatase inhibitor (per physician’s choice) or standard endocrine therapy alone.
Invasive disease–free survival (DFS) was the primary efficacy measure. In the intent-to-treat population, a statistically significant difference was seen, which was primarily attributed to the patients in cohort 1 (N = 5120 [91%]; invasive DFS hazard ratio, 0.653; 95% confidence interval [CI], 0.567-0.753). At 48 months, 85.5% (95% CI, 83.8-87.0) of the abemaciclib plus standard endocrine therapy group had invasive DFS, whereas the invasive DFS rate in the standard endocrine therapy alone group was 78.6% (95% CI, 76.7-80.4).
The overall survival data were immature at the time of this approval; however, in cohort 2, more deaths occurred with abemaciclib plus standard endocrine therapy versus standard endocrine therapy alone (10/253 vs 5/264). Because of this, the indication was restricted to cohort 1.
The most common (≥20%) adverse events included diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache.
The recommended starting dose of abemaciclib is 150 mg twice daily with tamoxifen or an aromatase inhibitor through 2 years of treatment or until disease recurrence or unacceptable toxicity.