FDA Approval Summary: Abemaciclib With Endocrine Therapy for High-Risk Early Breast Cancer

Abstract

PURPOSE The US Food and Drug Administration approved abemaciclib in combination with endocrine therapy (ET) for the adjuvant treatment of adult patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative, node-positive, early breast cancer (EBC) at high risk of recurrence and a Ki-67 score ≥ 20%. PATIENTS AND METHODS The approval was based on monarchE, a phase III, open-label, 2-cohort, multicenter trial of patients with EBC randomly assigned to receive abemaciclib plus ET (n = 2,808) or ET alone (n = 2,829). Abemaciclib was given at 150 mg orally twice daily for 2 years. RESULTS Invasive disease-free survival (IDFS) in the intent-to-treat population was statistically significant at the second IDFS interim analysis (IA; March 2020; hazard ratio [HR; 95% CI], 0.747 [0.598 to 0.932]; P = .0096); however, only 12.5% of patients had completed adjuvant therapy, and the HR for overall survival (OS) was > 1. A prespecified, controlled analysis of IDFS in patients with Ki-67 ≥ 20% in cohort 1 was statistically significant at the final IDFS analysis (July 2020; HR [95% CI], 0.643 [0.475 to 0.872]; P = .0042). At the first OS IA (April 2021), the majority of patients had completed adjuvant therapy, IDFS remained consistent, and potential detriment in OS was not observed for this subgroup (HR [95% CI], 0.767 [0.511 to 1.152]). The HR for OS in the intent-to-treat population at OS IA remained > 1 (HR [95% CI], 1.091 [0.818 to 1.455]). More patients in the abemaciclib plus ET arm experienced treatment emergent adverse events (all grades 98.4% v 88.8%, grade 3 ≥ 49.7% v 16.3%). CONCLUSION The approval of abemaciclib in adjuvant EBC was limited to patients with high risk of recurrence and Ki-67 ≥ 20%, given their favorable benefit:risk with a statistically significant IDFS advantage and no observed detriment on survival.

Association of Ki-67 Change Pattern After Core Needle Biopsy and Prognosis in HR+/HER2− Early Breast Cancer Patients

“…Nonetheless, due to the positive results from the MonarchE study, Ki-67 ≥ 20% is necessary for choosing the adjuvant abemaciclib treatment in HR+/HER2− early breast cancer patients (25,26). In our cohort, 16.9% of patients had Ki-67 level <20% in CNB but ≥20% on surgical specimens and they would potentially become candidates for adjuvant CDK 4/6 inhibitor.…”

“…Future studies may focus on topographical localizations of the Ki-67 expressing cells and expression levels of wound healing proteins to evaluate the association of wound healing reaction with Ki-67 change. Nonetheless, due to the positive results from the MonarchE study, Ki-67 ≥ 20% is necessary for choosing the adjuvant abemaciclib treatment in HR+/HER2− early breast cancer patients ( 25 , 26 ). In our cohort, 16.9% of patients had Ki-67 level <20% in CNB but ≥20% on surgical specimens and they would potentially become candidates for adjuvant CDK 4/6 inhibitor.…”

“…In the neoadjuvant setting, Ki-67 can be used as a surrogate of pCR to monitor treatment response and thus tailor decision-making in HR+/HER2− breast cancer, as in the IMPACT, POETIC, and WSG ADAPT HR+/HER2− trials (22)(23)(24). Moreover, Ki-67 ≥ 20% is used as an inclusion criterion in some clinical trials such as the MonarchE which evaluates the efficiency of an adjuvant CDK4/6 inhibitor in early high-risk HR+/HER2− breast cancer patients (25,26).…”

Improving Outcomes for High-Risk Hormone Receptor–Positive Breast Cancer With CDK Inhibition

“…Case 2, although similarly high risk, would not qualify for the addition of abemaciclib to ET on the basis of the FDA approval, given that the expression of Ki67 both before and after treatment is < 20%. There was considerable discussion regarding the use of adjuvant abemaciclib in this patient, and although most leaned toward recommending it, an extensive discussion of risks, as nicely outlined by Royce et al, 9 and benefits with this patient is clearly warranted.…”

“…Results of the Monarch E trial 4 led to the recent approval of adjuvant abemaciclib in patients with high-risk, node-positive breast cancer with a Ki67 expression of ≥ 20%. The rationale behind the decision to focus specifically on breast cancers with high expression of Ki67 is explained in the companion to this article by Royce et al 9…”