With 27 months median follow-up and 90% of patients having completed or discontinued the 2 year study treatment period, invasive disease-free survival (IDFS) benefit deepened and distant relapse-free survival (DRFS) benefit was maintained in patients with hormone receptors (HR)-positive, HER2-negative, node-positive, high risk early breast cancer treated with adjuvant CDK4/6 inhibitor, abemaciclib and endocrine therapy. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Safety profile was tolerable and manageable. Updated results from the monarchE study were presented by Dr. Joyce O’Shaughnessy of the Baylor University Medical Center, Texas Oncology and US Oncology in Dallas, TX, USA on 14 October 2021 at the ESMO Virtual Plenary session and also published in the Annals of Oncology by Prof. Nadia Harbeck of Brustzentrum, LMU Klinikum in Munich, Germany and colleagues. 

At a previous preplanned interim analysis, monarchE met its primary endpoint when abemaciclib plus endocrine therapy demonstrated a statistically significant improvement in IDFS in the intent-to-treat (ITT) population compared with endocrine therapy alone. Now the monarchE researchers present updated results from the prespecified primary outcome analysis and an additional follow-up analysis, conducted at regulatory request. Outcomes are also reported from prespecified subpopulations based on Ki-67 levels.

The monarchE is a global, phase III, open-label, randomised (1:1) study conducted in 5637 patients with HR-positive, HER2-negative, node-positive, high risk early breast cancer who received either adjuvant endocrine therapy for ≥5 years with or without abemaciclib for 2 years. Cohort 1 enroled patients with ≥4 positive axillary lymph nodes, or 1-3 positive axillary lymph nodes and either grade 3 disease or tumour ≥5 cm. Cohort 2 enroled patients with 1-3 positive axillary lymph nodes and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the ITT population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety.

The study team reported that the magnitude of IDFS benefit deepened (hazard ratio [HR] 0.696, 95% confidence interval [CI] 0.588, 0.823; nominal p < 0.0001) and DRFS benefit was maintained (HR 0.687, 95% CI 0.571, 0.826; nominal p < 0.0001). At 3 years, absolute improvement in IDFS and DRFS rates were 5.4% and 4.2%, respectively. Abemaciclib benefit deepened during the treatment period and persisted after the 2 years treatment period.

Estimated IDFS rates in the control arm of Cohort 1 (Ki-67 high versus low) confirmed the prognostic value of Ki-67. However, abemaciclib benefit was consistent regardless of Ki-67 index.

Safety data were consistent with the known abemaciclib risk profile.

The authors concluded that the robust treatment benefit of abemaciclib extended beyond the 2 year treatment period. High Ki-67 was prognostic, but not predictive of abemaciclib benefit. Ki-67 ≥20% may be used with clinicopathological features to identify patients at high risk of recurrence. Safety data were consistent with the known abemaciclib risk profile and safety profile remains acceptable for patients with early breast cancer treated with curative intent.

The study was funded by Eli Lilly and Company.

FDA approves abemaciclib with endocrine therapy for early breast cancer

On 12 October 2021, the Food and Drug Administration (FDA) approved abemaciclib (Verzenio, Eli Lilly and Company) with endocrine therapy (tamoxifen or an aromatase inhibitor) for adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score ≥20%, as determined by an FDA approved test.

This is the first CDK 4/6 inhibitor approved for adjuvant treatment of breast cancer.

FDA also approved the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay, submitted by Agilent, Inc., as a companion diagnostic for selecting patients for this indication.

Efficacy was evaluated in monarchE (NCT03155997), a randomised (1:1), open-label, two-cohort multicentre study that included adult women and men with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathological features consistent with a high risk of disease recurrence. Patients were randomised to receive either 2 years of abemaciclib plus their physician’s choice of standard endocrine therapy or standard endocrine therapy alone.

The major efficacy outcome measure was IDFS. In patients with high risk of recurrence and Ki-67 score ≥20% (N=2003), the study demonstrated a statistically significant improvement in IDFS (HR 0.626; 95% CI 0.488, 0.803; p = 0.0042). IDFS at 36 months was 86.1% (95% CI 82.8, 88.8) for patients receiving abemaciclib plus tamoxifen or an aromatase inhibitor and 79.0% (95% CI 75.3, 82.3) for those receiving tamoxifen or an aromatase inhibitor. Overall survival data were not mature at the time of the IDFS analysis.

The most common adverse reactions (≥20%) were diarrhoea, infections, neutropenia, fatigue, leukopenia, nausea, anaemia, and headache.

The recommended abemaciclib starting dose is 150 mg taken twice daily in combination with tamoxifen or an aromatase inhibitor until completion of 2 years of treatment or until disease recurrence, or unacceptable toxicity.

Full prescribing information for Verzenio is available here.

This review used the Real-Time Oncology Review pilot programme, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA’s Oncology Center of Excellence Project Excellence.