Around 70% of patients with early-stage breast cancer (EBC) have hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) disease. The treatment approach for these patients depends on the risk of recurrence and may include combinations of surgery, radiotherapy, neo/adjuvant chemotherapy, and endocrine therapy (ET). For the majority of patients, the current standard treatments significantly reduce the risk of distant recurrence. However, up to 30% of patients have clinical and pathological characteristics of high-risk disease and often experience distant disease recurrence, especially in the first few years on adjuvant ET, with a negative impact on prognosis. Thus, there is an unmet need to optimize adjuvant therapy to overcome primary resistance to ET and prevent metastatic recurrences for these high-risk patients.

Given the proven efficacy and safety of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in the metastatic setting, the global, open-label, randomized phase III monarchE trial was initiated to explore the efficacy of abemaciclib when added to standard adjuvant ET in patients with HR+, HER2-, node-positive high-risk EBC. High risk was defined as ≥4 positive pathologic axillary lymph nodes or 1–3 positive axillary lymph nodes plus at least one of the following: tumor size ≥5 cm, histologic grade 3, or centrally assessed Ki-67 ≥20%. Results from a pre-planned efficacy interim analysis were presented by Stephen Johnston, MD, PhD (Royal Marsden Hospital NHS Foundation Trust, London, UK) at the ESMO 2020 virtual meeting and were simultaneously published in the Journal of Clinical Oncology. A total of 5,637 patients, who had undergone surgery and may have received radiotherapy and/or adjuvant/neoadjuvant chemotherapy, were randomly assigned to receive abemaciclib (150 mg twice daily for 2 years) plus adjuvant ET, or adjuvant ET alone. The primary endpoint was invasive disease-free survival (IDFS); secondary endpoints included distant relapse-free survival (DRFS), overall survival (OS), and safety. Median follow-up was approximately 15.5 months in both arms. Abemaciclib combined with ET showed a statistically significant improvement in IDFS (hazard ratio [HR], 0.75; P=0.01) with a 3.5% absolute improvement in 2-year IDFS rates (92.2% versus 88.7%). Treatment benefit was consistent across all prespecified subgroups. The greatest reduction in distant metastases was to the liver and bone. Similarly, DRFS was significantly improved with abemaciclib plus ET versus ET alone (HR, 0.72; nominal P=0.01), with 2-year rates of 93.6% versus 90.3%, respectively. OS data were immature, and the study will continue to a final analysis of OS. The most frequent treatment-related adverse events (AEs) in the abemaciclib plus ET arm were diarrhea, neutropenia, and fatigue, with the majority being grade 1/2. Diarrhea was effectively managed with antidiarrheal medication and dose adjustments. AEs led to dose reductions in 41.2% of patients in the abemaciclib plus ET arm, and treatment was discontinued in 16.5% of patients (4.8% due to diarrhea) versus 0.8% with ET alone. Of note, arthralgia and hot flushes – common AEs associated with ET alone – were significantly reduced by 30% in patients who received abemaciclib plus ET.

The investigators concluded that abemaciclib is the first CDK 4/6 inhibitor to show a significant clinically meaningful improvement in IDFS when combined with ET compared with ET alone in patients with HR+, HER2-, node-positive EBC at high risk of early recurrence. In an accompanying editorial, Antonio Wolff, MD (The Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, US) commented that the data from the positive monarchE trial are “unequivocal”, suggesting a potential new role for CDK4/6 inhibition in the management of patients with high-risk EBC. However, he cautioned that the long-term impact of adjuvant CDK4/6 inhibitors in this setting is unclear and noted that the biology of early versus late disease recurrence may be different. He stressed the importance of long-term follow-up to properly assess the role of CDK4/6 inhibition in high-risk EBC.

References

Johnston SRD, et al. J Clin Oncol. 2020 Sep 20; JCO2002514 [Online ahead of print].

Wolf AC. J Clin Oncol. 2020 Sep 20; JCO2002688 [Online ahead of print].