The combination of adjuvant abemaciclib and endocrine therapy led to a clinically meaningful benefit at 3 years in patients with hormone receptor–positive, HER2-negative, node-positive, early breast cancer.
The combination of adjuvant abemaciclib (Verzenio) and endocrine therapy (ET) led to a clinically meaningful benefit at 3 years in patients with hormone receptor (HR)–positive, HER2-negative, node-positive, early breast cancer, as seen in longer follow-up from the phase 3monarchE trial (NCT03155997) that was presented during the 39th Annual Miami Breast Cancer Conference®.1
At the 3-year mark, abemaciclib and ET achieved a 30.4% reduction in the risk of developing an invasive disease-free survival (iDFS) event, showing an absolute difference of 5.4% compared with the standard of care arm of ET alone.
In an earlier analysis of the study, abemaciclib/ET showed clinical meaningful improvement in both iDFS and distant relapse-free survival (DRFS), showing positive results for the primary end point and 1 key secondary end point. Once the threshold for statistical significance was reached, follow-up in the monarchE trial was limited with a median 15.5 months. The combination of abemacilib and ET was granted FDA approval in October 2021 for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score of ≥ 20% (high Ki-67) with supportive data from monarchE.2
The newly presented data were based on a median follow-up of 27 months carried out at the request of health authorities.1
The monarchE study included 5,637 patients with HR-positive, HER2-negative, high-risk early breast cancer. Patients were divided into 2 cohorts based on clinical pathological features. Those in cohort 1 had ≥ 4 axillary lymph nodes (ALN) or 1-3 ALN along with either grade 3 disease or a tumor size of ≥ 5 cm. In cohort 2, patients had 1-2 ALN and a Ki-67 ≥ 20% with no grade 3 disease and a tumor size of ≥ 5 cm. Both cohorts 1 and 2 represented the intention-to-treat population.
Patients were randomized 1:1 to received abemaciclib 150 mg twice daily with ET or ET alone. The patients were on study treatment for 2 years with a 3 to 8-year follow-up period receiving ET. Patients were stratified by prior chemotherapy, menopausal status, and region to evaluate the primary end point (iDFS), and the secondary end points which included iDFS in the high Ki-67 population, DRFS, overall survival (OS), safety, pharmacokinetics, and patient-reported outcomes.
Of the 2,808 patients in the abemaciclib/ET arm, 84.4% were less than 65 years old with a median age of 51 years (range, 23-89). Only 4.5% did not have prior chemotherapy. Of those who received prior chemotherapy, 37.0% were treated in the neoadjuvant setting and 58.5% were treated in the adjuvant setting. In terms of menopausal status, 43.5% of the experimental arm population were premenopausal, and 56.5% were postmenopausal.
In the ET-only arm, there were 2,829 patients and 85.4% of them were younger than 65 years with a median population age of 51 years (range, 22-86). Prior chemotherapy was given in the neoadjuvant setting to 37.0% of the group and in the adjuvant setting to 58.2% of the group, and only 4.7% did not received prior chemotherapy. Matching the characteristics of the experimental arm, 43.5% of those treated with ET alone were premenopausal and 56.5% were postmenopausal.
Results showed that the addition of abemaciclib had an increasing magnitude of iDFS and DRFS effect size between year 1 and year 2. The benefit was maintained beyond the 2-year treatment period. Using a piecewise hazard ratio (HR) to assess yearly treatment effect size, at the 1-2 landmark analysis, there were 98 iDFS events in the combination arm versus 146 in the ET arm (piecewise HR, 0.681; 95% CI, 0.523-0.869). DRFS event were observed in 85 patients in the combination arm versus 129 in the ET arm (piecewise HR, 0.675; 95% CI, 0.507-0.875).
Landmark analysis data for year 2 and beyond showed 41 iDFS event with abemaciclib/ET versus 71 with ET alone (piecewise HR, 0.596; 95% CI, 0.397-0.855). DRFS events were seen in 39 patients in the abemaciclib/ET arm compared with 58 events in the ET-only arm (piecewise HR, 0.692; 95% CI, 0.448-1.032).
Efficacy was also investigated in the Ki-67 subgroups among patients with high Ki-67 in the ITT population. With abemaciclib plus ET, the 2-year iDFS rate was 91.9% versus 87.9% with ET alone. The 3-year iDFS rate with abemaciclib/ET was 86.8% compared with 80.8% with ET alone. Overall, there were 18 iDFS events observed in the abemaciclib-containing arm versus 172 with ET alone (HR, 0.663; 95% CI, 0.524-0.839; nominal P =.0006) showing a 33.7% reduction in the risk of developing an iDFS event with abemaciclib plus ET. The absolute difference at 3 years.
Among the cohort 1 patients with high Ki-67, the 2-year iDFS rate was 91.5% with abemaciclib/ET compared with 86.4% with ET alone. At 3 years, the iDFS rate was 86.1% versus 79.0%, respectively. Looking at the number of iDFS events, there were 104 in the abemaciclib/ET arm compared with 158 in the ET-only arm (HR, 0.626; 95% CI, 0.488-0.803; nominal P =.0002). The reduction in the risk of developing an iDFS event with abemaciclib/ET versus ET alone was 37.4% for an absolute difference of 7.1% at 3 years.
Based on findings from cohort 1, high Ki-67 may be predictive of worse outcomes, even though the combination of abemaciclib and ET demonstrated benefit regardless of Ki-67 index.
As of the data cutoff data, 90% of the patients in monarchE are off treatment and safety data are mature. Overall, the safety profile of abemaciclib in the study is consistent with the known safety profile of the agent and was acceptable for patients with high-risk early breast cancer.
All patients who received at least 1 dose of treatment were evaluated for safety. The median duration of abemaciclib was 23.7 months in the study. The most common any-grade adverse events (AEs) with abemaciclib/ET were diarrhea (84%), neutropenia (46%), fatigue (41%), and leukopenia (38%). In the ET-alone arm, the most common any-grade AEs were arthralgia (38%), hot flush (23%), fatigue (18%), and abdominal pain (10%). Few grade 3 or higher AEs were observed in either treatment arm.
Other any-grade events of interest occurring in the abemaciclib/ET arm versus the ET-only arm were venous thromboembolism (2.5% vs 0.6%), pulmonary embolism 1.0% vs 0.1%, and interstitial lung disease (3.2% vs 1.3%).
Overall, the benefit of abemaciclib in combination with SOC was considered robust in terms of IDFS and DRFS. Follow-up in the study is ongoing to assess final OS results of abemaciclib/ET in patients with HR-positive, HER2-negative, high-risk early breast cancer.