Benefit of adjuvant abemaciclib deepens at 4-year landmark analysis in high-risk HR+/HER2- breast cancer patients

The monarchE trial previously demonstrated that adjuvant abemaciclib combined with endocrine therapy (ET) significantly improves invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) vs. ET alone in high-risk, HR+/HER2-, node-positive early breast cancer patients. After four years of follow-up, the benefit of adjuvant abemaciclib deepened in magnitude, with an increase in absolute IDFS and DRFS benefit compared to 2-3 year rates.

Previously, results from the monarchE trial demonstrated that adjuvant abemaciclib combined with endocrine therapy (ET) significantly improves invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in high-risk, HR+/HER2-, node positive early breast cancer (EBC) patients. At the time statistical significance was first met, follow-up was limited (median of 15.5 months). However, a subsequent analysis confirmed that abemaciclib treatment benefit persisted beyond the 2-year treatment period. At SABCS 2022, the results of a pre-planned OS interim analysis were presented. This analysis was performed two years following the primary analysis (median follow-up of 42 months), when all patients were off abemaciclib.

Study design

The monarchE trial recruited high-risk node-positive HR+ HER2- EBC patients. Overall, 95% of the patients had received (neo)adjuvant chemotherapy, indicating a high level of risk. Patients with metastatic disease were excluded. The intention-to-treat (ITT) population consisted of two cohorts. Cohort 1 (91% of the patients) included patients with high risk based on clinical pathological features (≥4 axillary lymph nodes [ALN] or 1-3 ALN with  grade 3 disease or tumour size ≥ 5 cm). While the proliferation biomarker Ki-67 was centrally assessed in all patients with available tissue sample, an additional smaller group of patients with 1-3 positive ALN and central Ki-67 ≥20% as the only high-risk feature were included (Cohort 2). All patients were randomised 1:1 to ET for up to ten years with or without abemaciclib (150 mg twice daily) for two years. Thereafter, adjuvant endocrine therapy was administered for a period of 3-8 years. Primary endpoint was IDFS. Key secondary endpoints included DRFS and OS.

Results

After a median follow-up of 42 months, the IDFS benefit of abemaciclib persisted beyond completion of abemaciclib, suggesting a carry-over effect. There was a 33.6% reduction in the risk of developing an IDFS event with abemaciclib (HR[95%CI]: 0.664[0.578-0.762], p< 0.0001). In four years, the absolute benefit in IDFS rates was 6.4% in favour of abemaciclib, compared to 4.8% and 2.8% at three and two years. Consistent IDFS benefit was observed in all prespecified subgroups. DRFS benefit of abemaciclib also persisted beyond treatment completion, and there was a 34.1% reduction in the risk of developing a DRFS event in the abemaciclib+ET arm (HR[95%CI]: 0.659[0.567-0.767], p< 0.0001). At four years, the absolute difference in DRFS rates was 5.9% in favour of abemaciclib+ET vs. ET alone, compared to 4.1% and 2.5% at three and two years. In an exploratory analysis, HRs were estimated within each year for both IDFS and DRFS, showing that the magnitude of abemaciclib benefit increases year after year beyond completion of the study treatment period, again suggesting a potential carry-over effect. OS data remain immature in the ITT population. However, a numerical difference can be observed between abemaciclib+ET and ET arms, with 157 vs. 173 deaths, respectively ([HR[95%CI]: 0.929[0.748-1.153]; p= 0.5027). Among the patients who developed a DRFS event, namely death of any cause or metastatic event, there were 118 vs. 139 deaths due to breast cancer in the abemaciclib+ET and ET arms, and 125 vs. 249 patients developed metastatic disease but were still alive.  In the efficacy analysis by subpopulations of the trial, HRs in cohort 1 were 0.653, 0.652 and 0.890 for IDFS, DRFS and OS, respectively. In cohort 2, the number of events were still too few and the data was too immature to draw conclusions. As previously described, within Cohort 1, a Ki-67 index of ≥20% was associated with a worse prognosis, but similar abemaciclib treatment effects were observed regardless of Ki-67 index. Safety was consistent with previous analysis and no new safety signals were observed.

Conclusions

With additional follow-up, the benefit of adjuvant abemaciclib deepened in magnitude, with an increase in absolute IDFS and DRFS benefit at 4 years as compared to 2-3 year rates. Abemaciclib benefit appeared to be independent of the Ki-67 index. While OS data remain immature at this time, fewer deaths were observed with abemaciclib+ET vs. ET alone. These data further support the addition of adjuvant abemaciclib to ET for patients with HR+ HER2-, node-positive, high-risk EBC.

Reference

Johnston S, Toi M, O’Shaughnessy J, et al. Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: results from a pre-planned monarchE overall survival interim analysis, including 4-year efficacy outcomes. Presented at SABCS 2022; Abstract GS1-09.