"The data are consistent with a carryover effect and further support the addition of adjuvant abemaciclib to ET for patients with HR-positive, HER2-negative, node-positive, high-risk early breast cancer," according to Nadia Harbeck, MD, PhD.

Patients with hormone receptor (HR)–positive, HER2-negative, node-positive, high-risk early breast cancer experienced benefits with respect to invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) with adjuvant abemaciclib (Verzenio) plus endocrine therapy (ET), according to 5-year efficacy findings from a prespecified overall survival (OS) interim analysis of the phase 3 monarchE trial (NCT03155997).¹

These data were presented at the 2023 European Society for Medical Oncology Congress (ESMO).

“The data are consistent with a carryover effect and further support the addition of adjuvant abemaciclib to ET for patients with HR-positive, HER2-negative, node-positive, high-risk early breast cancer,” Nadia Harbeck, MD, PhD, director of the Breast Center, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Munich, Ludwig Maximilians University Hospital, Munich, Germany, said of the 5-year follow-up data.

Sustained Benefit

In the third interim analysis, the data cutoff was July 3, 2023, at a median follow-up of 54 months. “At the critical 5-year landmark, all patients are now off abemaciclib, and I think it's noteworthy that more than 80% of the patients have been followed for at least 2 years,” Harbeck said.

In the intent-to-treat (ITT) population, IDFS benefit with the addition of abemaciclib to ET was sustained, with 407 events occurring in the investigative arm vs 585 with ET alone, reducing the risk for invasive disease by 32% (HR, 0.680; 95% CI, 0.599-0.772). The 5-year IDFS rates were 83.6% and 76.0%, respectively.

IDFS benefit from abemaciclib was consistent across subgroups. “[This was] independent of age [P = 0.229]; menopausal status [P = .095]; the type of setting of chemotherapy given [neoadjuvant vs adjuvant; P = .596]; the number of positive lymph nodes [P = .438]; and, I think is also very important, the endocrine agent combined with abemaciclib [P = .054]. In this study tamoxifen as well as the aromatase inhibitor could be used,” Harbeck added.

Similarly, in the ITT population, DRFS benefit continued with the addition of abemaciclib, with 345 events vs 501 with ET alone, reducing the risk for distant relapse by 32.5% (HR, 0.675; 95% CI, 0.588-0.774). Five-year DRFS rates were 86.0% and 79.2%, respectively.

The Kaplan Meier curves continued to separate for both IDFS and DRFS, resulting in 5-year absolute improvement rates of 7.6% and 6.7%, respectively.

Lastly, OS was still immature; however, there were fewer deaths reported in the abemaciclib arm, compared with placebo (208 vs 234, respectively; HR, 0.903; 95% CI, 0.749-1.088; P = .284).

"The mature recurrence efficacy benefit demonstrated in monarchE, achieved with a 2-year treatment duration, reinforce [abemaciclib] as the standard of care in this curative setting, where [abemaciclib] is the only CDK4/6 inhibitor approved to treat people with HR-positive, HER2-negative, node-positive, high risk early breast cancer," David Hyman, MD, chief medical officer, Lilly, said in a press release.² "Reaching the 5-year outcomes benchmark with adjuvant [abemaciclib] should provide further confidence for those patients where treatment intensification is needed to help them achieve their goal of remaining cancer-free.”

Further Benefit Among Cohorts

The investigators separated patients into 2 cohorts:

• Cohort 1: patients with ≥4 positive axillary lymph nodes or 1 to 3 positive axillary lymph nodes with at least grade 3 disease and/or tumor size of ≥5 cm; and
• Cohort 2: patients with 1 to 3 or more positive axillary lymph nodes, central Ki67 ≥20%, grade 3 disease, and tumor size of ≥5 cm

The benefit seen in the ITT population was consistent with that seen in cohort 1.

Among those treated with abemaciclib, the risk for invasive disease was reduced by 33% (HR, 0.670; 95% CI, 0.588-0.764; P < .001). The 5-year IDFS rates in the abemaciclib and ET-alone groups were 83.2% (95% CI, 81.5%-84.7%) and 75.3% (95% CI, 76.6%-80.3%), respectively.

Similarly, DRFS benefit continued with the addition of abemaciclib, compared with ET alone, reducing the risk for distant relapse by 33.5% (HR, 0.665; 95% CI, 0.577-0.765; P < .001). The 5-year DRFS rates were 85.6% (95% CI, 84.0%-87.1%) and 78.5% (95% CI, 76.6%-80.3%), respectively.

For those treated with abemaciclib plus ET vs placebo, these treatment effects in cohort 1 were observed, regardless of Ki-67 Index, for both IDFS (HR, 0.643 [95% CI, 0.530-0.781; P < .001]; 5-year rates, 81.0% [95% CI, 78.1%-83.4%] vs 72.0% [95% CI, 68.7%-75.0%], respectively) and DRFS (HR, 0.634 [95% CI, 0.515-0.781; P < .001]; 5-year rates, 83.4% [95% CI, 80.7%-85.8%] vs 75.2% [95% CI, 72.1%-78.0%], respectively).

Harbeck noted that cohort 2 data remained immature.

Safety

No new safety signals were identified, and Harbeck noted the safety results were similar to the previous analyses.

The most frequent AEs associated with abemaciclib included diarrhea, neutropenia, and fatigue, with the most common grade 3 to 4 AEs being neutropenia, leucopenia, and diarrhea.²

Among those treated with abemaciclib, vs those who were not, more patients experienced 1 or more treatment-emergent adverse events (TEAE; 98.4% v 88.9%, respectively), at least 1 or more grade 3 or higher TEAE (50.0% v 16.9%), and 1 or more serious AE (15.6% v 9.2%).¹

However, Harbeck noted that serious AEs, regardless of causality, reported for patients in the 5-year, long-term follow-up were higher in the ET-alone arm (7.3%), compared with those treated with abemaciclib plus ET (6.5%).

monarchE Trial

In the open-label, randomized, phase 3 trial, investigators aimed to evaluate if adjuvant abemaciclib plus ET improved IDFS and DRFS among 5637 patients with hormone receptor-positive, HER2-negative node-positive, high-risk, early breast cancer. Patients were randomized 1:1 to receive standard-of-care endocrine therapy of physician's choice for up to 10 years, either with or without 150 mg abemaciclib orally twice a day for 2 years.

“monarchE is the only adjuvant CDK4/6 inhibitor trial designed exclusively for patients with high-risk disease,” Harbeck explained. “…A goal of optimal adjuvant therapy is to eradicate micrometastatic disease within an achievable treatment period in order to maximize treatment adherence. Abemaciclib induces a potent and sustained apoptotic effect and is dosed continuously, in contrast with other CDK4/6 inhibitors that are administered intermittently and induce senescence.”

To be eligible, patients had to be 18 years of age or older, have hormone receptor-positive, HER2-negative, node-positive, early breast cancer at a high risk of recurrence, and an ECOG performance status of 0 or 1.

Patients were stratified for prior chemotherapy, menopausal status, and region.

IDFS served as the primary end point, while secondary end points included IDFS in high Ki67 populations, DRFS, OS, safety, pharmacokinetics, and patient-reported outcomes.

In a previously reported interim analysis³ published in The Lancet Oncology, IDFS was not reached in either group, with a sustained hazard ratio (HR) of 0.664 (95% CI, 0.578-0.762; P < .0001) after a median follow-up of 42 months (range, 37-47). The 4-year IDFS rate with the addition of abemaciclib was 85.8% (95% CI, 84.2%-87.3%), compared with 79.4% (95% CI, 77.5%-81.1%) in those who received ET alone.

During the 4-year follow-up, 2 treatment-related deaths had occurred in the abemaciclib plus ET group, vs none in the ET-alone group.

“Continued follow-up is ongoing until final assessment of OS,” Harbeck concluded.

References

1. Harbeck N, Rastogi P, O’Shaughnessy J, et al. Adjuvant abemaciclib plus endocrine therapy for HR+, HER2-, high-risk early breast cancer: Results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. Ann Onc. 2023;34(S2):S1255-S1256. doi:10.1016/j.annonc.2023.10.007.
2. Eli Lilly and Company Release. Landmark 5-Year monarchE outcome data demonstrate verzenio® (abemaciclib)'s long-term impact on cancer recurrence in high-risk early breast Cancer. Published: October 20, 2023. Accessed: October 20, 2023. https://prn.to/46CFcot
3. Johnston S, Toi M, O'Shaughnessy J, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):P77-P90. doi:10.1016/S1470-2045(22)00694-5.