Abemaciclib Delivers Consistent Benefit in High-Risk, Early Breast Cancer Regardless of Dose Reductions

Dose modification of adjuvant abemaciclib (Verzenio) to mitigate toxicity did not compromise benefit derived from treatment and was associated with improved retention among patients with high-risk, hormone receptor–positive, HER2-negative early breast cancer, according to results from subgroup analyses of the phase 3 monarchE trial (NCT03155997) presented at the 42nd Annual Miami Breast Cancer Conference.1

In the intention-to-treat (ITT) population, dose reduction of abemaciclib from the full 150-mg dose to doses of 100 mg or 50 mg produced outcomes that were comparable with those seen with the full dose regarding invasive disease–free survival (IDFS; HR, 0.905; 95% CI, 0.727-1.125), and distant relapse–free survival (DRFS; HR, 0.942; 95% CI, 0.742-1.195).

For patients in cohort 1—which comprised patients with either 4 or more positive axillary lymph nodes (pALNs), or 1 to 3 pALNs with at least grade 3 disease and/or tumor size of 5 cm or greater—the HRs for IDFS and DRFS between the full and reduced doses were also similar, at 0.899 (95% CI, 0.718-1.125) and 0.958 (95% CI, 0.750-1.223), respectively.1,2

Furthermore, IDFS outcomes at 4 years were generally consistent regardless of relative dose intensity (RDI).1 The 4-year IDFS rates for patients of all ages treated with abemaciclib at RDIs of 0% to 66% (n = 928), 66% to 93% (n = 928), and 93% or greater (n = 927) were 87.1%, 86.4%, and 83.7%, respectively. Similar findings were also observed in cohort 1.

“These data support the use of dose reductions as needed with adjuvant abemaciclib, with the goal of maximizing persistence to maintain benefit for [patients with] high-risk, hormone receptor–positive, HER2-negative early-breast cancer,” lead study author Joyce O’Shaughnessy, MD, and her colleagues wrote in a poster on the data. O’Shaughnessy is the Celebrating Women Chair in Breast Cancer Research at Baylor University Medical Center and the director of the Breast Cancer Research Program at Texas Oncology, US Oncology, in Dallas, Texas.

monarchE Overview

The monarchE trial enrolled 5637 patients across more than 600 sites in 38 countries.2,3 Upon enrollment, patients were assigned to 1 of 2 cohorts: cohort 1 (n = 5120; 91%), which was the FDA-approved population, or cohort 2 (n = 517; 9%), which consisted of patients with 1 to 3 pALNs and a centrally tested Ki-67 index of 20% or greater. The ITT population comprised both cohorts.2 Patients were randomly assigned 1:1 to receive at least 5 years of endocrine therapy with or without abemaciclib for 2 years.2,3Endocrine therapy was continued for at least 5 years if deemed medically appropriate. The study’s primary end point was IDFS.3

Previously reported data from a prespecified 5-year interim analysis showed that, at a median follow-up of 54 months (IQR, 49-59), superior IDFS benefit with abemaciclib plus endocrine therapy (n = 2808) vs endocrine therapy alone (n = 2829) was sustained in the ITT population, at 83.6% (95% CI, 82%-85.1%) vs 76% (95% CI, 74.1%-77.8%; HR, 0.680 [95% CI, 0.599-0.772; nominal P < .001]).2 This translated to an absolute improvement rate of 7.6% compared with 6% at 4 years and 4.8% at 3 years. Similarly, 5-year DRFS rates were 86% (95% CI, 84.5%-87.4%) with the abemaciclib regimen vs 79.2% (95% CI, 77.4%-80.9%) with endocrine therapy alone (HR, 0.675; 95% CI, 0.588-0.774; nominal P < .001). This translated to an absolute improvement rate of 6.7% compared with 5.3% at 4 years and 4.1% at 3 years. In cohort 1, IDFS, DRFS, and OS outcomes were consistent with those seen in the ITT population.

The current analysis was conducted to assess the effect of dose reduction on abemaciclib efficacy in monarchE.1

Additional Subgroup Data

Among patients in monarchE who received adjuvant abemaciclib, 43% underwent dose reduction due to adverse effects (AEs), most of which occurred within the first 6 months of treatment. Approximately half of patients who discontinued treatment early due to an AE had not previously undergone dose reduction, and 8.9% of patients discontinued treatment with abemaciclib following dose reduction. This suggests that dose reductions are an effective measure by which to proactively mitigate AEs in this patient population.

Further analysis of dose reductions according to age and comorbidity showed that patients 65 years of age or older and those with 4 or more comorbid conditions were more likely to undergo dose reduction of abemaciclib compared with those younger than 65 years of age or with fewer than 4 comorbidities. Among patients who received no dose reductions, 1 reduction, and 2 reductions, respectively, 12%, 18%, and 23% were at least 65 years of age; and 31%, 38%, and 41% had at least 4 comorbidities.

Although patients with dose reductions had a lower cumulative dose and RDI, they were more likely to remain on abemaciclib treatment, study authors reported. For patients who underwent 1 dose reduction (n = 832), the median treatment duration was 23.7 months (range quartile 1 [Q1]-Q3, 20.6-23.8). Most patients remained on treatment for more than 3 months (95%) and more than 6 months (90%). The median cumulative dose was 137,475 mg (range Q1-Q3, 98,825-151,950), and the RDI was 66.5% (range Q1-Q3, 59.5%-74.4%).

Patients who underwent 2 dose reductions (n = 389) had a median treatment duration of 23.7 months (range Q1-Q3, 13.2-23.8). Ninety-four percent of patients remained on treatment for longer than 3 months, and 86% of patients remained on treatment for longer than 6 months. The median cumulative dose for these patients was 77,200 mg (range Q1-Q3, 50,100-96,500), and the RDI was 40.2% (range Q1-Q3, 34.5%-50.7%).

Comparatively, the median duration of treatment for patients who did not undergo dose reduction (n = 1570) was 23.7 months (range Q1-Q3, 14.9-23.8). Eighty-six percent and 81% of patients remained on treatment for longer than 3 months or longer than 6 months, respectively. The median cumulative dose for these patients was 192,450 mg (range Q1-Q3, 112,900-210,900), and the RDI was 94.6% (range Q1-Q3, 83.4%-99.0%).

References

1. Megginson L, O’Shaughnessy J, Cicin I, et al. Impact of dose reductions on efficacy of adjuvant abemaciclib for patients with high-risk early breast cancer (EBC): analyses from the monarchE study. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2024; Miami, Florida. Poster 47.
2. Rastogi P, O'Shaughnessy J, Martin M, et al. Adjuvant abemaciclib plus endocrine therapy for hormone receptor–positive, human epidermal growth factor receptor 2–negative, high-risk early breast cancer: results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. J Clin Oncol. 2024;42(suppl 9):987-993. doi:10.1200/JCO.23.01994
3. Landmark 5-year monarchE outcome data demonstrate Verzenio (abemaciclib)’s long-term impact on cancer recurrence in high-risk early breast cancer. News Release. Lilly. October 20, 2023. Accessed March 8, 2025. https://investor.lilly.com/news-releases/news-release-details/landmark-5-year-monarche-outcome-data-demonstrate-verzenior