Abemaciclib Plus Endocrine Therapy Elicits Efficacy in High-Risk, HR+ Early Breast Cancer Regardless of Menopausal Status

The addition of abemaciclib (Verzenio) to endocrine therapy improved invasive disease-free survival (iDFS) and distant relapse-free survival (DRFS) vs endocrine therapy alone in patients with high-risk, hormone receptor–positive, HER2-negative, early-stage breast cancer, irrespective of menopausal status, according to data from a subgroup analysis of the phase 3 monarchE trial (NCT03155997).¹

Results, which were presented during the 2022 ESMO Breast Cancer Congress, showed that the combination (n = 1227) elicited a 2-year iDFS rate of 94.5% vs 90.4% with endocrine therapy alone (n = 1224) in premenopausal patients; these rates were 89.5% and 83.8%, respectively, at 3 years (HR, 0.578; 95% CI, 0.441-0.758; P < .0001). In the same patient population, the 2-year DRFS rates in the investigative and control arms were 95.4% and 92.0%, respectively; at 3 years, these rates were 90.5% and 86.1%, respectively (HR, 0.597; 95% CI, 0.445-0.801; P = .0005).

Among postmenopausal patients, abemaciclib plus endocrine therapy (n = 1576) resulted in a 2-year iDFS rate of 91.2% vs 89.7% with endocrine therapy alone (n = 1605); at 3 years, these rates were 88.2% and 83.1%, respectively (HR, 0.785; 95% CI, 0.634-0.973; P = .0268). The 2-year DRFS rates in the investigative and control arms were 93.2% and 91.3%, respectively; at 3 years, these rates were 90.1% and 86.1%, respectively (HR, 0.754; 95% CI, 0.595-0.956; P = .0193).

“In monarchE, abemaciclib plus endocrine therapy demonstrated a clinically meaningful treatment benefit in iDFS and DRFS vs endocrine therapy alone regardless of menopausal status, with a numerically greater relative risk reduction in the premenopausal group,” lead study author Shani Paluch-Shimon, MBBS, MS, of the Department of Oncology at Mayo Clinic, and colleagues, wrote. “The benefit of abemaciclib was consistent regardless of initial endocrine therapy. Safety data in premenopausal patients remain consistent with the overall safety profile of abemaciclib.”

monarchE enrolled patients with hormone receptor–positive, HER2-negative, high-risk early-stage breast cancer.² High-risk disease was defined as having 4 or more positive axillary lymph nodes, or 1-3 positive axillary lymph nodes and at least 1 of the following: grade 3 disease, a tumor size of at least 5 cm, or a Ki-67 of at least 20% per central testing.

A total of 5637 patients were randomized 1:1 to receive endocrine therapy with or without abemaciclib. Those in the investigative arm received abemaciclib at a twice-daily dose of 150 mg for up to 2 years or until treatment discontinuation. Patients were stratified by prior chemotherapy (neoadjuvant, adjuvant, or none), menopausal status (as determined at diagnosis), and region (North America/Europe, Asia, or other).

The primary end point of the trial was iDFS, and secondary end points included iDFS in the high Ki-67 population, DRFS, overall survival, safety, and pharmacokinetics.

In October 2021, the FDA approved abemaciclib in combination with endocrine therapy for the adjuvant treatment of adult patients with hormone receptor–positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score of 20% or higher. The regulatory decision was supported by data from monarchE.³

Among those in cohort 1 who had a Ki-67 score of 20% or higher (n = 2003), 104 patients who received abemaciclib plus endocrine therapy (n = 1017) experienced an iDFS event vs 158 of those who were given endocrine therapy alone (n = 986; HR, 0.626; 95% CI, 0.488-0.803; P = .0042). The 3-year iDFS rate in the investigative arm was 86.1% (95% CI, 82.8%-88.8%) vs 79.0% (95% CI, 75.3%-82.3% in the control arm.^3,4

At a median follow-up of 27 months, 85 of the patients in the investigative arm experienced a DRFS event vs 135 of those in the control arm (HR, 0.599; 95% CI, 0.456-0.787). The 3-year DRFS rate achieved with abemaciclib plus endocrine therapy was 87.8% vs 82.6% with endocrine therapy alone.

Since premenopausal patients with hormone receptor–positive, HER2-negative breast cancer may different tumor biology than postmenopausal patients, investigators set out to examine differences in efficacy between the 2 populations treated on the trial. Data from this analysis were reported during the 2022 ESMO Breast Cancer Congress.

Baseline characteristics were similar in the investigative and control arms among premenopausal and postmenopausal patients. The median age within the premenopausal subset in both treatment arms was 44 years (range, 22-65), and the median age among postmenopausal patients in both arms was 59 years (range, 27-89). Most patients received prior chemotherapy, had 4 or more positive lymph nodes, grade 2 disease, a radiological and pathological tumor size between 2 cm and 5 cm at diagnosis, and central Ki-67 of at least 20%.

Additional data showed that abemaciclib plus endocrine therapy elicited a benefit in premenopausal patients, regardless of the initial endocrine therapy received.

In premenopausal patients who received abemaciclib with tamoxifen (n = 697), the 2-year iDFS rate was 94.4% (95% CI, 92.3%-95.9%) vs 89.6% (95% CI, 87.0%-91.6%) in those who received tamoxifen alone (n = 718; HR, 0.522; 95% CI, 0.370-0.738). The 2-year DRFS rate was 95.3% (95% CI, 93.4%-96.7%) with abemaciclib/tamoxifen vs 91.7% (95% CI, 89.4%-93.6%) with tamoxifen alone (HR, 0.536; 95% CI, 0.367-0.783).

In premenopausal patients who received abemaciclib with an aromatase inhibitor (AI; n = 521), the 2-year iDFS rate was 94.9% (95% CI, 92.5%-96.5%) vs 91.6% (95% CI, 88.6%-93.8%) in those who received an AI alone (n = 478; HR, 0.680; 95% CI, 0.435-1.064). The 2-year DRFS rate with abemaciclib/AI was 95.5% (95% CI, 93.2%-97.0%) vs 92.5% (95% CI, 89.6%-94.6%) with an AI alone (HR, 0.719; 95% CI, 0.447-1.155).

Safety data in premenopausal patients remained consistent with the overall safety profile of abemaciclib. In this subset, the most common adverse effects of any grade experienced in the investigative and control arms, respectively, were diarrhea (84.7% vs 7.4%), neutropenia (48.4% vs 8.1%), leukopenia (38.6% vs 8.7%), abdominal pain (38.4% vs 10.4%), fatigue (38.2% vs 17.6%), nausea (27.7% vs 8.8%), arthralgia (24.6% vs 34.3%), anemia (23.0% vs 3.9%), headache (21.8% vs 17.6%), and hot flush (18.5% vs 27.5%).

The most common grade 3 or 4 toxicities experienced with abemaciclib plus endocrine therapy included diarrhea (grade 3, 5.8%), neutropenia (grade 3, 19.1%; grade 4, 0.7%), leukopenia (grade 3, 11.9%; grade 4, 0.1%), abdominal pain (grade 3, 1.5%), fatigue (grade 3, 1.8%), nausea (grade 3, 0.3%), arthralgia (grade 3, 0.2%), anemia (grade 3, 1.0%; grade 4, 0.1%), headache (grade 3, 0.2%), and hot flush (grade 3, 0.2%).

Notably, instances of venous thromboembolism (VTE) and pulmonary embolism (PE) were similar in premenopausal patients, irrespective of endocrine therapy. Any-grade VTE occurred in 2.7% of those who received abemaciclib plus tamoxifen and 1.0% with abemaciclib plus an AI. PEs were reported in 1.3% and 0.8% of patients who received abemaciclib plus tamoxifen and abemaciclib plus an AI, respectively.

References

1. Paluch-Shimon S, Neven P, Huober J, et al. Efficacy and safety results by menopausal status in monarchE: adjuvant abemaciclib combined with endocrine therapy in patients with HR+, HER2- high-risk early breast cancer. Ann Oncol. 2022;33(suppl 3):S148-S164. doi:10.1016/annonc/annonc889
2. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2–, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998. doi:10.1200/JCO.20.02514
3. Abemaciclib. Prescribing information. Eli Lilly and Company; 2021. Accessed May 9, 2022. https://bit.ly/3sfqW2U
4. O’Shaughnessy JO, Rastogi P, Harbeck N, et al. VP8-2021: adjuvant abemaciclib combined with endocrine therapy (ET): updated results from monarchE. Ann Oncol. 2021;32(suppl 12):1646-1649. doi:10.1016/j.annonc.2021.09.012