Adjuvant Abemaciclib Plus Endocrine Therapy in Patients With High-risk Early Breast Cancer (2024)

Key Points

Question Can treatment with abemaciclib provide good clinical outcomes for patients with high-risk early breast cancer who received neoadjuvant chemotherapy?

Findings In this prespecified analysis of the monarchE randomized clinical trial, treatment with abemaciclib and endocrine therapy demonstrated clinically meaningful benefit in invasive disease-free survival and distant relapse-free survival, with an absolute improvement of 6.6% in 2-year invasive disease-free survival rates and 6.7% in 2-year distant relapse-free survival rates. Consistent treatment benefit was observed by residual pathological breast tumor size or the number of positive lymph nodes at surgery.

Meaning The results of this analysis of the monarchE randomized clinical trial found that treatment with adjuvant abemaciclib plus endocrine therapy demonstrated benefit for patients with hormone receptor–positive, ERBB2⁻, node-positive, and high-risk early breast cancer who received neoadjuvant chemotherapy before trial enrollment.

Importance Patients selected to receive neoadjuvant chemotherapy (NAC) are usually those at higher risk of relapse, and there is a need to find better therapeutic options for these patients.

Objective To determine the efficacy and safety outcomes for patients with hormone receptor (HR)–positive, ERBB2 (formerly HER2)^–, high-risk early breast cancer enrolled in the randomized clinical trial monarchE who received NAC.

Design, Setting, and Participants The monarchE randomized clinical trial was a multicenter, phase 3, open-label study that evaluated adjuvant treatment with abemaciclib plus endocrine therapy (ET) compared with ET alone in patients with HR⁺, ERBB2^–, and node-positive early breast cancer who were at high risk of recurrence. Patients were recruited between July 2017 and August 2019 from 603 sites in 38 countries. This subgroup analysis was performed with primary outcome data, with a cutoff date of July 8, 2020.

Intervention Enrolled patients were randomized (1:1) to receive standard of care ET for at least 5 years with or without treatment with abemaciclib (150 mg, twice daily) for 2 years (treatment period) or until criteria were met for discontinuation.

Main Outcomes and Measures Prior chemotherapy (NAC vs adjuvant vs none) was a stratification factor in monarchE, and and a prespecified exploratory analysis included outcomes in patients who received NAC. The data presented in this article are from the primary outcome analysis (395 invasive disease-free survival [IDFS] events; cutoff date, July 8, 2020; median follow-up 19 months [IQR, 15.6-23.9 months]). Invasive disease-free survival (the primary end point of monarchE) and distant relapse-free survival (DRFS) were evaluated using the Cox proportional hazard model and Kaplan-Meier method.

Results Of the 5637 patients (mean [SD] age, 49.9 [10.6] years; 2046 women [99.5%]; 462 Asian [22.8%], 54 Black [2.7%], and 1473 White participants [70.8%]) enrolled in monarchE, 2056 (37%) received treatment with NAC. In this subgroup, treatment with abemaciclib and ET demonstrated clinically meaningful benefit in IDFS (hazard ratio, 0.61; 95% CI, 0.47-0.80) and DRFS (hazard ratio, 0.61; 95% CI, 0.46-0.81), which corresponded with an absolute improvement of 6.6% in 2-year IDFS rates and 6.7% in 2-year DRFS rates. A consistent treatment benefit was observed across subgroups of pathological breast tumor size or number of positive lymph nodes at surgery.

Conclusions and Relevance In the randomized clinical trial monarchE, treatment with adjuvant abemaciclib combined with ET demonstrated a clinically meaningful improvement in IDFS and DRFS for patients with HR⁺, ERBB2⁻, node-positive, high-risk early breast cancer who received NAC before trial enrollment.

Trial Registration ClinicalTrials.gov Identifier: NCT03155997

Neoadjuvant chemotherapy (NAC) is often offered to patients with hormone receptor–positive (HR⁺), ERBB2 (formerly HER2)^–, high-risk early breast cancer with higher disease burden to improve a patient’s likelihood of undergoing breast-conserving surgery.¹ Residual disease in the breast and/or lymph nodes at surgery following NAC is known to be associated with poorer outcomes in all breast cancer subtypes, including HR⁺, ERBB2^– breast cancer.² In other breast cancer subtypes, like triple-negative and ERBB2⁺, modern NAC has more than a 50% chance of inducing a pathological complete response (pCR), and subsequent treatment with adjuvant capecitabine or trastuzumab emtansine, respectively, has been shown to improve the outcomes in studies specifically designed to determine the effect of adjuvant therapy in patients with residual disease after treatment with NAC.^3,4

In contrast, most patients with HR⁺, ERBB2^– breast cancer have residual disease after receiving NAC,⁵ and although adjuvant endocrine therapy (ET) can reduce the risk of recurrence in these patients, a considerable risk remains. Novel therapeutic options are needed to prevent recurrences for these patients.

Based on results from the monarchE randomized clinical trial, abemaciclib, a cyclin-dependent kinase (CDK) 4 and 6 inhibitor, is the first CDK4 and 6 inhibitor approved for the adjuvant treatment of HR⁺, ERBB2^–, node-positive, early breast cancer at high risk of recurrence.⁶ In this article, we present efficacy and safety data from the primary outcome (PO) analysis for patients enrolled in monarchE who received NAC.

The monarchE study, an open-label, global, randomized, phase 3 clinical trial, investigated the addition of abemaciclib to ET in treating patients with HR⁺, ERBB2^–, node-positive, high-risk early breast cancer (Supplement 1 and Supplement 2).⁷ The study design was previously published⁷ (eFigure 1 in Supplement 3). Patients who received NAC as initial prior chemotherapy were stratified as NAC. This study, including all amendments, was approved by institutional review boards at the study institutions and was conducted in accordance with consensus ethical principles derived from international ethical guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences and the International Conference on Harmonisation-Good Clinical Practice guidelines.

As patients were eligible for enrollment based on the lymph node status either at diagnosis or at surgery, collection of the lymph node status was required only at 1 of the time points, and lymph node status at the time of surgery was not available in all patients. Thus, pCR status in the breast and axillary lymph nodes (ALNs) could not be calculated.

Study end points were previously described.⁷ A subgroup analysis per prior chemotherapy was a prespecified exploratory analysis. This subgroup analysis was performed with PO data (395 invasive disease-free survival [IDFS] events; cutoff, July 8, 2020; median [IQR] follow-up time, 19 [15.6-23.9] months).

Among the patients who received NAC, the efficacy and safety of treatment with abemaciclib and ET was evaluated in terms of IDFS, distant relapse-free survival (DRFS), and adverse events (AEs). Exploratory analyses on IDFS and DRFS were performed by residual pathological tumor size and by the number of positive nodes in those patients from whom lymph nodes status at surgery was available. All efficacy analyses were unadjusted. Analyses were conducted using SAS (version 9.4; SAS Institute).

In total, 2056 patients (36.5%) enrolled in monarchE received NAC (eTable 1 in Supplement 3). Most patients in the NAC subgroup received anthracycline/taxane–based regimens (eTable 1 in Supplement 3). Baseline characteristics of patients who received NAC are shown in eTables 1 and 2 in the Supplement 3.

Treatment with abemaciclib and ET demonstrated a 39% relative reduction in the risk of developing an IDFS event compared with ET alone (hazard ratio, 0.61; 95% CI, 0.47-0.80; nominal P < .001) in patients who received NAC. The 2-year IDFS rates reflected an absolute difference of 6.6% (Figure, A). In the NAC subgroup, the benefit of treatment with abemaciclib and ET in DRFS rates corresponded to a 39% relative risk reduction (hazard ratio, 0.61; 95% CI, 0.46-0.81; nominal P < .001) and an absolute improvement of 6.7% in 2-year DRFS rates (Figure, B).

Given the limited number of patients who had a pCR in the breast (1.6% in both arms) or no involved ALN at surgery (3.0% vs 2.9% between arms), efficacy analyses were not performed within those patients. Larger tumor size after treatment with NAC (>2 cm vs ≤2 cm) and more positive ALNs postsurgery (≥4 vs 1-3) were associated with a higher risk of developing an IDFS or DRFS event in the control arm. However, a consistent treatment benefit was observed in patients who received NAC regardless of the residual primary tumor size or number of positive ALNs at the time of surgical resection (Table).

Among the 2037 patients who received NAC and at least one dose of study treatment, the safety profile was consistent with the safety profile reported in the broader monarchE population. The abemaciclib and ET arm had higher incidence of treatment-emergent AEs (TEAEs), with the most frequent events being diarrhea, infections, neutropenia, and fatigue. The most common grade 3 or higher TEAEs were neutropenia and leucopenia. In the ET alone arm, the most frequent TEAEs were arthralgia, hot flashes, and fatigue (eTable 2 in Supplement 3).

In this prespecified analysis of the monarchE randomized clinical trial, patients who received NAC had a poorer prognosis than the monarchE intent-to-treat population, as suggested by the higher risk of recurrence at 2 years (19% vs 11% in the control arms). For those patients, the magnitude of treatment benefit from abemaciclib and ET in IDFS and DRFS rates was clinically meaningful and numerically greater than that in the intent-to-treat population.

In the subgroup exploratory analyses by the extent of residual disease, patients with a larger residual pathological tumor size (>2 cm) and higher numbers of positive ALNs (≥4) had higher rates of disease recurrence. However, the benefit of treatment with abemaciclib and ET in IDFS and DRFS rates was consistently observed independently of the extent of residual disease.

In contrast with the outcome in the NAC subgroup in monarchE, Penelope-B, a study investigating the efficacy of palbociclib as adjuvant treatment of HR⁺, ERBB2⁻ early breast cancer in patients with residual disease after receiving NAC, did not show any treatment benefit with 42.8 months follow-up.⁸ Differences in the schedules of administration and the pharmacological properties of both drugs may have influenced the different outcomes. Abemaciclib was administered continuously,⁷ while palbociclib was administered for 21 days, followed by 7 days of no use.⁸ The treatment duration also differed between monarchE and Penelope-B, with abemaciclib being administered for 2 years and palbociclib for 1 year.^7,8

Abemaciclib has demonstrated in biochemical and cell-based assays a stronger inhibition of CDK4 vs CDK6 relative to palbociclib.^9,10 This differentiated pharmacological profile allows abemaciclib to be dosed continuously. In vitro studies have shown that continuous drug exposure of HR⁺ BC cells is required for profound inhibition of DNA synthesis,⁸ and a similar effect in patients could play a role in the sustained tumor growth inhibition of micrometastatic disease. Moreover, CDK4 has been shown to play an essential role in the development/growth of breast cancer in animal models.¹¹ Also, in breast cancer cell lines, abemaciclib was a more potent inducer of senescence and apoptosis than palbociclib.¹²

The subgroup analyses are exploratory, as they were not sufficiently powered nor α controlled for statistical testing. Additionally, complete information on the tumor characteristics before and after NAC were not required; thus, further analyses by residual disease should be interpreted with caution. Despite these limitations, the treatment benefit of abemaciclib and ET within the NAC subgroup was statistically valid given the large size of this subgroup and prior chemotherapy being 1 stratification factor.

In the randomized clinical trial monarchE, treatment with abemaciclib combined with ET demonstrated a clinically meaningful improvement in IDFS and DRFS rates for patients with HR⁺, ERBB2^–, node-positive, high-risk early breast cancer who received NAC. To our knowledge, abemaciclib is the first agent added to standard adjuvant ET that has been shown to reduce the risk of recurrence in patients with HR⁺, ERBB2^–, early breast cancer with residual disease after NAC, and the efficacy was maintained regardless of residual tumor or nodal burden.

Accepted for Publication: February 23, 2022.

Published Online: June 2, 2022. doi:10.1001/jamaoncol.2022.1488

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2022 Martin M et al. JAMA Oncology.

Corresponding Author: Miguel Martin, MD, PhD, Medical Oncology Service, Hospital General Universitario Gregorio Marañon, Universidad Complutense, Centro de Investigación Biomédica en Red-Cáncer, GEICAM, Madrid, Spain (mmartin@geicam.org).

Author Contributions: Drs Martin and Johnston had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Martin, Denduluri, Headley, Johnston.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Martin, Schenker, Forrester, Munoz Fernandez, Zimmermann.

Critical revision of the manuscript for important intellectual content: Martin, Hegg, Kim, Schenker, Grecea, García-Sáenz, Papazisis, Ouyang, Lacko, Oksuzoglu, Reeves, Okera, Testa, Shimizu, Denduluri, Adamchuk, Dakhil, Wei, Forrester, Munoz Fernandez, Headley, Johnston.

Statistical analysis: Wei, Zimmermann.

Administrative, technical, or material support: Martin, Grecea, Ouyang, Oksuzoglu, Munoz Fernandez.

Supervision: Hegg, Schenker, Ouyang, Johnston.

Other - Served as PI for the trial for Virginia Cancer Specialists, enrolled most patients within The US Oncology Network: Denduluri.

Conflict of Interest Disclosures: Drs Wei and Munoz-Fernandez and Mses Forrester, Headley, and Zimmermann reported being full-time employees of Eli Lilly and Company at the time of the study and shareholders of Eli Lilly and Company. Dr Martin reported grants from Roche, Novartis, and Puma and personal fees from Novartis, Pfizer, Daiichi Sankyo, Eli Lilly and Company, SeaGen, and AstraZeneca outside the submitted work. Dr Kim reported grants from Novartis, Sanofi-Aventis, and Dongkook Pharm Co outside the submitted work as well as consulting fees from Novartis, AstraZeneca, Lilly, Dae Hwa Pharmaceutical Co, ISU Abxis, Daiichi-Sankyo, Beigene, Genopeaks, and NeoGene TC. Dr Schenker reported grants from Eli Lilly and Company, BMS, MSD, Roche, Novartis, Regeneron, Sanofi, Merck Serono, AstraZeneca, GlaxoSmithKline, Amgen, Astellas, AbbVie, Bioven, BeiGene, Bayer, Clovis, Gilead, Mylan, Pfizer, PharmaMar, Samsung Pharmaceuticals, and Tesaro outside the submitted work. Dr García-Sáenz reported grants from SeaGen, Gilead, Eli Lilly and Company, AstraZeneca, and Daiichi Sankyo and personal fees from Novartis, Eisai, and MSD outside the submitted work. Dr Papazisis reported honoraria from Novartis, Roche, GSK, MSD, AstraZeneca, Gilead, and Eli Lilly and Company outside the submitted work. Dr Lacko reported personal fees from Eli Lilly and Company, Roche, Pfizer, Egis, Novartis, Mylan, AstraZeneca, MSD, GlaxoSmithKline, Alvogen, the European School of Oncology, Exact Sciences, Teva, and Gilead outside the submitted work. Dr Reeves reported grants from Eli Lilly and Company, the Sarah Cannon Research Institute, Tesaro, TG Therapeutics, Genentech, Celgene, Merck, Bristol Myers Squibb, Boston Biomedical, AstraZeneca, Novocure, Calithera Biosciences, Novartis, Guardant, Acerta Pharma, Rhizen Pharmaceuticals, Takeda, Onconova, Sanofi, CTI Biopharma, Eisai, Janssen, Roche, Myriad Genetics, G1 Therapeutics, Daiichi Sankyo, Arvinas, Cytomix, Sermonix, SeaGen, Taiho, Boehringer Ingelheim, Hutchinson, Macrogenics, Ipsen, Loxo Oncology, Beigene, Acerta, Verastem, Pharmacyclics, AbbVie, Medimmune, Razor Oncology, BioAtla, GlaxoSmithKline, Jiangsu Hengrei, Arcus Biosciences, Amgen, Mirati, Array, Pfizer, Aravive, Ellipses, Immunogen, Karyopharm, Moderna, Thrive, Incyte, Astellas, Ideaya Bio, Appollomics, Tarveda, Ascentage, and Clovis outside the submitted work. Dr Testa reported personal fees from Lilly, Novartis, MSD, Roche, Amgen, Pfizer, and Daiichi-Sankyo and nonfinancial support from United Medical outside the submitted work. Dr Shimizu reported grants from Eli Lilly during the conduct of the study. Dr Denduluri reported research support from the US Oncology Network and being an employee of AstraZeneca outside the submitted work. Dr Johnston reported personal fees from Eli Lilly and Company during the conduct of the study and personal fees from Novartis and AstraZeneca and grants from Pfizer outside the submitted work. No other disclosures were reported.

Funding/Support: This study was sponsored by Eli Lilly and Company.

Role of the Funder/Sponsor: Eli Lilly and Company was involved in the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the patients who participated in the trial, as well as their families, and all those who provided support to the participants. We thank the investigators and their support staff who participated in this work. We are grateful for the time and efforts of the monarchE executive and steering committees. We thank Eglantine Julle-Daniere, PhD, Eli Lilly and Company, for her writing and editorial assistance, for which she was not compensated.