Abemaciclib: a newcomer in the treatment of HR+/HER2− early breast cancer
Breast cancer ranks as the most prevalent cancer worldwide and is a leading cause of cancer death in women1. In 2020, 2.3 million women across the globe were diagnosed with breast cancer, representing the highest number of all cancer diagnoses1
Article by Sharmini Rajanayagam BSc (Hons), PhD; Senior Medical Writer at EPG Health
About 90% of patients with breast cancer are diagnosed at an early stage2,3 and 65–75% of cases test positive for hormone receptors (HR+) and negative for human epidermal growth factor 2 (HER2−)3,4. Early detection is usually associated with a better prognosis as HR+/HER2− breast cancers are responsive to endocrine therapy; however, up to one-third of patients relapse after treatment3–5.
The development of selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors has been hailed as a game changer in the treatment of HR+/HER2− breast cancers that are resistant to endocrine therapy5–7. These agents target aberrant cell cycle function, preventing transition from G0 to S phase and thereby applying a brake on uncontrolled cell division and proliferation8. Clinical trials showed that CDK4/6 inhibitors, combined with endocrine therapy, significantly improved progression-free survival of patients with advanced HR+/HER2− breast cancer3. The successful outcome of these trials led to approval of the CDK4/6 inhibitors abemaciclib, palbociclib and ribociclib in the US and Europe for treatment of advanced HR+/HER2− breast cancer in combination with endocrine therapy3,5. These agents are now considered standard of care together with endocrine therapy for advanced HR+/HER2− breast cancer3,5,9,10.
Success of CDK4/6 inhibition in the treatment of advanced breast cancer prompted further investigation to determine whether this strategy would also be effective if introduced in the early stages of breast cancer in patients deemed to be at high risk of recurrence. Four phase 3 clinical trials – monarchE11,12 for abemaciclib, NATALEE13 for ribociclib, and PALLAS14 and PENELOPE-B15 for palbociclib – were initiated to answer this question.
The monarchE, NATALEE and PALLAS trials recruited patients with stage II or III invasive HR+/HER2− breast cancer. ‘High risk’ was defined by the presence of various clinical and pathological factors, including nodal involvement, histological grade and tumour size. PALLAS differed from the other trials in recruiting a small number of node-negative patients, while monarchE and NATALEE recruited a subset of patients with scores of at least 20% for the cellular proliferation marker Ki-67. Of the four trials, PENELOPE-B was the only double-blind, placebo-controlled trial, recruiting patients with residual disease after neoadjuvant chemotherapy (NACT) as well as nodal involvement11,12,14,15.
Consistent with the results for advanced breast cancer, the monarchE trial showed that addition of abemaciclib to endocrine therapy conferred a greater survival benefit, compared with endocrine therapy alone, in patients with high-risk HR+/HER2− early breast cancer11,12. Invasive disease-free survival (IDFS) rate at 2 years, the primary endpoint of the trial, was significantly higher in patients treated with abemaciclib plus endocrine therapy than in those who received endocrine therapy alone (92.2% vs 88.7%, P<0.01). Distant relapse-free survival (DRFS) and IDFS in the high Ki-67 (≥20%) cohort, key secondary endpoints, were also higher with abemaciclib, compared with endocrine therapy alone (DRFS: 93.6% vs 90.3%, P<0.01; IDFS in high Ki-67 cohort: 91.3% vs 86.1%, P<0.01)11. A follow-up analysis found that the survival benefit with abemaciclib was sustained at 3 years as shown by significantly higher IDFS rates, regardless of Ki-67 levels, and DRFS rates12. Diarrhoea was the most reported adverse event associated with abemaciclib but could be managed with anti-diarrhoeal agents and/or dose reductions16.
The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have now approved the use of abemaciclib in combination with endocrine therapy for adjuvant treatment of HR+/HER2− node-positive early breast cancer in patients at high risk of relapse17,18. A notable difference between the approvals granted by the two agencies is the FDA’s stipulation that to qualify for abemaciclib, patients must also have a Ki-67 score of ≥20%, assessed by an FDA-approved diagnostic test (Dako Omnis Ki-67 IHC MIB-1 pharma DX). The rationale for this additional requirement is that after analysing the safety data from the monarchE trial, the FDA were unable to rule out a potentially detrimental effect of abemaciclib in patients with a Ki-67 score of <20%. They concluded that abemaciclib treatment was appropriate only for patients with high-risk clinicopathological tumour features and a Ki-67 score of ≥20%19.
Following FDA approval of the extended indication for abemaciclib, the American Society for Clinical Oncology (ASCO) swiftly updated their guidelines to incorporate recommendation of abemaciclib for 2 years plus endocrine therapy for ≥5 years as a treatment option for HR+/HER2− high-risk early breast cancer20. The ASCO guidelines define high risk of recurrence according to the monarchE criteria of either 4 or more positive axial lymph nodes (ALNs) or 1–3 positive ALNs with one or more of: histological grade 3 disease, tumour size of at least 5 cm, and a Ki-67 score of ≥20%20.
Curiously, neither PALLAS nor PENELOPE-B trials were able to show superiority of palboclib plus endocrine therapy over endocrine therapy alone. This outcome is at odds with the success of palbociclib treatment in the metastatic setting, but more so with the results of the monarchE trial. Palbociclib and abemaciclib have similar efficacy in advanced HR+/HER2− breast cancer, so why the divergence in the setting of early breast cancer?
Explanations proposed for the discordant results seen in the monarchE trial and the PALLAS and PENELOPE-B trials include differences in eligibility criteria, definition of high-risk disease and discontinuation rates but, after consideration, these factors have been ruled out21. An important difference that is yet to be confirmed or discounted was the dosing schedules for abemaciclib, administered continuously, and palbociclib, administered on a 3 weeks on/1 week off basis. This could be a more plausible explanation as studies have shown that in early breast cancer, one week of rest from CDK4/6 inhibition is sufficient to increase cell proliferation3.
Could the success of CDK4/6 inhibition in early breast cancer rest on uninterrupted suppression of cell cycle activity? Or do differences in potency or other characteristics of the individual CDK4/6 inhibitors account for differences in activity despite a shared mechanism of action? The NATALEE trial might provide a clue. Results of the NATALEE trial are not expected until 2025 and we eagerly await the outcome – will ribociclib claim second place alongside abemaciclib as a treatment option for high-risk HR+/HER2− early breast cancer?
- Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249.
- NCI. Abemaciclib may be option for early-stage breast cancer https://www.cancer.gov/news-events/cancer-currents-blog/2021/abemaciclib-early-stage-breast-cancer.
- Gil-Gil M, Alba E, Gavilá J, de la Haba-Rodríguez J, Ciruelos E, Tolosa P, et al. The role of CDK4/6 inhibitors in early breast cancer. Breast. 2021;58:160–169.
- Lopez-Tarruella S, Echavarria I, Jerez Y, Herrero B, Gamez S, Martin M. How we treat HR-positive, HER2-negative early breast cancer. Future Oncol. 2022;18(8):1003–1022.
- Xu B, Fan Y. CDK4/6 inhibition in early-stage breast cancer: how far is it from becoming standard of care? Lancet Oncol. 2021;22(2):159–160.
- McCartney A, Migliaccio I, Bonechi M, Biagioni C, Romagnoli D, De Luca F, et al. Mechanisms of Resistance to CDK4/6 Inhibitors: Potential Implications and Biomarkers for Clinical Practice. Front Oncol. 2019;9.
- Preusser M, De Mattos-Arruda L, Thill M, Criscitiello C, Bartsch R, Ruhstaller T, et al. CDK4/6 inhibitors in the treatment of patients with breast cancer: summary of a multidisciplinary round-table discussion. ESMO Open. 2018;3(5):e000368.
- Loibl S, Furlanetto J. Integrating CDK4/6 inhibitors in the treatment of patients with early breast cancer. Breast. 2022;62 Suppl 1(Suppl 1):S70–s79.
- Agostinetto E, Vian L, Caparica R, Bruzzone M, Ceppi M, Lambertini M, et al. CDK4/6 inhibitors as adjuvant treatment for hormone receptor-positive, HER2-negative early breast cancer: a systematic review and meta-analysis. ESMO Open. 2021;6(2):100091.
- Hui R, de Boer R, Lim E, Yeo B, Lynch J. CDK4/6 inhibitor plus endocrine therapy for hormone receptor-positive, HER2-negative metastatic breast cancer: The new standard of care. Asia Pac J Clin Oncol. 2021;17(S1):3–14.
- Johnston SRD, Harbeck N, Hegg R, Toi M, Martin M, Shao ZM, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR1, HER22, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020;38(34):3987–3998.
- Harbeck N, Rastogi P, Martin M, Tolaney SM, Shao ZM, Fasching PA, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571–1581.
- Slamon DJ, Fasching PA, Patel R, Verma S, Hurvitz SA, Chia SKL, et al. NATALEE: Phase III study of ribociclib (RIBO) + endocrine therapy (ET) as adjuvant treatment in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) early breast cancer (EBC). J Clin Oncol. 2019;37(15_suppl):TPS597–TPS597.
- Mayer EL, Dueck AC, Martin M, Rubovszky G, Burstein HJ, Bellet-Ezquerra M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021;22(2):212–222.
- Loibl S, Marmé F, Martin M, Untch M, Bonnefoi H, Kim SB, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer-the penelope-B trial. J Clin Oncol. 2021;39(14):1518–1530.
- Rugo HS, O'Shaughnessy J, Boyle F, Toi M, Broom R, Blancas I, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: safety and patient-reported outcomes from the monarchE study. Ann Oncol. 2022;33(6):616–627.
- US Food and Drug Administration. FDA approves abemaciclib with endocrine therapy for early breast cancer | FDA. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abemaciclib-endocrine-therapy-early-breast-cancer.
- EMA. Summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/verzenios-epar-product-information_en.pdf.
- Royce M, Osgood C, Mulkey F, Bloomquist E, Pierce WF, Roy A, et al. FDA Approval Summary: Abemaciclib With Endocrine Therapy for High-Risk Early Breast Cancer. J Clin Oncol. 2022;40(11):1155–1162.
- Giordano SH, Freedman RA, Somerfield MR, Chemotherapy ftOA, Panel TTGE. Abemaciclib With Endocrine Therapy in the Treatment of High-Risk Early Breast Cancer: ASCO Optimal Adjuvant Chemotherapy and Targeted Therapy Guideline Rapid Recommendation Update. J Clin Oncol. 2022;40(3):307–309.
- Helwick C. Final Analysis of PALLAS Trial No Benefit of Adjuvant Palbociclib Plus Endocrine Therapy in Early Breast Cancer - The ASCO Post. ASCO Post. 2022.