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 stage^2,3 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 treatment^3–5.

Cell cycle arrest through CDK4/6 inhibition in advanced breast cancer

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 therapy^5–7. 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 therapy^3,5. These agents are now considered standard of care together with endocrine therapy for advanced HR+/HER2− breast cancer^3,5,9,10.

Transitioning to CDK4/6 inhibition in early breast cancer

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 – monarchE^11,12 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 involvement^11,12,14,15.

Abemaciclib: a beneficial addition in early breast cancer

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 cancer^11,12. 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 relapse^17,18. 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.

Palbociclib: same mechanism, different outcome

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?

Oncology

Breast Cancer

References 

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