Adding abemaciclib to hormonal therapy reduces the risk of cancer recurrence in patients with high-risk early HR+/HER2- breast cancer

Results of the phase III MonarchE trial show that the addition of the CDK4/6 inhibitor abemaciclib to adjuvant endocrine therapy (ET) significantly improves the invasive disease-free survival in patients with high-risk early hormone receptor positive (HR+)/ human oestrogen receptor 2 negative (HER2-) breast cancer. In addition, the study shows that adding abemaciclib effectively prevents early disease recurrence and significantly reduces the risk of distant recurrence by a clinically meaningful 28.3%.

Introduction

Over the last decades, significant progress has been made in the management of patients with HR+/HER2- early breast cancer, resulting in very high cure rates. Nevertheless, approximately 20% may experience disease recurrence or distant relapse in the first ten years. This risk of recurrence is higher for those patients with high-risk clinical and/or pathological features and is particularly pronounced during the first few years with adjuvant endocrine therapy. Abemaciclib is an oral, continuously dosed, CDK4/6 inhibitor that is routinely used in patients with HR+/HER2- advanced breast cancer in combination with ET. Building further on the proven efficacy and safety of abemaciclib in the metastatic setting, the potential of abemaciclib was subsequently tested in the adjuvant setting.

The international phase III MonarchE study included 5,637 patients with HR+/HER2- early breast cancer with high-risk clinical and/or pathological risk features. For this trial, high-risk was defined as having at least 4 positive axillary lymph nodes (ALN) or 1-3 ALN and at least one of the following characteristics: tumour size ≥ 5 cm, histologic grade 3 or centrally tested Ki67 ≥ 20%. After completing their primary treatment, patients were randomised (1:1) to abemaciclib (150 mg twice daily for two years) plus standard endocrine therapy (ET) or standard ET alone. In both arms the type and duration (5 or 10 years) of the ET was at the physician’s discretion. The primary endpoint of the study was invasive disease-free survival (IDFS) by STEEP criteria, with distant relapse-free survival (DRFS), overall survival (OS), safety and patient-reported outcomes (PROs) as secondary objectives.

Results

The median age of study participants was 51 years and 43.5% of patients were premenopausal at the time of their diagnosis. More than 90% of patients received prior treatment with chemotherapy in the neoadjuvant or adjuvant setting. The first on-study ET consisted of an aromatase inhibitor for most patients (around 70%) while other patients received tamoxifen (or toremifene in a small minority of cases). The median study follow-up for the presented interim analysis was 15.5 months in both treatment arms. In total, 12.5% of patients had completed the two-year treatment period while over 70% of patients were still in this treatment period.

Adding abemaciclib to ET resulted in a statistically significant improvement in IDFS (HR [95%CI]: 0.747 [0.598-0.932], p=0.0096), corresponding to a 25.3% reduction in the risk of an IDFS event. The two-year IDFS rate with the abemaciclib-ET combination was reported at 92.2%, while this was 3.5% lower with ET alone (88.7%). A similar improvement was observed in terms of DRFS (HR [95%CI]: 0.717 [0.559-0.920], 2-sided p=0.0085) with two-year DRFS rates of 93.6% and 90.3% for abemaciclib-ET and ET alone, respectively. Consistent benefit was seen in all prespecified subgroups. In the abemaciclib plus ET arm, 92 patients suffered a distant recurrence, as compared to 142 patients in the ET alone arm. Zooming in on the site of distant recurrences reveals that the addition of abemaciclib particularly reduced the number of bone (N = 32 vs. 81) and liver (N = 29 vs. 42) metastases.

The median duration of abemaciclib treatment was 14.0 months. Considering the 70% of patients who are still on treatment, this median will continue to increase. In total, 463 (16.6%) of patients discontinued abemaciclib due to adverse events (AEs). In the control arm, 21 patients (0.8%) discontinued ET due to AEs. As could be expected from the experience with abemaciclib in the metastatic setting, the most frequent treatment-emergent adverse events (TEAEs) seen in the abemaciclib-ET arm were diarrhoea (82%), neutropenia (45%) and fatigue (38%). With ET alone, the most common TEAEs were arthralgia (31%), hot flushes (21%) and fatigue (15%). The frequency and severity of the diarrhoea seen with abemaciclib decreased significantly over time and very few patients discontinued treatment due to the diarrhoea (4.8%). As such, this indicates that it was mostly manageable with anti-diarrhoeal medication and dose adjustments. Other events of interest were venous thromboembolic events, interstitial lung disease and febrile neutropenia. Although these events were more common in the abemaciclib arm, the overall incidence of these events remained very low (2.3%, 2.7% and 0.3%, respectively).

Conclusion

MonarchE is the first study to show that the addition of a CDK4/6 inhibitor to adjuvant ET significantly improves the IDFS in patients with HR+/HER2- high-risk breast cancer. The data indicate the prevention of early recurrence and a reduction in the risk of distant recurrence by a clinically meaningful 28.3%. Safety was consistent with the known profile of abemaciclib. Diarrhoea was the most common side effect but was manageable with anti-diarrhoeal medication and dose adjustments. More mature data of the trial, especially results with respect to overall survival, are eagerly awaited.

Reference

Johnston SR, Harbeck N, Hegg R, et al. Abemaciclib in high risk early breast cancer. Presented at ESMO 2020; Abstract LBA5.