As reported in the Journal of Clinical Oncology by Stephen R.D. Johnston, MD, PhD, of the Royal Marsden NHS Foundation Trust, London, and colleagues, an interim analysis in the phase III monarchE trial has shown that adjuvant abemaciclib plus endocrine therapy significantly improved invasive disease–free survival vs endocrine therapy alone in patients with hormone receptor (HR)–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence.¹

As stated by the investigators: “Many patients with HR[-positive], HER2[-negative] early breast cancer…will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients.”

Stephen R.D. Johnston, MD, PhD

Study Details

In the open-label trial, 5,637 patients from sites in 38 countries were randomly assigned between July 2017 and August 2019 to receive abemaciclib at 150 mg twice daily for 2 years plus standard-of-care endocrine therapy (n = 2,808) or endocrine therapy alone (n = 2,829). Patients had to have at least four positive nodes or one to three positive nodes and tumor size ≥ 5 cm, histologic grade 3, or central Ki67 index ≥ 20%.

Randomization was stratified by previous chemotherapy (neoadjuvant, adjuvant, or none), menopausal status at baseline, and region (North America/Europe, Asia, or other). The primary endpoint was invasive disease–free survival in the intent-to-treat population.

Aromatase inhibitors were the first endocrine therapy on study treatment in 68.3% of patients (including 14% who also received ovarian function suppression), and tamoxifen was the first endocrine therapy in 31.4% (including 7.6% who also received ovarian function suppression). Overall, 95.4% of patients had received prior radiotherapy, and 95.4% had received prior chemotherapy, including neoadjuvant chemotherapy in 37.0%, adjuvant chemotherapy in 58.3%, and both in 3.5% (counted in the neoadjuvant group). For the abemaciclib vs control groups, 43.5% of both were premenopausal at baseline, and 52.4% vs 52.3% were from North America/Europe, 20.4% vs 20.6% from Asia, and 27.2% vs 27.1% from other regions.

Invasive Disease–Free Survival

At the second preplanned efficacy interim analysis, with data cutoff in March 2020, median follow-up was approximately 15.5 months in each group. A total of 323 patients had invasive disease–free survival events, including 136 (4.8%) in the abemaciclib group and 187 (6.6%) in the control group. The hazard ratio for the abemaciclib vs control groups was 0.75 (95% confidence interval [CI] = 0.60–0.93, P = .01), with 2-year rates of 92.2% vs 88.7%.

For stratification factors, hazard ratios for invasive disease–free survival for the abemaciclib vs control groups were 0.69 (95% CI = 0.52–0.93) among patients who received neoadjuvant chemotherapy and 0.77 (95% CI = 0.54–1.10) among those who received adjuvant chemotherapy; 0.63 (95% CI = 0.44–0.92) among premenopausal women and 0.82 (95% CI = 0.62–1.08) among postmenopausal women; and 0.72 (95% CI = 0.52–1.00) among patients from North America/Europe, 0.93 (95% CI = 0.55–1.55) among patients from Asia, and 0.69 (95% CI = 0.48–1.00) among patients from other regions.

Most invasive disease–free survival events were distant recurrences, observed in 87 patients in the abemaciclib group vs 138 in the control group. Local/regional tumor recurrence was observed in 17 vs 26 patients, contralateral recurrence in 4 vs 9 patients, and a second primary neoplasm in 16 vs 12 patients.

The abemaciclib group had significantly improved distant metastasis–free survival (HR = 0.72, 95% CI = 0.56–0.92, nominal P = .01), with 2-year rates of 93.6% vs 90.3%. For stratification factors, hazard ratios were 0.70 (95% CI = 0.51–0.96) among patients who received neoadjuvant chemotherapy and 0.71 (95% CI = 0.47–1.07) among those who received adjuvant chemotherapy; 0.65 (95% CI = 0.43–0.98) among premenopausal women and 0.76 (95% CI = 0.56–1.04) among postmenopausal women; and 0.75 (95% CI = 0.52–1.08) among patients from North America/Europe, 0.91 (95% CI = 0.50–1.64) among patients from Asia, and 0.60 (95% CI = 0.39–0.90) among patients from other regions.

Overall survival data were immature at the time of analysis, with death occurring in 1.4% vs 1.3% of patients.

Adverse Events

The median duration of endocrine therapy was approximately 15 months in each group, and the median duration of abemaciclib treatment was 14 months.

The most common adverse events of any grade were diarrhea (82% vs 7%), neutropenia (45% vs 5%), and fatigue (38% vs 16%) in the abemaciclib group and arthralgia (31% vs 21%), hot flush (21% vs 14%), and fatigue in the control group. Grade ≥ 3 adverse events occurred in 46% vs 13% of patients, the most common in the abemaciclib group being neutropenia (19% vs 1%), leukopenia (11% vs < 1%), and diarrhea (7.6% vs < 1%). Venous thromboembolic events occurred in 2.3% vs 0.5% of patients, including pulmonary embolism in 0.9% vs 0.1%. Interstitial lung disease occurred in 2.7% vs 1.2% of patients.

Serious adverse events occurred in 12.3% vs 7.2% of patients, the most common in both groups being pneumonia (0.8% vs 0.5%). Adverse events led to discontinuation of abemaciclib treatment in 463 patients (17%), with 306 remaining on endocrine therapy; a total of 172 patients (6.2%) discontinued both treatments. Adverse events led to discontinuation of treatment in 21 patients (0.8%) in the control group. Adverse events led to death in 11 patients in the abemaciclib group, with 2 (diarrhea and pneumonitis) considered possibly related to treatment, and in 7 patients in the control group.

The investigators concluded: “Abemaciclib when combined with endocrine therapy is the first CDK4/6 inhibitor to demonstrate a significant improvement in [invasive disease–free survival] in patients with HR-positive, HER2-negative node-positive [early breast cancer] at high risk of early recurrence.” 

DISCLOSURE: The study was funded by Eli Lilly and Company. Dr. Johnston has received honoraria from AstraZeneca, Eisai, Eli Lilly, Novartis, Pfizer, and Roche; has served as a consultant or advisor to Lilly, Novartis, Pfizer, and Puma Biotechnology; and has received institutional research funding from Pfizer and Puma Biotechnology.

REFERENCE

1. 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. September 20, 2020 (early release online).