Adding Abemaciclib to Fulvestrant in Hormone Receptor–Positive, HER2-Negative Breast Cancer

Key Points

  • The addition of abemaciclib to fulvestrant significantly improved progression-free survival in women with hormone receptor–positive, HER2-negative advanced breast cancer.
  • Adverse events were more common with the combination treatment.

In the phase III MONARCH 2 trial reported at the recent ASCO Annual Meeting and in the Journal of Clinical Oncology by Sledge et al, the addition of the selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib to fulvestrant (Faslodex) improved progression-free survival in hormone receptor–positive, HER2-negative advanced breast cancer progressing on prior endocrine therapy.

Study Details

In the double-blind trial, 669 patients from 142 sites in 19 countries were randomized 2:1 between August 2014 and December 2015 to receive abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223). Patients had to have disease that progressed while receiving neoadjuvant or adjuvant endocrine therapy, ≤ 12 months after adjuvant endocrine therapy, or while receiving endocrine therapy for advanced disease. Patients could not have received more than one endocrine therapy or any prior chemotherapy for advanced disease.

Patients received 500 mg fulvestrant intramuscularly on days 1 and 15 of the first cycle and on day 1 of subsequent 28-day cycles. Abemaciclib and placebo were given twice daily during each cycle; the initial abemaciclib dose of 200 mg twice daily was reduced to 150 mg twice daily after review of safety data and dose-reduction rates, with all 27% of patients on 200 mg having their dose reduced to 150 mg. Treatment continued until progressive disease, death, or patient withdrawal. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population.

For the abemaciclib vs placebo groups, median age was 54 vs 62 years, endocrine therapy resistance was primary in 25% vs 26% and secondary in 73% in both, most recent endocrine therapy was neoadjuvant/adjuvant in 59% and 60% and metastatic in 38% in both, 71% vs 67% had received a prior aromatase inhibitor, progesterone receptor status was positive for 76% vs 77%, metastatic sites were visceral in 55% vs 57% and bone only in 28% vs 26%, 71% vs 74% had measurable disease, 53% vs 61% were white and 33% vs 29% were Asian, virtually all patents had an Eastern Cooperative Oncology Group performance status of 0 or 1, 60% in both had received neoadjuvant/adjuvant chemotherapy, and 83% vs 81% were postmenopausal.

Progression-Free Survival

Median follow-up was 19.5 months. Median progression-free survival was 16.4 months in the abemaciclib plus fulvestrant group vs 9.3 months in the control group (hazard ratio [HR] = 0.553, P < .001). Blinded central analysis showed similar results (HR = 0.460, P < .001). A sensitivity analysis including only patients enrolled after the change in abemaciclib starting dose was consistent with the primary analysis (HR = 0.588, 95% confidence interval [CI] = 0.458–0.754). Hazard ratios favored the addition of abemaciclib across all patient subgroups.

Response Rates

Among all patients, the objective response rate was 35.2%, including complete response in 3.1%, vs 16.1%, including complete response in 0.4% (P < .001). Response of ≥ 12 months was observed in 67.8% vs 66.9% of responders; median duration of response was not reached in the abemaciclib group, with 90 responders (57.3%) continuing to receive treatment at the time of analysis. Among patients with measurable disease, objective response rates were 48.1% vs 21.3% (P < .001). Overall survival results were not mature at data cutoff (February 2017), with death having occurred in 19.1% of the abemaciclib group vs 21.5% of the control group.

Adverse Events

The most common adverse events of any grade in the abemaciclib group were diarrhea (86.4% vs 24.7% in control group), neutropenia (46.0% vs 4.0%), nausea (45.1% vs 22.9%), and fatigue (39.9% vs 26.9%). Overall, there was a higher incidence of infections in the abemaciclib group (42.6% vs 24.7%). Grade 3 or 4 adverse events occurred in 61% vs 23%, with the most common in the abemaciclib group being neutropenia (27% vs 2%), diarrhea (13% vs < 1%), and leukopenia (9% vs 0%). Serious adverse events occurred in 22% vs 11%, with the most common in the abemaciclib group being thromboembolic events (2.0% vs 0.4%); four abemaciclib patients had pulmonary embolism (none fatal).

Adverse events led to dose interruption in 51.9% vs 11.7%, dose reduction in 42.9% vs 1.3%, and discontinuation of treatment in 15.9% vs 3.1%. Adverse events led to death in nine abemaciclib patients and two control patients; threedeaths in the abemaciclib group were considered related to treatment.

The investigators concluded: “Abemaciclib at 150 mg twice daily plus fulvestrant was effective, significantly improving [progression-free survival] and [objective response rate] and demonstrating a tolerable safety profile in women with hormone receptor-positive and human epidermal growth factor receptor 2-negative [advanced breast cancer] who progressed while receiving [endocrine therapy].”

The study was funded by Eli Lilly.

George W. Sledge, Jr, MD, of Stanford University School of Medicine, is the corresponding author of the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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