Abemaciclib Plus Fulvestrant Delays Breast Cancer Progression in MONARCH 2

Other ASCO Presentations Provide Additional Data on CDK4/6 Inhibitors

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In the treatment of metastatic estrogen receptor–positive breast cancer, a highly significant 45% reduction in progression was achieved with abemaciclib, combined with fulvestrant (Faslodex), in the global phase III MONARCH 2 trial, reported at the 2017 ASCO Annual Meeting by George W. Sledge, MD, Chief of the Division of Oncology at Stanford University School of Medicine, Palo Alto.1

George W. Sledge, MD

George W. Sledge, MD

Abemaciclib, an inhibitor of cyclin-dependent kinase 4/6 (CDK4/6), was granted Breakthrough Therapy status by the U.S. Food and Drug Administration (FDA) as a single agent for heavily pretreated refractory hormone receptor–positive metastatic breast cancer. Two other CDK4/6 inhibitors are also on the market: palbociclib (Ibrance), which has full FDA approval, and ribociclib (Kisqali), which was also granted a Breakthrough Therapy designation. Continuous inhibition of CDK4/6 leads to sustained cell-cycle arrest, which can trigger apoptosis or senescence.

Key Findings

MONARCH 2 involved 669 women with hormone receptor–positive HER2-negative advanced breast cancer resistant to endocrine therapy. They were randomized 2:1 to abemaciclib plus fulvestrant or to placebo and fulvestrant. Abemaciclib was initially dosed at 200 mg twice daily, but the dose was reduced to 150 mg twice daily due to a high rate of diarrhea. 

At a median follow-up of 19.5 months, median progression-free survival with the combination was 16.4 months, compared to 9.3 months with placebo (hazard ratio [HR] = 0.553, P < .0000001). The objective response rates were 48.1% vs 21.3%, respectively. 

“This response rate is, to the best of our knowledge, the highest recorded in an endocrine-resistant population,” Dr. Sledge noted. Median duration of response was not reached with the combination, while it was 25.6 months in the control arm. The benefit of the combination was observed across all patient subgroups.

The results of MONARCH 2 were simultaneously published in the Journal of Clinical Oncology.2

The most common treatment-related adverse events in the combination and control arms, respectively, were diarrhea (86.4% vs 24.7%) and neutropenia (46.0% vs 4.0%). Grade 3/4 diarrhea occurred in 13.4% vs 0.4%, and grade 3/4 neutropenia occurred in 26.5% vs 1.7%.

Based on these results, a study of abemaciclib in combination with endocrine therapy as adjuvant treatment for hormone receptor–positive/HER2-negative high-risk breast cancer will begin recruitment later in 2017.

Abemaciclib in Brain Metastases

Also at the ASCO Annual Meeting, Sara M. Tolaney, MD, MPH, Associate Director of Clinical Research, Breast Oncology, at the Susan F. Smith Center for Women’s Cancers, Dana--Farber Cancer Institute, Boston, reported that -abemaciclib has activity against brain metastases, based on an objective response rate of 8.7% and a clinical benefit rate of 17.4% in 23 patients with brain metastases secondary to breast cancer in an open-label, phase II study.3 The metastases had either not been previously irradiated or could have been irradiated but progressed. Median progression-free survival was 4.04 months among abemaciclib-treated patients at the time of this interim analysis. 

Sara M. Tolaney, MD, MPH

Sara M. Tolaney, MD, MPH

“Data from a surgical cohort on this trial provided evidence that abemaciclib penetrates brain metastases in patients with hormone receptor–positive, HER2-negative metastatic breast cancer,” Dr. Tolaney said. She told The ASCO Post that surgical resection of the lesions after treatment with abemaciclib has revealed drug levels that are similar to plasma concentrations. “And now we have clinical data to suggest there are responses in the central nervous system as well.”

PALOMA-1/TRIO-18 Overall Survival 

In the same session where the MONARCH 2 results were reported, Richard S. Finn, MD, Associate Professor of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, reported the final overall survival results of -PALOMA-1/TRIO-18, which he noted represents “the longest survival and safety follow-up data for any CDK4/6 inhibitor in breast cancer.”4

“PALOMA-1/TRIO-18 was the first study evaluating the role of CDK4/6 inhibition in breast cancer, and it has served as the proof of concept for this target, showing a 10-month improvement in progression-free survival that was perfectly recapitulated in PALOMA-2, the blinded phase III trial,” he said. 


  • In the phase III MONARCH 2 study, the CDK4/6 inhibitor abemaciclib plus fulvestrant reduced the risk of progression by 45%, over fulvestrant alone.
  • At a median follow-up of 19.5 months, median progression-free survival with the combination was 16.4 months, compared to 9.3 months with placebo (HR = 0.553; P < .0000001). The objective response rate was 48.1%, vs 21.3%.

At a median follow-up of 65 months, patients receiving palbociclib plus letrozole in PALOMA-1 had a longer survival time (an increase of 3 months) than those receiving letrozole alone, but the difference was not statistically significant. Median overall survival in the entire population was 37.5 months with the combination and 34.5 months with letrozole alone (HR = 0.897, P = .281). 

Survival was looked at in the entire population as well as in part 1 (women enrolled with estrogen receptor–positive, HER2-negative, locally recurrent or metastatic breast cancer) and part 2 (women enrolled with the additional selection of having CCND1 amplification and/or loss of p16) separately. While there was a difference seen in the part 1 population, no difference between arms was observed in the subset of patients in part 2 of the study. The combination cohort did experience a longer time before starting chemotherapy: 26.7 months compared to 17.7 months (HR = 0.662). 

According to Dr. Finn, an overall survival difference may be very difficult to show with CDK4/6 inhibitors in metastatic estrogen receptor–positive disease, as has been true for essentially all other agents given the long postprogression survival in the first-line setting. “Based on previous analyses and given the longer median postprogression survival time, a larger sample size would be needed to detect a significant difference in overall survival in front-line estrogen receptor–positive breast cancer,” he said. ■

DISCLOSURE: Drs. Sledge and Finn reported no conflicts of interest. Dr. Tolaney has received research funding from Genentech, Lilly, Novartis, Pfizer, Nektar, -Exelixis, and Merck. 


1. Sledge GW, et al: 2017 ASCO Annual Meeting. Abstract 1000

2. Sledge GW, et al: J Clin Oncol. June 3, 2017 (early release online).

3. Tolaney SM, et al: 2017 ASCO Annual Meeting. Abstract 1019

4. Finn RS, et al: 2017 ASCO Annual Meeting. Abstract 1001.

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Richard S. Finn, MD, of the David Geffen School of Medicine at UCLA, Los Angeles, commented on MONARCH 2 and the field of cyclin-dependent kinase 4/6 (CDK4/6) inhibition in general in an interview with The ASCO Post.

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