Significant Increase in PFS With Abemaciclib Plus Fulvestrant in Metastatic Breast Cancer

Significant Increase in PFS With Abemaciclib Plus Fulvestrant in Metastatic Breast Cancer

The CDK4/6 inhibitor abemaciclib combined with the estrogen inhibitor fulvestrant may significantly reduce the risk of disease progression and increase the objective response rate in women with metastatic breast cancer, according to the results of the MONARCH 2 study presented during the Breast Cancer—Metastatic Oral Abstract Session on June 3 (Abstract 1000).

Dr. George W. Sledge presents Abstract 1000.
The combination protocol reduced the risk of disease progression by 45% with a tolerable side effect profile, lead author and presenter George W. Sledge Jr., MD, FASCO, of Stanford University, said. The results were simultaneously published in the Journal of Clinical Oncology.

The MONARCH 2 study was a double-blind, phase III trial involving 669 women with hormone receptor–positive, HER2-negative advanced breast cancer resistant to endocrine therapy.

Participants were randomly assigned 2:1 to either a combination of abemaciclib and fulvestrant or to placebo and fulvestrant. The initial dose of 200 mg twice daily of abemaciclib was reduced to 150 mg twice daily because of diarrhea after 178 patients enrolled, Dr. Sledge said. The fulvestrant dose was 500 mg twice daily. The dose reduction did not change study results, he added.

At the median follow-up of 19.5 months, the median progression-free survival (PFS) in the combination treatment arm was 16.4 months compared with 9.3 months in the placebo arm (hazard ratio [HR] 0.553, 95% CI [0.449, 0.681]; p < 0.0000001) in all patient subgroups.

Patients with measurable disease receiving combination treatment achieved a twofold higher objective response rate compared with those receiving fulvestrant alone (48.1%, 95% CI [42.6%, 53.6%] for abemaciclib vs. 21.3%, 95% CI [15.1%, 27.6%] for placebo).

“This response rate is, to the best of our knowledge, the highest recorded in an endocrine-resistant population,” Dr. Sledge said.

The median duration of response has not yet been reached in the combination group, he added. It was 25.6 months in the placebo cohort.

The most common treatment-related adverse events in the combination arm compared with the placebo arm were diarrhea (86.4% vs. 24.7%) and neutropenia (46.0% vs. 4.0%). Grade 3/4 neutropenia occurred in 26.5% of the combination treatment arm compared with 1.7% in the placebo arm with few instances of febrile neutropenia, and grade 3/4 diarrhea in 13.4% compared with 0.4% of patients, respectively.

The diarrhea occurred early, typically in the first treatment cycle, Dr. Sledge said, and the intensity and frequency was “strongly related” to the starting dose of abemaciclib. Instances of severe diarrhea were quite rare after dose reduction, he added.

Dr. Ingrid Mayer discusses Abstract 1000.
Adverse events led to dose reduction in 42.9% of patients in the abemaciclib arm compared with 1.3% in the placebo arm, and discontinuation of the study drug in 15.9% compared with 3.1%, respectively. There were no significant differences in deaths between the two arms.

Discussant Ingrid A. Mayer, MD, MSCI, of Vanderbilt-Ingram Cancer Center and Vanderbilt University Medical Center, noted the differences between the PFS in MONARCH 2 and that seen in the recently published results of the PALOMA-3 trial, which compared palbociclib and fulvestrant with placebo and fulvestrant.1

Although the two trials had similar HRs, the shorter median PFS in PALOMA-3 
(9.5 months in the palbociclib arm vs. 4.6 months in the placebo arm) was likely due to the fact that patients in the MONARCH 2 trial had received less treatment because they were required to be chemotherapy-naive and received no more than one trial of an estrogen inhibitor. There were no such restrictions in PALOMA-3.

Dr. Mayer suggested that clinicians choose from two management scenarios based on data from MONARCH 2, as well as other studies on the CDK4/6 inhibitors palbociclib and ribociclib, which all have similar PFS rates (Table).

“Given how expensive these treatments are, how do we choose?” she asked. “The answer should rely on biology.”

Scenario 1 is likely best for patients with a long disease-free interval who have acquired estrogen therapy resistance, she said, while scenario 2 appears most appropriate for patients with primary estrogen therapy resistance. Those patients are unlikely to experience long-term response with an aromatase inhibitor alone.

–Debra Gordon, MS

For more information, read the JCO Original Report and companion Editorial, Oncology Grand Rounds, and Biology of Neoplasia articles at


Table. Treatment Scenarios Using CDK4/6 Inhibitors



Scenario 1


Scenario 2


First-line treatment


15 months

CDK4/6 inhibitor + AI

25 months

Second-line treatment

CDK4/6 inhibitor + fulvestrant

16 months


4 months

Third-line treatment

mTOR inhibitor + AI

8 months

mTOR inhibitor + AI

8 months

Total PFS


40 months


37 months

Abbreviations: AI = aromatase inhibitor; PFS = progression-free survival