MONARCH Studies of Abemaciclib Meet Progression-Free Survival End Point

TON Web Exclusives - Breast Cancer

Abemaciclib, an investigational, selective CDK4/6 inhibitor, added to fulvestrant, yielded superior outcomes compared with fulvestrant plus placebo in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer who received previous endocrine therapy. Preliminary data from the phase 3 MONARCH 2 trial showed that the study met its primary outcome of improvement in progression-free survival (PFS) with the combination compared with fulvestrant.

In MONARCH, 2669 patients with HR-positive/HER2-negative breast cancer were randomized in a 2:1 ratio to abemaciclib plus fulvestrant or fulvestrant plus placebo. Pre- and perimenopausal women also received a gonadotropin-releasing hormone agonist; 82% enrolled were postmenopausal. Fifty-six percent of the study population had visceral disease. As reported at the 2017 meeting of the American Society of Clinical Oncology, 379 investigator-assessed PFS events occurred, with a median PFS of 16.4 months in the patients randomized to abemaciclib plus fulvestrant compared with 9.3 months in those randomized to fulvestrant plus placebo (hazard ratio, 0.553; P <.0000001).

The manufacturer also noted in a press release that in the MONARCH 3 study, abemaciclib in combination with an aromatase inhibitor (AI; letrozole or anastrozole) significantly improved PFS compared with an AI alone in patients with HR-positive/HER2-negative advanced breast cancer who had not previously received treatment for advanced disease.

These findings add to those from the single-arm phase 2 MONARCH 1 study, which showed that abemaciclib monotherapy induced tumor responses in patients with previously treated HR-positive/HER2-negative metastatic breast cancer following multiple previous therapies. Median PFS in MONARCH 1 was 6 months, and median overall survival was 17.7 months. The confirmed objective response rate was 19.7% and the rate of stable disease ≥6 months was 22.7%, leading to a clinical benefit rate of 42.4%. The median time to response was 3.7 months, and the median duration of response was 8.6 months.

The most common nonlaboratory adverse events in MONARCH 1 were diarrhea (90.2%), fatigue (65.2%), nausea (64.4%), decreased appetite (45.5%), and abdominal pain (38.6%). The rates of grade 3 adverse events were 19.7% for diarrhea, 12.9% for fatigue, 4.5% for nausea, 3.0% for decreased appetite, and 2.3% for abdominal pain.

Leukopenia (27.4%) and neutropenia (22.3%) were the most common laboratory adverse events. The only grade 4 adverse event was neutropenia, which occurred in 4.6% of patients.

Based on the results of MONARCH 1, a new drug application for single-agent abemaciclib will be submitted to the US Food and Drug Administration in the second quarter of 2017, and an additional application based on the results from MONARCH 2 will be submitted in the third quarter of 2017.

MONARCH 2 was a global double-blind study that aimed to evaluate abemaciclib plus fulvestrant in patients with locoregionally recurrent or metastatic breast cancer. The intent-to-treat population consisted of 669 patients who were randomized to receive abemaciclib or placebo twice daily on a continuous schedule, given in combination with fulvestrant at its approved dose and schedule, until disease progression. Patients enrolled in MONARCH 2 had experienced disease progression within 12 months of receiving endocrine treatment in the neoadjuvant or adjuvant setting or while receiving first-line endocrine therapy for metastatic disease. Patients who had received chemotherapy in the metastatic setting were not eligible to participate in this trial. 

In MONARCH 3, 493 postmenopausal women with locoregionally recurrent or metastatic breast cancer who received no previous systemic treatment for advanced disease were randomized to 150 mg of abemaciclib or placebo given orally twice daily, in combination with 1 mg of anastrozole or 2.5 mg of letrozole once daily until disease progression or unacceptable toxicity.

The recognition that breast cancer is cyclin-dependent led to the development of abemaciclib and other CDK4/6 inhibitors, which act on the cyclin D-CDK4/6-INK4-Rb pathway, reported William J. Gradishar, MD, Professor of Breast Oncology at the Feinberg School of Medicine, Northwestern University, Chicago, at the National Comprehensive Cancer Network (NCCN) 22nd Annual Conference held in Orlando, FL.

“Cyclin D in particular interacts with the cyclin D kinase [CDK], and by doing so causes phosphorylation of Rb, which then causes Rb to lose its tumor suppressor function,” said Dr Gradishar. “If you can inhibit the effect at the CDK level you may be able to inhibit cancer cells from going thru the cell cycle and this is the rationale for developing CDK4/6 inhibitors,” he said.

The updated guidelines from NCCN (version 1.2017) for endocrine treatment of recurrent or stage IV breast cancer now includes combinations of palbociclib plus letrozole (category 1 recommendation) and palbociclib plus fulvestrant (category 1 recommendation). Since ribociclib was only recently approved, it has not yet been incorporated into the guidelines, but the NCCN panel will take on this issue soon, he said.

These agents “should not be assumed to be exactly the same—clinically, pharmacodynamically or kinetically,” said Dr Gradishar. “We believe these drugs are not identical, either in terms of efficacy or side effects. We should learn more about their distinguishing features as we see more data from the pivotal trials.”


Sledge GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in patients with HR+/HER2-advanced breast cancer who progressed on endocrine therapy. Presented at: 2017 Meeting of the American Society of Clinical Oncology, June 2-6, 2017; Chicago, IL. Abstract 1000.

Lilly Announces Phase 3 MONARCH 3 Breast Cancer Study of Abemaciclib Demonstrated Superior Progression-Free Survival at Interim Analysis. Accessed June 5, 2017.

Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2-breast cancer, after chemotherapy for advanced disease. J Clin Oncol. 2016;34(suppl): Abstract 510.

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Last modified: August 7, 2017