PFS Improved With Abemaciclib in Phase III Breast Cancer Trial


Progression-free survival was improved by adding abemaciclib to fulvestrant compared with fulvestrant alone in women with HR+/HER2-negative breast cancer enrolled in the phase III MONARCH 2 study.

Levi Garraway, MD, PhD

Levi Garraway, MD, PhD

Progression-free survival (PFS) was improved by adding abemaciclib to fulvestrant compared with fulvestrant alone in women with HR+/HER2-negative breast cancer enrolled in the phase III MONARCH 2 study, according to Eli Lilly and Company, the manufacturer of the CDK4/6 inhibitor.

"We are excited about the outcome of our first phase III study for abemaciclib. These data are an important milestone in our goal of bringing abemaciclib to patients with advanced breast cancer, and we look forward to our upcoming conversations with regulators," Levi Garraway, MD, PhD, senior vice president, global development and medical affairs, Lilly Oncology, said in a statement.

The international, double-blind phase III MONARCH 2 trial randomized 669 patients in a 2:1 ratio to abemaciclib plus fulvestrant or fulvestrant alone. Patients had progressed during or within 1 year of receiving endocrine therapy in the neoadjuvant or adjuvant setting, or during frontline endocrine treatment for metastatic disease. Individuals were excluded from enrollment if they were administered chemotherapy in the metastatic setting. The primary endpoint for the trial was PFS.

According to Lilly, the safety data were consistent with results reported in previous trials of abemaciclib. The most common adverse events (AEs) observed were diarrhea, neutropenia, nausea, and fatigue.

Lilly plans to submit the MONARCH 2 data to the FDA for regulatory review by the third quarter of this year. Prior to that submission, the company intends to submit an application, based on the MONARCH 1 trial, for single-agent abemaciclib for the treatment of patients with refractory metastatic breast cancer who have disease progression after endocrine therapy and 1 to 2 chemotherapy regimens in the metastatic setting.

In previously reported results from the phase II MONARCH 1 trial, abemaciclib induced a response rate of nearly 20% in heavily pretreated patients with refractory HR+, HER2-negative advanced breast cancer.1

In the single-arm phase II study, the median PFS was 6 months (95% CI, 4.2-7.5) and the median overall survival (OS) was 17.7 months (95% CI, 16 to not reached). Abemaciclib previously received a breakthrough therapy designation in this setting from the FDA in October 2015.

The MONARCH 1 trial included 132 patients with HR+/HER2- metastatic breast cancer who progressed during or after endocrine therapy and chemotherapy. The median age was 58 years (range, 36-89), 44.7% of patients had an ECOG performance status of 1, 90.2% had visceral disease, and 85.6% had at least 2 metastatic sites. Patients with CNS metastases were excluded from enrollment.

Patients had received a median of 3 (range, 1-8) prior lines of therapy—including a median of 2 lines of chemotherapy—for metastatic disease. Sixty-seven patients (50.8%) had received fulvestrant in the metastatic setting. With chemotherapy, 68.9% (n = 91) of patients had received a taxane and 55.3 % (n = 73) of patients had received capecitabine in the metastatic setting.

Abemaciclib was administered at 200 mg orally every 12 hours on a continuous schedule until progression or unacceptable toxicity. At the 8-month interim analysis, 35.6% of patients had received at least 8 cycles of the CDK4/6 inhibitor.

Objective response rate (ORR) was the primary outcome measure. Secondary endpoints included duration of response, PFS, OS, clinical benefit rate, and safety.

The investigator-assessed, confirmed ORR was 19.7% (n = 26; 95% CI, 13.3-27.5), which included all partial responses (PR). The rate of patients with stable disease (SD) ≥6 months was 22.7%, leading to a clinical benefit rate (complete response + PR + SD ≥6 months) of 42.4%. The median time to response was 3.7 months and the median duration of response was 8.6 months. Thirty-four patients had progressive disease.

The most common non-laboratory, all-grade AEs were diarrhea (90.2%), fatigue (65.2%), nausea (64.4%), decreased appetite (45.5%), and abdominal pain (38.6%). The grade 3 rates of these 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 AEs. The only grade 4 AE of any kind in the trial was neutropenia, which occurred in 4.6% of patients.

Serious AEs occurred in 24.2% (n = 32) of patients, with AEs leading to treatment discontinuation in 7.6% (n = 10) of patients. Dose reductions were required for 49.2% of patients (n = 65). The most common reason for dose reductions were diarrhea (20.5%) and neutropenia (10.6%). There were 2 patient deaths during treatment and 1 patient death within 30 days after study discontinuation.

The median time to the onset of diarrhea was 7 days. Standard antidiarrheal regimens and dose reductions were used to manage diarrhea. The median duration of grade 2 and grade 3 diarrhea was 7.5 and 4.5 days, respectively. There were no incidents of grade 4 diarrhea and only 1 patient discontinued treatment due to diarrhea.

The FDA breakthrough designation was based on a phase I trial in which single-agent abemaciclib demonstrated an ORR of 33.3% in patients with heavily pretreated HR-positive breast cancer (n = 36).2When including those with SD for ≥24 weeks, the clinical benefit rate with abemaciclib was 61.1%. The median duration of response was 13.4 months and the median PFS was 8.8 months, according to data presented at the 2014 San Antonio Breast Cancer Symposium.

Beyond the MONARCH 1 and 2 trials, the phase III MONARCH 3 trial (NCT02246621) is examining abemaciclib in combination with anastrozole or letrozole in patients with HR+, HER2- advanced breast cancer. Another study, the phase II monarcHER trial (NCT02675231), is assessing abemaciclib plus trastuzumab (with or without fulvestrant) in patients with HR+/HER2+ locally advanced or metastatic breast cancer.


  1. 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 Oncol34, 2016 (suppl; abstr 510).
  2. Tolaney SM, Rosen LS, Beeram M, et al. Clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract P5-19-13.
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