Early Abemaciclib Data Not Sufficient to Halt Phase III Breast Cancer Trial

The phase III MONARCH 2 study assessing abemaciclib in HR-positive, HER2-negative advanced breast cancer will continue after the CDK4/6 inhibitor did not meet the efficacy criteria at an interim analysis required to stop the trial early.

Richard Gaynor, MD

The phase III MONARCH 2 study assessing abemaciclib in HR-positive, HER2-negative advanced breast cancer will continue after the CDK4/6 inhibitor did not meet the efficacy criteria at an interim analysis required to stop the trial early, according to Eli Lilly and Company, the manufacturer of the treatment.

"We had stringent criteria set for this interim analysis and we look forward to receiving the final MONARCH 2 results in the first half of 2017," Richard Gaynor, MD, senior vice president, product development and medical affairs for Lilly Oncology, said in a statement. "We remain optimistic that treatment with abemaciclib, in combination with fulvestrant could offer improved outcomes for patients."

MONARCH 2 follows the phase II MONARCH 1 trial, in which abemaciclib induced a response rate of nearly 20% in heavily pretreated patients with refractory HR—positive, 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 adverse events (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).2 When 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.

In Lilly’s press release updating the status of MONARCH 2, the company reported that it will “await further data and continue to work with the FDA to inform its submission plan for single-agent abemaciclib, based on the MONARCH 1 study.”


  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 Oncol 34, 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.

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 is progression-free survival (PFS).

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