Abemaciclib Demonstrates Notable Response in HR+/HER2- Breast Cancer

Maura N. Dickler, MD

When tested in heavily pretreated patients with refractory, hormone-receptor (HR)—positive, HER2-negative advanced breast cancer, abemaciclib, a CDK4/6 inhibitor, produced a positive response rate of approximately 20%, results from the phase II MONARCH 1 trial showed when presented at the 2016 ASCO Annual Meeting.¹

In the single-arm phase II study, the median progression-free survival (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.

“MONARCH 1 confirms single-agent activity with abemaciclib, a CDK 4/6 inhibitor, in heavily pretreated patients with HR-positive, HER2-negative metastatic breast cancer,” lead study author Maura N. Dickler, MD, Memorial Sloan Kettering Cancer Center, said when presenting the data at ASCO.

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.

Addressing the high incidence of diarrhea in the study, Dickler said, “Generally, diarrhea was experienced during the first cycle of treatment and resolved quickly.”

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.

Commenting on the MONARCH 1 results, senior study author, José Baselga, MD, PhD, physician-in-chief and chief medical officer, Memorial Sloan Kettering Cancer Center, said in a statement, "After endocrine therapies are no longer considered appropriate for HR+ metastatic breast cancer patients, when the disease is refractory or aggressive, chemotherapy is the only option. The side effects can be distressing and may be long lasting, limiting the options for patients. To see this level of antitumor activity, combined with the toxicity profile observed in MONARCH 1, is compelling."

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). 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.²

The combination of abemaciclib and fulvestrant is being studied in the phase III MONARCH-2 study for postmenopausal patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer. This study is currently ongoing and recruiting, with an enrollment goal of 630 participants. Patients are being randomized in a 2:1 ratio to abemaciclib plus fulvestrant or fulvestrant alone following no more than 1 prior endocrine therapy. Those pretreated with chemotherapy are not eligible for the study (NCT02107703).

In earlier settings, the MONARCH-3 study is assessing abemaciclib with a nonsteroidal aromatase inhibitor in patients with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer. This study is also randomized 2:1, with an enrollment goal of 450 patients (NCT02246621).

In addition to breast cancer, abemaciclib has also show early promise in several other tumor types, including non—small cell lung cancer, glioblastoma, melanoma, and colorectal cancer.

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).

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.