Abemaciclib Granted FDA Breakthrough Status for Refractory Breast Cancer

The CDK4/6 inhibitor abemaciclib (LY2835219) has been granted FDA breakthrough therapy designation as monotherapy for heavily pretreated patients with refractory hormone-receptor-positive advanced breast cancer.

The CDK4/6 inhibitor abemaciclib (LY2835219) has been granted FDA breakthrough therapy designation as monotherapy for heavily pretreated patients with refractory hormone-receptor (HR)-positive advanced breast cancer, based on data from a phase I study.

"We are pleased that the FDA has designated abemaciclib as a breakthrough therapy for patients with advanced breast cancer, and Lilly will work closely with the FDA in this process to expedite its development and review," said Richard Gaynor, MD, senior vice president of product development and medical affairs for Lilly Oncology, the company developing the drug, in a statement.

In the small clinical trial, single-agent abemaciclib demonstrated an objective response rate (ORR) of 33.3% in patients with heavily pretreated HR-positive breast cancer (n = 36). When including those with stable disease for ≥24 weeks, the clinical benefit rate with abemaciclib was 61.1%. The median duration of response was 13.4 months and the median progression-free survival (PFS) was 8.8 months, according to data presented at the 2014 San Antonio Breast Cancer Symposium.1

In the phase I study, abemaciclib was evaluated in 132 patients with glioblastoma, melanoma, lung cancer, colorectal cancer, and breast cancer. In the breast cancer cohort, abemaciclib was tested as a monotherapy and in combination with fulvestrant. In the single-agent arm, 47 patients were treated with oral abemaciclib at 150 mg (n = 25) or 200 mg (n = 22) every 12 hours on a continuous schedule.

The median age of patients in the monotherapy cohort was 55 years and the median number of prior therapies was 7 (range, 2-16). The location of metastatic disease was primarily the bone (61.7%) and 76.6% of patients had visceral disease. Overall, 11 patients were both HR and HER2 positive and 25 were HR positive and HER2 negative. The rest of the patients enrolled were HR negative (n = 11).

Across all patients enrolled in the single-agent breast cancer cohort (N = 47), the ORR was 25.5% and the stable disease rate was 44.7%, for an overall disease control rate of 70.2%. When looking specifically at those with stable disease for ≥24 weeks, the rate was 23.4%, which dropped the clinical benefit rate to 48.9%. The median duration of response was 13.4 months and the median PFS was 5.8 months.

Patients with HR-negative disease did not experience a response with abemaciclib monotherapy. The stable disease rate at ≥24 weeks was 11.1%. The median PFS was 1.1 months. The response rate in HR- and HER2-positive breast cancer was 33.3%. In the HR-positive, HER2-negative group, the response rate was 66.7%.

The most commonly reported all-grade adverse events (AEs) with single-agent abemaciclib across all doses were diarrhea (68.1%), nausea (59.6%), fatigue (44.7%), vomiting (44.7%), neutropenia (40.4%), thrombocytopenia (31.9%), leukopenia (29.8%), and anemia (19.1%). The only grade 4 AE reported in the study was neutropenia, which occurred in one patient. The most frequent nonhematologic grade 3 AEs were diarrhea (8.5%) and nausea (4.3%).

Monotherapy with abemaciclib is currently being assessed in the phase II MONARCH-1 study for patients with previously treated HR-positive and HER2-negative metastatic breast cancer. The study active but currently not recruiting participants, with an estimated enrollment of 128 patients. A primary assessment of the study is anticipated in December 2015 (NCT02102490).

"If caught before it spreads, patients can survive breast cancer," Gaynor noted. "However, for the nearly 10% of patients who are initially diagnosed at stage IV, and the nearly 30% of patients whose early-stage cancer will reoccur as metastatic disease, there remains an urgent need for effective therapy options."

In the 19-patient combination cohort, 18 patients had HR-positive, HER2-negative metastatic breast cancer, with 1 patients having unknown biomarker status. Patients received abemaciclib at 200 mg orally every 12 hours on a continuous schedule and fulvestrant was administered at 500 mg intramuscularly every month.

Of these 19 patients enrolled, 11 had measurable disease (57.9%) and bone metastases were present in 73.7%. The median number of prior therapies was 4 (range, 1-11) and 2 patients had previously progressed on fulvestrant.

The ORR with the combination was 21.1% across the full cohort (N = 19). In those with measurable disease at baseline, there was a 36.4% response rate. The rate of stable disease at ≥24 weeks was 42.1%, for a clinical benefit rate of 63.2% across the full population. At the time of the analysis, the duration of response had not yet been reached and the median PFS was 10 months.

The most common grade 3 AEs were neutropenia (31.6%), leukopenia (26.3%), abdominal pain (10.5%), anemia (10.5%), diarrhea (5.3%), vomiting (5.3%), and fatigue (5.3%). No grade 4 toxicities were reported in the study. The most frequent all-grade AEs were diarrhea (78.9%), fatigue (68.4%), and nausea (63.2%).

"We have seen patients with hormone receptor-positive metastatic breast cancer whose tumors respond to treatment with abemaciclib alone even after their disease stopped responding to other treatments," said principal investigator Amita Patnaik, MD, associate director of clinical research at South Texas Accelerated Research Therapeutics, in a statement when earlier findings were presented at the 2014 ASCO Annual Meeting.2"The results of this study cohort evaluating the combination of abemaciclib and fulvestrant are encouraging and support further development."

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 indications, abemaciclib has also shown promise for patients with non—small cell lung cancer (NSCLC), and could represent a useful therapy for combination strategies. In an early phase study, the AE profiles for various combinations were similar to experiences with single-agents.

A phase I study is currently assessing abemaciclib in combination with pemetrexed, gemcitabine, ramucirumab, or the PI3K/mTOR dual inhibitor LY3023414. Those treated with abemaciclib/pemetrexed are required to have nonsquamous histology. For the remaining arms, all histologies are eligible. The study hopes to enroll 126 patients (NCT02079636).


  1. 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.
  2. Patnaik A, Rosen LS, Tolaney SM, et al. LY2835219, a novel cell cycle inhibitor selective for CDK4/6, in combination with fulvestrant for patients with hormone receptor positive (HR+) metastatic breast cancer.J Clin Oncol.32:5s; 2014 (suppl; abstr 534).