Good News for a Different Type of CDK4/CDK6 Inhibitor in Early Breast Cancer
San Antonio, TX—Neoadjuvant therapy with the investigative CDK4/CDK6 inhibitor abemaciclib, alone or in combination with anastrozole (Arimidex), showed promising activity in postmenopausal hormone receptor (HR)-positive, HER2-negative breast cancer enrolled in the phase 2 NeoMONARCH study. Correlative tissue studies demonstrated that abemaciclib inhibited cell-cycle proliferation and activated the immune system, supporting its anticancer activity. Abemaciclib received a breakthrough therapy designation in 2015 as monotherapy for the treatment of patients with refractory HR-positive advanced breast cancer in heavily pretreated patients.
These promising study results justify going forward with phase 3 studies in the adjuvant setting, according to experts who discussed the NeoMONARCH study at the 2016 San Antonio Breast Cancer Symposium. Studies of abemaciclib are ongoing in patients with metastatic breast cancer.
“The majority of patients who received abemaciclib plus anastrozole experienced an objective response, and there were no new safety signals when the drug was combined with anastrozole,” said lead investigator Sara A. Hurvitz, MD, Medical Director, Clinical Research Unit, Los Angeles Jonsson Comprehensive Cancer Center, Santa Monica.
“Tissue analysis is a novel aspect of this trial, allowing for correlative studies. This study is in early breast cancer. It is a large study with a rich histological evaluation, and the data will become important to us as we move forward in developing this drug,” Dr Hurvitz said.
The phase 2 study included 220 postmenopausal women with HR-positive, HER2-negative breast cancer who are suitable for neoadjuvant endocrine therapy (ie, stage II, IIIA, or IIIB). At baseline, a core biopsy was obtained from each patient. Patients were randomized to anastrozole 1 mg, abemaciclib 150 mg every 12 hours plus anastrozole at the same dose, or to abemaciclib alone at the same dose. After 14 days of treatment, a second core biopsy was obtained.
The primary end point was to compare the changes from baseline to 14 weeks in the expression of Ki67, a marker of cell-cycle progression and a potential surrogate for disease-free survival, according to recent studies. All patients who received abemaciclib also received prophylactic loperamide for 28 days, because diarrhea was a side effect of concern.
After the 2-week assessment of Ki67 expression, patients continued to receive the combination of abemaciclib and anastrozole for another 14 weeks and had a third core biopsy, at which time they could undergo surgery. “Treatment with abemaciclib did not delay surgery,” Dr Hurvitz noted.
For the primary end point, the mean change in Ki67 expression in each arm was significant for both abemaciclib-containing arms versus anastrozole, with a 92.6% decrease in Ki67 expression for abemaciclib plus anastrozole, a 90.6% decrease for abemaciclib alone, and a 63.2% decrease for anastrozole (P <.001 for both arms vs anastrozole).
The most common adverse effect associated with abemaciclib was diarrhea (55.2%, primarily grades 1 and 2, with only 4% grade 3, as a result of loperamide prophylaxis). Neutropenia of all grades occurred in 61%, with grades 3 and 4 neutropenia in 3.2%.
New CDK4/CDK6 Inhibitor Options
Palbociclib (Ibrance) is a CDK4/CDK6 inhibitor approved by the FDA for the treatment of breast cancer. The second CDK4/CDK6 inhibitor, ribociclib (Kisqali), was just approved by the FDA on March 13, 2017 (see Kisqali, a New CDK4/CDK6 Inhibitor, Approved for First-Line Therapy in HR-Positive, HER2-Negative Advanced Breast Cancer), based on results of the MONALEESA trial, which were presented at ESMO 2016.
A Different Type?
Unlike palbociclib and ribociclib, abemaciclib can be used continuously. Palbociclib and ribociclib are administered on a 3-week-on, 1-week-off dosing schedule, during which time there is concern regarding rebound in cell proliferation, Dr Hurvitz explained.
All CDK4/CDK6 inhibitors are not alike, commented Carlos Arteaga, MD, Director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN. “This drug is not necessarily the same as palbociclib or ribociclib,” he said. Dr Arteaga moderated the press conference at which Dr Hurvitz presented his study results.
“This study is preliminary and is not a green light for using this drug in clinical practice. More studies of CDK4/CDK6 agents are ongoing, and they will likely be positive. I wouldn’t be surprised if we have 3 FDA-approved CDK4/CDK6 inhibitors, and that is good news,” Dr Arteaga concluded.