Sara A. Hurvitz, MD
The neoadjuvant combination of CDK4/6 inhibitor abemaciclib plus anastrazole may represent a novel therapeutic option for patients with hormone receptor (HR)-positive, HER2-negative early breast cancer, according to results presented during the 2016 San Antonio Breast Cancer Symposium1
In the phase II neoMONARCH trial, patients underwent a core biopsy at baseline and were then randomized 1:1:1 to monotherapy with anastrozole (1 mg daily) or abemaciclib (150 mg every 12 hours), or a combined regimen of the 2 drugs at the same doses.
According to the combined data of all 3 trial arms, patients experienced an overall response rate of 54.7%. The study’s primary endpoint—a reduction in Ki67 expression level at week 2 with the combination—was met, with a geometric mean change in Ki67 from baseline to day 15 of -92.6%.
In an interview with OncLive
during the conference, lead study author Sara A. Hurvitz, MD, associate professor of medicine at UCLA and medical director of UCLA’s Jonsson Comprehensive Cancer Center Clinical Research Unit, gave an overview of the neoMONARCH study. She also shed light on the unique mechanistic properties of abemaciclib as well as its potential for combination with immunotherapy.
OncLive: Can you provide an overview of the neoMONARCH trial?
: neoMONARCH is a phase II randomized clinical trial in the neoadjuvant setting addressing a new therapy, abemaciclib, which is a CDK4/6 inhibitor in combination with anastrozole. This study is enrolling patients who are postmenopausal with HR-positive, HER2-negative breast cancer. Eligible patients are undergoing a baseline core biopsy; they are then randomized to receive anastrozole alone, the combination of abemaciclib with anastrozole, or abemaciclib alone for 2 weeks.
After 2 weeks, they get a second biopsy and at that point, all patients merge onto the combination therapy arm and receive 14 weeks of abemaciclib and anastrozole. At that time, a third biopsy is done. The primary endpoint was actually looking at what happens at day 14 in terms of that tumor biopsy—does that Ki67 or that proliferation drop at day 15 compared with the baseline Ki67. Results from prior studies suggest that a drop in Ki67 may be predictive of disease-fee survival. It might be a good surrogate measure of a long-term outcome.
What we showed with 161 evaluable patients was that both abemaciclib arms actually statistically significantly increased the drop in Ki67 [levels] more when looking at the geometric mean change compared with anastrozole alone. Around 60% of patients in the anastrozole arm had a drop in their Ki67 after 2 weeks of therapy, and it was over 90% in each of the abemaciclib-based arms. Our primary endpoint was met.
Moreover, when you look at the proportion of patients whose tumors underwent complete cell cycle arrest, which is a Ki67 [level] of less than 2.7% at that 2-week time point, a significantly higher percentage of patients in the abemaciclib arms achieved complete cell cycle arrest compared with the anastrozole arm.
What did the toxicity profile look like?
In terms of safety, 1 of the concerns with abemaciclib was the rate of diarrhea seen in the early studies. In our study, we utilized prophylaxis with loperamide in the first month, and thereafter at the investigators’ discretion. The highest rates of adverse events were diarrhea, but only 4% were of grade 3.
In addition, abemaciclib is given continuously. This is in contrast to other CDK4/6 inhibitors, which have to be given on a 3-week on/1-week off schedule because of the risk of neutropenia. Our study only demonstrated an 8% risk of grade 3/4 neutropenia. It appears to be well tolerated with continuous dosing.
Abemaciclib seems to be the 1 CDK4/6 inhibitor with single-agent activity. Can you speak to that?
Abemaciclib is the only 1 that has demonstrated single-agent activity. It’s the only 1 that has been looked at in a larger study, as well. It may have to do with its relative potency on CDK4 versus CDK6 that may also explain its relative lack of cytopenias when compared with the other CDK4/6 inhibitors.