Lead neoMONARCH Researcher Provides Insight on Abemaciclib Potential in HR-Positive Breast Cancer

Recent promising findings with the neoadjuvant combination of the CDK4/6 inhibitor abemaciclib with anastrozole could lead to a novel therapeutic option for patients with hormone receptor (HR)–positive, HER2-negative early breast cancer.

Sara A. Hurvitz, MD

Recent promising findings with the neoadjuvant combination of the CDK4/6 inhibitor abemaciclib with anastrozole could lead to a novel therapeutic option for patients with hormone receptor (HR)—positive, HER2-negative early breast cancer.

In the phase II neoMONARCH trial, results of which were presented during the 2016 San Antonio Breast Cancer Symposium,1patients 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.

Patients then received treatment for 14 days, followed by a second core biopsy. After this test, all patients received combination therapy with anastrozole and abemaciclib for 14 weeks, at which point another biopsy was performed, followed by optional surgery in some patients.

Combined data of all 3 trial arms demonstrated that 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 also met as it yielded a geometric mean change in Ki67 from baseline to day 15 of -92.6%.

In an interview during the meeting, 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, provides a detailed overview of neoMONARCH, abemaciclib’s unique mechanistic properties, and what potential the CDK4/6 inhibitor could have in combination with immunotherapy.

TARGETED ONCOLOGY: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.

TARGETED ONCOLOGY: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.

TARGETED ONCOLOGY: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.

That said, it would probably be developed in combination with hormonally targeted therapies. I don’t see it being a single agent going forward. Moreover, its important to clarify that there has not been a head-to-head comparison of these CDK4/6 inhibitors that are all in development, so clinically gauging what is the best in class is hard to do. However, there are unique features that stand out with this molecule.

TARGETED ONCOLOGY:Does the dosing schedule have anything to do with its efficacy?


The continuous dosing may be related to the single-agent efficacy. There is some data that suggest that during that off week, when you’re allowing the white cells to recover, the tumor may actually rebound and increase in cell cycling. That was shown in another neoadjuvant study looking at palbociclib (Ibrance), which was led by Dr. Cynthia Ma. We will be looking at the 4-month biopsy samples and selected tumor samples of when patients have been off of abemaciclib for a period of time to see if we are also seeing that rebound effect in patients after being off of abemaciclib.

TARGETED ONCOLOGY:What other ongoing work is exploring abemaciclib’s uniqueness?


A unique feature of our clinical trial is the fact that we have begun looking at the serial tumor biopsies from patients to look at the T-cell infiltrate scene in the tumor microenvironment. What is interesting is that on day 1 and day 15, we aren’t seeing any T cells infiltrating that tumor bed. But, by cycle 5, day 28, we are seeing a large amount of CD3-positive and CD8-positive cytotoxic T cells infiltrating that tumor bed. This is on our first glimpse of the data, but it does seem to represent the 20 to 30 samples that we have already looked at.

At a later conference, we’re hoping to present the data as a whole because if the CDK4/6 inhibition is stimulating an immune infiltrate after 4 months of therapy, that would be a very novel and important finding.

TARGETED ONCOLOGY:What is actually happening during tumor immune infiltrating?


It’s the first time we have seen it. It may be that as cells die, it calls in the immune infiltrate. We demonstrated that with this first cohort of patients we have begun to look at; we are seeing the cells that are active potentially against the tumor CD3-positive and CD8-positive cells, but the regulatory T cells are not found in the tumor bed at the 4-month time point.

This is interesting because regulatory T cells dampen the immune response against the tumor. It’s a very complex relationship, but I can tell you that people are interested and have begun looking clinically at the combination of immunotherapies with CDK4/6 inhibitor therapies.

TARGETED ONCOLOGY:Could these neoMONARCH findings provide rationale to the ongoing trial that is looking at abemaciclib plus pembrolizumab (Keytruda)?


There is an ongoing study looking at pembrolizumab plus CDK4/6 inhibition, and these data do provide even more rationale to be looking at that sort of combination.


Hurvitz S, Martin M, Abad MF, et al. Biological and clinical effects of abemaciclib in a phase 2 neoadjuvant study for postmenopausal patients with HR+, HER2- breast cancer. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10; San Antonio, TX. Abstract S4-06.