Abemaciclib Active in HR+/HER2- Breast Cancer Patients With Brain Mets

Sara M. Tolaney, MD, MPH

Preliminary evidence suggests that abemaciclib penetrated brain metastases and had antitumor activity in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer.

Results were presented in a poster at the 2017 ASCO Annual Meeting for 23 patients from a stage 1 efficacy analysis from a phase II study.

“What we found were 2 patients who experienced partial responses within the CNS, suggesting there is activity of the agent in the brain and in patients who have HR-positive disease,” explained lead author Sara M. Tolaney, MD, MPH.

At the time of analysis, the 2 patients who experienced partial response had completed 14 to 15 cycles of therapy.

In an interview with OncLive at ASCO Tolaney, assistant professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, discussed abemaciclib the potential for abemaciclib in breast cancer patients with brain metastases and the next steps with the CDK4/6 inhibitor.

OncLive: Can you give an overview of the phase II study and findings?

Tolaney: We conducted a trial that looked at the use of abemaciclib in patients who have breast cancer with brain metastases. There were 2 breast cancer cohorts in this study. One was for patients who have HR-positive, HER2-positive tumors. The other cohort was patients who had HR-positive, HER2-negative tumors. We’re just reporting the results for the cohort whose patients are HR-positive and HER2-negative.

This is an interim analysis of that cohort. We’re reporting data for the first 23 patients that were enrolled. What we found were 2 patients who experienced partial responses within the CNS, suggesting there is activity of the agent in the brain and in patients who have HR-positive disease.

Is there anything that was surprising or unexpected from this analysis?

I don’t think there was anything that was unexpected. I do think it is interesting because we have previously presented work looking at a CNS penetration of the drug itself.

One of the other cohorts on the trial that has been previously reported was the surgical window cohort. Patients received upfront abemaciclib and then went to surgery for resection of their brain metastases. In that study, we did look at levels of the drug within the tumor itself and with the cerebrospinal fluid (CSF) and compared that to drug levels in the plasma. It was shown that they’re all comparable, suggesting that the drug is getting into the tumor and into the CSF, which is comforting to know. Now, seeing the clinical responses in the brain is confirming that not only does it get there but it does have activity.

What do you think that this analysis says about abemaciclib and its efficacy as an agent for these patients?

This trial is only looking at the response with the CNS. It’s looking at a patient population that’s different in a sense that two-thirds of these patients had chemotherapy and one-third of those patients had more than 2 lines of chemotherapy, making it a heavily pretreated group of patients.

It is a group of patients who are also CDK4/6 naïve. There is a subset of patients who did get concurrent endocrine therapy with the CDK4/6 inhibitor. They could use an agent that they had previously received and progressed on if they wanted to add it to the CDK4/6 inhibitor and there were 7 patients who did that among the 23 patients.

This shows that the agent itself has activity in the brain. We’ve seen other trials that suggests that the agent has systemic activity. Previous data looking at the MONARCH 2 trial was very impressive, so I believe that it shows it’s not only working systemically but can also have a response in the CNS.

What remaining questions are there with abemaciclib?

The main question everyone is always asking is how do the 3 CDK4/6 inhibitors compare to one another. We know palbociclib (Ibrance) and ribociclib (Kisqali) seem to be more similar structurally. They’re also given on intermittent schedules. Additionally, they both have similar rates of grade 3/4 neutropenia, whereas abemaciclib is slightly different.

Abemaciclib hits CDK4 harder than it hits CDK6. We know that it can be dosed continuously, that it has single-agent monotherapy response in heavily pretreated patients, and now we see it also has activity in the CNS. The toxicity profiles are also different, with abemaciclib having more GI toxicity relative to marrow toxicity.

Unfortunately, we don’t have any data comparing them clinically, which is what I think everybody really wants to see in order to help them make decisions for what to give to patients.

Is there a trial looking at comparing them?

There is no trial that I am aware of that is comparing the 3 agents to each other.

Do you think they will conduct a trial looking at this?

I think it’s similar to the issue with aromatase inhibitors and how we’ve done all of these trials comparing letrozole to anastrozole to [exemestane]. It’s hard to know if that’s worthwhile to do.

What do you think about abemaciclib in combination with other agents?

There is an ongoing study that’s looking at abemaciclib in combination with pembrolizumab (Keytruda). This is based on preclinical work that suggests that abemaciclib can augment the immune system and then it acts synergistically.

That trial has 3 different cohorts of patients, 2 of which are lung cancer cohorts, 1 of which is a breast cancer cohort. The breast cancer cohort has now completed enrollment and data will be presented at the next San Antonio Breast Cancer Symposium. That is looking at a population of patients that’s the same as those who were entered into MONARCH 1, meaning patients who have had 1 to 2 prior lines of chemotherapy in the metastatic setting. I think that will be helpful to look at that response data and compare it to MONARCH 1 to determine if there is a signal that adding pembrolizumab is beneficial.

Would you be able to give any comment on the MONARCH 2 study?

I thought it was an impressive improvement in progression-free survival. I think what was also unique was that it was associated with a high objective response rate, which is not something that we typically see with endocrine therapy or with the other CDK4/6 endocrine therapy combinations that have been previously reported. That was encouraging and I thought the data looked outstanding. Everyone wants to compare the MONARCH 2 data to the PALOMA-3 data; however, they are not the same patient population, so I don’t think you can make such a comparison.

Please provide an overview of the ongoing monarcHER study?

The monarcHER study is a randomized phase II trial for patients who have HR-positive, HER2-positive metastatic breast cancer. It’s for patients who have previously received at least 2 lines of anti-HER2 therapy in the metastatic setting—one of which must have been prior trastuzumab emtansine (T-DM1; Kadcyla)—and patients are randomized into 1 of 3 arms. They can receive fulvestrant with abemaciclib and trastuzumab, abemaciclib and trastuzumab, or physician’s choice of chemotherapy with trastuzumab.

The rationale for this study is the significant preclinical work suggesting that in the trastuzumab-refractory population, these tumors seem to be driven by cyclin D. Additionally, there is preclinical work suggesting that there is synergistic activity between abemaciclib and anti-HER2 therapy. Some of the previous phase I trials have also shown responses with abemaciclib in heavily pretreated HER2-positive patients. I think it’s an exciting study and it’s currently enrolling.

Tolaney SM, Lin NU, Thornton D, et al. Abemaciclib for the treatment of brain metastases (BM) secondary to hormone receptor positive (HR+), HER2 negative breast cancer. J Clin Oncol. 2017;35 (suppl; abstr 1019).