CDK4/6 Inhibitor Shows Promise as Single Agent in HR+ Breast Cancer

Maura Dickler, MD

As a single agent, abemaciclib has shown exciting potential in heavily pretreated patients with refractory, hormone-receptor (HR)—positive, HER2-negative advanced breast cancer, following phase II findings of the MONARCH 1 trial.

Results of the single-arm study, which were presented during the 2016 ASCO Annual Meeting¹, show that the CDK4/6 inhibitor induced a response rate of nearly 20% in this patient population. The median progression-free survival (PFS) was 6 months (95% CI 4.2-7.5) and the median overall survival (OS) was 17.7 months (95% CI, 16 to not reached). Previously, abemaciclib received a breakthrough therapy designation in this setting from the FDA in October 2015.

"The MONARCH 1 study was really a proof-of-concept trial, so it's a relatively small phase II study looking at a cell-cycle inhibitor as a single-agent," explains lead investigator Maura Dickler, MD. "At least to date, this is the first cell-cycle inhibitor that has single-agent activity. So that was really the intent of the trial, to confirm the activity that was seen in the phase I trial. I think doctors in the community should look for the results of MONARCH 2 and MONARCH 3, which should be coming soon."

Objective response rate (ORR) was the primary outcome measure. Secondary endpoints included duration of response, PFS, OS, clinical benefit rate, and safety. The investigator-assessed, confirmed ORR was 19.7% (n = 26; 95% CI, 13.3-27.5), which included all partial responses (PR). The rate of patients with stable disease (SD) ≥6 months was 22.7%, leading to a clinical benefit rate (complete response + PR + SD ≥6 months) of 42.4%. The median time to response was 3.7 months and the median duration of response was 8.6 months. Thirty-four patients had progressive disease.

The MONARCH 1 trial included 132 patients with HR+/HER2- metastatic breast cancer who progressed during or after endocrine therapy and chemotherapy. Additionally, patients had received a median of 3 (range, 1-8) prior lines of therapy—including a median of 2 lines of chemotherapy—for metastatic disease. Sixty-seven patients (50.8%) had received fulvestrant in the metastatic setting. With chemotherapy, 68.9% (n = 91) of patients had received a taxane and 55.3 % (n = 73) of patients had received capecitabine in the metastatic setting.

OncLive: Can you tell us about the MONARCH1 trial?

In an interview with OncLive, Dickler, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses findings from the recent phase II study exploring abemaciclib as a single agent in patients with HR-positive breast cancer, along with an upcoming phase III trial looking at combination strategies. Dickler also discusses the PI3K-alpha inhibitor taselisib, which was examined in combination with fulvestrant in a phase II study.Dickler: MONARCH 1 was a straight phase II study of single-agent abemaciclib, a CDK4 and CDK6 inhibitor, in previously treated women with hormone receptor (HR)-positive metastatic breast cancer. It was a multicenter trial. The study enrolled 132 women who had previously received endocrine therapy and also at least one, but not more than two, chemotherapies for metastatic disease. It was a group of women where we typically wouldn't offer additional endocrine therapy, and that their typical next treatment would be chemotherapy. We know in that setting, response rates for chemotherapy are in the order of 10% to 20% with progression-free survival (PFS) of about 3 to 4 months.

This trial was specifically testing single-agent abemaciclib in a more heavily-pretreated patient population, and I mention that because it's different from the other abemaciclib studies that are ongoing, which are actually earlier in metastatic disease, either in first-line endocrine therapy with the aromatase inhibitors, or in combination with second-line endocrine therapy like fulvestrant.

What are the next steps after this study?

Can you tell us about the mechanism of action for abemaciclib?

What they found was that women treated with abemaciclib in this setting had a response rate of 19.7% and a clinical benefit rate of about 42%, which was impressive because it was not only a heavily-pretreated population, but about 90% of the patient had visceral metastases, 70% had liver metastases, more than half had 3 sites of metastatic disease, and then in terms of prior therapy, all patients had received taxanes, with about 70% receiving taxanes in the metastatic setting.Abemaciclib is presently in phase III studies in combination with endocrine therapy. There's the MONARCH2 study, which is a fulvestrant backbone with and without abemaciclib, and MONARCH3 is an aromatase-based study, looking at either letrozole or anastrozole, plus or minus abemaciclib. They're really looking at abemaciclib in combination with endocrine therapy because there's a rationale for dual ER and cell-cycle inhibition. I suspect those trials will probably provide the best insight as to where this drug might be used in the future.Abemaciclib inhibits both CDK4 and CDK6. It inhibits CDK4 more potently than CDK6, and therefor it's thought to impact potentially its toxicities, in that there appears to be less myelosuppression with abemaciclib. So continuous dosing is feasible. With some of the other cell-cycle inhibitors, the dose-limiting toxicity is neutropenia and continuous dosing is not possible.

Is this already being investigated in HER2-positive patients?

Can you also tell us about the phase II study looking at taselisib combined with fulvestrant?

What do you think are some of the big takeaways from this study?

With palbociclib, the present dosage is 125 mg for 21 out of 28 days, and that 7-day break is needed for recovery of the white blood cell count. With abemaciclib, neutropenia is less of a problem. However, with abemaciclib, diarrhea is more of a problem. This diarrhea is typically seen early. The average onset was 7 days, but the diarrhea was responsive to supportive measures, to anti-diarrheal agents, and then dose reduction.Actually, the biomarker to best select patients that might be responsive to abemaciclib, and cell-cycle inhibitors in general, is ER-positivity. In the phase I study of abemaciclib, there was activity in ER-positive/HER2-negitive and ER-positive/HER2-positive, and a study looking at abemaciclib in the HER2-positive population is recently open and now accruing. It's called the MONARCH HERS trial.This was a phase II study of fulvestrant in combination with taselisib in women with hormone-receptor positive/HER2-negative breast cancer. This was really a phase II study that was embedded in a phase I/II trial, and this study enrolled 60 women with HR-positive/HER2-negative breast cancer. Of them, 30 of the patients were required to have a PIC3CA mutation, and the other half were required to be wild type. This study was performed to get a signal of activity in women with HR-positive disease. Patients who were enrolled were allowed to have only up to one line of prior chemotherapy, and they were not allowed to have had prior fulvestrant. They were required to have prior therapy with an aromatase inhibitor.This was a small phase II study and definitely showed some activity of this agent in combination with fulvestrant. It really wasn't powered to look at activity in the PIC3CA wild type versus mutant population, but numerically there was a higher clinical benefit rate and response rate in the patients who were ER-positive and PIC3CA mutant compared to the patients who were ER-positive and PIC3CA wild type.

A randomized trial is now ongoing called the SANDPIPER trial, which is fulvestrant with or without taselisib in a similar patient population. HR-positive, HER2-positive, prior treatment with endocrine therapy with a limitation on prior chemotherapy. The SANDPIPER trial will enroll patients with wild type and mutant PIC3CA and the trial will be adequately powered to answer the question as to whether there's activity in the wild type population.

1. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. J Clin Oncol 34, 2016 (suppl; abstr 510).