MONARCH 1: Abemaciclib Monotherapy for HR+ mBC



Hope S. Rugo, MD: Abemaciclib is a really interesting drug. It is given continuously, as we’ve discussed, so dosed continuously without a break. In the phase I trial looking at abemaciclib in the treatment of heavily pretreated metastatic breast cancer, the investigators were surprised to see an overall response rate of about 30%, quite intriguing for a class of drugs where we think of the overall response rate as being significantly less than 20%. And if you looked at the phase I trials with ribociclib and palbociclib, in fact, the response rates were less than 10%—again, heavily pretreated endocrine refractory disease—but for abemaciclib, it seemed to be better.

That actually started the first trial of abemaciclib in treating metastatic hormone receptor-positive breast cancer, which was a phase II, single-agent trial called MONARCH 1, where patients who had relatively endocrine refractory disease were treated with single-agent abemaciclib with a primary endpoint of overall response. Shortly thereafter, the randomized phase III MONARCH 2 trial was started, which was the definitive trial to lead to FDA or regulatory approval of abemaciclib.

So, we treated quite a number of patients, over 100 patients, in the MONARCH 1 trial and showed an impressive response rate of just under 20%—so 19.5%—in that group of patients. And the response rates were quite durable in a number of patients with progression-free survival, about 6 months, which I think was very impressive for using a single agent that was reasonably well tolerated in fairly heavily pretreated patients with metastatic breast cancer. But our endpoint was a response rate of 30%, so we didn’t meet the endpoint. But to me, it’s still very impressive, and I think that one of the areas where abemaciclib may be used as we move forward and seeing approval of abemaciclib will be in patients who progressed on a prior CDK4/6 inhibitor, even though we don’t have any data about this as a single agent in late-line therapy.

I think also that patients who went on chemotherapy who didn’t get a CDK4/6 inhibitor in the indicated settings may receive abemaciclib as well as a single agent later-line with or without a hormonal agent. But it gives us a lot of information about the potency of this drug in patients with hormone receptor-positive metastatic breast cancer in a later line setting. It’s important to keep in mind that MONARCH 1 treated patients who had never been exposed to a prior CDK4/6 inhibitor. But there will be a trial that looks at abemaciclib after treatment with the other 2 more similar CDK4/6 inhibitors to get an idea of what the response rates are in that setting.

Sara Hurvitz, MD: Abemaciclib has demonstrated single-agent activity in a phase II clinical trial as well as phase I clinical trials. Early phase clinical trials, including a phase II single arm clinical trial, have indicated that abemaciclib does have single-agent activity. However, I won’t be using this as a single agent in the absence of a randomized clinical trial, given the fact that we have such impressive data with the use of CDK4/6 inhibitors in combination with hormonal therapy. So, while the single agent activity of abemaciclib is very intriguing and may speak to its underlying potency, I don’t think it’s time for us clinically to be using any of these drugs as single agents.

We’re just beginning to see clinical data of the use of abemaciclib for central nervous system disease, and actually the data are quite intriguing and promising. Sara Tolaney at the Dana-Farber Cancer Institute presented the results of a phase II clinical trial in which somewhere around 20 patients, who had CNS metastases, were given doses of abemaciclib prior to surgery and then had their tumor samples, plasma, and CSF-tested for abemaciclib levels. And in this clinical trial, it was very interesting that they showed abemaciclib levels are similar in tumor, plasma, and CSF. So, this is indicating that abemaciclib can cross the blood-brain barrier. Moreover, several responses were seen in her clinical trial.

I’m very interested in seeing the longer-term results and follow-up of this study as more patients are accrued to her clinical trial. This is an area of unmet need, even though patients with hormone receptor-positive breast cancer are less likely to have CNS metastases than patients with HER2-positive or triple-negative breast cancer. The activity of abemaciclib in the central nervous system is very intriguing and might actually be shown to be active as well in other subtypes of breast cancers, such as HER2-positive.

Transcript Edited for Clarity

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