DR LOVE: So let’s talk about other CDK4/6 inhibitors. And you had a big presentation at the ASCO meeting of the so-called MONARCH 1 study looking at abemaciclib. What exactly is this agent? How is it different from palbo? And what did you present?

DR DICKLER: So abemaciclib is also a CDK4 and CDK6 inhibitor. It more potently inhibits CDK4 than CDK6. And it’s thought that that differential potency may impact its side effects and there’s less myelosuppression. So with less myelosuppression, you don’t need the 7-day break to recover the counts the way you do with palbociclib. And abemaciclib can be dosed continuously.

And whether continuous inhibition of the target is important or not is not known. There is some preclinical data to suggest that continuous inhibition of the CDK4/6 target is important, but I think there’s more work to be done.

This study tested abemaciclib as a single agent in a more heavily pretreated population of patients than participated in the palbociclib studies. Palbociclib as a single agent has a response rate of about 6%.

And in our study of abemaciclib in this Phase II study of about 132 patients, the primary endpoint, which was response rate, was 19.7%, or almost 20%. And the responses were durable. Typically, the duration of response was 8.7 months. So for the folks who responded, they were on it for almost 9 months. And the progression-free survival was about 6 months.

And you have to remember the population of patients that we tested abemaciclib. Patients had to have prior endocrine therapy and were really no longer thought to be candidates for endocrine therapy. So they had several lines of endocrine therapy. And they had to have at least 1 chemotherapy for metastatic disease, but they were allowed to have up to 2. And about half of the patients had 2 prior chemotherapies for metastatic disease, and everyone had to have had a prior taxane.

So it was a taxane-pretreated group of patients. And if you look at chemotherapy that’s approved in that setting, response rates are on the order of 10% to 20%. And progression-free survival in that group is usually about 3 to 4 months. So abemaciclib, a cell cycle inhibitor, as a single agent was really as good as chemotherapy in this setting.

DR LOVE: So what is the ideal, the optimal way from your point of view at this point based on the information you have to really move this drug forward? Is the thinking to explore the monotherapy or with hormonal therapy primarily?

DR DICKLER: Definitive Phase III trials are ongoing in earlier-stage disease. One study, which is MONARCH 3, is a study of AIs plus or minus abema. And MONARCH 2 is a fulvestrant backbone with or without abema. And probably those trials will more likely dictate use should this drug get approved. And you have to remember the MONARCH 1 study, the single-agent trial, tested abema in patients who had not had prior CDK4/6 inhibition. So I’m not saying that we would get the same results if patients had previously received palbo.

This trial, MONARCH 1, was not testing whether abemaciclib has activity postpalbo. It was in a CDK4/6-naïve group of patients. My guess is most of the play of abema will get used earlier in combinations. And then the most important biomarker to select patients for this treatment is actually the estrogen receptor, ER-positive disease.

DR LOVE: So what about tolerability compared to, say, palbo?

DR DICKLER: So the toxicity profile is very different, a very important point. There is more diarrhea with this agent. Really, diarrhea isn’t a big problem with palbo, but it was seen. And patients had Grade 2 and even Grade 3 diarrhea. I think about 19% of patients had Grade 3 diarrhea, which is pretty significant. The diarrhea was seen early, typically in the first 2 weeks of study therapy. So you know who’s going to get it. It’s very responsive to a hold of the medication and also with dose reduction. So although patients who are at risk for diarrhea get it early and Grade 2 or 3 is generally what you see right away, it is a manageable type of diarrhea.

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CDK4/6 inhibitors for the treatment of BC

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