So, monarchE is a large randomized Phase III trial that I think our viewers are very much aware of, that looked at the CDK4/6 inhibitor abemaciclib in combination with endocrine therapy in patients with high-risk, early stage hormone receptor-positive, HER2-negative breast cancer. And in this study, patients were eligible in a big cohort, cohort one, and then about 9% of the enrolled patients were in a small cohort...
So, monarchE is a large randomized Phase III trial that I think our viewers are very much aware of, that looked at the CDK4/6 inhibitor abemaciclib in combination with endocrine therapy in patients with high-risk, early stage hormone receptor-positive, HER2-negative breast cancer. And in this study, patients were eligible in a big cohort, cohort one, and then about 9% of the enrolled patients were in a small cohort. That was exploratory cohort two. So, in cohort one you had to have 1-3 positive nodes, and there were two options, two additional factors. So, grade three histology or tumor greater than five, five centimeters at greater, and then you could have 4 or more positive nodes and anything, and that was fine. So that’s cohort one. Cohort two were patients who had 1-3 positive nodes, but they couldn’t have any of the other things, so they couldn’t have the grade three or et cetera.
But they had to have Ki-67 of 20% or greater. That was centrally confirmed. So, that’s actually a really interesting cohort and there’s a lot more follow up that was a later cohort that was enrolled. But this is now about four years of follow up on monarchE that was presented by Stephen Johnston and is published already, same day it was presented. So that’s very exciting for us, I think, to have the data available right away. And this is really important because there’s been a lot of questions. PENELOPE-B looked at palbociclib in high risk early stage breast cancer, question about the risk, how we determine risk. And maybe the population wasn’t as high a risk population early, but they only gave a year of palbo. And what we saw was the curves were separated and then over time they came together. So, there was a big question in everybody’s minds about whether or not two years of abemaciclib would still be effective at four years because maybe it only works while you’re giving it and then the effect would be lost.
So, at this time, at four years almost essentially all of the patients are off study drug, 99% plus, right. Nobody’s still taking the first two years of abemaciclib. So, it’s a much more mature analysis. And the factors for eligibility actually, were focused on a population of patients that has a relatively higher risk of earlier relapse. We know that very slow growing lower risk disease, you can relapse at 10, 15 years. They really focused on an earlier relapse risk population by those criteria that I just went through. And what we saw was so striking, actually. So, instead of the difference narrowing, the difference favoring abemaciclib is increasing over time. It’s very cool. It went from 2% to 4% to 6%, a little over 6% absolute difference in invasive disease-free survival and distant recurrence-free survival. So, what that really suggested, that there’s a carryover effect after you finish the two years, you’re still seeing benefit and benefit out to four years, and that the benefit is widening over time.
So, that’s the first time we’ve seen anything like this with a targeted agent outside of trastuzumab. And certainly, in the hormone receptor-positive population, there are no new safety signals, of course, because everybody’s off drug. There’s no like carryover safety effects. You don’t still have diarrhea when you stop the drug goes away. So, that’s very comforting. And the Ki-67 subset, again, these differences are widening over time. So, Ki-67 is a bad prognostic factor in hormone receptor positive disease, but it doesn’t predict the benefit of abemaciclib. Both groups low and high, Ki-67 benefited from abemaciclib. So, this is great data. We hope that abemaciclib is available to patients who have high-risk disease in most places in the world because it’s clearly changing the outcome for patients with hormone receptor-positive breast cancer. And we’re waiting for more events, which thankfully are very slow coming in to get a mature overall-survival analysis.
