Abemaciclib plus NSAI for HR+, HER2- advanced breast cancer - MONARCH 3 interim data

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Published: 12 Sep 2022
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Prof Matthew P Goetz - Mayo Clinic, Rochester, USA

MONARCH 2 led to abemaciclib plus fulvestrant approval in patients with HR+, HER2- advanced breast cancer, with disease progression on prior endocrine therapy and demonstrated significant OS benefit.

In the second interim prespecified overall survival analysis from MONARCH 3, longer OS was observed in both the intention to treat section and subgroup with visceral disease (an increase in the median OS by over 12 months with the addition of abemaciclib to NSAI), however neither group met the threshold for formal statistical significance according to the alpha spend procedure. 

This study is ongoing and with final OS analysis in 2023.

The background to MONARCH 3, and in general the first line CDK4/6 inhibitor trials, is that aromatase inhibitors have been the standard of care for many years. We started to see the emergence of the data with palbociclib, certainly with ribociclib and these trials were all designed in that 2013, 2014, 2015 time period. They were designed to test whether the addition of a CDK4/6 inhibitor, that is in this case abemaciclib, when added to an aromatase inhibitor would improve progression free survival. 

MONARCH 3 focussed on women with ER positive/HER2 negative metastatic breast cancer, first line setting. These are women, again, where an aromatase inhibitor would be the standard of care. They were randomised in a 2:1 fashion to receive an aromatase inhibitor plus placebo or an aromatase inhibitor plus abemaciclib. Primary results from the trial have been reported out; final results additionally demonstrating that the addition of abemaciclib to an aromatase inhibitor improved progression free survival. This led to global regulatory approval. Here at ESMO we reported out the second planned interim analysis as it relates to overall survival. 

What we found was that the addition of abemaciclib to an aromatase inhibitor in the intent to treat population improved overall survival by a little more than 12 months. Important, however, was that the trial was set up to determine whether or not to stop; the trial was what we call a crossing boundary. That was not crossed with a p-value of little less than 0.04. 

Similarly, there was also a population of patients, pre-planned, with visceral disease. Now, this is a group of patients that we know tends to have a worse prognosis. There were some fairly substantial data early on demonstrating that abemaciclib had a substantial benefit in patients with high risk or concerning characteristics such as liver metastases, high grade tumours, progesterone receptor negative. So this was a very important group, again pre-planned, to look at the benefit of abemaciclib. What we saw was that the addition of abemaciclib to an aromatase inhibitor in this group improved survival by a little over 16 months. Again, it did not meet the criteria or the crossing boundary and so we continue to follow patients for that final overall survival result which we expect in 2023.

What can be done with the information that was found?

There are a couple of things that are quite important and reassuring to clinicians. First of all, as we look at the three CDK4/6 inhibitors it’s very important to note that it’s difficult to do cross-trial comparisons. Why? Because sometimes the populations might be slightly different. But, in general, as we’ve looked across these CDK4/6 inhibitors we can see that the control arm for survival is doing about the same. For the ribociclib, of course, we’ve seen that there has been consistent improvement in overall survival and now abemaciclib what we’re seeing is a fairly large improvement in terms of the delta, that is the number of months, in this case more than 12 months and in the visceral disease more than 16 months. So although that didn’t quite meet statistical significance, we could say that the data are maturing quite favourably while we obviously wait for the overall survival results. But for clinicians this is quite reassuring. It’s reassuring because we’ve had these questions as we’ve looked across the CDK4/6 inhibitors and we’re seeing no overall survival benefit with palbociclib. Again, lots of questions why that is, we’re not quite sure, but clearly with the drug abemaciclib we’re seeing a relatively large delta in terms of improvement in overall survival.