Part 2: Recommending Abemaciclib for Early Breast Cancer Based on Ki67 Status

Lowell Hart, MD

Scientific Director of Clinical Research

Florida Cancer Specialists & Research Institute

Associate Professor

Wake Forest School of Medicine

Targeted Oncology^TM: What were the findings related to patients with Ki67-high status in the monarchE (NCT03155997) trial of abemaciclib (Verzenio)?

LOWELL HART, MD: In this trial, most of the patients have high Ki67 but there was about a third of them that did not have a high Ki67.

For patients with high Ki67, [based on invasive disease-free survival data,] there was a 30% relative risk reduction in the patients that got abemaciclib vs the ones who didn’t, and then the absolute benefit comes out to a 5% or 6% range.¹ This was very similar to the overall results.

This showed that aside from anything else, having a high Ki67 made a difference. This was true in patients in [the higher-risk] cohort 1 who had high levels or low levels of Ki67, but the interesting thing is that even if the level was low, [abemaciclib benefit was consistent].

What are the outcomes for patients with low Ki67 levels?

Patients with low Ki67 do better even if they don’t get abemaciclib.¹ However, if they did, there was a very significant benefit. It looks like the magnitude of benefit is very similar, so Ki67 is prognostic of the worst outcome, but you got benefit from taking the adjuvant abemaciclib and you did better whether you had a high Ki67 or you didn’t. So, it was independent [Ki67 level].

I think that gives us some comfort in not using Ki67 as the only indicator of who should get abemaciclib and who should not get abemaciclib.

How should physicians practice based on these data, considering that the FDA only approved abemaciclib for patients with high Ki67 and high risk?

Officially, patients have to have a high risk and a high Ki-67.² When I’ve talked to leaders in the field…I was in the advisory panel with some oncologists from Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, and a couple of other large cancer centers a few weeks ago and they were struggling with the same thing. Most of them said [that abemaciclib could be given to patients without high Ki67], and I would agree.

My personal practice is that if you were otherwise eligible to go on to the monarchE trial, I would consider this and I would fight with a patient’s insurance company. If they were eligible to go on the trial and the intent-to-treat [ITT] data are positive in the trial, then I think they need to go to the trial. That’s generally what I’ve heard from thought leaders in the field, although I admit there could be other people that say something else. But that’s what I’ve heard from some.

If the trial had showed that if the patient’s Ki67 is low, [and] the drug can’t work, I would follow that, but that’s not what we’re seeing here.

What was the rationale for the FDA indication that resulted from this trial?

In terms of overall survival, it looks better in the overall ITT population, which was everybody, but again, this is hormone receptor-positive primary breast cancer. It will take a long time to really get a very significant survival benefit. So, the data are immature at this point. There has been uncertainty regarding the rationale for the indication granted by the FDA because a lot of us, including my practice in Fort Myers, have not routinely been testing patients’ Ki67 level. Now we are sending it out to have it done, but I think there will be a divergence between the 2 results and it’s going to be a difficult thing to settle out.

I think that sometime in the next few years, this will settle out. Or if we see a clear-cut survival benefit comes out in the ITT population a year or so from now, I believe the FDA will drop that eventually.

[Patients with Ki67-high status are] going to have earlier events and then the later events are going to happen in the Ki67 lower group. So, it’s going to take a while for that to show up in the whole ITT population.

What stood out about the safety profile of abemaciclib in this trial?

We know that this drug has been used in the metastatic setting now for a few years. Everyone has their favorite drugs or their less favorite drugs of the 3 that are available, but we’ve all used [abemaciclib].

There were quite a bit of dose adjustments that were in the trial. About 40% of the patients had to have some dose reductions.¹ Discontinuations were needed in about 15% of the patients and they stayed on endocrine therapy.

A few patients in the study, 6%, are those patients that can’t tolerate aromatase inhibitors [AIs]. Oncologists who have been in practice for longer have had number of patients over the years that just could not take AIs no matter what you do and I’ve had patients that can’t take tamoxifen either, so that’s going to happen.

So, I think [this level of discontinuation] is reasonable to expect. Again, these are going to be very motivated patients that are going to clinical trial so it might be a little bit higher in the real world. I would say it’s reasonable to expect that there’s going to be maybe 20% or 25% of patients that may not be able to take abemaciclib.

In general, we found that there has been lower incidence of diarrhea in these early patients. I personally haven’t had anybody drop off their study just due to diarrhea. The grade 3 and grade 4 diarrhea [incidence] is fairly low, 7.5% and 0% respectively.¹

There’s less neutropenia with abemaciclib and some of the other CDK inhibitors based on its mechanism of action. One nice thing is that as an adjuvant drug, you can just take the drug continuously. You don’t have to be going on and off of it. And if the patients stay on, the diarrhea tends to get better with time. Patients get more used to it and how to deal with it. So, nothing too unexpected was found as far as that goes.

_References:

_{1. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571-1581. doi:10.1016/j.annonc.2021.09.015}

_{2. FDA approves abemaciclib with endocrine therapy for early breast cancer. FDA. Published October 12, 2021. Accessed January 20, 2022. https://bit.ly/3fKnXJ6}