Selecting CDK4/6 Inhibitors for Patients With ER-Positive Early Breast Cancer

Systemic Treatments for ER-Positive Early Breast Cancer: Part 2

In this expert roundtable series, Cynthia Ma, MD, Washington University School of Medicine in St Louis, Missouri, leads a 4-part roundtable panel discussion on selecting the optimal treatment for ER-positive early breast cancer with Neelima Vidula, MD, Massachusetts General Hospital, Boston, Massachusetts, and Seth Wander, MD, Massachusetts General Hospital.

In part 2 of this discussion, our experts look at the issue of CDK4/6 inhibitors, discussing the latest data from the NATALEE and monarchE studies and eligibility differences between the available agents.

Transcript:

Dr Cynthia Ma:
Now, we want we want to switch gears to CDK 46 Inhibitors. Dr Vidula, would you like to comment on how you select patients for adjuvant abemaciclib and the data behind that.

Dr Neelima Vidula:
Thank you, Dr Ma. The data that has led to the approval of adjuvant abemaciclib based on the monarchE study, that was a phase 3 study that enrolled patients with high-risk hormone receptor-positive HER2-negative node-positive disease. In order to have qualified for the study, patients had to have at least 4 nodes involved, or 1 to 3 lymph nodes involved with either a grade 3 histology or a tumor that was greater than 5 centimeters. They did also include a small cohort of patients that had a Ki67 that was above 20%.

In this study, patients were randomized to adjuvant treatment with abemaciclib for 2 years in combination with endocrine therapy or endocrine therapy alone. The primary outcome was disease-free survival. And at 4 years, there actually was a significant difference in disease-free survival between the 2 arms. In patients who received abemaciclib in combination with endocrine therapy, their disease-free survival was 85.8% compared to 79.4% in the endocrine therapy alone arm. And their overall survival data is currently immature, so we'll look out for that in the future.

This data is very compelling. It suggests that in some high-risk patients with hormone receptor-positive HER2-negative lymph node-positive disease, there may be a benefit to adding abemaciclib in terms of reducing their risk of a recurrence. In terms of selecting patients, Typically, the patients that I'm thinking about for adding adjuvant abemaciclib are those who met the trial's criteria: they had 4 or more lymph nodes that were involved, or 1 to 3 lymph nodes involved with a tumor that was above 5 centimeters or grade 3 status. It's worth noting that the Ki67 criteria is no longer really being used for selection of patients in this setting. We don't have to routinely test for Ki67 unless that's indicated for some other clinical reason.

I think it's also important to note that these agents can be difficult to tolerate with abemaciclib. We see a fair amount of diarrhea, cytopenia, fatigue, and so forth. It's important to see patients regularly in clinic to make sure that they're getting appropriate supportive care, such as loperamide [Imodium] to help with the diarrhea, and also being monitored carefully in in the event that they need a dose reduction because, again, this is in the adjuvant setting. These are patients who have their lives to live. We want to be mindful of quality of life while we are trying to reduce the risk of recurrence.

Dr Cynthia Ma:
Thank you for that very comprehensive, nice discussion on that. Dr Wander, maybe you can comment on those reductions. Does that affect outcomes for patient on adjuvant abemaciclib?

Dr Seth Wander:
Thank you. This is obviously a rapidly evolving area of our practice. We have lots of new data for adjuvant CDK4/6 inhibitors across the spectrum: palbociclib, ribociclib, abemaciclib. I'm sure we can talk about and compare and contrast. We've experienced them now in both the metastatic setting and in the adjuvant setting.

Dose-reducing these agents actually does not seem to impact efficacy longer term — patients that in the metastatic setting, for example, require dose reductions in palbociclib on the PALOMA studies. And now we have data from monarchE, that Dr Vidula just described, patients who have to dose-reduce on the abemaciclib either for cytopenia or diarrhea, et cetera, don't seem to glean less clinical benefits. Clinicians should feel comfortable moving forward with those reductions as necessary, particularly because we really, as we talked about earlier, want to manage quality of life. These are extended durations of treatment in otherwise healthy, adjuvant patients. We want to be cognizant of these kind of side effects.

Dr Cynthia Ma:
That's great. Also, Dr Wander, you were talking about earlier the different CDK4/6 inhibitors. Can you comment on the ribociclib data from the NATALEE trial?

Dr Seth Wander:
Sure. To put that into context, I'm going to briefly mention, we have 2 studies for palbociclib in the adjuvant setting. We have the PALLAS study And the PENELOPE-B study. Then we have monarchE study, that Dr Vidula just described, and then we have the NATALEE study, which is the most recent study to provide data.

First, PALLAS and PENELOPE-B looked at different durations of palbociclib in in this patient population, and they were slightly different patient populations. PALLAS had over 5,000 patients as did NATALEE and monarchE. These were stage 2 or stage 3 breast cancer patients who had 24 months of Palbociclib. PENELOPE-B had over 1200 patients, so the smallest of the 4 studies, but they were higher risk patients. They received preoperative chemotherapy. They had residual disease, node-positive disease, and they got 1 year of palbociclib. Both of those studies were negative.

I bring that up because the PENELOPE-B curves for invasive disease-free survival (iDFS) were quite interesting. When you looked at them at that sort of 2 to 3 year mark, there was an initial indication of benefit on the order of a 2% to 3% improvement in that high-risk population that got 1 year of adjuvant palbociclib. But when they followed that out for another 2 to 3 years, over years 3 into 4 into 5, you start to see that those curves actually collapsed. And the overall study was read as negative.

When we compare that to monarchE and the data that we just heard about, as we move on from year 2, year 3, year 4, year 5, even when the patients are off of the abemaciclib, the distance between the iDFS curves are actually expanding opposite to what they did in PENELOPE-B. For monarchE, it went from 3% to 5% to 6% percent to 7% to 8%. Every year that goes by with follow-up, we're actually seeing improvement with abemaciclib. And as Dr Vidula said, we'll eventually see the survival data. It will take more time to mature.

When you think about the NATALEE study, you had over 5,000 patients receiving ribociclib. Now, a couple of important things: compared to the other studies, NATALEE actually had 3 years of adjuvant therapy. So, monarchE had 2 years of abemaciclib. PALLAS had 2 years of pablociclib. PENELOPE-B Had 1 year of palbociclib. So, NATALEE had the longest duration, 36 months, 3 years of ribociclib. We're using ribociclib at a slightly lower dose. The dose there was 400 mg, not the 600 mg we typically start with in the metastatic setting. And we now have data from the 3-year time point from NATALEE showing about a 3% benefit in invasive disease-free survival in that population. So, from about 87% to about 90%.

Now, when you compare that, and these cross-trial comparisons are perilous for a variety of reasons, but it’s tracking a little bit below what we saw at the same time point on monarchE. The question on everyone's mind now is, as we get the next 2 to 3 years on NATALEE, will the curves look like monarchE where they actually start to separate a little bit farther, suggesting that you've actually used the CDK4/6 inhibitor to eradicate potentially micrometastatic disease, or will the curves come back together like they did in PENELOPE-B, suggesting that there was some occult disease that you may have kind of delayed outgrowth, but you weren't actually eradicating longer term.

The last distinction I want to make is, NATALEE allowed lower risk patients than the criteria that Dr Vidula was just alluding to. You could get on to NATALEE even with node-negative disease, with several other features including tumor grade and primary tumor size. Depending on what the FDA decides and what the follow-up data is, NATALEE will provide a really important perspective for patients who would not otherwise have met the kind of strict high-risk criteria of monarchE and would open an opportunity to use a CDK inhibitor in patients with lower-risk, stage 2 disease even without lymph node positivity.

That's a very nice if the option will be available in the future. Assuming that NATALEE is going to continue to show benefit of ribociclib and if the benefit seems to be a parallel to what we see in monarchE, if the FDA approves it in the future, how do you think people may select ademiciclib versus ribociclib, and how would that change your management?

Dr Neelima Vidula:
I think that if, based on the NATALEE data, the FDA decides to approve ribociclib, we'll have another option. What I would probably do is reach for ribociclib in those patients that had lymph negative-disease, who had higher-risk tumors, similar to the NATALEE population. Patients who maybe had a larger tumor or a grade 3 tumor. And then I think they also included some patients that had grade 2 tumors with a higher Oncotype score, so that would also be a consideration. I think some of the patients will overlap. They'll be they'll be able to qualify for both abemaciclib and ribociclib.

Seeing the longer term follow-up data and eventually the survival data, even though we'll have to wait for that, will be helpful to decide which of these drugs might be more helpful in that situation for a patient who might fit into both those populations. Some of it would also depend on the patient's comorbidities and the type of side effects they're willing to endure. Again, this is adjuvant treatment, quality of life is very important. Some patients might be more inclined to just stick with 2 years of abemaciclib rather than being on a drug for 3 years. That could definitely factor in. And if they're individual comorbidities you might want to stay away from ribociclib because that tends to have a little bit more elevation in liver enzymes.

Dr Cynthia Ma:
Very good. Dr Wander, do you have any additional comments on this?

Dr Seth Wander:
I agree. It’s going to come down to a lot of drug-specific and patient-specific factors. Dr Ma, in the theoretical world that you're alluding to, 3 years from now, if the curves are to some extent superimposable, even though we don't like cross-trial comparisons, you have 2 good agents. For the higher risk, multi–node-positive, high-grade larger tumors, you could use either. You could argue some patients may feel better being on a longer duration for 3 years. Some patients may want to get it done sooner and use the 2 years of the abemaciclib. It'll come down to whether they have prior GI issues, whether they have prior blood count issues, et cetera. To the point that we were just discussing, it's going to open up an opportunity for a lot of patients that wouldn't have met criteria for monarchE study, with that kind of intermediate-risk node-negative disease to access a CDK inhibitor. I think that's where you'll see most of the use of ribociclib.

Dr Cynthia Ma:
I agree completely.