番茄社区

In this exclusive virtual roundtable video from 番茄社区, three expert leaders in the field of breast cancer discuss the latest emerging and potentially practice-changing data from the virtual San Antonio Breast Cancer Symposium.

Moderator , is joined by , and in this second of four episodes, where they discuss the monarchE trial of abemaciclib (Verzenio) and the PENELOPE-B and PALLAS trials of palbociclib (Ibrance), which investigated CDK4/6 inhibitor therapy in the adjuvant, hormone receptor (HR)-positive, early-stage breast cancer setting.

Episode 1: Immunotherapy Options

Following is a transcript of their remarks:

Rugo: Hello and welcome to this virtual roundtable where we will be discussing some of the key data that emerged from this year's San Antonio Breast Cancer meeting. I'm Hope Rugo, professor of medicine at the University of California San Francisco's Comprehensive Cancer Center, and I'm joined today by two expert leaders in the field of breast cancer and great colleagues, Dr. Jennifer Litton from the MD Anderson Cancer Center and Dr. Jo Chien from the University of California San Francisco's Comprehensive Cancer Center. Thanks for joining me today.

Now at San Antonio this year we saw an update of the really interesting monarchE data, the adjuvant trial looking at abemaciclib versus not additional therapy combined with endocrine therapy in the adjuvant setting for 2 years in patients who have quite high-risk early-stage hormone receptor-positive, HER2-negative breast cancer.

That data was first presented at ESMO this year and published at the same time. The data from PALLAS was also presented at ESMO, showing no benefit from 2 years of palbociclib. The same kind of trial design, but a lower-risk group of patients, very interesting data. Also at San Antonio, right after the monarchE update, we saw data from PENELOPE-B that looked at palbociclib for just 1 year in patients with high-risk disease after neoadjuvant therapy.

The update from monarchE this time looked at the subset of patients who had a Ki67 of 20% or greater and tried to see whether or not there was a differential benefit of abemaciclib in that group. Jennifer, do you want to summarize some of that data for us and tell us your take on it?

Litton: Sure. The monarchE we got a further update. When it was previously presented, it was a median follow-up of about 15.5 months (now at about 19.1 months of median follow-up), and interestingly still only about 25% have completed the full 2 years -- we still need to watch this trial as it matures.

The improved iDFS [invasive disease-free survival] curves separate and they are still separated with a hazard ratio of 0.713. It's really interesting in this cohort, especially of the one to three positive nodes, but the high Ki67 of over 20% grade 3, these patients had a much higher benefit. It was almost a 4.5% absolute difference, so these higher-risk patients are the ones likely getting the bigger benefit of the addition of the CDK inhibitor.

The overall survival is still pending and the distant recurrence-free survival stayed really the same at about 3%. Just like you said, right after the PENELOPE-B presents... and this was looking at palbociclib after neoadjuvant chemotherapy with residual disease with a median of about 43 months, and still no difference there.

Interestingly, too, the PALLAS trial, which we heard as well, is also looking at a very similar population, potentially less aggressive disease. Really interesting in the PALLAS was a 42% discontinue rate, which really puts it out of sync with both the PENELOPE-B and the monarchE trial.

The ongoing NATALEE trial, looking at ribociclib, has gone on for 3 years. We have one positive trial, the monarchE, which gave abemaciclib for 2 years. We have the PENELOPE-B, which was essentially a negative trial with only 1 year of adjuvant palbo [palbociclib], and the PALLAS trial that had 2 years of palbo but a 42% discontinue rate. Really still trying to put that all together, but at this point we still have confirmation with further follow-up of a positive, abemaciclib in this situation.

Rugo: Yeah. I thought that the data on Ki67 was quite interesting, and just to clarify, it was the entire trial population. It included patients who had one to three positive nodes, grade 3 disease, or a tumor of 5 centimeters of greater, and patients who had four or more positive nodes, plus the small cohort B, which is that one to three positive nodes and high Ki67.

If you took all of those patients together and looked at the high Ki67 group, that's where the 4.5% absolute improvement in iDFS was seen, which again I think is quite clinically relevant.

I think that the other thing that's interesting about all of this is the, already, difference in distant recurrence rates, albeit very short outcome data in terms of follow-up. It's interesting because we think of ER-positive breast cancer as having this very long natural history, so you're basically plucking out the people who have an earlier recurrence risk. I think that's really important when we think about this, is that PALLAS suggests if we think about the agents not being agent-specific, that the patients who had a low risk in the first 2 years of recurrence don't benefit, and so we're really selecting that group out. How are you going to take this into your clinical practice, Jo? Do you think we're ready to use abemaciclib as an adjuvant therapy for very high-risk disease?

Chien: I think we need to see longer follow-up. I think it's very unique for such early data to be presented, right? I'm trying to think of other studies where we're presenting data where more than 50% are still on the study.

I think when we look at these results in context of PENELOPE-B, where at the 2-year iDFS you saw a difference between the two arms that looks similar to the difference in monarchE, and at 3 years, and then further at 4 years, those curves narrow and actually now are crossing. Does that mean that duration really matters? Because remember in PENELOPE-B you come off at 1 year and that's when you start to see these curves narrow.

I think we really need to wait to look at survival. We have to see are we sort of pushing out and delaying recurrence. Is that because they're coming off the agent after 1 or 2 years? I think it's not clear how these agents will benefit in the long term.

Having said that, right now, as we are waiting for that data, what do we do? I think these data are compelling. In my highest-risk patients, four positive nodes, young, I am doing this sometimes sort of off-label, and I think it's something I do discuss with patients as long as they understand that these data are conflicting. Is it that it's abema [abemaciclib] versus palbo? Is it the duration? Is it discontinuation? We don't know and I think it's really important for us to look at the survival benefit. But in the meantime, I do discuss this with many high-risk patients.

Rugo: And you, Jen?

Litton: It's really hard for me to believe that these three different CDK inhibitors are so biologically different. We are not getting a hint of that, really, in the metastatic [setting], but I think that we're really digging down into the differences of the design of these trials, the length of the therapy, and the patients that accrue to it. At the end of the day, the data is where we are. With monarchE being the one where we do see that difference statistically significant, if I were to offer a CDK inhibitor, it would be abema at this point.

Rugo: It may be that in our very high-risk patients, where we have some data on also safety, which seems to be reasonably safe, that combining abemaciclib with an AI [aromatase inhibitor] is not an unreasonable approach with patients who have the highest risk of relapsing in the first 2 to 3 years, where distant recurrence is really such a terrible outcome in these patients.

We just want to be careful. Also, until we see the data breakdown in terms of the risk of thromboembolic events with AIs versus tamoxifen, I probably would only use abemaciclib with an AI at the moment, given the fact that there was a slight increase in that risk.

It is fascinating and we'll look forward to more data. I'm sure we're going to see more data next year, even, on the early use of CDK4/6 inhibitors in the adjuvant setting. It will be fascinating to see if we ever do see survival benefits because these patients will also receive the agents in the metastatic setting as well. We're going to have interesting discussions about sequencing, etc., so thank you very much.

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