Phase III NATALEE Trial Finds Ribociclib Effective in Reducing Risk of High-Risk Node-Negative Breast Cancer

Kisqali - Ribociclib (Photo: Novartis)

The latest analysis from the phase III NATALEE trial demonstrated that adding ribociclib (Kisqali) to endocrine therapy improved rates of invasive disease-free survival (iDFS), distant recurrence-free survival, and distant disease-free survival in high-risk early breast cancer patients with node-negative disease.

The findings were reported at the recent American Society of Clinical Oncology (ASCO) annual meeting.

MedPage Today brought together three expert leaders in the field for a virtual roundtable discussion: moderator Hope S. Rugo, MD, of the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, was joined by Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology in Dallas, and Sara Tolaney, MD, MPH, of Dana-Farber Cancer Institute in Boston.

Following is a transcript of their remarks:

Rugo: We’ve been so excited about the monarchE data with abemaciclib (Verzenio) in early-stage high-risk disease, followed shortly thereafter by the NATALEE data, which is a little less mature with a medium follow-up of about 3 months, giving ribociclib for 3 years at a slightly lower dose than is approved in the metastatic setting, 400 mg.

But NATALEE, in addition to changing the dose and the duration compared to what the monarchE trial did, also included a lower-risk population.

They have a lot of patients with high-risk disease, but they included a group of patients who had a lower node-negative disease but had some high-risk features. So high grade, high genomic risk score, and T2 tumors. And of course, they’re interested in expanding that further.

But then there’s been a lot of questions — does it work in these lower-risk patients and how much does it need to work to make it worth it to give this drug that requires blood monitoring, liver enzyme monitoring, and causes a little thinning of the hair and fatigue for 3 years in patients who finished therapy?

Now our node-negative patients are going to have finished less therapy. We don’t give them more intensive chemo. But what was your take? Denise Yardley did a lovely job of presenting in 6 minutes. It was the new rapid orals here in early-stage disease, but really interesting data.

Tolaney: Yeah, I mean, I was actually really looking forward to this because that’s been one of the big questions in my head.

Obviously, monarchE was a fully node-positive population. We didn’t have any patients who’d been exposed to [abemaciclib] in a node-negative setting. And here they selected the node-negatives, right?

They had to be over 2 cm if you’re a node-negative, you had to be either high-grade or if you’re intermediate-grade, you had to have another high-risk feature like high Ki67 or high genomic risk score.

So you picked people who had more risk than maybe the average node-negative patient, but they did show about a 3% benefit in terms of invasive disease-free survival with the majority of the events being distant events.

The number of events here is not large. And so I do think we have to keep that in mind.

The follow-up is still short. And so I think it’s saying that there’s benefit, and I think the question is very much in line with what you had said up front, is it worth it? It’s 3 years of therapy.

Right now the iDFS is over 90% in both arms. Are we really having a large enough impact to make it worth it? And I think this is a tough one.

I think we’re going to weigh it based on how risky is that node-negative patient, right? Is it a larger node-negative cancer that’s high-grade, high-Oncotype. That’s someone I would think about it in.

Kisqali – Ribociclib (Photo: Novartis)

But in my mind, this is a discussion with the patient because they have to be open to taking an extra drug for 3 years, as you point out, it does have some impact because they are coming in and out of the clinic a lot more than they would be if they weren’t on these agents. But definitely I think worth the discussion for the higher-risk patients.

Rugo: Yeah, I mean, of course, we don’t have ribociclib approved yet, but we expect that we will see an approval and they only had 3 years of follow-up.

To me, and maybe I think for all of us, it might’ve been a little more impressive because with a node-negative group where you selected them for early recurrence, they did see a difference. But 3 years is just at the end of treatment. So now what we want to see is the same kind of carryover effect.

And also for both drugs, what happens to the dormancy, the later recurrence risks? So far, the patients that have been included are not the ones who are highest for later recurrence.

They were selected for higher recurrence risk. So the planned WIDER trial that would include a lower-risk population — maybe for somebody else’s career, I’m thinking it’s going to take 10 years — might show some benefit in that population with carryover.

But Joyce, what will you do with that data come next week? I mean, if you had ribociclib, would you give it to those patients?

O’Shaughnessy: Yes, everybody who was eligible for NATALEE, I would. Because as I think about what’s the risk for our patients with the T2 or T3, N0, and as Sara said, if they’re T2, high recurrence score or high MammaPrint, those are high-risk women.

Or grade 3, the Ki67, 20% or above, that’s a mixed population. If you start getting 30%, 40%, 50%, now you’re really getting high risk. But 20%, 25% isn’t that high risk. So that’s a mixed bag.

But, those are high-risk patients and chemotherapy doesn’t work great in ER [estrogen receptor]-positive breast cancer.

Endocrine therapy, it was obviously effective. But I think these patients, this node-negative patient population, has a residual risk of 20-plus% over their lifetime. That’s high, one in five to me, so I’m going to talk to each and every patient about it.

One thing that’s good that they needed to get down on the dose to 200; it did not lose efficacy.

And so that becomes, and then they could get out to the every-3-monthly follow-up before too long. You know what I mean? So I’m going to offer it to everybody.

Tolaney: I think, I don’t know. I feel like I’m not quite ready to offer it to everyone. I think these drugs are highly effective drugs, but I think we have to weigh risk-benefit, and we still do see high liver enzymes, neutropenia, needing to come back and forth from the clinic.

And so I think it has an impact on patients’ quality of life. And so I think I would definitely offer it to maybe the higher-risk of the node-negative, of the enriched high-risk patients already and definitely have a discussion about it.

But I think once I had longer follow-up, maybe then I would turn to offering it to more patients. But it is a smaller subset of the trial and that’s what makes me feel quite not as confident.

Rugo: And it is quite, I mean, it is a small subset because they amplified the high-risk group once they saw the monarchE results, which turned out to be a very clever move. So it’s really interesting. So hopefully we’ll see.

They’re reformulating the pill now and hopefully we’ll see some indication about approval or not later this year. And then the WIDER trial, which will look at a lower-risk population and is not randomized — it’s enrolling quite a number of patients, several thousand — will also hopefully open this fall.

So I think there’ll be lots of opportunities to learn more. And I think that the monitoring for toxicity in particular, the liver function in addition to the neutropenia we’re all used to managing, is really important.

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