Reviewing Ribociclib's Role in HR+, HER2- Early Breast Cancer

Hormone receptor (HR)-positive, HER2-negative breast cancer treatment strategies often involve endocrine therapy and aromatase inhibition (AI). At a live Case-Based Roundtable event in New York, Neil M. Iyengar, MD, director of survivorship services at Winship Cancer Institute of Emory University and associate professor and co-director of the Breast Medical Oncology Program in the Department of Hematology and Medical Oncology at Emory University School of Medicine, covered the NCCN guideline recommendations for endocrine and CDK4/6 inhibitor selection in premenopausal patients. He also looked at the design and updated outcomes of the phase 3 NATALEE trial (NCT03701334) for ribociclib (Kisqali) in the early-stage setting.

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Targeted Oncology: What does the NCCN recommend when treating patients with premenopausal HER2-negative breast cancer?

Neil M. Iyengar, MD: If we look at our patients who are premenopausal at diagnosis, your initial selection of endocrine therapy depends on their risk factors and your decision to use a CDK4/6 inhibitor or not. The NCCN specifically says, if you're using tamoxifen, consider adjuvant abemaciclib [Verzenio] in eligible patients.¹

If you're using AI and ovarian suppression, you can consider abemaciclib or ribociclib, depending on the patient's situation. When they transition to the post-menopausal state, this is where the NCCN says you could switch to an AI, or you could consider continuing tamoxifen if you started them on tamoxifen. But we do know from some of those trials that there was a small benefit to switching to an AI after they become post-menopausal…. For our patients who are post-menopausal at diagnosis, I think most of us are using an AI as our standard, but there are exceptions to the rule where we may use tamoxifen, perhaps for patients who have severe osteoporosis or terrible arthralgias or something like that, where we don't anticipate that an AI will be tolerable. The NCCN built in flexibility for that.

How was the NATALEE trial designed for the adjuvant breast cancer setting?

This was for patients with HR-positive, HER2-negative early breast cancer. Prior endocrine therapy was allowed up to 12 months prior to randomization. This gives you flexibility, [when you think about] staggering the endocrine therapy followed by the CDK4/6 inhibitor. The trial was built with that flexibility in mind, that you essentially have up to 1 year after starting their endocrine therapy to get them onto a CDK4/6 inhibitor. In my experience, it takes about 2 to 3 months to get them stable on an AI. Some patients [do well] and I'm able to start their CDK4/6 inhibitor earlier than that, but that's generally where I've been doing it. I haven't had to wait out to 1 year. I would get a little nervous waiting out to 1 year.²

In terms of the eligibility by anatomic stage, it was divided into N0 [node negative] and N1 [node positive] disease. N1 and N0 was allowed if they were stage IIA, but there were a couple of caveats for N0. If they're stage IIA and N0, they also need to be grade 2 and have evidence of high risk. What defines evidence of high risk is a Ki-67 of 20% or greater, an Oncotype DX recurrence score of 26 or greater or some other high-risk genomic profiling, or if they're grade 3.. They're grade 3, N0, with to stage IIA disease, they're eligible. For patients who are in the IIB category, they could be N0 or N1, and then [all] patients with stage III were eligible.

Patients were randomly assigned on a 1:1 basis in NATALEE to receive ribociclib [plus nonsteroidal AI vs nonsteroidal AI alone]. Note the dose was 400 mg a day—I'll come back to that point—on the usual schedule for ribociclib, 3 weeks on, 1 week off. This was a 3-year duration for ribociclib, and that is in addition to the AI plus ovarian suppression for premenopausal women vs AI plus placebo arm. The primary end point was invasive disease-free survival [iDFS], defined by Standardized Definitions for Efficacy End Points, and then some key secondary end points.

What are some of the differences in eligible populations for NATALEE vs monarchE (NCT03155997)?

If they're N1, N1mi, or even N1 and they're in the stage I or II setting, they're only eligible for abemaciclib based on monarchE criteria if they have grade 3 or with Ki-67 of 20% or greater—that was dropped from the label—so it's that grade 3 if they're N1 and you're considering abemaciclib for that population. With ribociclib, what you have to keep in mind is that they're eligible across nodal status if they are N0 and in stage IIA.³ That's the only category where you have to keep in mind some of those additional risk factors that they have to meet in order to be eligible.

How did the baseline characteristics impact these data?

The variables were pretty well balanced across the arms in terms of the distribution of pre- and post-menopausal women. I was pleased to see this, because we don't often have robust representation of our premenopausal women in these trials, but about 44% of the patients were premenopausal to 56% post-menopausal. In terms of the nodal status, the other thing I'll point out here is that the N0 population was close to 30% so a fairly substantial population there, with the majority being N1, and then 18% to 19% in the N2 and N3 category.³

Nearly three-quarters of patients had come in on endocrine therapy already, and then 88% of patients had received prior chemotherapy. That gives you a sense of the risk stratification of this population.

What did the updated data with 4-year follow-up show for patients on NATALEE?

The median follow-up time for the iDFS end point was 44.2 months.² There was a separation of the curves widening the longer they follow these patients. There was a difference in terms of the recurrence event rate or the iDFS event rate. At the 48-month mark, 4-year follow-up, the iDFS rate was 88.5% in the ribociclib arm and 83.6% in the AI-alone arm, representing a delta benefit of 4.9%. Sixty-three percent of patients completed 3 years of ribociclib.

With the burden of metastatic disease, one of the factors that plays into that is that is, where is it metastasizing to? It is interesting here to see that you sort of have a proportional reduction, as you might expect, in sites of burden of disease. But one of the worries that was voiced early was, if we're using the CDK4/6 inhibitor up front, for those who do recur, are we making it worse? These data tell us very clearly that we're not. We're not making it worse. But when the recurrence happens, it mirrors, but to a lesser degree, what happens with our AI alone arm, and so I do find these data to be helpful there.

How did patients with N0 disease do with ribociclib in the subgroup analysis?

There were wide confidence intervals [for the N0 population] because it is a smaller subpopulation within this trial, but it is still favoring the use of ribociclib, and this is, ultimately, when you look at the numbers in terms of how small that subpopulation was, and that HR in the N0 population was 0.666, despite the wide confidence intervals. That benefit was clear enough for the FDA to include that N0 population in the label for ribociclib. I generally agree with that, because we're seeing it going in the right direction with the short-term follow-up.

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DISCLOSURES: There were no known disclosures.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer; version 4.2025. Accessed September 9, 2025. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf}

_{2. Fasching PA, Stroyakovskiy D, Yardley D, et al. Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (Pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial. Ann Oncol. 2024;35(suppl 2):S1207. doi:10.1016/j.annonc.2024.08.2251}

_{3. Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. N Eng J Med. 2024;390(12):1080-1091.doi:10.1056/NEJMoa2305488}