Adjuvant Ribociclib Approval Expands Access to CDK4/6 Inhibition in High-Risk HR+/HER2– Breast Cancer

The highly-anticipated FDA approval of adjuvant ribociclib (Kisqali) plus a nonsteroidal aromatase inhibitor (NSAI) provides a necessary alternative to abemaciclib (Verzenio) for patients with hormone receptor–positive, HER2-negative breast cancer who are at high risk of recurrence and might benefit from, but did not previously qualify for, a CDK4/6 inhibitor in this setting, according to Bora Lim, MD.¹

The regimen received approval on September 17, 2024, based on data from the phase 3 NATALEE trial (NCT03701334), in which ribociclib and endocrine therapy generated a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS) vs endocrine therapy alone. Patients who received the ribociclib regimen (n = 2549) experienced an iDFS rate of 90.7% at 36 months (95% CI, 89.3%-91.8%) vs 87.6% (95% CI, 86.1%-88.9%) for those who received endocrine therapy alone (n = 2552; HR, 0.749; 95% CI, 0.628-0.892). Notably, overall survival (OS) data were immature at the time of analysis.²

Prior to this regulatory decision, abemaciclib was the sole CDK4/6 inhibitor FDA-approved for use in the adjuvant setting based on results from the phase 3 monarchE trial (NCT03155997), Lim noted.

“Although there are some new learning points that we’re going to have to discuss, this [approval] is exciting because there are now more opportunities for patients [in the curative setting] to get [therapy] from this new indication,” said Lim, who is an associate professor in the Department of Breast Medical Oncology, chief of the Translational Research section, and director of Translational Research at The University of MD Anderson Cancer Center in Houston, Texas. “There will have to be a lot of heart-to-heart discussions between physicians and their patients [now that we have this approval].”

In an interview with OncLive^®, Lim expanded on the significance of this approval for patients with high-risk disease who are ineligible for abemaciclib based on monarchE criteria; detailed key efficacy data and safety considerations for the regimen based on data from NATALEE; and expressed the importance of evaluating the distinct eligibility criteria, safety profiles, and dosing schedules for both adjuvant CDK4/6 inhibitors to ensure informed, tailored treatment decision-making.

OncLive: How does the approval of adjuvant ribociclib address the need for effective alternatives to abemaciclib for patients with high-risk disease following resection?

Lim: Abemaciclib has helped a lot of patients who have high-risk disease. However, if we [examine] which patients [were] approved [to receive a CDK4/6 inhibitor] in monarchE vs NATALEE, there was a slight difference as to who could have been receiving [abemaciclib]. There were still patients in the clinic who we thought might need some additional protections, but didn’t meet the criteria of the monarchE trial. We were all waiting [for this approval] as these patients could have been eligible for [CDK4/6 inhibition with ribociclib based on] NATALEE [enrollment criteria].

As a breast oncologist, we used to carry comparison notes between the monarchE and NATALEE trials. When we treat individual patients in the clinic, each one has a different T stage, N stage, and risk factors. For example, if a patient had a T3 N0 tumor they would not have qualified for monarchE. If we think that such a patient [has] high enough risk [disease], we would want to offer CDK4/6 inhibition in the adjuvant setting. For the next few weeks or months, we will continue to carry those charts and [evaluate] who [should receive a given CDK4/6 inhibitor based on] which trial criteria they [meet].

What are the most recent efficacy findings from NATALEE that supported this approval?

[Although] we had preliminary data [from NATALEE] showing initial benefit [with ribociclib plus an NSAI vs an NSAI alone], one of the key pieces of data we were waiting on was whether [ribociclib] would continue to [confer an] iDFS benefit over time. Also, the data had to be mature, especially because the duration of ribociclib treatment here was 3 years. When there’s an active treatment that is ongoing, there may be [a] direct effect of the minimal residual disease that could be still impacted by the ongoing systemic therapy.

With that, we wanted to see more extended data and continued benefit. The most recent data presented at the 2024 ESMO Congress showed that there was an absolute difference of [approximately] 3% in iDFS between the treatment and control arms, at 90.8% vs 88.1%, which is [as expected]. If you look at any comparison between a standard and new adjuvant therapy intervention, there’s [typically] a 2% to 4% absolute difference. The other important factor was the continuous HRs with ribociclib vs [an NSAI alone]. The HR presented was [approximately] 0.75, which could indicate that it might range between 0.7 up to 0.85 in real-world analyses. Having a persistent, consistent, HR [that favors] the addition of ribociclib to an NSAI was important for the approval.

A lot of physicians are interested in noting that the OS data with our adjuvant endocrine therapies are a slightly mixed group because there are a lot of new treatments that could continue to improve OS even after a patient does recur in the metastatic setting. It is debatable whether OS data in this setting are critical or not. It certainly was not a primary end point. [However], a lot of people are still anxiously awaiting these data as [OS] data are still immature at this time.

What should be known about the regimen’s safety profile?

One thing that is interesting about this study is that the metastatic dosing for ribociclib [typically] starts at the full dose of 600 mg. However, many patients may not tolerate the full dose for different reasons such as fatigue, gastrointestinal toxicities, or count issues. Because of that reason, patients in NATALEE were treated with the medium dose, which is 400 mg. That was very thoughtful process. Kudos to the study team for realizing that this could potentially mitigate unnecessary adverse effects [AEs] that, especially with ribociclib, could [lead to] cardiovascular [complications] such as QTc prolongation.

Because [they went with] the medium 400 mg dose, the total duration of treatment was 3 years, which is slightly different from other trials such as monarchE. [This begs the question] of what would happen if the dose was [substantially] reduced. If some patients would have to go down to the lower dose, if there’s any kind of cardiac history, should we then avoid ribociclib and consider abemaciclib instead? [NATALEE] did not note any new AEs that we didn’t know about with ribociclib, so there was nothing surprising or practice-changing there. We need to keep [using] the same precautions that we would in the metastatic setting.

Based on this approval, how will adjuvant ribociclib be incorporated into current clinical practice?

Because their indications are slightly different, I would [consider using ribociclib] for [select] patients who are ineligible to receive [abemaciclib] as their additional CDK4/6 inhibitor. [For example], patients who have micrometastases in the lymph nodes or no nodal disease but have a big tumor would be the first ones who I would start with.

We must sit down with our patients now that there’s a different medication approved. It has a similar but slightly different AE profile and dosing schedule. Adjuvant therapy is slightly different in the metastatic setting. For abemaciclib, both pills are [administered] every day, and with ribociclib, [treatment is administered] 3 weeks on and 1 week off. Sometimes we may have to delay [dosing], and neutropenia [may also occur] even with the medium dose. All [these considerations] will have to go hand-in-hand. There will also have to be a discussion [about the fact that] we’re going to give [the patient an] additional pill for 3 years.

What are some ongoing challenges in balancing cost and long-term benefits when using adjuvant CDK4/6 inhibition for patients with high-risk breast cancer?

Even with the success of improving the [iDFS by approximately] 3%, there are a lot of patients who will recur and end up having metastatic disease. Therefore, there has to be a better biomarker [elucidating] how to [treat] somebody who didn’t [end up benefitting] from this approach.

Two years ago, I was giving a talk about adjuvant management in patients with high-risk disease, and one of the physicians came up and said to me, ‘These drugs costs so much. You are spending all this money to save a smaller number of patients in this population.’ My argument was that if we are curing this patient who may have presented with stage IV disease later on, maybe as a society, we save on total cost. Can you imagine the length of life that we may lose, especially in the younger patients [if we don’t provide the best available therapy]? All those AEs and complications [are things] we also [contend] with in metastatic settings. Ultimately there are still a lot of conversations we still need to have as a field, but it’s a good problem to have.

References

1. FDA approves Novartis Kisqali to reduce risk of recurrence in people with HR+/HER2- early breast cancer. News release. Novartis. September 17, 2024. Accessed September 23, 2024. https://www.novartis.com/news/media-releases/fda-approves-novartis-kisqali-reduce-risk-recurrence-people-hrher2-early-breast-cancer
2. Fasching PA, Stroyakovskiy D, Yardley DA, et al. Adjuvant ribociclib plus nonsteroidal aromatase inhibitor in patients with HR+/HER2– early breast cancer: 4-year outcomes from the NATALEE trial. Presented at the 2024 European Society for Medical Oncology Congress (ESMO); September 13-17, 2024; Barcelona, Spain. LBA13.