NATALEE Trial Results Add Ribociclib to CDK4/6 Inhibitor Options in Early-Stage Breast Cancer


The benefit of ribociclib was seen as consistent against all of the stratification factors in the phase III study.

There were 6 abstracts from the American Society of Clinical Oncology 2023 Annual Meeting that are likely to have a significant impact on oncology pharmacy in the breast cancer space, explained Danielle Roman, PharmD, BCOP, during the inaugural 2023 PTCE Oncology Pharmacists Connect conference in Austin, Texas. Those abstracts are from the NATALEE trial (abstract LBA500), the X-7/7 trial (abstract 1007), the Ovarian Ablation or Suppression trial (abstract 503), the HER3-Dxd trial (abstract 1004), the PALMIRA trial (abstract 1001), and the CAPItello-291 trial (abstract 1067).

3d rendered illustration - breast cancer. Credit: SciePro -

Credit: SciePro -

“The one that I think generated the most excitement in terms of breast cancer at ASCO this past year was the phase III NATALEE trial [NCT03701334],” Roman, manager of Oncology Clinical Pharmacy Services at Allegheny Health Network, said during the presentation. “A little bit of background here: CDK4/6 inhibitors have revolutionized the treatment of metastatic breast cancer. They are preferred in combination with endocrine therapy in the first line setting for nearly all patients with metastatic breast cancer.”

Roman explained further that, as with a lot of other areas of oncology, treatments start as later lines of therapy and eventually tend to move their way up. Specifically, there's been significant interest in expanding the use of CDK4/6 inhibitors to early-stage breast cancer.

“Really the data here have been variable in what we've seen in trials that have reported out thus far. We’ve had 2 trials with palbociclib [Ibrance; Pfizer] in the PENELOPE-B trial [NCT01864746] and PALLAS trial [NCT02513394] that did not show favor for palbociclib in early-stage breast cancer,” Roman said. “We then had the monarchE trial [NCT03155997] published more recently with abemaciclib [Verzenio; Eli Lilly and Company], and this did show benefit in high-risk, early-stage breast cancer.”

However, Roman noted that the monarchE trial was limited to looking at patients with lymph node-positive disease and additional high-risk features. For this reason, abemaciclib is now being routinely used with endocrine therapy in the adjuvant setting for those high-risk patients with node-positive disease.

The NATALEE trial looks at adjuvant ribociclib (Kisqali; Novartis), which is the third CDK4/6 inhibitor in the early-stage setting. NATALEE was a phase III, open label study, with 5001 patients that included men and pre- and post-menopausal women with good performance status. Additionally, all of these patients had HR-positive (HR+)/HER2-negative (HER2-) disease, which is the most common subtype of breast cancer. Patients in the trial were also those with stage 2A, 2B, or 3 HR+/HER2− early breast cancer at risk for recurrence, with patients with no nodal involvement included.

“So one of the big differences to point out with this particular trial compared to what we have published with monarchE is that these patients may have been lymph node-negative. Previously, the data mentioned before was with lymph node positive patients,” Roman said. “So there's been a lot of anticipation for the results of this trial in those patients with lymph node-negative disease and whether we would still have benefit with the addition of CDK4/6 inhibitor.”

Patients were randomized 1:1 to ribociclib at 400 mg/day, 3 weeks on and 1 week off for 3 years plus endocrine therapy (letrozole 2.5 mg/day or anastrozole 1 mg/day, for ≥ 5 y) or endocrine therapy alone. Men and premenopausal women also received gonadotrophin-releasing hormone (GnRH) agonist goserelin (Zoladex; TerSera Therapeutics LLC). Eligible patients had an ECOG PS of 0-1 and breast cancer anatomic stage 2A (either node-negative with additional risk factors or 1-3 axillary lymph nodes), stage 2B, or stage 3 per AJCC (8th ed).

Further, prior (neo)adjuvant endocrine therapy was allowed if initiated at 12 months or earlier before randomization. During the trial, the stratification factors were menopausal status, disease stage, prior (neo)adjuvant chemotherapy, and geographic region.

“One thing to point out here with ribociclib is the dose and the duration of therapy. Ribociclib in the metastatic setting has 600 mg as the recommended dose, so there’s a lower dose here. The reason for that is that ribociclib can be a toxic medication, and the thought was to try to improve duration of therapy for these patients by giving them a lower dose,” Roman said. “What we've seen in the metastatic setting is those patients that require dose reductions still had good efficacy for the medication. So the thought was to start with the 400 mg dose for tolerability reasons, and also to do this for 3 years compared to the monarchE trial with abemaciclib that did 2 years.”

The primary outcome of the NATALEE trial was invasive disease-free survival (iDFS), and secondary outcomes were overall survival (OS), recurrence-free survival, and distant disease–free survival. The median follow-up was approximately 3 years, the iDFS was 90.4% in the ribociclib and endocrine therapy arm compared to 87.1% in the placebo arm.

“There was a 25% risk of progression or death in patients that received the addition of ribociclib. So 3.3% absolute benefit, but looking at that hazard ratio, this was really considered to be very positive. It's clinically, as well as statistically significant results. So a lot of excitement generated here,” Roman said. “I do want to note that 75% of patients remain on study. So it's still an ongoing study as this is just their first interim analysis. Also, in terms of that ribociclib therapy, only 20% of patients thus far have completed that 3 years of ribociclib. So definitely anticipate future analysis of this study continuing to drive what we see here, but overall very positive results.”

The benefit of ribociclib was also seen as consistent against all of the stratification factors, such as menopausal status and disease status, and, in particular, showed benefit in those patients with node negative disease, according to Roman.

“So again, this is really the exciting part. What we're seeing here is potentially being able to use CDK4/6 inhibitors for those patients,” Roman said. “However, OS data is still immature here. So again, waiting longer follow up here to have that information, but looks really promising with the addition of ribociclib for these patients with stage 2 or 3 disease.”

Some key insights from the NATALEE trial are that this combination improves iDFS in early-stage breast cancer, adding to our CDK4/6 options. The benefit was also consistent across all subgroups, including among those patients with stage 2 node-negative disease.

“This expands the role of CDK4/6 inhibitors. That 400 mg lower dose of ribociclib, which is lower than what we see in the metastatic setting, does appear to be efficacious and better tolerated,” Roman said. “So just looking at the safety data from this trial compared to a pooled analysis of ribociclib used in the metastatic setting, there was lower incidence of neutropenia and lower incidence of QTc prolongation that we know are problematic with this agent.”


Roman D. New Evidence in Breast Cancer and the Impact to Care. Presented at: 2023 PTCE Oncology Pharmacists Connect in Austin, Texas; June 16, 2023.

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