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Significant iDFS Benefit with Adding Ribociclib to a Nonsteroidal Aromatase Inhibitor in the Adjuvant Treatment for HR-positive, HER2-negative EBC

Findings from a protocol-specified interim analysis of the NATALEE study
26 Mar 2024
Endocrine Therapy;  Targeted Therapy
Breast Cancer

An international, open-label, randomised, phase III NATALEE study examined CDK4/6 inhibition in stage II or III, hormon receptor (HR)-positive, HER2-negative breast cancer by evaluating the addition of 3 years of ribociclib to a standard nonsteroidal aromatase inhibitor (NSAI) as adjuvant treatment. The results show a significant invasive disease-free survival (iDFS) benefit over NSAI alone with an absolute iDFS benefit of 3.3% at 3 years.

Overall survival data are currently immature. No new safety signals were observed for either ribociclib or the NSAIs. Findings from a protocol-specified interim analysis are published by Dr. Dennis Slamon of the David Geffen School of Medicine at the University of California in Los Angeles, CA, USA and colleagues in 21st March 2024 issue of The New England Journal of Medicine.

HR-positive, HER2-negative breast cancer is the most common subtype of breast cancer. The majority of cases with this subtype are diagnosed at early stage. Adjuvant endocrine treatment improves outcomes in these patients; however, recurrence occurs in 27-37% of patients with stage II disease and in 46-57% of patients with stage III disease and can occur up to 20 years after diagnosis.

The authors wrote in the background that in early breast cancer, the use of CDK4/6 inhibitors has had varying results. In the PENELOPE-B and PALLAS studies, palbociclib plus endocrine treatment did not show a significant iDFS benefit. However, a significant iDFS benefit was seen in the monarchE study after 2 years of adjuvant treatment with abemaciclib; these results led to the approval of abemaciclib for the treatment of HR-positive, HER2-negative early breast cancer in patients with node-positive disease at high risk for recurrence.

In NATALEE, international, open-label, randomised, phase III study, patients with HR-positive, HER2-negative early breast cancer were randomly assigned in a 1:1 ratio to receive ribociclib at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years plus an NSAI, either letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer.

In the latest article published in The New England Journal of Medicine, the study team report the results of a prespecified interim analysis of iDFS, the primary endpoint; other efficacy and safety results are also reported. iDFS was evaluated with the use of the Kaplan–Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided p-value threshold of 0.0128 for superior efficacy.

As of the data cut-off date for this prespecified interim analysis on 11 January 2023, a total of 426 patients had had invasive disease, recurrence, or death. A significant iDFS benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, iDFS was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone with hazard ratio for invasive disease, recurrence, or death of 0.75 (95% confidence interval 0.62 to 0.91; p = 0.003).

Secondary endpoints, distant DFS and recurrence-free survival also favoured ribociclib plus an NSAI. Furthermore, the 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals.

The authors commented that the NATALEE study showed that ribociclib treatment benefits a broad population of patients with early breast cancer who are at increased risk for recurrence. Abemaciclib treatment also showed a significant iDFS benefit in patients with node-positive early breast cancer in the monarchE study, which was conducted in a population that was enriched for high-risk patients. The monarchE study also required additional high-risk features in patients with one to three lymph nodes, as part of the inclusion criteria. By contrast, the NATALEE included patients with node-negative or node-positive disease as well as those with stage II or stage III disease.

The difference in the risk profiles of the NATALEE and monarchE populations is evident when the Kaplan–Meier 3-year invasive-disease estimates in the groups that received endocrine treatment alone in these two studies are compared. At 28 months of follow-up, the 3-year estimate of iDFS was 87.1% with NSAI alone in the NATALEE study; in the monarchE study, at 27 months of follow-up, the estimate was 83.4% with endocrine treatment alone, a result that was consistent with the higher-risk population of that trial.

The endocrine treatment used in these two studies differed. In the monarchE, both NSAIs and tamoxifen were allowed, whereas only NSAIs were allowed in the NATALEE study. Aromatase inhibitors have shown superior efficacy in patients at increased risk for recurrence in early breast cancer. The results of the SOFT, TEXT, and BIG 1-98 have all shown that aromatase inhibitors have advantages over tamoxifen.

All the premenopausal women in the NATALEE study received ovarian function–suppression therapy in addition to an NSAI, unlike the monarchE, in which only 48% received such therapy. In the monarchE, the incidence of venous thromboembolic events was higher among the premenopausal patients who were receiving tamoxifen than among those who were receiving an aromatase inhibitor. Ribociclib is not indicated for patients who are also receiving treatment with tamoxifen.

The authors also underlined that a key feature of the NATALEE study design was the use of a reduced dose of ribociclib (400 mg per day) to improve safety and adherence over a 3-year period while maintaining efficacy. In addition, a 3-year duration of ribociclib treatment was implemented with the goal of preventing recurrences. Although caution is advised when comparing dose levels between early and advanced breast cancer, the 400-mg dose was associated with a lower incidence of known dose-dependent side effects (neutropenia and QT prolongation) than that seen with the 600-mg dose, a finding that was also observed in the AMALEE study.

The NATALEE study is supported by Novartis. Ribociclib was discovered by Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceuticals.


Slamon D, Lipatov O, Nowecki, Z, et al. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med 2024;390:1080-1091.

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