Protocol-specified final analysis of invasive disease-free survival (iDFS) in an international, randomised, open-label, phase III NATALEE study, with most patients being off ribociclib treatment, showed consistent with the prior interim efficacy analysis, reduction in the risk of iDFS events with ribociclib plus nonsteroidal aromatase inhibitor over nonsteroidal aromatase inhibitor alone. The secondary endpoints of recurrence-free survival (RFS) and distant DFS also favoured ribociclib plus nonsteroidal aromatase inhibitor, while overall survival (OS) data were immature at the time of this analysis.
Most adverse events (AEs) were asymptomatic, and the safety profile remained consistent with that observed in previous interim analyses. The findings are published by Prof. Gabriel N. Hortobagyi of the Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center in Houston, TX, US, and colleagues on 21 October 2024 in the Annals of Oncology.
Contemporary clinical trials in patients with HR-positive, HER2-negative early breast cancer receiving endocrine therapy as part of the standard-of-care found that up to 13% of patients experience disease recurrence within 3 years of starting the endocrine treatment. Up to half of patients with ER-positive breast cancer experience a metastatic event within 20 years, depending on disease characteristics at initial diagnosis. A variety of anatomical, pathological, and genomic characteristics impact recurrence risk and therefore, escalation of adjuvant treatment is warranted in this group of patients.
CDK4/6 inhibitors have emerged as effective therapeutic interventions for patients with HR-positive/HER2-negative breast cancer and have become the standard-of-care for patients with metastatic disease. Currently, only two phase III trials using CDK4/6 inhibitors have shown positive efficacy for iDFS in patients with HR-positive, HER2-negative early breast cancer: the monarchE evaluating abemaciclib plus endocrine therapy, and the NATALEE evaluating ribociclib plus nonsteroidal aromatase inhibitor.
The NATALEE study was designed to evaluate the efficacy and tolerability of ribociclib plus nonsteroidal aromatase inhibitor with a 3-year treatment duration in a population of patients with stage II and III HR-positive, HER2-negative early breast cancer, including a select group of patients without nodal involvement. To improve tolerability, NATALEE assessed a lower daily dose of ribociclib 400 mg in patients with early breast cancer compared to the starting dose that is approved in advanced breast cancer of 600 mg.
Results from the second prespecified interim efficacy analysis of NATALEE found a statistically significant 25% reduction in iDFS events in patients receiving ribociclib plus nonsteroidal aromatase inhibitor compared with nonsteroidal aromatase inhibitor alone (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.62-0.91; p = 0.003). In the latest manuscript published in the Annals of Oncology, the authors report efficacy and safety results from the protocol-specified final analysis of iDFS in the NATALEE study.
In total, 2549 premenopausal and postmenopausal women and men were randomised 1:1 to ribociclib (400 mg/day, 3 weeks on/1 week off for 36 months) plus nonsteroidal aromatase inhibitor (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) and 2552 patients to nonsteroidal aromatase inhibitor alone. Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were RFS, distant DFS, and OS. This final iDFS analysis was planned after approximately 500 events.
At data cut-off on 21 July 2023, ribociclib was stopped for 1996 patients (78.3%); 1091 patients (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 patients (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus nonsteroidal aromatase inhibitor versus nonsteroidal aromatase inhibitor alone.
Ribociclib plus nonsteroidal aromatase inhibitor demonstrated significant iDFS benefit over nonsteroidal aromatase inhibitor alone (HR 0.749, 95% CI 0.628-0.892; p = 0.0012). The 3-year iDFS rates were 90.7% (95% CI 89.3%-91.8%) versus 87.6% (95% CI 86.1%-88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (positive/negative). Distant DFS and RFS favoured ribociclib plus nonsteroidal aromatase inhibitor; OS data were immature.
No new safety signals were observed. Since the previous interim analysis, the incidence rates of the most frequently observed AEs remained stable, and the absolute increase for any AE of special interest or clinically relevant AE was less than 1%. Similarly, discontinuations due to AEs only increased by 0.8%, despite more than three-quarters of patients off ribociclib at the time of this analysis.
The authors commented that future analyses are planned and will continue to elucidate the sustained benefit of ribociclib plus nonsteroidal aromatase inhibitor for long-term outcomes and among specific subgroups of interest. At the ESMO Congress 2024, the researchers presented 4-year outcomes from the NATALEE study. At data cut-off on 29 April 2024, all 2549 patients in the ribociclib plus nonsteroidal aromatase inhibitor arm were off ribociclib treatment: 1601 patients (62.8%) completed 3 years of ribociclib and 509 patients (20.0%) stopped ribociclib early due to AEs.
Median iDFS follow-up was 44.2 months. Ribociclib plus nonsteroidal aromatase inhibitor demonstrated a significant iDFS benefit over nonsteroidal aromatase inhibitor alone (HR 0.715; 95% CI 0.609-0.840; p < 0.0001), with iDFS rates of 90.8% versus 88.1% at 3 years and 88.5% versus 83.6% at 4 years (absolute improvement of 2.7% and 4.9%, respectively).
This iDFS benefit was observed across subgroups, including nodal status (absolute 4-years benefit of 5.1% in N0 and 5.0% in node-positive) and stage (absolute 4-years benefit of 4.3% in stage II and 5.9% in stage III). Ribociclib plus nonsteroidal aromatase inhibitor versus nonsteroidal aromatase inhibitor alone had a distant DFS benefit (HR 0.715, 95% CI 0.604-0.847). OS remains immature, but trended to favouring ribociclib (HR 0.827; 95% CI 0.636-1.074). Safety remained consistent with prior analyses.
The authors concluded that these results further support the addition of ribociclib to adjuvant nonsteroidal aromatase inhibitor in a broad population of patients with HR-positive, HER2-negative early breast cancer at risk of recurrence.
The study was funded by Novartis Pharmaceuticals Corporation. Ribociclib was discovered by Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceuticals.
References
- Hortobagyi GN, Lacko A, Sohn J, et al. A phase III trial of adjuvant ribociclib plus endocrine therapy vs endocrine therapy alone in patients with HR+/HER2− early breast cancer: final invasive disease–free survival results from the NATALEE trial. Annals of Oncology; Published online 21 October 2024. DOI: https://doi.org/10.1016/j.annonc.2024.10.015
- LBA13 – 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. Annals of Oncology 2024;35(Suppl 2):S1207.