Abstract GS03-03: Ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) as adjuvant treatment in patients with HR+/HER2− early breast cancer: final invasive disease–free survival (iDFS) analysis from the NATALEE trial
Authors: Hortobagyi Gabriel , Stroyakovsky Daniil , Yardley Denise , Huang Chiun-Shen , Fasching Peter A. , Crown John , Bardia Aditya , Chia Stephen , Im Seock-Ah , Martín Miguel , Loi Sherene , Xu Binghe , Hurvitz Sara , Barrios Carlos , Untch Michael , Moroose Rebecca , Visco Frances , Parnizari Federico , Ghaznawi Farhat , Li Zheng , Waters Sorcha , Chakravartty Arunava , Slamon Dennis 
Published: May 2024

Abstract
Background: Interim results from the phase 3 NATALEE trial demonstrated that adding RIB to standard-of-care adjuvant NSAI had a statistically significant iDFS benefit in patients with stage II and III HR+/HER2− early breast cancer at risk of recurrence, including those with node-negative disease (Slamon et al, ASCO 2023). We present the final protocol-specified analysis of the primary endpoint of iDFS.
Methods: A total of 5101 pre-/postmenopausal women and men underwent 1:1 randomization to receive RIB (400 mg/day; 3 weeks on/1 week off for 36 months) + NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for ≥60 months) or NSAI alone. Men and premenopausal women received goserelin (3.6 mg once every 28 days). Patients were required to have anatomic stage IIA (either N0 with additional risk factors or N1), IIB, or III breast cancer per the AJCC (8th edition). Patients remained on trial as long as they were continuing on NSAI (≤5 years), regardless of RIB discontinuation. The primary endpoint was iDFS according to STEEP v1.0 criteria, and the secondary efficacy endpoints were recurrence-free survival (RFS), distant disease–free survival (DDFS), and overall survival (OS). This final analysis was planned after approximately 500 iDFS events. iDFS was evaluated by the Kaplan-Meier method, and statistical comparison was made by a stratified log-rank test. P values were not corrected for multiple comparisons.
Results: At the data cutoff (July 21, 2023), among the 2549 patients in the RIB + NSAI arm, 1091 (42.8%) completed 3 years of RIB treatment, and 905 (35.5%) discontinued RIB or RIB + NSAI early and 528 patients (20.7%) remained on RIB. 1748 patients (68.5%) remain on treatment in the NSAI arm.
Median follow-up for iDFS was 33.3 months, an additional 5.6 months from the previous interim analysis. A total of 509 iDFS events were observed, 226 (8.9%) in the RIB + NSAI arm and 283 (11.1%) in the NSAI alone arm. RIB + NSAI demonstrated a significant iDFS benefit over NSAI alone (HR, 0.749; 95% CI, 0.628-0.892; P=.0006). The 3-year iDFS rates were 90.7% (95% CI, 89.3%-91.8%) vs 87.6% (95% CI, 86.1%-88.9%). A consistent benefit was observed across patient subgroups, including those with node-negative, stage II, or stage III disease (Table). Secondary endpoints of DDFS and RFS favored RIB + NSAI over NSAI alone (Table). OS data were immature, with 84 (3.3%) and 88 (3.4%) total events in the RIB + NSAI and NSAI alone arms, respectively. No new safety signals were observed since the prior interim analysis. Discontinuation of RIB due to adverse events was observed in 19.5% of patients (a &lt;1% increase from the prior interim analysis).
Conclusions: With a substantial proportion of patients completing 3 years of RIB treatment, NATALEE continues to demonstrate a significant iDFS improvement with RIB + NSAI over NSAI alone. Efficacy results confirm continued improvement in benefit across subgroups, including stage II disease. Safety findings support the manageable toxicity profile of RIB at the 400-mg starting dose in early breast cancer.
Table.
Citation Format: Gabriel Hortobagyi, Daniil Stroyakovsky, Denise Yardley, Chiun-Shen Huang, Peter A. Fasching, John Crown, Aditya Bardia, Stephen Chia, Seock-Ah Im, Miguel Martín, Sherene Loi, Binghe Xu, Sara Hurvitz, Carlos Barrios, Michael Untch, Rebecca Moroose, Frances Visco, Federico Parnizari, Farhat Ghaznawi, Zheng Li, Sorcha Waters, Arunava Chakravartty, Dennis Slamon. Ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) as adjuvant treatment in patients with HR+/HER2− early breast cancer: final invasive disease–free survival (iDFS) analysis from the NATALEE trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-03.