Ribociclib Plus Endocrine Therapy in Hormone Receptor–Positive/ERBB2-Negative Early Breast Cancer: 4-Year Outcomes From the NATALEE Randomized Clinical Trial

Peter A Fasching; Daniil Stroyakovskiy; Denise A Yardley; Chiun-Sheng Huang; John Crown; Aditya Bardia; Stephen Chia; Seock-Ah Im; Miguel Martin; Binghe Xu; Sherene Loi; Carlos Barrios; Michael Untch; Rebecca Moroose; Frances Visco; Gabriel N Hortobagyi; Dennis J Slamon; Rodrigo Fresco; Juan Pablo Zarate; Zheng Li; Sorcha Waters; Sara A Hurvitz

doi:10.1001/jamaoncol.2025.3700

. 2025 Sep 25;11(11):1364–1372. doi: 10.1001/jamaoncol.2025.3700

Ribociclib Plus Endocrine Therapy in Hormone Receptor–Positive/ERBB2-Negative Early Breast Cancer

4-Year Outcomes From the NATALEE Randomized Clinical Trial

Peter A Fasching ^1,^✉, Daniil Stroyakovskiy ², Denise A Yardley ³, Chiun-Sheng Huang ⁴, John Crown ⁵, Aditya Bardia ⁶, Stephen Chia ⁷, Seock-Ah Im ⁸, Miguel Martin ⁹, Binghe Xu ¹⁰, Sherene Loi ¹¹, Carlos Barrios ¹², Michael Untch ¹³, Rebecca Moroose ¹⁴, Frances Visco ¹⁵, Gabriel N Hortobagyi ¹⁶, Dennis J Slamon ⁶, Rodrigo Fresco ¹⁷, Juan Pablo Zarate ¹⁸, Zheng Li ¹⁸, Sorcha Waters ¹⁹, Sara A Hurvitz ²⁰

¹University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany

²Moscow City Oncology Hospital No. 62 of Moscow Healthcare Department, Moscow Oblast, Russia

³Sarah Cannon Research Institute, Nashville, Tennessee

⁴National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan

⁵St. Vincent’s University Hospital, Dublin, Ireland

⁶David Geffen School of Medicine at UCLA, University of California, Los Angeles

⁷BC Cancer Agency, Vancouver, British Columbia, Canada

⁸Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

⁹Instituto de Investigación Sanitaria Gregorio Marañón, Centro de Investigación Biomédica en Red de Cáncer, Grupo Español de Investigación en Cáncer de Mama, Universidad Complutense de Madrid, Madrid, Spain

¹⁰Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences (CAMS), Peking Union Medical College (PUMC), Beijing, China

¹¹Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

¹²Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Brazil

¹³Interdisciplinary Breast Cancer Center, Helios Klinikum Berlin-Buch, Berlin, Germany

¹⁴Orlando Health Cancer Institute, Orlando, Florida

¹⁵National Breast Cancer Coalition (NBCC), Washington, DC

¹⁶Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston

¹⁷Translational Research in Oncology (TRIO), Montevideo, Uruguay

¹⁸Novartis Pharmaceuticals Corporation, East Hanover, New Jersey

¹⁹Novartis Ireland, Dublin, Ireland

²⁰Fred Hutchinson Cancer Center, University of Washington, Seattle

Accepted for Publication: July 29, 2025.

Published Online: September 25, 2025. doi:10.1001/jamaoncol.2025.3700

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2025 Fasching PA et al. JAMA Oncology.

^✉

Corresponding Author: Peter A. Fasching, MD, University Hospital Erlangen, Comprehensive Cancer Centre Erlangen-EMN, Friedrich Alexander University Erlangen-Nuremberg, Universitätsstraße 21-23, D-91054 Erlangen, Germany (peter.fasching@uk-erlangen.de).

Author Contributions: Dr Fasching had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Fasching, Stroyakovskiy, Bardia, Chia, Im, Martin, Barrios, Moroose, Visco, Hortobagyi, Slamon, Zarate, Li, Waters, Hurvitz.

Acquisition, analysis, or interpretation of data: Fasching, Yardley, Huang, Crown, Chia, Im, Martin, Xu, Loi, Barrios, Untch, Fresco, Zarate, Li, Waters.

Drafting of the manuscript: Fasching, Chia, Slamon, Zarate, Li, Waters.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Chia, Martin, Li.

Obtained funding: Chia.

Administrative, technical, or material support: Fasching, Yardley, Crown, Bardia, Im, Xu, Hortobagyi, Fresco, Zarate, Waters.

Supervision: Loi, Barrios, Moroose, Hortobagyi, Zarate.

Conflict of Interest Disclosures: Dr Fasching reported personal fees from Novartis during the conduct of the study; grants from Cepheid and personal fees from Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, BioNtech, Merck Sharp & Dohme, Lilly, Seagen, Roche, Agendia, Gilead, Mylan, Menarini Stemline, Veracyte, and Guardant Health outside the submitted work; and serving as director of TRIO, which is an uncompensated role. Dr Yardley reported institutional grants from Novartis during the conduct of the study, as well as institutional grants from AbbVie, Ambrx, AstraZeneca, Dana-Farber Cancer Institute, Lilly, Roche/Genentech, G1 Therapeutics, Gilead Sciences, Innocrin Pharmaceuticals, Merck, Polyphor, Stemline Therapeutics, US Oncology, and UT Southwestern, and other institutional support from Arvinas, AstraZeneca, Daiichi Sankyo, Gilead Sciences, Novartis, Pfizer, and Stemline Therapeutics outside the submitted work. Prof Huang reported institutional grants and personal fees from Novartis during the conduct of the study, as well as institutional grants from Daiichi Sankyo, AstraZeneca, EirGenix, Eli Lilly, MSD, OBI Pharma, Pfizer, Roche, Novartis, Seagen, Gilead, and Aston Sci; personal fees from Daiichi Sankyo, AstraZeneca, EirGenix, Eli Lilly, Pfizer, Roche, Novartis, and Gilead; and nonfinancial support from Pfizer, Roche, and Gilead outside the submitted work. Prof Crown reported personal fees from Novartis during the conduct of the study, personal fees from Novartis and Pfizer outside the submitted work, and speakers bureau conference attendance. Prof Bardia reported grants and personal fees from Novartis, Genentech, Merck, Pfizer, Menarini, AstraZeneca, Daiichi Sankyo, Alyssum, and Eli Lilly during the conduct of the study. Dr Chia reported personal fees from Novartis and Eli Lilly during the conduct of the study, as well as personal fees from AstraZeneca, Roche, Daiichi Sankyo, and Exact Sciences outside the submitted work. Dr Im reported grants from Novartis during the conduct of the study, as well as grants from AstraZeneca, Eisai, Daiichi Sankyo, Roche, Daewon Pharm, and Boryung Pharm; personal fees from AstraZeneca, Novartis, Hanmi, Pfizer, Daiichi Sankyo, Eisai, Roche, Lilly, MSD, Bertis, and Idience; and nonfinancial support from GSK outside the submitted work. Dr Martin reported personal fees from Pfizer, Novartis, MSD, Lilly, Bayer, Roche, GSK, and Menarini outside the submitted work. Dr Xu reported personal fees from Novartis and AstraZeneca outside the submitted work. Prof Loi reported institutional research funding from Novartis, Bristol Myers Squibb, Puma Biotechnology, AstraZeneca/Daiichi Sankyo, Roche-Genentech, and Seagen, as well as consulting (compensated and noncompensated) for Roche-Genentech, MSD, Gilead Sciences, AstraZeneca/Daiichi Sankyo, Bristol Myers Squibb, Novartis, Amaroq Therapeutics, Mersana Therapeutics, and Domain Therapeutics outside the submitted work; institutional research funding from Novartis, Bristol Myers Squibb, AstraZeneca/Daiichi Sankyo, Roche-Genentech, MSD, Pfizer, Gilead Sciences, Nektar Therapeutics, and Eli Lilly; and consulting for Roche-Genentech, MSD, Gilead Sciences, AstraZeneca/Daiichi Sankyo, Bristol Myers Squibb, Novartis, Eli Lilly, Amaroq Therapeutics, Mersana Therapeutics, Domain Therapeutics, BioNTech, Bicycle Therapeutics, Exact Sciences, Menarini Asia-Pacific, SAGA Diagnostics, and Adanate. Dr Barrios reported institutional grants from Amgen, AstraZeneca, Aveo Oncology, BioNTech, BMS, Daiichi Sankyo, Dizal Pharma, Exelixis, Fortrea, Gilead Sciences, GSK, ICON, IQVIA, Janssen, Labcorp, Lilly, Medpace, MSD, Novartis, Novocure, Nuvisan, OBI Pharma, Parexel, Pfizer, PharmaMar, PPD, PSI, Regeneron, Roche/Genentech, Samsung, Sandoz, Sanofi, Seagen, Servier, Stemline, Syneos Health, Taiho, Takeda, Tolmar, TRIO, and Worldwide during the conduct of the study, as well as personal fees from Adium, Novartis, Pfizer, Roche/Genentech, MSD, AstraZeneca, Lilly, Daiichi Sankyo, and Gilead outside the submitted work. Prof Untch reported fees to employer/institution from Agendia, AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD/Merck, Myriad Genetics, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi, Seagen, and Menarini Stemline during the conduct of the study, as well as fees to employer/institution from Agendia, AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD/Merck, Myriad Genetics, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi, Seagen, and Menarini Stemline outside the submitted work. Dr Hortobagyi reported consulting and serving as a member of a trial steering committee for Novartis outside the submitted work. Dr Slamon reported serving as founder of and stock ownership in TORL BioTherapeutics and 1200 Pharma; serving on the board of directors for, stock ownership in, and travel expenses from BioMarin; grants and research funding from and stock ownership in from Pfizer; consulting and serving on the advisory board for and grants, research funding, and travel expenses from Novartis; consulting for Eli Lilly; and stock ownership in Amgen and Seagen outside the submitted work. Dr Fresco reported institutional contracting with Novartis to conduct the NATALEE trial. Dr Zarate reported personal fees from and stock ownership in Novartis Pharmaceuticals as an employee during the conduct of the study as well as outside the submitted work. Dr Li reported stock ownership in Novartis during the conduct of the study. Dr Waters reported employment and stock ownership in Novartis outside the submitted work. Dr Hurvitz reported nonfinancial support from Novartis for manuscript preparation during the conduct of the study; institutional grants from and serving as an unpaid steering committee member for Arvinas/Pfizer, AstraZeneca/Daiichi Sankyo, Genentech/Roche, Gilead/Immunomedics, Greenwich LifeSciences, Eli Lilly (including Loxo Oncology), Puma, Sanofi, Seagen, Jazz/Zymeworks, Novartis, and Celcuity; institutional grants from Dantari, Roche, G1 Therapeutics, Orinove, Orum, and Radius/Stemline/Menarini; nonfinancial support from Boehringer Ingelheim and MEDSIR as a steering committee member; consulting fees paid to institution from BridgeBio, Daiichi Sankyo, Roche, Mersana, BeOne Medicines, and Blueprint; and personal fees from the Atossa/InClin Data Safety and Monitoring Board outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by Novartis Pharmaceuticals Corporation.

Role of the Funder/Sponsor: Novartis Pharmaceuticals Corporation was responsible for the design and conduct of the study; analysis and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the patients who participated in the trial and their families and caregivers, the members of the independent data monitoring committee, the members of the trial steering committee, the staff members who assisted with the trial at each site, and Casey Nielsen, PhD, of Nucleus Global, for medical editorial assistance with earlier versions of the article, for which no additional compensation outside of salary was provided. We also thank Arunava Chakravartty, PhD, for contributions to study design, statistical support, and data interpretation, for which no additional compensation outside of salary was provided. Ribociclib was discovered by Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceuticals.

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Corresponding author.

PMCID: PMC12464853 PMID: 40996773

This exploratory 4-year analysis of the NATALEE randomized clinical trial evaluates efficacy and safety of adjuvant ribociclib beyond the planned 3-year treatment period.

Key Points

Question

Is the efficacy benefit of ribociclib sustained beyond the planned 3-year treatment duration for patients with hormone receptor–positive/ERBB2 (formerly HER2)-negative early breast cancer in the NATALEE randomized clinical trial?

Findings

In this exploratory 4-year analysis of 5101 patients from the NATALEE trial, ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) continued to demonstrate an invasive disease-free survival and distant disease-free survival benefit over NSAI alone by reducing the disease recurrence risk by 28.5%. The absolute iDFS benefit continued to increase from 3 to 4 years.

Meaning

NATALEE results continue to support the benefit of adding 3 years of ribociclib to adjuvant NSAI in patients with hormone receptor–positive/ERBB2-negative early breast cancer at risk of recurrence.

Abstract

Importance

Ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) has demonstrated a statistically significant invasive disease-free survival (iDFS) benefit over NSAI alone in patients with hormone receptor–positive/ERBB2 (formerly HER2)-negative early breast cancer. Evaluating the efficacy and safety of adjuvant ribociclib beyond the planned 3-year treatment period is critical for understanding the long-term impact on recurrences.

Objective

To evaluate efficacy and safety of adjuvant ribociclib in an exploratory 4-year analysis of the NATALEE (New Adjuvant Trial With Ribociclib [LEE011]) randomized clinical trial, with all patients no longer receiving ribociclib treatment.

Design, Setting, and Participants

This exploratory analysis of an international, open-label, randomized phase 3 trial analyzed adjuvant treatment for premenopausal and postmenopausal women and men with hormone receptor–positive/ERBB2-negative early breast cancer. Eligible patients had anatomic stage IIA (either N0 with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III disease per the American Joint Committee on Cancer Staging Manual, eighth edition. The data cutoff date was April 29, 2024.

Interventions

Patients were randomized 1:1 to receive ribociclib (400 mg once daily, days 1-21 of a 28-day cycle, over 36 months) plus NSAI (letrozole, 2.5 mg, or anastrozole, 1 mg, once daily continuously for 60 months) or NSAI alone. Men and premenopausal women also received goserelin (3.6 mg once every 28 days administered subcutaneously).

Main Outcomes and Measures

The primary end point was iDFS, and secondary efficacy end points included distant disease-free survival, recurrence-free survival, and overall survival. Survival was evaluated by the Kaplan-Meier method.

Results

Among 5101 patients included in the analysis (median [range] age, 52 [24-90] years; 5081 [99.6%] female), the median follow-up for iDFS was 44.2 months (range, 0-63 months). Ribociclib plus NSAI continued to show iDFS benefit over NSAI alone (hazard ratio, 0.72; 95% CI, 0.61-0.84), with 3-year iDFS rates of 90.8% vs 88.1% (difference, 2.7 percentage points) and 4-year rates of 88.5% vs 83.6% (difference, 4.9 percentage points). The efficacy benefit was consistent across subgroups and secondary end points. Overall survival data remain immature, although a trend in favor of ribociclib plus NSAI over NSAI alone was observed (hazard ratio, 0.83; 95% CI, 0.64-1.07). The incidence of adverse events has remained stable.

Conclusions and Relevance

This exploratory analysis of the NATALEE randomized clinical trial, with a median follow-up beyond the 3-year treatment duration, demonstrated consistent iDFS benefit with ribociclib plus NSAI over NSAI alone.

Trial Registration

ClinicalTrials.gov Identifier: NCT03701334

Introduction

The most prevalent breast cancer subtype is hormone receptor (HR) positive/ERBB2 (formerly HER2) negative, which accounts for more than 70% of all cases.¹ Adjuvant endocrine therapy (ET) improves outcomes for patients with HR-positive/ERBB2-negative early breast cancer (EBC) and is standard of care (SOC) in this setting.² However, many patients experience disease recurrence.³ Approximately 50% of recurrences occur within 5 years of diagnosis and continue beyond 20 years even with SOC adjuvant ET.^4,5,6,7 Most of these events are distant recurrences, which are incurable.^8,9,10,11,12 Consequently, reducing risk of recurrence is a critical unmet need for patients with HR-positive/ERBB2-negative EBC.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the SOC in the advanced breast cancer (ABC) setting, with ribociclib being the only CDK4/6i to demonstrate statistically significant progression-free survival and overall survival benefit as either first- or second-line treatment for patients with HR-positive/ERBB2-negative ABC.^{13,14,15,16,17,18} In the adjuvant setting, 2 CDK4/6is (ribociclib and abemaciclib) have shown statistically significant improvements in invasive disease-free survival (iDFS) in patients with HR-positive/ERBB2-negative EBC; however, there are key differences in the respective phase 3 trials: patient selection, CDK4/6i initiation window, dose, and duration.^10,19 The monarchE trial assessed 2 years of adjuvant abemaciclib in combination with ET vs ET alone in patients with high-risk node-positive HR-positive/ERBB2-negative EBC.¹⁹ The NATALEE (New Adjuvant Trial With Ribociclib [LEE011]) trial evaluated the addition of 3 years of ribociclib to SOC adjuvant nonsteroidal aromatase inhibitor (NSAI) vs NSAI alone in a broad population of patients with stage II/III HR-positive/ERBB2-negative EBC with high-risk node-negative (N0) or node-positive disease.¹⁰

In the second interim NATALEE efficacy analysis (median follow-up for iDFS, 27.7 months), ribociclib plus NSAI demonstrated statistically significant improvement in iDFS (hazard ratio, 0.75; 95% CI, 0.62-0.91; 2-sided P = .003) and distant disease-free survival (DDFS; hazard ratio, 0.74; 95% CI, 0.60-0.91) over NSAI alone.^10,20 In the protocol-specified final iDFS analysis in NATALEE (median follow-up for iDFS, 33.3 months), ribociclib continued to show improvement in iDFS (hazard ratio, 0.75; 95% CI, 0.63-0.89; nominal 2-sided P = .001) and DDFS (hazard ratio, 0.75; 95% CI, 0.62-0.90) over NSAI alone.²¹

Extended follow-up is critical for understanding whether and to what degree the adjuvant treatment benefit is sustained after the end of treatment. We present NATALEE results with extended follow-up data, including a descriptive exploratory 4-year analysis. All patients had completed or stopped ribociclib treatment by this time point.

Methods

Study Design and Patients

NATALEE study design and patient population details have been previously published.^10,22 In brief, 5101 patients with HR-positive/ERBB2-negative EBC were randomized 1:1 to receive ribociclib (400 mg once daily, days 1-21 of a 28-day cycle, over 36 months) with an NSAI (letrozole, 2.5 mg, or anastrozole, 1 mg, once daily continuously for 60 months) or an NSAI alone (eFigure 5 in Supplement 2). Men and premenopausal women also received goserelin (3.6 mg once every 28 days administered subcutaneously). Patients were considered to be receiving study treatment if they continued taking an NSAI (up to 5 years), regardless of ribociclib discontinuation. Randomization was stratified by menopausal status (men/premenopausal women or postmenopausal women), anatomic stage (II or III), prior neoadjuvant and/or adjuvant chemotherapy (yes or no), and geographic location (North America, Western Europe, Oceania, or rest of the world). Eligible patients had anatomic stage IIA (N0 with a grade 2 tumor with a Ki-67 index ≥20% or high genomic risk, N0 with a grade 3 tumor, or N1), stage IIB, or stage III disease per classification in the American Joint Committee on Cancer Staging Manual, eighth edition.²³

NATALEE was conducted across 384 sites in 20 countries and in accordance with the provisions of the International Council for Harmonisation’s Good Clinical Practice guidelines, with applicable local regulations and the ethical principles in the Declaration of Helsinki. The study protocol (Supplement 1) was reviewed and approved by the institutional review board or ethics committee for each participating center. An independent data monitoring committee reviewed safety and efficacy data per study protocol. All patients provided written informed consent. The Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines were followed.

End Points

The primary end point was iDFS, defined according to STEEP (Standardized Definitions for Efficacy Endpoints) criteria, version 1.0 (eTable 1 in Supplement 2). Secondary end points included DDFS, recurrence-free survival (RFS), overall survival, safety, quality of life, and pharmacokinetics. Distant recurrence-free survival (DRFS) was an exploratory end point. Treatment-emergent adverse events (AEs) were monitored for 36 months or up to the last dose of ribociclib for patients who discontinued treatment early from the time of randomization plus an additional 30-day follow-up. Serious AEs were monitored throughout the trial. We used the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03, to grade AEs and serious AEs.

Statistical Analysis

Primary and secondary end points were evaluated using the Kaplan-Meier method. Hazard ratios were calculated using a stratified Cox proportional hazards model, which included 95% CIs. Efficacy analyses were performed in the intent-to-treat (ITT) population. Safety analyses were conducted in patients who received 1 or more doses of ribociclib or ET. SAS, version 9.4 (SAS Institute), was used to perform analyses.

Results

Patients and Treatment

Baseline patient characteristics were balanced across treatment arms. Among the 5101 patients included in the analysis, the median (range) age was 52 (24-90) years, 5081 patients (99.6%) were female, and 20 patients (0.4%) were male. At the data cutoff (April 29, 2024), all patients in the ribociclib plus NSAI arm (n = 2549) were no longer receiving ribociclib treatment: 1601 (62.8%) completed 3 years of ribociclib treatment, and 509 (20.0%) stopped taking ribociclib early due to AEs. Complete patient disposition details and therapy discontinuations are summarized in Table 1.

Table 1. Patient Disposition by Treatment Arm.

Characteristic	No. (%)
Characteristic	Ribociclib + NSAI (n = 2549)		NSAI alone (n = 2552)
Randomized	2549 (100)		2552 (100)
Treated	2526 (99.1)		2441 (95.7)
NSAI treatment ongoing	1794 (70.4)		1628 (63.8)
Completed 3-y ribociclib treatment	1601 (62.8)		NA
Completed 5-y study treatment	10 (0.4)		9 (0.4)
Treatment discontinuation	Ribociclib	NSAI	NSAI alone
Early discontinuation	923 (36.2)	722 (28.3)	804 (31.5)
Primary reason for early discontinuation
Adverse event^a	509 (20.0)	136 (5.3)	124 (4.9)
Disease relapse	127 (5.0)	196 (7.7)	267 (10.5)
Patient/physician decision	160 (6.3)	206 (8.1)	189 (7.4)
Lost to follow-up	8 (0.3)	15 (0.6)	21 (0.8)
Death	5 (0.2)	9 (0.4)	6 (0.2)
Other^b	114 (4.5)	160 (6.3)	197 (7.7)

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Abbreviations: NA, not applicable; NSAI, nonsteroidal aromatase inhibitor.

^{^a}

The most frequent adverse events leading to ribociclib discontinuation were alanine aminotransferase increase (all grades: 182 patients [7.2%]) and aspartate aminotransferase increase (all grades: 67 patients [2.7%]).

^{^b}

Other includes withdrawal by patient and protocol deviation, among other reasons.

For 901 patients (56.3%), it had been more than 1 year since completing ribociclib treatment. Median follow-up for iDFS was 44.2 months (range, 0-63 months). In the safety set, the mean (SD) relative dose intensity was 83.4% (19.7%), accounting for dose adjustments and dose holds and corresponding to a mean (SD) dose intensity of 333.58 (78.98) mg/d. The mean (SD) duration of exposure was 26.5 (13.7) months. Median duration of treatment was 35.7 months (range, 0-37.0 months) for ribociclib and 45.0 months (range, 0-60.8 months) for NSAI in the ribociclib plus NSAI arm and 44.7 months (range, 0-60.1 months) for NSAI alone. Ten of 2549 patients (0.4%) in the ribociclib plus NSAI arm and 9 of 2552 patients in the NSAI alone arm completed 5 years of study treatment, and 1794 (70.4%) and 1628 (63.8%), respectively, had NSAI treatment ongoing. NSAI discontinuations were most commonly due to recurrence in both arms (196 patients [7.7%] in the ribociclib plus NSAI arm vs 267 patients [10.5%] in the NSAI alone arm). Among patients who did not complete the planned 3-year ribociclib treatment duration, median time receiving treatment was 5.7 months (range, 0.03-35.5 months), with AEs being the primary reason for early discontinuation.

Efficacy

In this exploratory 4-year analysis, 603 iDFS events were documented; this includes an additional 94 events recorded since the protocol-specified final iDFS analysis.²¹ Of the 603 iDFS events, 263 (10.3%) were in the ribociclib plus NSAI arm and 340 (13.3%) were in the NSAI alone arm. With all patients no longer taking ribociclib, adjuvant ribociclib plus NSAI continued to demonstrate an iDFS benefit over NSAI alone, with a 28.5% reduction in the risk of iDFS events (hazard ratio, 0.72; 95% CI, 0.61-0.84; Figure 1). Three-year iDFS rates were 90.8% vs 88.1% (difference, 2.7 percentage points). Four-year iDFS rates were 88.5% with ribociclib plus NSAI and 83.6% with NSAI alone, representing a 4.9 (95% CI, 2.7-7.1) percentage point absolute iDFS benefit as the Kaplan-Meier curves continue to separate.

Figure 1. — The dashed lines at 36 and 48 months represent the planned 3-year treatment duration and 4-year exploratory treatment analysis, respectively. NSAI indicates nonsteroidal aromatase inhibitor.

A consistent iDFS benefit with ribociclib plus NSAI was also observed across subgroups (Figure 2). An absolute iDFS benefit at 4 years was seen regardless of stage or nodal status (eFigure 1 and eTable 2 in Supplement 2). iDFS benefit with ribociclib plus NSAI at 4 years was consistent regardless of prior ET (eFigure 2 and eTable 3 in Supplement 2).

Most iDFS events were distant recurrence, with 176 (6.9%) occurring in the ribociclib plus NSAI arm and 246 (9.6%) occurring in the NSAI alone arm (eTable 4 in Supplement 2). The most frequent disease-recurrence sites were bone and liver in both treatment arms.

Ribociclib plus NSAI demonstrated a consistent DDFS (hazard ratio, 0.72; 95% CI, 0.60-0.85; Figure 3A), RFS (hazard ratio, 0.70; 95% CI, 0.58-0.83; Figure 3B), and DRFS (hazard ratio, 0.71; 95% CI, 0.59-0.84; Figure 3C) benefit over NSAI alone in the ITT population. At the data cutoff, overall survival data were immature, although a trend for benefit with ribociclib plus NSAI over NSAI alone was observed (hazard ratio, 0.83; 95% CI, 0.64-1.07; Figure 3D).

The DDFS benefit at 4 years was consistent across other clinically relevant subgroups, including menopausal status and Ki-67 status (eFigure 3 in Supplement 2). The DDFS benefit with ribociclib plus NSAI was consistent across anatomic stages (stage IIA: hazard ratio, 0.40; 95% CI, 0.22-0.72; stage IIB: hazard ratio, 0.81; 95% CI, 0.52-1.24; stage IIIA: hazard ratio, 0.70; 95% CI, 0.52-0.93; stage IIIB: hazard ratio, 0.57; 95% CI, 0.33-0.99; stage IIIC: hazard ratio, 0.88; 95% CI, 0.65-1.19; eFigure 3 in Supplement 2). The absolute DDFS benefit with ribociclib plus NSAI vs NSAI alone at 4 years was 5.1% for stage IIA, 2.6% for stage IIB, 4.6% for stage IIIA, 11.4% for stage IIIB, and 4.5% for stage IIIC. A consistent DDFS benefit was observed with ribociclib plus NSAI regardless of nodal status (N0: hazard ratio, 0.70; 95% CI, 0.40-1.20; node positive: hazard ratio, 0.73; 95% CI, 0.61-0.87; eFigure 3 in Supplement 2), with 4-year absolute DDFS benefit of 4.2% in the N0 subgroup and 4.6% in the node-positive subgroup. A consistent DDFS benefit with ribociclib plus NSAI was observed regardless of prior ET (eFigure 4 in Supplement 2).

Safety

No new safety signals were observed with additional follow-up. At least 1 treatment-emergent AE occurred in 2478 patients (98.1%) in the ribociclib plus NSAI arm vs 2155 patients (88.3%) in the NSAI alone arm. Serious AEs occurred in 375 patients (14.8%) in the ribociclib plus NSAI arm vs 267 patients (10.9%) in the NSAI alone arm.

Consistent with prior analyses, the most common all-grade AEs in the ribociclib plus NSAI arm were neutropenia, arthralgia, and nausea (Table 2). Liver-related AEs were predominantly alanine aminotransferase or aspartate aminotransferase elevations without concomitant bilirubin increase. All-grade QT interval prolongation events occurred in 136 patients (5.4%) in the ribociclib plus NSAI arm vs 38 patients (1.6%) in the NSAI alone arm. Grade 3 or higher QT interval prolongation events were rare (25 patients [1.0%] with ribociclib plus NSAI vs 17 patients [0.7%] with NSAI alone).

Table 2. Adverse Events by Treatment Arm.

Adverse event^a	No. (%)
	Ribociclib + NSAI (n = 2526)				NSAI only (n = 2441)
	All grades	Grade 3	Grade 4	Grade 5	All grades	Grade 3	Grade 4	Grade 5
Treatment-emergent adverse event	2478 (98.1)	1471 (58.2)	140 (5.5)	11 (0.4)	2155 (88.3)	437 (17.9)	40 (1.6)	4 (0.2)
Neutropenia^b	1587 (62.8)	1065 (42.2)	56 (2.2)	0	111 (4.5)	18 (0.7)	3 (0.1)	0
Arthralgia	979 (38.8)	25 (1.0)	0	0	1083 (44.4)	31 (1.3)	0	0
Nausea	594 (23.5)	6 (0.2)	0	0	192 (7.9)	1 (<0.1)	0	0
Headache	579 (22.9)	11 (0.4)	0	0	420 (17.2)	4 (0.2)	0	0
Fatigue	575 (22.8)	21 (0.8)	0	0	329 (13.5)	4 (0.2)	0	0
COVID-19^c	569 (22.5)	17 (0.7)	0	3 (0.1)	358 (14.7)	11 (0.5)	0	1 (<0.1)
SARS-CoV-2 positive test^c	550 (21.8)	1 (<0.1)	0	0	340 (13.9)	0	0	0
Alanine aminotransferase increase	497 (19.7)	161 (6.4)	33 (1.3)	0	140 (5.7)	16 (0.7)	1 (<0.1)	0
Hot flush	492 (19.5)	6 (0.2)	0	0	493 (20.2)	3 (0.1)	0	0
Aspartate aminotransferase increase	434 (17.2)	101 (4.0)	16 (0.6)	0	143 (5.9)	14 (0.6)	0	0
Asthenia	426 (16.9)	15 (0.6)	0	0	293 (12.0)	3 (0.1)	0	0
Alopecia	386 (15.3)	0	0	0	113 (4.6)	0	0	0

Open in a new tab

Abbreviation: NSAI, nonsteroidal aromatase inhibitor.

^{^a}

At least 15% in either treatment arm.

^{^b}

This is a grouped term that combines neutropenia and neutrophil count decrease.

^{^c}

There is overlap between cases of COVID-19 and SARS CoV-2–positive tests.

At the time of this analysis, 687 patients (27.2%) required a ribociclib dose reduction, with the primary reason being AEs (582 patients [23.0%]). Early discontinuation due to AEs occurred in 509 patients (20.0%) in the ribociclib plus NSAI arm, representing a less than 1% increase from the protocol-specified final iDFS analysis (498 patients [19.5%]). The most frequent AEs leading to ribociclib discontinuation were alanine aminotransferase increase (all grades: 182 patients [7.2%]) and aspartate aminotransferase increase (all grades: 67 patients [2.7%]). Reasons for on-treatment deaths have been previously published, and no additional on-treatment deaths occurred since the protocol-specified final iDFS analysis.¹⁰

Discussion

This exploratory 4-year analysis demonstrated a consistent iDFS benefit with ribociclib plus NSAI with additional follow-up, with a 28.5% reduction in the risk of recurrence over NSAI alone and confidence intervals that continue to narrow. The absolute improvement in iDFS with ribociclib plus NSAI continued to increase from 2.7% at 3 years to 4.9% at 4 years. The iDFS, DDFS, RFS, and DRFS benefits were observed with ribociclib plus NSAI over NSAI alone beyond the planned 3-year ribociclib treatment duration, as all patients were no longer receiving ribociclib treatment at the data cutoff. A sustained iDFS benefit with ribociclib plus NSAI was seen across subgroups, including anatomic stage and nodal status, with a consistent reduction in risk of distant recurrences across subgroups. The safety profile remained unchanged with additional follow-up.

In prior analyses, an iDFS benefit was observed with ribociclib plus NSAI over NSAI alone.^10,21 However, at the time of those analyses, all patients had not yet discontinued ribociclib treatment (54.0% in the second interim efficacy analysis and 78.3% in the protocol-specified final analysis were no longer receiving treatment).^10,21 Thus, the efficacy of ribociclib beyond the planned treatment period was unknown. In this analysis, all patients had stopped ribociclib treatment, with 62.8% of patients having completed the planned 3-year treatment duration. At 4 years, the absolute improvement in iDFS increased and the Kaplan-Meier curves continue to separate with additional follow-up, suggesting a persistent benefit of adjuvant ribociclib beyond the planned 3-year treatment duration.

An iDFS benefit was observed with ribociclib plus NSAI over NSAI alone in patients with high-risk N0 disease. While this subgroup of patients in NATALEE do not have nodal involvement, enrolled patients with stage IIA node-negative (T2N0) disease were required to have additional high-risk features, including grade 3 disease or grade 2 disease with Ki-67 20% or higher or high genomic risk. Previous meta-analyses and population-based studies have shown risk of recurrence across patients with and without nodal involvement; however, many of the patient samples in these studies were enrolled decades prior to the follow-up analyses.^5,24 The cohorts in these long-term studies may not be reflective of contemporary treatment standards, which has the potential to overinflate the recurrence risk among some subgroups. Updated analyses from these long-term studies have also demonstrated that patients diagnosed and treated after 2000 have a lower risk of recurrence compared with those diagnosed and treated before 2000.⁷ A recent empirical analysis demonstrated risk of overall recurrences (any locoregional or distant recurrence, excluding mortality as an event) and distant recurrences (any event involving distant recurrence only, excluding mortality as an event) at the 3-year and 7-year time points for patients with N0 high-risk disease (3 years: 8.1% and 6.0%; 7 years: 16.9% and 13.6%), N1 disease (3 years: 7.5% and 5.5%; 7 years: 17.1% and 13.7%), and N2-3 disease (3 years: 21.7% and 19.7%; 7 years: 43.7% and 40.1%).²⁵ The risk of recurrence observed in the N0 high-risk group, which was defined using the same eligibility criteria as NATALEE (T4N0, T3N0, or T2N0 with additional criteria [grade 2 with Ki-67 ≥20% or high genomic risk, or grade 3]), was comparable to that for patients with N1 disease. Similarly, in this analysis of NATALEE, 3-year iDFS rates in the control arm in the N0 subgroup underscored the risk of recurrence in this patient population, with 9.2% of patients having an iDFS event at 3 years and 13.0% having an iDFS event at 4 years. These results demonstrate that patients with N0 disease have a risk of recurrence and adding ribociclib to adjuvant NSAI is beneficial to these patients. It is important to consider that the majority of patients with HR-positive/ERBB2-negative EBC who experience recurrence have distant metastatic disease, which is currently incurable.^8,9,10,11 Thus, understanding the impact of adjuvant treatment on reducing these events is critical. In NATALEE, the majority of iDFS events recorded were distant recurrences, which were more common in the NSAI alone arm. This analysis demonstrated improvement in DDFS with ribociclib beyond the 3-year treatment window in the ITT population and across multiple patient subgroups, including nodal status, anatomic stage, menopausal status, and Ki-67 status. With all patients no longer taking ribociclib in NATALEE, the risk of distant recurrence was reduced by 30.4% in the N0 population and by 27.4% in the node-positive population, with an absolute benefit of approximately 4% to 5% with ribociclib plus NSAI vs NSAI alone at 4 years regardless of nodal status. Ribociclib plus NSAI also improved DRFS in the ITT population. Given the recurrence risk among all subgroups and the DDFS and DRFS benefit with ribociclib, the results from NATALEE support the escalation of adjuvant treatment in a broad population of patients with HR-positive/ERBB2-negative EBC at risk of recurrence, including those with high-risk N0 disease.

Patients with high-risk node-positive HR-positive/ERBB2-negative EBC may be eligible for adjuvant ribociclib or adjuvant abemaciclib.^26,27,28,29 As such, differences in these treatment regimens should be considered when making clinical decisions. Abemaciclib was approved in patients with high-risk node-positive disease in 2023 for continuous dosing at 150 mg twice daily for a total of 300 mg/d, the same starting dose used in the ABC setting, for a duration of 2 years, whereas ribociclib was approved in 2024 in patients with both high-risk node-negative and node-positive disease and is dosed 3 weeks on, 1 week off at 400 mg, which is a lower starting dose than that used in the ABC setting (600 mg), for a duration of 3 years. The duration of CDK4/6 inhibition with adjuvant ribociclib in NATALEE was selected to prolong cell cycle arrest and increase the likelihood of driving more tumor cells into irreversible senescence. Extended cell cycle arrest may decrease recurrences that can occur up to 20 years after diagnosis as a result of circulating tumor cells.^{6,24,30,31,32} Given that approximately 50% of recurrences occur beyond 5 years, prolongation of CDK4/6 inhibition may be critical to prevent these events.^4,6 Additionally, the 400-mg starting dose of adjuvant ribociclib in NATALEE was selected with the objective of improving safety and adherence while maintaining efficacy. The results from this exploratory 4-year analysis continue to support that the 3-year duration of adjuvant ribociclib plus NSAI reduces the risk of disease recurrence over NSAI alone regardless of nodal status, with absolute iDFS and DDFS benefit at 4 years. Data with longer follow-up will be critical to evaluate the long-term impact of adjuvant CDK4/6i on reducing recurrences. Protocol-specified analyses are planned at 5 and 6 years, including a descriptive analyses of overall survival at both time points.

No new safety signals were identified with additional follow-up of NATALEE. In this exploratory 4-year analysis, the rates of the most frequent AEs and AEs of special interest, such as liver-related AEs and QT interval prolongation, increased by less than 0.5% since the prior analysis.^10,21 Ribociclib discontinuations due to AEs increased by only 0.5% compared with the prior analysis (20.0% vs 19.5%).²¹ Prior analyses of safety in NATALEE demonstrated that most AEs occurred early in treatment, with the median time to dose reduction and discontinuation due to AEs being 3 and 4 months, respectively.³³ Importantly, dose reductions did not appear to impact efficacy. Thus, with prompt identification and management, patients can continue treatment and maximize their benefit with ribociclib. Consistent with prior NATALEE analyses, these results demonstrated that 3 years of treatment with adjuvant ribociclib was tolerable with no new safety signals. Based on the consistent benefit and tolerable safety profile observed in NATALEE, adjuvant ribociclib received regulatory approval by the US Food and Drug Administration and the European Medicines Agency for patients with stage II or III HR-positive/ERBB2-negative EBC at high risk of recurrence.

Limitations

This study has some limitations. First, this is an exploratory analysis of the NATALEE trial and was thus not powered for formal statistical assessment. Additionally, analyses with longer follow-up will be needed to further characterize the long-term impact of adjuvant ribociclib on reducing recurrences.

Conclusions

In this exploratory 4-year analysis of the NATALEE randomized clinical trial, a consistent benefit was shown over time for ribociclib plus NSAI over NSAI alone in a broad population of patients with HR-positive/ERBB2-negative EBC, which continues beyond the specified treatment duration.

Supplement 1.

Trial Protocol

jamaoncol-e253700-s001.pdf^{(5.6MB, pdf)}

Supplement 2.

eTable 1. Trial endpoint definitions

eTable 2. Three- and four-year iDFS rates by stage and nodal status

eTable 3. Three- and four-year iDFS rates by prior ET

eTable 4. Type and site of first invasive disease–free survival event

eFigure 1. iDFS across subgroups

eFigure 2. iDFS by prior ET

eFigure 3. DDFS by subgroups

eFigure 4. DDFS by prior ET

eFigure 5. CONSORT Diagram

jamaoncol-e253700-s002.pdf^{(1.3MB, pdf)}

Supplement 3.

Data Sharing Statement

jamaoncol-e253700-s003.pdf^{(17.9KB, pdf)}

References

1.Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5):dju055. doi: 10.1093/jnci/dju055 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Davies C, Godwin J, Gray R, et al. ; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) . Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771-784. doi: 10.1016/S0140-6736(11)60993-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Pan H, Gray R, Braybrooke J, et al. ; EBCTCG . 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846. doi: 10.1056/NEJMoa1701830 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Gomis RR, Gawrzak S. Tumor cell dormancy. Mol Oncol. 2017;11(1):62-78. doi: 10.1016/j.molonc.2016.09.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Pedersen RN, Mellemkjær L, Ejlertsen B, Nørgaard M, Cronin-Fenton DP. Mortality after late breast cancer recurrence in Denmark. J Clin Oncol. 2022;40(13):1450-1463. doi: 10.1200/JCO.21.02062 [DOI] [PubMed] [Google Scholar]
6.Foldi J, O’Meara T, Marczyk M, Sanft T, Silber A, Pusztai L. Defining risk of late recurrence in early-stage estrogen receptor-positive breast cancer: clinical versus molecular tools. J Clin Oncol. 2019;37(16):1365-1369. doi: 10.1200/JCO.18.01933 [DOI] [PubMed] [Google Scholar]
7.Early Breast Cancer Trialists’ Collaborative Group . Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analysis of 155 746 women in 151 trials. Lancet. 2024;404(10461):1407-1418. doi: 10.1016/S0140-6736(24)01745-8 [DOI] [PubMed] [Google Scholar]
8.Johnston SRD, Toi M, O’Shaughnessy J, et al. ; monarchE Committee Members . Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77-90. doi: 10.1016/S1470-2045(22)00694-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Gnant M, Dueck AC, Frantal S, et al. ; PALLAS groups and investigators . Adjuvant palbociclib for early breast cancer: the PALLAS trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40(3):282-293. doi: 10.1200/JCO.21.02554 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med. 2024;390(12):1080-1091. doi: 10.1056/NEJMoa2305488 [DOI] [PubMed] [Google Scholar]
11.Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) . Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341-1352. doi: 10.1016/S0140-6736(15)61074-1 [DOI] [PubMed] [Google Scholar]
12.Başaran GA, Twelves C, Diéras V, Cortés J, Awada A. Ongoing unmet needs in treating estrogen receptor-positive/HER2-negative metastatic breast cancer. Cancer Treat Rev. 2018;63:144-155. doi: 10.1016/j.ctrv.2017.12.002 [DOI] [PubMed] [Google Scholar]
13.Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-1748. doi: 10.1056/NEJMoa1609709 [DOI] [PubMed] [Google Scholar]
14.Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386(10):942-950. doi: 10.1056/NEJMoa2114663 [DOI] [PubMed] [Google Scholar]
15.Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472. doi: 10.1200/JCO.2018.78.9909 [DOI] [PubMed] [Google Scholar]
16.Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514-524. doi: 10.1056/NEJMoa1911149 [DOI] [PubMed] [Google Scholar]
17.Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-915. doi: 10.1016/S1470-2045(18)30292-4 [DOI] [PubMed] [Google Scholar]
18.Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi: 10.1056/NEJMoa1903765 [DOI] [PubMed] [Google Scholar]
19.Rastogi P, O’Shaughnessy J, Martin M, et al. Adjuvant abemaciclib plus endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, high-risk early breast cancer: results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. J Clin Oncol. 2024;42(9):987-993. doi: 10.1200/JCO.23.01994 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(17)(suppl):LBA500. doi: 10.1200/JCO.2023.41.17_suppl.LBA500 [DOI] [Google Scholar]
21.Hortobagyi GN, Lacko A, Sohn J, et al. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2025;36(2):149-157. doi: 10.1016/j.annonc.2024.10.015 [DOI] [PubMed] [Google Scholar]
22.Slamon DJ, Fasching PA, Hurvitz S, et al. Rationale and trial design of NATALEE: a phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer. Ther Adv Med Oncol. 2023;15:17588359231178125. doi: 10.1177/17588359231178125 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-99. doi: 10.3322/caac.21388 [DOI] [PubMed] [Google Scholar]
24.Pan H, Gray R, Braybrooke J, et al. ; EBCTCG . 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846. doi: 10.1056/NEJMoa1701830 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Jhaveri K, Pegram M, Neven P, et al. Real-world evidence on risk of recurrence in patients with node-negative and node-positive HR+/HER2− early breast cancer from US electronic health records. Poster presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain. Accessed August 19, 2025. https://www.medicalcongresspresentations.com/ESMO24/BC/pdf/292P_Poster.pdf
26.Kisqali. Prescribing information. Novartis; 2017.
27.Kisqali. Prescribing information. Novartis Europharm; 2024.
28.Verzenio. Prescribing information. Eli Lilly and Company; 2017.
29.Verzenios. Prescribing information. Eli Lilly Nederland BV; 2022.
30.Bria E, Carlini P, Cuppone F, Vaccaro V, Milella M, Cognetti F. Early recurrence risk: aromatase inhibitors versus tamoxifen. Expert Rev Anticancer Ther. 2010;10(8):1239-1253. doi: 10.1586/era.10.54 [DOI] [PubMed] [Google Scholar]
31.Hess KR, Pusztai L, Buzdar AU, Hortobagyi GN. Estrogen receptors and distinct patterns of breast cancer relapse. Breast Cancer Res Treat. 2003;78(1):105-118. doi: 10.1023/A:1022166517963 [DOI] [PubMed] [Google Scholar]
32.Zhang XH, Giuliano M, Trivedi MV, Schiff R, Osborne CK. Metastasis dormancy in estrogen receptor–positive breast cancer. Clin Cancer Res. 2013;19(23):6389-6397. doi: 10.1158/1078-0432.CCR-13-0838 [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Barrios CH, Harbeck N, Hortobagyi GN, et al. NATALEE update: safety and treatment (tx) duration of ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2− early breast cancer (EBC). ESMO Open. 2024;9(suppl 4):103101. doi: 10.1016/j.esmoop.2024.103101 [DOI] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

jamaoncol-e253700-s001.pdf^{(5.6MB, pdf)}

Supplement 2.

eTable 1. Trial endpoint definitions

eTable 2. Three- and four-year iDFS rates by stage and nodal status

eTable 3. Three- and four-year iDFS rates by prior ET

eTable 4. Type and site of first invasive disease–free survival event

eFigure 1. iDFS across subgroups

eFigure 2. iDFS by prior ET

eFigure 3. DDFS by subgroups

eFigure 4. DDFS by prior ET

eFigure 5. CONSORT Diagram

jamaoncol-e253700-s002.pdf^{(1.3MB, pdf)}

Supplement 3.

Data Sharing Statement

jamaoncol-e253700-s003.pdf^{(17.9KB, pdf)}

[coi250058r1] 1.Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5):dju055. doi: 10.1093/jnci/dju055 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250058r2] 2.Davies C, Godwin J, Gray R, et al. ; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) . Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771-784. doi: 10.1016/S0140-6736(11)60993-8 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250058r3] 3.Pan H, Gray R, Braybrooke J, et al. ; EBCTCG . 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846. doi: 10.1056/NEJMoa1701830 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250058r4] 4.Gomis RR, Gawrzak S. Tumor cell dormancy. Mol Oncol. 2017;11(1):62-78. doi: 10.1016/j.molonc.2016.09.009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250058r5] 5.Pedersen RN, Mellemkjær L, Ejlertsen B, Nørgaard M, Cronin-Fenton DP. Mortality after late breast cancer recurrence in Denmark. J Clin Oncol. 2022;40(13):1450-1463. doi: 10.1200/JCO.21.02062 [DOI] [PubMed] [Google Scholar]

[coi250058r6] 6.Foldi J, O’Meara T, Marczyk M, Sanft T, Silber A, Pusztai L. Defining risk of late recurrence in early-stage estrogen receptor-positive breast cancer: clinical versus molecular tools. J Clin Oncol. 2019;37(16):1365-1369. doi: 10.1200/JCO.18.01933 [DOI] [PubMed] [Google Scholar]

[coi250058r7] 7.Early Breast Cancer Trialists’ Collaborative Group . Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analysis of 155 746 women in 151 trials. Lancet. 2024;404(10461):1407-1418. doi: 10.1016/S0140-6736(24)01745-8 [DOI] [PubMed] [Google Scholar]

[coi250058r8] 8.Johnston SRD, Toi M, O’Shaughnessy J, et al. ; monarchE Committee Members . Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77-90. doi: 10.1016/S1470-2045(22)00694-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250058r9] 9.Gnant M, Dueck AC, Frantal S, et al. ; PALLAS groups and investigators . Adjuvant palbociclib for early breast cancer: the PALLAS trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40(3):282-293. doi: 10.1200/JCO.21.02554 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250058r10] 10.Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med. 2024;390(12):1080-1091. doi: 10.1056/NEJMoa2305488 [DOI] [PubMed] [Google Scholar]

[coi250058r11] 11.Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) . Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341-1352. doi: 10.1016/S0140-6736(15)61074-1 [DOI] [PubMed] [Google Scholar]

[coi250058r12] 12.Başaran GA, Twelves C, Diéras V, Cortés J, Awada A. Ongoing unmet needs in treating estrogen receptor-positive/HER2-negative metastatic breast cancer. Cancer Treat Rev. 2018;63:144-155. doi: 10.1016/j.ctrv.2017.12.002 [DOI] [PubMed] [Google Scholar]

[coi250058r13] 13.Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-1748. doi: 10.1056/NEJMoa1609709 [DOI] [PubMed] [Google Scholar]

[coi250058r14] 14.Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386(10):942-950. doi: 10.1056/NEJMoa2114663 [DOI] [PubMed] [Google Scholar]

[coi250058r15] 15.Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472. doi: 10.1200/JCO.2018.78.9909 [DOI] [PubMed] [Google Scholar]

[coi250058r16] 16.Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514-524. doi: 10.1056/NEJMoa1911149 [DOI] [PubMed] [Google Scholar]

[coi250058r17] 17.Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-915. doi: 10.1016/S1470-2045(18)30292-4 [DOI] [PubMed] [Google Scholar]

[coi250058r18] 18.Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi: 10.1056/NEJMoa1903765 [DOI] [PubMed] [Google Scholar]

[coi250058r19] 19.Rastogi P, O’Shaughnessy J, Martin M, et al. Adjuvant abemaciclib plus endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, high-risk early breast cancer: results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. J Clin Oncol. 2024;42(9):987-993. doi: 10.1200/JCO.23.01994 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250058r20] 20.Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(17)(suppl):LBA500. doi: 10.1200/JCO.2023.41.17_suppl.LBA500 [DOI] [Google Scholar]

[coi250058r21] 21.Hortobagyi GN, Lacko A, Sohn J, et al. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2025;36(2):149-157. doi: 10.1016/j.annonc.2024.10.015 [DOI] [PubMed] [Google Scholar]

[coi250058r22] 22.Slamon DJ, Fasching PA, Hurvitz S, et al. Rationale and trial design of NATALEE: a phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer. Ther Adv Med Oncol. 2023;15:17588359231178125. doi: 10.1177/17588359231178125 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250058r23] 23.Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-99. doi: 10.3322/caac.21388 [DOI] [PubMed] [Google Scholar]

[coi250058r24] 24.Pan H, Gray R, Braybrooke J, et al. ; EBCTCG . 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846. doi: 10.1056/NEJMoa1701830 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250058r25] 25.Jhaveri K, Pegram M, Neven P, et al. Real-world evidence on risk of recurrence in patients with node-negative and node-positive HR+/HER2− early breast cancer from US electronic health records. Poster presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain. Accessed August 19, 2025. https://www.medicalcongresspresentations.com/ESMO24/BC/pdf/292P_Poster.pdf

[coi250058r26] 26.Kisqali. Prescribing information. Novartis; 2017.

[coi250058r27] 27.Kisqali. Prescribing information. Novartis Europharm; 2024.

[coi250058r28] 28.Verzenio. Prescribing information. Eli Lilly and Company; 2017.

[coi250058r29] 29.Verzenios. Prescribing information. Eli Lilly Nederland BV; 2022.

[coi250058r30] 30.Bria E, Carlini P, Cuppone F, Vaccaro V, Milella M, Cognetti F. Early recurrence risk: aromatase inhibitors versus tamoxifen. Expert Rev Anticancer Ther. 2010;10(8):1239-1253. doi: 10.1586/era.10.54 [DOI] [PubMed] [Google Scholar]

[coi250058r31] 31.Hess KR, Pusztai L, Buzdar AU, Hortobagyi GN. Estrogen receptors and distinct patterns of breast cancer relapse. Breast Cancer Res Treat. 2003;78(1):105-118. doi: 10.1023/A:1022166517963 [DOI] [PubMed] [Google Scholar]

[coi250058r32] 32.Zhang XH, Giuliano M, Trivedi MV, Schiff R, Osborne CK. Metastasis dormancy in estrogen receptor–positive breast cancer. Clin Cancer Res. 2013;19(23):6389-6397. doi: 10.1158/1078-0432.CCR-13-0838 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250058r33] 33.Barrios CH, Harbeck N, Hortobagyi GN, et al. NATALEE update: safety and treatment (tx) duration of ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2− early breast cancer (EBC). ESMO Open. 2024;9(suppl 4):103101. doi: 10.1016/j.esmoop.2024.103101 [DOI] [Google Scholar]

PERMALINK

Ribociclib Plus Endocrine Therapy in Hormone Receptor–Positive/ERBB2-Negative Early Breast Cancer

Peter A Fasching, MD

Daniil Stroyakovskiy, MD, PhD

Denise A Yardley, MD

Chiun-Sheng Huang, MD

John Crown, MD

Aditya Bardia, MD

Stephen Chia, MD

Seock-Ah Im, MD, PhD

Miguel Martin, MD, PhD

Binghe Xu, MD, PhD

Sherene Loi, MD, PhD

Carlos Barrios, MD

Michael Untch, MD, PhD

Rebecca Moroose, MD

Frances Visco, JD

Gabriel N Hortobagyi, MD

Dennis J Slamon, MD, PhD

Rodrigo Fresco, MD

Juan Pablo Zarate, MD

Zheng Li, PhD

Sorcha Waters, PhD

Sara A Hurvitz, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design and Patients

End Points

Statistical Analysis

Results

Patients and Treatment

Table 1. Patient Disposition by Treatment Arm.

Efficacy

Figure 1. Invasive Disease-Free Survival in the Intent-to-Treat Population.

Figure 2. Forest Plot of Invasive Disease-Free Survival (iDFS) Across Clinically Relevant Subgroups.

Figure 3. Survival Outcomes in the Intent-to-Treat Population.

Safety

Table 2. Adverse Events by Treatment Arm.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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