ASCO Perspective 

“While early, these results are very promising and suggest that there will be a role for adjuvant ribociclib for stage II and higher hormone receptor-positive (HR-positive), HER2-negative breast cancer,” said Rita Nanda, MD, ASCO Expert. 

ALEXANDRIA, Va. — Adding the targeted therapy drug ribociclib (Kisqali^®) to hormonal (endocrine) therapy showed a significant improvement in invasive disease-free survival (iDFS) for people with HR-positive, HER2-negative early-stage breast cancer. The research will be presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

HR-positive, HER2-negative breast cancer is the most common subtype of the disease, making up nearly 70% of all breast cancer cases in the United States.¹

Study at a Glance 

Key Findings 

Study participants were randomly assigned to receive either adjuvant ribociclib for 3 years with hormonal therapy for at least 5 years or hormonal therapy alone. At a median follow-up of 34 months, 20.2% of participants in the ribociclib group had completed 3 years of treatment and 56.8% had completed 2 years of treatment. Overall, 74.7% of participants remained on the study treatment at data cutoff, with 1,984 patients on ribociclib and 1,826 patients on hormonal therapy alone.

The study found that adding ribociclib to hormonal therapy led to a significant improvement in iDFS compared with hormonal therapy alone. Researchers evaluated iDFS after 426 iDFS events occurred, a number that was prespecified for the interim analysis. Of those events, 189 occurred in the ribociclib group (7.4% of patients) vs. 237 in the hormonal therapy alone group (9.2% of patients). The 3-year iDFS rates were 90.4% in the ribociclib group compared with 87.1% in the hormonal therapy alone group. Overall, the addition of ribociclib reduced the risk for recurrence by 25%. The iDFS benefit seen in the ribociclib group was generally consistent across clinically relevant patient subgroups. Ribociclib also showed more favorable outcomes in overall survival, recurrence-free survival, and distant disease-free survival.

For patients receiving ribociclib, the most common adverse effects were neutropenia and joint pain. Rates of gastrointestinal adverse effects and fatigue were low in patients receiving ribociclib. For patients receiving hormonal therapy alone, the most common adverse effects were joint pain and hot flash.

“Currently approved targeted treatments can only be used in a small population of patients diagnosed with HR-positive, HER2-negative early breast cancer, leaving many without an effective treatment option for reducing risk of the cancer returning,” said lead author Dennis J. Slamon, MD, PhD, Director of Clinical/Translational Research and Director of the Revlon/UCLA Women's Cancer Research Program at the UCLA Jonsson Comprehensive Cancer Center in Los Angeles, California. “Thus, there is a significant unmet need for both reducing the risk of recurrence and providing a tolerable treatment option that keeps patients cancer-free without disrupting their daily life. The NATALEE study investigated the addition of ribociclib to standard-of-care adjuvant endocrine therapy and was specifically designed to address these unmet needs.”

HR-positive breast cancer makes up about two-thirds of breast cancers and is more common after menopause.² According to the authors, about one-third of people with stage II HR-positive, HER2-negative disease experience a recurrence following standard-of-care treatment and more than one-half of people with stage III disease experience a recurrence. If a recurrence occurs, it is often at a more advanced stage.

Ribociclib is a type of targeted therapy called a small molecule inhibitor. It works by targeting proteins in breast cancer cells called CDK4 and CDK6, which modulate cell growth, including the growth of cancer cells. Ribociclib is currently approved by the U.S. Food and Drug Administration to treat HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor for premenopausal people or in combination with fulvestrant for postmenopausal people. While ribociclib has previously shown survival benefits in people with metastatic disease, in this study, researchers showed that it may also improve outcomes for people with earlier-stage disease, including those with cancer that has not yet spread to the lymph nodes.

About the Study 

The NATALEE phase III clinical trial included men and premenopausal or postmenopausal women from 20 different countries with stage IIA, IIB, or III HR-positive, HER2-negative breast cancer at risk for recurrence. Participants were randomly assigned to receive either 400 milligrams (mg) of adjuvant ribociclib for 3 years with hormonal therapy for at least 5 years (2,549 patients) or hormonal therapy alone for at least 5 years (2,552 patients). Men and premenopausal women also received goserelin (Zoladex), an ovarian suppression drug. Prior hormonal therapy use was allowed if it was initiated no more than 1 year before the start of the study.

The current recommended starting dose of ribociclib for people with metastatic disease is 600 mg. However, an extended duration of treatment can help to stop cells from duplicating and dividing and destroy any remaining cancer cells. Because of this, study authors chose a 3-year treatment duration of ribociclib at a dose of 400 mg to reduce side effects while maintaining efficacy.

Next Steps  

Researchers will continue to evaluate how the addition of ribociclib to hormonal therapy impacts quality of life and will follow patients to observe long-term outcomes.

The study was funded by Novartis Pharmaceuticals Corporation.

View the full embargoed abstract: 

LBA500: Phase III NATALEE trial of ribociclib + endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer.  

Authors: Dennis J. Slamon, Daniil Stroyakovskiy, Denise A. Yardley, Chiun-Sheng Huang, Peter A. Fasching, John Crown, Aditya Bardia, Stephen Chia, Seock-Ah Im, Miguel Martin, Sherene Loi, Binghe Xu, Sara A. Hurvitz, Carlos Barrios, Michael Untch, Rebecca L. Moroose, Fran Visco, Rodrigo Fresco, Tetiana Taran, Gabriel N. Hortobagyi; David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA; Moscow City Oncology Hospital No.62, Moscow, Russian Federation; Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN; National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taipei, Taiwan; University Hospital Erlangen, Comprehensive Cancer Center (CCC) Erlangen-EMN, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; St. Vincent's University Hospital, Dublin, Ireland; Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; British Columbia Cancer Agency, Vancouver, BC; Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Instituto de Investigación Sanitaria Gregorio Marañon, Centro de Investigación Biomédica en Red de Cáncer, Grupo Español de Investigación en Cáncer de Mama, Universidad Complutense, Madrid, Spain; Peter MacCallum Cancer Centre, Melbourne, Australia; Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; University of California Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA; Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Brazil; Interdisciplinary Breast Cancer Center, Helios Klinikum Berlin-Buch, Berlin, Germany; Orlando Health Cancer Institute, Orlando, FL; National Breast Cancer Coalition, Washington, DC; TRIO - Translational Research in Oncology, Montevideo, Uruguay; Novartis Pharma AG, Basel, Switzerland; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 

Background: RIB + ET has demonstrated significant survival benefits in pre- and postmenopausal pts with HR+/HER2− metastatic BC. To investigate whether RIB + ET also improves outcomes in early BC (EBC), the Phase III NATALEE trial (NCT03701334) evaluated adjuvant RIB + ET in a broad population of pts with stage II or III HR+/HER2− EBC at risk for recurrence, including pts with no nodal involvement (N0). As extended duration of tx is crucial to prolong cell cycle arrest and drive more tumor cells into senescence or death, a 3-y duration of RIB tx at a dose of 400 mg was chosen to improve tolerability while maintaining efficacy. Results from a prespecified interim analysis of invasive disease–free survival (iDFS; primary endpoint) are presented.  Methods: Men and pre- or postmenopausal women were randomized 1:1 to RIB (400 mg/day; 3 wk on/1 wk off for 3 y) + ET (letrozole 2.5 mg/day or anastrozole 1 mg/day, for ≥ 5 y) or ET alone. Men and premenopausal women also received goserelin. Eligible pts had an ECOG PS of 0-1 and BC anatomic stage IIA (either N0 with additional risk factors or 1-3 axillary lymph nodes [N1]), stage IIB, or stage III per AJCC (8th ed); prior (neo)adjuvant ET was allowed if initiated ≤ 12 mo before randomization. Stratification factors were menopausal status, disease stage, prior (neo)adjuvant chemotherapy, and geographic region. This prespecified interim analysis of iDFS, defined per STEEP criteria, was planned after ≈ 425 iDFS events (≈ 85% of planned total events). iDFS was evaluated by Kaplan-Meier methods, and statistical comparison was made by a stratified log-rank test, with a protocol-defined Lan-DeMets (O'Brien-Flemming) stopping boundary of a 1-sided P < .0128 for superior efficacy.  Results: From 10 Jan 2019 to 20 April 2021, 5101 pts were randomized (RIB+ET, n = 2549; ET alone, n = 2552). As of the data cutoff (11 Jan 2023), median follow-up was 34 mo (min, 21 mo). 3- and 2-y RIB tx was completed by 515 pts (20.2%) and1449 pts (56.8%), respectively; 3810 (74.7%) remained on study tx (RIB+ET, n = 1984; ET alone, n = 1826). iDFS was evaluated after 426 events (RIB + ET, n = 189; ET alone, n = 237). RIB + ET demonstrated significantly longer iDFS than ET alone (HR, 0.748; 95% CI, 0.618-0.906; P = .0014); 3-y iDFS rates were 90.4% vs 87.1%. iDFS benefit was generally consistent across stratification factors and other subgroups. Secondary endpoints of overall survival, recurrence-free survival, and distant disease–free survival consistently favored RIB. RIB at 400 mg had a favorable safety profile with no new signals.  Conclusions: Ribociclib added to standard-of-care ET demonstrated a statistically significant, clinically meaningful improvement in iDFS with a well-tolerated safety profile. The NATALEE results support ribociclib + ET as the treatment of choice in a broad population of pts with stage II or III HR+/HER2− EBC, including pts with N0 disease.

View disclosures for:  

• Authors – in the abstract (will be available on May 30)
• ASCO Cancer Communications Committee 
• Dr. Nanda
• Dr. Gralow

For your readers: 

• Breast Cancer: Types of Treatment
• What is Targeted Therapy?
• What Is Hormone Therapy 

References:

1. Cancer Stat Facts: Female Breast Cancer Subtypes: https://seer.cancer.gov/statfacts/html/breast-subtypes.html

2. Breast Cancer: Introduction: https://www.cancer.net/cancer-types/breast-cancer/introduction

ATTRIBUTION TO THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING IS REQUESTED IN ALL COVERAGE. 

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