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

Dennis J Slamon; Peter A Fasching; Sara Hurvitz; Stephen Chia; John Crown; Miguel Martín; Carlos H Barrios; Aditya Bardia; Seock-Ah Im; Denise A Yardley; Michael Untch; Chiun-Sheng Huang; Daniil Stroyakovskiy; Binghe Xu; Rebecca L Moroose; Sherene Loi; Frances Visco; Valerie Bee-Munteanu; Karen Afenjar; Rodrigo Fresco; Tetiana Taran; Arunava Chakravartty; Juan Pablo Zarate; Agnes Lteif; Gabriel N Hortobagyi

doi:10.1177/17588359231178125

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 May 29:15:17588359231178125. doi: 10.1177/17588359231178125. eCollection 2023.

Authors

Dennis J Slamon¹, Peter A Fasching², Sara Hurvitz³, Stephen Chia⁴, John Crown⁵, Miguel Martín⁶, Carlos H Barrios⁷, Aditya Bardia⁸, Seock-Ah Im⁹, Denise A Yardley¹⁰, Michael Untch¹¹, Chiun-Sheng Huang¹², Daniil Stroyakovskiy¹³, Binghe Xu¹⁴, Rebecca L Moroose¹⁵, Sherene Loi¹⁶, Frances Visco¹⁷, Valerie Bee-Munteanu¹⁸, Karen Afenjar¹⁸, Rodrigo Fresco¹⁹, Tetiana Taran²⁰, Arunava Chakravartty²¹, Juan Pablo Zarate²¹, Agnes Lteif²¹, Gabriel N Hortobagyi²²

Affiliations

¹ David Geffen School of Medicine at UCLA, 10945 Le Conte Ave. Suite 3360, Los Angeles, CA 90095, USA.
² University Hospital Erlangen Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
³ University of California, Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
⁴ British Columbia Cancer Agency, Vancouver, BC, Canada.
⁵ St. Vincent's Hospital, Dublin, Ireland.
⁶ 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.
⁷ Centro de Pesquisa em Oncologia, Hospital São Lucas, PUCRS, Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Brazil.
⁸ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
⁹ Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
¹⁰ Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN, USA.
¹¹ Interdisciplinary Breast Cancer Center, Helios Klinikum Berlin-Buch, Berlin, Germany.
¹² National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City, Taiwan.
¹³ Moscow City Oncology Hospital No. 62 of Moscow Healthcare Department, Moscow Oblast, Russia.
¹⁴ Department of Medical Oncology Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹⁵ Orlando Health Cancer Institute, Orlando, FL, USA.
¹⁶ Peter MacCallum Cancer Centre, Melbourne, Australia.
¹⁷ National Breast Cancer Coalition, Washington, DC, USA.
¹⁸ TRIO - Translational Research in Oncology, Paris, France.
¹⁹ TRIO - Translational Research in Oncology, Montevideo, Uruguay.
²⁰ Novartis Pharma AG, Basel, Switzerland.
²¹ Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
²² Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Abstract

Background: Ribociclib has demonstrated a statistically significant overall survival benefit in pre- and postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced breast cancer. New Adjuvant Trial with Ribociclib [LEE011] (NATALEE) is a trial evaluating the efficacy and safety of adjuvant ribociclib plus endocrine therapy (ET) versus ET alone in patients with HR+/HER2- early nonmetastatic breast cancer (EBC).

Methods/design: NATALEE is a multicenter, randomized, open-label, Phase III trial in patients with HR+/HER2- EBC. Eligible patients include women, regardless of menopausal status, and men aged ⩾18 years. Select patients with stage IIA, stage IIB, or stage III disease (per the anatomic classification in the AJCC Cancer Staging Manual, 8th edition) with an initial diagnosis ⩽18 months prior to randomization are eligible. Patients receiving standard (neo)adjuvant ET are eligible if treatment was initiated ⩽12 months before randomization. Patients undergo 1:1 randomization to ribociclib 400 mg/day (3 weeks on/1 week off) +ET (letrozole 2.5 mg/day or anastrozole 1 mg/day [investigator's discretion] plus goserelin [men or premenopausal women]) or ET alone. Ribociclib treatment duration is 36 months; ET treatment duration is ⩾60 months. The primary end point is invasive disease-free survival.

Discussion: The 36-month treatment duration of ribociclib in NATALEE is extended compared with that in other adjuvant cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor trials and is intended to maximize efficacy due to longer duration of CDK4/6 inhibition. Compared with the 600-mg/day dose used in advanced breast cancer, the reduced ribociclib dose used in NATALEE may improve tolerability while maintaining efficacy. NATALEE includes the broadest population of patients with HR+/HER2- EBC of any Phase III trial currently evaluating adjuvant CDK4/6 inhibitor treatment.

Trial registration: ClinicalTrials.gov identifier: NCT03701334 (https://clinicaltrials.gov/ct2/show/NCT03701334).

Keywords: CDK4/6 inhibitors; HR+/HER2– early breast cancer; NATALEE; adjuvant therapy; ribociclib.

Associated data

ClinicalTrials.gov/NCT03701334