Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 May 29:15:17588359231178125.
doi: 10.1177/17588359231178125. eCollection 2023.

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  1 , Peter A Fasching  2 , Sara Hurvitz  3 , Stephen Chia  4 , John Crown  5 , Miguel Martín  6 , Carlos H Barrios  7 , Aditya Bardia  8 , Seock-Ah Im  9 , Denise A Yardley  10 , Michael Untch  11 , Chiun-Sheng Huang  12 , Daniil Stroyakovskiy  13 , Binghe Xu  14 , Rebecca L Moroose  15 , Sherene Loi  16 , Frances Visco  17 , Valerie Bee-Munteanu  18 , Karen Afenjar  18 , Rodrigo Fresco  19 , Tetiana Taran  20 , Arunava Chakravartty  21 , Juan Pablo Zarate  21 , Agnes Lteif  21 , Gabriel N Hortobagyi  22
Affiliations

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 et al. Ther Adv Med Oncol. .

Erratum in

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.

PubMed Disclaimer

Conflict of interest statement

Dr. Slamon reports stock ownership from BioMarin, Pfizer, Amgen, Seattle Genetics, TORL BioTherapeutics, 1200 Pharma; travel support from BioMarin, Pfizer, Novartis; personal fees from Novartis, Eli Lilly; grants from Pfizer, Novartis; founder of 1200 Pharma, TORL BioTherapeutics. Dr. Fasching reports personal fees from Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, MSD, Lilly, Pierre Fabre, Seagen, F. Hoffmann-La Roche, Hexal, Agendia, Sanofi, Gilead; institutional funding from BioNTech, Pfizer, Cepheid; research grant from Pfizer. Dr. Hurvitz has nothing to disclose. Dr. Chia reports personal fees and grants to institution from Novartis, Pfizer, F. Hoffmann-La Roche, Eli Lilly. Prof. Crown has nothing to disclose. Dr. Martín reports personal fees from Lilly, Pfizer, AstraZeneca, Novartis, Roche/Genentech, GSK, PharmaMar, Taiho Oncology; research grants from Novartis, Roche-Genentech. Dr. Barrios reports institutional research grants from Pfizer, PharmaMar, Polyphor, Henlius Biotech, Shanghai, Merck KGaA, Millennium, LEO Pharma, ImClone Systems, Exelixis, Medivation, Asana Biosciences, AB Science, Abraxis Biosciences, Daiichi Sankyo, Bristol Myers Squibb, BioMarin, Astellas Pharma, AbbVie, Merck (MSD), Merrimack, Mylan, Taiho Pharmaceutical, Sanofi, GSK, Roche/Genentech, Lilly, Boehringer Ingelheim, Novartis, AstraZeneca, Amgen, Pfizer; personal fees from Boehringer Ingelheim, Sanofi, Lilly, Zodiac, AstraZeneca, MSD, Bayer, Eisai, Roche/Genentech, Pfizer, Novartis, GSK, Daiichi Sankyo; stock from MEDSIR, Thummi. Dr. Bardia reports research grants to institution from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Mersana, Innocrin; personal fees from Biothermostics, Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Spectrum Pharma, Taiho, Sanofi, Daiichi Sankyo, Puma. Dr. Im reports personal fees from AstraZeneca, Novartis, Hanmi, Pfizer, Eisai, Amgen, Roche, Lilly, GSK, MSD; research grants from AstraZeneca, Pfizer, Eisai, F. Hoffmann-La Roche, Daewoong Pharmaceuticals. Dr. Yardley reports research funding to institution from Daiichi Sankyo/Lilly, Eisai, Roche/Genentech, Novartis, AbbVie, AstraZeneca, Clovis Oncology, Immunomedics, InventisBio, Lilly, MedImmume, Medivation, Merck, Oncothyreon, Pfizer, Syndax, Tesaro; personal fees from Biotheranostics, Bristol Myers Squibb, Celgene, Daiichi Sankyo/Lilly, Eisai, Roche/Genentech, Novartis, NanoString Technologies. Dr. Untch has nothing to disclose. Dr. Huang reports grants to institution from Novartis, Daiichi Sankyo, AstraZeneca, EirGenix, Eli Lilly, MSD, OBI Pharma, Pfizer, F. Hoffmann-La Roche; personal fees from Novartis, Daiichi Sankyo, AstraZeneca, Eli Lilly, Pfizer, F. Hoffmann-La Roche; nonfinancial support from AstraZeneca, EirGenix, Eli Lilly, OBI Pharma, Roche, Novartis. Dr. Stroyakovskii has nothing to disclose. Dr. Xu reports personal fees from Novartis, AstraZeneca, Pfizer, Roche, Eisai. Dr. Moroose reports personal fees from Gilead, Lilly, Pfizer, Seagen, Genentech, Johnson & Johnson. Dr. Loi reports research funding grants to institution from Novartis, Bristol Myers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche/Genentech, Seagen; uncompensated consultant for Seagen, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, Roche/Genentech; consultant with fees paid to institution from Aduro Biotech, Novartis, GSK, Roche/Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seagen, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, Bristol Myers Squibb. Ms. Visco has nothing to disclose. Ms. Bee-Munteanu has nothing to disclose. Ms. Afenjar has nothing to disclose. Dr. Fresco reports other advising institution is contracted by Novartis as CRO conducting the NATALEE trial. Dr. Taran, Dr. Chakravartty, Dr. Zarate, Dr. Lteif report employment and stock ownership. Dr. Hortobagyi reports personal fees and grants to institution from Novartis.

Figures

Figure 1.
Figure 1.
Trial design. aStage IIB or IIA that is either: N1 or N0 with: Grade 3 or Grade 2 with any of the following criteria: Ki67 ⩾ 20%, or Oncotype DX Breast Recurrence Score ⩾26, or categorized as high risk via Prosigna/PAM50, MammaPrint or EndoPredict EPclin Risk Score. ctDNA, circulating tumor DNA; ctRNA, circulating tumor RNA; EBC, early nonmetastatic breast cancer; HER2−, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; iDFS, invasive disease–free survival; NSAI, nonsteroidal aromatase inhibitor; OS, overall survival; PK, pharmacokinetic; PRO, patient-reported outcome; R, randomization; STEEP, Standardized Definitions for Efficacy End Points.
Figure 2.
Figure 2.
Trial visits and assessments. aFor all visits, a ±3-day window is permitted for the applicable assessments (except for ECGs required on cycle 1 day 1), to take into account scheduling issues. bTrial visits are scheduled on day 1 and day 15 for the first two treatment cycles, then on day 1 for cycles 3–6, followed by one visit every third cycle from day 1 of cycle 7.
Figure 3.
Figure 3.
NATALEE and monarchE patient populations. NATALEE included patients with N0 disease and a broader population of patients with stage II and III disease than monarchE. NATALEE inclusion is driven by anatomical staging. In monarchE, inclusion criteria restricted enrollment to patients with node-positive disease: four or more positive axillary lymph nodes or one to three positive axillary lymph nodes and either tumor size ⩾5 cm or histologic grade 3 (cohort 1) or one to three positive axillary lymph nodes, tumor grade <3, tumor size <5 cm, and Ki-67 score ⩾20% (cohort 2).
Figure 4.
Figure 4.
Comparison of NATALEE and monarchE populations. AJCC, American Joint Committee on Cancer; G, grade; M, metastasis; N, node; NA, not applicable; T, tumor.
See this image and copyright information in PMC

References

    1. Iqbal J, Ginsburg O, Rochon PA, et al. Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States. JAMA 2015; 313: 165–173. - PubMed
    1. Guo F, Kuo YF, Berenson AB.Breast cancer incidence by stage before and after change in screening guidelines. Am J Prev Med 2019; 56: 100–108. - PMC - PubMed
    1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209–249. - PubMed
    1. Pistilli B, Lohrisch C, Sheade J, et al. Personalizing adjuvant endocrine therapy for early-stage hormone receptor-positive breast cancer. Am Soc Clin Oncol Educ Book. 2022; 42: 1–13. - PubMed
    1. Acheampong T, Kehm RD, Terry MB, et al. Incidence trends of breast cancer molecular subtypes by age and race/ethnicity in the US from 2010 to 2016. JAMA Netw Open 2020; 3: e2013226. - PMC - PubMed

Associated data