# NATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancer

Source: https://onco.cc/key-papers/paper-natalee-nejm-2024/  
OnCo record `paper-natalee-nejm-2024` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Three years of the CDK4/6 inhibitor ribociclib added to hormone therapy reduced relapses in stage II-III hormone-receptor-positive breast cancer, including some node-negative patients.

## Summary

Open-label phase 3 trial of 5,101 patients with hormone-receptor-positive, HER2-negative stage II or III early breast cancer, including node-negative patients with high-risk features, randomised to a non-steroidal aromatase inhibitor with or without three years of ribociclib at a reduced dose (400 mg daily). Primary endpoint was invasive disease-free survival.

Three-year iDFS was 90.4% vs 87.1% (HR 0.75). Together with monarchE it established adjuvant CDK4/6 inhibition, but in a broader, lower-risk population and with a longer, lower-dose schedule.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2024
- DOI: 10.1056/NEJMoa2305488
- Authors: Slamon D, Lipatov O, Nowecki Z, et al.
- Findings: Three-year invasive disease-free survival 90.4% vs 87.1%; HR 0.75 (95% CI 0.62-0.91).; Benefit was consistent across stage II and III and in node-negative and node-positive subgroups.; Distant disease-free survival HR 0.74.; Grade 3 or higher neutropenia in roughly 44% and liver enzyme elevation in roughly 8% of ribociclib patients; about one in five discontinued for adverse events.; Overall survival immature at the primary analysis.
- What it means: Ribociclib is a second adjuvant CDK4/6 option, and the only one with data in node-negative stage II disease. Roughly 3 in 100 patients avoid a relapse or death at three years, so the decision depends heavily on individual risk, tolerance of a three-year oral drug, and cost. Whether the benefit persists after treatment ends, as it did with abemaciclib, needs longer follow-up.
- Caveats: Absolute benefit at three years is about 3 percentage points and the trial included many patients whose baseline risk was modest.; Follow-up beyond the three years of treatment is limited, so durability is not yet established.; Open-label; a large proportion of patients stopped ribociclib early.; Cost of three years of therapy is substantial; cost-effectiveness has been questioned in several health systems.

## Sources

- NEJM 2024: https://doi.org/10.1056/NEJMoa2305488
- ClinicalTrials.gov NCT03701334: https://clinicaltrials.gov/study/NCT03701334

## Connected records

- cancers: [High-risk early HR-positive breast cancer](https://onco.cc/cancers/hr-positive-early-high-risk/), [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/)
- technologies: [CDK4/6 inhibitors](https://onco.cc/technologies/cdk46-inhibitor/), [Endocrine therapy (SERMs, AIs, SERDs)](https://onco.cc/technologies/endocrine-therapy/)
- targets: [CDK4/6](https://onco.cc/targets/cdk4-6/), [Estrogen receptor (ERα)](https://onco.cc/targets/estrogen-receptor/)
- drugs: [Ribociclib](https://onco.cc/drugs/ribociclib/)
- companies: [Novartis](https://onco.cc/companies/novartis/)
- terms: [Hazard ratio (HR)](https://onco.cc/terms/hazard-ratio/), [Neoadjuvant / adjuvant / perioperative](https://onco.cc/terms/neoadjuvant-adjuvant/)
- trials: [monarchE](https://onco.cc/trials/monarche/), [NATALEE](https://onco.cc/trials/natalee/)
- people: [Binghe Xu](https://onco.cc/people/xu-binghe/), [Carlos Barrios](https://onco.cc/people/barrios-carlos/), [Dennis J. Slamon](https://onco.cc/people/dennis-slamon/), [Gabriel N. Hortobagyi](https://onco.cc/people/gabriel-hortobagyi/), [Miguel Martín](https://onco.cc/people/miguel-martin/), [Sara A. Hurvitz](https://onco.cc/people/sara-hurvitz/), [Seock-Ah Im](https://onco.cc/people/im-seock-ah/), [Sherene Loi](https://onco.cc/people/loi-sherene/)
- bottlenecks: [Dormant cells and minimal residual disease](https://onco.cc/bottlenecks/b-dormancy-mrd/), [Prices and value](https://onco.cc/bottlenecks/b-drug-pricing/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)

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