Clinical trialPhase 3Breast cancer

Ribociclib plus Endocrine Therapy in Early Breast Cancer

N Engl J Med · 20245101 patients

Slamon D, Lipatov O, Nowecki Z, McAndrew N, Kukielka-Budny B, Stroyakovskiy D, et al. N Engl J Med. 2024. 390:1080-1091

A newer report of this study has been published: Adjuvant ribociclib plus nonsteroidal aromatase inhibitor therapy in patients with HR-positive/HER2-negative early breast cancer: 5-year follow-up of NATALEE efficacy outcomes and updated overall survival (2025)

Study type: Clinical trial
Study name: NATALEE
Phase: Phase 3
Design: International, open-label, randomised trial (1:1 ratio)
Sample size: 5101 patients
Source: N Engl J Med · 2024
Trial registration: NCT03701334

In plain words

In stage II or III hormone-positive, HER2-negative breast cancer, adding ribociclib tablets (at a lower dose than usually used for metastatic disease) to hormone therapy for three years lowered the risk of the disease coming back by about 25%. Unlike the abemaciclib trial, this study also included patients at more moderate risk, including some patients whose lymph nodes were not affected.

Key results

90.4% vs 87.1%

3-year iDFS

HR 0.75 (95% CI 0.62–0.91); P=0.003

426 events

iDFS events at the interim analysis

Data cut-off 11 January 2023

Drugs in this study:Goserelin (Zoladex)Letrozole (Femara)Anastrozole (Arimidex)Ribociclib (Kisqali)

Dose and schedule cards

Ribociclib + nonsteroidal aromatase inhibitor (NATALEE)

HR-positive/HER2-negative stage IIB–III, or stage IIA with nodal involvement, or node-negative stage IIA with grade 3, or grade 2 with Ki-67 ≥20% or high genomic riskEach drug’s schedule in the tableOn the page “Breast cancer” · Early hormone receptor-positive disease: hormone therapy ± CDK4/6 inhibitor

HR-positive/HER2-negative stage IIB–III, or stage IIA with nodal involvement, or node-negative stage IIA with grade 3, or grade 2 with Ki-67 ≥20% or high genomic risk

Drug	Dose	Route	Schedule
Ribociclib	400 mg once daily	Oral	Days 1–21, every 28 days
Letrozole or anastrozole (± goserelin)	2.5 or 1 mg daily	Oral	Continuous

Cycle schedule: Ribociclib 21 days on and 7 days off; letrozole or anastrozole daily and continuously
Duration: Ribociclib for 3 years

Liver tests and blood counts: after the first 2 cycles, at the start of each of the next 4 cycles. Dose reduction: 200 mg daily; below that, discontinue.

On the page “Breast cancer” · Early hormone receptor-positive disease: hormone therapy ± CDK4/6 inhibitor

Early breast cancer, adjuvant treatment (NATALEE)

HR-positive/HER2-negative stage II and III at high risk of recurrenceEach drug’s schedule in the tableOn the page “Ribociclib (Kisqali)” · Standard doses (FDA label)

HR-positive/HER2-negative stage II and III at high risk of recurrence

Drug	Dose	Route	Schedule
Ribociclib	400 mg (2 × 200 mg tablets)	Oral, with or without food, preferably in the morning	Once daily, days 1 to 21, every 28 days
Letrozole or anastrozole	2.5 mg or 1 mg	Oral	Daily, continuously
Pre- or perimenopausal women and men
Goserelin	3.6 mg	Subcutaneous	Day 1, every 28 days

Cycle schedule: Ribociclib 21 days on and 7 days off; letrozole or anastrozole daily and continuously; goserelin every 28 days
Duration: Ribociclib for 3 years or until recurrence or unacceptable toxicity; aromatase inhibitor for at least 5 years

Accompanying doses as described for NATALEE in the FDA label. The only dose reduction level: 200 mg a day.

On the page “Ribociclib (Kisqali)” · Standard doses (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Ribociclib + non-steroidal aromatase inhibitor

Ribociclib 400 mg daily for 3 weeks followed by 1 week off, for 3 years; with letrozole 2.5 mg daily or anastrozole 1 mg daily for at least 5 years. Premenopausal women and men also received goserelin every 28 days.

2Non-steroidal aromatase inhibitor alone

Letrozole 2.5 mg or anastrozole 1 mg daily for at least 5 years (± goserelin every 28 days in premenopausal women and men).

Source of the regimen details: Abstract of the paper (ribociclib 400 mg 3 weeks on/1 week off for 3 years; letrozole 2.5 or anastrozole 1 mg daily; goserelin every 28 days)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with HR-positive, HER2-negative early breast cancer of anatomical stage II or III (including a group of node-negative patients with high-risk features).

Endpoints

Primary outcome: invasive disease-free survival (iDFS). Secondary: distant disease-free survival, recurrence-free survival, overall survival and safety.

Safety and side effects

The 3-year ribociclib regimen at a starting dose of 400 mg with an aromatase inhibitor raised no new safety signals. Neutropenia, liver enzyme elevation and QT prolongation are known adverse effects of ribociclib, and periodic blood tests and ECG monitoring are needed.

Clinical significance and place in guidelines

NATALEE extended adjuvant CDK4/6 inhibitor use to a broader population of stage II–III patients. The FDA approved ribociclib with an aromatase inhibitor in September 2024 for high-risk HR-positive/HER2-negative early breast cancer. The Pan-Asian adapted ESMO guideline (2024) did not add ribociclib to its recommendations because it lacked FDA/EMA approval at the time of drafting; see newer guidelines for current status.

Limitations

Open-label design; interim analysis with relatively short follow-up (many patients had not yet completed treatment); immature overall survival; the absolute benefit in lower-risk patients is small.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.