Ribociclib Plus Endocrine Therapy Extends Invasive Disease-Free Survival in Early-Stage Breast Cancer


Patients with early-stage breast cancer treated with ribociclib plus a nonsteroidal aromatase inhibitor provided a greater invasive disease-free survival benefit compared with nonsteroidal aromatase inhibitor therapy alone.

Ribociclib Plus Endocrine Therapy Extends Invasive Disease-Free Survival in Early-Stage Breast Cancer

Ribociclib Plus Endocrine Therapy Extends Invasive Disease-Free Survival in Early-Stage Breast Cancer

Patients with hormone receptor–positive, HER2-negative early-stage breast cancer treated with ribociclib (Kisqali) in combination with a nonsteroidal aromatase inhibitor (NSAI) experienced a significant improvement in invasive disease-free survival (iDFS) vs NSAI monotherapy, according to findings from the phase 3 NATALEE trial (NCT03701334) published in The New England Journal of Medicine.

At the January 11, 2023, data cutoff, at a median follow-up of 27.7 months, patients who received the combination (n = 2549) achieved a 3-year iDFS rate of 90.4% compared with 87.1% among those who received an NSAI only (n = 2552; HR, 0.75; 95% CI, 0.62-0.91; 2-sided P = .003). Moreover, the 3-year distant disease-free survival (DDFS) rates were 90.8% vs 88.6%, respectively (HR, 0.74; 95% CI, 0.60-0.91).

“This prespecified interim analysis showed a significantly lower risk of invasive disease, recur­rence, or death with adjuvant ribociclib plus an NSAI than with an NSAI alone in patients with stage II or III hormone receptor–positive, HER2-negative early breast cancer. The absolute benefit with ribociclib plus an NSAI at 3 years was 3.3 percentage points. These results support the use of ribociclib in the treatment of [patients with] HR-positive, HER2-negative early breast cancer,” study authors wrote.

NATALEE was an international, open-label study that enrolled patients with hormone receptor–positive, HER2-negative stage II or III breast cancer. Patients with stage IIB or III disease were permitted to be enrolled regardless of nodal status; those with stage IIA disease were eligible if they had at least 1 involved node and those with grade II disease and no nodal involvement needed to have a Ki-67 proliferation index of at least 20% or be of a high genomic risk group. Prior adjuvant or neoadjuvant endocrine therapy was permitted for up to 12 months prior to randomization. Patients who underwent previous CDK4/6 inhibitor treatment and those with clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormali­ties were excluded.

Eligible patients were randomly assigned 1:1 to receive oral ribociclib 400 mg once daily for 21 consecutive days followed by 7 days off in 28-day cycles for 36 months plus either oral letrozole 2.5 mg or anastrozole 1 mg orally once daily, or an NSAI alone. Patients in the combination arm continued to receive the NSAI after 36 months of combination therapy. Patients were stratified by anatomical stage (II vs III), menopausal status (premenopausal women and men vs postmenopausal women), previous adjuvant or neoadjuvant chemotherapy (yes vs no), and geographic location (North America, Western Eu­rope, Oceania, vs rest of the world).

The primary end point was investigator-assessed iDFS. Secondary end points included DDFS, recurrence-free survival, overall survival (OS), safety, quality of life, and pharmacokinetics. Distant recurrence-free survival represented an exploratory end point.

The baseline characteristics were well balanced between the 2 arms; the median age was 52 years (range, 24-90) in the combination arm compared with 52 years (range, 24-89) in the monotherapy arm. Most patients in both arms received prior endocrine therapy (71.6% vs 70.6%), received any prior chemotherapy (88.2% vs 88.0%), were treated with a prior aromatase inhibitor (62.8% vs 62.4%), had histologic grade 2 disease at diagnosis (57.2% vs 56.9%), had anatomical stage III disease (59.9% vs 59.2%), and were postmenopausal women (55.8% vs 55.6%). Additionally, a majority of patients had an ECOG performance status of 0 (82.6% vs 83.5%) and invasive ductal not otherwise specified histology (72.9% vs 73.7%).

Additional findings from NATALEE demonstrated that the combination provided a distant recurrence-free survival benefit over NSAI monotherapy (HR, 0.72 (95% CI, 0.58-0.89). The 3-year recurrence-free survival rates were 91.7% vs 88.6%, respectively (HR, 0.72; 95% CI, 0.58-0.88). Regarding OS, at a median follow-up of 30 months, OS favored the combination arm (HR, 0.76; 95% CI, 0.54-1.07); 2.4% of patients died in the combination arm vs 2.9% in the monotherapy arm.

In terms of safety, patients in the combination and monotherapy arms experienced any-grade adverse effects (AEs) at a rate of 97.9% vs 87.1%, respectively. The most common any-grade AEs included neutropenia (62.1% vs 4.5%), arthralgia (36.5% vs 42.5%), and liver-related events (25.4% vs 10.6%). Serious AEs occurred at a rate of 13.3% vs 9.9%, respectively; AEs leading to early discontinuation occurred at a rate of 3.3% in both arms.

“In the NATALEE trial, we examined CDK4/6 inhi­bition in hormone receptor–positive, HER2-negative disease by evaluating the addition of 3 years of ribociclib treatment to a standard NSAI as adjuvant thera­py in a broad population of patients with early breast cancer. The results of this trial showed a significant iDFS benefit over NSAI alone as adjuvant therapy in stage II or III hormone receptor–positive, HER2-negative early breast cancer; a 25.2% lower risk of invasive disease, recurrence, or death; and an absolute iDFS benefit of 3.3 percentage points at 3 years. OS data are cur­rently immature. No new safety signals were observed for either ribociclib or the NSAIs.”


Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med. 2024;390:1080-1091. doi:10.1056/NEJMoa2305488

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