NATALEE updates: Ribociclib benefit in HR+, ERBB– EBC sustained at 4 years

In an updated analysis of the NATALEE* trial, the efficacy benefit of adjuvant ribociclib remains consistent even after the planned 3-year treatment duration for patients with HR+, ERBB2– early breast cancer (EBC).

“In this exploratory 4-year analysis, ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) continued to demonstrate invasive disease-free survival (iDFS) and distant DFS (dDFS) benefits over NSAI alone … The absolute iDFS benefit continued to increase from 3 to 4 years,” said the researchers.

All participants had completed or discontinued ribociclib treatment by this point. Yet, adjuvant ribociclib plus NSAI continued to show an iDFS benefit over NSAI alone after a median follow-up of 44.2 months (hazard ratio [HR], 0.72). The 4-year iDFS rates with ribociclib plus NSAI vs NSAI alone were 88.5 percent and 83.6 percent, respectively, representing a 4.9-percentage point absolute iDFS benefit. [JAMA Oncol 2025;11:1364-1372]

Ribociclib plus NSAI also showed consistent dDFS (HR, 0.72), recurrence-free survival (RFS; HR, 0.70), and distant RFS (HR, 0.71) benefits over NSAI alone in the intention-to-treat cohort.

The iDFS and dDFS benefits with ribociclib plus NSAI remained consistent across clinically relevant subgroups, including anatomic stage, nodal status, or prior ET.

Overall survival data were immature at data cutoff, but there was a trend toward benefit with the experimental regimen compared with NSAI alone (HR, 0.83).

No new safety signals

The researchers noted that no new safety signals were observed with the additional follow-up, and that the incidence of serious adverse events (AEs) was similar between the experimental and comparator arms (14.8 percent vs 10.9 percent).

During this analysis, 27.2 percent required a reduction in ribociclib dose, primarily due to AEs (23 percent). Twenty percent of patients in the ribociclib arm discontinued treatment early due to AEs, which mirrors that observed in the final iDFS analysis (19.5 percent).

The most common all-grade AEs in the ribociclib arm were neutropenia, arthralgia, and nausea, which align with previous analyses. The most common all-grade AEs leading to ribociclib discontinuation were ALT/AST** elevations (7.2 percent/2.7 percent).

A critical unmet need

Despite standard adjuvant endocrine therapy, many patients with HR+, ERBB2– EBC experience disease recurrence, with ~50 percent occurring within 5 years of diagnosis and continuing beyond 20 years, the researchers noted. “Most events are distant recurrences, which are incurable. Consequently, reducing the risk of recurrence is a critical unmet need for patients with HR+, ERBB2– EBC.”

Ribociclib plus NSAI significantly improved iDFS and dDFS over NSAI alone in the second interim efficacy and final iDFS analyses of NATALEE. [N Engl J Med 2024;390:1080-1091; J Clin Oncol 2023;41:LBA500; Ann Oncol 2025;36:149-157] “Extended follow-up is critical for assessing whether and to what extent the adjuvant treatment benefit is sustained beyond the end of treatment,” the researchers noted.

In NATALEE, 5,101 participants (median age 52 years, 99.6 percent women) were randomized 1:1 to an NSAI (letrozole 2.5 mg or anastrozole 1 mg QD continuously for 60 months) with or without ribociclib 400 mg QD over 36 months. Men (n=20) and premenopausal women were also given subcutaneous goserelin 3.6 mg once every 28 days.

“[With a median follow-up beyond the 3-year treatment duration, these] results continue to support the benefit of adding 3 years of ribociclib to adjuvant NSAI in patients with HR+, ERBB2– EBC at risk of recurrence,” the researchers said.

However, the exploratory nature of this analysis precludes formal statistical assessment, they noted. Further analyses with longer follow-up are thus warranted to ascertain the long-term effect of adjuvant ribociclib on reducing recurrences.