September 16, 2024
By Dibash Kumar Das, PhD
The NATALEE trial has revealed promising results for younger women with hormone receptor-positive (HR+), HER2-negative early breast cancer (EBC). Research shows that ribociclib (RIB), when paired with a nonsteroidal aromatase inhibitor (NSAI), significantly improves invasive disease-free survival (iDFS). This breakthrough is particularly notable for women under 40, a group historically associated with more aggressive disease and poorer outcomes.
The findings were presented by Sherene Loi, FRACP, PhD, FAHMS, at the ESMO Congress 2024 (Abstract 235MO). She is a medical oncologist and clinician scientist specializing in breast cancer genomics and drug development at the Peter MacCallum Cancer Centre in Melbourne, Australia.
The NATALEE trial, a multinational Phase III study, evaluated over 5,100 patients with HR+/HER2− EBC. Among them, a key focus was the 543 women under 40 representing 10.6 percent of the study population. Of these younger patients, 93.9 percent were premenopausal. This younger cohort presented with more aggressive disease characteristics, including higher rates of neoadjuvant chemotherapy (61.1% vs. 40.5% in older patients), Grade 3 tumors (26.5% vs. 20.3%), and more extensive nodal involvement (N1-3, 70.0% vs. 58.5%). The older cohort comprised 4,558 patients with 38.2 percent of them being premenopausal.
For women under 40, the combination of RIB + NSAI reduced the risk of invasive disease recurrence or death by approximately 45 percent with a hazard ratio (HR) for iDFS of 0.546 (95% CI, 0.321-0.929). In comparison, women aged 40 and above also saw improved outcomes, though to a lesser degree, with a 22 percent reduction in the risk of recurrence or death (HR for iDFS: 0.780; 95% CI, 0.648-0.939).
These improvements were echoed in other key endpoints, such as distant recurrence-free survival. Younger patients had a 46 percent reduction in the risk of distant recurrence (HR: 0.539; 95% CI: 0.300-0.968), while older patients saw a 23 percent reduction (HR: 0.771; 95% CI: 0.626-0.950).
At the 3-year mark, the data underscored the drug's efficacy: 90.1 percent of younger patients on the RIB + NSAI combination remained disease-free compared to 85.0 percent on NSAI alone. For patients over 40, iDFS rates were 90.7 percent for the RIB + NSAI group versus 87.9 percent for those on NSAI only.
The safety profile of ribociclib was consistent across age groups with neutropenia emerging as the most common adverse event. It affected 71 percent of patients under 40 and 62 percent for those over 40. While the incidence of Grade 3/4 neutropenia was high, it was generally manageable, with dose reductions needed in 27 percent of younger patients and 22 percent of older ones.
Loi highlighted that ribociclib dose reductions due to adverse events were comparable across age groups with 26.5 percent of patients under 40 and 22.4 percent of those 40 and older requiring dose adjustments. Notably, a smaller proportion of younger patients discontinued ribociclib early for any reason (28.4% vs. 36.3%) or specifically due to adverse events (9.6% vs. 20.6%) compared to their older counterparts.
“Discontinuation due to AEs without prior RIB dose reduction occurred in 4.4 percent of patients aged <40 years and 15.0 percent of patients aged ≥40 years,” she observed.
Loi emphasized the significance of the findings for younger women, a group that often faces worse treatment outcomes.
“Adjuvant treatment with RIB at 400 mg for 3 years in combination with NSAI showed a consistent treatment benefit over NSAI alone in patients with HR+/HER2− EBC, including patients <40 years. Safety profiles were similar in patients aged <40 and ≥40 years and no new safety signals of RIB at 400 mg were identified in either age group.” She added that the quality of life for patients was comparable between those on the RIB + NSAI combination and those on NSAI alone, regardless of age.
“These results from NATALEE demonstrate that 3 years of ribociclib at 400 mg consistently provides an iDFS benefit in patients with Stage II or Stage III HR+/HER2− EBC regardless of age, including in younger patients who have historically shown worse treatment outcomes,” Loi concluded.
Dibash Kumar Das is a contributing writer.