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A post hoc exploratory analysis using the most recent data cut from the phase 3 NATALEE trial (NCT03701334) showed that the clinical benefit of treatment with ribociclib (Kisqali) persisted despite dose reduction in patients with hormone receptor (HR)–positive, HER2-negative early breast cancer, according to findings that were presented at the 42nd Annual Miami Breast Cancer Conference.
Findings from the analysis demonstrated that, at a median invasive disease–free survival (iDFS) follow-up of 44.2 months across both the overall population and the ribociclib-plus-nonsteroidal aromatase inhibitor (NSAI) arm, ribociclib dose reductions—primarily due to adverse effects (AEs)—occurred early in treatment and did not compromise iDFS benefit. Notably, an analysis of iDFS by relative dose intensity (RDI) showed consistent outcomes across dose levels, even after adjusting for patients who discontinued ribociclib before 36 months of treatment.
Moreover, a landmark analysis of dose reduction demonstrated no significant differences in iDFS outcomes between patients who did or did not undergo dose reduction. These findings suggest that reducing the dose of ribociclib to 200 mg per day from 400 mg per day—when necessary to manage AEs—may help maintain treatment adherence without compromising efficacy in patients with hormone receptor–positive, HER2-negative early breast cancer.
NATALEE Exploratory Analysis Design
The NATALEE trial is a randomized, open-label study evaluating the efficacy and safety of ribociclib in combination with a NSAI compared with a NSAI alone in patients with stage II/III hormone receptor–positive, HER2-negative early breast cancer at risk for recurrence. Patients were randomly assigned in a 1:1 ratio to receive ribociclib at 400 mg daily for 3 weeks on, 1 week off for 3 years plus an NSAI for at least 5 years or an NSAI alone. Men and premenopausal women also received goserelin. Notably, for the management of AEs, 1 ribociclib dose reduction from 400 mg per day to 200 mg per day was permitted; however, dose re-escalation to 400 mg per day was not allowed.
The primary end point of the trial is iDFS using Standard Definitions for Efficacy End Points criteria. Secondary end points include recurrence-free survival, distant disease–free survival, overall survival, safety, patient-reported outcomes, and pharmacokinetics.
To assess the efficacy of ribociclib dose intensity, an exploratory analysis was conducted with a data cutoff of April 29, 2024. RDI was defined as the actual cumulative dose per duration of exposure (adjusted for the 3-week-on/1-week-off schedule) divided by the planned dose intensity of 400 mg per day. Patients were categorized into low, medium, or high RDI tertiles.
Two Cox proportional hazards models with time-varying covariates were used to evaluate the association between dose reductions and iDFS. Additionally, landmark analyses were performed to assess the relationship between dose reductions and iDFS, as well as to address potential immortal time bias. Patients were grouped based on whether dose reduction occurred before a specific landmark time; patients with exposure that ended before the landmark time were excluded.
The adjusted RDI model accounted for patients who discontinued ribociclib before 36 months due to an iDFS event. For those who discontinued due to an iDFS effect, RDI was calculated using actual ribociclib exposure time. For patients who discontinued for other reasons, RDI was calculated using either time to iDFS event (if the iDFS event occurred before 36 months and after dose reduction) or 36 months (if the iDFS event occurred after 36 months or was not observed).
This exploratory analysis focused on the effect of RDI on iDFS with ribociclib but did not assess the effect of treatment duration on ribociclib efficacy.
Baseline Patient Information
Among the 2526 patients treated in the ribociclib-plus-NSAI arm, 687 (27.2%) underwent a ribociclib dose reduction, and 1839 (72.8%) did not. The median time to ribociclib dose reduction was 3.3 months, and the most common reason for dose reduction was an AE (84.7%), followed by dosing error (13.7%) and physician decision (2.2%). The median duration of ribociclib exposure was 35.7 months in the group of patients with a dose reduction, as well in the group of those without a dose reduction.
Baseline characteristics were well balanced between patients with and without a dose reduction. The median age at baseline was 52.0 years (range, 25-90) in the dose reduction group and 52.0 years (range, 24-84) in the non–dose reduction group. Among patients who underwent dose reduction, 50.3% were men or premenopausal women, and 57.1% were postmenopausal women; these rates were 44.7% and 55.3%, respectively, among patients in the non–dose reduction cohort.
Regarding disease characteristics, most patients had stage II (37.4%) or stage III (62.0%) disease in the dose reduction group, whereas 40.3% and 59.4% of patients in the non–dose reduction group had stage II and III disease, respectively. Nodal status at diagnosis was comparable between the groups, with N1 status observed in 41.3% of patients in the dose reduction cohort and 41.1% of those in the non–dose reduction cohort.
A history of endocrine therapy was documented in 74.5% of patients in the dose reduction group and 70.8% of those in the non–dose reduction group. Prior neoadjuvant or adjuvant chemotherapy was more common among patients who required a dose reduction (90.0%) than those who did not (87.7%). ECOG performance status was 0 in 81.5% of patients who underwent dose reduction and 83.0% of those who did not.
Safety and Efficacy Continued
Kaplan-Meier plots showed that the incidence of iDFS events was similar across low (< 82.27%; n = 833; 81 events), medium (82.27% to < 97.44%; n = 840; 89 events), and high (≥ 97.44%; n = 853; 92 events) RDI groups. The HR was 0.931 (95% CI, 0.69-1.25; P = .32) between the low and high groups and 0.985 (95% CI, 0.74-1.32; P = .46) between the medium and high groups.
When adjusted RDI was used to account for patients who discontinued ribociclib before 36 months of treatment, the incidence of iDFS events remained stable across all RDI groups, with an HR of 0.83 (95% CI, 0.60-1.15; P = .13) between the low (< 50.73%; n = 831) and high (≥96.4%l n = 834) groups and 1.12 (95% CI, 0.85-1.48; P .79) between the medium (50.73%-96.47%; n = 861) and high groups. In total, 60, 106, and 96 iDFS events occurred in the low, medium, and high RDI groups, respectively.
A time-dependent RDI2 analysis showed that iDFS incidence was similar across patients regardless of RDI2. The HRs between the low and high RDI2 groups and the medium and high RDI groups were 1.07 (95% CI, 0.78-1.48) and 1.32 (95% CI, 0.99-1.74), respectively.
Furthermore, a landmark analysis confirmed comparable post-landmark iDFS rates between patients who underwent ribociclib dose reduction and those who did not. At a landmark time of 3 months, 87.3% of patients had received treatment longer than the landmark time; the 3-year post-landmark time iDFS rates among those who had dose reduced prior to the landmark time (11.4%) and those who had not (88.6%) were 93.1% (95% CI, 89.0%-95.7%) and 90.4% (95% CI, 89.0%-91.7%), respectively (HR, 0.84; 95% CI, 0.54-1.30). At a landmark time of 6 months, 80.8% of patients had received treatment longer than the landmark time; the 3-year post-landmark time iDFS rates among those who had dose reduced prior to the landmark time (17.6%) and those who had not (82.4%) were 91.9% (95% CI, 88.4%-94.4%) and 90.6% (95% CI, 89.0%-92.0%), respectively (HR, 0.80; 95% CI, 0.54-1.19). At a landmark time of 12 months, 75.5% of patients had received treatment longer than the landmark time; the 3-year post-landmark time iDFS rates among those who had dose reduced prior to the landmark time (21.2%) and those who had not (78.8%) were 92.2% (95% CI, 88.9%-94.5%) and 91.0% (95% CI, 89.2%-92.4%), respectively (HR, 0.81; 95% CI, 0.54-1.21).
Regarding safety, AEs leading to ribociclib dose reduction in at least 0.5% of patients included neutropenia (any-grade, 14.1%; grade ≥ 3, 12.2%), leukopenia (1.7%; 0.6%), increased alanine aminotransferase levels (1.9%; 0.9%), fatigue (1.1%; 0.2%), and increased aspartate aminotransferase levels (0.7%; 0.1%). Among the 509 patients who discontinued ribociclib treatment because of an AE, 70.3% had undergone no prior dose reduction.
Reference
Hamilton E, Decker T, Rugo HS, et al. Impact of ribociclib dose reduction on efficacy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer in NATALEE. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami, FL. Poster 20.