Among patients with stage 2/3 hormone receptor–positive, HER2-negative early breast cancer, Kisqali (ribociclib) plus nonsteroidal aromatase inhibitor (NSAI) showed consistent benefits in invasive disease-free survival (iDFS), distant disease-free survival (DDFS), recurrence-free survival (RFS) and distant relapse-free survival (DRFS), according to an analysis of the phase 3 NATALEE trial presented at the 2025 ASCO Annual Meeting.
At a median follow-up of 44.2 months, results showed that the 4-year iDFS rates in premenopausal patients were 90.6% with the Kisqali-plus-NSAI regimen with letrozole or anastrozole (1115 patients) versus 85.3% with a NSAI alone (1123 patients), leading to an absolute improvement of Δ5.3%. In postmenopausal patients, the 4-year iDFS rates were 86.8% with the Kisqali-plus-NSAI regimen versus 82.2% with NSAI alone, which was a Δ4.6% absolute improvement.
“This analysis showed that [Kisqali] in combination with letrozole or anastrozole lowered the chance of the cancer returned was safe to use in a broad population of patients with HR-positive, HER2-negative early breast cancer,” lead study author Dr. Kevin Kalinsky, professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, and the director of the Glenn Family Breast Center at Winship Cancer Institute, said in an oral presentation during the meeting. “[Kisqali] plus a NSAI provides treatment benefit to a broad range of patients with stage 2/stage 3 HR-positive, HER2-negative early breast cancer across menopausal status and age.”
Although survival outcomes in patients with hormone receptor–positive, HER2-negative early breast cancer have improved with the use of adjuvant endocrine therapy, there is still a risk of recurrence, influenced by menopausal status and age, Kalinsky explained.
To be eligible for NATALEE, patients must have had hormone receptor–positive/HER2-negative early breast cancer and prior endocrine therapy was permitted within 12 months prior to randomization. Patients had to have:
- anatomical stage 2a disease, which could be N0 with grade 2 and evidence of high risk, a Ki-67 of at least 20%, Oncotype DX Breast Recurrence Score at least 26 or high risk via genomic risk profiling, or grade 3, or N1 disease;
- anatomical stage 2b, which was N0 or N1;
- or anatomical stage 3, which was N0, N1, N2 or N3.
Patients who were premenopausal were required to undergo ovarian suppression.
A total 5101 patients were randomized 1:1 to receive 400 milligrams of daily Kisqali on a three-weeks-on/1-week-off schedule for three years plus an NSAI regimen of letrozole or anastrozole for at least five years plus goserelin in men and premenopausal women, or the NSAI regimen alone.
The primary end point was iDFS using STEEP criteria; secondary end points were RFS, DDFS, overall survival, safety and tolerability, patient-reported outcomes and pharmacokinetics.
Stratification factors included anatomical stage (2 versus 3), menopausal status (men and premenopausal women versus postmenopausal women), receipt of prior neo(adjuvant) chemotherapy (yes versus no), and geographic location (North America/Western Europe/Oceania versus rest of world).
Prior NATALEE data showed a statistically significant benefit with iDFS with Kisqali plus NSAI versus NSAI alone in a larger population of patients with hormone receptor–positive/HER2-negative early breast cancer at risk of recurrence. Additionally, the absolute iDFS benefit had increased to 4.9% in a 4-year landmark analysis and was observed across subgroups.
In the analysis presented at the 2025 ASCO Annual Meeting, investigators reported on 4-year efficacy, safety and quality-of-life (QOL) outcomes with Kisqali plus NSAI specific to menopausal status and age from the NATALEE study.
Kalinsky noted that more premenopausal patients versus postmenopausal had an ECOG performance status of 0 (86.8% versus 80.1%, respectively), Ki-67 greater than 20% (39.9% versus 34.4%), stage 3 (62.2% versus 58.3%), N1 to N3 nodal stage (63.4% versus 56.9%) and T3/T4 tumors (28.7% versus 24.0%) at diagnosis.
The data cutoff date was April 29, 2024. Efficacy outcomes were further explored via menopausal status and then grouped by age. Overall, in premenopausal patients, the 4-year DDFS rates were 91.6% with Kisqali/NSAI and 86.6% with NSAI alone, 4-year RFS rates were 92% and 86.6%, respectively, and 4-year DRFS rates were 92.7% and 87.6%, respectively.
When examined in premenopausal patients younger than 40 years, the absolute benefit rate with Kisqali (237 patients) versus NSAI alone (276 patients) across iDFS, DDFS, RFS and DRFS end points were Δ6.3%, Δ7%, Δ5.5% and Δ6.5%, respectively.
These rates were slightly lower in premenopausal patients 40 years or older with Kisqali (878 patients) versus NSAI alone (847 patients): iDFS (Δ5%); DDFS (Δ4.4%), RFS (Δ5.3%) and DRFS (Δ4.7%).
The same analysis was conducted in postmenopausal patients. Overall, in this subgroup, the 4-year DDFS rates were 87.7% versus 83.6% with Kisqali or NSAI, respectively (Δ4.1%). The 4-year RFS rates were 88.8% versus 84.5% (Δ4.3%), and the 4-year DRFS rates were 89.2% versus 85.6% (Δ3.6%).
The outcomes were explored further in postmenopausal patients younger than 60 years. The absolute benefit rate with Kisqali (703 patients) versus NSAI alone (735 patients) across iDFS, DDFS, RFS and DRFS end points were Δ2.7%, Δ2.2%, Δ2.8% and Δ2.1%, respectively.
These absolute benefit rates were higher in postmenopausal patients 60 years or older with Kisqali (721 patients) versus NSAI alone (685 patients): iDFS (Δ6.4%); DDFS (Δ5.9%), RFS (Δ5.8%) and DRFS (Δ5%).
Kalinsky emphasized that the trial was not powered to detect differences with these exploratory analyses, adding that the data should be interpreted with caution.
Safety and dose modifications due to adverse effects (AEs) were examined by menopausal status. Kalinsky highlighted that in premenopausal patients overall (2178 patients), the Kisqali discontinuation rate due to AEs was 16.1%, and 75.4% discontinued without dose reductions; in patients younger than 40 years, these respective rates were 10.5% and 52%, and in patients 40 years and older, they were 17.5% and 79.2%, respectively.
The Kisqali dose reduction rate due to AEs was 22.4% in all premenopausal patients, followed by 27% and 21.1% in patients younger than 40 years and at least 40 years old, respectively.
“Premenopausal women were more likely to discontinue [Kisqali] without having had a dose reduction,” Kalinsky said.
In postmenopausal patients overall (2771 patients), the Kisqali discontinuation rate was 22.9% and 67.5% stopped treatment without experiencing dose reductions. These rates were 17.8% and 68% in patients younger than 60 years and 27.9% and 67.2% in patients 60 years and older. The Kisqali dose reduction rate due to AEs was 23.6% in all postmenopausal patients, followed by 24.2% and 22.9% in patients younger than 60 years and at least 60 years old, respectively.
Time to deterioration (TTD) in global health status (GHS) and physical functioning scales of the EORTC QLQ-C30 was similar between arms for all patient subgroups.
References:
- “Efficacy and safety of Kisqali plus nonsteroidal aromatase inhibitor in NATALEE: analysis across menopausal status and age” by Dr. Kevin Kalinsky, et al., Journal of Clinical Oncology.
- “Kisqali plus endocrine therapy in early breast cancer” by Dr. Dennis Slamon, et al., New England Journal of Medicine.
- “Adjuvant Kisqali plus nonsteroidal aromatase inhibitor in hormone receptor–positive/HER2-negative early breast cancer: 4-year outcomes from the NATALEE trial” by Dr. Peter Fasching, et al., Annals of Oncology.
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