Ribociclib and endocrine therapy extend invasive disease-free survival in early breast cancer

Hormone receptor-positive, HER2-negative early-stage breast cancer patients treated with nonsteroidal aromatase inhibitors (NSAIs) in combination with ribociclib (Kiskari) showed improved invasive disease-free survival (iDFS) compared to NSAI monotherapy. has improved significantly.Results of the Phase 3 NATALEE study (NCT03701334) presented at New England Medical Journal.

As of data cutoff on January 11, 2023, with a median follow-up of 27.7 months, the 3-year iDFS rate was 90.4% for patients receiving combination therapy (n = 2549) compared to 90.4% for patients receiving NSAI. The rate was 87.1% in patients who had cancer.only (n = 2552; HR, 0.75; 95% CI, 0.62-0.91; bilateral P = .003). Furthermore, 3-year distant disease-free survival (DDFS) was 90.8% vs. 88.6%, respectively (HR, 0.74; 95% CI, 0.60-0.91).

“In this prespecified interim analysis, we found that in patients with stage II or III hormone receptor-positive, HER2-negative early-stage breast cancer, adjuvant ribociclib in combination with NSAI was associated with greater risk of invasive disease, recurrence, or The risk of death was shown to be significantly lower. The 3-year absolute benefit of combining ribociclib with an NSAI was 3.3 percentage points. These results support the use of ribociclib in treatment. [patients with] HR-positive, HER2-negative early breast cancer,” the 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 allowed to enroll regardless of lymph node status. Patients with stage IIA disease are eligible if they have at least one involved lymph node, have grade II disease, have a Ki-67 proliferation index of at least 20%, or are in a high genomic risk group Patients without nodal metastases were eligible. Prior adjuvant or neoadjuvant endocrine therapy was allowed for up to 12 months before randomization. Patients previously treated with CDK4/6 inhibitors and those with clinically significant uncontrolled cardiac disease and/or cardiac repolarization abnormalities were excluded.

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

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

Baseline characteristics were balanced between the two arms. Median age was 52 years (range, 24-90 years) in the combination therapy group versus 52 years (range, 24-89 years) in the monotherapy group. Most of the patients in both groups had previously received endocrine therapy (71.6% vs. 70.6%), chemotherapy (88.2% vs. 88.0%), and had been previously treated with an aromatase inhibitor ( 62.8% vs. 62.4%) had histological grade 2 disease at time point. diagnosed (57.2% vs 56.9%), had anatomic stage III disease (59.9% vs 59.2%), and postmenopausal women (55.8% vs 55.6%). Furthermore, the majority of patients had her ECOG performance status of 0 (82.6% vs. 83.5%) and the histology of the invasive ducts was not specified (72.9% vs. 73.7%).

Additional findings from NATALEE demonstrated that this combination therapy had a benefit in distant recurrence-free survival over NSAI monotherapy (HR, 0.72 (95% CI, 0.58-0.89); 3-year recurrence-free survival Survival rates were 91.7% vs. 88.6%, respectively) (HR, 0.72; 95% CI, 0.58-0.88) Regarding OS, with 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 in the combination therapy group had a mortality rate of 2.9% compared with 2.9% in the monotherapy group.

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

“The NATALEE study aims to improve CDK4/6 inhibition in hormone receptor-positive, HER2-negative disease by evaluating the addition of 3 years of ribociclib treatment to standard NSAIs as adjuvant therapy in a broad population of early-stage breast cancer patients. The results of this trial showed that iDFS was significantly more beneficial than NSAI alone as adjuvant therapy for stage II or III hormone receptor-positive, HER2-negative early-stage breast cancer. 25.2% reduction in risk of disease, recurrence, and death. Absolute benefit of iDFS is 3.3 percentage points over 3 years. OS data are immature at this time. New safety signals for either ribociclib or NSAIs was not observed.”

reference

Slamon D, Lipatov O, Nowecki Z, et al. Combination of ribociclib and endocrine therapy for early breast cancer. N English J Medicine. 2024;390:1080-1091. doi:10.1056/NEJMoa2305488