The European Commission has approved ribociclib (Kisqali) in combination with an aromatase inhibitor (AI) for the adjuvant treatment of patients with hormone receptor–positive, HER2-negative early breast cancer at high risk of recurrence. This decision follows positive data from the phase 3 NATALEE trial, which demonstrated a significant reduction in the risk of invasive disease recurrence or death. Furthermore, the National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology, recommending ribociclib plus an AI as a Category 1 preferred CDK4/6 inhibitor–based regimen for the adjuvant treatment of the same patient population.
NATALEE Trial Results
The approval and recommendation are based on the phase 3 NATALEE trial, which enrolled patients with stage II or III hormone receptor–positive, HER2-negative early breast cancer. The trial compared ribociclib at 400 mg once daily for 21 days of each 28-day cycle for up to 36 months, in combination with an AI, against an AI alone. At a median follow-up of 27.7 months, the combination reduced the risk of invasive disease, recurrence, or death by 25% (HR, 0.75; 95% CI, 0.62-0.91; P = .003). The estimated 3-year invasive disease-free survival (iDFS) rate was 90.4% with ribociclib plus AI, compared to 87.1% with AI alone.
Additional data from the NATALEE trial showed a 3-year distant disease-free survival (DDFS) rate of 90.8% in the ribociclib arm versus 88.6% in the control arm (HR, 0.74; 95% CI, 0.60-0.91). The 3-year recurrence-free survival (RFS) rates were 91.7% and 88.6%, respectively (HR, 0.72; 95% CI, 0.58-0.88).
NCCN Recommendation
The NCCN's updated guidelines recommend ribociclib as the only Category 1 CDK4/6 inhibitor for all patients with node-positive disease and for patients with no nodal involvement but with high-risk characteristics. These characteristics include a tumor size larger than 5 cm or tumors sized 2 cm to 5 cm that are either grade 2 with genomic risk/a Ki-67 index of at least 20% or grade 3. A Category 1 recommendation indicates high levels of clinical evidence and uniform consensus among the NCCN.
Safety Profile
In the NATALEE trial, any-grade adverse effects (AEs) occurred in 97.9% of patients treated with the ribociclib regimen versus 87.1% of patients who received AI monotherapy. The most common any-grade AEs included neutropenia (62.1% vs 4.5%), arthralgia (36.5% vs 42.5%), and liver-related AEs (25.4% vs 10.6%). The most common grade 3 or higher AE was neutropenia, reported in 43.8% of patients in the experimental arm versus 0.8% in the control arm.
Clinical Implications
These regulatory and guideline updates mark a significant advancement in the treatment of early HR+/HER2- breast cancer. Ribociclib, in combination with an aromatase inhibitor, now offers a valuable option for reducing the risk of recurrence in a broader patient population, including those with limited nodal involvement and high-risk node-negative disease. The NATALEE trial's robust data and the NCCN's endorsement underscore the importance of considering ribociclib as part of the adjuvant treatment strategy for eligible patients.
