US Food and Drug Administration Approval Summary: Ribociclib With an Aromatase Inhibitor in the Adjuvant Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Stage II and III High-Risk Early Breast Cancer Treatment Setting

PURPOSE On September 17, 2024, the US Food and Drug Administration (FDA) approved ribociclib in combination with an aromatase inhibitor (AI) for the adjuvant treatment of adults with hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative stage II and III early breast cancer (EBC) who are at high risk of recurrence. PATIENTS AND METHODS The FDA approval was based on NATALEE, a randomized (1:1), open-label, multicenter, multinational trial in adults of any sex or menopausal status with hormone receptor–positive, HER2-negative stage II and III EBC who received ribociclib plus an AI (Ribo + AI, n = 2,549) versus an AI (n = 2,552); patients also received goserelin as clinically indicated. Ribociclib was given at 400 mg once daily (3 weeks on/1 week off) for up to 36 months. AI was given per standard of care for at least 5 years. The primary end point was invasive disease-free survival (iDFS), defined according to Standardized Definitions for Efficacy End Points version 1.0 criteria. Overall survival (OS) was a secondary end point. RESULTS iDFS was statistically significant at the third interim analysis (IA3; January 2023; hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.91]) in the intent-to treat (ITT) population. However, at IA3, there was a large amount of censoring for iDFS as only 20% of patients had completed 3 years of adjuvant therapy and OS was immature. Because of these concerns, FDA requested that NATALEE continue until the final iDFS analysis. At the final iDFS analysis, the iDFS at 36 months was 90.7% (95% CI, 89.3 to 91.8) for Ribo + AI versus 87.6% (95% CI, 86.1 to 88.9) for AI, with a HR of 0.75 (95% CI, 0.63 to 0.89). More patients who received ribociclib experienced all-grade (98% Ribo + AI v 88% AI) and grade ≥3 (64% Ribo + AI v 19% AI) adverse reactions (ARs). CONCLUSION Addition of adjuvant ribociclib to NSAI for adults with high-risk stage II and III hormone receptor–positive, HER2-negative EBC demonstrated a favorable benefit-risk profile with a statistically significant iDFS advantage. OS data remain immature.