Lower Ribociclib Dose Maintains Efficacy With Reduced Toxicity in Advanced HR-Positive, HER2-Negative Breast Cancer

Results from the phase 2 AMALEE trial demonstrate that a 400 mg starting dose of ribociclib, when combined with a nonsteroidal aromatase inhibitor, reduced the incidence of dose-dependent adverse events while maintaining comparable efficacy to the standard 600 mg dose among patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. 

“Ribociclib, 600 mg, showed substantial survival benefits…but was associated with dose-dependent adverse events that were manageable with dose reductions,” stated Fatima Cardoso, MD, Champalimaud Clinical Center, Lisbon, Portugal, et al. The investigators sought to determine whether “ribociclib, 400 mg, preserve[s] efficacy with reduced toxic effects.” 

In this open-label, multicenter study, 376 newly diagnosed pre- and postmenopausal patients were randomized 1:1 to receive either 400 mg (n = 188) or 600 mg (n = 188) of ribociclib plus a nonsteroidal aromatase inhibitor in continuous 28-day cycles. Premenopausal patients also received goserelin. 

The primary end point was overall response rate (ORR). Key secondary end points included duration of response (DOR), time to response, progression-free survival (PFS), pharmacokinetics, and safety. 

At analysis, the ORR was 48.9% in the 400 mg arm and 56.1% in the 600 mg arm. Median PFS was 26.9 months in the 400 mg arm and 25.1 months in the 600 mg arm. The DOR was 26.5 months and 28.8 months, respectively, and time to response was 13.1 months and 9 months, respectively. The 400 mg dose had 28% lower maximal plasma concentration and 42.7% lower 24-hour area under the curve. 

Grade ≥3 adverse events were reported in 65.4% of patients in the 400 mg arm and 79.3% in the 600 mg arm, most frequently including neutropenia and increased alanine aminotransferase (ALT) level. Serious adverse events occurred in 20.2% and 19.7% of patients, respectively; the most frequent serious adverse event was dyspnea. Neutropenia, leukopenia, anemia, thrombocytopenia, and infection occurred less often in the 400 mg arm. Incidences of liver-related adverse events, kidney toxic effects, and interstitial lung disease or pneumonitis were similar between treatment arms.  

Adverse events led to dose reductions in 15.4% of patients in the 400 mg arm and 51.6% in the 600 mg arm, and to dose interruptions in 36.8% and 61% of patients, respectively. Treatment discontinuations due to adverse events occurred in 22.3% and 19.8% of patients, respectively. Across both treatment arms, 32 patients initiated new antineoplastic (ANP) therapy. Adverse events led to the initiation of additional therapy in 70.7% of patients in the 400 mg arm and 81.4% in the 600 mg arm. Two treatment-related deaths were reported in the 400 mg arm and 3 in the 600 mg arm. 

“The AMALEE randomized clinical trial did not demonstrate ORR noninferiority of ribociclib, 400 mg, versus ribociclib, 600 mg, with comparable DOR and PFS between doses,” concluded Dr Cardoso and colleagues. “The trial results suggest that the ribociclib starting dose for HR-positive, HER2-negative advanced breast cancer should remain 600 mg, but dose reduction can help manage certain adverse events.”

Source:

Cardoso F, Jacot W, Kuemmel S, et al. 600- vs 400-mg first-line ribociclib in hormone receptor–positive/ERBB2–negative advanced breast cancer. JAMA Oncol. Published online September 25, 2025. doi:10.1001/jamaoncol.2025.3687