Ribociclib 200mg tablets

Importance: Ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) has demonstrated a statistically significant invasive disease-free survival (iDFS) benefit over NSAI alone in patients with hormone receptor-positive/ERBB2 (formerly HER2)-negative early breast cancer. Evaluating the efficacy and safety of adjuvant ribociclib beyond the planned 3-year treatment period is critical for understanding the long-term impact on recurrences. Objective: To evaluate efficacy and safety of adjuvant ribociclib in an exploratory 4-year analysis of the NATALEE (New Adjuvant Trial With Ribociclib [LEE011]) randomized clinical trial, with all patients no longer receiving ribociclib treatment. Design, Setting, and Participants: This exploratory analysis of an international, open-label, randomized phase 3 trial analyzed adjuvant treatment for premenopausal and postmenopausal women and men with hormone receptor-positive/ERBB2-negative early breast cancer. Eligible patients had anatomic stage IIA (either N0 with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III disease per the American Joint Committee on Cancer Staging Manual, eighth edition. The data cutoff date was April 29, 2024. Interventions: Patients were randomized 1:1 to receive ribociclib (400 mg once daily, days 1-21 of a 28-day cycle, over 36 months) plus NSAI (letrozole, 2.5 mg, or anastrozole, 1 mg, once daily continuously for 60 months) or NSAI alone. Men and premenopausal women also received goserelin (3.6 mg once every 28 days administered subcutaneously). Main Outcomes and Measures: The primary end point was iDFS, and secondary efficacy end points included distant disease-free survival, recurrence-free survival, and overall survival. Survival was evaluated by the Kaplan-Meier method. Results: Among 5101 patients included in the analysis (median [range] age, 52 [24-90] years; 5081 [99.6%] female), the median follow-up for iDFS was 44.2 months (range, 0-63 months). Ribociclib plus NSAI continued to show iDFS benefit over NSAI alone (hazard ratio, 0.72; 95% CI, 0.61-0.84), with 3-year iDFS rates of 90.8% vs 88.1% (difference, 2.7 percentage points) and 4-year rates of 88.5% vs 83.6% (difference, 4.9 percentage points). The efficacy benefit was consistent across subgroups and secondary end points. Overall survival data remain immature, although a trend in favor of ribociclib plus NSAI over NSAI alone was observed (hazard ratio, 0.83; 95% CI, 0.64-1.07). The incidence of adverse events has remained stable. Conclusions and Relevance: This exploratory analysis of the NATALEE randomized clinical trial, with a median follow-up beyond the 3-year treatment duration, demonstrated consistent iDFS benefit with ribociclib plus NSAI over NSAI alone. Trial Registration: ClinicalTrials.gov Identifier: NCT03701334.

Abstract licence: CC BY-NC-ND

Importance: Ribociclib, 600 mg showed substantial survival benefits in patients with hormone receptor-positive (HR+)/ERRB2-negative (ERBB2-; formerly HER2) advanced breast cancer (ABC) in the phase 3 MONALEESA trials but was associated with dose-dependent adverse events (AEs) that were manageable with dose reductions. Objective: To investigate whether a 400-mg ribociclib starting dose could reduce the incidence of AEs while maintaining efficacy in ABC. Design, Setting, and Participants: The AMALEE phase 2, multicenter, randomized, open-label, interventional noninferiority study was conducted between June 18, 2019, and December 8, 2020, and included pre- and postmenopausal women with newly diagnosed HR+/ERBB2- ABC. The study was conducted across 107 sites in 23 countries (across Europe and Australia, Latin America, North America, and Asia). The data were analyzed at the final data cutoff (August 30, 2024). Interventions: Randomization 1:1 to ribociclib, 400 mg + a nonsteroidal aromatase inhibitor or ribociclib, 600 mg + a nonsteroidal aromatase inhibitor (premenopausal patients also received goserelin). Main Outcomes and Measures: Overall response rate (ORR; primary end point); ΔFridericia-corrected QT interval (QTcF) from baseline to cycle 1 day 15, 2 hours postdose (ΔQTcF; secondary end point); duration of response (DOR); time to response (TTR); progression-free survival (PFS); pharmacokinetics; and safety. Final analysis results are reported. Results: Baseline characteristics and prior anticancer therapy were balanced among the 376 patients (median [range] age, 58.0 [27-96] years). Median (range) follow-up from randomization was 53.5 (36.0-64.0) months (final data cutoff: August 30, 2024). The absolute ORR difference between ribociclib, 400 mg and ribociclib, 600 mg was -7.2% (ORR ratio, 0.87; 90% CI, 0.74-1.03). With ribociclib, 400 mg vs ribociclib, 600 mg, median PFS (26.9 vs 25.1 months) and DOR (26.5 vs 28.8 months) were similar; TTR was longer (13.1 vs 9.0 months). The maximal plasma concentration after dose and the 24-hour area under the curve (measured at the primary data cutoff) were 28.0% and 42.7% lower, respectively, with ribociclib, 400 mg than ribociclib, 600 mg. Ribociclib, 400 mg had a shorter ΔQTcF (12.5 vs 19.7 milliseconds at cycle 1 day 15, 2 hours postdose), lower grade 3 or4 neutropenia rate (41.0% vs 58.5%), and fewer patients who required dose reduction due to AEs (29 patients [15.4%] vs 69 patients [36.9%]). Liver-related AEs, kidney toxic effects, interstitial lung disease or pneumonitis, and AE-prompted discontinuation rates were similar between arms. Conclusions and Relevance: The AMALEE randomized clinical trial did not demonstrate ORR noninferiority of ribociclib, 400 mg vs ribociclib, 600 mg, with comparable DOR and PFS between doses. Ribociclib, 400 mg had longer TTR, lower pharmacokinetic exposure, and lower rates of QTcF prolongation and neutropenia. The final results confirmed the standard ribociclib, 600 mg starting dose in HR+/ERBB2- ABC while supporting dose reduction to manage dose-dependent AEs. Trial Registration: ClinicalTrials.gov Identifier: NCT03822468.

Abstract licence: CC BY-NC-ND