600- vs 400-mg First-Line Ribociclib in Hormone Receptor-Positive/ERBB2-Negative Advanced Breast Cancer: The AMALEE Randomized Clinical Trial.

Background

To investigate whether a 400-mg ribociclib starting dose could reduce the incidenceof AEs while maintaining efficacy in ABC.

研究400毫克的Ribociclib起始剂量是否能在保持ABC疗效的同时降低不良事件的发生率。

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.

AMALEE 第 2 期，多中心、随机、开放标签、非劣效性干预研究，于 2019 年 6 月 18 日至 2020 年 12 月 8 日进行，纳入了具有新诊断的 HR+/ERBB2- ABC 的绝经前和绝经后女性。

The study was conducted across 107 sites in 23 countries (across Europe and Australia, Latin America, North America, and Asia).

该研究在 23 个国家的 107 个地点进行（包括欧洲和澳大利亚、拉丁美洲、北美和亚洲）。

The data were analyzed at the final data cutoff (August 30, 2024).

数据在最终数据截止日期（2024年8月30日）进行了分析。

Methods

Randomization 1:1 to ribociclib, 400 mg + a nonsteroidal aromatase inhibitor or ribociclib, 600 mg + a nonsteroidal aromatase inhibitor (premenopausal patients also received goserelin).

随机分配比例为1:1，分别接受400毫克利博西利+一种非甾体芳香酶抑制剂或600毫克利博西利+一种非甾体芳香酶抑制剂（绝经前患者还接受了戈舍瑞林治疗）。

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.

总体反应率（ORR; 主要终点）; 从基线到第1周期第15天，给药后2小时的Fridericia校正QT间期（QTcF）变化（ΔQTcF; 次要终点）; 反应持续时间（DOR）; 反应时间（TTR）; 无进展生存期（PFS）; 药代动力学; 以及安全性。

Final analysis results are reported.

最终分析结果已报告。

Results

Baseline characteristics and prior anticancer therapy were balanced among the 376 patients (median [range] age, 58.0 [27-96] years).

376名患者的基线特征和先前的抗癌治疗是平衡的（中位年龄[范围]，58.0[27-96]岁）。

Median (range) follow-up from randomization was 53.5 (36.0-64.0) months (final data cutoff: August 30, 2024).

从随机分组开始的中位（范围）随访时间为53.5（36.0-64.0）个月（最终数据截止日期：2024年8月30日）。

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).

在使用400 mg和600 mg的ribociclib治疗组之间，客观缓解率（ORR）的绝对差异为-7.2%（ORR比率，0.87；90%置信区间，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).

使用400 mg和600 mg的ribociclib治疗组，中位无进展生存期（PFS）分别为26.9个月和25.1个月，而持续缓解时间（DOR）分别为26.5个月和28.8个月，两者相似；但治疗开始到反应时间（TTR）更长（13.1个月对比9.0个月）。

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.

在剂量后最大血浆浓度和24小时曲线下面积（在主要数据截止时测量）分别比600毫克的利博西利低28.0%和42.7%。

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%]).

400毫克的利博西利在第一个周期的第15天，剂量后2小时的ΔQTcF较短（12.5毫秒对比19.7毫秒），3级或4级中性粒细胞减少症的发生率较低（41.0%对比58.5%），并且因不良事件需要减少剂量的患者较少（29名患者[15.4%]对比69名患者[36.9%]）。

Liver-related AEs, kidney toxic effects, interstitial lung disease or pneumonitis, and AE-prompted discontinuation rates were similar between arms.

在两组之间，与肝脏相关的不良事件、肾脏毒性、间质性肺病或肺炎以及因不良事件导致的停药率相似。

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.

AMALEE 随机临床试验未证明400毫克与600毫克利博西利的客观缓解率（ORR）非劣效性，两剂量组的缓解持续时间（DOR）和无进展生存期（PFS）相当。

Ribociclib, 400 mg had longer TTR, lower pharmacokinetic exposure, and lower rates of QTcF prolongation and neutropenia.

400 mg的Ribociclib具有更长的TTR（治疗反应持续时间）、较低的药代动力学暴露量以及较低的QTcF延长和中性粒细胞减少症发生率。

The final results confirmed the standard ribociclib, 600 mg starting dose in HR+/ERBB2- ABC while supporting dose reduction to manage dose-dependent AEs.

最终结果确认了在HR+/ERBB2- ABC中，标准的Ribociclib起始剂量为600 mg，同时支持降低剂量以管理剂量依赖性不良事件。

trial_registration

ClinicalTrials.gov Identifier: NCT03822468.

临床试验注册号：NCT03822468。