BACKGROUND Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα (ESR1). METHODS In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib. Primary end points were investigator-assessed progression-free survival with imlunestrant as compared with standard therapy among patients with ESR1 mutations and among all patients and with imlunestrant-abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently. RESULTS Overall, 874 patients underwent randomization, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant-abemaciclib. Among 256 patients with ESR1 mutations, the median progression-free survival was 5.5 months with imlunestrant and 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) with imlunestrant and 5.4 months (95% CI, 4.6 to 6.2) with standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P<0.001). In the overall population, the median progression-free survival was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; P = 0.12). Among 426 patients in the comparison of imlunestrant-abemaciclib with imlunestrant, the median progression-free survival was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; P<0.001). The incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant-abemaciclib. CONCLUSIONS Among patients with ER-positive, HER2-negative advanced breast cancer, treatment with imlunestrant led to significantly longer progression-free survival than standard therapy among those with ESR1 mutations but not in the overall population. Imlunestrant-abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of ESR1-mutation status. (Funded by Eli Lilly; EMBER-3 ClinicalTrials.gov number, NCT04975308.).

中文翻译：

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Imlunestrant 联合或不联合 Abemaciclib 治疗晚期乳腺癌。


背景Imlunestrant 是下一代、可透过脑渗透的口服选择性雌激素受体 （ER） 降解剂，即使在编码 ERα （ESR1） 基因突变的癌症中也能提供持续的 ER 抑制。方法 在一项 3 期开放标签试验中，我们招募了 ER 阳性、人表皮生长因子受体 2 （HER2） 阴性晚期乳腺癌患者，这些患者在芳香化酶抑制剂治疗期间或之后复发或进展，单独给药或与细胞周期蛋白依赖性激酶 4 和 6 （CDK4/6） 抑制剂联合给药。患者以 1：1：1 的比例分配接受 imlunestrant、标准内分泌单药治疗或 imlunestrant-abemaciclib。主要终点是研究者评估的 imlunestrant 与标准治疗相比，在 ESR1 突变患者和所有患者中的无进展生存期，以及 imlunestrant-abemaciclib 与imlunestrant 相比，在所有同时接受随机分组的患者中。结果 总体而言，874 例患者接受了随机分组，其中 331 例被分配到 imlunestrant，330 例被分配到标准治疗组，213 例被分配到 imlunestrant-abemaciclib 组。在 256 例 ESR1 突变患者中，imlunestrant 组的中位无进展生存期为 5.5 个月，标准治疗组的中位无进展生存期为 3.8 个月。估计 19.4 个月时的限制性平均生存时间为 7.9 个月 （95% 置信区间 [CI]，6.8 至 9.1），标准治疗组为 5.4 个月 （95% CI，4.6 至 6.2） （差异，2.6 个月;95% CI，1.2 至 3.9;P<0.001）。在总人群中，imlunestrant 组的中位无进展生存期为 5.6 个月，标准治疗组为 5.5 个月（进展或死亡风险比，0.87;95% CI，0.72 至 1.04;P = 0.12）。 在 imlunestrant-abemaciclib 与 imlunestrant 对照组的 426 例患者中，中位无进展生存期分别为 9.4 个月和 5.5 个月（风险比，0.57;95% CI，0.44 至 0.73;P<0.001）。3 级或更高级别不良事件的发生率为 imlunestrant 组 17.1%，标准治疗组 20.7%，imlunestrant-abemaciclib 组 48.6%。结论在 ER 阳性、 HER2 阴性晚期乳腺癌患者中，imlunestrant 治疗导致 ESR1 突变患者的无进展生存期显著延长于标准治疗，但在总体人群中未获。与 imlunestrant 相比，Imlunestrant-abemaciclib 显着提高了无进展生存期，无论 ESR1 突变状态如何。（由 Eli Lilly 资助;EMBER-3 ClinicalTrials.gov 编号，NCT04975308.）。