Jhaveri Komal L, Neven Patrick, Casalnuovo Monica Lis, Kim Sung-Bae, Tokunaga Eriko, Aftimos Philippe, Saura Cristina, O'Shaughnessy Joyce, Harbeck Nadia, Carey Lisa A, Curigliano Giuseppe, Llombart-Cussac Antonio, Lim Elgene, García Tinoco María de la Luz, Sohn Joohyuk, Mattar André, Zhang Qingyuan, Huang Chiun-Sheng, Hung Chih-Chiang, Martinez Rodriguez Jorge Luis, Ruíz Borrego Manuel, Nakamura Rikiya, Pradhan Kamnesh R, Cramer von Laue Christoph, Barrett Emily, Cao Shanshan, Wang Xuejing Aimee, Smyth Lillian M, Bidard François-Clément
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.
University Hospitals Leuven, Leuven, Belgium.
N Engl J Med. 2025 Mar 27;392(12):1189-1202. doi: 10.1056/NEJMoa2410858. Epub 2024 Dec 11.
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 ().
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 mutations and among all patients and with imlunestrant-abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently.
Overall, 874 patients underwent randomization, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant-abemaciclib. Among 256 patients with 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.
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 mutations but not in the overall population. Imlunestrant-abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of -mutation status. (Funded by Eli Lilly; EMBER-3 ClinicalTrials.gov number, NCT04975308.).
Imlunestrant是一种新一代的、可穿透血脑屏障的口服选择性雌激素受体（ER）降解剂，即使在编码ERα的基因发生突变的癌症中也能持续抑制ER。
在一项3期开放标签试验中，我们纳入了雌激素受体阳性、人表皮生长因子受体2（HER2）阴性的晚期乳腺癌患者，这些患者在芳香化酶抑制剂治疗期间或之后复发或进展，单独使用或与细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂联合使用。患者按1:1:1的比例分配，分别接受Imlunestrant、标准内分泌单药治疗或Imlunestrant-阿贝西利。主要终点是研究者评估的在有特定突变的患者中以及在所有患者中Imlunestrant与标准治疗相比的无进展生存期，以及在所有同时接受随机分组的患者中Imlunestrant-阿贝西利与Imlunestrant相比的无进展生存期。
总体而言，874例患者接受了随机分组，331例分配至Imlunestrant组，330例分配至标准治疗组，213例分配至Imlunestrant-阿贝西利组。在256例有特定突变的患者中，Imlunestrant组的中位无进展生存期为5.5个月，标准治疗组为3.8个月。Imlunestrant组在19.4个月时的估计受限平均生存时间为7.9个月（第95百分位数可信区间[CI]，6.8至9.1），标准治疗组为5.4个月（95%CI，4.6至6.2）（差异为2.6个月；95%CI，1.2至3.9；P<0.001）。在总体人群中，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（进展或死亡的风险比为0.87；95%CI，0.72至1.04；P = 0.12）。在Imlunestrant-阿贝西利与Imlunestrant比较的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（风险比为0.57；95%CI，0.44至0.73；P<0.001）。3级或更高等级不良事件的发生率在Imlunestrant组为17.1%，标准治疗组为20.7%，Imlunestrant-阿贝西利组为48.6%。
在雌激素受体阳性、HER2阴性的晚期乳腺癌患者中，Imlunestrant治疗在有特定突变的患者中导致的无进展生存期显著长于标准治疗，但在总体人群中并非如此。与Imlunestrant相比，Imlunestrant-阿贝西利显著改善了无进展生存期，无论特定突变状态如何。（由礼来公司资助；EMBER-3临床试验注册号，NCT04975308。）
