Green Angela K, Zhou Qin, Iasonos Alexia, Zammarrelli William A, Weigelt Britta, Ellenson Lora H, Chhetri-Long Rashmi, Shah Pooja, Loh Jade, Hom Vania, Selenica Pier, Erinjeri Joseph, Petkovska Iva, Chandarlapaty Sarat, Cohen Seth, Grisham Rachel, Konner Jason, Rubinstein Maria M, Tew William, Troso-Sandoval Tiffany, Aghajanian Carol, Makker Vicky
Memorial Sloan Kettering Cancer Center, New York, United States.
Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Clin Cancer Res. 2024 Nov 19. doi: 10.1158/1078-0432.CCR-24-1999.
Inhibition of the cyclin D-cyclin dependent kinase (CDK)4/6-INK4-retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer (EC) are suboptimal, perhaps due to genomic alterations that promote estrogen receptor (ER)-independent cyclin D1-CDK4/6 activation. We hypothesized that addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant will be an effective therapeutic strategy in patients with advanced or recurrent EC.
In this phase II study, patients with advanced or recurrent EC received 150 mg of abemaciclib orally twice daily with 500 mg of fulvestrant intramuscularly monthly with a 2-week loading dose. Eligibility included ER or progesterone receptor expression ³1% by immunohistochemistry, measurable disease, £2 prior lines of chemotherapy, and £1 prior line of hormonal therapy. The primary endpoint was objective response rate (ORR) by RECIST v1.1.
Twenty-seven patients initiated therapy and 25 were evaluable for efficacy. Eleven patients achieved partial response; 10 responses (91%) were in copy number-low/no specific molecular profile tumors, 1 (9%) was in a microsatellite instability-high tumor, and no responses were observed in copy number-high/TP53abnormal tumors. The ORR was 44% (90% CI, 27.0%-62.1%). Median duration of response was 15.6 months. Median progression-free survival was 9.0 months (90% CI: 1.8-20.4). The most common grade ³3 treatment-related adverse events were neutropenia (26%) and anemia (19%); no new safety signals were identified.
The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent EC; a randomized trial is planned.
抑制细胞周期蛋白D - 细胞周期蛋白依赖性激酶（CDK）4/6 - INK4 - 视网膜母细胞瘤通路可克服对内分泌单药治疗获得性或原发性的耐药。晚期子宫内膜癌（EC）对内分泌单药治疗的反应欠佳，这可能是由于促进雌激素受体（ER）非依赖性细胞周期蛋白D1 - CDK4/6激活的基因组改变所致。我们假设，在氟维司群抗雌激素治疗基础上加用CDK4/6激酶抑制剂阿贝西利，对于晚期或复发性EC患者将是一种有效的治疗策略。
在这项II期研究中，晚期或复发性EC患者每日口服两次150 mg阿贝西利，并每月肌肉注射500 mg氟维司群，初始剂量为期2周。入选标准包括免疫组化显示ER或孕激素受体表达≥1%、可测量的疾病、既往化疗不超过2线以及既往激素治疗不超过1线。主要终点是根据RECIST v1.1标准评估的客观缓解率（ORR）。
27例患者开始治疗，25例可评估疗效。11例患者获得部分缓解；10例缓解（91%）出现在拷贝数低/无特定分子特征的肿瘤中，1例（9%）出现在微卫星高度不稳定的肿瘤中，拷贝数高/TP53异常的肿瘤中未观察到缓解。ORR为44%（90%CI，27.0% - 62.1%）。中位缓解持续时间为15.6个月。中位无进展生存期为9.0个月（90%CI：1.8 - 20.4）。最常见的3级及以上治疗相关不良事件是中性粒细胞减少（26%）和贫血（19%）；未发现新的安全信号。
阿贝西利与氟维司群联合应用在晚期或复发性EC中具有良好活性和持久反应；计划开展一项随机试验。
