Purpose: 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. Methods: 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. Results: 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. Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent EC; a randomized trial is planned.

中文翻译：

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氟维司群联合 Abemaciclib 治疗激素受体阳性晚期或复发性子宫内膜癌的 II 期研究


目的：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以克服对内分泌单药治疗的获得性或新发治疗耐药性。晚期子宫内膜癌 （EC） 对内分泌单药治疗的反应并不理想，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。我们假设在氟维司群抗雌激素治疗中加入 abemaciclib（一种 CDK4/6 激酶抑制剂）将是晚期或复发性 EC 患者的有效治疗策略。方法：在这项 II 期研究中，晚期或复发性 EC 患者接受 150 mg abemaciclib 口服，每天两次，每月肌肉注射 500 mg 氟维司群，负荷剂量为 2 周。资格包括免疫组化 ER 或孕激素受体表达 ³1%、可测量的疾病、2 英镑的既往化疗和 1 英镑的激素治疗。主要终点是 RECIST v1.1 的客观缓解率 （ORR）。结果： 27 例患者开始治疗，25 例可评估疗效。11 例患者达到部分反应;10 例反应 （91%） 发生在低拷贝数/无特异性分子特征肿瘤中，1 例 （9%） 发生在微卫星不稳定性高肿瘤中，在拷贝数高/TP53 异常肿瘤中未观察到反应。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 ³3 级治疗相关不良事件是中性粒细胞减少症 （26%） 和贫血 （19%）;未发现新的安全信号。 结论： abemaciclib 和氟维司群的组合在晚期或复发性 EC 中具有有希望的活性和持久的反应;计划进行一项随机试验。