E2112：内分泌治疗联合恩替诺特或安慰剂治疗激素受体阳性晚期乳腺癌的随机 III 期试验。ECOG-ACRIN 癌症研究组的一项试验。
E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group.
机构信息
The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
Cancer Research at UCC, College of Medicine and Health, University College Cork, Cork, Ireland.
出版信息
J Clin Oncol. 2021 Oct 1;39(28):3171-3181. doi: 10.1200/JCO.21.00944. Epub 2021 Aug 6.
PURPOSE
Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.
PATIENTS AND METHODS
E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15.
RESULTS
Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients.
CONCLUSION
The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.
目的
晚期乳腺癌的内分泌治疗耐药仍是一个重大的临床问题，使用组蛋白去乙酰化酶抑制剂（如恩替诺特）可能会克服这一问题。ENCORE301 期 2 研究报告称，在晚期激素受体（HR）阳性、人表皮生长因子受体 2（HER2）阴性乳腺癌中，与安慰剂相比，添加恩替诺特可延长甾体芳香酶抑制剂（AI）依西美坦的无进展生存期（PFS）和总生存期（OS）。
患者和方法
E2112 是一项多中心、随机、双盲、安慰剂对照的 3 期研究，纳入了疾病进展后的非甾体 AI 治疗的 HR 阳性、HER2 阴性晚期乳腺癌的男性或女性患者。参与者被随机分配至依西美坦 25mg 口服，每日一次，恩替诺特（EE）或安慰剂（EP）5mg 口服，每周一次。主要终点为中心审查的 PFS 和 OS。次要终点包括安全性、客观缓解率以及基线至第 1 周期第 15 天外周血单核细胞中的赖氨酸乙酰化变化。
结果
2014 年 3 月至 2018 年 10 月期间共随机分配了 608 例患者。中位年龄为 63 岁（范围 29-91），60%有内脏疾病，84%在转移性疾病中进展后接受了非甾体 AI 治疗。既往治疗包括化疗（60%）、氟维司群（30%）和细胞周期蛋白依赖性激酶抑制剂（35%）。EE 臂中最常见的 3 级和 4 级不良事件包括中性粒细胞减少症（20%）、低磷血症（14%）、贫血（8%）、白细胞减少症（6%）、疲劳（4%）、腹泻（4%）和血小板减少症（3%）。中位 PFS 为 3.3 个月（EE）与 3.1 个月（EP；风险比=0.87；95%CI，0.67 至 1.13；=0.30）。中位 OS 为 23.4 个月（EE）与 21.7 个月（EP；风险比=0.99；95%CI，0.82 至 1.21；=0.94）。客观缓解率为 5.8%（EE）和 5.6%（EP）。药效学分析证实了恩替诺特治疗患者的靶抑制。
结论
在 AI 耐药的 HR 阳性、HER2 阴性晚期乳腺癌中，依西美坦和恩替诺特联合治疗并未改善患者的生存。
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