Princess Margaret Cancer Centre, Toronto, Canada.
Department of Medicine, University of Toronto, Toronto, Canada.
Sci Rep. 2019 May 14;9(1):7390. doi: 10.1038/s41598-019-43222-6.
ENMD-2076, an aurora-A kinase inhibitor with anti-angiogenic properties, has shown activity in solid and hematologic malignancies. We investigated oral ENMD-2076 in an open-label, single-arm phase II study using 275 mg daily on a 28-day cycle in patients with advanced soft-tissue sarcomas (STS) receiving ≤1 line of prior therapy. Primary endpoint was 6-month progression-free survival (PFS) with ≤15% indicating no interest, and ≥40% indicating further interest in ENMD-2076. Secondary/exploratory endpoints included clinical benefit (CBR ≥6-months) and objective response (ORR) rates, PFS, OS, safety, and whole-exome sequencing (WES) for potentially associated biomarkers. Overall, 23/25 (92%) patients receiving ENMD-2076 were efficacy evaluable with median follow-up of 14 months (range 2.2-39.5). Common subtypes were leiomyosarcoma (n = 10), undifferentiated pleomorphic sarcoma (n = 3), angiosarcoma (n = 3), and alveolar soft-part sarcoma (n = 3). The 6-month PFS was 20.8% (95% CI:3.2-38.4) with a CBR of 17% (95% CI:1.55-33.23) and ORR of 9% (95% CI:3.08-20.46). Median PFS was 2.5 months (95% CI:2.20-4.47) and OS was 14.1 months (95% CI:6.07-20.07). The most common high-grade treatment-related adverse event was hypertension (60%). WES identified PTPRB mutations in 3/4 patients (p = 0.018) benefiting from ENMD-2076. Although this study failed to meet its primary endpoint, occasional responses and prolonged stable disease was noted. ENMD-2076 evaluation in PTPRB mutated tumors and/or angiosarcoma is warranted.
ENMD-2076 是一种具有抗血管生成特性的极光激酶抑制剂，已在实体瘤和血液恶性肿瘤中显示出活性。我们在一项开放标签、单臂 II 期研究中研究了口服 ENMD-2076，该研究中，晚期软组织肉瘤（STS）患者接受每日 275mg 剂量的治疗，每 28 天为一个周期，这些患者在接受 ≤1 线既往治疗后入组。主要终点为 6 个月无进展生存率（PFS），如果 6 个月无进展生存率（PFS）≤15%，表明对 ENMD-2076 没有兴趣；如果 6 个月无进展生存率（PFS）≥40%，表明对 ENMD-2076 进一步感兴趣。次要/探索性终点包括临床获益率（CBR≥6 个月）和客观缓解率（ORR）、PFS、OS、安全性和全外显子组测序（WES）以确定潜在的相关生物标志物。总体而言，25 例接受 ENMD-2076 治疗的患者中，有 23 例（92%）可进行疗效评估，中位随访时间为 14 个月（范围 2.2-39.5）。常见的亚型是平滑肌肉瘤（n=10）、未分化多形性肉瘤（n=3）、血管肉瘤（n=3）和腺泡状软组织肉瘤（n=3）。6 个月的 PFS 为 20.8%（95%CI：3.2-38.4），CBR 为 17%（95%CI：1.55-33.23），ORR 为 9%（95%CI：3.08-20.46）。中位 PFS 为 2.5 个月（95%CI：2.20-4.47），OS 为 14.1 个月（95%CI：6.07-20.07）。最常见的 3 级治疗相关不良事件是高血压（60%）。WES 发现 4 例患者中有 3 例（p=0.018）存在 PTPRB 突变，这些患者从 ENMD-2076 中获益。尽管这项研究未能达到主要终点，但仍观察到偶发反应和延长的疾病稳定。ENMD-2076 在 PTPRB 突变肿瘤和/或血管肉瘤中的评估是合理的。
