Xia Yang, Tian Panwen, Zhou Mo, Zhao Jun, Jin Yang, Guo Zhiyuan, Li Xiuzhen, Lu Weina, Miao Da, Lu Yuefei, Xu Wanting, Zhang Yongchang, Le Xiuning, Li Wen
Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
EClinicalMedicine. 2025 Feb 12;81:103099. doi: 10.1016/j.eclinm.2025.103099. eCollection 2025 Mar.
exon14 skipping mutations (ex14) is an established actionable driver oncogene of non-small-cell lung cancer (NSCLC). While ensartinib is a known second-generation tyrosine kinase inhibitor with primary activity against translocation, it is also classified as a type Ia MET inhibitor. We have previously shown anti-tumor activity against ex14 positive NSCLC both and . The EMBRACE trial aims to evaluate the clinical efficacy and safety of ensartinib for treatment of ex14 positive NSCLC.
This is a multicenter single arm phase II investigator-initiated study that enrolled ex14 positive lung cancer after failing first line chemotherapy and/or immunotherapy. Eligible patients received ensartinib 225 mg orally once daily in a continuous 28-day treatment cycle until disease progression, unacceptable side effect, or death. Primary endpoint was investigator-assessed objective response rate (ORR), and the secondary end point included disease control rate (DCR), progression-free survival (PFS), duration of response (DoR) and safety profiles. The study was registered with the Chinese Clinical Trial Registry (ChiCTR2100048767).
From July 2021 to February 2024, a total of 31 patients were enrolled and received ensartinib. Median follow-up time of the 30 evaluable patients was 9.2 months (95% Confidence Interval [CI], 6.3-not estimable). The ORR was 53.3% (16/30; 95% CI, 35.5-71.2) and DCR was 86.7% (26/30; 95% CI, 74.5-98.8). Median PFS was 6.0 months (95% CI, 3.0-8.8) and median DoR was 7.9 months (95% CI, 4.8-8.7). Adverse events (AEs) were reported in 24 patients (80%), with 7 (23.3%) of grade 3. The most common AEs were rash (14/30, 46.7%), followed by anemia (7/30, 23.3%), increased ALT (7/30, 23.3%), increased AST (7/30, 23.3%), and pruritus (6/30, 20%). No serious adverse events or treatment-related deaths occurred. Importantly, the exploratory ctDNA analysis indicates that clearance of circulating tumor DNA (ctDNA) at four weeks treatment was associated with more favorable treatment outcomes comparing with patients having positive ctDNA.
Ensartinib has a promising anti-tumor activity and manageable safety in previously treated patients with ex14 positive lung cancer.
This work was supported by the National Natural Science Foundation of China [82370028, 82422001] and the CSCO-MET Aberrant Solid Tumor Research Grant [Y-2022METAZMS-0066].
外显子14跳跃突变（ex14）是非小细胞肺癌（NSCLC）中一种已确定的可靶向驱动致癌基因。恩沙替尼是一种已知的第二代酪氨酸激酶抑制剂，主要作用于转位，也被归类为Ia型MET抑制剂。我们之前已证明其对ex14阳性NSCLC具有抗肿瘤活性。EMBRACE试验旨在评估恩沙替尼治疗ex14阳性NSCLC的临床疗效和安全性。
这是一项多中心单臂II期研究者发起的研究，纳入一线化疗和/或免疫治疗失败后的ex14阳性肺癌患者。符合条件的患者在连续28天的治疗周期中，每天口服一次225mg恩沙替尼，直至疾病进展、出现不可接受的副作用或死亡。主要终点是研究者评估的客观缓解率（ORR），次要终点包括疾病控制率（DCR）、无进展生存期（PFS）、缓解持续时间（DoR）和安全性。该研究已在中国临床试验注册中心注册（ChiCTR2100048767）。
2021年7月至2024年2月，共纳入31例患者并接受了恩沙替尼治疗。30例可评估患者的中位随访时间为9.2个月（95%置信区间[CI]，6.3 - 不可估计）。ORR为53.3%（16/30；95%CI，35.5 - 71.2），DCR为86.7%（26/30；95%CI，74.5 - 98.8）。中位PFS为6.0个月（95%CI，3.0 - 8.8），中位DoR为7.9个月（95%CI，4.8 - 8.7）。24例患者（8%）报告了不良事件（AE），其中3级AE有7例（23.3%）。最常见的AE是皮疹（14/30，46.7%），其次是贫血（7/30，23.3%）、ALT升高（7/30，23.3%）、AST升高（7/30，23.3%）和瘙痒（6/30，20%）。未发生严重不良事件或与治疗相关的死亡。重要的是，探索性循环肿瘤DNA（ctDNA）分析表明，与ctDNA阳性的患者相比，治疗四周时循环肿瘤DNA（ctDNA）的清除与更有利的治疗结果相关。
恩沙替尼在先前接受治疗的ex14阳性肺癌患者中具有有前景的抗肿瘤活性和可管理的安全性。
本研究得到中国国家自然科学基金[82370028, 82422001]和中国临床肿瘤学会 - MET异常实体瘤研究基金[Y-2022METAZMS-0066]的支持。
