固体瘤中的YAP/TEAD抑制剂VT3989:一个1/2阶段试验
Timothy A Yap1, David J Kwiatkowski2, Ibiayi Dagogo-Jack3
1The University of Texas MD Anderson Cancer Center, Houston, TX, USA. tyap@mdanderson.org.
Nature medicine
|October 19, 2025
概括
一种新型TEAD抑制剂VT3989通过破坏YAP信号传递,在治疗美索瘤方面表现有前途. 早期试验表明,它具有良好的安全性和有前途的疗效,在间皮瘤患者中,总体应答率为32%.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药物开发 药物开发
背景情况:
- 失调的Hippo信号传递和构成性YAP激活驱动中瘤的进展.
- 针对YAP-TEAD通路提供了治疗癌症的治疗策略,包括大皮质瘤.
- VT3989是一种第一类口服TEAD棕化抑制剂,旨在破坏YAP转录活性.
研究的目的:
- 为了评估VT3989的安全性和有效性,在人类第一阶段1/2试验中,对耐火实体瘤患者进行试验,重点是中皮瘤.
- 报告剂量升级和扩展队列的临时疗效结果.
- 为针对Hippo-YAP-TEAD途径提供早期临床概念证明.
主要方法:
- 1/2期临床试验,包括剂量升级 (n=85) 和扩展 (n=87) 队列.
- 招募了172名患者,其中135人被诊断为间皮瘤.
- 从正在进行的招聘中分析了临时疗效和安全数据.
主要成果:
- VT3989表现出良好的安全性,可控毒性,主要是1-2级.
- 观察到尿中白蛋白:肌素比率 (UACR) 和蛋白尿的增加,但可逆,无功能障碍.
- 在优化剂量和UACR值下,在间皮瘤患者中观察到32%的整体应答率 (ORR) 和86%的疾病控制率,中位数无进展生存时间为10个月.
结论:
- VT3989在间皮瘤治疗中表现出有前途的安全性和有效性.
- 这些发现代表了针对Hippo-YAP-TEAD途径的首次临床验证.
- VT3989已从FDA获得孤儿药物和快速通道指标,用于间皮瘤治疗.
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