Cancer cell · 2026
JYP0322, a highly selective and brain-penetrant ROS1 inhibitor, overcomes ROS1G2032R resistance mutation in NSCLC: The first-in-human phase 1 trial.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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Ma Yuxiang, Xue Jinhui, Gao Fangfang, Yang Yunpeng, Zhao Yuanyuan, Wang Linlin, Huang Zhangzhou, Wu Chunjiao, Luo Yongzhong, Li Juan, Fang Jian, Song Zhengbo, Li Yongsheng, Ma Huiwen, Guo Qinxiang, Yi Tienan, Liu Xiting, Liu Zhihua, Zhou Jianya, Dong Xiaorong, Yu Qitao, He Jianbo, Yang Liuzhong, Fang Wenfeng, Sun Yuping, Qi Yaling, Lv Jing, Ge Zhen, Xia Binyan, Li Lei, Wang Wei, Huang Yan, Zhang Li, Zhao Hongyun
Аннотация
Targeted therapies against ROS1-rearrangements face limitations due to resistance mutations, brain metastases, and central nervous system toxicities. We have developed a next-generation, brain-penetrant ROS1 inhibitor, JYP0322, that can overcome resistance mutations (e.g., ROS1G2032R) while minimizing off-target inhibition. In preclinical studies, JYP0322 demonstrated >130-fold selectivity over TRKA, potent antitumor activity in ROS1 re-arrangement and ROS1G2032R tumor models, and effective brain penetration (CSF/plasma AUC ratio 0.893). In a phase I trial (NCT06128148) enrolling 89 non-small cell lung cancer (NSCLC) patients with ROS1-fusion (36% with brain metastases), JYP0322 was well tolerated with low TRK-related neurologic events (dizziness: 6.7%; headache: 3.4%). Among 80 efficacy-evaluable patients, the objective response rate (ORR) was 95.7% in TKI-naive, 57.1% in those with ≥2 prior TKIs, and 77.8% in ROS1G2032R-mutant patients. Intracranial ORR was 55.6% among brain-metastatic patients. These findings highlight JYP0322 as a promising therapy for heavily pretreated NSCLC patients, including those with brain metastases or ROS1G2032R mutations.