JYP0322, a highly selective and brain-penetrant ROS1 inhibitor, overcomes ROS1G2032R resistance mutation in NSCLC: The first-in-human phase 1 trial

  • Cancer Cell. 2026 May 11;44(5):983-994.e5. doi: 10.1016/j.ccell.2026.03.018.
Yuxiang Ma  1 ,  Jinhui Xue  1 ,  Fangfang Gao  2 ,  Yunpeng Yang  1 ,  Yuanyuan Zhao  1 ,  Linlin Wang  3 ,  Zhangzhou Huang  4 ,  Chunjiao Wu  5 ,  Yongzhong Luo  6 ,  Juan Li  7 ,  Jian Fang  8 ,  Zhengbo Song  9 ,  Yongsheng Li  10 ,  Huiwen Ma  10 ,  Qinxiang Guo  11 ,  Tienan Yi  12 ,  Xiting Liu  13 ,  Zhihua Liu  14 ,  Jianya Zhou  15 ,  Xiaorong Dong  16 ,  Qitao Yu  17 ,  Jianbo He  17 ,  Liuzhong Yang  18 ,  Wenfeng Fang  1 ,  Yuping Sun  3 ,  Yaling Qi  19 ,  Jing Lv  19 ,  Zhen Ge  20 ,  Binyan Xia  19 ,  Lei Li  19 ,  Wei Wang  19 ,  Yan Huang  21 ,  Li Zhang  22 ,  Hongyun Zhao  23
Affiliations
  • 1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 2. Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
  • 3. Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China.
  • 4. Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, China.
  • 5. Jilin Cancer Hospital, Jilin 130051, China.
  • 6. The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410031, China.
  • 7. Sichuan Cancer Hospital, Chengdu 610041, China.
  • 8. Peking University Cancer Hospital, Beijing 100142, China.
  • 9. Zhejiang Cancer Hospital, Hangzhou 310011, China.
  • 10. Chongqing University Cancer Hospital, Chongqing 400030, China.
  • 11. Shanxi Cancer Hospital, Taiyuan 030013, China.
  • 12. Xiangyang Central Hospital, Xiangyang 441106, China.
  • 13. Gansu Provincial Cancer Hospital, Lanzhou 730050, China.
  • 14. Jiangxi Cancer Hospital, Nanchang 330029, China.
  • 15. The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
  • 16. Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430023, China.
  • 17. Guangxi Medical University Cancer Hospital, Nanning 530012, China.
  • 18. The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, China.
  • 19. Guangzhou Joyo Pharma Co., LTD, Shanghai 201203, China.
  • 20. Guangzhou Joyo Pharma Co., LTD, Shanghai 201203, China; Hangzhou Chengbang Pharmaceutical Technology Co., Ltd., Hangzhou, Zhejiang 310051, China.
  • 21. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: [email protected].
  • 22. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: [email protected].
  • 23. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: [email protected].
PMID: 42030931 DOI: 10.1016/j.ccell.2026.03.018
Abstract

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.

Keywords
G2032R mutation; ROS1 inhibitor; brain metastases; phase 1 trial; tyrosine kinase inhibitor.
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