Abstract CT052: A highly selective, brain-penetrant and overcoming G2032R resistance ROS1 inhibitor JYP0322 in NSCLC patients with ROS1 fusion
Authors: Hongyun Zhao, Yanqiu Zhao, Yuxiang Ma, Yan Zhang, Zhangzhou Huang, Ying Cheng, Zhengbo Song, Yongzhong Luo, Juan Li, Wei Wei, Yaling Qi, Binyan Xia, Yuexia Zeng, Jing Lv, Li Zhang
Journal: Cancer Research (2025)

Abstract Background: JYP0322 is a potent, brain-penetrant and highly selective ROS1 inhibitor, demonstrating over 100-fold selectivity for ROS1 compared to TRKA and sub-nanomolar potency against the ROS1 G2032R resistance mutation. JYP0322 is designed to simultaneously address the key clinical challenges including ROS1 resistance mutations, tumor brain metastases while avoiding the off-target neurotoxicity associated with TRK inhibition. Method: The Phase I study (NCT06128148) was designed to evaluate safety, pharmacokinetics (PK), and preliminary clinical efficacy in patients with locally advanced or metastatic ROS1+NSCLC, including both ROS1 TKI pre-treated patients as well as TKI naïve patients. Response was assessed by investigators according to RECIST V1.1. Results: As of December 10, 2024, dose escalation study was conducted across 7 dose levels: 50mg qd, 100mg qd, 200mg qd, 100mg bid, 150mg bid, 200mg bid, 150mg tid and dose expansion stage is ongoing at doses of 100mg bid, 150mg bid and 150mg tid. A total of 73 NSCLC patients were enrolled. No dose-limiting toxicities were observed. The most frequently reported treatment related adverse events (TRAE) were low grade including weight gains (32.9%), hyperglyceridemia (31.5%), hypercholesteremia (26%), and AST elevation (21.9%). Grade 3-5 TRAE occurred in 12.3% patients. Only low grade neurotoxicities (6.8%) occurred. Among 58 efficacy evaluable patients, objective response rates (ORRs) were 85.7% (12/14) for ROS1 TKI naive, 54.5% (12/22) for patients previously received ≥2L systemic therapy and ≥1 prior ROS1 TKIs including 19 patients pre-treated with 2 to 4 ROS1 TKIs (Table). In ROS1 G2032R mutant cancers, ORR was 71.4% (5/7) with 3 patients pre-treated with Lorlatinib. In patients with measurable brain metastasis at baseline, intracranial ORR was 33.3% (2/6) and intracranial DCR was 83.3%. JYP0322 showed significantly brain penetration ability with the brain to plasma ration 1.20. Enrollment in the dose expansion stage is ongoing. Conclusions: JYP0322 had a favorable safety profile with a low incidence of neurotoxicities. It showed highly promising anti-tumor effects in patients with ROS1+NSCLC including both TKI-naïve and TKI pre-treated patients, as well as those with TKI-heavily treated, brain metastases, or harboring ROS1 G2032R mutation. Citation Format: Hongyun Zhao, Yanqiu Zhao, Yuxiang Ma, Yan Zhang, Zhangzhou Huang, Ying Cheng, Zhengbo Song, Yongzhong Luo, Juan Li, Wei Wei, Yaling Qi, Binyan Xia, Yuexia Zeng, Jing Lv, Li Zhang. A highly selective, brain-penetrant and overcoming G2032R resistance ROS1 inhibitor JYP0322 in NSCLC patients with ROS1 fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT052.