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Ref Type Abstract
PMID
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
Title Abstract CT052: A highly selective, brain-penetrant and overcoming G2032R resistance ROS1 inhibitor JYP0322 in NSCLC patients with ROS1 fusion
Journal Vol Issue Date Pages Journal Short Title
Cancer Research 85 8_Supplement_2 April 25 2025 Cancer Res
URL https://aacrjournals.org/cancerres/article/85/8_Supplement_2/CT052/761656/Abstract-CT052-A-highly-selective-brain-penetrant
Abstract Text 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.

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