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

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.