What question did this study set out to answer?

To evaluate the efficacy and safety of JYP0322, a brain-penetrant ROS1 inhibitor, in NSCLC patients with ROS1 reorganizations and resistance mutations.

April 27, 2026Cancer Cell0 citationsOpen Access

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

YMYuxiang Ma JXJinhui Xue FGFangfang Gao

Key Points

To evaluate the efficacy and safety of JYP0322, a brain-penetrant ROS1 inhibitor, in NSCLC patients with ROS1 reorganizations and resistance mutations.
Phase 1 trial (NCT06128148) involving 89 NSCLC patients with ROS1 fusions, 36% with brain metastases.
Patients received JYP0322, with safety monitored for neurologic events and response rates assessed in efficacy-evaluable population.
Outcomes included objective response rate (ORR) and intracranial ORR among specific subgroups.
Objective response rate (ORR) was 95.7% in TKI-naive patients, 57.1% in prior TKI-treated patients, and 77.8% in ROS1<sup>G2032R</sup>-mutant patients.
Intracranial ORR was 55.6% among patients with brain metastases, indicating effective central nervous system penetration.
JYP0322 was well tolerated, with low rates of TRK-related neurologic events (dizziness: 6.7%; headache: 3.4%).

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.

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Cite This Study

Ma et al. (Wed,) studied this question.

synapsesocial.com/papers/69eefc23fede9185760d352d https://doi.org/https://doi.org/10.1016/j.ccell.2026.03.018

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