Multicenter phase 1 trial of JYP0322 for non-small cell lung cancer with ROS1-fusion

Targeted therapies against ROS1-rearrangements face limitations due to resistence mutations, brain metastases, and central nervous toxicities. JYP0322 is a next-generation, brain-penetrant, selective ROS1 inhibitor, that is designed to overcome resistance mutation, such as ROS1^G2032R, while minimizing off-target inhibition. In preclinical studies, JYP0322 demonstrated >130-fold selectivity over TRKA, potent antitumor activity in ROS1 rearrangement and ROS1^G2032R tumor models, and effective brain penetration. A multicenter phase 1 trial in China evaluated JYP0322 for non-small cell lung cancer (NSCLC) with ROS1 fusion. Among 89 enrolled patients, 32 had brain metastases (36%). 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-naïve patients, 57.1% in TKI-pretreated patients, and 77.8% in ROS1^G2032R-mutant patients. Among the 32 patients with baseline brain metastases, 28 were evaluable. The ORR was 83.3% in TKI-naïve patients and 36.4% in TKI-pretreated patients. Among 9 patients evaluable for intracranial ORR, the intracranial ORR was 100% in TKI-naïve patients and 33.3% in TKI-pretreated patients. The authors conclude that these findings highlight JYP0322 as a promising therapy for heavily pretreated NSCLC patients, including those with brain metastases or ROS1^G2032R mutations.