(Barcelona, Spain September 7, 2025, 10:45 a.m. CEST / UTC +2 ) — Zidesamtinib, an investigational next-generation ROS1 tyrosine kinase inhibitor (TKI) designed to be highly selective, brain-penetrant, and TRK-sparing, demonstrated clinically meaningful activity and durability in patients with ROS1-positive (ROS1+) non-small cell lung cancer (NSCLC) who had progressed on prior TKI therapy.
ROS1-positive NSCLC occurs in approximately 1–2% of all NSCLC cases.
The results from the Phase 1/2 ARROS-1 trial were presented at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC) by Dr. Alexander Edward Drilon of Memorial Sloan Kettering Cancer Center, New York City.
The global, single-arm ARROS-1 trial (NCT05118789) enrolled patients with advanced or metastatic ROS1+ NSCLC. The pivotal analysis included TKI pre-treated patients with measurable disease who started zidesamtinib 100 mg once daily by May 31, 2024. Preliminary data were also collected from TKI-naïve patients treated by August 31, 2024. Key endpoints included objective response rate (ORR) by blinded independent central review (BICR), duration of response (DOR), intracranial ORR (IC-ORR), and safety. Data cutoff was March 21, 2025.
A total of 432 patients (36% Asia-Pacific, 32% North America, 32% Europe) received zidesamtinib at 100 mg once daily. Among the 117 efficacy-evaluable TKI pre-treated patients, median prior therapies were two, with 50% having received two or more prior ROS1 TKIs and 93% exposed to lorlatinib, repotrectinib, and/or taletrectinib. CNS disease was present in 49% of patients.
Durable responses were observed in TKI pre-treated patients, including in those with CNS involvement, ROS1 G2032R mutations, and those with multiple prior ROS1 TKIs.
- Any TKI pre-treated (n = 117): ORR of 44%, with a 12-month DOR rate of 78%.
- Prior crizotinib or entrectinib only (n = 55): ORR of 51%, with a 12-month DOR rate of 93%.
Preliminary data were reported for 35 TKI-naïve patients:
- TKI-naïve patients (n=35): ORR of 89%, with a 12-month DOR rate of 96%.
- Intracranial activity: IC-ORR of 83%, including four complete responses; no CNS progression events at data cutoff.
Zidesamtinib was generally well tolerated and the most common treatment-emergent adverse events (TEAEs; ≥15% of patients) included peripheral edema (36%), constipation (17%), creatine phosphokinase (CPK) increase (16%), fatigue (16%), and dyspnea (15%). Grade ≥3 events were infrequent. Dose reductions occurred in 10% of patients and treatment discontinuations in 2%.
"Zidesamtinib's highly selective, brain-penetrant, TRK-sparing design allowed for meaningful disease control in patients who had exhausted available options," said Dr. Drilon. "The promising preliminary results in TKI-naïve patients also support further development."
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