Promising Results of Zidesamtinib in Treating ROS1-Positive NSCLC Patients Post-TKI Therapy

Zidesamtinib, an innovative next-generation ROS1 tyrosine kinase inhibitor (TKI), has demonstrated significant clinical activity and sustained responses in patients with ROS1-positive non-small cell lung cancer (NSCLC) who previously undergone TKI treatment. This highly selective, brain-penetrant, and TRK-sparing agent was evaluated in the Phase I/II ARROS-1 trial, with results presented at the 2025 World Conference on Lung Cancer by Dr. Alexander Edward Drilon from Memorial Sloan Kettering Cancer Center.

The trial enrolled patients with advanced or metastatic ROS1+ NSCLC, with a focus on those who had received prior TKI therapies. The pivotal analysis included 117 efficacy-evaluable patients who started on a daily dose of 100 mg zidesamtinib before May 31, 2024. Additionally, preliminary data from 35 TKI-naive patients showed remarkable outcomes.

Among the TKI pre-treated group, which had a median of two prior therapies—including multiple ROS1 TKIs like lorlatinib, repotrectinib, and taletrectinib—durable responses were observed, even in patients with brain metastases or ROS1 mutations like G2032R. The objective response rate was 44%, and at 12 months, 78% of responders maintained response. Notably, patients with prior crizotinib or entrectinib alone exhibited an ORR of 51%, with a 12-month DOR rate of 93%.

In the TKI-naive cohort, the results were particularly encouraging with an ORR of 89% and a 96% DOR rate at 12 months. Intracranial activity was notable, with an intracranial ORR of 83%, including complete responses, and no CNS progression observed at data cutoff.

The treatment was generally well tolerated; common adverse events included peripheral edema, constipation, elevated CPK, fatigue, and dyspnea, with most being manageable and severe cases being rare. Dose reductions were needed in 10% of patients, and only 2% discontinued treatment due to side effects.

Dr. Drilon emphasized that zidesamtinib’s design allows for significant disease control in patients with few options left, especially given its brain-penetrance and selectivity. The positive findings in both pre-treated and treatment-naive populations advocate for further development of this promising agent.

Source: https://medicalxpress.com/news/2025-09-zidesamtinib-durable-responses-ros1-tki.html