Zidesamtinib, an investigational, next-generation ROS1 tyrosine kinase inhibitor (TKI), demonstrated clinically meaningful activity and durability among patients with advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) who had previously received treatment with a ROS1 TKI.

These data were first presented by Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center, New York, New York, United States, at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC) in Barcelona, Spain.

In the global, single-arm, phase 1/2 ARROS-1 trial, 432 patients with advanced or metastatic ROS1-positive NSCLC. All patients received 100 mg zidesamtinib once daily. Key end points were objective response rate (ORR) by blinded independent central review, duration of response (DOR), intracranial ORR, and safety. The pivotal efficacy analysis included patients who had received prior treatment with a ROS1 TKI with measurable disease by blinded independent central review who started zidesamtinib at 100 mg by May 31, 2024. There was also a preliminary analysis of TKI-naïve patients who started on treatment by August 31, 2024.

Of the 432 patients overall, there were 117 who had previously received treatment with a TKI and were efficacy-evaluable. These patients had a median of 2 prior anticancer therapies, with 50% having received ≥ 2 prior ROS1 TKIs (92% received prior lorlatinib, repotrectinib, and/or taletrectinib). There were 36% of patients with secondary ROS1 resistance mutations and 49% (n = 56) with central nervous system (CNS) disease by blinded independent central review. Of these patients previously treated with ROS1 TKI, the ORR was 44% (complete response, n = 1). The DOR rate at 6 months was 84%, at 12 months was 78%, and at 18 months was 62%. Among the pretreated patients with CNS disease, the intracranial ORR was 48% and the intracranial DOR rate at 6 months was 79%, and at 12 months was 71%. For patients who were TKI-naïve (n = 35), the ORR was 89%, with a DOR rate at 12 months of 96% and an intracranial ORR of 83% (5/6).

Among the total 432 patients, treatment-emergent adverse events occurring in ≥ 15% of patients included constipation, CPK increase, fatigue, and dyspnea. Treatment-emergent adverse events resulted in dose reductions for 10% of patients and in discontinuation for 2% of patients.

Dr Drilon et al, concluded, among patients pre-treated with ROS1 TKIs, “zidesamtinib demonstrated clinically meaningful activity and durability, including in patients with CNS disease and/or ROS1 G2032R-mutations, and/or in patients who had exhausted available options.” They added “encouraging preliminary activity was also observed in TKI-naïve patients.”

Source:

Drilon AE, Cho BC, Lin JJ, et al. Pivotal ARROS-1 efficacy and safety date: Zidesamtinib in TKI pre-treated patients with advanced/metastatic ROS1+ NSCLC. Presented at the IASLC 2025 WCLC. September 6-9, 2025; Barcelona, Spain. Abstract PL02.15