Treatment with the next-generation ROS1 tyrosine kinase inhibitor (TKI) zidesamtinib led to antitumor activity in patients with ROS1-positive non‒small cell lung cancer (NSCLC) who had experienced disease progression on prior TKI treatments. These findings from the phase I/II ARROS-1 trial were presented at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC; Abstract PL02.15).
Subgroups of patients who were naive to prior TKI treatments and patients with intracranial activity demonstrated significant benefit warranting further investigation.
“Zidesamtinib’s highly selective, brain-penetrant, TRK-sparing design allowed for meaningful disease control in patients who had exhausted available options,” said lead study author Alexander E. Drilon, MD, thoracic medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center, New York. “The promising preliminary results in TKI-naive patients also support further development.”
Study Methods and Patient Characteristics
The WCLC presentation represented the first presentation of data for the pretreated population in the ARROS-1 trial and the first report of preliminary data from TKI-naive patients. ARROS-1 is a global, single-arm phase I/II trial of 432 patients with advanced or metastatic ROS1-positive NSCLC treated with zidesamtinib at 100 mg daily.
The TKI-pretreated group (n = 117) was the primary efficacy focus of the study. These patients had received a median of two prior therapies, including prior chemotherapy in 53%; 50% had received at least two prior ROS1 TKIs, including lorlatinib, repotrectinib, and/or taletrectinib in 93%. Secondary ROS1 resistance mutations were found in 36% of patients, and 49% had central nervous system disease.
Key Findings
Among all pretreated patients, the objective response rate was 44% (95% confidence interval [CI] = 34%‒53%), which included a complete response in one patient. The duration of response rates were 84% at 6 months, 78% at 12 months, and 62% at 18 months or more. The intracranial response rate was 48% (95% CI = 35%‒62%), with intracranial complete responses seen in 20%. The duration of intracranial response rates were 79% at 6 months and 71% at 12 months or more.
In the patients who were naive to prior TKIs, the objective response rate was 89%, with a 1-year duration of response rate of 96%. The intracranial objective response rate was 83% with no central nervous system disease progression events reported as of data cutoff.
Treatment-emergent adverse events in all patients included most commonly peripheral edema (36%), constipation (17%), creatine phosphokinase increase (16%), fatigue (16%), and dyspnea (15%). a total of 10% of patients required a dose reduction because of a treatment-emergent adverse event, and events led to treatment discontinuation in 2%.
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