Zidesamtinib—a ROS1-selective, brain-penetrant, and tropomyosin receptor kinase (TRK)-sparing TKI—showed promising efficacy and durability in patients with ROS1-positive non-small cell lung cancer (NSCLC).
“Zidesamtinib was designed to inhibit ROS1 fusion and ROS1 resistance mutations, to be brain penetrant, and to avoid TRK inhibition,” said Benjamin Besse, MD, Director of Clinical Research at the Gustave Roussy Institute and a Professor of Medical Oncology at Paris-Saclay University, France.
Prof. Besse presented findings from the phase I/II ARROS-1 trial of zidesamtinib in ROS1 fusion-positive solid tumors during a mini-oral session at the European Society for Medical Oncology Congress 2024 in Barcelona. The study aimed to evaluate the safety and tolerability of zidesamtinib in patients with advanced ROS1-positive NSCLC.
The trial enrolled 104 patients with advanced solid tumors harboring ROS1 fusions, who had received at least one prior ROS1 TKI for NSCLC. There was no limit to the number of prior chemotherapies or immunotherapies that patients could have undergone.
The recently completed phase I portion of the study was designed to establish the recommended phase II dose and the maximum tolerated dose (MTD) of zidesamtinib in patients with advanced ROS1-positive solid tumors. As of the data cut-off date (July 1, 2024), the recommended phase II dose was determined to be 100 mg once daily, with no observed dose relationships affecting safety or efficacy.
The median age of enrollees was 57 years; the majority were female (63%). Among the 104 patients, just over half (52%) had a history of central nervous system (CNS) metastases, and more than one-third (38%) had a secondary ROS1 mutation. Most patients (69%) had received prior chemotherapy, while 30% had received at least one prior ROS1 TKI, and 69% had received at least two prior TKIs.
The overall response rate (ORR) was 44% for all patients with NSCLC who were evaluable for response, and 51% for patients who were repotrectinib-naïve. The ORR in patients who had received at least two prior TKIs was 41%, compared to 73% for patients who had received crizotinib alone as the prior ROS1 TKI.
The median duration of response (mDOR) was not reached in most cohorts, except for patients who received at least two ROS1 TKIs where the mDOR was 12 months.
Eight patients exhibited CNS activity and durable intracranial responses. The intracranial overall response rate (IC-ORR) among patients evaluable for response was 50%. Of the eight patients who demonstrated intracranial responses, seven had previously been treated with at least two ROS1 TKIs, which included the brain-penetrant TKIs lorlatinib or repotrectinib.
Treatment-related adverse events (TRAEs) were observed in at least 10% of patients. While TRAEs resulted in dose reductions for some patients (8%), they did not lead to treatment discontinuation. The phase II investigation of zidesamtinib for patients with ROS1-positive NSCLC is ongoing and is currently recruiting both pre-treated and TKI-naïve patients.
