Dr Liu on the Efficacy of Zidesamtinib in ROS1 Fusion+ NSCLC

“[We saw] promising efficacy, [including] greater efficacy in the TKI-naive setting [and] impressive efficacy in the previously treated setting. This is a drug that blows us away as initial therapy.”

Stephen Liu, MD, division chief of Hematology Oncology at MedStar Georgetown University Hospital, part of the MedStar Georgetown Cancer Institute; as well as an associate professor of medicine, director of Thoracic Oncology, and director of Developmental Therapeutics at the Georgetown Lombardi Comprehensive Cancer Center of Georgetown University, discussed key efficacy findings from the phase 1/2 ARROS-1 trial (NCT05118789) of zidesamtinib (NVL-520) in patients with ROS1 fusion–positive non–small cell lung cancer (NSCLC).

The initial analysis included patients who had exposure to a previous ROS1 TKI. This population has a significant unmet clinical need, requiring effective agents capable of restoring disease control following acquired resistance mechanisms, Liu emphasized.

In the overall previously treated population of ARROS-1 (n = 117), zidesamtinib generated an objective response rate (ORR) per RECIST 1.1 criteria of 44% (95% CI, 34%-53%). Among patients who had received only 1 prior ROS1 TKI (n = 55), the ORR increased to 51% (95% CI, 37%-65%). Importantly, promising clinical activity was maintained even among patients pretreated with next-generation ROS1 inhibitors, such as repotrectinib (Augtyro) or taletrectinib (Ibtrozi), according to Liu.

The duration of response (DOR) outcomes in the single prior TKI cohort proved compelling, with the rate of patients achieving a DOR lasting at least 1 year and at least 18 months maintained at 93% (95% CI ,74%-98%) at both 1 year and 18 months, Liu said. The median DOR has not yet been reached, although the data remain immature.

Crucially, zidesamtinib exhibited high efficacy in targeting specific resistance mechanisms, Liu summarized. In the subpopulation of patients characterized by exposure to 1 prior TKI and the presence of the acquired G2302R ROS1 resistance mutation (n = 6), the ORR was 83% (95% CI, 36%-100%). Furthermore, the intracranial ORR (IC-ORR) among previously treated patients with measurable central nervous system (CNS) lesions by blinded independent central review at baseline (n = 56) was 48% (95% CI, 35%-62%).

The most significant measure of efficacy was observed in the TKI-naive setting, where zidesamtinib was used as the initial targeted therapy for patients with ROS1 fusion–positive NSCLC, Liu reported. In this first-line setting, the drug demonstrated an ORR of 89%. CNS efficacy remained impressive, with an IC-ORR of 83%, Liu noted. Furthermore, the rate of patients achieving a DOR lasting at least 1 year was 96%. Although the efficacy of zidesamtinib in the previously treated setting was impressive, the greater efficacy in the TKI-naive setting suggests that this agent may serve as a preferred initial therapeutic option for ROS1 fusion–positive NSCLC, Liu concluded.