Real-World Outcomes of Crizotinib in ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer

Simple Summary Crizotinib, an oral tyrosine kinase inhibitor that targets ALK, MET, and ROS1 kinase, has emerged as an effective treatment for ROS1-rearranged NSCLC. In South Korea's real-world setting, characterized by a higher elderly population and increased brain/central nervous system metastasis rates, crizotinib remains a cornerstone in treating ROS1-rearranged NSCLC, providing lasting clinical benefits with a favorable safety profile. Liquid biopsies, utilizing biomarkers, are instrumental in detecting targetable mutations, monitoring the disease burden, and identifying resistance mechanisms. In our study, next-generation sequencing using cell-free total nucleic acids enables the detection of ROS1 fusions and the identification of resistance mechanisms during disease progression.Abstract Real-world data on the use and outcomes of crizotinib in ROS1-rearranged non-small-cell lung cancer (NSCLC) are limited. This study aims to analyze the real-world efficacy of crizotinib in South Korea and explore the utilization of liquid biopsies that implement next-generation sequencing (NGS) using cell-free total nucleic acids. In this prospective multicenter cohort study, 40 patients with ROS1-rearranged NSCLC, either starting or already on crizotinib, were enrolled. Patients had a median age of 61 years, with 32.5% presenting brain/central nervous system (CNS) metastases at treatment initiation. At the data cutoff, 48.0% were still in treatment; four continued with it even after disease progression due to the clinical benefits. The objective response rate was 70.0%, with a median duration of response of 27.8 months. The median progression-free survival was 24.1 months, while the median overall survival was not reached. Adverse events occurred in 90.0% of patients, primarily with elevated transaminases, yet these were mostly manageable. The NGS assay detected a CD74-ROS1 fusion in 2 of the 14 patients at treatment initiation and identified emerging mutations, such as ROS1 G2032R, ROS1 D2033N, and KRAS G12D, during disease progression. These findings confirm crizotinib's sustained clinical efficacy and safety in a real-world context, which was characterized by a higher elderly population and higher rates of brain/CNS metastases. The study highlights the clinical relevance of liquid biopsy for detecting resistance mechanisms, suggesting its value in personalized treatment strategies.