The influence of <i>ROS1</i> fusion partners and resistance mechanisms in <i>ROS1</i> ‐ <scp>TKI</scp> ‐treated non‐small cell lung cancer patients

Clinical outcomes in ROS1-fusion positive (ROS1+) non-small cell lung cancer (NSCLC) by fusion partner and resistance mechanisms are limited. This cohort study included 56 ROS1+ patients (FISH or NGS confirmed); fusion partners were identified in 27 cases, including CD74 (n = 10), EZR (n = 7), and SDC4 (n = 7). Clinical data were available for 50 patients (median age 62; 51% female; 32% never-smokers). Forty patients received tyrosine kinase inhibitors (TKIs), mostly crizotinib (n = 38). Crizotinib showed a 55% objective response rate (ORR) and a median progression-free survival (mPFS) of 5.3 months. Brain metastases (HR 2.65, 95% CI 1.06-6.60, P = 0.037) and prior chemotherapy (HR 3.17, 95% CI 1.35-7.45, P = 0.008) had a higher risk of progression. Sixteen patients received subsequent lorlatinib, with an ORR of 28% and mPFS of 3.7 months. G2032R and L2026M resistance mutations were identified in four lorlatinib non-responders, and in vitro studies confirmed resistance to lorlatinib. Fusion partners did not affect crizotinib outcomes. Lorlatinib was ineffective against on-target resistance. Real-world data showed lower TKI efficacy than clinical trials, highlighting the role of clinical and molecular factors in treatment response.