The influence of ROS1 fusion partners and resistance mechanisms in ROS1 ‐ TKI ‐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.