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C‐ros oncogene 1 receptor tyrosine kinase (ROS1) rearrangement has been detected in patients with advanced non‐small cell lung cancer (NSCLC). Although ROS1 tyrosine kinase inhibitors (TKIs) provide a survival benefit for patients with ROS1‐rearranged advanced NSCLC, subsequent therapy remains limited. Small cell transformation is an important mechanism of drug resistance in epidermal growth factor receptor‐mutant NSCLC. However, its significance in mediating ROS1 resistance has not been determined yet. Here, we present the case of a 63‐year‐old man with ROS1‐rearranged advanced NSCLC who had disease progression with small cell transformation of the mediastinal lymph node after 8 months of treatment with crizotinib. More importantly, fluorescence in situ hybridization of post‐progression tumor biopsy demonstrated retention of ROS1 rearrangement. Tissue biopsy remains indispensable for patients who acquire resistance to ROS1 TKIs.

Small cell transformation in crizotinib‐resistant ROS1 ‐rearranged non‐small cell lung cancer with retention of ROS1 fusion: A case report