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ROS1 comprises a small molecular subset of NSCLC, and several fusion partners have been discovered. Concomitant mutations of EGFR and ROS1 in NSCLC have been occasionally reported, while no clear standard of treatment has been revealed. Here we report a case with metastatic lung adenocarcinoma detected to have EGFR 21 exon L858R mutation at diagnosis, who responded to first-line gefitinib and second-line osimertinib treatment. Next-generation sequencing during the treatment course revealed multiple alterations, including an OPRM1-ROS1 Ointergenic: R36 fusion. We reviewed the related literatures but found no report of this fusion type previously. The application of ctDNA detection results in the finding of new alterations, which need further confirmation.