Acquired CD74–ROS1 fusion–mediated osimertinib resistance successfully treated with osimertinib and crizotinib: a case report

In EGFR T790M-mutant lung adenocarcinoma, the strong and early clinical responses achieved with osimertinib may be limited by the emergence of diverse resistance mechanisms over time. In this case report, we describe an acquired CD74-ROS1 fusion that developed during osimertinib therapy in a patient who had an EGFR exon 20 T790M mutation detected in the treatment-naive setting. The fusion, identified through a tissue biopsy performed at the time of progression, suggests that the tumor had activated an alternative oncogenic driver under therapeutic pressure. The combination of osimertinib and crizotinib resulted in a marked clinical and metabolic response, was well tolerated, and the patient remained in remission. This rare case highlights that acquired CD74-ROS1 fusions may contribute to osimertinib resistance and suggests that combination targeted therapy may represent a potential therapeutic approach in selected patients.