Acquired RUFY1-RET rearrangement as a mechanism of resistance to lorlatinib in a patient with CD74-ROS1 rearranged non-small cell lung cancer: A case report

<i>ROS1</i> and <i>RET</i> fusions are targetable mutations that occur in a subset of patients with non-small cell lung cancer (NSCLC). <i>ROS1</i> and <i>RET</i> have been understood to be independent oncogenic drivers which do not co-occur with other common tyrosine kinase receptor mutations except in the acquired resistance setting. Here we present a case of a patient with stage IV <i>CD-74-ROS1</i> fusion NSCLC discovered initially with RNA next generation sequencing (NGS) who acquired resistance to lorlatinib after 6 months on therapy through a novel <i>RUFY1-RET</i> fusion, detected only through RNA NGS. Combination therapy targeting RET and ROS1 using pralsetinib and lorlatinib achieved a partial response with limited durability of only four months. This is the first reported case of a <i>RET</i> fusion as a potential mechanism of resistance to lorlatinib, it identifies a novel <i>RET</i> fusion partner, and it emphasizes the importance of testing for acquired resistance mutations with both DNA and RNA at the time of progression in patients with targetable oncogenic drivers.