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

Abstract

ROS1 and RET fusions are targetable mutations that occur in a subset of patients with non-small cell lung cancer (NSCLC). ROS1 and RET 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 CD-74-ROS1 fusion NSCLC discovered initially with RNA next generation sequencing (NGS) who acquired resistance to lorlatinib after 6 months on therapy through a novel RUFY1-RET 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 RET fusion as a potential mechanism of resistance to lorlatinib, it identifies a novel RET 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.