Abstract
RET fusions, the most common oncogenic RET alterations, occur in approximately 1-2% of non-small cell lung cancer (NSCLC) cases and represent well-established therapeutic targets. Pralsetinib, a selective RET kinase inhibitor, has demonstrated significant efficacy and tolerability in patients with RET fusion-positive NSCLC. However, the clinical management of NSCLC with non-fusion RET structural variants remains challenging. Here, we report a case of a middle-aged male diagnosed with stage IV lung adenocarcinoma, in whom initial next-generation sequencing (NGS) revealed no actionable mutations. The patient achieved a partial response to pemetrexed and platinum-based chemotherapy, but disease progression occurred 9 months later. Upon re-biopsy, a large intragenic RET deletion involving exons 2-11 was detected. Based on this finding, the patient was treated with pralsetinib and achieved radiological tumor regression, with a progression-free survival of 5 months to date. This case highlights a potential therapeutic role for RET inhibitors even in the absence of canonical fusions, and underscores the importance of reassessing the tumor's molecular profile following treatment failure, as acquired genomic alterations may provide new targets for precision therapy.