Klin Onkol 2026; 39(5): 368-371. DOI: 10.48095/ccko2026368.
Background: RET gene fusions represent a rare but clinically relevant genetic alteration in non-small cell lung cancer (NSCLC), particularly in adenocarcinoma, with a prevalence of approximately 1–2%. Identification of this driver mutation has enabled the development of selective RET tyrosine kinase inhibitors, which significantly improve treatment outcomes in these patients. Molecular testing, including detection of RET fusions, is currently a standard component of the diagnostic algorithm for advanced NSCLC. Case report: We present the case of a 55-year-old female non-smoker diagnosed with metastatic lung adenocarcinoma with central nervous system (CNS) involvement. Initial molecular testing revealed no alterations in EGFR, ALK, or ROS1, and PD-L1 expression was negative. The patient underwent hippocampus-avoiding whole-brain radiotherapy followed by three lines of systemic treatment including chemotherapy and immunotherapy. Upon disease progression, next--generation sequencing analysis of a rebiopsy specimen obtained from a supraclavicular metastasis identified a RET gene fusion. Based on this finding, treatment with selpercatinib was initiated in January 2022 as the fourth-line therapy. Treatment resulted in a rapid and profound response, including complete regression of CNS metastases. Therapy was well tolerated; initial hepatotoxicity was successfully managed by dose reduction. The patient has remained on RET inhibitor therapy for nearly 4 years with sustained disease control. Conclusion: This case highlights the importance of comprehensive molecular testing in patients with advanced NSCLC. Identification of RET fusion may enable the use of highly effective targeted therapy even after failure of multiple lines of systemic treatment.