RET Fusion–Positive Lung Adenocarcinoma: Partner-Specific Clinicopathological Characteristics, Co-Mutation Profiles, and Implications for Targeted and Immunotherapy

BACKGROUND: RET fusions represent actionable oncogenic drivers in lung adenocarcinoma (LUAD). However, the clinicopathological features, co-mutation landscape, and therapeutic outcomes across different fusion partners remain incompletely characterized. METHODS: We retrospectively analyzed 268 patients with RET fusion-positive LUAD diagnosed between July 2017 and December 2024. Clinicopathological features, metastatic patterns, and concomitant genomic alterations were compared between KIF5B and non-KIF5B subgroups. Treatment outcomes of selective RET inhibitors, multikinase inhibitors (MKIs), and immunotherapy combined with chemotherapy were evaluated, with subgroup analyses according to fusion partners. RESULTS: The median age at diagnosis was 58 years; most patients were female (57.0%) and never/light smokers (60.8%). Bone (12.3%), pleural (11.9%), and brain metastases (6.7%) were the most common metastatic sites. KIF5B-RET fusions were more frequently detected in earlier disease stages compared with non-KIF5B (p = 0.0531). Among 274 RET fusion events, KIF5B-RET was predominant (65%), followed by CCDC6-RET (16%) and NCOA4-RET (1%). Concomitant mutations were identified in 28.7% of patients, most commonly TP53 (39.0%) and CDKN2A (13.0%), with CDKN2A alterations predominantly consisting of functionally inactivating SNVs concurrent with shallow deletions more enriched in non-KIF5B (p = 0.0393). Nineteen patients received targeted therapy, including pralsetinib, selpercatinib, and cabozantinib, achieving an overall ORR of 57.9% and mPFS of 12.0 months. Notably, non-KIF5B patients demonstrated longer median PFS than KIF5B patients under pralsetinib (17.0 vs. 5.5 months, p = 0.0473). Fifteen patients received first-line immunochemotherapy, achieving a median PFS of 17.0 months, ORR of 40.0%, and DCR of 80.0%, comparable to targeted therapy (p = 0.3871). CONCLUSIONS: RET fusion-positive LUAD comprises biologically heterogeneous subsets defined by fusion partners. KIF5B-RET tend to occur at earlier stages, whereas non-KIF5B are more frequently associated with CDKN2A co-mutations and may derive greater benefit from selective RET inhibition. Immunochemotherapy demonstrates comparable efficacy regardless of fusion partner, highlighting the need for partner-specific therapeutic strategies in RET fusion-positive LUAD.