RET fusion–positive lung adenocarcinoma: Partner-specific clinicopathological characteristics, co-mutation profiles, and implications for targeted and immunotherapy.

8615 Background: RET fusions represent actionable oncogenic drivers in lung adenocarcinoma (LUAD). However, the clinicopathological features, co-mutation landscape, and therapeutic outcomes across different RET fusion partners remain incompletely characterized. Methods: We retrospectively analyzed 268 patients with RET fusion–positive LUAD diagnosed between July 2017 and December 2024. Clinicopathological characteristics, metastatic patterns, and concomitant mutations were compared between KIF5B and non- KIF5B subgroups. Treatment outcomes of selective RET inhibitors, multikinase inhibitors (MKIs), and immunotherapy combined with chemotherapy were assessed, with subgroup analyses according to RET fusion partners. Results: The median age at diagnosis was 58 years, and 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 fusions (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 more enriched in the non- KIF5B group (p = 0.0393). Nineteen patients received targeted therapy, including pralsetinib (n=12), selpercatinib (n=2), and cabozantinib (n=5), achieving an overall ORR of 57.9% and median PFS 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). PD-L1 expression showed no correlation with outcomes. Conclusions: RET fusion–positive LUAD comprises biologically heterogeneous subsets defined by fusion partners. KIF5B-RET fusions tend to occur at earlier stages, whereas non- KIF5B fusions are more frequently associated with CDKN2A co-mutations and appear to 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.