Background: There is limited understanding of the clinico-genomic differences among ALK/ROS1/RET-rearranged NSCLC due to their low frequency. We aimed to characterize these fusions using a large-scale LC-SCRUM-Asia/TRY database. Methods: We conducted a prospective screening of treatment-naïve and refractory lung cancer to identify genomic alterations using RT-PCR and/or targeted next-generation sequencing (NGS) assays in LC-SCRUM-Asia/TRY. We compared clinico-genomic characteristics, treatment outcomes and resistant mechanisms among ALK/ROS1/RET-rearranged NSCLC. Results: Between February 2013 and December 2022, 18,616 lung cancer patients (pts) were enrolled in LC-SCRUM-Asia/TRY and 16,583 were NSCLC pts. ALK/ROS1/RET fusions were identified in 430 (2.6%)/240 (1.4%)/202 (1.2%) pts in NSCLC. The patient characteristics were as follows (ALK/ROS1/RET): median age, 58/60/63 years; females, 53/54/54%; never-smokers, 57/55/59%; adenocarcinoma, 93/95/96%. The frequencies of brain metastasis at diagnosis were 26/20/19% (p = 0.15). Among pts tested by NGS, the frequencies of TP53, TET2 and NOTCH1 mutations were lower in ALK than in ROS1 and RET (TP53; 23/34/27%, NOTCH1; 17/34/35%, TET2; 17/30/32%). Overall survival (OS) was significantly longer in ALK than in ROS1 (mOS [ALK/ROS1/RET] 108.8 vs. 43.6 vs. not reached [NR] months, ALK vs. ROS1; p < 0.01, ALK vs. RET; p = 0.04) among stage IV pts underwent TKI therapy. TP53 mutation was associated with shorter OS in all three fusions (mOS [TP53 mt+/mt-] ALK; 35.7 vs. 108.8, p < 0.01, ROS1; 26.4 vs. 47.4, p = 0.06, RET; 28.9 vs. 76.1 months, p = 0.05), shorter PFS with first line alectinib in ALK (mPFS [TP53 mt+/mt-] 11.0 vs. 38.4 months, hazard ratio [HR] 2.5 [95% CI, 1.5-4.2], p < 0.01) and shorter PFS with initial crizotinib in ROS1 (mPFS [TP53 mt+/mt-] 5.8 vs. 25.2 months, HR 2.6 [95% CI, 1.3-4.8], p < 0.01). There was no significant difference in PFS with first-line platinum plus pemetrexed among fusions (mPFS 12.6 vs. 10.7 vs. 9.2 months) and PFS with initial immune checkpoint inhibitors among fusions (mPFS 3.9 vs. 5.1 vs. 3.0 months). Among 60/13/10 re-biopsy samples refractory to TKI, on-target resistant mutations were identified in 14 (23%) /3 (23%) /1 (10%) samples. Conclusions: Pts with ALK/ROS1/RET-rearranged NSCLC shared similar characteristics, but the occurrence of concomitant mutations was lower in ALK than in ROS1 and RET. TP53 mutation was associated with worse prognosis in pts with ALK/ROS1/RET-rearranged NSCLC. Among those received TKI, pts with ALK-rearranged NSCLC had better prognosis than those with ROS1 and RET-rearranged NSCLC. The development of highly effective molecular targeted therapies for ROS1- and RET-rearranged NSCLC is warranted.