Background: Oncogenic gene fusions can be observed across numerous solid tumor types with therapies targeting fusion events emerging as important treatment modalities. The occurrence of rare fusion events and response to targeted therapy inclusive of off-label drug use has not been fully elucidated. We describe a real-world (RW) landscape of gene fusions in solid tumors and treatment outcomes of targeted therapies. Methods: Patients with solid tumors harboring a gene fusion or rearrangement were retrospectively identified through review of a clinical molecular database housing sequencing data on 6,800 patients from a single-center between 1/1/2015 – 12/31/2019. Patients who received targeted therapy for gene fusions were divided into three arms: off-label, on-label, and clinical trial use. Clinical characteristics were summarized using descriptive statistics. Overall survival (OS) and Progression free survival (PFS) between the three arms were compared using the Kaplan-Meier estimates. Results: A total of 336 (4.9%) patients had a fusion positive solid tumor with 197 (2.9%) having a fusion event predicted to be oncogenic and could be targeted with a drug. Thirty different cancer types had targetable fusions with the three most common types being lung adenocarcinoma (41%), glioblastoma (10.2%), and melanoma (7.1%). The most common observed targetable fusions included ALK (21.3%), RET (11.7%), ROS1 (9.1%), and FGFR2 (8.1%). A total of 71 patients received targeted therapy; 37 (52%) received therapies on-label, 20 (28%) off-label, and 14 (20%) on-trial (Table). The median PFS was 4 months for off-label, 16 months for on-label, and 9 months for on trial-therapy (p=0.02). The median OS was 8 months for off-label, 51 months for on-label, and 11 months for on-trial therapy (p=0.001). Seven out of twenty patients (35%) in the off-label group had PFS for at least 6 months. Three patients had a response for more than one year. However, higher toxicity related discontinuation rate was observed (30%, 8%, 7% for off-label, on-label, and on-trial, p=0.03). Conclusions: Off-label targeted therapy had shorter PFS and OS when compared to on-label therapy. However, 35% patients in the off-label group had at least 6 months PFS. Off-label therapy remained a valuable option for patients who were not candidate for clinical trials or with rare fusions. Further studies are needed to determine which patients are most likely to benefit from targeting gene fusion events.