Abstract only 589 Background: ALK, ROS1, and NTRKs fusions occur in 0.2-2.4% of CRCs, and represent therapeutic targets, as indicated by promising reports of individual patients treated with tyrosine kinase inhibitors. Clinical and molecular features of mCRCs harboring these fusions have not been elucidated. Methods: mCRC harboring ALK, ROS1 and NTRKs fusions were identified taking advantage of screening programs worldwide (Ignyta STARTRK trials; Foundation Medicine Database; Memorial Sloan Kettering-IMPACT; Australian MAX trial post-hoc analysis). Clinicopathological and molecular characteristics of ALK, ROS1, NTRKs rearranged cases were compared with those of non-rearranged cases, included in Ignyta’s STARTRK trials program. Results: 27 ALK, ROS1 or NTRKs rearranged (including a novel SCYL3-NTRK1 fusion) and 319 not rearranged mCRCs patients were included. Rearrangements were more frequent in older patients (p = 0.024), and tumors that were right-sided (80% vs 30%; p < 0.001), RAS wild-type (93% vs 52%; p < 0.001), MSI-high (48% vs 8%; p < 0.001) and spread more frequently to lymph nodes (46% vs 25%; p = 0.03) and less frequently to the liver (42% vs 66%; p = 0.026). At a median follow-up of 28.5 months, patients bearing rearranged tumors had a shorter overall survival (OS) when compared to non-rearranged (15.6 vs 33.7 mos; HR: 2.17, 95% CI 1.03-4.57; p < 0.001). In the multivariable model including significant prognostic variables (primary site, primary resection, BRAF and MMR status), rearrangements were still associated with shorter OS (HR: 2.78, 95% CI 1.27-6.07; p = 0.011). All of the 4 patients with rearranged tumors evaluable for benefit from anti-EGFRs experienced disease progression as best response. One patient with an MSI-high EML4-ALK rearranged tumor experienced durable response to PD-1 blockade. Conclusions: ALK, ROS1 and NTRKs rearrangements define a new molecular subtype of mCRCs associated with unfavorable prognosis, and specific clinicopathological and molecular features. Since sensitivity to available treatment options, including anti-EGFRs, is very limited, targeted approaches with or without immunotherapy should be investigated in these patients.