11508 Background: Almost half of RAS and BRAFwt mCRC patients do not respond to anti-EGFRs. Different molecular alterations suggested as predictors of resistance have not been validated. Methods: We conducted a case-control study to prospectively demonstrate the negative predictive impact of HER-2 amplification or mutations (mut), MET amplification, NTRK/ROS1/ALK/RET rearrangements, and mut activating MAPKs or PI3K/Akt axis. Patients with RAS and BRAFwt mCRC clearly resistant (cases) or clearly sensitive (controls) to anti-EGFRs were selected. Hypothesizing a prevalence of candidate alterations of 0% and 15% among controls and cases, 47 cases and 47 controls were needed to be able to reject the null hypothesis of equally prevalent alterations, with a- and b- error 0.05 and 0.20. Since hypermutated tumors may hardly rely on a single pathway for their growth, we also evaluated the impact of microsatellite instability. Results: 47 cases and 47 controls were included. Primary endpoint was met: mentioned alterations were reported in 20 (42.6%) cases and 1 (2.1%) control (p<0.001). MSI-high was significantly more frequent among resistant than sensitive tumos (15% vs 0%, p<0.001). Conclusions: This is the first prospective demonstration that the combined assessment of these rare alterations allows to better select patients for anti-EGFRs, while opening the way to other tailored therapies. [Table: see text]