3600 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for RAS wild-type (WT) mCRC. Limited data suggest a correlation between Cet clearance and progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts with KRAS WT mCRC who participated in the randomized phase III NCIC CO.20 trial. Methods: Standard Cet doses ± brivanib (Briv) were administered. Intermittent blood samples were obtained, and analyzed by ELISA for Cet. Pop-pK analysis was conducted to estimate Cet clearance. Pts were divided into quartiles according to clearance parameters to evaluate exposure-outcome with overall survival (OS), PFS, response rate (RR), and toxicity. Results: Blood samples were available from 703 pts. Cet clearance was best described as a one-compartment model with a saturable elimination (defined by Vmax and Km). Mean values (± standard deviation) were 5.6 ± 1.4 L for V, 10.5 ± 2.8 mg/h for Vmax, and 403.1 ± 2.0 mg/L for Km. Vmax and Km were significantly associated with OS, but not PFS or RR. Median OS for pts in the highest quartile of Vmax was 7.8 versus (vs.) 11.6 ms for pts in the lowest Vmax quartile (HR 1.12, 95% confidence interval (CI) 1.05-1.20, p< 0.001). In the highest Km quartile, median OS was 11.6 vs. 7.6 ms in the lowest Km quartile (HR 0.89, 95% CI 0.83-0.96, p= 0.001). Pts with the lowest clearance parameters (lowest Vmax and highest Km) had significantly longer OS (11.6 ms) compared to pts with the highest clearance (highest Vmax and lowest Km) (7.6 ms) (HR 0.67, 95% CI 0.53-0.83, p< 0.001). Overall incidences of grade 3/4 toxicity were not associated with Cet clearance. However, pts with the lowest clearance parameters had more frequent grade 3 diarrhea (OR 0.23, p= 0.005). Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with lower Cet clearance have significantly improved OS and increased likelihood of grade 3 diarrhea. Further studies are needed to identify individual patient factors associated with Cet clearance, and to optimize Cet dosing based on individual pk assessments.