162 Background: In the randomized phase 3 BEACON study, encorafenib + binimetinib + cetuximab (triplet) and encorafenib + cetuximab (doublet) regimens improved overall survival (OS) and objective response rate (ORR) versus standard of care (control) in patients (pts) with previously treated BRAF V600E-mutant metastatic colorectal cancer. To identify whether detection of a BRAF V600E mutation in baseline circulating tumor DNA (ctDNA) correlated with response, we evaluated the status and allele frequency of BRAF V600E compared with clinical outcomes. Methods: Plasma samples were collected at Cycle 1 Day 1 and end of treatment for ctDNA analysis and analyzed using GuardantOMNI. Variant allele frequency (VAF) of BRAF V600E was grouped into high (> median) and low (≤median) categories. Low VAF samples included those where BRAF V600E mutation was not detected or no ctDNA was detected. ORR, based on blinded independent central review, and OS were compared between treatment arms according to VAF levels. ORR comparisons used Chi-square test and logistic regression. OS was summarized using the Kaplan-Meier method. HRs and 95% CIs were estimated using a Cox model. Additional correlation analyses between BRAF V600E status in baseline tumor tissue, as well as clonality, will be presented. Results: Baseline plasma samples were analyzed from 544 of 631 pts in the ctDNA analysis: 88.3% (196/222) in the triplet arm, 86.6% (187/216) in the doublet arm, and 83.4% (161/193) in the control arm. BRAF V600E mutations were detected in 90.4% (492/544) of pts (90.3% [177/196] triplet, 90.4% [169/187] doublet, and 90.7% [146/161] control). Pts with BRAF V600E mutations with high VAF had significantly ( P≤0.0001) increased ORR (95% CI) in the triplet and doublet arms (27.3% [19.5–36.8] and 15.9% [9.7–25.0], respectively) compared with control (0% [0.0–4.3]). Similar response trends were observed in pts with BRAF V600E mutations with low VAF (triplet: 28.9% [20.8–38.9]; doublet: 25.3% [17.7–34.6]; control: 5.3% [2.1–12.8]). OS decreased in BRAF V600E pts with high VAF (median OS [95% CI]: triplet 7.2 [6.0–8.0] months, n = 99; doublet 5.4 [4.4–6.1] months, n = 88; control 4.2 [3.4–4.8] months, n = 85) compared with pts with low VAF (triplet 14.8 [10.2–19.8] months, n = 97; doublet 14.8 [11.7–23.0] months, n = 99; control 9.3 [7.5–11.3] months, n = 76). Conclusions: ctDNA analyses showed the majority of pts in BEACON analyzed at baseline had a detectable BRAF V600E mutation. Increased response rates were observed in pts treated with triplet or doublet therapy compared with control, independent of VAF. Pts with a higher VAF for BRAF V600E may have a worse prognosis. Clinical trial information: NCT04607421.