Background: The SLI of the BEACON CRC phase 3 study assessed the safety and efficacy of the combination of the BRAF inhibitor encorafenib (ENCO) + MEK inhibitor binimetinib (BINI) + anti-EGFR antibody cetuximab (CETUX) in pts with BRAF^V600E-mutant mCRC after 1 or 2 prior regimens. CEA and CA19-9 are tumor markers that are widely used to monitor the effectiveness of systemic therapies for mCRC; here we report on the association of CEA and CA19-9 changes while on treatment with clinical outcomes in pts from the SLI. Methods: Pts in the SLI received the triplet of ENCO 300 mg QD + BINI 45 mg BID + CETUX 400 mg/m² (initial dose) then 250 mg/m² QW in 28-day cycles. Pts were evaluated for safety, radiographic response, and change in tumor markers CEA and CA19-9. Results: 30 pts were treated. The triplet was generally well tolerated, and adverse events were consistent with known BRAF, MEK, and EGFR inhibitor toxicities. The rate of severe skin toxicities (grade 3/4) was lower than generally observed for CETUX in mCRC. Of the 29 pts with a BRAF^V600E mutation, the median time on study treatment was 5.6 mo (range, 1.0–9.3 mo), and 22 (76%) remained on study treatment at the time of data cutoff. The confirmed overall response rate (ORR) was 41%, with 1 complete and 11 partial responses. In addition, 9 pts had prolonged stable disease (SD) up to 9.3 mo.CEA and CA19-9 were analyzed in 28 pts. CEA and CA19-9 decreased in 96% and 82% of these pts, respectively. Among 15 pts with treatment duration ≥5.6 mo, median/mean % decreases were 97%/79% for CEA and 92%/82% for CA19-9 in confirmed responders (n=6). Respective decreases in pts with prolonged SD (n=9) were similar: 84%/68% for CEA and 89%/68% for CA19-9. Updated safety, efficacy, and tumor marker results will be provided. Conclusions: ENCO + BINI + CETUX is generally well tolerated and has encouraging clinical activity in BRAF^V600E mCRC, with a confirmed ORR of 41%. In pts with study treatment duration ≥5.6 mo, the tumor markers CEA and CA19-9 decreased markedly and to the same degree in responders vs pts with prolonged SD, providing additional evidence of the meaningful clinical activity of this regimen. Clinical trial information: NCT02928224