Background: BRAF V600E mutations are present in 8-12% worldwide of patients with metastatic colorectal cancer (mCRC) and linked with a poor prognosis. Encorafenib + cetuximab (E+C) was approved by the FDA and EMA for patients with BRAF V600E-mutant mCRC who received prior systemic therapy, based on data from the BEACON CRC study. Methods: This Phase II, multicenter, randomized, open-label, 2-arm study evaluated E+C vs irinotecan + cetuximab or FOLFIRI + cetuximab (control arm) in Chinese patients with BRAF V600E mutant mCRC whose disease progressed after 1 or 2 prior treatment lines in the metastatic setting. A safety lead-in initially conducted in 10 patients reported no DLTs. Eligible patients had mCRC and a BRAF V600E mutation in tumor tissue determined by a local assay before screening and centrally confirmed. Patients were randomly assigned to the doublet arm (E+C) or the control arm in a 2:1 ratio, respectively. Randomization was stratified by baseline ECOG performance status (0 vs 1) and prior use of irinotecan (yes vs no). The primary objective of the randomized phase was to compare the efficacy of E+C vs the control arm, as measured by PFS (assessed by blinded independent central review). Secondary objectives included PFS assessed by the investigator, ORR, DOR, DCR, TTR, OS, QoL, and safety and tolerability of E+C. Results of the randomized phase of the study are reported. Results: At data cut-off (19 Dec 2023), 65 patients were enrolled in the E+C arm and 32 in the control arm. Median patient age was 56 years, the primary cancer site was the left colon in 56.7% of patients, 48.5% had metastases to >= 3 organs, 56.7% had liver metastases, 77.3% received one prior metastatic treatment, and 22.7% received 2 prior metastatic treatments. Results are shown below for E+C vs the control arm, respectively. Median PFS assessed by BICR was 4.2 mo vs 2.5 mo (HR 0.37; 95% CI: 0.20, 0.68; P=0.0004). Median OS was 11.6 mo vs 8.2 mo (HR for death 0.55; 95% CI: 0.31, 0.99). Confirmed ORR was 24.6% (95% CI: 14.8, 36.9) vs 6.3% (95% CI: 0.8, 20.8). Treatment emergent adverse events (TEAEs) of grade 3 or higher occurred in 47.7% vs 51.9% of patients. Treatment-related grade 3 or higher occurred in 24.6% and 44.4% of patients. The most frequent TEAEs were anemia (30.8% vs 37%), vomiting (26.2% vs 33.3%), rash (24.6% vs 29.6%), weight loss (23.1% vs 18.5%), hypoalbuminemia (21.5% vs 22.2%), and melanocytic naevus (21.5% vs 0%). Three patient deaths were reported during treatment: unknown cause (n=1) and pneumonia (n=1) in the E+C arm and septic shock (n=1) in the control arm. Conclusions: Treatment with a combination of encorafenib and cetuximab is effective and well tolerated in Chinese patients with BRAF V600E mutant mCRC, resulting in a significantly longer PFS than standard therapies. These results are consistent with those previously reported in the BEACON study. Clinical trial information: NCT05004350.