Background: The prevalence of BRAF V600E in colorectal cancer (CRC) was about 10%. Despite recent therapeutic advances, BRAF V600E mutant CRC is still a challenge with a low response rate and suboptimal survival. Here we reported the safety and preliminary anti-tumor activity of vemurafenib and cetuximab in combination with FOLFIRI for BRAF V600E-mutated advanced CRC patients.Methods: In this single-arm, single-center trial, we are currently in enrollment of patients with BRAF V600E-mutated, RAS-wild type advanced CRC. Patients received vemurafenib 960mg orally every 12 hours, cetuximab 500mg/m 2 in combination with FOLFIRI, consisting of irinotecan 180mg/m 2 2 hour-intravenous infusion, leucovorin 400mg/m 2 , 5-fluorouracil (5-FU) 400mg/m 2 intravenous injection on day 1, followed by a 46-h continuous infusion of 5-FU (2400 mg/m 2 ). The primary objective was to measure the objective response rate (ORR). And the secondary objective included safety, progression-free survival and overall survival.Results: 18 patients were enrolled in this study and 16 patients completed at least 3 sessions of treatment for efficacy assessment. The ORR was 81.3% with 2 complete response (CR) and 11 partial response (PR). The disease control rate (CR+PR+SD) was 100%. Out of 7 patients receiving the treatment at second or third line, 5 patients (1 CR, 4 PR) had an objective response (71.4%). 81.8% of the adverse events (AEs) were grade 1 or 2. Grade 3/4 AEs (2 patients) included neutropenia (8 pts, 44.4%), rash (3 pts, 16.7%), anemia (3 pts, 16.7%), fatigue (2 pts, 11.11%), diarrhea (2 pts, 11.11%), and leukopenia (2 pts, 11.11%),. 12 out of 18 patients (66.7%) reduced vemurafenib dose due to AEs, in which 4 patients reduced once from 960mg to 720mg and the remaining 8 patients reduced twice from 720mg to 480mg. Only one patient dropped out due to the intestinal obstruction.Conclusions: A combination of vemurafenib, cetuximab and FOLFIRI was generally well-tolerated and the preliminary result indicated considerably increased response rate for advanced colorectal cancer patients with BRAF V600E mutation. The enrollment for the trial is still under way.Clinical trial identification: NCT03727763.