Background: The low efficacy of single-agent BRAF inhibitor in metastatic colorectal cancer (mCRC) is usually due to EGFR feedback upregulation caused by BRAF blockade. Therefore, multi-drug combination therapy with BRAF inhibitor has been tried. Here, we reported the preliminary results of quadruple therapy with dabrafenib, a selective BRAF inhibitor, trametinib, a selective MEK inhibitor, irinotecan and cetuximab in patients with BRAF V600E-mutated mCRC. Methods: This was an ongoing phase Ib study, patients with mCRC who relapse or refractory to standard treatments were enrolled. Patients were treated with dabrafenib (150mg/150mg doses orally twice daily), trametinib (2mg orally once daily), irinotecan (80mg/m² weekly) and cetuximab (400mg/m² in first dose and 250mg/m² weekly). Treatment was continued until disease progression, development of unacceptable toxicity, or drawal of consent. The primary end-point was disease control rate (DCR), and the secondary end-points included progression-free survival (PFS) and duration of disease remission (DOR). This trial is registered with Chinese ClinicalTrials.gov, number ChiCTR2200063316. Results: From July 2018 to January 2021, 10 patients were enrolled. The median age was 53.5 (age 25-65), nine with colon cancer and one with rectal cancer. The most common adverse events (AEs) (50% or more) were fatigue, fever, rash, vomit, leukopenia, anemia, ALT elevation, and AST elevation. Four patients suffered rash which was the most common severe AE (SAE). Two patients presented with grade 3/4 anemia. Only one patient suffered grade 3/4 AEs with nausea and vomit. The DCR was 90% (9/10). After a median follow-up of 19.7 months, the median PFS was 7.5 months (range 1.8-32.4 months). The median DOR was 5.2 months (range 0-27.7 months). Conclusions: Dabrafenib, trametinib, irinotecan and cetuximab has tolerable toxicity and promising antitumor activity in BRAF V600E-mutated mCRC. This regimen warrants a further phase II clinical trial. Clinical trial information: ChiCTR2200063316.