Background: The standard third-line treatment for mCRC is regorafenib, fruquintinib or TAS-102. However, the efficacy was not satisfied. Since VEGF and EGFR share the downstream signaling pathway, targeting these two pathways may have synergistic efficacy. The phase Ib trial with regorafenib combined with cetuximab have shown preliminary benefit. Fruquintinib is a small molecule highly selective VEGFR1/2/3 molecule inhibitor. Here, we evaluate the safety and efficacy of fruquintinib plus cetuximab in previously treated RAS/BRAF wild-type mCRC. Methods: This is an open-label phase I/IIa study. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3+3 dose escalation strategy in phase I and safety, grade 3/4 adverse events in phase IIa. Secondary objectives include ORR, mPFS, and mOS. Eligible patients were diagnosed as advanced RAS/BRAF wild-type CRC and had received at least two prior regimens of standard therapies. Exclude patients who have previously used other small molecule anti-vascular inhibitors. The planned number of cases is 20(including phaseⅠandⅡa). ChiCTR2000038227. Results: Between Sep, 2020 to Sep, 2022, 21 pts were enrolled including 7 patients of phase Ⅰ. The RP2D is fruquintinib 4 mg QD (3 weeks on/1 week off) plus cetuximab 500mg/m2 every two weeks, received by 17 pts. Two patient dropped out，one because of refusing treatment and another due to severe allergic reaction. 15 pts were included in the efficacy analysis and 16 pts in the safety analysis. The left side mCRC accounted for 87.5%. 68.8% have received cetuximab and 75% have received bevacizumab. The overall TRAE was 75.0%, with 25.0% grade 3 or above. The most common treatment-related AEs were acneiform rash, hypoproteinemia and dry skin (Table1). One patient had dose reduction of fruquintinib due to acneiform rash. Evaluation in 15 treated patients showed 2 cases were PR, 10 were SD and 3 were PD. DCR was 80%. mPFS was 128 days(95%CI:49.7-206.3). mOS was 229 days(95%CI: 104.0-354.0). Conclusions: Cetuximab combined with fruquintinib showed promising anti-tumor activity in CRC with resistance to at least two prior regimens. The toxicity was tolerable and no unexpected toxicities were observed (Table 1). Clinical trial information: Clinical trial information: ChiCTR2000038227.