Background: Colorectal cancer (CRC) poses a significant global health burden. Cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody, and irinotecan, a topoisomerase I inhibitor, are established therapeutic agents for CRC. Although cetuximab can be administered as monotherapy or in combination with irinotecan, the differences in efficacy and safety between these treatment strategies remain unclear. Therefore, this meta-analysis aimed to comprehensively compare the efficacy and safety between cetuximab alone and cetuximab plus irinotecan for treating patients with CRC.

Methods: Studies about randomized controlled trials on cetuximab monotherapy or combination therapy with irinotecan for treating CRC were retrieved from Cochrane Library, PubMed, and China National Knowledge Infrastructure (CNKI) since inception until 1 April 2024. The subjects were categorized into combination and monotherapy groups. The quality assessment of literature was analyzed using Cochrane risk-of-bias tool. Review Manager Software was utilized for meta-analysis. Progression-free survival (PFS) and grade 3–4 adverse events (AEs) were applied as primary outcome indicators. Overall survival (OS), objective remission rate (ORR) and disease control rate (DCR) were used as secondary outcome indicators.

Results: Six studies and 875 CRC patients were finally included. Meta-analysis results showed that the combination group had a longer PFS than the monotherapy group (hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.42–1.16, p = 0.16), while there was no significant difference in OS between the two groups (HR = 0.84, 95% CI: 0.70–1.00, p = 0.05). The incidence of grade 3–4 AEs was higher in the combination group than in the monotherapy group (relative risk [RR] = 1.38, 95% CI: 1.17–1.64, p = 0.0002). In addition, the DCR of the combination group was significantly higher than that of the monotherapy group (RR = 1.45, 95% CI: 1.16–1.81, p = 0.001), while the ORR was not significantly different between the two groups (RR = 1.12, 95% CI: 0.96–1.31, p = 0.13).

Conclusion: Our findings indicate that cetuximab plus irinotecan confers higher anti-tumor protection than the monotherapy, with a compromise in an evidently increased risk of severe adverse events. The trade-off between efficacy and toxicity must be carefully considered in clinical decision-making.

Registration number: CRD420251124881.