Comparative efficacy and safety of first‑line treatments for RAS wild‑type metastatic colorectal cancer: A systematic review and network meta‑analysis

Optimal first-line treatments for RAS wild-type metastatic colorectal cancer (mCRC) remain uncertain, despite the availability of numerous targeted therapies.Direct comparisons between all available regimens are limited, necessitating indirect evidence synthesis.A systematic review and network meta-analysis of randomized controlled trials (RCTs) comparing first-line treatments for RAS wild-type mCRC was conducted in the present study.MEDLINE/PubMed, Embase, Cochrane Central Register of Controlled Trials and Web of Science were searched from inception to September 2025.Primary outcomes included overall survival (OS) and progression-free survival (PFS), while secondary outcomes included objective response rate (ORR) and safety profiles.Random-effects network meta-analyses were performed and treatments were ranked using P-scores.In total, 15 RCTs involving 6,298 patients and seven primary treatment nodes were included.The network demonstrated high levels of consistency for OS (I 2 = 0%) and moderate heterogeneity for PFS (I 2 =44.8%) and ORR (I 2 =40.9%).For OS, both cetuximab + chemotherapy [hazard ratio (HR)= 0.853; 95% CI: 0.775-0.938;P= 0.001] and panitumumab + chemotherapy (HR= 0.855; 95% CI: 0.738-0.992;P= 0.038) exhibited statistically significant superiority compared with bevacizumab + chemotherapy.Cetuximab + chemotherapy ranked highest for OS (P-score= 0.814) and PFS (P-score= 0.914).Subgroup analysis demonstrated a pronounced tumor sidedness effect.Anti-EGFR therapy provided a 25.0% reduction in OS risk for left-sided tumors (HR= 0.750; 95% CI: 0.672-0.836;I 2 = 0%), whereas no survival benefit was observed for right-sided tumors (HR=1.097;95% CI: 0.909-1.325).Anti-EGFR regimens were associated with higher rates of grade ≥3 toxicities, reaching up to 83.3%, compared with bevacizumab-based regimens, which fell between 23.4-68.3%.In the present sensitivity analysis, UDP glucuronosyltransferase family 1 member A1-guided bevacizumab + 5-fluorouracil, leucovorin and irinotecan demonstrated favorable outcomes, with OS and PFS P-scores of 0.932 and 0.992, respectively; however, these findings were derived from a single trial with limited comparability.Overall, anti-EGFR antibodies combined with chemotherapy demonstrated consistent and statistically significant survival benefits as first-line treatment for RAS wild-type mCRC, with cetuximab + chemotherapy ranking as the optimal regimen.Treatment benefit from anti-EGFR therapy was markedly influenced by primary tumor location, with notable benefit observed in left-sided tumors and no benefit in right-sided tumors.These findings support tumor sidedness-guided treatment selection in clinical practice, favoring anti-EGFR-based therapy for left-sided and bevacizumab-based therapy for right-sided RAS wild-type mCRC.