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

Abstract

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 (I²=0%) and moderate heterogeneity for PFS (I²=44.8%) and ORR (I²=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; I²=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.