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 (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.