KRASG12C inhibitors versus chemotherapy alone for KRASG12C-mutated non-small cell lung cancer: a pooled analysis of CodeBreaK 200 and KRYSTAL-12 trials

Background The KRAS G12C mutation is a common oncogenic driver in non-small cell lung cancer (NSCLC). This study aimed to evaluate the clinical efficacy and safety profile of KRAS G12C inhibitors (KGIs) compared with conventional chemotherapy regimens in patients with KRAS G12C -mutant NSCLC. Methods A comprehensive literature search was undertaken across six databases to identify phase 3 randomized controlled trials (RCTs) evaluating KGIs versus conventional chemotherapy. Progression-free survival (PFS) was the primary endpoint, while secondary endpoints included central nervous system (CNS)-PFS, treatment responses, and treatment-related adverse events (TRAEs). Results Two phase 3 RCTs (CodeBreaK 200 and KRYSTAL-12) involving 798 patients were included. The meta-analysis showed that KGIs significantly improved PFS (HR: 0.62 0.51, 0.74, P 0.00001) and CNS-PFS (HR: 0.55 0.32, 0.94, P = 0.03). The survival rates of PFS at 1–12 months were also improved in the KGI group. Subgroup analyses demonstrated a consistent PFS benefit of KGIs over chemotherapy across all predefined subgroups. The objective response rate (ORR, RR: 2.73 1.93, 3.85, P 0.00001) and disease control rate (DCR, RR: 1.35 1.22, 1.50, P 0.00001) were also higher in the KGI group. Total and grade 3–5 TRAEs were similar between groups, although more TRAEs leading to dose interruption were observed in the KGI group (RR: 3.13 2.37, 4.13, P 0.00001). The top 3 grade 3–5 TRAEs in the KGI group were diarrhea (7.63%), alanine aminotransferase increased (7.63%), and aspartate aminotransferase increased (5.93%). Conclusion KGIs demonstrated superior PFS, CNS-PFS, and response rates, with a manageable toxicity profile, suggesting that they represent a preferred treatment option for this population. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251272701 , identifier CRD420251272701.