Meta-analysis shows KRASG12C inhibitors improve outcomes versus chemotherapy in KRAS-mutant NSCLC

BackgroundThe KRASG12C 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 KRASG12C inhibitors (KGIs) compared with conventional chemotherapy regimens in patients with KRASG12C-mutant NSCLC.MethodsA 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).ResultsTwo 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%).ConclusionKGIs 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 Registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251272701, identifier CRD420251272701.