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

Background: -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.