Efficacy and Safety of KRAS G12C Inhibitor Monotherapy in Treatment of Non-Small Cell Lung Cancer: A Single-Arm Meta-Analysis

To systematically synthesize evidence on multiple KRAS G12C inhibitors(KRAS G12C inhibitors, KRAS G12Ci) as monotherapy within a unified population and recommended-dose framework, establish a comparable benchmark range of efficacy and safety for previously treated patients with advanced or metastatic KRAS G12C-mutant non-small cell lung cancer(NSCLC), and explore potential effect modifiers.

We systematically searched PubMed, Embase, the Cochrane Library, Web of Science, ClinicalTrials.gov, and major international conference abstracts, and included clinical-trial cohorts enrolling patients with advanced or metastatic KRAS G12C-mutant NSCLC who were G12Ci-naïve and received recommended-dose G12Ci monotherapy. Random-effects models were used to pool objective response rate(ORR), disease control rate(DCR), median progression-free survival(mPFS), median overall survival(mOS), and the incidence of any-grade and grade ≥3 treatment-related adverse events(TRAEs). For biomarker stratification, pooled odds ratios(OR) were calculated to assess associations between co-mutations and programmed death-ligand 1 expression and ORR.

The single-arm meta-analysis included 11 independent study cohorts. The pooled ORR using a random-effects model was 44%(95% CI: 38%-49%) and the pooled DCR was 86%(95% CI: 82%-88%). The pooled mPFS was 7.70 months(95% CI: 5.82-10.20) and the pooled mOS was 12.63 months(95% CI: 10.07-15.83). For safety, the pooled incidence of any-grade TRAEs was 92%(95% CI: 86%-96%), and grade ≥3 TRAEs was 39%(95% CI: 33%-45%). The toxicity profile was dominated by hepatobiliary laboratory abnormalities, renal dysfunction/proteinuria, and gastrointestinal events. Exploratory stratified analyses suggested that KEAP1 co-mutation was significantly associated with a lower ORR(OR=0.37, 95% CI: 0.21-0.65); no significant stratification effect was observed for TP53 co-mutation or PD-L1 expression(at 1% and 50% cutoffs); and the association between STK11 co-mutation and ORR did not reach statistical significance(OR=0.63, 95% CI: 0.37-1.08).

In previously treated patients with advanced KRAS G12C -mutant NSCLC, KRAS G12Ci monotherapy achieves stable overall response rates and disease control rates, yielding an efficacy and safety benchmark range that may facilitate clinical interpretation and cross-study comparisons. During treatment, standardized monitoring of hepatobiliary biochemistry, renal function, proteinuria, and gastrointestinal toxicities should be emphasized. Exploratory evidence indicates that KEAP1 co-mutation may represent a more actionable negative stratification signal.