KRAS G12C-associated immunotherapy benefit in NSCLC is substantially mediated by tobacco-induced tumor mutation burden, not allele-specific effects

Background

KRAS G12C mutations in non-small cell lung cancer (NSCLC) have been associated with improved immune-checkpoint inhibition (ICI) outcomes. However, it remains unclear whether this benefit reflects allele-intrinsic biology or shared dependence on tobacco-induced mutagenesis and elevated tumor mutation burden (TMB).

Methods

We analyzed 9,230 lung adenocarcinoma (LUAD) tumors to assess the mutational context and oncogenic potential of KRAS G12 variants. For each variant, we estimated cancer effect sizes, and assessed associations with tobacco-related mutational signature SBS4 exposure and TMB. We applied regression models to evaluate the linkage between SBS4 exposure, TMB, and ICI outcomes.

Results

KRAS G12C and G12D mutations exhibited comparable oncogenic effect sizes. However, G12C mutations were significantly enriched in tumors with higher tobacco-associated SBS4 exposure and higher TMB. SBS4 exposure and TMB were highly correlated. Models of ICI outcomes as functions of TMB as a consequence of SBS4 exposure recapitulated observed clinical trends: hazard ratios decreased and response rates increased as observed.

Conclusions

The improved ICI response observed in KRAS G12C-mutant tumors is more likely driven by tobacco-induced hypermutation and its immunogenic consequences than by G12C-specific biological properties. When available, smoking history and TMB remain more cogent biomarkers for ICI stratification than KRAS G12C-variant NSCLC.