Efficacy of first‐line immunochemotherapy across <scp>KRAS</scp> mutation subtypes in advanced lung adenocarcinoma

The impact of KRAS mutation subtypes on treatment response to first-line immunochemotherapy in advanced lung adenocarcinoma (LUAD) remains uncertain. This study evaluated treatment efficacy across KRAS subtypes and examined the role of programmed death-ligand 1 (PD-L1) expression and co-mutations. We retrospectively analyzed 335 patients with advanced KRAS-mutant LUAD treated with first-line immunochemotherapy between 2018 and 2022 at two centers. Patients were categorized into G12A (n = 36), G12C (n = 116), G12D (n = 62), G12V (n = 56), and other subtypes (n = 65). PD-L1 tumor proportion score (TPS) was stratified as <1%, 1-49%, or ≥50%. Endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Median PFS in the overall cohort was 8.6 months, with an ORR of 34.0% and a DCR of 87.8%. Median PFS did not differ significantly among KRAS subtypes (p = .617), nor within PD-L1 TPS groups: <1% (p = .740), 1-49% (p = .652), and ≥50% (p = .481). In the major subtypes (G12A, G12C, G12D, and G12V), PD-L1 expression showed no significant association with PFS. STK11 co-mutations were enriched in G12C, G12V, and other subtypes (p = .004) and correlated with shorter PFS (p = .006). In conclusion, first-line immunochemotherapy yields comparable efficacy across KRAS subtypes, independent of PD-L1 expression. Within the major subgroups (G12A, G12C, G12D, and G12V), PD-L1 levels were not predictive of PFS. STK11 co-mutations were enriched in G12C, G12V, and other subtypes and were associated with shorter PFS.