Molecular and clinical characteristics of patients with non-small cell lung cancer (NSCLC) harboring the rare <i>KRAS</i> codon 12 mutations G12A, G12S, G12R, and G12F.

Abstract

e20647 Background: KRAS mutations occur in approximately 30% of non-small cell lung cancers (NSCLC) and frequently involve the hotspot codon G12. While common variants such as G12C, G12V and G12D have been extensively studied, data on rare G12A, G12S, G12R and G12F substitutions remain limited. This real-world analysis characterizes the molecular and clinical features of a large cohort of NSCLC patients harboring rare KRAS codon 12 mutations. Methods: We looked for stage IV NSCLC at initial diagnosis harboring rare KRAS codon 12 mutations (G12A, G12S, G12R and G12F) from the national Network Genomic Medicine (nNGM) database diagnosed between 2018 and 2024. Clinical, pathological and molecular characteristics were analyzed, including co-mutations, smoking-history, PD-L1 expression, treatment patterns and outcomes. Results: A total of 527 individuals were included. KRAS G12A mutations were identified by next-generation sequencing (NGS) in 316 cases (60%), followed by G12S (15%), G12R (13%) and G12F (12%). The median age of the cohort was 66 years (range: 38–89), with no major differences in sex distribution (47% female, 53% male). Most patients were former or current smokers (overall: 477 (91%), G12A/S/R/F: 91/94/82/93%) and adenocarcinoma was the predominant histology (overall: 480 (91%), G12A/S/R/F: 90/89/93/99%). Median PD-L1 tumor proportion score (TPS) in the overall cohort was 5% (range: 0–100), with differences between subtypes (G12A/S/R/F: 5/30/1/10%). The most frequent co-mutations in the overall cohort were TP53 , STK11 , KEAP1 and SMARCA4 , showing subtype-specific patterns ( TP53 : 43/43/36/43%, STK11 : 21/23/36/29%, KEAP1 : 21/16/26/18%, SMARCA4 : 9/29/0/14% for G12 A/S/R/F respectively). At initial diagnosis the most common metastatic sites were bone (38%) and lung (38%) metastasis, with notable differences between subtypes (bone: 44/36/11/40%, lung: 40/36/45/21% for G12 A/S/R/F). Treatment data were available for 285 patients, of whom 36 (13%) received chemotherapy, 199 (70%) chemo-immunotherapy, and 50 (18%) immune checkpoint inhibitor monotherapy. Median overall survival (mOS) did not significantly differ between subtypes, however a trend toward shorter survival was observed in G12R-mutated tumors (mOS: 6.7 months (95% CI, 4.1–15.9)), whereas longer survival was seen in G12A-mutated tumors (mOS: 11.7 (95% CI, 9.2–16.6). Conclusions: NSCLC harboring rare KRAS codon 12 mutations (G12A, G12S, G12R and G12F) are characterized by a high prevalence of tobacco exposure, frequent co-mutations in clinically relevant genes, and a heterogeneous molecular landscape across the four analyzed subtypes. Despite comparable median overall survival, the observed subtype-specific patterns underscore the biological diversity of rare KRAS codon 12 mutations and suggest that these subgroups be considered in future clinical trials.