Pan-cancer KRAS atlas of 9,056 Chinese patients: Subtype-specific immuno-genomic profiling to guide G12C, G12D, and pan- KRAS strategies.

3128 Background: KRAS therapy is shifting from allele-specific inhibitors to pan- KRAS strategies. However, pivotal trials are largely Western, and Asian subtype-specific immunogenicity and co-mutation benchmarks remain limited. We present the largest pan-cancer Asian KRAS clinogenomic atlas to define these benchmarks and inform treatment selection and trial stratification for the pan- KRAS inhibitor era. Methods: We analyzed 9,056 Chinese patients with KRAS mutations across over 30 tumor types, including pancreatic 27.4%, colorectal 25.1%, NSCLC 20.8%, and biliary tract 10.0%. All underwent ~600 gene next generation sequencing profiling in a CAP/CLIA certified laboratory including all classes of genomic alterations with integrated analysis of clinical variables, treatment history, co-mutations, TMB, MSI, and PD-L1. Results: KRAS mutations clustered at four hotspot codons: G12 (80%), G13 (9%), Q61 (6%), and A146 (3%). Alleles were dominated by G12D (33.3%), G12V (22.8%), and G12C (11.8%), followed by G13D (7.8%) and G12R (4.6%), together covering 80.3% of patients. Overall, 55% carried non-G12C/D variants. More than one KRAS point mutations occurred in 1.8% of the patients and KRAS amplification in 2.5%. Co-mutations were common, led by TP53 (61.7%), APC (22.2%), SMAD4 (17.9%), CDKN2A (17.1%), PIK3CA (12.5%), ARID1A (11.9%), and STK11 (7.7%). TMB in 98.5% (median 4.0 mut/Mb) with 19.2% TMB-high (≥10 mut/Mb), MSI in 97.4% with 3.5% MSI-H, and PD-L1 in 58.0% with 49.5% positive expression. Subtype patterns were distinct. G12C had the highest TMB-high rate (42.4%) with rare MSI-H (0.8%), supporting targeted inhibition with rational IO combination evaluation. In contrast, G13D showed an Asian-enriched immunogenic phenotype with MSI-H 16.1%, higher than Western benchmarks (7.9%, P<0.001), and elevated TMB-high (30.8%). Clinically relevant stratification emerged in NSCLC G12C, with 82.5% male predominance versus about 40% in Western populations (P<0.0001) and an age gradient consistent with smoking (67% male <50 years rising to 89% at ≥70 years). Adverse co-mutations were enriched in G12C, including STK11 (14.4%) and KEAP1 (9.1%). Multi- KRAS mutations were strongly associated with MSI-H (OR 5.48, P<0.0001). Conversely, G12R showed an immune-cold profile (TMB-high 3.2%, MSI-H 0.2%), supporting reliance on targeted inhibition rather than IO-based approaches. Nineteen percent of patients were treatment-naive at profiling, most commonly in NSCLC (30%). Versus post-treatment cases, treatment-naive patients were enriched for G12C (15.9% vs 10.4%, P<0.0001) and showed higher TMB and PD-L1positives. Conclusions: This largest Asian KRAS atlas defines actionable benchmarks for precision therapy and provides a molecular rationale for region-specific stratification in global pan- KRAS trials.