The distribution of genetic mutations correlated with resistance to KRAS^G12C inhibitors in Chinese patients with lung cancer.

3141 Background: In lung cancer, p.G12C is the most frequent variant in Kirsten rat sarcoma viral oncogene homologue (KRAS) gene. KRASG12C inhibitors have shown promising efficacy in lung cancer in recent clinical trials, acquired resistance, however, eventually occurred in most patients. Preliminary studies revealed that a number of genetic mutations were correlated with resistance to this type of drugs, including KRAS secondary mutations, KRAS activating mutations, mutations in RTK-RAS-MAPK signaling pathways members, oncogene rearrangements and copy number gain. To clarify the potential clinical application of KRASG12C inhibitors, herein we analyzed the distribution of reported resistance gene alterations in a large and natural group of Chinese lung cancer, as well as the gene mutation landscape of the subset of patients with suspected resistant mutations. Methods: A total of 32878 Chinese lung cancer including early-stage, late-stage without treatment or late-stage with previously treated were analyzed in this study. Wide NGS panel testing was used to detected single nucleotide variants (SNV), copy number variants (CNV) and oncogenic gene rearrangements. Results: KRAS mutations were detected in 2767 (8.4%) cases, of which KRAS G12C was the most common variant (30.86%). Among 854 patients (2.6%) harbored KRAS G12C, 75 (10%) carried the above resistance mutations, such as G12D/R/V (n = 7). Fusions (20%) which previously observed only in coloretal cancer were unexpectedly detected in this corhort, including EML4-ALK (n = 1), FGFR1-MECOM (n = 1), EWSR1-CHEK2 (n = 2), SPEN-KAZN (n = 2), MET-KCNB2 (n = 1), NOTCH2-NOTCH2NLA (n = 5), SMARCA4-DNAH8 (n = 1), and LIPM-FAS (n = 1). Furthermore, KRAS (46.7%), MYC (25.3%) and MET (10.7%) were amplified. Among this subset of patients with resistant mutations, TP53 (66%), LRP1B (25%), and STK11 (22%) were the most frequently mutated genes. It is noteworthy that STK11/KEAP1 /NFE2L2 gene mutation was detected in nearly 30% in this group of patients. Conclusions: The results of our analysis suggested that about 10% KRAS G12C-mutated Chinese lung cancer patients would be resistant to KRAS G12C inhibitors. Moreover, a small number patients have co-mutated genes which were negatively related to immunotherapy in NSCLC, indicating they were also inappropriate for immunotherapy.