Abstract
INTRODUCTION: Kras mutation is the most common driver oncogene present in patients with NSCLC. Recently, the precision medicine for patients with Kras-mutated NSCLC has been under investigation, but the best treatment is still unknown. This study aimed to analyze the clinical characteristics, immune checkpoint inhibitor (ICI) response, and prognostic factors of patients with NSCLC with different Kras mutation subtypes. METHODS: From 2005 to 2018, we collected nonsquamous NSCLC tissue samples for Kras mutation analysis using direct Sanger sequencing or MassARRAY genotyping (Agena Bioscience, San Diego, CA) at the National Taiwan University Hospital. Clinical characteristics, ICI treatment effectiveness, time-to-tumor recurrence (TTR), and overall survival (OS) were analyzed using multivariate Cox models, to estimate adjusted hazard ratios (HRs). RESULTS: Among 5278 patients with nonsquamous NSCLC, 246 (4.7%) had Kras mutations. The major Kras mutation subtypes were G12C (32.9%), G12D (23.7%), and G12V (18.9%). Patients with Kras-G12C had a higher proportion of male individuals (p = 0.018) and smokers (p < 0.001). Among the 25 patients treated with ICIs, patients with Kras-G12C had a higher response rate (53.8% versus 8.3%, p = 0.030) and longer progression-free survival (4.8 mo versus 2.1 mo, p = 0.028) than those with Kras-non-G12C. For the 85 patients with early-stage NSCLC, those with G12C had shorter TTR (22.8 mo) than those with Kras-non-G12C (97.7 mo, p = 0.004). For the 143 patients with advanced-stage NSCLC, there was a significant difference in OS between patients with Kras-G12C and Kras-non-G12C (7.7 mo versus 6.0 mo, p = 0.018) and patients with Kras-G12V had the shortest OS (5.2 mo). Multivariate analysis revealed association of shorter OS with Kras-G12V (HR = 2.47, p = 0.002), stage IV disease status (HR = 2.69, p = 0.008), and NSCLC-not otherwise specified histology (HR = 3.12, p = 0.002). CONCLUSIONS: Kras-G12C was associated with favorable ICI treatment effectiveness in patients with NSCLC. Kras-G12C mutation was associated with shorter TTR in patients with early-stage NSCLC, and Kras-G12V mutation was associated with shorter OS in patients with advanced-stage NSCLC when comparing with Kras-G12C.