Molecular and clinical characteristics of patients with non-small cell lung cancer (NSCLC) harboring KRAS Q61 mutations to assess therapeutic responses

INTRODUCTION: KRAS Q61 mutations represent a heterogeneous molecular subgroup and account for 1-7% of allKRAS mutations in non-small cell lung cancer (NSCLC). The prognostic value of this cohort and its response to different treatment regimens remain unclear. METHODS: Between 2011 and 2023, diagnostic samples from patients with NSCLC were analyzed by next-generation sequencing (NGS). Molecular data were correlated with clinical records and time-to-event analyses were performed using the Kaplan-Meier estimate. RESULTS: Of the 8862 analyzed probes, we identified 487 patients (5.5%) with KRAS Q61 mutations and further analyzed 365 patients. Most presented with Q61H (74.0%) and Q61L (20.8%) mutations which demonstrated distinct patterns in smoking history (7% versus 3.3% never-smokers) and co-mutational landscape. The most frequent co-mutations in Q61H were STK11 (45.8%), TP53 (32.1%) and KEAP1 (31.3%), whereas Q61L was mutually exclusive to STK11 and had a lower incidence of co-occuring KEAP1 mutations (11.5%). Median overall survival for the entire cohort was 12.3 months with a favorable survival of 22.1 and 65.4 months for patients receiving combined chemoimmunotherapy and immunotherapy as first-line treatment, respectively. Real-world progression-free survival was significantly prolonged in patients receiving immunotherapy, either as monotherapy or combined therapy, versus chemotherapy in the first-line setting (p<0.01). CONCLUSION: KRAS Q61H and Q61L were the predominant mutational subtypes and demonstrated distinct molecular and clinical characteristics, with differences in co-mutational landscape and survival differences. Immunotherapy-based regimens were associated with more favorable outcomes compared to chemotherapy, particularly in patients with high PD-L1 expression, underscoring the importance of subtype-specific molecular characterization in clinical decision-making.