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

Abstract

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. 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. 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). 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.