KRAS Mutations Impact Clinical Outcome in Metastatic Non-Small Cell Lung Cancer.

There is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PT) and immune checkpoint blockade (ICB). Here, we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (Stage IV) non-small cell lung cancer (NSCLC). All consecutive patients molecularly assessed and diagnosed between 2016-2018 with Stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. The primary study outcome was overall survival (OS). Out of 580 Stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene ( KRAS MUT ). Compared to KRAS wild-type ( KRAS WT ), KRAS MUT was a negative factor for OS ( p = 0.014). On multivariate analysis, KRAS MUT persisted as a negative factor for OS (HR 1.478, 95% CI 1.207-1.709, p < 0.001). When treated with first-line platinum doublet ( n = 195), KRAS MUT was a negative factor for survival ( p = 0.018), with median OS of 9 months vs. KRAS WT at 11 months. On multivariate analysis, KRAS MUT persisted as a negative factor for OS (HR 1.564, 95% CI 1.124-2.177, p = 0.008). KRAS MUT patients with high PD-L1 expression (PD-L1 high ) had better OS than PD-L1 high KRAS WT patients ( p = 0.036). In response to first-line ICB, KRAS MUT patients had a significantly ( p = 0.006) better outcome than KRAS WT patients, with a median OS of 23 vs. 6 months. On multivariable Cox analysis, KRAS MUT status was an independent prognostic factor for better OS (HR 0.349, 95% CI 0.148-0.822, p = 0.016). kRAS mutations are associated with better response to treatment with immune checkpoint blockade and worse response to platinum doublet chemotherapy as well as shorter general OS in Stage IV NSCLC.