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

SIMPLE SUMMARY: In this retrospective study including 580 patients with metastatic (Stage IV) non-small cell lung cancer, we investigated whether KRAS mutational status had any impact on clinical outcome. First, we analyzed overall survival of patients grouped based on absence (KRAS(WT)) or presence (KRAS(MUT)) of mutations in KRAS. Next, we assessed the effect of first-line therapies on both groups: platinum doublet chemotherapy (PT), the backbone treatment for most patients with metastatic non-small cell lung cancer, and immune checkpoint blockade (ICB) given to Stage IV patients with high PD-L1 expressing tumors. We found that KRAS(MUT) patients had better response to ICB, but worse response to PT compared to KRAS(WT) patients and that KRAS(WT) patients with high PD-L1 expressing tumors responded better to PT than ICB. Our findings will have immediate clinical value, as KRAS mutations and PD-L1 expression are routinely assessed in most patients diagnosed with lung cancer. ABSTRACT: 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.