KRAS mutations predict better response to first-line monotherapy with pembrolizumab for patients with PD-L1high metastatic Non-Small Cell Lung Cancer: a retrospective study

Background: Pembrolizumab, a humanized antibody targeting Programmed Cell Death 1 (PD-1), is used as first-line therapy for patients with metastatic Non-Small Cell Lung Cancer (NSCLC) expressing Programmed Death Ligand 1 (PD-L1). However, not all PD-L1 expressing patients respond to pembrolizumab. Thus, there is an urgent need to identify new predictive biomarkers for response to immune checkpoint blockade (ICB) therapy. KRAS mutational status has been suggested to affect treatment outcome, but no clear consensus could be drawn for previous studies. Methods: All consecutive patients diagnosed between 2016-2018 with metastatic NSCLC (stage IV) in the region of West Sweden with molecular characterization available were included in this multi-centers retrospective study. Primary study outcome was overall survival (OS). Baseline patients characteristics, histology type, mutational status, PD-L1 expression and first-line treatment were collected from patient charts and the Swedish Lung Cancer registry. Results: Out of 580 stage IV NSCLC patients, 35.5% harbored a mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.288, 95% CI 1.091-1.521, p = 0.003). When treated with first-line platinum doublet, KRASMUT (n = 219) is a significant (p = 0.001) negative factor for survival with median OS 9 months vs KRASWT 14 months. Patients on KRAS mutational status and PD-L1 expression levels had a significant better OS in KRASMUT with increased PD-L1 expression (p = 0.036) but not for KRASWT. On first-line ICB, KRASMUT had a significant (p = 0.006) better outcome than KRASWT with a median OS 23 vs 6 months. On multivariable Cox analysis, KRASMUT status and Performance Status (PS) 0-1 were independent prognostic factors for better OS (HR 0.349, 95%CI 0.148-0.822, p = 0.016 and HR 0.398, 95 % CI 0.165-0.963, p =0.041). Conclusions: KRAS mutations combined with PD-L1high is a better predictive marker for response to first-line monotherapy with pembrolizumab than only PD-L1high in patients with metastatic NSCLC.