Abstract
Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment option in the fight against advanced non-small-cell lung cancer (NSCLC). KRAS is the most frequently mutated oncogene in NSCLC. We performed this meta-analysis to investigate if KRAS mutation status affects survival benefits of ICIs in patients with advanced NSCLC. Electronic databases were searched for eligible studies. We included randomized trials with the data of overall survival stratified by KRAS mutation status. From 3 eligible studies, 138 patients with KRAS mutant NSCLC and 371 with KRAS wild-type tumor were included in the meta-analysis. Compared to chemotherapy with docetaxel, ICIs improved overall survival in patients with previously treated KRAS mutant NSCLC (hazard ratio = 0.64 [95% confidence interval, 0.43–0.96], P = 0.03). For patients with KRAS wild-type NSCLC, however, ICIs did not prolong overall survival over that with chemotherapy (hazard ratio = 0.88 [95% confidence interval, 0.68–1.13], P = 0.30). In conclusion, ICIs as a salvage therapy improved overall survival over that with docetaxel in advanced NSCLC patients with KRAS mutation, but not in those with KRAS wild-type tumor. These results suggest that KRAS mutation status may be a potential biomarker for survival benefits to ICIs.
Highlights
Treatment of advanced non-small-cell lung cancer (NSCLC) progressed dramatically with the introduction of targeted agents in the last 15 years
Immune checkpoint inhibitors (ICIs) as a salvage therapy improved overall survival over that with docetaxel in advanced NSCLC patients with KRAS mutation, but not in those with KRAS wild-type tumor. These results suggest that KRAS mutation status may be a potential biomarker for survival benefits to ICIs
Out of the remaining 29 potentially relevant prospective studies, 23 were excluded according to the inclusion criteria: four trials had no data to assess hazard ratio (HR) or 95% confidence interval (CI) of overall survival (OS) stratified by KRAS mutation status [7, 8, 12, 17]
Summary
Treatment of advanced non-small-cell lung cancer (NSCLC) progressed dramatically with the introduction of targeted agents in the last 15 years. The binding of PD-L1 with programmed death 1 (PD-1) receptors on activated T-cells induces tumor immune escape by downregulating antitumoral T-cell function [4, 5]. Patients with PD-L1 expression on tumor cells and/or tumor-infiltrating immune cells showed better outcomes, compared with those with no PD-L1 expression [7,8,9,10]. Tumor mutational burden has been proposed as a potential marker for response to ICIs in advanced NSCLC [13, 14]. High mutational burden contributes to tumor immunogenicity and may affect response to ICIs [6]. Subgroup analysis of the CheckMate 057 trial www.impactjournals.com/oncotarget showed that patients with KRAS mutation were more like to benefit from nivolumab in term of an improved overall survival (OS) [9].
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