Clinical Outcome With Platinum-Based Chemotherapy in Patients With Advanced Nonsquamous EGFR Wild-Type Non-Small-Cell Lung Cancer Segregated According to KRAS Mutation Status

Kirsten rat sarcoma viral oncogene (KRAS) mutation negatively affects survival of patients with advanced none small-cell lung cancer (NSCLC). In a population of patients with advanced nonsquamous epidermal growth factor receptor (EGFR) wild-type (WT) NSCLCs, we investigated whether patients with KRAS mutations treated with first-line platinum-based chemotherapy derive less benefit than a historical control of patients with KRAS WT. In so doing, we reported a significantly inferior clinical outcome for patients with KRAS mutations, strongly supporting a role for KRAS mutations in driving resistance to platinum-based chemotherapy. Background: We hypothesized that KRAS mutations function as a marker of poor sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type (WT) non-small-cell lung cancer (NSCLC). Patients and Methods: Consecutive advanced nonsquamous EGFR WT NSCLCs treated at the Medical Oncology of Perugia with simultaneous assessment of KRAS mutation status were eligible. Anaplastic lymphoma kinase (ALK) gene status was known in roughly half of the patients who had KRAS WT. Results: Two hundred four patients were included. Among them, the 77 individuals carrying a KRAS-mutant phenotype experienced a significantly inferior outcome in terms of response rate (P=.04), disease control rate (P=.05), and progression-free survival (PFS) (P=.05) compared with the EGFR WT/KRAS WT population. The association between KRAS mutation and shorter PFS remained statistically significant at multivariate analysis (hazard ratio [HR], 1.45). In addition, patients with KRAS mutations reported a significantly shorter overall survival (OS) compared with patients with EGFR WT/KRAS WT/ALK negativity (n=64) (P=.02). Among patients with KRAS mutations, those harboring a mutation at codon 13 (n=12) performed worse than those with a mutation at codon 12 (n=62) in terms of both PFS and OS (P=.09 for both). Conclusion: KRAS mutation appears to negatively affect sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR WT NSCLC. Studies on larger case series are needed to address differences in clinical outcome according to the type of mutation. (C) 2014 Elsevier Inc. All rights reserved.