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

BackgroundWe 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 MethodsConsecutive 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.ResultsTwo 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).ConclusionKRAS 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.     

Analysis of Progression Patterns and Failure Sites of Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations Receiving First-line Treatment of Tyrosine Kinase Inhibitors

BackgroundReliable prediction of progression patterns and failure sites for patients with stage IV lung adenocarcinoma is valuable for physicians to deliver personalized tyrosine kinase inhibitor (TKI) treatment.Patients and MethodsWe retrospectively enrolled 266 patients who had stage IV lung adenocarcinoma and received first-line TKI treatment from 2013 to 2017 in Shanghai Chest Hospital. The clinical characteristics at initial diagnosis, progression patterns, and failure sites were analyzed with the attempt to identify some predictive factors for progression patterns and failure sites.ResultsAmong all patients, 62.4% developed systemic progression, and 37.6% developed oligoprogression. Both cohorts had a median progression-free survival (PFS) of 9 months. The percentage of patients who developed original and distant failure was 39.1% and 60.9%, respectively. Patients with oligometastasis at initial diagnosis were more prone to develop oligoprogression (odds ratio [OR], 4.370; 95% confidence interval [CI], 1.881-10.151; P = .001), whereas pulmonary metastasis was negatively correlated with oligoprogression (OR, 0.567; 95% CI, 0.330-0.974; P = .04). Both oligometastasis diagnosis (OR, 2.959; 95% CI, 1.347-6.500; P = .007) and the maximum diameter of the primary lung lesion (threshold 3.25 cm: OR, 3.646; 95% CI, 2.041-6.515; P = .0001) were strong predictive factors for original failures. Osseous metastasis at initial diagnosis might be an indication for distant failure (OR, 0.536; 95% CI, 0.316-0.909; P = .021).ConclusionOver one-half of patients with stage IV lung adenocarcinoma receiving first-line TKI treatment developed systemic progression and distant failure. Metastasis patterns at initial diagnosis was the most important predictive factor for progression patterns and failure sites. The maximum diameter of the primary lung lesion and evidence of osseous metastasis were also found to be significant indicative factors for failure sites.     

Role of Antiangiogenic Agents Combined With EGFR Tyrosine Kinase Inhibitors in Treatment-naive Lung Cancer: A Meta-Analysis

BackgroundAntiangiogenic agents combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered potentially effective biologically synergistic drug combinations for EGFR-mutant advanced non–small-cell lung cancer (NSCLC), although some controversy remains. The European Commission has approved the use of bevacizumab plus erlotinib as first-line treatment of EGFR-mutated NSCLC; however, it has not yet been approved by the U.S. Food and Drug Administration. Recently, several phase III, randomized controlled trials of combinations of antiangiogenic agents and EGFR-TKIs have been reported. These studies have not yet been included in any previous meta-analysis.Materials and MethodsWe performed a meta-analysis to compare antiangiogenic agents plus EGFR-TKIs versus EGFR-TKIs alone for treatment of EGFR-mutant NSCLC. The main outcomes were progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), and adverse events (AEs).ResultsWe identified 9 previous reports of 6 randomized controlled trials and 1 prospective cohort study, involving 1295 patients. Compared with EGFR-TKIs alone, antiangiogenic agents plus EGFR-TKIs resulted in a higher PFS (hazard ratio, 0.58; 95% confidence interval [CI], 0.50-0.67; P < .001). However, no significant differences in OS (hazard ratio, 0.79; 95% CI, 0.53-1.18; P = .26) and ORR (risk ratio, 1.03; 95% CI, 0.97-1.10; P = .30) were found between the 2 groups. An increased risk of serious AEs (risk ratio, 1.41; 95% CI, 1.11-1.79; P = .005) was found in the combination drug therapy group.ConclusionsAntiangiogenic agents plus EGFR-TKIs enhanced PFS for patients with EGFR-mutant NSCLC but with a greater risk of serious AEs. No significant benefits for OS and ORR were found between the 2 groups.