Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial.

To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head-to-head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first-line therapy, in terms of efficacy and safety. A total of 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin or gefitinib alone. The progression-free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3-19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2-6.3) or gefitinib (11.9 months, 95% CI, 9.1-14.6) group. The (hazard ratios) HRs of PFS for the combination group vs. chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09-0.29, p < 0.001) and 0.48 (95% CI, 0.29-0.78, p = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group and the gefitinib group was 82.5%, 32.5% and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, p = 0.016) or gefitinib (HR = 0.36, p = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations.

Potential Antitumor Activity of SIM-89 in Non-Small Cell Lung Cancer Cells.

PURPOSE: c-Met and its ligand, hepatocyte growth factor (HGF), play a critical role in oncogenesis and metastatic progression. The aim of this study was to identify inhibited enzymogram and to test the antitumor activity of SIM-89 (a c-Met receptor tyrosine kinase inhibitor) in non-small cell lung cancer. MATERIALS AND METHODS: Z'-LYTE kinase assay was employed to screen the kinase enzymogram, and mechanism of action (MOA) analysis was used to identify the inhibited kinases. Cell proliferation was then analyzed by CCK8 assay, and cell migration was determined by transwell assay. The gene expression and the phosphorylation of c-Met were examined by realtime-PCR and western blotting, respectively. Finally, the secretion of HGF was detected by ELISA assay. RESULTS: c-Met, activated protein kinase (AMPK), and tyrosine kinase A (TRKA) were inhibited by SIM-89 with the IC50 values of 297 nmol/L, 1.31 µmol/L, and 150.2 nmol/L, respectively. SIM-89 exerted adenosine triphosphate (ATP) competitive inhibition on c-Met. Moreover, the expressions of STAT1, JAK1, and c-Met in H460 cells were decreased by SIM-89 treatment, and c-Met phosphorylation was suppressed in A549, H441, H1299, and B16F10 cells by the treatment. In addition, SIM-89 treatment significantly decreased the level of HGF, which accounted for the activation of c-Met receptor tyrosine kinase. Finally, we showed cell proliferation inhibition and cell migration suppression in H460 and H1299 cells after SIM-89 treatment. CONCLUSION: In conclusion, SIM-89 inhibits tumor cell proliferation, migration and HGF autocrine, suggesting it's potential antitumor activity.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Advanced Squamous Cell Lung Cancer.

BACKGROUND: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in squamous cell carcinoma (SCC) of the lung remains controversial, and the role of EGFR testing in patients with SCC of the lung remains debatable. PATIENTS AND METHODS: We retrospectively identified patients with stage IIIB or IV SCC of the lung who had undergone EGFR testing at Shanghai Chest Hospital from January 2009 to December 2013. RESULTS: A total of 29 EGFR mutation-positive patients (22 patients had received TKI therapy and 7 had not) and 151 EGFR wild-type patients (27 patients had received TKI therapy and 124 had not) were available for an analysis of efficacy. The EGFR mutation-positive patients had significantly improved overall survival (OS) with EGFR TKI therapy compared with those who had not received EGFR TKIs (18.04 months [95% confidence interval (CI), 13.47-22.61 months] vs 13.18 months [95% CI, 5.22-21.13]; P = .015). Patients with wild-type EGFR did not have an improvement in OS with TKI therapy compared with those who had not received TKIs (14.03 months [95% CI, 11.11-16.9 months] vs. 13.63 months [95% CI, 11.91-15.36]; P = .927). The progression-free survival (PFS) for EGFR mutation-positive and EGFR wild-type patients was 3.94 months (95% CI, 2.73-5.15 months) and 1.94 months (95% CI, 0.89-2.99 months), respectively (P = .004). CONCLUSION: EGFR TKIs could be an option for the treatment of SCC, and EGFR mutation detection can help to select a subgroup of patients who would have the best response to TKIs.