Inhibitory effects of icotinib combined with antiangiogenic drugs in human non-small cell lung cancer xenograft models are better than single target drugs.

BACKGROUND: This study aimed to evaluate the inhibitory effects and potential mechanisms of icotinib combined with antiangiogenic drugs on lung adenocarcinoma in vivo. METHODS: A total of 72 mouse xenograft models established with human lung adenocarcinoma cells (HCC827) were randomly divided into six groups, including control, icotinib (Ic), bevacizumab (Bev), recombinant human endostatin (En), Ic + Bev and Ic + En groups. Mouse weights and tumor volumes were measured regularly. Half of the nude mice in each group were sacrificed after 16 days of drug treatment. The remaining animals were observed for another 16 days without drug supply. Immunohistochemical staining was performed to detect microvessel density in tumor heart, liver, brain specimens from the nude mice and Ki67 expression. Differential expression of vascular endothelial growth factor (VEGFA) in tumor tissue specimens was determined by ELISA and Western blot. RESULTS: The results showed that the combined drugs inhibited tumor growth more substantially compared with single drugs, without increasing the toxic effects. The antiangiogenesis effect of the combination was better than that of single drug treatment. In addition, both types of targeted drugs and combination medication not only significantly reduced microvessel density in the tumor tissue itself, but also had a certain impact on decreasing microvessel density in the liver. The combination decreased VEGFA and Ki-67 amounts significantly more than icotinib or endostatin as a monotherapy. CONCLUSIONS: Icotinib combined with bevacizumab or rh-endostatin has a stronger inhibitory effect on tumor growth than single-target drug in vivo, with no additional side effects.

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

OBJECTIVE: To explore the efficacy and safety of icotinib with chemotherapy as first-line therapy for advanced lung adenocarcinoma in patients with sensitive epidermal growth factor receptor (EGFR) mutations. METHODS: This prospective, randomized, controlled trial was conducted in 10 general hospitals in Shandong Province, China. Previously untreated patients with advanced lung adenocarcinoma and sensitive EGFR mutations were recruited between January 16, 2014 and December 31, 2016 and randomly allocated to the combination group (icotinib plus pemetrexed and carboplatin) or the icotinib only group. The patients were followed up until May 23, 2018. The primary endpoint was progression-free survival (PFS). RESULTS: The efficacy analysis (intention-to-treat analysis) include 179 patients (n = 90 in the combination group and n = 89 in the icotinib only group). PFS was significantly longer in the combination group than in the icotinib only group (16.0 months vs. 10.0 months, hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.42-0.84, P = 0.003). The objective response rate and the disease control rate for the combination group were significantly higher than those for the icotinib only group (77.8% vs. 64.0%, χ2 = 4.094, P = 0.043; 91.1% vs. 79.8%, χ2 = 4.632, P = 0.031). However, overall survival did not differ between the two groups (36.0 months vs. 34.0 months, HR = 0.81, 95%CI 0.54-1.22, P = 0.309). The incidence rates of leukopenia and liver function damage of grades 3-4 were higher in the combination group than in the icotinib only group (12.2% vs. 0%, χ2 = 11.086, P = 0.001; 12.2% vs. 3.5%, χ2 = 4.488, P = 0.034). However, adverse events were resolved in most patients. CONCLUSION: Use of the combination of icotinib and chemotherapy as first-line therapy significantly improved the PFS of advanced lung adenocarcinoma patients with sensitive EGFR mutations. Although the combination therapy increased the incidence of leukopenia and liver function damage, the observed adverse events were tolerable and manageable.

Efficacy of combined icotinib and pemetrexed in EGFR mutant lung adenocarcinoma cell line xenografts.

BACKGROUND: The combination of EGFR tyrosine kinase inhibitors (TKIs) and chemotherapy is thought to increase treatment efficacy in non-small-cell lung cancer (NSCLC). This study investigated the efficacy and potential mechanisms of different combined modes of icotinib plus pemetrexed in EGFR-mutant lung adenocarcinoma cell line xenograft models. METHODS: Nude mice were subcutaneously injected with EGFR-mutant human lung adenocarcinoma cells (HCC827) and randomized into six treatment groups. Tumor xenograft volumes were monitored and recorded. Microvessel density (MVD) and proliferation and apoptosis rates were evaluated with CD34 positive cell counting, and Ki-67 and caspase-3 scores, respectively, and determined via immunohistochemistry. Thymidylate synthase (TS), EGFR, and downstream signaling molecule expression was detected by Western blotting. RESULTS: The volume and weight of tumor xenografts in the sequential pemetrexed followed by icotinib (Pem-Ico) group and the concurrent icotinib and pemetrexed (Ico + Pem) group were significantly smaller than those in the control, pemetrexed (Pem), icotinib (Ico), and sequential icotinib followed by pemetrexed (Ico-Pem) groups. Compared to other groups, a decrease in the MVD and proliferation rate and an increase in the apoptosis rate were observed in the Pem-Ico and Ico + Pem groups. TS expression and EGFR, AKT, and MAPK phosphorylation were significantly reduced in the Pem-Ico or Ico + Pem groups. CONCLUSIONS: Pem-Ico had additive antitumor activity in vivo, similar to Ico + Pem, both of which are suggested as potentially optimized strategies for treating EGFR-mutant lung adenocarcinoma.