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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.

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