Abstract: Background and purpose: New treatment methods should be explored for non-small cell lung cancer (NSCLC) patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). This study compared the curative effect of pemetrexed with gefitinib or pemetrexed alone in advanced NSCLC with acquired resistance to EGFR-TKI. Methods: This study included 62 NSCLC patients with advanced EGFR gene mutation and acquired resistance to EGFR-TKI. Among those, 32 patients were treated with pemetrexed and gefitinib, and 30 patients treated with gefitinib alone. The differences in outcomes between the two strategies were assessed. Results: Objective response rate (ORR) was 46.9% for those treated with pemetrexed and gefitinib and 20% for those treated with pemetrexed alone(χ²=4.933, P<0.05). There was no significant differences between the two groups on disease control rate (DCR) (P>0.05). The median progression-free survival (PFS) was 8.0 months on pemetrexed and gefitinib group and 6.3 months on pemetrexed alone (χ²=8.063, P<0.05). There was no significant differences between the two groups on overall survival (OS) (P>0.05). Higher occurrence of leukocytopenia and rash was observed in the pemetrexed and gefitinib group than in the pemetrexed group (P<0.05). There was no significant differences between the two groups on grade 3-4 toxicities (P>0.05). Conclusion: This study was to demonstrate that continuation of EGFR-TKI with pemetrexed in patients with acquired resistance improves outcomes compared with pemetrexed alone. An improved response rate and PFS were observed in this study. A larger prospective clinical trial is needed to  further evaluate this promising strategy.

Key words: Pemetrexed, Gefitinib, Advanced non-small cell lung cancer, Epidermal growth factor receptor-tyrosine kinase inhibitor