Pemetrexed With Gefitinib Or Pemetrexed Alone In Advanced Lung Adenocarcinoma With Acquired Resistance To EGFR Tyrosine Kinase Inhibitors

Background and objectiveEpidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI) have shown a high tumor response rate and long progression-free surival(PFS) and overall survival(OS) in the treatment of advanced lung adenocarcinoma with EGFR mutation. Nonetheless, most patients developed treatment failure because of getting acquired resistance to EGFR-TKI. The explore of subsequent effective therapies to EGFR-TKI faliure is challenging. In the study, we enrolled patients with EGFR mutation and acquired resistance to erlotinib or gefitinib, and then treat them with gefitinib plus pemetrexed or pemetrexed alone, by asseing the efficacy and safety of the two groups, we are trying to find a bitter treatment for patients with acquired EGFR-TKI resistanceMethods1 In the study, we enrolled 62 patients with EGFR mutation and histologically confirmed stage ?B/?lung adenocarcinoma, who had received first-line platinum-based chemotherapy and developed an acquired resistance to the maintain or second-line EGFR-TKI therapy in Second Affiliated Hospital of Zhengzhou University during March 2012 to October 2014.2 62 participants were randomly assigned:32 to the gefitinib plus pemetrexed group and 30 to the pemetrexed group. The gefitinib plus pemetrexed group received oral gefitinib 250 mg once daily and pemetrexed 500 mg/m2 on the first day, and pemetrexed single group received pemetrexed 500 mg/m2 on the first day. This treatment regimen was repeated every 3 weeks until disease progression or adverse reactions cannot tolerate.3 We compare objective response rate(ORR), disease control rate(DCR), adverse reactions, PFS and OS between the two groups.Results1 The objective response rate was 63.3% for those treated with pemetrexed plus gefitinib versus 33.3% for those treated with pemetrexed alone(x2=4.218, P=0.04). The disease control rate was 84.4% for pemetrexed plus gefitinib group versus 80.0% for pemetrexed group(x2=0.203,P=0.652).2 The median progression-free survival was 8.0 months for pemetrexed plus gefitinib group and 6.3 months for pemetrexed alone (x2=8.063,P=0.040). Median overall survival showed no difference between two groups (x2=8.063, P=0.040).3 The most common adverse events associated with both treatments were hematologic toxicity and nausea or vomit, most were grade 1 or 2 in severity. Adverse events that occurred higher in the pemetrexed plus gefitinib group than pemetrexed group were leukocytopenia(x2=4.089, P=0.043)and Rash(x2=5.858, P=0.027). No discontinutation of treatment or dose reduction caused by untolerable toxicity was required.ConclusionsThis study suggests that continuation of EGFR-TKI with pemetrexed in patients with acquired EGFR-TKI resistance improves outcomes compared with pemetrexed alone. We observed an improved objective response rate and an longer median progression-free survival in the EGFR TKI plus pemetrexed group. But, there was no difference in overall survival. A larger prospective clinical trial is needed to evaluate this promising strategy further.