Clinical Study Of The Efficacy Of First-generation Tyrosine Kinase Inhibitor Combined With Thalidomide In Patients With Advanced Non-small-cell Lung Cancer With EGFR-sensitive Mutation

Objective:To observe the efficacy,tolerability and safety of the first-generation epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)combined with thalidomide in the treatment of advanced non-small-cell lung cancer(NSCLC)with EGFR-sensitive mutations.Methods:The patients with advanced NSCLC who were hospitalized and diagnosed as EGFR-sensitive mutations in the Department of Oncology,Shaanxi Provincial People's Hospital from September 2013 to August 2017 were enrolled.The observation group was treated with the first generation EGFR-TKI combined with thalidomide in 9 patients.The control group was 21 patients with advanced NSCLC who had EGFR-sensitive mutations treated with the first-generation EGFR-TKI in the same period.The observation group and the control group were retrospectively studied.The observation group received oral ectinib(125mg tid)or erlotinib(150mg qd)or gefitinib(250mg qd)daily,and oral thalidomide tablets 100~200mg qd before bedtime(initial dose is 25 mg qd,according to the patient's tolerance and adverse reactions,the maximum dose is 200 mg qd).After two months of treatment,biochemical indicators(blood routine,liver and kidney function,blood coagulation,tumor markers,etc.)and imaging indicators(CT,PET/CT,ultrasound,etc.)were reviewed and the assessment of imaging measurable lesions was performed according to the RESIST 1.1 standard(Schedule 1).They stopped taking drugs untill the patient died or the patient could not tolerate the adverse reaction.The primary outcome measures were progression free survival(PFS),and secondary outcome measures were overall survival(OS),objective response rate(ORR),and disease control rate(DCR)and adverse reactions.Results:1.There was no significant difference between the observation group and the control group in age,gender,smoking history,pathological tissue type,clinical stage,and EGFR mutation classification(P>0.05).2.The PFS of the observation group was significantly longer than that of the control group [median PFS: 15.6 months(95%CI : 14.431-16.769)vs 6.9 months(95%CI :4.209-9.591],the difference was statistically significant(P=0.003).There was no significant difference in the PFS of the observation group between different genders and age groups(P>0.05).3.As of March 9,2019,the follow-up rate of 9 patients in the observation group was100%,4 patients died,5 patients were alive,and 4 patients in the control group were lost to follow-up.The follow-up rate was 81%,and the remaining 17 patients were included.9cases died and 8 cases survived.The median OS of the observation group did not reach,and the median OS of the control group reached.Kaplan-Meier survival analysis was performed in the control group according to the full analysis set(FAS).The median OS was 28.9 months(95% CI: 9.927-47.873),the difference was statistically significant(P=0.039).The Kaplan-Meier survival analysis was performed according to the per protocol set(PPS).The median OS was 24.5 months(95% CI: 10.511-38.489),and the difference was statistically significant(P=0.029).4.Among the 9 patients in the observation group,complete remission(CR)was performed in 0 cases,partial remissin(PR)in 3 cases,stable disease(SD)in 6 cases,and progressive disease(PD)in 0 cases,ORR 33.3%,DCR 100%.Among the 21 patients in the control group,CR was 0,PR was 10,SD was 10 and PD was 1,ORR was 47.6%,and DCR was 95.2%.There were no significant differences between the two groups in ORR and DCR(ORR: 33.3% vs 47.6%;DCR: 100.0% vs 95.2%)(P>0.05).5.Of the 21 patients in the control group,2 had missing data on adverse events.The adverse reactions of 9 patients in the observation group and 19 patients in the control group were mainly skin reactions(66.7% vs 31.6%),gastrointestinal reactions(33.3% vs26.3%),myelosuppression(22.2% vs 10.5%),liver function damage(22.2% vs 47.4%),and all patients had grade I-II adverse reactions,and the patients were tolerated.There was no significant difference between the two groups(P>0.05).Among them,2 cases(22.2%)had constipation in the observation group and 2 cases(22.2%)had adverse reactions of peripheral neuritis.The control group did not occur.There were no serious adverse reactions of venous thrombosis,hemorrhage and interstitial pneumonia in both groups.Conclusions:1.The first-generation EGFR-TKI combined with thalidomide in the treatment of advanced NSCLC with EGFR-sensitive mutations,compared with TKI alone,prolonged PFS and OS.2.The first-generation EGFR-TKI combined with thalidomide in the treatment of advanced NSCLC with EGFR-sensitive mutations showed no improvement in ORR and DCR compared with TKI monotherapy.3.When the dose of thalidomide is?200mg/d,the adverse reactions can be tolerated,or it can be relieved by symptomatic treatment,and the safety is better.