Comparative Efficacy And Safety Of First-line Treatments For Epidermal Growth Factor Receptor Mutation-positive Advanced Non-small Cell Lung Cancer

BackgroundNon-small cell lung cancer(NSCLC)is a common type of lung cancer,accounting for approximately80-85%of all lung cancers.Epidermal growth factor receptor(EGFR)mutation is one of the major mutations in NSCLC and is mostly found in Asian,female,non-smoking,and lung adenocarcinoma patients.Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)significantly prolonged the survival of patients with EGFR mutation-positive NSCLC advanced.Currently,the first-line treatment strategies for patients with EGFR mutation-positive advanced NSCLC mainly include EGFR-TKIs monotherapy and EGFR-TKIs combination therapy.However,the differences in efficacy and safety between the regimens are uncertain,and the selection of treatment options for patients with different clinicopathological characteristics is a major challenge for clinicians.ObjectiveA network meta-analysis(NMA)was used to compare the efficacy and safety of firstline treatment for EGFR mutation-positive advanced NSCLC to provide clinicians a reference for choosing the most accurate first-line treatment option.MethodsPubmed,Embase,and Cochrane Library databases were searched from inception to June 3,2021,and abstracts from the American society of clinical oncology(ASCO),the European society for medical oncology(ESMO),and the World conference on lung cancer(WCLC)were combined to find relevant studies.Clinical randomized controlled trials(RCTs)that enrolled untreated patients with EGFR mutation-positive advanced NSCLC were included.The main endpoint was progression-free survival(PFS),and secondary endpoints were overall survival(OS),objective response rate(ORR),and grade 3 or higher adverse events(≥3AEs).The quality of each RCT was assessed by Cochrane risk assessment criteria.A Bayesian network meta-analysis(NMA)was performed by R and Stata software.Simultaneously,subgroup analysis were also performed for EGFR mutation type and clinicopathological factors(age,gender,physical performance status,brain metastasis history,ethnicity,and smoking history),and the efficacy and safety of different first-line regimens were ranked by calculating the surface area under the cumulative ranking curve(SUCRA).Results25 RCTs were included,with a total of 6965 patients and 14 treatment regimens.The NMA results were categorized into the following three areas1.The overall population results showed all EGFR-TKIs-related treatments significantly prolonged PFS compared with chemotherapy,especially osimertinib(OSI)(HR 0.17,95%Cl 0.09-0.28);while gefitinib plus pemetrexed-based chemotherapy(GEF+PB)significantly prolonged OS(HR 0.58,95%Cl 0.44-0.76)compared with chemotherapy.In terms of ORR,all EGFR-TKIs-related treatments improved ORR compared with chemotherapy,especially GEF+PB(OR 10.51,95%Cl 6.33-18.06).As for>=3AEs,EGFR-TKIs monotherapy resulted in a lower incidence of adverse effects compared with chemotherapy,especially OSI(OR 0.14,95%Cl 0.03-0.63);while EGFR-TKIs combination therapy led to more incidence of adverse effects than EGFR-TKIs,especially gefitinib plus apatinib(GEF+APA)(OR 2.31,95%Cl 0.47-11.10).2.EGFR sensitive mutation results showed GEF+PB significantly prolonged PFS compared with chemotherapy in patients with the Leu858Arg(L858R)mutation(HR 0.19,95%Cl 0.10-0.34);while aumolertinib(AUM)significantly prolonged PFS in patients with 19 deletion(19DEL)mutation(HR 0.10,95%Cl 0.05-0.20).3.clinicopathological factors results showed that GEF+PB significantly prolonged PFS compared with chemotherapy in patients with physical status(PS)=1(HR 0.15,95%Cl 0.060.35),Asian(HR 0.17,95%Cl 0.11-0.25),age<65(HR 0.11,95%Cl 0.03-0.36),smoking(HR 0.16,95%Cl 0.04-0.58)and ranked 1st in the above subgroups.AUM significantly prolonged PFS in patients with PS=0(HR 0.09,95%Cl 0.03-0.26),female(HR 0.14,95%Cl 0.05-0.43);while OSI significantly improved PFS in patients without brain metastasis(HR 0.17,95%Cl 0.09-0.31)compared with chemotherapy and ranked 1st.Compared with chemotherapy,icotinib pluse pemetrexed-based chemotherapy(ICO+PB)significantly prolonged PFS in patients of aged≥65(HR 0.06,95%Cl 0.01-0.26)and no-smoking(HR 0.09,95%Cl 0.03-0.29).Afatinib pluse cetuximab(AFA+CET)(HR 0.17,95%Cl 0.03-0.92),GEF+PB(HR 0.20,95%Cl 0.07-0.51)significantly improved PFS efficacy in male patients compared with chemotherapy,which ranked 1st and 2nd,respectively.Conclusions1.In the overall population,OSI and GEF+PB were associated with the most benefit on PFS and OS,respectively.2.AUM is probably the best first-line treatment for patients with EGFR 19DEL mutation,while GEF+PB is most likely to be the most effective first-line treatment option for patients with EGFR L858R mutation.3.In terms of clinicopathological factors,GEF+PB is probably the most effective firstline for patients with PS=1,Asian,age<65,and smoking;while AUM is likely to be the best first-line regimen for patients with PS=0,female.OSI is likely to be the preferred first-line regimen for patients without brain metastases,and ICO+PB is probably the most effective first-line regimen for patients with non-smoking and aged≥65.