Application Of Anti-angiogenic Drug Combination Therapy In Non-small Cell Lung Cancer And Exploration Of Circulating Tumor DNA Based Prognostic Biomarkers In Small Cell Lung Cancer

Purpose:New anti-tumor drugs are currently a research hotspot in the field of lung cancer.The purpose of this study is to report the efficacy and safety data of immune checkpoint inhibitors(ICI)plus angiogenic inhibitors treatment in lung adenocarcinoma patients.Methods:Eligible patients with pathological or cytological confirmed lung adenocarcinoma and treated with ICI plus angiogenic inhibitors were enrolled.Kaplan-Meier method was used to draw survival curves,and comparison between subgroups was performed using Log-rank test and Cox regression analysis.The primary endpoints were progression-free survival(PFS).The secondary endpoints were objective response rate(ORR),disease control rate(DCR),overall survival(OS),and safety.Results:A total of 46 consecutive enrolled patients received ICI plus angiogenic inhibitor,and the median follow-up was 9.6 months(range,1.5-32.5).The ORR and DCR were 8.7%and 50%,respectively.Median PFS and OS were 2.9 months(95%CI,2.1-3.7)and 12.3 months(95%CI,7.6-17.0),respectively.Patients at stage IVB had an inferior median PFS than stage ⅢC or ⅣA(2.8 months vs.4.4 months,P=0.003).The median PFS of patients who were treated with ICI plus bevacizumab was shorter than ICI plus anlotinib or apatinib(1.2 months vs.3.3 months,P=0.005).The occurrence of hypertension during the combination treatment has been related to a tendency for prolonged median PFS(5.5 months vs.2.6 months;P=0.05).The overall incidence of treatment-related adverse events(TRAE)was 89.1%,and grade 3-4 TRAE was occupied 21.4%.Conclusion:This study objectively demonstrated that the treatment of ICI and antiangiogenic agents in lung adenocarcinoma could be a promising alternative therapeutic regimen,and the toxic effects were manageable.Subgroup analysis revealed that small molecular angiogenic inhibitors plus ICI and low tumor burden during treatment were better prognostic factors.Background:Real-world application of osimertinib with antiangiogenic agents in non-small cell lung cancer(NSCLC)is common,but the efficacy data are rarely reported.Methods:Eligible patients with pathological or cytological confirmed NSCLC and treated with osimertinib plus antiangiogenic agents were enrolled.Kaplan-Meier method was used to draw survival curves,and comparison between subgroups was performed using Log-rank test and Cox regression analysis.The primary endpoint was overall survival(OS).The secondary endpoints were progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),and safety.Results:A total of 54 patients with NSCLC were enrolled into the study.Twelve(22.2%)who received a combination of antiangiogenic agents,when there was a trend of osimertinib resistance but did not reach imageology progressive disease(PD),were assigned to Group A,with a median overall survival(OS)and progression-free survival(PFS)of 48.0(95%CI,not reached)and 21.0(95%CI:16.7-25.3)months,respectively.Thirty(55.6%)who received a combination of antiangiogenic agents when there was imageology PD during treatment with osimertinib were assigned to Group B,with a median OS and PFS of 31.8(95%CI:26.6-37.1)and 9.2(95%CI:5.9-12.6)months,respectively.Twelve(22.2%)who received a combination of antiangiogenic agents at the initial treatment with osimertinib were assigned to Group C,with a median OS and PFS of 28.5(95%Cl:15.2-41.8)and 15.3(95%CI:7.922.7)months,respectively.Patients in Group A achieved a significant prolonged median PFS(P<0.001)compared with Groups B and C.Absence of epidermal growth factor receptor(EGFR)T790M mutations(P=0.043;hazard ratio[HR]=2.124,95%CI:1.023-4.413)and no previous antiangiogenic agent application(P=0.012;HR=0.362,95%CI:0.163-0.863)were the independent prognostic factors of OS.Conclusion:The well-timed action to combine antiangiogenic agents was when there was a trend of osimertinib resistance.The absence of EGFR T790M mutations and previous use of antiangiogenic agents were poor prognostic factors.Purpose:This study aimed to investigate the feasibility of biomarkers based on dynamic circulating tumor DNA(ctDNA)to classify small cell lung cancer(SCLC)into different subtypes.Materials and Methods:Tumor and longitudinal plasma ctDNA samples were analyzed by next-generation sequencing of 1021 genes.PyClone was used to infer the molecular tumor burden index(mTBI).Pre-treatment tumor tissues(T1)and serial plasma samples were collected(pre-treatment[B1],after two[B2],six[B3]cycles of chemotherapy and at progression[B4]).Results:Overall concordance between T1 and B1 sequencing(n=30)was 66.5%,and 89.5%in the gene of RBl.A classification method was designed according to the changes of RBI mutation,named as subtype Ⅰ(both positive at B1 and B2),subtype Ⅱ(positive at B1 but negative at B2),and subtype Ⅲ(both negative at B1 and B2).The median progressive-free survival for subtype Ⅰ patients(4.5 months[95%confidence interval(CI),2.6 to 5.8])was inferior to subtype Ⅱ(not reached,P<0.001)and subtype Ⅲ(10.8 months[95%CI,6.0 to 14.4],P=0.002).The median overall survival for subtype I patients(16.3 months[95%CI,5.3 to 22.9])was inferior to subtype Ⅱ(not reached,P=0.01)and subtype Ⅲ(not reached,P=0.02).Patients with a mTBI dropped to zero at B2 had longer median overall survival(not reached vs.19.5 months,P=0.01).The changes of mTBI from B4 to B1 were sensitive to predict new metastases,with a sensitivity of 100%and a specificity of 85.7%.Conclusion:Monitoring ctDNA based RB1 mutation and mTBI provided a feasible tool to predict the prognosis of SCLC.