Meta Analysis Of Efficacy And Safety Of PD-1/PD-L1 Or CTLA-4 Inhibitors Combined With Chemotherapy In The Treatment Of Non-small Cell Lung Cancer

Background: Lung cancer is the world’s leading malignant tumor,with more than 1.7 million deaths in 2018,accounting for 18.4% of the total cancer deaths in the world.The 5-year overall survival rate of patients with non-small cell lung cancer（NSCLC）is less than 20%.Today,the treatment of tumor has broken the old inherent model and moved towards "individualized treatment" and "precision treatment".Radiotherapy,chemotherapy,targeted therapy and immunotherapy are the main treatment methods for patients with advanced NSCLC.The emergence of immunotherapy breaks the first-line treatment pattern of double platinum drugs and has become the most revolutionary treatment method in solid tumors.However,with the continuous progress of immunotherapy research,the treatment results are not satisfactory,and fall into the dilemma of adverse reactions,drug resistance and low responsiveness caused by immune dysfunction,which also makes immune combined chemotherapy,immune combined radiotherapy and immune combined targeted therapy.Double immune therapy came into being and set off an upsurge of immune combined therapy.Objective: The efficacy and safety of programmed cell death-1（PD-1）/programmed cell death ligand-1（PD-L1）or cytotoxic T lymphocyte associated antigen-4（CTLA-4）inhibitors combined with chemotherapy in the treatment of NSCLC were evaluated by meta-analysis.Methods:The randomized controlled trial（RCT）of PD-1 / PD-L1 or CTLA-4 inhibitors combined with chemotherapy in the treatment of NSCLC was searched in Pub Med,the Cochrane Library and EMBASE.Two researchers independently searched the literature,screened the follow-up literature,extracted relevant information and assessed the bias risk of the included literature.In case of disagreement,the third researcher will decide to solve it if it cannot be solved after discussion between both parties.The software of Revman Version5.4 was used for data analysis.Results: A total of 15 clinical studies were included,all of which were stage II or III RCTs,including 8400 patients with NSCLC.There were nine studies using PDone inhibitor combined chemotherapy,involving four drugs: pembrolizumab,nivolumab,sintilimab and camrelizumab.Among them,four studies were pembrolizumab combined chemotherapy,two were sintilimab combined chemotherapy,one was camrelizumab combined chemotherapy and one was nivolumab combined chemotherapy,Another one is nivolumab combined with bevacizumab on the basis of chemotherapy.Four studies used PD-L1 inhibitor combined chemotherapy,of which three were atezolizumab combined with chemotherapy alone and one was atezolizumab combined with chemotherapy plus bevacizumab.There is one study of CTLA-4inhibitor combined with simple chemotherapy,involving the drug ipilimumab,and another study is double immune checkpoint inhibitor combined with two cycles of chemotherapy.The intervention measure is nivolumab+ipilimumab+chemotherapy.Meta analysis showed that compared with chemotherapy alone or chemotherapy combined with targeted therapy,the combined use of PD-1/PD-L1 or CTLA-4inhibitors could significantly improve OS（HR=0.74,95%CI: 0.67-0.83,P<0.00001）and PFS（HR= 0.62,95%CI: 0.57-0.68,P<0.00001）and ORR（RR=1.54,95%CI: 1.40-1.69,P<0.00001）.In this meta-analysis on the effectiveness of treatment,subgroup analysis was carried out according to histopathological classification,PD-L1 expression level,type of immune checkpoint inhibitor,age,gender,ECOG scoring standard,smoking or not,and race.The results showed that there was no significant difference in OS among the three subgroups except white,black and non-smoking patients,The combined results of OS and PFS in other subgroups showed the therapeutic advantage of PD-1/PD-L1 or CTLA-4 inhibitor combined with chemotherapy.In the safety analysis,the results showed that the incidence of all grade adverse reactions between the two groups（RR=1.02,95%CI: 1.00-1.04,P=0.03）and the incidence of grade 3 and above adverse reactions（RR=1.12,95%CI: 1.04-1.21,P=0.002）.The incidence of immune combined chemotherapy group was slightly higher than that of chemotherapy group.The incidence of immune related adverse events（ir AEs）in the immune combined chemotherapy group was significantly higher than that in the chemotherapy group.The ir AEs with statistical difference included hypothyroidism,hyperthyroidism,pneumonia,hepatitis,colitis,hypophysitis,pancreatitis,infusion reaction and rash.Conclusion: Compared with chemotherapy alone or chemotherapy combined with targeted therapy,the combination of PD-1 / PD-L1 or CTLA-4 inhibitors in the above treatment schemes can significantly improve the OS,PFS and ORR of patients with advanced NSCLC.However,in the course of treatment,the combination of immune checkpoint inhibitors also increased the incidence of all grade adverse reactions,grade 3 and above adverse reactions and ir AEs compared with chemotherapy alone or chemotherapy combined with targeted therapy.