The Efficacy And Safety Of Combined Immune Checkpoint Inhibitors In The First-line Treatment Of Advanced Lung Cancer:a Network Meta-analysis

Background:Lung cancer is the malignant tumor with the highest morbidity and mortality in the world.However,it is difficult for conventional treatment methods to benefit patients with advanced lung cancer.In recent years,immune checkpoint inhibitors(ICIS)have become the focus of anti-tumor therapy.Studies have shown that ICIs treatment of programmed cell death protein 1/programmed cell death ligand 1(PD-1 /PD-L1)improves the 5-year survival rate of patients with advanced lung cancer.ICIs of cytotoxic lymphocyte antigen 4(CTLA4)was also approved by the United States Food and Drug Administration(FDA)for the treatment of malignant melanoma in 2011.The emergence of ICIs is another revolutionary change after molecular targeted therapy.At present,pembrolizumab,nivolumab and atezolizumab have been approved for the treatment of lung cancer.Pembrolizumab has been approved by FDA for the first-line treatment of patients with PD-L1 expression ≥ 50% who lack EGFR or ALK mutation and metastasis NSCLC.In June 2018,China food and Drug Administration(CFDA)approved the launch of nivolumab.For non-small cell lung cancer without sensitive gene mutation and after systematic treatment,PD-L1 detection is not required.Atezolizumabcombined with chemotherapy in the first-line treatment of small cell lung cancer obtained the FDA priority review qualification in December2018.The combination of chemotherapy and ICIs treatment is expected to be the standard first-line treatment for advanced lung cancer patients without driving gene mutations and PD-L1 expression related or unrelated.At present,a large number of studies on ICIs treatment combined with other treatment methods(such as chemotherapy,radiotherapy,targeted treatment and other ICIs treatment)are under way.Some research results have been published,but there is still a lack of direct head-to-head comparison of the efficacy and safety of different combined treatment schemes.Network meta analysis can make up for the deficiency that traditional meta-analysis can only compare two kinds of head-to-head interventions.The former can compare a variety of direct or indirect interventions,so as to obtain more complete analysis results.In conclusion,in order to compare the efficacy and safety of ICIs in the treatment of advanced lung cancer(IIIB / IV / recurrent non-small cell lung cancer and extensive small cell lung cancer),this network meta-analysis was designed.Purpose:The purpose of this study is to evaluate the efficacy and safety of ICIs in the first-line treatment of advanced lung cancer with different combined regimens,and to provide a reference for clinical work.Method:From its establishment to November 1,2019,published in Pubmed,Embase,Cochrane Library and web of science database,the literatures of different combinations of ICIs treatment(including ICIs combined chemotherapy,ICIs combined with other ICIs,ICIs combined radiotherapy and ICIs combined targeted treatment)as the experimental group was searched.Eligible studies reported at least one of the following clinical outcome indicators: progression-free survival(PFS),overall survival(OS)and occurrence of grade 3 and above adverse events.According to Cochrane risk bias evaluation criteria,the quality of the included study was evaluated,and statistical analysis was carried out by using Stata SE 15.1,Gemtc and R software.At the same time,subgroup analysis of different pathological types(small cell lung cancer and non-small cell lung cancer)was performed,and the efficacy and safety ranking of different treatment schemes were carried out.Result:A total of 12 studies were included involving 7253 patients and 8treatment options: chemotherapy alone,bevacizumab combined with chemotherapy,nivolumab combined with ipilimumab,atezolizumab combined with chemotherapy,atezolizumab combined with bevacizumab plus chemotherapy,durvalumab combined with chemotherapy,ipilimumab combined with chemotherapy,and pembrolizumab combinedwith chemotherapy.Pembrolizumab combined with chemotherapy and atezolizumab combined with bevacizumab + chemotherapy are superior to other treatment schemes in improving OS and PFS of patients with advanced lung cancer,but atezolizumab combined with bevacizumab +chemotherapy has a high incidence of serious adverse events.In the treatment of advanced NSCLC,pembrolizumab combined with chemotherapy,atezolizumab combined with bevacizumab +chemotherapy and nivolumab combined with ipilimumab were the top three in the prolongation of OS and PFS;Atezolizumab combined with chemotherapy was the best on the improvement of OS and PFS in small cell lung cancer.Compared with chemotherapy alone,bevacizumab combined chemotherapy and durvalumab combined chemotherapy had no significant improvement in the prolongation of OS and PFS,and ipilimumab combined chemotherapy had no significant benefit in OS improvement compared with chemotherapy alone.Conclusion:(1)Pembrolizumab combined with chemotherapy is the first choice of first-line treatment for patients with advanced lung cancer;(2)In the first-line treatment of patients with advanced lung cancer,atezolizumab combined with bevacizumab + chemotherapy and pembrolizumab combined with chemotherapy have similar efficacy,but the former is less safe,so attention should be paid to prevent theoccurrence of serious adverse events when used;(3)Pembrolizumab combined with chemotherapy,atezolizumab combined with bevacizumab + chemotherapy,and nivolumab combined with ipilimumab are superior to other therapies in the first-line treatment of advanced non-small cell lung cancer;(4)Atezolizumab combined with chemotherapy is the first recommended treatment for for patients with advanced small cell lung cancer in the first line;(5)Not all combined programs are better than chemotherapy alone,so we should balance the advantages and disadvantages in the choice of programs to avoid unnecessary losses to patients.