The Safety Of Immune Checkpoint Inhibitors Monotherapy Or Combined Therapy Of Non-small Cell Lung Cancer:A Systematic Review And Network Meta-analysis

Background:Immune checkpoint inhibitors(ICIs)have yielded significant treatment progress in cancer and reshaped the landscape of non-small cell lung cancer(NSCLC)therapy.With the significantly oncologic efficacy,ICIs monotherapy,ICIs combined with chemotherapy and dual ICIs have gradually been approved for the treatments of non-small cell lung cancer.However,immune-related adverse events(irAEs)were observed in clinical trials and clinical applications.Although various irAEs have been reported from multiple clinical trials,we believe it is necessary to aggregate data from lots of trials to estimate the more accurate incidences of irAEs.Because the incidences of adverse events(AEs)were lack of consistency between ClinicalTrials.gov and published journal articles,We aimed to mainly based on data from ClinicalTrials.gov to systematically assess the incidences of AEs in immunotherapy of NSCLC.Methods:We searched randomized controlled trials(RCTs)in PubMed/MEDLINE,Embase,Cochrane,and ClinicalTrial.gov before May 2021,and grouped arms into 10 treatment categories as chemotherapy(Chemo),programmed cell death protein 1 inhibitors monotherapy(PD1)group,programmed cell death ligand 1 inhibitors monotherapy(PDL1)group,cytotoxic Lymphocyte Antigen 4 inhibitors monotherapy(CTLA4)group,PD1 combined with Chemo(PD1_Chemo)group,PDL1 combined with Chemo(PDL1_Chemo)group,CTLA4 combined with Chemo(CTLA4_Chemo)group,PD1 combined with CTLA4(PD1_CTLA4)group,PDL1 combined with CTLA4(PDL1_CTLA4)group,ICIs combined with targeted therapy(ICI_Target).We extracted AEs as serious(grade 3-5)or other(grade 1-2)grade from all systems,and we pooled their incidences by random effects model.For arm-based pair-wise comparisons,we employed Bayesian network meta-analysis.Meta-regression is used to assess the contribution of coefficients.Results:Totally 23,322 patients from 52 RCTs(45 from ClinicalTrial.gov)were included in the analysis.The overall incidences of serious AEs were 36.8%in Chemo,33.5%in PD1,37.0%in PDL1 groups,and 51.6%in CTLA4 group.The pooled incidences were all higher in combined treatment groups than in monotherapies such as 47.0%in PDL1_Chemo,43.0%in PD1_CTLA4,and 48.0%in ICI_Target.For irAEs such as serious pneumonitis,the pooled incidence rate is 3.24%(95%CI,2.51%-4.18%)in PD1,2.01%(95%CI,1.47%-2.75%)in PDL1 and 0.88%(95%CI,0.66%-1.17%)in Chemo group,while combined treatment groups appeared similar(2.78%in PD1_Chemo,2.78%in PDL1_Chemo,3.43%in CTLA4_Chemo and 2.11%in ICI_Target).Overall,the incidence of each serious AE was less than 4%in monotherapy,and slightly higher in combined groups.In network meta-analysis,the immune therapy groups presented a significant higher incidence rank in colitis,hepatitis,pneumonitis and rash compared with chemotherapy.The rate of serious pneumonitis was significantly positively related to PFS in PD1 treatment arms(p=0.0049),likewise the rate of rash(p<0.0001)and the rate of hepatitis in PDL1 treatment arms.Conclusion:The overall incidences of serious AEs were similar in PD1,PDL1 and Chemo groups and higher in combined groups.The incidence of each kind of serious AE was less than 4%in monotherapy,while slightly higher in combined groups.The occurrence of some irAEs such as serious pneumonitis,hepatitis and rash was significantly associated with better treatment efficacy.