Efficacy And Immune-related Adverse Events Induced By PD-1/PD-L1 And CTLA-4 Inhibitors In Advanced NSCLC

Objective:In recent years targeted therapy has improved overall survival for advanced Non-small Cell Lung Cancer（NSCLC）patients harboring driver genes mutations as the discovery ofepidermal growth factor receptor（EGFR）mutation and anaplastic lymphoma kinase（ALK）rearrangement.However,we should realize that most NSCLC patients are not driver genes positive.For these patients,first-line treatment options have been limited to cytotoxic chemotherapy in the past decades which has limited survival benefits.At present immune checkpoint inhibitors（ICPIs）targeting PD-1/PD-L1 and CTLA-4 have brought new hope for advanced NSCLC patients.Clinical trials have shown that the immune checkpoint inhibitors such as nivolumab can provide longer survival and better tolerance than standard second-line chemotherapy^[1].Nevertheless,the concomitant novel immune-mediated toxicities,also known as the immune-related adverse events（ir-AEs）,including pneumonitis^[2]and hypothyroidism^[3]et al,induced by ICPIs have been commonly reported due to the uniqueness and severity;early recognition and prompt intervention are essential.This article is to summarize and evaluate the efficacy and ir-AEs induced by PD-1/PD-L1and CTLA-4 inhibitors.Hopefully it can provide guidance for advanced NSCLC patients treatment options,early recognition and treatment of ir-AEs.Methods:Randomized controlled trials which involved PD-1/PD-L1 and CTLA-4inhibitors in the treatment of advanced NSCLC were retrieved in the Cochrane Libraby,PubMed,EMBASE and other databases.The quality evaluation and cross-checked data were independently performed by two investigators according to the Cochrane Systematic Reviews Handbook.The Stata 15.0 and RevMan 5.3 software are used to conduct the meta analysis.To compare the overall survival（OS）,progression free survival（PFS）,objective response rate（ORR）and the incidence,grade and organ specificity of ir-AEs associated with ICPIs with those associated with chemotherapy;to compare the overall survival,progression free survival,objective response rate and the incidence,grade and organ specificity of ir-AEs associated with different ICPIsResults:（1）A total of 14 RCTs were included,3 of which were multi-arm studies（each ICPIs intervention group in the multi-arm study was compared with the control group,respectively）.There were 17 arms in the ICPIs group,including 10 arms in the anti-PD-1 group,3 arms in the anti-PD-L1 group,3 arms in the anti-CTLA-4 group,and1 arm in the anti-PD-1 and anti-CTLA-4 combination group.There were 14 arms in the conventional chemotherapy group.Their adverse events data are all available at ClinicalTrials.gov.（2）Patients with advanced NSCLC treated by ICPIs showed significant improvement in OS（HR 0.71,95%CI 0.63,0.80,P<0.00001）,PFS（HR0.74,95%CI 0.65,0.85,P<0.0001）and ORR（RR 1.48,95%CI 1.25,1.76,P<0.00001）compared with the conventional chemotherapy group.（3）In the subgroup of PD-L1≥10%and PD-L1≥50%,the improvement of OS,PFS and ORR in ICPIs arms were more significant than that in the traditional chemotherapy group.Meanwhile improved OS was observed in the PD-L1<1%,PD-L1 1-49%subgroup which was not as significant as that in the PD-L1 high expression group.In the PD-L1<5%,PD-L1<10%subgroup there was no difference in the improvement of OS by ICPIs compared with chemotherapy.At the same time,no significant improvement in the PFS and ORR were observed in the subgroups of PD-L1<1%,PD-L1<5%,PD-L1<10%and PD-L11-49%compared with traditional chemotherapy.（4）ICPIs have different toxicity profiles compared with traditional chemotherapy,and the immune-related adverse events were generally more than those in the traditional chemotherapy group,but the risk of garstrointestinal ir-AEs（P=0.22）and hypersensitivity（P=0.38）were similar between the two groups,and the difference was not statistically significant.（5）The risk and severity of ir-AEs induced by ICPIs combined group were generally higher than that of ICPIs monotherapy,while the incidence of severe ir-AEs induced by ICPIs combination therapy was similar to that of anti-CTLA-4 group.Conclusions:（1）PD-1/PD-L1 and CTLA-4 inhibitors are better choices for the treatment of advanced NSCLC patients than traditional chemotherapy.（2）Although the benefit of ICPIs treatment is higher in patients with high PD-L1 expression,survival benefits have been observed in the PD-L1 low expression group.So further studies are needed to identify more biomarkers to select patients suitable for ICPIs treatment.（3）ICPIs have different toxicity profile compared with chemotherapy,and their immune-related toxicity is stronger than that of traditional chemotherapy.（4）ICPIs induced ir-AEs is organ-specific,and different ICPIs have specific immuno-related toxicity profiles.As ICPIS represent a new and distinct class of treatment for NSCLC,this article has systemetically illustrated the efficacy and ir-AEs induced by ICPIs,hopefully it can be useful for clinicians and patients to get a further understanding of ICPIs,and facilitate early prediction,comprehensive diagnosis,and prompt management of ir-AEs by providing status reference and management suggestions,so that ICPIs can bring more benefit for advanced NSCLC patients.