Efficacy And Safety Of PD-1/PD-L1 Inhibitors Combinationtherapy In Advanced Colorectal Cancer:A Meta Analysis

BackgroundColorectal cancer is one of the most common malignant cancer in the gastrointestinal.Due to insidious onset of disease,most patients are already in an advanced stage at the time of first diagnosed,which seriously threaten the life and health of people.Although systemic treatment of advanced colorectal cancer has progressed in recent years,most patients lack effective treatment options after disease progression.Therefore,there is still an urgent need to explore new treatment modalities for patients with advanced colorectal cancer.In recent years,programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)have rapidly become a major treatment modality for many solid tumors due to their superior efficacy.However,the efficacy of PD-1/PD-L1 inhibitors in colorectal cancer is still unsatisfactory.Only some patients with microsatellite highly unstable(MSI-H)/mismatch repair defect(d MMR)advanced colorectal cancer benefit significantly.PD-1/PD-L1 inhibitors have been reported to combine with other antitumor treatments(including chemotherapy,radiotherapy,targeted therapy,other immunotherapies)have been found to be more effective in recent clinical trials.Combination therapy with PD-1/PD-L1 inhibitors is being studied to improve survival in patients with advanced colorectal cancer.ObjectivesTo comprehensively evaluate the efficacy and safety of PD-1/PD-L1 inhibitors combination therapy in patients with advanced colorectal cancer.MethodsThe databases such as Pub Med,Embase,Web of Science,and Cochrane Library were searched by computer to collect literatures from the time of library construction to December 2022.Studies about PD-1/PD-L1 inhibitors combination therapy for the treatment of advanced colorectal cancer were searched and included.According to the set inclusion and exclusion criteria,the literature was screened to determine the literature that was finally included in the study.Data collection was performed independently by two investigators to extract the median progression-free(m PFS),median overall survival(m OS),objective response rate(ORR),disease control rate(DCR),treatment related adverse events(TRAEs),and their 95%confidence intervals(95%CI)from each study.Meta-analysis of the data was conducted by Review Manager 5.4 and Stata16 software.ResultsA total of 3740 relevant literatures were retrieved from the database.11 literatures were finally included through hierarchical screening,including 5 randomized controlled trials and 6 single-arm trials.A total of 1547 patients were enrolled,which 1129 patients were treated with PD-1/PD-L1 inhibitors combination therapy,and 418 patients were treated with conventional therapy.Meta-analysis results showed that:(1)PD-1/PD-L inhibitors combination therapy versus conventional therapy for advanced colorectal cancer: m OS(HR=0.88,95%CI:0.74-1.05,P=0.16)and m PFS(HR=0.93,95%CI:0.78-1.10,P=0.39).(2)The results of subgroup analysis of m PFS showed that: patients without liver metastasis m PFS:(HR=0.73,95%CI:0.55-0.96,P=0.03),male patients m PFS:(HR=0.75,95%CI:0.59-0.95,P=0.02),first-line patients m PFS(HR=0.84,95%CI:0.71-0.99,P=0.04),and patients without prior adjuvant therapy m PFS:(HR=0.77,95%CI:0.63-0.96,P=0.02).(3)PD-1/PD-L1 inhibitors combination for advanced colorectal cancer: ORR was 13%(95%CI:0.06-0.20),DCR was 44%(95%CI:0.27-0.61);Subgroup analysis showed that:The ORR and DCR of PD-1 inhibitors was 11%(95%CI:0.06-0.16),48%(95%CI:0.32-0.63)and that of PD-L1 inhibitors was 6%(95%CI:0.02-0.1),41%(95%CI:0.15-0.67).The ORR of patients with first-line,second-line,third-line and higher was 36%(95 % CI:0.08-0.81),8%(95% CI:-0.01-0.16),5%(95 % CI:0.02-0.07),The DCR of patients with second-line,third-line and higher was 38%(95 %CI:0.07-0.68),40%(95 % CI:0.27-0.53).(4)PD-1/PD-L1 inhibitors combination therapy versus conventional regimens for advanced colorectal cancer: TRAEs(RR=1.06,95%CI:0.99-1.12,P=0.09),≥grade 3 TRAEs(RR=1.33,95%%CI:0.97-1.81,P=0.07);(5)incidence of adverse reactions to the combination of PD-1/PD-L1 inhibitors in advanced colorectal cancer:TRAEs 97%(95%CI:0.94-0.99),≥grade 3 TRAEs 44%(95%CI:0.26-0.61).Conclusions(1)Efficacy:1.PD-1/PD-L1 inhibitors combined with chemotherapy,molecular targeted drugs or dual immunosuppressant combination for advanced colorectal cancer have certain efficacy,and in the subgroup analysis,patients without liver metastasis,male patients,first-line patients and patients without prior adjuvant therapy of m PFS benefited;2.The efficacy of PD-1 inhibitor combined with advanced colorectal cancer is better than that of PD-L1 inhibitor combined therapy.(2)Safety:Although PD-1/PD-L1 inhibitors combined therapy increases the incidence of treatment related adverse events in patients with advanced colorectal cancer,its safety is controllable.