Efficacy And Safety Analysis Of PD-1 Inhibitor Combined With Chemotherapy Versus Chemotherapy Alone In First-line Treatment Of Advanced Pancreatic Cancer

Objective:Pancreatic cancer is one of the most common malignant tumors of the digestive system,and the prognosis is very poor.The median survival time of metastatic pancreatic cancer is only 3-6 months.albumin paclitaxel+gemcitabine(AG)chemotherapy is a commonly used first-line treatment for advanced pancreatic cancer.The unique immunosuppressive microenvironment of pancreatic cancer makes it less sensitive to immune-monotherapy,while chemotherapy has a positive effect on the immune microenvironment.Previous studies have shown that the combination of immunotherapy and chemotherapy has achieved better results than chemotherapy alone in the treatment of various solid tumors.Therefore,the purpose of this study was to retrospectively explore the efficacy and safety of PD-1 inhibitor combined with Ag chemotherapy versus Ag chemotherapy alone for first-line treatment of advanced pancreatic cancer,explore the associated factors affecting patient prognosis,and analyze the correlation between KRAS gene and TP53 gene and the immune microenvironment.Methods:This study retrospectively collected all clinical information of patients with advanced metastatic(stageⅣ)pancreatic ductal adenocarcinoma who were admitted to The Center for Precision Medicine of Oncology,Affiliated Hospital of Qingdao University from September 2018 to July 2020,including age,gender,ECOG score,pathological type and surgical site treatment plan,etc.According to the different treatment methods,48patients with advanced pancreatic cancer were divided into AG group(N=31)and PD-1+AG group(N=17).The PD-1 inhibitors were as follows:Toripalimab 240mg or Camrelizumab 200mg or Tiselizumab 200mg or Sintilimab 200mg;The specific chemotherapy for AG was gemcitabine 1000 mg/m~2 and albumin-bound paclitaxel 125mg/m~2 once every 6 weeks.The efficacy was evaluated by CT or MRI to measure the maximum diameter of target lesions,and the efficacy and adverse reactions of the two groups were compared.The primary endpoints of the study were progression-free survival(PFS)and overall survival(OS),and the secondary endpoints were adverse effects,objective response rate(ORR)and disease control rate(DCR).SPSS23.0 was used for statistical analysis,chi-square test was used for qualitative data,non-parametric Rank sum test was used for continuous quantitative data with non-normal distribution,Kaplan-Meier method was used to obtain the survival curves of PFS and OS,and log-rank non-parametric test was used to compare the differences between the two groups.Univariate and multivariate analyses were performed using Cox proportional risk model.Two-sided P<0.050 was considered statistically significant.Bioinformatics analysis applied TCGA database,cbioportal database,timer 2.0 database and R software packages ggplot2 and pheatmap.Results1.There were no statistical differences in the baseline characteristics between the two groups(P>0.050).2.The last follow-up was on October 10,2021.The median PFS was 4.90 months(95%CI:4.14-5.66)and the median OS was 9.30 months(95%CI:8.78-9.85)in the AG group;The median PFS of the PD-1+AG group was 5.0 months(95%CI:3.28-6.72),and the median OS was 12.10 months(95%CI:8.07-16.13)there was no significant difference in PFS between the two groups(P=0.154),the OS was significantly different(P=0.000),and the immune combination chemotherapy group reduced the risk of death by approximately 20.0%compared with the chemotherapy alone group(HR=0.203,95%CI:0.090-0.459,P<0.001).3.Most adverse effects were grade 1-2 in severity in both groups,and the incidence of hypothyroidism and reactive cutaneous capillary hyperplasia was higher in the PD-1+AG group than in the AG group(P<0.05);Grade 3-4 adverse reactions were mainly hematologic adverse reactions and abnormal liver function,and the incidence of grade 3-4adverse reactions was 38.7%(95%CI:20.5%-56.9%)and 35.3%(95%CI:10.0%-60.6%)in both groups,respectively,with no fatal adverse events in either group.4.The NGS results of 48 patients in this study showed that KRAS mutation rate was the highest,which was 75.0%(36/48),followed by TP53 mutation(66.7%,32/48).There were four KRAS mutation subtypes:G21D mutation,G12V mutation,G12C mutation and K117N mutation;TP53 gene mutation types are different.Microsatellite instability(MSI)was microsatellite stabilization(MSS),and tumor mutation burden(TMB)was less than10muts/MB.5.Among the 36 patients with KRAS mutation,20 patients had TP53 co-mutation at the same time.Among the patients with KRAS and TP53 co-mutation,PD-1 inhibitors combined with chemotherapy also improved the OS(8.0 months vs 10.2 months,P=0.004).6.Subgroups of KRAS and TP53 genes were analyzed by bioinformatics techniques.The results showed that KRAS mutation accounted for 91%and TP53 mutation accounted for70%in pancreatic cancer in TCGA Fierhose Legacy dataset.Spearman and Pearson correlation coefficients of TP53 and KRAS were-0.19 and-0.17,respectively(P<0.05).KRAS gene was significantly correlated with CD8~+T cell infiltration,TP53 gene was significantly correlated with CD4~+T cell infiltration.HAVCR2 is a common immune checkpoint-related gene of KRAS and TP53 genes,and its expression level is significantly different between KRAS group and TP53 group.Conclusions:PD-1 inhibitor plus AG chemotherapy improves OS,reduces the risk of death,and has a favorable safety profile in patients with advanced pancreatic cancer.KRAS and TP53 genes are related to immune cells and immune checkpoint related genes.The scheme of immune combined chemotherapy also improves the OS of patients with KRAS and TP53co-mutation.