Analysis Of Treatment Patterns And Exploration Of Prognostic Factors For Extensive-stage Small Cell Lung Cance

[Background]Programmed cell death ligand 1(PD-L1)inhibitors combined with chemotherapy have made substantial progress in extensive-disease small cell(ED-SCLC),but the survival benefit is limited.Therefore,to explore a new combination regimen is urgent.More importantly,the clinical and molecular characteristics of ED-SCLC who benefit from immune checkpoint inhibitors(ICIs)are still unclear.Therefore,further studies are needed to differentiate the superior patients to prolong overall survival.(Methods]In first section,a total of 386 patients were included.The potential prognostic factors were identified by univariate analysis,followed by Cox risk proportional model analysis to identify independent prognostic factors,and a regression modeling strategy(rms)was applied to draw visual nomogram to establish a survival prognostic model,and the receiver operating characteristic curve(ROC)and consistency index(C-index)were applied to assess the prognostic model performance.In second section,a total of 53 patients were included.The progression-free survival(PFS)was as the primary endpoint.To compare the antitumor efficacy and safety between patients who received IP/IC in combination with camrelizumab(n=19)and CE/EP in combination with PD-L1 inhibitor(n=34)at first line therapy.In the third section,a total of 22 tissue samples were collected for RNA-seq assay to investigate irAE-related immune differential genes and differentially infiltrating immune cells.The primary aim is to obtain survival-related immune differential genes.Data analysis and data visualization were performed by SPSS version 23.0,GraphPad prism 8.4.0,and RStudio 1.2.5001 software.The mean and standard deviation were used to express continuous variables,and frequency distribution and percentages were used to express categorical variables;the chi-square test was used for comparison between groups(P<0.05 suggested statistical differences).Kaplan-Meier and Cox risk regression analyses were performed to assess the prognostic value of the independent variables on the dependent variable.[Results]1.The results of the first section showed that the number of ED-SCLC in our hospital was on the rise during the 8 years from 2013 to 2021.The median age at diagnosis was 65 years,78.8%were male,254(65.8%)patients had respiratory symptoms when patients admitted to hospital,275(71.2%)had comorbidities,370(95.4%)patients were with ECOG physical score from 0 to 1,and 344 cases were diagnosed at Ⅳ stage.Among first-line treatment pattern,CE/EP regimen(78.8%)was the most popular,ICIs combined with chemotherapy(18.9%)in second place;192 cases(49.7%)received second-line treatment,topotecan(24.0%)in first place and CE/EP(22.9%)in second place;94 cases(24.4%)received third-line treatment,topotecan(19.1%)、ifosfamide combined with epirubincin(19.1%)and paclitaxel(14.9%)were the main chemotherapy regimens.Median progression-free survival(mOS)was 7.918 months(95%CI 7.381-8.455),and median overall survival(mOS)reached 14.420 months(95%CI 7.381-8.455).With OS and survival status as argument,first-line chest radiotherapy and first-line ICIs combined with chemotherapy were identified as independent prognostic factors after univariable Cox regression analysis,least absolute systolic selection operator(Lasso)regression and Cox risk regression model analysis.The Kaplan-Meier curve showed a 1.14-fold increased risk of mortality in high-risk patients(95%CI 1.661-2.765).Based on the independent prognostic factor coefficients to calculate the risk of risk score for each patient.The rms package was applied to draw a prognostic risk model.The model had an area under the ROC curve of 0.677 and a consistency index of 0.71.2.The results of second section showed that the baseline characteristics of the two groups IP/IC+camrelizumab(N=19)and CE/EP+PD-L1 inhibitor(N=34)were balanced.The objective remission rate(ORR)of IP/IC+camrelizumab and CE/EP+PD-L1 inhibitor was 89.6%and 82.4%,respectively.The disease control rate of the two group was 100%and 94.1%,respectively.At a median follow-up time of 12.1 months,mPFS was 10.251 months(95%CI 9.397-NA)and 7.097 months(95%CI 5.793-8.400),respectively;median duration of disease remission(DoR)was 8.74 months and 4.40 months,respectively;6-month PFS rates was 63.2%、38.3%,respectively;1-year overall survival rate was 26.3%、17.6%,respectively.Compared IP/IC+camrelizumab with CE/EP+PD-L1 inhibitors,the progressive risk reduced 42%(HR 0.58,95%CI 0.42-0.81;p<0.001).A11 53 patients were available for safety assessment.The treatment-related adverse events(TRAE)in IP/IC+camrelizumab group dominated by grade 1-2 neutropenia(52.6%),reactive capillary hyperplasia(52.6%),diarrhea(36.8%),and nausea(36.8%);the immune-related adverse events(irAE)included reactive capillary hyperplasia(52.6%),liver injury(21.1%),rash(10.5%),hypothyroidism(5.3%%),actinic nerve palsy(5.3%),and renal impairment(5.3%);The TRAE in CE/EP+PD-L1 group were dominated by grade 1-2 neutropenia(55.9%),nausea and vomiting(32.4%),decreased hemoglobin(29.4%),and malaise(26.5%);the irAE included hypothyroidism(8.8%),liver injury(5.9%),pneumonia(5.9%),myelitis(2.9%),and elevated creatine kinase(2.9%).The occurrence of irAE was found to be associated with a good prognosis in the subgroup analysis(HR 4.638,95%CI 1.924-11.183,p<0.001).3.The raw data of third section was excluded 4 samples,due to low gene expression during data quality control.In the end,a total of 18 samples were included in the outcome analysis.The results showed that there were 781 differential genes in the irAE group(N=7)and the non-irAE group(N=11),including 396 up-regulated genes and 385 down-regulated genes.The GO enrichment analysis showed that the differential genes were mainly concentrated in the glutamate receptor signaling pathway(BP),NMDA-selective glutamate receptor complex(CC)and ionotropic glutamate receptor activity.The KEGG enrichment analysis showed that the differential genes were mainly concentrated in the glutamatergic synaptic signaling pathway.Differential genes intersected with immune-related genes resulted in 64 immune differential genes.Kaplan-Meier analysis showed that protein tyrosine kinase 2β(PTK2β)expression was negatively correlated with PFS(p=0.009)and hepatocyte nuclear factor 1A(HNF1A)expression was positively correlated with PFS(p=0.001).Applying CIBERSORTx calculated naive CD4+T cells and mast cells resting as differentially infiltrating immune cells between irAE and non-irAE.Kaplan-Meier showed no statistical correlation between PFS and naive CD4+T cell(p=0.239)nor mast cell resting(p=0.306).[Conclusions]We developed a validated nomogram prognostic model for ED-SCLC patients based on summarizing the clinical data,treatment modalities,test results and survival of ED-SCLC in our institution during 8-year;by comparing the efficacy and safety of IP/IC combined with camrelizumab and CE/EP combined with PD-L1 inhibitor,we found that IP/IC combined with camrelizumab in first-line treatment of ED-SCLC prolonged progression-free survival with a favorable safety profile;by analyzing the RNA data of irAE and non-irAE groups,PTK2 β and HNF1A were screened as immune differential genes that may be associated with survival,and naive CD4+T cells and mast cells resting were differentially infiltrating immune cells.