Exploration Of Predictive Biomarkers And Treatment Strategies For Immunotherapy In Advanced Non-small Cell Lung Cancer

Background:Immune checkpoint inhibitor(ICI)combined with chemotherapy is one of the standards of care for advanced Non-small cell lung cancer(NSCLC)without driver mutations.However,the biomarker of combination therapy is still unknown.Although previous studies have confirmed that low allele frequency adjusted blood-based tumor mutational burden(LAF-bTMB)is associated with the efficacy of ICI monotherapy,there has been no report on the correlation between the efficacy of LAF-bTMB and ICI combined chemotherapy.This study aimed to explore whether LAF-bTMB can be used as a biomarker for the efficacy of immunotherapy combined with chemotherapy in advanced NSCLC.Methods:This study enrolled patients diagnosed with advanced NSCLC and who received ICI combined with chemotherapy for first-line therapy from May 2020 to December 2021 at Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College.Clinical information,treatment information,survival data,and peripheral blood samples of every patient before treatment were collected.Next-generation sequencing was performed on plasma samples collected before treatment to evaluate bTMB and LAF-bTMB.Results:A total of 42 patients with NSCLC were included in the study.In this cohort,19 patients achieved partial response(PR),and the objective response rate(ORR)was 45%.The median progression-free survival(PFS)of all patients was 13.4 months.Both PFS and the overall survival(OS)were significantly longer in the responder(R)group than in the non-responder(NR)group(mPFS:16.4months vs.7.2months,p=0.028;mOS:NEvs.9.3months,p=0.016).There was no significant difference in bTMB and LAF-BTMB between the R group and the NR group.The ORR of patients with LAF-bTMB<8muts/Mb was significantly higher than that of patients with LAF-BTMB>8muts/Mb(ORR 61%vs.26%,respectively,p=0.033).No correlation has been found between LAF-bTMB and PFS or OS.Conclusions:LAF-bTMB has some limitations as a predictor of first-line immunochemotherapy for advanced NSCLC.More suitable biomarkers need to be explored to screen patients with better efficacy of immunotherapy combined with chemotherapy in the futureBackground:Immune checkpoint inhibitor monotherapy or in combination with chemotherapy is now one of the standards of care in the first line for advanced non-small cell lung cancer(NSCLC)without driver mutations.PD-L1 expression has been shown to be associated with the efficacy of ICI in serval clinical trials.However,there is no largescale research reported on the predictive effect of PD-L1 on ICI efficacy in the real world in China.This study aimed to explore the predictive effect of PD-L1 in immunotherapy for advanced NSCLC patients in the real world.Methods:This is a multi-center retrospective study.Clinical data of advanced NSCLC patients who received ICI therapy were collected between January 2018 and December 2021 in National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Peking Union Medical College Hospital,Peking University Third Hospital,Beijing Chest Hospital.Survival data of patients were followed up until March 2022.The detection percentage of PD-L1 expression,the relationship of PD-L1 expression level with clinical efficacy and survival were analyzed.Results:A total of 551 patients with advanced NSCLC were enrolled in this study and divided into three groups according to the different treatment line and regimens.(1)67 patients with PD-L1≥50%used ICI as their first-line therapy.The objective response rate(ORR)and progression-free survival(PFS)did not differentiate significantly between patients treated with ICI monotherapy and ICI combined chemotherapy(ORR:41.2%vs.50%,p=0.529;PFS 7.6 vs.12.5 months,HR 0.300,95%CI 0.313-1.431,P=0.142).Patients treated with ICI alone were more likely to have disease progression within 3 months than those treated with ICI plus chemotherapy(p=0.021).(2)279 patients were treated with ICI monotherapy or ICI-based therapy in first-line.67%of 279 patients underwent PD-L1 testing before treatment.64%patient treated with immunochemotherapy detected PD-L1 expression in the baseline.The ORR of patients with PD-L1≥50%receiving first-line immunotherapy was significantly higher than that of patients with PD-L1<1%(47.8%vs.26.4%,p=0.017).PFS of patients with PD-L1≥50%was significantly longer than that of patients with PD-L1 1-49%(HR 0.619,95%CI 0.384-0.998,p=0.049).The overall survival(OS)of patients with PD-L1≥50%was worse than that of patients with PD-L1 149%(HR 2.821,95%CI 1.041-7.65,p=0.042).(3)272 patients received ICI in the second and posterior line.46%of them received PD-L1 test before immunotherapy.ORR of patients with PD-L1≥50%was significantly higher than that of patients with PD-L1≤49%.There were no significant difference observed in both PFS(log-rankp=0.1105)and OS(log-rank p=0.2647)of patients with PD-L1≥50%,PD-L1 1-49%and PD-1<1%.Conclusions:ICI monotherapy and ICI combined chemotherapy can improve PFS and OS in advanced NSCLC patients with PD-L1≥50%,but the risk of rapid progression caused by ICI alone should be warned.PD-L1 high expression was associated with better response to first-line immunotherapy.In second-line and posterior line treatment,PD-L1 detection can be used as a supplementary diagnosis before immunotherapy.Background:Patients treated with epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)will inevitably face the problem of drug resistance.To date,multiple clinical studies have reported promising results using immune checkpoint inhibitors(ICIs)or antiangiogenic therapy for EGFR-TKI resistance.But the combination therapy of immunotherapy plus antiangiogenic drugs is still controversial.In this study,we propose to evaluate the efficacy and safety of toripalimab combined with anlotinib in patients with advanced non-small cell lung cancer(NSCLC)after the failure of EGFR-TKI treatment.Methods:Previously the EGFR-TKI treated patients with advanced NSCLC were enrolled in this study.Patients were given intravenous toripalimab(240mg,day 1)combined with oral anlotinib(12mg,once daily,day 1-day 14)for each therapy cycle of 21 days.Efficacy assessment was performed after 2 cycles of treatment.Patients without progressive disease after 4 cycles received the original regimen for maintenance treatment until disease progression or unacceptable adverse events.The primary endpoint is objective response rate(ORR)and the secondary endpoint is progression-free survival(PFS).The frequency of gene mutation was detected by NGS and TMB was calculated.The expression level of soluble PD-L1 was determined by ELISA.Results:A total of 19 patients with EGFR mutation were enrolled,including 12 cases of 19 DEL,6 cases of EGFR 21 L858R mutation and 1 patient with T790M mutation.The median treatment cycle was 2(range 2-14 cycles).The best response was stable disease(SD)which was observed in 11 patients(57.9%)and progressive disease(PD)in 8 patients.The ORR was 0%,and the median PFS was 2.1 months(95%CI 0.251-3.949).The PFS of patients with SD was approximately 2 months longer than that of patients with PD(mPFS 3.5 vs.1.4 months,HR 0.104,95%CI0.0021-0.521).The incidence of grade Ⅲ or higher adverse events(AEs)was 11%.The most common AEs was hypothyroidism(12/19),and no new adverse events were found that had not been reported in previous studies.Exploratory analysis showed that EGFR allele frequence(AF)at baseline in the SD group was lower than in the PD group(p=0.147).When the cut-off value of EGFR AF was 2%,patients with low EGFR AF had a PFS benefit trend,but there was no statistical significance(log-rankp=0.059).Conclusions:Ttoripalimab combined with anlotinib did not show antitumor activity in EGFR-TKI resistant patients.EGFR mutation AF,sPD-L1 may be related to the efficacy of immunotherapy after EGFR-TKI resistance,which needs to be further explored in subsequent trials.