| Background:Afatinib is a second-generation EGFR-TKI that can significantly prolong the PFS of advanced NSCLC patients with common or uncommon EGFR mutations in the first-line setting.Previous studies indicated that TP53 mutation was associated with inferior PFS and OS of first-or second-generation EGFR-TKIs.However,the sample size of patients with uncommon EGFR mutations or receiving second-generation EGFR-TKIs in these studies was very small,which greatly reflected the impact of TP53 mutation on the efficacy of firstgeneration EGFR-TKIs in the treatment of patients with EGFR 19del or 21L858R mutations.Therefore,our study retrospectively collected advanced EGFR-mutant NSCLC patients treated with afatinib to explore the efficacy of afatinib in the real-world setting and its corresponding influential factors,especially the impact of TP53 mutation on the clinical outcomes of afatinib.Methods:We retrospectively screened advanced EGFR-mutant NSCLC patients who were treated with afatinib at Cancer Hospital,Chinese Academy of Medical Sciences from June 1,2017 to December 31,2020,and patients with baseline genomic information were finally included into the study.Demographic and clinical data,baseline genomic profiles,treatment of each line and corresponding efficacy,and survival data were collected.The K-M method was used to calculate the PFS and OS,and Cox proportional hazards regression model was used to explore the factors affecting PFS and OS.Pearson’s chi-square test or Fisher’s exact test was used to compare the differences in demographic and clinical characteristics and the differences in ORRs between groups.Results:A total of 43 EGFR-mutant advanced NSCLC patients treated with afatinib were included in this study,including 25 patients(58.1%)with uncommon EGFR mutations,32 patients(74.4%)receiving first-line afatinib treatment and 29(67.4%)patients with TP53 mutations.Among patients receiving first-line afatinib treatment,the ORR was 39.3%;the median PFS was 10.8 months(95%CI,6.8-14.8);and the median OS was 45.5 months(95%CI,30.5-60.5).There was no significant difference in ORRs between TP53-mutant and TP53wildtype groups(38.9%vs.40.0%,p=1.000).The risks of both disease progression(HR,0.327;95%CI,0.119-0.899;p=0.030)and death(HR,0.093;95%CI,0.012-0.705;p=0.022)were significantly lower in TP53-wildtype patients than those in TP53-mutant patients.There were no significant differences in the median PFS(p=0.851)and OS(p=0.136)between patients with TP53 missense and non-missense mutations.There were also no significant differences in the median PFS(p=0.481)and OS(p=0.193)between patients with TP53 destructive and non-destructive mutations.Multivariate Cox regression analysis revealed that TP53 mutation was an independent risk factor for the PFS of first-line afatinib treatment(HR,3.022;95%CI,1.084-8.429;p=0.035),but was not independently associated with the OS(p=0.194),while intracranial progression after afatinib treatment was an independent risk factor for the OS(HR,6.297;95%CI,1.461-27.136;p=0.014).Conclusion:TP53 mutation is an independent risk factor for the PFS of first-line afatinib treatment in advanced EGFR-mutant NSCLC,but it is not an independent risk factor for the OS.There are no significant differences in the PFS and OS among different subtypes of TP53 mutations.Background:EGFR-TKIs have been established as the standardized first-line monotherapy for LUAD patients harboring sensitive EGFR mutations.However,the resistance to EGFR-TKIs is inevitable.Additionally,EGFR-mutant patients with TP53 mutation would experience significantly inferior prognosis of EGFR-TKIs comparing to patients without TP53 mutation.Therefore,the subsequent systemic treatment strategy for EGFR+/TP53+patients would be even more important.ICIs have demonstrated promising antitumor efficacy in advanced LUAD patients.Nevertheless,previous studies revealed that the efficacy and prognosis of ICIs in EGFR-mutant LUAD patients were significantly inferior to those in EGFR-wildtype patients.Unfortunately,commonly used biomarkers,such as PDL1 expression and TMB can’t effectively predict the clinical outcomes among EGFR-mutant patients.The potential that EGFR+/TP53+patients could benefit more from ICIs would be even more important for the subsequent treatment strategy after resistance to EGFR-TKIs.This study aims to investigate the influence of TP53 mutation in the efficacy of anti-PD-1/PDL1 antibodies and TME among EGFR-mutant LUAD patients.Methods:This study retrospectively collected EGFR-mutant advanced LUAD patients who received anti-PD-1/PD-L1 antibody treatment at Cancer Hospital,Chinese Academy of Medical Sciences,and analyzed the value of TP53 mutation in predicting clinical outcomes of ICIs.Then,through an integrated analysis of the genomic and transcriptomic data of sensitive EGFR-mutant LUAD patients from TCGA database,we explored the impact of TP53 mutation on PD-L1 expression,TMB,and TIICs.Finally,paired tissue samples before and after EGFR-TKI treatment of EGFR-mutant LUAD patients from the local cohort were collected.The dynamic changes of the TME were analyzed by immunohistochemical staining to explore the impact of TP53 mutation on TME.Results:A total of 42 SEGFR-mutant LUAD patients were included in the retrospective study.The median PFS of TP53-mutant patients was significantly longer than that of TP53wildtype patients(6.7 vs.2.6 months;p=0.003).Multivariate Cox regression analysis revealed that TP53 mutation was independently associated with superior PFS(HR,0.38;95%CI,0.17-0.84;p=0.016).There were no significant differences in TMB(mutant vs.wildtype:1.3 muts/Mb vs.1.1 muts/Mb;p=0.274),PD-L1(CD274)expression[mutant vs.wildtype:log2(FPKM),1.3 VS.0.8;p=0.172]and TIICs between TP53-mutant and TP53wildtype patients among 43 EGFR-mutant LUAD patients from TCGA database.There were also no significant differences in the densities(counts/mm2)of TIICs between TP53-mutant and TP53-wildtype patients in both baseline and re-biopsy samples from the local cohort.However,analysis of 20 paired samples indicated that the median density of CD8+T cells increased significantly during EGFR-TKI treatment only in TP53-mutant patients(re-biopsy vs.baseline:14.6 vs.3.2;p=0.008),not in TP53-wildtype patients(21.9 vs.13.6;p=0.422).Conclusion:TP53 mutation is an independent predictive factor of superior efficacy of anti-PD-1/PD-L1 antibody treatment among EGFR-mutant LUAD patients after resistance to EGFR-TKIs,which may result from the trend to be more inflamed in TME during EGFR-TKI treatment in TP53-mutant patients.Background:With their potential to elicit durable antitumor response,ICIs have revolutionized the treatment strategies for advanced LUAD patients.However,the ORR of unselected advanced lung cancer patients treated with anti-PD-1 antibodies is only about 20%.Previous studies have found that although TP53 mutation is associated with the efficacy of ICIs,not all TP53 mutation subtypes can predict the efficacy.Only patients with TP53 missense mutations can obtain better clinical outcomes when treated with anti-PD-1/PD-L1 antibody monotherapy.When it comes to gene mutations,in addition to paying attention to the specific mutation subtypes,we also pay attention to the variant allele frequency(VAF)of the mutations.Whether TP53 VAF can be used as a biomarker like specific TP53 mutation subtypes to predict the efficacy of ICIs remains unknown.Therefore,the aim of this study is to fully explore the potential of TP53 VAF in tissue samples as a predictor for the efficacy of ICIs in advanced LUAD patients from both clinical data analysis and mechanism exploration.Methods:Published clinical data from the MSKCC database were collected as the discovery cohort,and two cohorts,the Rizvi cohort from the published research and the local cohort from the Cancer Hospital,Chinese Academy of Medical Sciences,were collected as the validation cohorts to discover and validate the relationship between TP53 VAF and clinical efficacy of anti-PD-1/PD-L1 monotherapy.LUAD data from TCGA database were included to analyze the differences in genome,transcriptome and tumor microenvironment between TP53-wildtype,low TP53 VAF and high TP53 VAF groups.Results:Among 159 patients in the discovery cohort,low TP53 VAF patients(VAF<25%)experienced significantly longer PFS than both high TP53 VAF(5.4 vs.3.3 months,p=0.021)and TP53-wildtype patients(5.4 vs.2.5 months;p=0.011).Multivariate Cox regression analysis also revealed the value of low TP53 VAF as an independent biomarker for better efficacy of immune monotherapy.Among 50 patients in the combined validation cohort,the median PFS of low TP53 VAF patients was also significantly longer than that of high TP53 VAF patients(12.0 vs.2.1 months,p=0.037).Analyzed with 469 TCGA LUAD samples,low TP53 VAF is associated with significantly higher PD-L1 expression,enrichment of gene sets related to T cell activation,T cell mediated immunity and IFN-y signaling pathways,and independently associated with more tumor infiltrating CD8+T cells comparing with both high TP53 VAF and TP53-wildtype.Conclusion:Low TP53 VAF,instead of high TP53 VAF,is the biomarker for better efficacy of anti-PD-(L)1 monotherapy in LUAD,which may result from the higher PD-L1 expression and more tumor infiltrating CD8+T cells in low TP53 VAF patients.Background:In previous studies,TP53 mutation was found to be associated with better efficacy of ICIs in LUAD patients.However,TP53 mutations were all detected from tissue samples in these studies and patients included all received immune monotherapy or combination of anti-PD(L)-1 and anti-CTLA-4 antibodies.A study of TP53 mutation status in blood samples pointed out that,contrary to the results of TP53 mutation status in tissue samples,the PFS and OS of TP53-mutant NSCLC patients were significantly inferior to those of TP53-wildtype patients.But this study did not analyze the relationship between ICI efficacy and TP53 mutation subtypes.Therefore,our study prospectively collected baseline peripheral blood samples from NSCLC patients who received first-line immunotherapy combined with chemotherapy or anti-angiogenic therapy,and explored the impact of TP53 mutation status,mutation subtypes,mutant exons,and VAF on the efficacy of ICI treatment.Methods:This study prospectively enrolled locally advanced or advanced NSCLC patients who received first-line immunotherapy at Cancer Hospital,Chinese Academy of Medical Sciences from January 1,2019 to June 30,2021.Demographic and clinical characteristics,response to the first-line treatment and survival information were collected.Baseline genomic information was obtained through 825-gene panel NGS using patients’blood samples.In this study,the K-M method was used to calculate the PFS and OS of the first-line immunotherapy,and Cox proportional hazards regression model was used to explore the clinical and genomic factors that influenced the PFS and OS.Pearson’s chi-square test or Fisher’s exact test was used to compare differences in demographic and clinical characteristics and ORRs between groups.Results:A total of 59 locally advanced or advanced NSCLC patients who received firstline immunotherapy were enrolled in this study,of which 34(57.6%)were TP53-mutant patients.Among the total population,the ORR was 52.5%;the median PFS was 7.8 months(95%CI,6.7-8.9);and the median OS was not reached.There was no significant difference in the median PFS between TP53-wildtype and TP53-mutant patients(8.5 vs.7.2 months,p=0.356),but TP53-wildtype patients tended to have longer median OS than TP53-mutant patients(not reached vs.22.0 months,p=0.060).There were no significant differences in the median PFS(p=0.633)and OS(p=0.167)between patients with TP53-wildtype,TP53disruptive mutation and TP53-nondisruptive mutation.There was also no significant difference in the median PFS between patients with TP53-wildtype,TP53 missense mutation and TP53 non-missense mutation(p=0.189).But the median OS of TP53-wildtype patients was significantly longer than that of patients with non-missense mutation(not reached vs.19.8 months,p=0.045).The median PFS and OS of patients with different TP53 mutant exons were similar,and only the median OS of patients with exon 6 mutation was significantly shorter than that of TP53-wildtype patients(p<0.001).The median PFS of low TP53 VAF patients(≤7.9%)was significantly longer than that of high TP53 VAF patients(7.7 vs.4.6 months,p=0.011),but was similar to that of TP53-wildtype patients(p=0.878).Likewise,the median OS of low TP53 VAF patients was also significantly longer than that of high TP53 VAF patients(not reached vs.11.7 months,p=0.030),but similar to that of TP53-wildtype patients(p=0.233).Multivariate Cox regression analysis indicated that TP53 VAF was independently associated with both PFS(low vs.high:HR,0.240;95%CI,0.085-0.680;p=0.007)and OS(low vs.high:HR,0.129;95%CI,0.023-0.721;p=0.020).Conclusion:In locally advanced or advanced NSCLC patients treated with first-line immunotherapy,the baseline TP53 mutation status in the blood was not associated with the PFS,while the median OS of TP53-wildtype patients tended to be longer than that of TP53mutant patients.TP53 VAF was independently associated with both PFS and OS.The median PFS and OS of low TP53 VAF patients were significantly longer than those of high TP53 VAF patients,and similar to those of TP53-wildtype patients. |
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