Background:Tumor mutation burden(TMB)remains a promising but ambiguous predictive biomarker for the efficacy of immune checkpoint inhibitors(ICIs).We investigated the predictive value of TMB in patients with advanced ...Background:Tumor mutation burden(TMB)remains a promising but ambiguous predictive biomarker for the efficacy of immune checkpoint inhibitors(ICIs).We investigated the predictive value of TMB in patients with advanced non-small cell lung cancer(NSCLC)treated by ICI-containing therapies under strictly matched clinical settings.Methods:PubMed,Embase,Cochrane Central,ClinicalTrials.gov,and bioRxiv databases were searched till October 16,2021.All randomized controlled trials(RCTs)that compared patients with high TMB(TMB-H)and low TMB(TMB-L)and provided hazard ratio(HR)and corresponding 95%confidence interval(CI)in advanced NSCLC patients receiving ICIs were included,and mirror-based meta-analysis was performed(Part1).Bayesian network meta-analysis was conducted to investigate the efficacy of distinct first-line regimens in TMB-H and TMB-L groups(Part2).Public cohorts were used for validation and further exploration(Part3).Results:Twelve RCTs(n=5527)and 5 public cohorts(n=573)were included.In Part1,TMB-H patients generally exhibited a more significant progression-free survival(PFS)benefit from ICI-containing therapies compared to TMB-L patients(HR=0.58,95%CI:0.49-0.67,P<0.0001).In Part2,anti-PD-1 plus chemotherapy ranked best for PFS in both TMB-H and TMB-L groups.Anti-PD-L1 plus anti-CTLA-4 therapies indicated better PFS and overall survival(OS)benefit than single ICI and chemotherapy in the TMB-H group,but ranked worst in the TMB-L group.Finally,TMB was validated to be an independent predictive biomarker from programmed cell death-ligand 1(PD-L1)expression in Part3,which could further distinguish beneficiaries of ICI-containing therapies with PD-L1<50%.Conclusion:TMB-H could be a predictive biomarker independent of PD-L1 expression to identify beneficiaries of ICI-containing therapy in advanced NSCLC patients.展开更多
Flexible pressure sensors have come under the spotlight because of their widespread adoption in human motion detection and human‒machine interactions.However,manufacturing pressure sensors with broad sensing ranges an...Flexible pressure sensors have come under the spotlight because of their widespread adoption in human motion detection and human‒machine interactions.However,manufacturing pressure sensors with broad sensing ranges and large sensitivities continues to be a daunting task.Herein,a pressure sensor based on a gradient wrinkled electrospun polyurethane membrane with MXene-embedded ZnO nanowire arrays(ZAGW)was proposed.Under tiny pressure,dramatic increases in the contact area caused by interlocks of MXene-embedded ZnO nanowire arrays contributed to realizing a high sensitivity(236.5 kPa^(−1)).Additionally,the wide-sensing range(0–260 kPa)came from the fact that a wrinkled membrane with a gradient contact height ensured a continuous contact area change by gradually activating contact wrinkles.Meanwhile,the contact states of the gradient wrinkled membrane at varying pressures were investigated to expound the sensing mechanism of the ZAGW sensor.These exceptional performances enabled the ZAGW sensor to have vast application potential in human motion monitoring and tactile sensing.Furthermore,the ZAGW sensor can be integrated into the sensor array to monitor the pressure distribution.Considering the outstanding performance,the combination of ZnO nanowire arrays and electrospun membrane gradient wrinkles provides an innovative avenue for future sensing research.展开更多
Targeted therapy has ushered in a new era of precision medicine for non-small cell lung cancer(NSCLC).Currently,epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)stand as the recommended first-lin...Targeted therapy has ushered in a new era of precision medicine for non-small cell lung cancer(NSCLC).Currently,epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)stand as the recommended first-line therapy for advanced NSCLC harboring sensitive EGFR mutations.Nevertheless,most patients inevitably confront the challenge of drug resistance.This phenomenon arises not solely from intrinsic alterations within cancer cells but also from the intricate dynamics of the tumor microenvironment and the complex interactions that occur between cancer cells and their immediate surroundings.This review consolidates the current knowledge regarding EGFR-TKI resistance mechanisms,with a specific emphasis on unraveling the role played by the tumor microenvironment.In addition,the review delineates strategic approaches to surmount TKI resistance,thereby enriching the understanding of the interplay between therapeutic agents and the intricate milieu surrounding cancer cells.展开更多
With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly t...With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations (“target-dependent resistance”) and in the parallel and downstream pathways (“target-independent resistance”). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.展开更多
Small-cell lung cancer(SCLC)is the most aggressive and lethal subtype of lung cancer,for which,better understandings of its biology are urgently needed.Single-cell sequencing technologies provide an opportunity to pro...Small-cell lung cancer(SCLC)is the most aggressive and lethal subtype of lung cancer,for which,better understandings of its biology are urgently needed.Single-cell sequencing technologies provide an opportunity to profile individual cells within the tumor microenvironment(TME)and investigate their roles in tumorigenic processes.Here,we performed high-precision single-cell transcriptomic analysis of~5000 individual cells from primary tumors(PTs)and matched normal adjacent tissues(NATs)from 11 SCLC patients,including one patient with both PT and relapsed tumor(RT).The comparison revealed an immunosuppressive landscape of human SCLC.Malignant cells in SCLC tumors exhibited diverse states mainly related to the cell cycle,immune,and hypoxic properties.Our data also revealed the intratumor heterogeneity(ITH)of key transcription factors(TFs)in SCLC and related gene expression patterns and functions.The non-neuroendocrine(non-NE)tumors were correlated with increased inflammatory gene signatures and immune cell infiltrates in SCLC,which contributed to better responses to immune checkpoint inhibitors.These findings indicate a significant heterogeneity of human SCLC,and intensive crosstalk between cancer cells and the TME at single-cell resolution,and thus,set the stage for a better understanding of the biology of SCLC as well as for developing new therapeutics for SCLC.展开更多
In order to meet the design requirements of the aging treatment process of a 4th generation nickel-based single crystal superalloy(Ni-SX)developed independently,the effects of aging temperatures and aging times on the...In order to meet the design requirements of the aging treatment process of a 4th generation nickel-based single crystal superalloy(Ni-SX)developed independently,the effects of aging temperatures and aging times on the precipitation and morphological evolution ofγprecipitates are studied.The morphological evolution behavior ofγprecipitates during the aging process is summarized subsequently and the coarsening behavior ofγprecipitates is discussed by comparing with the Lifshitz-Slyozov-Wagner model(LSW)and the trans-interface diffusion-controlled model(TIDC).It is demonstrated that primary aging temperature and secondary aging time dominate the size and squareness ofγprecipitates respectively,a narrow primary aging temperature range and a suitable secondary aging time are allowed to obtain the optimized morphology ofγprecipitates.The optimal aging process of the Ni-SX investigated in the present work is obtained for 1100-1120°C/4 h and 870°C/16 h,confirmed by the corresponding creep tests.The coarsening growth ofγprecipitates in short-term aging also conforms to the LSW model well.Besides,the aging process design rules of various Ni-SXs of different generations are also summarized.展开更多
探索具有优异导电性和稳定性的非贵金属电催化剂对氢经济至关重要.本研究将杂原子掺杂和石墨烯包覆相结合,以控制NiCo_(2)S_(4)(NCS)蛋黄壳微球的电子性能,并抵抗酸性介质中H_(2)O和O_(2)的腐蚀.密度泛函理论(DFT)模拟结合综合表征和实...探索具有优异导电性和稳定性的非贵金属电催化剂对氢经济至关重要.本研究将杂原子掺杂和石墨烯包覆相结合,以控制NiCo_(2)S_(4)(NCS)蛋黄壳微球的电子性能,并抵抗酸性介质中H_(2)O和O_(2)的腐蚀.密度泛函理论(DFT)模拟结合综合表征和实验首次揭示了在NCS中引入P杂原子不仅加速了电子从体相向表面的转移动力学,而且降低了掺杂P原子附近活性S位上的析氢反应势垒.利用DFT计算的穿透能垒预测了rGO覆盖层在P掺杂NCS(P-NCS)表面对质子的渗透性和对H_(2)O和O_(2)分子的抵抗性等重要功能,并用X射线光电子能谱对新催化剂和回收催化剂进行了验证.利用P掺杂剂和rGO覆盖层分别辅助电荷传递和质子传递,通过二者的协同作用获得了催化活性和耐久性之间的平衡.因此,优化后的P-NCS/rGO在70 mV的低过电位下实现了10 mA cm^(-2)的电流密度,并具有令人满意的80小时耐用性.本工作阐明了石墨烯覆盖硫化物催化剂可通过调控电子结构和质子/分子穿透提高电催化性能.展开更多
Malignant pleural mesothelioma(MPM)is a rare and aggressive malignant disease.Currently,the platinum doublet of pemetrexed and cisplatin is the standard first-line treatment for unresectable MPM.However,recent promisi...Malignant pleural mesothelioma(MPM)is a rare and aggressive malignant disease.Currently,the platinum doublet of pemetrexed and cisplatin is the standard first-line treatment for unresectable MPM.However,recent promising results of immunotherapy have markedly changed the landscape of MPM treatment.Further,the ongoing innovative therapeutic strategies are expected to expand the range of treatment options;however,several questions remain unanswered.First,establishing predictive biomarkers with high potency is urgently needed to optimize the patient selection process.Second,further exploration of the combination algorithm is expected to unveil more effective and safe regimens.Moreover,other dilemmas,such as the resistance mechanism of immunotherapy and the role of immunotherapy in perioperative settings,still warrant further exploration.展开更多
A randomized double-blind phase 3 trial(CHOICE-01,NCT03856411)demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival(PFS)in advanced non-small cell lung cancer(NSCLC...A randomized double-blind phase 3 trial(CHOICE-01,NCT03856411)demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival(PFS)in advanced non-small cell lung cancer(NSCLC)patients without pretreatment.This study presents the prespecifiedfinal analysis of overall survival(OS)and biomarkers utilizing circulating tumor DNA(ctDNA)and tissuebased sequencing.Additionally,the analysis revealed a higher median overall survival(OS,23.8 months)in the toripalimab group than that in the control group(17.0 months).(HR=0.69,95%CI:0.57-0.93,nominal P=0.01).This survival benefit was particularly notable in the nonsquamous subgroup.As thefirst phase 3 study to perform both baseline tissue whole-exome sequencing(WES)and peripheral blood ctDNA testing,we investigated efficacy predictive biomarkers based on both tissue and ctDNA,Genomic sequencing of ctDNA showed high concordance with tumor tissue independently confirmed that individuals exhibiting a high tumor mutational burden,as well as mutations in the FA-PI3K-Akt and IL-7 signaling pathways benefited more from the toripalimab treatment.Furthermore,a ctDNA response observed on cycle 3 day 1,was associated with improved clinical outcomes for patients treated with the combination therapy.In conclusion,Toripalimab plus chemotherapy yields significant improvements in OS as afirst-line treatment.The study highlights the utility of ctDNA as a proxy for tumor tissue,providing novel prospects for predicting efficacy of immuno-chemotherapy through continuous ctDNA monitoring.展开更多
基金supported by the National Key Research and Devel-opment Project(2019YFC1315700)the National Natural Science Foundation of China(81871889,82072586).
文摘Background:Tumor mutation burden(TMB)remains a promising but ambiguous predictive biomarker for the efficacy of immune checkpoint inhibitors(ICIs).We investigated the predictive value of TMB in patients with advanced non-small cell lung cancer(NSCLC)treated by ICI-containing therapies under strictly matched clinical settings.Methods:PubMed,Embase,Cochrane Central,ClinicalTrials.gov,and bioRxiv databases were searched till October 16,2021.All randomized controlled trials(RCTs)that compared patients with high TMB(TMB-H)and low TMB(TMB-L)and provided hazard ratio(HR)and corresponding 95%confidence interval(CI)in advanced NSCLC patients receiving ICIs were included,and mirror-based meta-analysis was performed(Part1).Bayesian network meta-analysis was conducted to investigate the efficacy of distinct first-line regimens in TMB-H and TMB-L groups(Part2).Public cohorts were used for validation and further exploration(Part3).Results:Twelve RCTs(n=5527)and 5 public cohorts(n=573)were included.In Part1,TMB-H patients generally exhibited a more significant progression-free survival(PFS)benefit from ICI-containing therapies compared to TMB-L patients(HR=0.58,95%CI:0.49-0.67,P<0.0001).In Part2,anti-PD-1 plus chemotherapy ranked best for PFS in both TMB-H and TMB-L groups.Anti-PD-L1 plus anti-CTLA-4 therapies indicated better PFS and overall survival(OS)benefit than single ICI and chemotherapy in the TMB-H group,but ranked worst in the TMB-L group.Finally,TMB was validated to be an independent predictive biomarker from programmed cell death-ligand 1(PD-L1)expression in Part3,which could further distinguish beneficiaries of ICI-containing therapies with PD-L1<50%.Conclusion:TMB-H could be a predictive biomarker independent of PD-L1 expression to identify beneficiaries of ICI-containing therapy in advanced NSCLC patients.
基金supported by National Natural Science Foundation of China(No.22378253,22078188,52073164,and 21908141).
文摘Flexible pressure sensors have come under the spotlight because of their widespread adoption in human motion detection and human‒machine interactions.However,manufacturing pressure sensors with broad sensing ranges and large sensitivities continues to be a daunting task.Herein,a pressure sensor based on a gradient wrinkled electrospun polyurethane membrane with MXene-embedded ZnO nanowire arrays(ZAGW)was proposed.Under tiny pressure,dramatic increases in the contact area caused by interlocks of MXene-embedded ZnO nanowire arrays contributed to realizing a high sensitivity(236.5 kPa^(−1)).Additionally,the wide-sensing range(0–260 kPa)came from the fact that a wrinkled membrane with a gradient contact height ensured a continuous contact area change by gradually activating contact wrinkles.Meanwhile,the contact states of the gradient wrinkled membrane at varying pressures were investigated to expound the sensing mechanism of the ZAGW sensor.These exceptional performances enabled the ZAGW sensor to have vast application potential in human motion monitoring and tactile sensing.Furthermore,the ZAGW sensor can be integrated into the sensor array to monitor the pressure distribution.Considering the outstanding performance,the combination of ZnO nanowire arrays and electrospun membrane gradient wrinkles provides an innovative avenue for future sensing research.
基金supported by National Key Research and Development Project(Nos.2022YFC2505004,2022YFC2505000 to Z.W.and J.W.)NSFC special program(No.82241229 to J.W.)+2 种基金the National Youth Talent(to Z.W)CAMS Innovation Fund for Medical Sciences(No.2021-1-I2M-012 to Z.W.)National Natural Sciences Foundation of China(Nos.81871889 and 82072586 to Z.W.)。
文摘Targeted therapy has ushered in a new era of precision medicine for non-small cell lung cancer(NSCLC).Currently,epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)stand as the recommended first-line therapy for advanced NSCLC harboring sensitive EGFR mutations.Nevertheless,most patients inevitably confront the challenge of drug resistance.This phenomenon arises not solely from intrinsic alterations within cancer cells but also from the intricate dynamics of the tumor microenvironment and the complex interactions that occur between cancer cells and their immediate surroundings.This review consolidates the current knowledge regarding EGFR-TKI resistance mechanisms,with a specific emphasis on unraveling the role played by the tumor microenvironment.In addition,the review delineates strategic approaches to surmount TKI resistance,thereby enriching the understanding of the interplay between therapeutic agents and the intricate milieu surrounding cancer cells.
基金Beijing Natural Science Foundation(No.7222144)National Key Research and Development Project(No.2019YFC1315700)CAMS Key Laboratory of Translational Research on Lung Cancer(No.2018PT31035).
文摘With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations (“target-dependent resistance”) and in the parallel and downstream pathways (“target-independent resistance”). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.
基金Beijing Advanced Innovation Center for Genomics,the National Natural Sciences Foundation Key Program(8163007)Ministry of Education Innovation Team Development Project(IRT-17R10)+1 种基金Qingqing Li was supported in part by the Postdoctoral Fellowship of Peking-Tsinghua Center for Life SciencesSome of the bioinformatics analysis were carried out on High Performance Computing Platform of the Center for Life Science.
文摘Small-cell lung cancer(SCLC)is the most aggressive and lethal subtype of lung cancer,for which,better understandings of its biology are urgently needed.Single-cell sequencing technologies provide an opportunity to profile individual cells within the tumor microenvironment(TME)and investigate their roles in tumorigenic processes.Here,we performed high-precision single-cell transcriptomic analysis of~5000 individual cells from primary tumors(PTs)and matched normal adjacent tissues(NATs)from 11 SCLC patients,including one patient with both PT and relapsed tumor(RT).The comparison revealed an immunosuppressive landscape of human SCLC.Malignant cells in SCLC tumors exhibited diverse states mainly related to the cell cycle,immune,and hypoxic properties.Our data also revealed the intratumor heterogeneity(ITH)of key transcription factors(TFs)in SCLC and related gene expression patterns and functions.The non-neuroendocrine(non-NE)tumors were correlated with increased inflammatory gene signatures and immune cell infiltrates in SCLC,which contributed to better responses to immune checkpoint inhibitors.These findings indicate a significant heterogeneity of human SCLC,and intensive crosstalk between cancer cells and the TME at single-cell resolution,and thus,set the stage for a better understanding of the biology of SCLC as well as for developing new therapeutics for SCLC.
基金supported by the National Natural Science Foundation of China(No.91960201)the Zhejiang Provincial Natural Science Foundation of China(Nos.LR22E010003,LY20E010004)+3 种基金the Key Basic Research Program of Zhejiang Province(No.2020C01002)the Fundamental Research Funds for the Central Universities(No.226-2022-00050)the Fundamental Research Funds of the Zhejiang Provincial Universities(No.2021XZZX011)National Science and Technology Major Project of China(No.J2019-Ⅲ-0008-0051)。
文摘In order to meet the design requirements of the aging treatment process of a 4th generation nickel-based single crystal superalloy(Ni-SX)developed independently,the effects of aging temperatures and aging times on the precipitation and morphological evolution ofγprecipitates are studied.The morphological evolution behavior ofγprecipitates during the aging process is summarized subsequently and the coarsening behavior ofγprecipitates is discussed by comparing with the Lifshitz-Slyozov-Wagner model(LSW)and the trans-interface diffusion-controlled model(TIDC).It is demonstrated that primary aging temperature and secondary aging time dominate the size and squareness ofγprecipitates respectively,a narrow primary aging temperature range and a suitable secondary aging time are allowed to obtain the optimized morphology ofγprecipitates.The optimal aging process of the Ni-SX investigated in the present work is obtained for 1100-1120°C/4 h and 870°C/16 h,confirmed by the corresponding creep tests.The coarsening growth ofγprecipitates in short-term aging also conforms to the LSW model well.Besides,the aging process design rules of various Ni-SXs of different generations are also summarized.
基金supported by the National Key R&D Program of China(2021YFA1501900)the National Natural Science Foundation of China-Yunnan Joint Fund(U2102215)+4 种基金the National Natural Science Foundation of China(22209203)China Postdoctoral Science Foundation(2021M693419)Jiangsu Key Laboratory of Coal-based Greenhouse Gas Control and Utilization(PCSX202202)the Material Science and Engineering Discipline Guidance Fund of China University of Mining and Technology(CUMTMS202202 and CUMTMS202207)the Open Sharing Fund for the Large-scale Instruments and Equipment of China University of Mining and Technology。
文摘探索具有优异导电性和稳定性的非贵金属电催化剂对氢经济至关重要.本研究将杂原子掺杂和石墨烯包覆相结合,以控制NiCo_(2)S_(4)(NCS)蛋黄壳微球的电子性能,并抵抗酸性介质中H_(2)O和O_(2)的腐蚀.密度泛函理论(DFT)模拟结合综合表征和实验首次揭示了在NCS中引入P杂原子不仅加速了电子从体相向表面的转移动力学,而且降低了掺杂P原子附近活性S位上的析氢反应势垒.利用DFT计算的穿透能垒预测了rGO覆盖层在P掺杂NCS(P-NCS)表面对质子的渗透性和对H_(2)O和O_(2)分子的抵抗性等重要功能,并用X射线光电子能谱对新催化剂和回收催化剂进行了验证.利用P掺杂剂和rGO覆盖层分别辅助电荷传递和质子传递,通过二者的协同作用获得了催化活性和耐久性之间的平衡.因此,优化后的P-NCS/rGO在70 mV的低过电位下实现了10 mA cm^(-2)的电流密度,并具有令人满意的80小时耐用性.本工作阐明了石墨烯覆盖硫化物催化剂可通过调控电子结构和质子/分子穿透提高电催化性能.
基金National Natural Sciences Foundation(Grant/Award Numbers:81871889,82072586,82102886)CAMS Innovation Fund for Medical Sciences(Grant/Award Number:2021-I2M-1-012)Beijing Natural Science Foundation(Grant/Award Number:7212084)。
文摘Malignant pleural mesothelioma(MPM)is a rare and aggressive malignant disease.Currently,the platinum doublet of pemetrexed and cisplatin is the standard first-line treatment for unresectable MPM.However,recent promising results of immunotherapy have markedly changed the landscape of MPM treatment.Further,the ongoing innovative therapeutic strategies are expected to expand the range of treatment options;however,several questions remain unanswered.First,establishing predictive biomarkers with high potency is urgently needed to optimize the patient selection process.Second,further exploration of the combination algorithm is expected to unveil more effective and safe regimens.Moreover,other dilemmas,such as the resistance mechanism of immunotherapy and the role of immunotherapy in perioperative settings,still warrant further exploration.
基金supported by National key R&D program of China(2022YFC2505000)to J.WNSFC general program(82272796)NSFC special program(82241229)to J.W+1 种基金CAMS Innovation Fund for Medical Sciences(CIFMS 20adjuvant-I2M-1-009)to J.W,CAMS Key Laboratory of Translational Research on Lung Cancer(2018PT31035)to J.WAiyou foundation(KY201701)to J.W,CAMS Innovation Fund for Medical Sciences(2021-1-I2M-012)to Z.W.Beijing Natural Science Foundation(7222144)to J.Z,NSFC program(82303969)to J.Z.
文摘A randomized double-blind phase 3 trial(CHOICE-01,NCT03856411)demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival(PFS)in advanced non-small cell lung cancer(NSCLC)patients without pretreatment.This study presents the prespecifiedfinal analysis of overall survival(OS)and biomarkers utilizing circulating tumor DNA(ctDNA)and tissuebased sequencing.Additionally,the analysis revealed a higher median overall survival(OS,23.8 months)in the toripalimab group than that in the control group(17.0 months).(HR=0.69,95%CI:0.57-0.93,nominal P=0.01).This survival benefit was particularly notable in the nonsquamous subgroup.As thefirst phase 3 study to perform both baseline tissue whole-exome sequencing(WES)and peripheral blood ctDNA testing,we investigated efficacy predictive biomarkers based on both tissue and ctDNA,Genomic sequencing of ctDNA showed high concordance with tumor tissue independently confirmed that individuals exhibiting a high tumor mutational burden,as well as mutations in the FA-PI3K-Akt and IL-7 signaling pathways benefited more from the toripalimab treatment.Furthermore,a ctDNA response observed on cycle 3 day 1,was associated with improved clinical outcomes for patients treated with the combination therapy.In conclusion,Toripalimab plus chemotherapy yields significant improvements in OS as afirst-line treatment.The study highlights the utility of ctDNA as a proxy for tumor tissue,providing novel prospects for predicting efficacy of immuno-chemotherapy through continuous ctDNA monitoring.
