Objective: To evaluate the efficacy and safety profile of first-line bevacizumab(Bev)-containing pemetrexedplatinum chemotherapy in a real-world Chinese cohort with advanced non-squamous non-small cell lung cancer(NS-...Objective: To evaluate the efficacy and safety profile of first-line bevacizumab(Bev)-containing pemetrexedplatinum chemotherapy in a real-world Chinese cohort with advanced non-squamous non-small cell lung cancer(NS-NSCLC).Methods: A total of 415 eligible patients with NS-NSCLC who received first-line pemetrexed-platinum chemotherapy at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between February 2010 and September 2017 were reviewed retrospectively: 309 Bev(-) and 106 Bev(+) cases. Bev was administered at 7.5 mg/kg every 3 weeks in the Bev(+) group. To reduce the risk of a selection bias, a propensity score-matching(PSM) was conducted and 105 pairs of Bev(-) and Bev(+) cases were identified.Results: The median duration of follow-up was 15.8 months. The median progression-free survival(PFS) was prolonged significantly in the Bev(+) group than in the Bev(-) group in overall(9.8 vs. 7.8 months, P=0.006) and PSM pairs(9.8 vs. 6.6 months, P<0.001). Moreover, patients receiving maintenance therapy with pemetrexed plus Bev had longer PFS than those interrupted after induction chemotherapy, or those receiving mono-maintenance with pemetrexed(12.3 vs. 4.8 vs. 8.6 months;P<0.001). Multivariate analyses revealed Bev to be one of the favorable prognostic factors for PFS, along with the predictor of maintenance therapy.Conclusions: First-line induction and maintenance therapy with Bev(7.5 mg/kg every 3 weeks) combined with pemetrexed-platinum chemotherapy was efficacious and superior to non-Bev chemotherapy in Chinese patients with advanced NS-NSCLC.展开更多
Background： To determine the safety and therapeutic efficacy of nimotuzumab （h-R3） combined with docetaxel in advanced non-small-cell lung cancer （NSCLC） patients who have failed to respond to prior first-line ch...Background： To determine the safety and therapeutic efficacy of nimotuzumab （h-R3） combined with docetaxel in advanced non-small-cell lung cancer （NSCLC） patients who have failed to respond to prior first-line chemotherapy. Methods： In this single-center, open-label, dose-escalating phase I trial, patients with epidermal growth factor receptor （EGFR）-expressing stage IV NSCLC were treated with nimotuzumab plus doeetaxel according to a dose escalation schedule. The safety and efficacy of the combination treatment were observed and analyzed.Results： There were 12 patients with EGFR-expressing stage IV NSCLC enrolled. The dose of nimotuzumab was escalated from 200 to 600 mg/week. The longest administration of study drug was 40 weeks at the 600 mg/week dose level. Grade Ⅲ-Ⅳ toxicities included neutropenia and fatigue, and other toxicities included rash. Dose-limiting toxicity occurred with Grade 3 fatigue at the 200 mg dose level of nimotuzumab and Grade 4 neutropenia with pneumonia at the 600 mg dose level of nimotuzumab. No objective responses were observed, and stable disease was observed in eight patients （66.7%）. The median progression-free survival （PFS） was 4.4 months in all patients, 1.3 months in patients with the EGFR mutation, and 4.4 months in those with wild type EGFR （EGFR WT）. The median survival time （MST） was 21.1 months in all patients, 21.1 months in patients with EGFR mutation, and 26.4 months in patients with EGFR WT. Conclusions： Nimotuzumab and docetaxel combination therapy was found to be well tolerated and efficacious. Further study of nimotuzumab is warranted in advanced NSCLC patients.展开更多
Objective： To investigate PIK3CA mutation in Chinese patients with lung squamous cell carcinoma （LSCC） and explore their relationship with clinicopathological profiles. Methods： Tumor samples from 123 cases of LSC...Objective： To investigate PIK3CA mutation in Chinese patients with lung squamous cell carcinoma （LSCC） and explore their relationship with clinicopathological profiles. Methods： Tumor samples from 123 cases of LSCC were included in this study. PIK3CA mutations in exon 9 and 20 were screened by pyrosequencing and confirmed by clone sequencing or amplification refractory mutation system （ARMS）. Denaturing performance liquid chromatography （DHPLC） was employed for evaluation of EGFR mutation in exon 19, 21 and KRAS mutation. Results： PIK3CA mutations were found in 3 （2.4%） patients. The mutation type included E545K, E452Q and H1047R. Of these three patients, one coupled with EGFR mutation, and the other two coupled with PIK3CA amplification. All the three patients shared the same clinicopathologic characteristics： male, less than 60 years old, had smoke history, stage III and carried wild-type KRAS. Conclusions： The frequency of PIK3CA mutation is low in Chinese patients with LSCC. The mutational status of PIK3CA is not mutually exclusive to EGFR mutation.展开更多
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
Lung cancer is the leading cause of cancer-related deaths worldwide.Bone is a common metastatic site of lung cancer,about 50%of bone metastatic patients will experience skeletal related events(SREs).SREs not only seri...Lung cancer is the leading cause of cancer-related deaths worldwide.Bone is a common metastatic site of lung cancer,about 50%of bone metastatic patients will experience skeletal related events(SREs).SREs not only seriously impact the quality of life of patients,but also shorten their survival time.The treatment of bone metastasis requires multi-disciplinary therapy(MDT)and development of individualized treatment plan.In order to standardize the diagnosis and treatment of bone metastasis in lung cancer,the expert group of the MDT Committee of the Chinese Medical Doctor Association has developed the expert consensus on the diagnosis and treatment of lung cancer bone metastasis.展开更多
Objective:Immune checkpoint inhibitors(ICIs)targeting programmed cell death-1/ligand-1(PD-1/PD-L1),cy-totoxic T lymphocyte antigen-4(CTLA-4),and lymphocyte-activation gene-3(LAG-3)have been widely studied and applied ...Objective:Immune checkpoint inhibitors(ICIs)targeting programmed cell death-1/ligand-1(PD-1/PD-L1),cy-totoxic T lymphocyte antigen-4(CTLA-4),and lymphocyte-activation gene-3(LAG-3)have been widely studied and applied throughout the course of cancer treatment.This study aimed to provide a comprehensive profile of ICI-associated toxicity and elucidate the toxicity patterns of ICIs across different treatment lines.Methods:In total,155 cohorts comprising 24539 eligible patients were included in the safety analysis.Trial name,registration number,cancer type,trial phase,clinical setting,trial design,regimen,dosing schedule,age,sex and ethnicity distributions,number of patients,number of treatment-related adverse events(trAEs),and number of treatment-related death were extracted.We defined a timeline from the neoadjuvant setting to the third-line setting.We also introduced a synthesizing principle for adverse event rates(SPAER)of immunotherapy to ensure the comparability and reliability across different treatment lines.The study protocol was registered and approved by the PROSPERO protocol review committee(CRD42021242368).Results:After excluding the neoadjuvant setting group,we observed a distinct reduction in the incidence of treatment-related adverse events(trAEs)with an advancement of the line of ICI treatment.The incidence of trAEs was negatively correlated with the line of treatment,irrespective of whether monotherapy or dual-ICI combination therapy was administered.Sensitivity analyses also confirmed the coincident negative correlations.Conclusion:In summary,using a timeline-based concept centered around treatment lines,we revealed the dy-namic landscape of ICI-associated toxicity and found that patients treated with ICIs during later lines of therapy may have a lower risk of trAEs.展开更多
The publisher regrets that some of the authors’affiliations were mistakenly annotated in the manuscript.Hence,the authors of the below article were contacted after publication to request a correction of the author af...The publisher regrets that some of the authors’affiliations were mistakenly annotated in the manuscript.Hence,the authors of the below article were contacted after publication to request a correction of the author affliction and responded with the correct by the time this erratum is being published.展开更多
Background:Small cell lung cancer(SCLC)transformation had previously been reported mainly in epidermal growth factor receptor(EGFR)mutant adenocarcinoma.However,the underlying genomic profile remains un-clear.Our stud...Background:Small cell lung cancer(SCLC)transformation had previously been reported mainly in epidermal growth factor receptor(EGFR)mutant adenocarcinoma.However,the underlying genomic profile remains un-clear.Our study aimed to find the evolution and genotypic characteristic of SCLC transformation.Methods:Thirty-one SCLC transformation patients who were initially diagnosed as non-small cell lung cancer(NSCLC)patients were included.Whole exome sequencing(WES)of both primary and transformed re-biopsy lesions was conducted on 12 patients.Clinical characteristics were analyzed using R software(v.3.6.1).Results:Our study included 31 patients,of whom,three had lung squamous cell carcinoma,6 patients did not carry EGFR mutations,and 30 patients received chemotherapy for SCLCs.The disease control rate(DCR)was 96.7%,and the median progression-free survival(PFS)was 4.03 months.The median time to transformation was 33.07 months,and the median overall survival(OS)was 62.08 months.Somatic mutation analysis showed that besides TP53,RB1,and EGFR,there was a high occurrence of mutations to CSMD3 and ADAMTS19,espe-cially in the EGFR-wild type(EGFR-wt)group.Concerning mutational signature,the EGFR-mutant(EGFR-mut)transformed group favored an apolipoprotein B(APOBEC)mRNA editing catalytic polypeptide-like-associated mutation pattern(P=0.16).DNA damage repair(DDR)-related signatures were significantly enriched in the EGFR-wt transformed group(P=0.034).Additionally,clonal evolution analysis revealed that all patients had the same main trunk genes in the phylogenetic tree.Transformed SCLCs are not sensitive to immunotherapy,possibly due to increased tumor heterogeneity.Conclusions:Our results indicate that the EGFR-wt patients could also transform to SCLCs,but they have different genetic features with EGFR-mut patients.SCLC-transformed patients respond to classical chemotherapy and have a better prognosis than those with classical SCLCs.展开更多
Background:The initial randomized,double-blinded,actively controlled,phase III ANEAS study(NCT03849768)demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal g...Background:The initial randomized,double-blinded,actively controlled,phase III ANEAS study(NCT03849768)demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor(EGFR)-mutated advanced non-small cell lung cancer(NSCLC).Metastatic disease in the central nervous system(CNS)remains a challenge in the management of NSCLC.This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study.Methods:Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion.Patients with asymptomatic,stable CNS metastases were included.Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months,then every 12weeks.CNS responsewas assessed by a neuroradiological blinded,independent central review(neuroradiological-BICR).The primary endpoint for this subgroup analysis was CNS progression-free survival(PFS).Results:Of the 429 patients enrolled and randomized in the ANEAS study,106 patients were found to have CNS metastases(CNS Full Analysis Set,cFAS)at baseline by neuroradiological-BICR,and 60 of them had CNS target lesions(CNS Evaluable for Response,cEFR).Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS(29.0 vs.8.3 months;hazard ratio[HR]=0.31;95%confidence interval[CI],0.17-0.56;P<0.001)and cEFR(29.0 vs.8.3 months;HR=0.26;95%CI,0.11-0.57;P<0.001).The confirmed CNS overall response rate in cEFRwas 85.7%and 75.0%in patients treated with aumolertinib and gefitinib,respectively.Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNSmetastases at baseline.No new safety findings were observed.Conclusions:These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases.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
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
In non-small cell lung cancers,the non-squamous and squamous subtypes(nsqNSCLC and sqNSCLC)exhibit disparities in pathophysiology,tumor immunology,and potential genomic correlates affecting responses to immune checkpo...In non-small cell lung cancers,the non-squamous and squamous subtypes(nsqNSCLC and sqNSCLC)exhibit disparities in pathophysiology,tumor immunology,and potential genomic correlates affecting responses to immune checkpoint inhibitor(ICI)-based treatments.In our inhouse training cohort(n=85),the presence of the LRP1B deleterious mutation(LRP1B-del)was associated with longer and shorter progression-free survival(PFS)on ICIs alone in nsqNSCLCs and sqNSCLCs,respectively(Pinteraction=0.008).These results were validated using a larger public ICI cohort(n=208,Pinteraction<0.001).Multiplex immunofluorescence staining revealed an association between LRP1B-del and increased and decreased numbers of tumor-infiltrating CD8+T cells in nsqNSCLCs(P=0.040)and sqNSCLCs(P=0.014),respectively.In the POPLAR/OAK cohort,nsqNSCLCs with LRP1B-del demonstrated improved PFS benefits from atezolizumab over docetaxel(hazard ratio(HR)=0.70,P=0.046),whereas this benefit was negligible in those without LRP1B-del(HR=1.05,P=0.64).Conversely,sqNSCLCs without LRP1Bdel benefited more from atezolizumab(HR=0.60,P=0.002)than those with LRP1B-del(HR=1.30,P=0.31).Consistent results were observed in the in-house CHOICE-01 cohort,in which nsqNSCLCs with LRP1B-del and sqNSCLCs without LRP1B-del benefited more from toripalimab plus chemotherapy than from chemotherapy alone(Pinteraction=0.008).This multi-cohort study delineates the antithetical impacts of LRP1Bdel in nsqNSCLCs and sqNSCLCs on predicting the benefits from ICI alone or with chemotherapy over chemotherapy alone.Our findings highlight the distinct clinical utility of LRP1B-del in guiding treatment choices for nsqNSCLCs and sqNSCLCs,emphasizing the necessity for a detailed analysis based on pathological subtypes when investigating biomarkers for cancer therapeutics.展开更多
基金supported by Wu Jieping Fund (No. 320.6750.14266)
文摘Objective: To evaluate the efficacy and safety profile of first-line bevacizumab(Bev)-containing pemetrexedplatinum chemotherapy in a real-world Chinese cohort with advanced non-squamous non-small cell lung cancer(NS-NSCLC).Methods: A total of 415 eligible patients with NS-NSCLC who received first-line pemetrexed-platinum chemotherapy at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between February 2010 and September 2017 were reviewed retrospectively: 309 Bev(-) and 106 Bev(+) cases. Bev was administered at 7.5 mg/kg every 3 weeks in the Bev(+) group. To reduce the risk of a selection bias, a propensity score-matching(PSM) was conducted and 105 pairs of Bev(-) and Bev(+) cases were identified.Results: The median duration of follow-up was 15.8 months. The median progression-free survival(PFS) was prolonged significantly in the Bev(+) group than in the Bev(-) group in overall(9.8 vs. 7.8 months, P=0.006) and PSM pairs(9.8 vs. 6.6 months, P<0.001). Moreover, patients receiving maintenance therapy with pemetrexed plus Bev had longer PFS than those interrupted after induction chemotherapy, or those receiving mono-maintenance with pemetrexed(12.3 vs. 4.8 vs. 8.6 months;P<0.001). Multivariate analyses revealed Bev to be one of the favorable prognostic factors for PFS, along with the predictor of maintenance therapy.Conclusions: First-line induction and maintenance therapy with Bev(7.5 mg/kg every 3 weeks) combined with pemetrexed-platinum chemotherapy was efficacious and superior to non-Bev chemotherapy in Chinese patients with advanced NS-NSCLC.
文摘Background： To determine the safety and therapeutic efficacy of nimotuzumab （h-R3） combined with docetaxel in advanced non-small-cell lung cancer （NSCLC） patients who have failed to respond to prior first-line chemotherapy. Methods： In this single-center, open-label, dose-escalating phase I trial, patients with epidermal growth factor receptor （EGFR）-expressing stage IV NSCLC were treated with nimotuzumab plus doeetaxel according to a dose escalation schedule. The safety and efficacy of the combination treatment were observed and analyzed.Results： There were 12 patients with EGFR-expressing stage IV NSCLC enrolled. The dose of nimotuzumab was escalated from 200 to 600 mg/week. The longest administration of study drug was 40 weeks at the 600 mg/week dose level. Grade Ⅲ-Ⅳ toxicities included neutropenia and fatigue, and other toxicities included rash. Dose-limiting toxicity occurred with Grade 3 fatigue at the 200 mg dose level of nimotuzumab and Grade 4 neutropenia with pneumonia at the 600 mg dose level of nimotuzumab. No objective responses were observed, and stable disease was observed in eight patients （66.7%）. The median progression-free survival （PFS） was 4.4 months in all patients, 1.3 months in patients with the EGFR mutation, and 4.4 months in those with wild type EGFR （EGFR WT）. The median survival time （MST） was 21.1 months in all patients, 21.1 months in patients with EGFR mutation, and 26.4 months in patients with EGFR WT. Conclusions： Nimotuzumab and docetaxel combination therapy was found to be well tolerated and efficacious. Further study of nimotuzumab is warranted in advanced NSCLC patients.
基金supported by grants from National Natural Sciences Foundation Distinguished Young Scholars(81025012)National Natural Sciences Foundation General Program (81172235)+2 种基金the Capital Development Foundation(2007-1023)Beijing Health Systems Academic Leader(2011-2-22)Science and Technology Project of Beijing(Z090507017709015)
文摘Objective： To investigate PIK3CA mutation in Chinese patients with lung squamous cell carcinoma （LSCC） and explore their relationship with clinicopathological profiles. Methods： Tumor samples from 123 cases of LSCC were included in this study. PIK3CA mutations in exon 9 and 20 were screened by pyrosequencing and confirmed by clone sequencing or amplification refractory mutation system （ARMS）. Denaturing performance liquid chromatography （DHPLC） was employed for evaluation of EGFR mutation in exon 19, 21 and KRAS mutation. Results： PIK3CA mutations were found in 3 （2.4%） patients. The mutation type included E545K, E452Q and H1047R. Of these three patients, one coupled with EGFR mutation, and the other two coupled with PIK3CA amplification. All the three patients shared the same clinicopathologic characteristics： male, less than 60 years old, had smoke history, stage III and carried wild-type KRAS. Conclusions： The frequency of PIK3CA mutation is low in Chinese patients with LSCC. The mutational status of PIK3CA is not mutually exclusive to EGFR mutation.
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.
文摘Lung cancer is the leading cause of cancer-related deaths worldwide.Bone is a common metastatic site of lung cancer,about 50%of bone metastatic patients will experience skeletal related events(SREs).SREs not only seriously impact the quality of life of patients,but also shorten their survival time.The treatment of bone metastasis requires multi-disciplinary therapy(MDT)and development of individualized treatment plan.In order to standardize the diagnosis and treatment of bone metastasis in lung cancer,the expert group of the MDT Committee of the Chinese Medical Doctor Association has developed the expert consensus on the diagnosis and treatment of lung cancer bone metastasis.
基金supported by National Natural Sciences Foundation of China(grant num-bers:81630071 and 81871889).
文摘Objective:Immune checkpoint inhibitors(ICIs)targeting programmed cell death-1/ligand-1(PD-1/PD-L1),cy-totoxic T lymphocyte antigen-4(CTLA-4),and lymphocyte-activation gene-3(LAG-3)have been widely studied and applied throughout the course of cancer treatment.This study aimed to provide a comprehensive profile of ICI-associated toxicity and elucidate the toxicity patterns of ICIs across different treatment lines.Methods:In total,155 cohorts comprising 24539 eligible patients were included in the safety analysis.Trial name,registration number,cancer type,trial phase,clinical setting,trial design,regimen,dosing schedule,age,sex and ethnicity distributions,number of patients,number of treatment-related adverse events(trAEs),and number of treatment-related death were extracted.We defined a timeline from the neoadjuvant setting to the third-line setting.We also introduced a synthesizing principle for adverse event rates(SPAER)of immunotherapy to ensure the comparability and reliability across different treatment lines.The study protocol was registered and approved by the PROSPERO protocol review committee(CRD42021242368).Results:After excluding the neoadjuvant setting group,we observed a distinct reduction in the incidence of treatment-related adverse events(trAEs)with an advancement of the line of ICI treatment.The incidence of trAEs was negatively correlated with the line of treatment,irrespective of whether monotherapy or dual-ICI combination therapy was administered.Sensitivity analyses also confirmed the coincident negative correlations.Conclusion:In summary,using a timeline-based concept centered around treatment lines,we revealed the dy-namic landscape of ICI-associated toxicity and found that patients treated with ICIs during later lines of therapy may have a lower risk of trAEs.
文摘The publisher regrets that some of the authors’affiliations were mistakenly annotated in the manuscript.Hence,the authors of the below article were contacted after publication to request a correction of the author affliction and responded with the correct by the time this erratum is being published.
基金supported by the Beijing Municipal Administration of Hospitals Incubating Program(PX2019038,PX2020044)Beijing Youth Program for Outstanding Talents(2018000021469G262)+3 种基金National Key Research and Development Project(2019YFC1315700)NSFC Key Program(81630071)NSFC General Program(81871889,81972905)CAMS Key Lab of Translational Research on Lung Cancer(2018PT31035)and Aiyou Foundation(KY201701).
文摘Background:Small cell lung cancer(SCLC)transformation had previously been reported mainly in epidermal growth factor receptor(EGFR)mutant adenocarcinoma.However,the underlying genomic profile remains un-clear.Our study aimed to find the evolution and genotypic characteristic of SCLC transformation.Methods:Thirty-one SCLC transformation patients who were initially diagnosed as non-small cell lung cancer(NSCLC)patients were included.Whole exome sequencing(WES)of both primary and transformed re-biopsy lesions was conducted on 12 patients.Clinical characteristics were analyzed using R software(v.3.6.1).Results:Our study included 31 patients,of whom,three had lung squamous cell carcinoma,6 patients did not carry EGFR mutations,and 30 patients received chemotherapy for SCLCs.The disease control rate(DCR)was 96.7%,and the median progression-free survival(PFS)was 4.03 months.The median time to transformation was 33.07 months,and the median overall survival(OS)was 62.08 months.Somatic mutation analysis showed that besides TP53,RB1,and EGFR,there was a high occurrence of mutations to CSMD3 and ADAMTS19,espe-cially in the EGFR-wild type(EGFR-wt)group.Concerning mutational signature,the EGFR-mutant(EGFR-mut)transformed group favored an apolipoprotein B(APOBEC)mRNA editing catalytic polypeptide-like-associated mutation pattern(P=0.16).DNA damage repair(DDR)-related signatures were significantly enriched in the EGFR-wt transformed group(P=0.034).Additionally,clonal evolution analysis revealed that all patients had the same main trunk genes in the phylogenetic tree.Transformed SCLCs are not sensitive to immunotherapy,possibly due to increased tumor heterogeneity.Conclusions:Our results indicate that the EGFR-wt patients could also transform to SCLCs,but they have different genetic features with EGFR-mut patients.SCLC-transformed patients respond to classical chemotherapy and have a better prognosis than those with classical SCLCs.
基金Hansoh Pharmaceutical Group Co.LtdNational Natural Science Foundation of China,Grant/Award Numbers:82030045,82241227+3 种基金National Multi-disciplinary Treatment Project for Major Diseases,Grant/Award Number:2020NMDTPCollaborative Innovation Center for Clinical and Translational Science by Ministry of Education&Shanghai,Grant/Award Numbers:CCTS-202204,CCTS-202304Shanghai Chest Hospital Basic Research Project,Grant/Award Number:2023YNKT-1Pujiang Program,Grant/Award Number:22PJ1420700。
文摘Background:The initial randomized,double-blinded,actively controlled,phase III ANEAS study(NCT03849768)demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor(EGFR)-mutated advanced non-small cell lung cancer(NSCLC).Metastatic disease in the central nervous system(CNS)remains a challenge in the management of NSCLC.This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study.Methods:Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion.Patients with asymptomatic,stable CNS metastases were included.Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months,then every 12weeks.CNS responsewas assessed by a neuroradiological blinded,independent central review(neuroradiological-BICR).The primary endpoint for this subgroup analysis was CNS progression-free survival(PFS).Results:Of the 429 patients enrolled and randomized in the ANEAS study,106 patients were found to have CNS metastases(CNS Full Analysis Set,cFAS)at baseline by neuroradiological-BICR,and 60 of them had CNS target lesions(CNS Evaluable for Response,cEFR).Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS(29.0 vs.8.3 months;hazard ratio[HR]=0.31;95%confidence interval[CI],0.17-0.56;P<0.001)and cEFR(29.0 vs.8.3 months;HR=0.26;95%CI,0.11-0.57;P<0.001).The confirmed CNS overall response rate in cEFRwas 85.7%and 75.0%in patients treated with aumolertinib and gefitinib,respectively.Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNSmetastases at baseline.No new safety findings were observed.Conclusions:These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases.
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 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.
基金supported by the National Natural Science Foundation of China (82170108, 81700092, 81871889, 82072586, 81630071)the Clinical Research Projects in Health industry of Shanghai Municipal Health Commission (202340017)+6 种基金the Foundation of the Center for Medical and Engineering Interdisciplinary Innovation, University of Shanghai for Science and Technology (2023GD-XK08Z)the National Youth Talent (to Z. Wang)Basic Research Foundation of Shanghai Chest Hospital (2020YNJCM05)the National Key Research and Development Project of China (2022YFC2505004, 2022YFC2505000)CAMS Innovation Fund for Medical Sciences (2021-1-I2M-012)CAMS Key lab of translational research on lung cancer (2018PT31035)Beijing Natural Science Foundation (7212084)
文摘In non-small cell lung cancers,the non-squamous and squamous subtypes(nsqNSCLC and sqNSCLC)exhibit disparities in pathophysiology,tumor immunology,and potential genomic correlates affecting responses to immune checkpoint inhibitor(ICI)-based treatments.In our inhouse training cohort(n=85),the presence of the LRP1B deleterious mutation(LRP1B-del)was associated with longer and shorter progression-free survival(PFS)on ICIs alone in nsqNSCLCs and sqNSCLCs,respectively(Pinteraction=0.008).These results were validated using a larger public ICI cohort(n=208,Pinteraction<0.001).Multiplex immunofluorescence staining revealed an association between LRP1B-del and increased and decreased numbers of tumor-infiltrating CD8+T cells in nsqNSCLCs(P=0.040)and sqNSCLCs(P=0.014),respectively.In the POPLAR/OAK cohort,nsqNSCLCs with LRP1B-del demonstrated improved PFS benefits from atezolizumab over docetaxel(hazard ratio(HR)=0.70,P=0.046),whereas this benefit was negligible in those without LRP1B-del(HR=1.05,P=0.64).Conversely,sqNSCLCs without LRP1Bdel benefited more from atezolizumab(HR=0.60,P=0.002)than those with LRP1B-del(HR=1.30,P=0.31).Consistent results were observed in the in-house CHOICE-01 cohort,in which nsqNSCLCs with LRP1B-del and sqNSCLCs without LRP1B-del benefited more from toripalimab plus chemotherapy than from chemotherapy alone(Pinteraction=0.008).This multi-cohort study delineates the antithetical impacts of LRP1Bdel in nsqNSCLCs and sqNSCLCs on predicting the benefits from ICI alone or with chemotherapy over chemotherapy alone.Our findings highlight the distinct clinical utility of LRP1B-del in guiding treatment choices for nsqNSCLCs and sqNSCLCs,emphasizing the necessity for a detailed analysis based on pathological subtypes when investigating biomarkers for cancer therapeutics.
