Tyrosine kinase inhibitors(TKIs)have emerged as the first-line small molecule drugs in many cancer therapies,exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine...Tyrosine kinase inhibitors(TKIs)have emerged as the first-line small molecule drugs in many cancer therapies,exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways.However,there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites,which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments,alongside other potential side effects or adverse reactions.Therefore,an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods,clinical pharmacokinetics,and therapeutic drug monitoring of different TKIs.This paper provides a comprehensive overview of the advancements in pretreatment methods,such as protein precipitation(PPT),liquid-liquid extraction(LLE),solid-phase extraction(SPE),micro-SPE(μ-SPE),magnetic SPE(MSPE),and vortex-assisted dispersive SPE(VA-DSPE)achieved since 2017.It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography(HPLC)and high-resolution mass spectrometry(HRMS)methods,capillary electrophoresis(CE),gas chromatography(GC),supercritical fluid chromatography(SFC)procedures,surface plasmon resonance(SPR)assays as well as novel nanoprobes-based biosensing techniques.In addition,a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.展开更多
Objective： A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase （PI3K） and mitogen-activated protein kinase （MAPK） pathways on the...Objective： A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase （PI3K） and mitogen-activated protein kinase （MAPK） pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor （EGFR-TKI） treatment of non-small cell lung cancer （NSCLC） patients. Methods： Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios （ORs） for objective response rate （ORR） and hazard ratios （HRs） for progression-free survival （PFS） and overall survival （OS） were calculated. Results： Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval （CI）, 0.13-0.35], shorter PFS （HR =1.56; 95% CI, 1.27-1.92）, and shorter OS （HR =1.59; 95% CI, 1.33-1.91） in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA significantly predicted shorter OS （HR =1.83; 95% CI, 1.05-3.20）, showed poor ORR （OK =0.70; 95% CI, 0.22-2.18）, and shorter PFS （HR = 1.79; 95% CI, 0.91-3.53） in NSCLC patients treated with EGFR-TKIs. Conclusion： K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR- TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.展开更多
As of today, only two antiangiogenic monoclonal antibodies plus epidermal growth factor receptor-tyrosine kinaseinhibitor (EGFR-TKI) combinations are FDA and EMA-approved and are recommended by American Society ofClin...As of today, only two antiangiogenic monoclonal antibodies plus epidermal growth factor receptor-tyrosine kinaseinhibitor (EGFR-TKI) combinations are FDA and EMA-approved and are recommended by American Society ofClinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network for thefirst-line treatment of EGFR+ advanced non-small cell lung cancer patients: erlotinib plus bevacizumab anderlotinib plus ramucirumab. However, all treated patients eventually become unresponsive to such drugs, due toseveral different acquired resistance mechanisms, mainly represented by T790M substitutions and METamplifications. While osimertinib treatment in T790M+ patients still represents the only approved treatment,MET-TKIs will likely change this status quo in the near future. In fact, existing clinical data strongly support a rolefor MET-TKI-based combinations in EGFR+ MET-amplified patients, possibly revolutionizing our current treatmentalgorithm. Chemotherapy plus immunotherapy plus antiangiogenic therapy combinations could also representanother useful addition.展开更多
The effect of immune‐based therapies on patients with epidermal growth factor receptor(EGFR)-positive advanced non-small cell lung cancer(NSCLC)resistant to EGFR tyrosine kinase inhibitor(TKI)therapy remains unclear....The effect of immune‐based therapies on patients with epidermal growth factor receptor(EGFR)-positive advanced non-small cell lung cancer(NSCLC)resistant to EGFR tyrosine kinase inhibitor(TKI)therapy remains unclear.The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart,an anti-programmed cell death ligand 1 antibody,and anlotinib,a small-molecule multi-target anti-angiogenic TKI,in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy.Patients were enrolled in a phase I/II study.In phase I(dose-escalation),patients received anlotinib(8,10,12 mg)plus benmelstobart(1200 mg).Recommended phase II dose,determined during phase I,was used in phase II dose-expansion cohort.Primary endpoints were maximum tolerable dose in phase I and progression-free survival(PFS)in phase II.At the data cutoff date(March 10,2024),55 patients were enrolled in phase II dose-expansion cohort.Median PFS of patients included in phase II cohort was 9.0 months,median overall survival was 28.9 months,objective response rate was 25.5%,disease control rate was 87.3%,and median duration of response was 19.8 months.Incidence of grade≥3 treatment-related adverse events in study population was 25.5%(14/55),whereas grade≥3 immune-related adverse events occurred in 10.9%(6/55)of patients.Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile,supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy.Trial Registration:ChiCTR1900026273.展开更多
Background Lung adenocarcinoma(LUAD)is the most predominant histological subtype of lung cancer character-ized by driver mutations detected in a substantial proportion of the cases.Tyrosine kinase inhibitors(TKIs)are ...Background Lung adenocarcinoma(LUAD)is the most predominant histological subtype of lung cancer character-ized by driver mutations detected in a substantial proportion of the cases.Tyrosine kinase inhibitors(TKIs)are stand-ard care for the patients with these mutations.In this study,we evaluated the efficiency of an NGS-based 8-gene test in selecting TKIs-sensitive patients in a cohort of treatment-naive Chinese LUAD patients and evaluated the sensitivity of rare compound mutations to different EGFR-TKIs in vitro.Material and methods Targeted sequencing covering the hotspot regions of eight LUAD driver genes was per-formed across 853 treatment-naive LUAD patients admitted in Henan Cancer Hospital(HNCH cohort).The mutational landscape of HNCH patients was compared with TCGA patients.Logistic regression analysis was used to determine the factors associated with presence of these mutations.Genetically modified LUAD PC9 cells were established to evaluate the sensitivity of selected EGFR rare compound mutations to different EGFR-TKIs.Results A total of 574 single nucleotide variants(SNVs),270 indels,88 amplifications,and 87 rearrangements were identified in this study,with EGFR and KRAS being the most frequently mutated genes.Females,mostly life-long non-smokers,had significantly higher EGFR mutation rates than males.Males,primarily smokers,more frequently had KRAS mutations.HNCH patients in general had a higher mutation count than TCGA patients(1.09 vs 0.93 mutations per patient(m/p)),in consistent with its higher proportion of patients with advanced disease.Rare EGFR compound mutations identified in this study,including Exon19del plus L747S/I744V and L858R plus V843I/T854A/G873,conferred genetically modified PC9 cells more sensitive to second-generation EGFR-TKI afatinib in-vivo.Conclusion This NGS-based 8-gene test efficiently identified over 70%of Chinese treatment-naive LUAD patients who are targetable for TKIs.Patients with rare EGFR compound mutations might consider second-generation EGFR-TKIs for treatment.展开更多
Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),h...Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),have demonstrated promise but encounter resistance challenges.Erlotinib(ER),a widely used EGFR TKI,often faces the emergence of resistance^([1]).Th erefore,understanding therapeutic targets for ER resistance is crucial.AKR1C3 plays a pivotal role as a key enzyme in the biosynthesis of androgens,serving as a regulator of hormone activity and prostaglandin F synthase.展开更多
Epidermal growth factor receptor(EGFR)mutations are among the most prevalent driver gene alterations in non-small cell lung cancer(NSCLC).Osimertinib,with or without chemotherapy,the first-line standard treatment for ...Epidermal growth factor receptor(EGFR)mutations are among the most prevalent driver gene alterations in non-small cell lung cancer(NSCLC).Osimertinib,with or without chemotherapy,the first-line standard treatment for patients with advanced NSCLC bearing sensitive EGFR mutations,significantly prolongs the progression-free survival(PFS)to 25.5 months1.Despite great breakthroughs in survival data,patients inevitably experience disease progression.A large meta-analysis has indicated that,compared with chemother-apy,immuno-based therapies achieve longer PFS in patients with EGFR mutation who progressed on third-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)2.Therefore,immunotherapies are often used after EGFR-TKI resistance is observed.展开更多
Background:Non-small cell lung cancer(NSCLC)is often accompanied by brain metastasis(BM),and the prognosis of patients with BM is poor.This study assesses the prognostic impact of BM in NSCLC patients with epidermal g...Background:Non-small cell lung cancer(NSCLC)is often accompanied by brain metastasis(BM),and the prognosis of patients with BM is poor.This study assesses the prognostic impact of BM in NSCLC patients with epidermal growth factor receptor(EGFR)mutations.Methods:We retrospectively evaluated 692 advanced NSCLC patients with EGFR mutations treated with tyrosine kinase inhibitors(TKIs)at West China Hospital from 2015 to 2019.The overall survival rate(OS),progression-free survival rate(PFS),objective response rate(ORR),disease control rate(DCR),and clinical parameters of the BM and non-BM groups were compared.Univariable and multivariable regressions were performed to identify independent prognostic factors,followed by validation of a predictive nomogram using receiver operating characteristics and calibration curves.Immune infiltration in tumor tissues was assessed by immunostaining.Results:NSCLC patients with BM exhibited a higher frequency of other-site and multi-organ metastases than those without BM.The BM group demonstrated significantly worse OS(26.2 vs.39.1 months,p<0.001)and PFS(12.3 vs.18.8 months,p<0.001),although the DCR(p=0.831)and ORR(p=0.653)were similar in both groups.BM was identified as an independent predictor of poor prognosis.The nomogram performed well,achieving a C index of 0.73,with consistent calibration curves for predicted and actual prognoses.Additionally,fewer peripheral lymphocytes were observed in the BM group.Conclusions:BM is a significant risk factor for NSCLC patients,potentially linked to lymphocytopenia.展开更多
基金supported by the Natural Science Foundation of Liaoning Province,China(Grant No.:2023-MS-172).
文摘Tyrosine kinase inhibitors(TKIs)have emerged as the first-line small molecule drugs in many cancer therapies,exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways.However,there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites,which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments,alongside other potential side effects or adverse reactions.Therefore,an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods,clinical pharmacokinetics,and therapeutic drug monitoring of different TKIs.This paper provides a comprehensive overview of the advancements in pretreatment methods,such as protein precipitation(PPT),liquid-liquid extraction(LLE),solid-phase extraction(SPE),micro-SPE(μ-SPE),magnetic SPE(MSPE),and vortex-assisted dispersive SPE(VA-DSPE)achieved since 2017.It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography(HPLC)and high-resolution mass spectrometry(HRMS)methods,capillary electrophoresis(CE),gas chromatography(GC),supercritical fluid chromatography(SFC)procedures,surface plasmon resonance(SPR)assays as well as novel nanoprobes-based biosensing techniques.In addition,a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.
基金supported by Key Projects in the National Science & Technology Pillar Program (Grant No. 2013ZX09303001, 2015BAI12B12, and 2015BAI12B15)National Natural Science Foundation of China (Grant No. 81472473 and 81272360)Tianjin Municipal Commission of Science & Technology Key Research Program (Grant No.13ZCZCSY20300)
文摘Objective： A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase （PI3K） and mitogen-activated protein kinase （MAPK） pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor （EGFR-TKI） treatment of non-small cell lung cancer （NSCLC） patients. Methods： Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios （ORs） for objective response rate （ORR） and hazard ratios （HRs） for progression-free survival （PFS） and overall survival （OS） were calculated. Results： Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval （CI）, 0.13-0.35], shorter PFS （HR =1.56; 95% CI, 1.27-1.92）, and shorter OS （HR =1.59; 95% CI, 1.33-1.91） in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA significantly predicted shorter OS （HR =1.83; 95% CI, 1.05-3.20）, showed poor ORR （OK =0.70; 95% CI, 0.22-2.18）, and shorter PFS （HR = 1.79; 95% CI, 0.91-3.53） in NSCLC patients treated with EGFR-TKIs. Conclusion： K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR- TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.
文摘As of today, only two antiangiogenic monoclonal antibodies plus epidermal growth factor receptor-tyrosine kinaseinhibitor (EGFR-TKI) combinations are FDA and EMA-approved and are recommended by American Society ofClinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network for thefirst-line treatment of EGFR+ advanced non-small cell lung cancer patients: erlotinib plus bevacizumab anderlotinib plus ramucirumab. However, all treated patients eventually become unresponsive to such drugs, due toseveral different acquired resistance mechanisms, mainly represented by T790M substitutions and METamplifications. While osimertinib treatment in T790M+ patients still represents the only approved treatment,MET-TKIs will likely change this status quo in the near future. In fact, existing clinical data strongly support a rolefor MET-TKI-based combinations in EGFR+ MET-amplified patients, possibly revolutionizing our current treatmentalgorithm. Chemotherapy plus immunotherapy plus antiangiogenic therapy combinations could also representanother useful addition.
基金funded by the Chia Tai Tianqing Pharmaceutical Group Co.,Ltd.,Jiangsu,China.
文摘The effect of immune‐based therapies on patients with epidermal growth factor receptor(EGFR)-positive advanced non-small cell lung cancer(NSCLC)resistant to EGFR tyrosine kinase inhibitor(TKI)therapy remains unclear.The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart,an anti-programmed cell death ligand 1 antibody,and anlotinib,a small-molecule multi-target anti-angiogenic TKI,in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy.Patients were enrolled in a phase I/II study.In phase I(dose-escalation),patients received anlotinib(8,10,12 mg)plus benmelstobart(1200 mg).Recommended phase II dose,determined during phase I,was used in phase II dose-expansion cohort.Primary endpoints were maximum tolerable dose in phase I and progression-free survival(PFS)in phase II.At the data cutoff date(March 10,2024),55 patients were enrolled in phase II dose-expansion cohort.Median PFS of patients included in phase II cohort was 9.0 months,median overall survival was 28.9 months,objective response rate was 25.5%,disease control rate was 87.3%,and median duration of response was 19.8 months.Incidence of grade≥3 treatment-related adverse events in study population was 25.5%(14/55),whereas grade≥3 immune-related adverse events occurred in 10.9%(6/55)of patients.Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile,supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy.Trial Registration:ChiCTR1900026273.
基金J.Li was supported by Henan Young Researcher training program(HNSWJW-2020007)supported by the Department of Science and Technology of Henan Province(212102310675,201300310400).
文摘Background Lung adenocarcinoma(LUAD)is the most predominant histological subtype of lung cancer character-ized by driver mutations detected in a substantial proportion of the cases.Tyrosine kinase inhibitors(TKIs)are stand-ard care for the patients with these mutations.In this study,we evaluated the efficiency of an NGS-based 8-gene test in selecting TKIs-sensitive patients in a cohort of treatment-naive Chinese LUAD patients and evaluated the sensitivity of rare compound mutations to different EGFR-TKIs in vitro.Material and methods Targeted sequencing covering the hotspot regions of eight LUAD driver genes was per-formed across 853 treatment-naive LUAD patients admitted in Henan Cancer Hospital(HNCH cohort).The mutational landscape of HNCH patients was compared with TCGA patients.Logistic regression analysis was used to determine the factors associated with presence of these mutations.Genetically modified LUAD PC9 cells were established to evaluate the sensitivity of selected EGFR rare compound mutations to different EGFR-TKIs.Results A total of 574 single nucleotide variants(SNVs),270 indels,88 amplifications,and 87 rearrangements were identified in this study,with EGFR and KRAS being the most frequently mutated genes.Females,mostly life-long non-smokers,had significantly higher EGFR mutation rates than males.Males,primarily smokers,more frequently had KRAS mutations.HNCH patients in general had a higher mutation count than TCGA patients(1.09 vs 0.93 mutations per patient(m/p)),in consistent with its higher proportion of patients with advanced disease.Rare EGFR compound mutations identified in this study,including Exon19del plus L747S/I744V and L858R plus V843I/T854A/G873,conferred genetically modified PC9 cells more sensitive to second-generation EGFR-TKI afatinib in-vivo.Conclusion This NGS-based 8-gene test efficiently identified over 70%of Chinese treatment-naive LUAD patients who are targetable for TKIs.Patients with rare EGFR compound mutations might consider second-generation EGFR-TKIs for treatment.
基金supported by the Health and Medical Research Fund,Food and Health Bureau,Hong Kong SAR Government(HMRF 07180186).
文摘Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),have demonstrated promise but encounter resistance challenges.Erlotinib(ER),a widely used EGFR TKI,often faces the emergence of resistance^([1]).Th erefore,understanding therapeutic targets for ER resistance is crucial.AKR1C3 plays a pivotal role as a key enzyme in the biosynthesis of androgens,serving as a regulator of hormone activity and prostaglandin F synthase.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82273162)Jiangsu Cancer Hospital Science and Technology Development Fund Project(Grant No.YSZD202409).
文摘Epidermal growth factor receptor(EGFR)mutations are among the most prevalent driver gene alterations in non-small cell lung cancer(NSCLC).Osimertinib,with or without chemotherapy,the first-line standard treatment for patients with advanced NSCLC bearing sensitive EGFR mutations,significantly prolongs the progression-free survival(PFS)to 25.5 months1.Despite great breakthroughs in survival data,patients inevitably experience disease progression.A large meta-analysis has indicated that,compared with chemother-apy,immuno-based therapies achieve longer PFS in patients with EGFR mutation who progressed on third-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)2.Therefore,immunotherapies are often used after EGFR-TKI resistance is observed.
基金supported by Sichuan Province Central Government Guide Local Science and Technology Development Project(No.2023ZYD0169).
文摘Background:Non-small cell lung cancer(NSCLC)is often accompanied by brain metastasis(BM),and the prognosis of patients with BM is poor.This study assesses the prognostic impact of BM in NSCLC patients with epidermal growth factor receptor(EGFR)mutations.Methods:We retrospectively evaluated 692 advanced NSCLC patients with EGFR mutations treated with tyrosine kinase inhibitors(TKIs)at West China Hospital from 2015 to 2019.The overall survival rate(OS),progression-free survival rate(PFS),objective response rate(ORR),disease control rate(DCR),and clinical parameters of the BM and non-BM groups were compared.Univariable and multivariable regressions were performed to identify independent prognostic factors,followed by validation of a predictive nomogram using receiver operating characteristics and calibration curves.Immune infiltration in tumor tissues was assessed by immunostaining.Results:NSCLC patients with BM exhibited a higher frequency of other-site and multi-organ metastases than those without BM.The BM group demonstrated significantly worse OS(26.2 vs.39.1 months,p<0.001)and PFS(12.3 vs.18.8 months,p<0.001),although the DCR(p=0.831)and ORR(p=0.653)were similar in both groups.BM was identified as an independent predictor of poor prognosis.The nomogram performed well,achieving a C index of 0.73,with consistent calibration curves for predicted and actual prognoses.Additionally,fewer peripheral lymphocytes were observed in the BM group.Conclusions:BM is a significant risk factor for NSCLC patients,potentially linked to lymphocytopenia.
