Background:Epidermal growth factor receptor(EGFR) mutations,including a known exon 19 deletion(19 del) and exon 21 L858 R point mutation(L858R mutation),are strong predictors of the response to EGFR tyrosine kinase in...Background:Epidermal growth factor receptor(EGFR) mutations,including a known exon 19 deletion(19 del) and exon 21 L858 R point mutation(L858R mutation),are strong predictors of the response to EGFR tyrosine kinase inhibitor(EGFR-TKI) treatment in lung adenocarcinoma.However,whether patients carrying EGFR 19 del and L858 R mutations exhibit different responsiveness to EGFR-TKls and what are the potential mechanism for this difference remain controversial.This study aimed to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858 R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes.Methods:Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858 R mutations,532 received EGFR-TKI treatment and were included in this study.EGFR 19 del and L858 R mutations were detected by using denaturing high-performance liquid chromatography(DHPLC).T790 M mutation,which is a common resistant mutation on exon 20 of EGFR,was detected by amplification refractory mutation system(ARMS).Next-generation sequencing(NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858 R mutations.Results:Of the 532 patients,319(60.0%) had EGFR 19 del,and 213(40.0%) had L858 R mutations.The patients with EGFR 19 del presented a significantly higher overall response rate(ORR) for EGFR-TKI treatment(55.2%vs.43.7%,P = 0.017) and had a longer progression-free survival(PFS) after first-line EGFR-TKI treatment(14.4 vs.11.4 months,P = 0.034) compared with those with L858 R mutations.However,no statistically significant difference in overall survival(OS) was observed between the two groups of patients.T790 M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment,and there was no significant difference in the co-existence of T790 M mutation with EGFR 19 del and L858 R mutations before EGFR-TKI treatment(5.6%vs.8.8%,P = 0.554)or after treatment(24.4%vs.35.4%,P = 0.176).In addition,24 patients with EGFR 19 del and 19 with L858 R mutations were analyzed by NGS,and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes.Conclusions:Patients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858 R mutations.Whether the heterogeneity of tumors with EGFR 19 del and L858 R mutations contribute to a therapeutic response difference needs further investigation.展开更多
Objective： Combined overall survival （OS） analysis of Lux-Lung 3 and Lux-Lung 6 demonstrated that patients with epidermal growth factor receptor （EGFR） exon 19 deletions （Del19） would benefit from first-line se...Objective： Combined overall survival （OS） analysis of Lux-Lung 3 and Lux-Lung 6 demonstrated that patients with epidermal growth factor receptor （EGFR） exon 19 deletions （Del19） would benefit from first-line second generation EGFR tyrosine kinase inhibitors （TKIs） afatinib but not for those with L858R. This study was to investigate the survival difference between first-line first generation EGFR-TKIs and chemotherapy in patients with either Del19 or L858R, and to directly compare OS in these two mutation groups. Methods： Eligibles were all prospective and retrospective studies comparing EGFR-TKIs with conventional chemotherapy or receiving single agent EGFR-TKIs and demonstrating survival analysis based on mutation types. The primary outcome was OS measured as pooled hazard ratios （HRs）. All measures were pooled using random- effects models and 95% confidential interval （95% CI） was calculated. Results： A total of 14 studies incorporating 1,706 patients with either Del19 or L858R were included. Enrolling patients with Del19 or L858R in randomized controlled trials （RCTs）, first-line first generation EGFR-TKIs were associated with no OS benefit, compared with chemotherapy （pooled HR_TKI/Chemo for Del19： 0.82, 95% CI： 0.64- 1.06, P=0.14; pooled HR_TKI/Chemo for L858R： 1.15, 95% CI： 0.85-1.56, P=0.38）. Direct comparison of Del19 with L858R receiving with first-line first generation EGFR-TKIs demonstrated no significant survival difference （pooled HR19/21： 0.88, 95% CI： 0.67-1.16, P=0.37）. Conclusions： Among patients with advanced non-small cell hmg cancer （NSCLC） harboring Del19 and L858R, first-line first generation EGFR-TKIs demonstrated no survival benefit comparing with chemotherapy. Direct comparison between Del19 and L858R revealed no significant survival difference after first-line first generation EGFR-TKIs.展开更多
目的比较一代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)联合化疗对两种表皮生长因子受体(EGFR)经典突变非小细胞肺癌(NSCLC)的疗效。方法选取2017年4月至2019年12月郑州大学第一附属医院肿瘤科收治的34例EGFR经典突变的晚期NSCLC患...目的比较一代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)联合化疗对两种表皮生长因子受体(EGFR)经典突变非小细胞肺癌(NSCLC)的疗效。方法选取2017年4月至2019年12月郑州大学第一附属医院肿瘤科收治的34例EGFR经典突变的晚期NSCLC患者。患者均接受一代EGFR-TKIs联合化疗治疗。按基因突变种类将患者分为两组,即EGFR基因19外显子缺失突变(19Del突变)为A组(18例),EGFR基因21外显子L858R点突变(21L858R突变)为B组(16例)。研究的主要终点为中位无进展生存时间(PFS)和1 a PFS率,次要终点为客观缓解率(ORR)。比较两组不良反应。结果治疗后,B组ORR[25.0%(4/16)]较A组[88.9%(16/18)]低(P<0.05)。B组1 a PFS率[25.0%(4/16)]与A组[44.4%(8/18)]比较,差异无统计学意义(P>0.05)。B组中位PFS短于A组(P<0.05)。两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论接受一代EGFR-TKIs联合化疗治疗的EGFR基因19Del突变的NSCLC患者较EGFR基因21L858R突变患者的PFS更长。展开更多
BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine-kinase inhibitors are widely used for the treatment of non-small-cell lung cancer with EGFR mutations.However,patients with rare,even compound EGFR mutations h...BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine-kinase inhibitors are widely used for the treatment of non-small-cell lung cancer with EGFR mutations.However,patients with rare,even compound EGFR mutations have different responses to EGFR-tyrosine-kinase inhibitors,which bring uncertainty to clinical treatment.CASE SUMMARY A 45-year-old female patient presented with a 3-mo history of cough and white sputum without chest pain.Chest computed tomography revealed lung spaceoccupying lesions and multiple lymphadenectasis.Bronchoscopy and pathology suggested lung adenocarcinoma.Compound variation of EGFR gene(exon 21 L858 R/V834 L)was detected in both tissue and circulating tumor deoxyribonucleic acid samples.As a result of next-generation sequencing and her family’s wishes,the patient was given oral treatment with icotinib hydrochloride(125 mg/d,tid)from March 21,2019 and has achieved stable disease for the last 1 year.CONCLUSION Non-small cell lung adenocarcinoma with EGFR L858 R/V834 L was treated successfully with icotinib,and it may be a new medication treatment option.展开更多
Based on our previous work,a series of hydrazone moiety-bearing aminopyrimidines were synthesized.The compounds were evaluated for inhibitory activities against EGFRT790M/L858 R and antiproliferative activities agains...Based on our previous work,a series of hydrazone moiety-bearing aminopyrimidines were synthesized.The compounds were evaluated for inhibitory activities against EGFRT790M/L858 R and antiproliferative activities against H1975 and A549 NSCLC cell lines harboring different forms of EGFR.Compounds 7f and7 k exhibited potent and selective activity in inhibition of gefitinib-resistant H1975 cancer cells（IC50;0.45,0.2μmol/L） while were much less active on A549 cancer cells（IC50;52.83,〉100μmol/L）.Both compounds could be served as promising lead compounds for further investigation.展开更多
Objective: to systematically evaluate and compare the efficacy and safety of 14 treatment options in patients with EGFR 19DEL mutation and EGFR 21L858R mutation in non-small cell lung cancer. Methods: the Pubmed, Coch...Objective: to systematically evaluate and compare the efficacy and safety of 14 treatment options in patients with EGFR 19DEL mutation and EGFR 21L858R mutation in non-small cell lung cancer. Methods: the Pubmed, Cochrane, Embase database and ASCO, ESMO, and WCLC conferences were retrieved to collect clinical randomized controlled trials (RCT) of first-line EGFR-related non-small cell lung cancer with TKIs. Based on the grouping of EGFR mutation types, Bayesian mesh meta-analysis (NMA) was performed by using GEMTC package Markov chain Monte Carlosimulation with R software, comparing the difference between progression-free survival (PFS) and grade 3 or above adverse reactions (≥3AES) in EGFR 19DEL and EGFR 21L858R mutations in patients with each treatment regimen. In addition, the efficacy and safety of the 14 treatment options were ranked according to the cumulative area of SUCRA (EGFR mutation type).Results: a total of 22 RCTs were included in the study, involving 14 treatment regimens. NMA results showed that for patients with EGFR 19DEL mutation, all EGFR TKIs related treatment schemes could prolong PFS more than chemotherapy, especially AUM and OSI (AUM vs PB:HR 0.17, 95%CI 0.08 ~ 0.35;OSI vs PB:HR 0.18, 95%CI 0.08 ~ 0.38);For patients with EGFR 21L858R mutation, GEF+PB and OSI could prolong PFS most (GEF+PB vs PB:HR 0.30, 95%CI 0.14 ~ 0.56;OSI vs PB:HR 0.35, 95%CI 0.15 ~ 0.74). Sucra ranking results showed that for patients with EGFR 19DEL mutation, AUM, OSI, GEF+PB ranked first, second and third in PFS respectively, while for patients with EGFR 21L858R mutation, the top three schemes were GEF+PB, OSI and ERL+BEV respectively. Conclusion: AUM and GEF+PB are the best treatment options for patients with EGFR 19DEL mutation and EGFR 21L858R mutation, respectively.展开更多
基金supported by grants from the National Natural Sciences Foundation Key Program(No.81330062)Education Ministry Innovative Research Team Program(No.IRT13003)+1 种基金Peking University-Tsinghua University Joint Center for Life Sciences Clinical Investigator,National High Technology Research and Development Program 863(No.SS2015AA020403)Beijing Technology Project(No.Z141100000214013)
文摘Background:Epidermal growth factor receptor(EGFR) mutations,including a known exon 19 deletion(19 del) and exon 21 L858 R point mutation(L858R mutation),are strong predictors of the response to EGFR tyrosine kinase inhibitor(EGFR-TKI) treatment in lung adenocarcinoma.However,whether patients carrying EGFR 19 del and L858 R mutations exhibit different responsiveness to EGFR-TKls and what are the potential mechanism for this difference remain controversial.This study aimed to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858 R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes.Methods:Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858 R mutations,532 received EGFR-TKI treatment and were included in this study.EGFR 19 del and L858 R mutations were detected by using denaturing high-performance liquid chromatography(DHPLC).T790 M mutation,which is a common resistant mutation on exon 20 of EGFR,was detected by amplification refractory mutation system(ARMS).Next-generation sequencing(NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858 R mutations.Results:Of the 532 patients,319(60.0%) had EGFR 19 del,and 213(40.0%) had L858 R mutations.The patients with EGFR 19 del presented a significantly higher overall response rate(ORR) for EGFR-TKI treatment(55.2%vs.43.7%,P = 0.017) and had a longer progression-free survival(PFS) after first-line EGFR-TKI treatment(14.4 vs.11.4 months,P = 0.034) compared with those with L858 R mutations.However,no statistically significant difference in overall survival(OS) was observed between the two groups of patients.T790 M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment,and there was no significant difference in the co-existence of T790 M mutation with EGFR 19 del and L858 R mutations before EGFR-TKI treatment(5.6%vs.8.8%,P = 0.554)or after treatment(24.4%vs.35.4%,P = 0.176).In addition,24 patients with EGFR 19 del and 19 with L858 R mutations were analyzed by NGS,and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes.Conclusions:Patients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858 R mutations.Whether the heterogeneity of tumors with EGFR 19 del and L858 R mutations contribute to a therapeutic response difference needs further investigation.
文摘Objective： Combined overall survival （OS） analysis of Lux-Lung 3 and Lux-Lung 6 demonstrated that patients with epidermal growth factor receptor （EGFR） exon 19 deletions （Del19） would benefit from first-line second generation EGFR tyrosine kinase inhibitors （TKIs） afatinib but not for those with L858R. This study was to investigate the survival difference between first-line first generation EGFR-TKIs and chemotherapy in patients with either Del19 or L858R, and to directly compare OS in these two mutation groups. Methods： Eligibles were all prospective and retrospective studies comparing EGFR-TKIs with conventional chemotherapy or receiving single agent EGFR-TKIs and demonstrating survival analysis based on mutation types. The primary outcome was OS measured as pooled hazard ratios （HRs）. All measures were pooled using random- effects models and 95% confidential interval （95% CI） was calculated. Results： A total of 14 studies incorporating 1,706 patients with either Del19 or L858R were included. Enrolling patients with Del19 or L858R in randomized controlled trials （RCTs）, first-line first generation EGFR-TKIs were associated with no OS benefit, compared with chemotherapy （pooled HR_TKI/Chemo for Del19： 0.82, 95% CI： 0.64- 1.06, P=0.14; pooled HR_TKI/Chemo for L858R： 1.15, 95% CI： 0.85-1.56, P=0.38）. Direct comparison of Del19 with L858R receiving with first-line first generation EGFR-TKIs demonstrated no significant survival difference （pooled HR19/21： 0.88, 95% CI： 0.67-1.16, P=0.37）. Conclusions： Among patients with advanced non-small cell hmg cancer （NSCLC） harboring Del19 and L858R, first-line first generation EGFR-TKIs demonstrated no survival benefit comparing with chemotherapy. Direct comparison between Del19 and L858R revealed no significant survival difference after first-line first generation EGFR-TKIs.
文摘目的比较一代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)联合化疗对两种表皮生长因子受体(EGFR)经典突变非小细胞肺癌(NSCLC)的疗效。方法选取2017年4月至2019年12月郑州大学第一附属医院肿瘤科收治的34例EGFR经典突变的晚期NSCLC患者。患者均接受一代EGFR-TKIs联合化疗治疗。按基因突变种类将患者分为两组,即EGFR基因19外显子缺失突变(19Del突变)为A组(18例),EGFR基因21外显子L858R点突变(21L858R突变)为B组(16例)。研究的主要终点为中位无进展生存时间(PFS)和1 a PFS率,次要终点为客观缓解率(ORR)。比较两组不良反应。结果治疗后,B组ORR[25.0%(4/16)]较A组[88.9%(16/18)]低(P<0.05)。B组1 a PFS率[25.0%(4/16)]与A组[44.4%(8/18)]比较,差异无统计学意义(P>0.05)。B组中位PFS短于A组(P<0.05)。两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论接受一代EGFR-TKIs联合化疗治疗的EGFR基因19Del突变的NSCLC患者较EGFR基因21L858R突变患者的PFS更长。
文摘BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine-kinase inhibitors are widely used for the treatment of non-small-cell lung cancer with EGFR mutations.However,patients with rare,even compound EGFR mutations have different responses to EGFR-tyrosine-kinase inhibitors,which bring uncertainty to clinical treatment.CASE SUMMARY A 45-year-old female patient presented with a 3-mo history of cough and white sputum without chest pain.Chest computed tomography revealed lung spaceoccupying lesions and multiple lymphadenectasis.Bronchoscopy and pathology suggested lung adenocarcinoma.Compound variation of EGFR gene(exon 21 L858 R/V834 L)was detected in both tissue and circulating tumor deoxyribonucleic acid samples.As a result of next-generation sequencing and her family’s wishes,the patient was given oral treatment with icotinib hydrochloride(125 mg/d,tid)from March 21,2019 and has achieved stable disease for the last 1 year.CONCLUSION Non-small cell lung adenocarcinoma with EGFR L858 R/V834 L was treated successfully with icotinib,and it may be a new medication treatment option.
基金supported by grants from Science Foundation of Shenyang Pharmaceutical University(No.QNJJ2014502)
文摘Based on our previous work,a series of hydrazone moiety-bearing aminopyrimidines were synthesized.The compounds were evaluated for inhibitory activities against EGFRT790M/L858 R and antiproliferative activities against H1975 and A549 NSCLC cell lines harboring different forms of EGFR.Compounds 7f and7 k exhibited potent and selective activity in inhibition of gefitinib-resistant H1975 cancer cells（IC50;0.45,0.2μmol/L） while were much less active on A549 cancer cells（IC50;52.83,〉100μmol/L）.Both compounds could be served as promising lead compounds for further investigation.
文摘Objective: to systematically evaluate and compare the efficacy and safety of 14 treatment options in patients with EGFR 19DEL mutation and EGFR 21L858R mutation in non-small cell lung cancer. Methods: the Pubmed, Cochrane, Embase database and ASCO, ESMO, and WCLC conferences were retrieved to collect clinical randomized controlled trials (RCT) of first-line EGFR-related non-small cell lung cancer with TKIs. Based on the grouping of EGFR mutation types, Bayesian mesh meta-analysis (NMA) was performed by using GEMTC package Markov chain Monte Carlosimulation with R software, comparing the difference between progression-free survival (PFS) and grade 3 or above adverse reactions (≥3AES) in EGFR 19DEL and EGFR 21L858R mutations in patients with each treatment regimen. In addition, the efficacy and safety of the 14 treatment options were ranked according to the cumulative area of SUCRA (EGFR mutation type).Results: a total of 22 RCTs were included in the study, involving 14 treatment regimens. NMA results showed that for patients with EGFR 19DEL mutation, all EGFR TKIs related treatment schemes could prolong PFS more than chemotherapy, especially AUM and OSI (AUM vs PB:HR 0.17, 95%CI 0.08 ~ 0.35;OSI vs PB:HR 0.18, 95%CI 0.08 ~ 0.38);For patients with EGFR 21L858R mutation, GEF+PB and OSI could prolong PFS most (GEF+PB vs PB:HR 0.30, 95%CI 0.14 ~ 0.56;OSI vs PB:HR 0.35, 95%CI 0.15 ~ 0.74). Sucra ranking results showed that for patients with EGFR 19DEL mutation, AUM, OSI, GEF+PB ranked first, second and third in PFS respectively, while for patients with EGFR 21L858R mutation, the top three schemes were GEF+PB, OSI and ERL+BEV respectively. Conclusion: AUM and GEF+PB are the best treatment options for patients with EGFR 19DEL mutation and EGFR 21L858R mutation, respectively.
