EGFR-TKI类药物治疗晚期非小细胞肺癌的研究进展
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摘要
表皮生长因子受体酪氨酸激酶抑制剂(epithelialgrowthfactorreceptortyrosinekinaseinhibitors,EGFR-TKI)引领EGFR突变的晚期非小细胞肺癌精准治疗十多年,EGFR-TKI对EGFR常见突变的晚期非小细胞肺癌的疗效已得到明确的证实。然而对于EGFR罕见突变,EGFR-TKI的疗效在临床上存在众多争议。本文列举了目前已经进入临床阶段的EGFR-TKI类药物在EGFR突变阳性晚期非小细胞肺癌中的中位无进展及总生存期并进行比较,增加了EGFR罕见突变对EGFR-TKI疗效的相关研究,以期为临床EGFR-TKI的合理使用提供参考。
Epidermal growth factor tyrosine kinase inhibitors(EGFR-TKI) has continued to lend to the precise treatment of EGFR mutations in advanced non-small cell lung cancer for more than ten years, which the efficacy of EGFR-TKI for patients with common EGFR mutations in advanced NSCLC has been demonstrated clearly. However, for uncommon EGFR mutations, the efficacy of EGFR-TKI is still exist many dispates. This article lists the median progression-free and overall survival of the drugs of EGFR-TKI that have entered the clinical stage in EGFR mutation-positive advanced NSCLC currently making comparisons, and add correlation studies on the efficacy of EGFR-TKI for those patients with uncommon EGFR mutation. It is hoped to provide reference for rational application of EGFR-TKI in clinical.
Epidermal growth factor tyrosine kinase inhibitors(EGFR-TKI) has continued to lend to the precise treatment of EGFR mutations in advanced non-small cell lung cancer for more than ten years, which the efficacy of EGFR-TKI for patients with common EGFR mutations in advanced NSCLC has been demonstrated clearly. However, for uncommon EGFR mutations, the efficacy of EGFR-TKI is still exist many dispates. This article lists the median progression-free and overall survival of the drugs of EGFR-TKI that have entered the clinical stage in EGFR mutation-positive advanced NSCLC currently making comparisons, and add correlation studies on the efficacy of EGFR-TKI for those patients with uncommon EGFR mutation. It is hoped to provide reference for rational application of EGFR-TKI in clinical.
引文
[1]REBECCA L,SIEGEL M P H,KIMBERLY D,et al.Cancer statistics[J].CA Cancer J Clin,2017,67(3):7-30.
[2]CHEN W,ZHENG R,BAADE P D,et al.Cancer statistics in China,2015[J].C A Cancer J Clin,2016,66(2):115-132.
[3]SHI Y,AU J S,THONGPRASERTS,et al.A propective,molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology(P10NEER)[J].J Thorac Oncol,2014,9(2):154-162.
[4]ESTEBAN E,MAJEM M,MARTINEZ AGUILLO M.et al.Prevalence of EGFR mutations in newly diagnosed locally advanced or metastatic non-small cell lung cancer Spanish patients and its association with histological subtypes and clinical features(REASON)[J].Cancer Epidemiol,2015,39(3):291-297.
[5]SIMASI J,SCHUBERT A,OELKRUG C,et al.Primary and secondary resistance to tyrosine kinase inhibitors in lung cancer[J].Anticancer Res,2014,34(6):2841-2850.
[6]LYNCH T J,BELL D W,SORDELLA R,et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib[J].NEngl J Med,2004,350(21):2129-2139.
[7]SHARMA S V,BELL D W,SETTLTMAN J,et al.Epidermal growth factor receptor mutations in lung cancer[J].Nat Rev Cancer,2007,7(3):169-181.
[8]BAEK J H,SUN J M,MIN Y J,et al.Efficacy of EGFRtyrosine kinase inhibitors in patients with EGFR mutated non-small cell lung cancer except both exon 19 deletion and exon 21L858R:a retrospective analysis in Korea[J].Lung Cancer,2015,87(2):148-154.
[9]TAN C S,CHO B C,SOO R A.Nexc-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor-mutant non-small cell lung cancer[J].Lung Cancer,2016(93):59-68.
[10]GAO G H,REN S X,LI A,et al.Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR:A meta-analysis from six phase IIIrandomized controlled trials[J].Int J Cancer,2012,131(5),E822-E829.
[11]SHI Y K,WANG L,HAN B H,et al.First-line icotinib versus cisplatine/pemetrexed plus pemetrexed maintenance therapy in lung adenocarcinoma patients with sensitizing EGFR mutation(CONVINCE)[J].J Clin Oncol,2016,27(suppl_6):1229.
[12]MINARI R,BORDI P,TISEO M,et al.Kinase inhibitors in T790M-positive non-small cell lung cancer:review on emerged mechanisms of resistance[J].Transl Lung Cancer Res,2016,5(6):695-708.
[13]NORMANNO N,MAIELLO MR,CHICCHINELLI N,et al.Targeting the EGFR T790M mutation in non-small-cell lung cancer[J].Expert Opin Ther Targets,2017,21(2):159-165.
[14]YU H A,ARCILA M E,HELLMANN M D,et al.Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing[J].Ann Oncol,2014,25(2):423-428.
[15]KATAKAMI N,ATAGI S,GOTO K,et al.LUX-Lung 4:a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib,gefitinib,or both[J].J Clin Oncol,2013,31(27):3335-3341.
[16]MILLER V A,HIRSH V,CADRANEL J,et al.Afatinib versus placebo for patients with advanced,metastatic non-small-cell lung cancer after failure of erlotinib,gefitinib,or both,and one or two lines of chemotherapy(LUX-Lung 1):a phase 2b/3 randomised trial[J].Lancet Oncol,2012,13(5):528-538.
[17]ELLIS P M,LIU G,MILLWARD M,et al.NCIC CTG BR.26:a phase III randomized,double blind,placebo controlled trial of dacomitinib versus placebo in patients with advanced/metastatic non-small cell lung cancer(NSCLC)who received prior chemotherapy and an EGFR TKI[J].J Clin Oncol,2014,32(Suppl):8036.
[18]PAZARES L,TAN E H,O’BYMEA K,et al.Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer:overall survival data from the phase IIb LUX-Lung 7 trial[J].Ann Oncol,2017,28(2):270-277.
[19]YANG J C,WU Y L,SCHULER M,et al.Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma(LUX-Lung 3 and LUX-Lung 6):analysis of overall survival data from two randomised,phase 3trials[J].Lancet Oncol,2015(16):141-151
[20]MOK T,CHENGN Y,ZHOU X,et al.Dacomitinib versus gefitinib for the first-line treatment of advanced EGFRmutation positive non-small cell lung cancer(ARCHER 1050):A randomized,open-label phase III trial[J].J Clin Oncol,2017,35(18_suppl):LBA9007-LBA9007.
[21]RAMALINGAM S S,O'BYRNE K,BOYER M,et al.Dacomitinib versus erlotinib in patients with EGFR-mutated advanced non-small-cell lung cancer(NSCLC):pooled subset analyses from two randomized trials[J].Ann Oncol,2016,27(3):423-429.
[22]ZHAO P,YAO M Y,ZHU S J,et al.Crystal structure of EGFR T790M/C797S/V948R in complex with EAI045[J].Biochem Biophys Res Commun,2018,502(3):332-337.
[23]JANNE P A,YANG J C,KIM D W,et al.AZD9291 in EGFRinhibitor-resistant non-small-cell lung cancer[J].N Engl JMed,2015;372(18):1689-1699.
[24]CROSS D A,ASHTON S E,GHIORGHIU S,et al.AZD9291,an irreversible EGFR TKI,overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer[J].Cancer Discov,2014,4(9):1046-1061.
[25]GOSS G,TSAI C M,SHEPHERD F A,et al.Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer(AURA2):a multicentre,open-label,single-arm,phase 2 study[J].Lancet Oncol,2016,17(12):1643-1652.
[26]MOK T S,WU Y L,AHN M J,et al.Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer(AURA3)[J].N Engl J Med,2017,376(7):629-640.
[27]PLANCHARD D,BOYER M,LEE J S,et al.128OOsimertinib vs standard of care(SoC)EGFR-TKI as first-line therapy in patients(pts)with untreated EGFRm advanced NSCLC:FLAURA post-progression outcomes[J].J Thoracic Oncol,2018,13(4):S72-S73.
[28]XU X,MAO L,XU W,et al.AC0010,an irreversible EGFRinhibitor selectively targeting mutated EGFR and overcoming T790M-induced resistance in animal models and lung cancer patients[J].Mol Cancer Ther,2016,15(11):2586-2597.
[29]WANG H,ZHANG L,HU P,et al.Penetration of the blood-brain barrier by avitinib and its control of intra/extracranial disease in non-small cell lung cancer harboring the T790M mutation[J].Lung Cancer,2018(122):1-6.
[30]NIEDERST M J,HU H,MULVEY H E,et al.The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies[J].Clin Cancer Res,2015,21(17):3924-3933.
[31]ERCAN D,CHOI H G,YUN C H,et al.EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors[J].Clin Cancer Res,2015,21(17):3913-3923.
[32]WANG S,TSUI S T,LIU C,et al.EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer[J].J Hematol Oncol,201,9(1):59.
[33]JIA Y,YUN C H,PARK E,et al.Overcoming EGFR T790Mand C797S resistance with mutant-selective allosteric inhibitors[J].Nature,2016,534(7605):129-132.
[34]ARRIETA O,CARDONA AF,CORRALES L,et al.The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small cell lung cancer[J].Lung Cancer,2015(87):169-175.
[35]CHEN Y R,FU Y N,LIN C H,et al.Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFRmutants[J].Oncogene,2006,25(8):1205-1215.
[36]KANCHA R K,PESCHEL C,DUYSTER J,et al.The epidermal growth factor receptorL861Q mutation increases kinase activity without leading to enhanced sensitivity toward epidermal growth factor receptor kinase inhibitors[J].J Thorac Oncol,2011(6):387-392.
[37]CHIU C H,YANG C T,SHIH J Y,et al.Epidermal growth factor receptor tyrosine kinase inhibitor treatment response in advanced lung adenocarcinomas with G719X/L861Q/S768Imutations[J].J Thorac Oncol,2015,10(5):793-799.
[38]SHI J P,YANG H,JIANG T,et al.Uncommon EGFRmutations in a cohort of Chinese NSCLC patients and outcomes of first-line EGFR-TKIs and platinumbased chemotherapy[J].Chin J Cancer Res,2017,29(6):543-552.
[39]WU J Y,YU C J,CHANG Y C,et al.Effectiveness of tyrosine kinase inhibitors on“uncommon”epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer[J].Clin Cancer Res,2011,17(11):3812-3821.
[40]WATANABE S,MINEGISHI Y,YOSHIZAWA H,et al.Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q[J].JThoracic Oncol,2014,9(2):189-194.
[41]YANG J C,SEQUIST L V,GEATER S L.Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations:a combined post-hoc analysis of LUX-Lung 2,LUX-Lung 3,and LUX-Lung 6[J].Lancet Oncol,2015,16(7):830-838.
[42]KOBAYASHI Y,MITSUDOMI T.Not all epidermal growth factor receptor mutations in lung cancer are created equal:Perspectives for individualized treatment strategy[J].Cancer Sci,2016,107(9):1179-1186.
[43]JIA Y,JUAREZ J,LI J,et al.EGF816 Exerts anticancer effects in non-small cell lung cancer by irreversibly and selectively targeting primary and acquired activating mutations in the EGF receptor[J].Cancer Res,2016;76(6):1591-1602
[2]CHEN W,ZHENG R,BAADE P D,et al.Cancer statistics in China,2015[J].C A Cancer J Clin,2016,66(2):115-132.
[3]SHI Y,AU J S,THONGPRASERTS,et al.A propective,molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology(P10NEER)[J].J Thorac Oncol,2014,9(2):154-162.
[4]ESTEBAN E,MAJEM M,MARTINEZ AGUILLO M.et al.Prevalence of EGFR mutations in newly diagnosed locally advanced or metastatic non-small cell lung cancer Spanish patients and its association with histological subtypes and clinical features(REASON)[J].Cancer Epidemiol,2015,39(3):291-297.
[5]SIMASI J,SCHUBERT A,OELKRUG C,et al.Primary and secondary resistance to tyrosine kinase inhibitors in lung cancer[J].Anticancer Res,2014,34(6):2841-2850.
[6]LYNCH T J,BELL D W,SORDELLA R,et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib[J].NEngl J Med,2004,350(21):2129-2139.
[7]SHARMA S V,BELL D W,SETTLTMAN J,et al.Epidermal growth factor receptor mutations in lung cancer[J].Nat Rev Cancer,2007,7(3):169-181.
[8]BAEK J H,SUN J M,MIN Y J,et al.Efficacy of EGFRtyrosine kinase inhibitors in patients with EGFR mutated non-small cell lung cancer except both exon 19 deletion and exon 21L858R:a retrospective analysis in Korea[J].Lung Cancer,2015,87(2):148-154.
[9]TAN C S,CHO B C,SOO R A.Nexc-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor-mutant non-small cell lung cancer[J].Lung Cancer,2016(93):59-68.
[10]GAO G H,REN S X,LI A,et al.Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR:A meta-analysis from six phase IIIrandomized controlled trials[J].Int J Cancer,2012,131(5),E822-E829.
[11]SHI Y K,WANG L,HAN B H,et al.First-line icotinib versus cisplatine/pemetrexed plus pemetrexed maintenance therapy in lung adenocarcinoma patients with sensitizing EGFR mutation(CONVINCE)[J].J Clin Oncol,2016,27(suppl_6):1229.
[12]MINARI R,BORDI P,TISEO M,et al.Kinase inhibitors in T790M-positive non-small cell lung cancer:review on emerged mechanisms of resistance[J].Transl Lung Cancer Res,2016,5(6):695-708.
[13]NORMANNO N,MAIELLO MR,CHICCHINELLI N,et al.Targeting the EGFR T790M mutation in non-small-cell lung cancer[J].Expert Opin Ther Targets,2017,21(2):159-165.
[14]YU H A,ARCILA M E,HELLMANN M D,et al.Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing[J].Ann Oncol,2014,25(2):423-428.
[15]KATAKAMI N,ATAGI S,GOTO K,et al.LUX-Lung 4:a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib,gefitinib,or both[J].J Clin Oncol,2013,31(27):3335-3341.
[16]MILLER V A,HIRSH V,CADRANEL J,et al.Afatinib versus placebo for patients with advanced,metastatic non-small-cell lung cancer after failure of erlotinib,gefitinib,or both,and one or two lines of chemotherapy(LUX-Lung 1):a phase 2b/3 randomised trial[J].Lancet Oncol,2012,13(5):528-538.
[17]ELLIS P M,LIU G,MILLWARD M,et al.NCIC CTG BR.26:a phase III randomized,double blind,placebo controlled trial of dacomitinib versus placebo in patients with advanced/metastatic non-small cell lung cancer(NSCLC)who received prior chemotherapy and an EGFR TKI[J].J Clin Oncol,2014,32(Suppl):8036.
[18]PAZARES L,TAN E H,O’BYMEA K,et al.Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer:overall survival data from the phase IIb LUX-Lung 7 trial[J].Ann Oncol,2017,28(2):270-277.
[19]YANG J C,WU Y L,SCHULER M,et al.Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma(LUX-Lung 3 and LUX-Lung 6):analysis of overall survival data from two randomised,phase 3trials[J].Lancet Oncol,2015(16):141-151
[20]MOK T,CHENGN Y,ZHOU X,et al.Dacomitinib versus gefitinib for the first-line treatment of advanced EGFRmutation positive non-small cell lung cancer(ARCHER 1050):A randomized,open-label phase III trial[J].J Clin Oncol,2017,35(18_suppl):LBA9007-LBA9007.
[21]RAMALINGAM S S,O'BYRNE K,BOYER M,et al.Dacomitinib versus erlotinib in patients with EGFR-mutated advanced non-small-cell lung cancer(NSCLC):pooled subset analyses from two randomized trials[J].Ann Oncol,2016,27(3):423-429.
[22]ZHAO P,YAO M Y,ZHU S J,et al.Crystal structure of EGFR T790M/C797S/V948R in complex with EAI045[J].Biochem Biophys Res Commun,2018,502(3):332-337.
[23]JANNE P A,YANG J C,KIM D W,et al.AZD9291 in EGFRinhibitor-resistant non-small-cell lung cancer[J].N Engl JMed,2015;372(18):1689-1699.
[24]CROSS D A,ASHTON S E,GHIORGHIU S,et al.AZD9291,an irreversible EGFR TKI,overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer[J].Cancer Discov,2014,4(9):1046-1061.
[25]GOSS G,TSAI C M,SHEPHERD F A,et al.Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer(AURA2):a multicentre,open-label,single-arm,phase 2 study[J].Lancet Oncol,2016,17(12):1643-1652.
[26]MOK T S,WU Y L,AHN M J,et al.Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer(AURA3)[J].N Engl J Med,2017,376(7):629-640.
[27]PLANCHARD D,BOYER M,LEE J S,et al.128OOsimertinib vs standard of care(SoC)EGFR-TKI as first-line therapy in patients(pts)with untreated EGFRm advanced NSCLC:FLAURA post-progression outcomes[J].J Thoracic Oncol,2018,13(4):S72-S73.
[28]XU X,MAO L,XU W,et al.AC0010,an irreversible EGFRinhibitor selectively targeting mutated EGFR and overcoming T790M-induced resistance in animal models and lung cancer patients[J].Mol Cancer Ther,2016,15(11):2586-2597.
[29]WANG H,ZHANG L,HU P,et al.Penetration of the blood-brain barrier by avitinib and its control of intra/extracranial disease in non-small cell lung cancer harboring the T790M mutation[J].Lung Cancer,2018(122):1-6.
[30]NIEDERST M J,HU H,MULVEY H E,et al.The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies[J].Clin Cancer Res,2015,21(17):3924-3933.
[31]ERCAN D,CHOI H G,YUN C H,et al.EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors[J].Clin Cancer Res,2015,21(17):3913-3923.
[32]WANG S,TSUI S T,LIU C,et al.EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer[J].J Hematol Oncol,201,9(1):59.
[33]JIA Y,YUN C H,PARK E,et al.Overcoming EGFR T790Mand C797S resistance with mutant-selective allosteric inhibitors[J].Nature,2016,534(7605):129-132.
[34]ARRIETA O,CARDONA AF,CORRALES L,et al.The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small cell lung cancer[J].Lung Cancer,2015(87):169-175.
[35]CHEN Y R,FU Y N,LIN C H,et al.Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFRmutants[J].Oncogene,2006,25(8):1205-1215.
[36]KANCHA R K,PESCHEL C,DUYSTER J,et al.The epidermal growth factor receptorL861Q mutation increases kinase activity without leading to enhanced sensitivity toward epidermal growth factor receptor kinase inhibitors[J].J Thorac Oncol,2011(6):387-392.
[37]CHIU C H,YANG C T,SHIH J Y,et al.Epidermal growth factor receptor tyrosine kinase inhibitor treatment response in advanced lung adenocarcinomas with G719X/L861Q/S768Imutations[J].J Thorac Oncol,2015,10(5):793-799.
[38]SHI J P,YANG H,JIANG T,et al.Uncommon EGFRmutations in a cohort of Chinese NSCLC patients and outcomes of first-line EGFR-TKIs and platinumbased chemotherapy[J].Chin J Cancer Res,2017,29(6):543-552.
[39]WU J Y,YU C J,CHANG Y C,et al.Effectiveness of tyrosine kinase inhibitors on“uncommon”epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer[J].Clin Cancer Res,2011,17(11):3812-3821.
[40]WATANABE S,MINEGISHI Y,YOSHIZAWA H,et al.Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q[J].JThoracic Oncol,2014,9(2):189-194.
[41]YANG J C,SEQUIST L V,GEATER S L.Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations:a combined post-hoc analysis of LUX-Lung 2,LUX-Lung 3,and LUX-Lung 6[J].Lancet Oncol,2015,16(7):830-838.
[42]KOBAYASHI Y,MITSUDOMI T.Not all epidermal growth factor receptor mutations in lung cancer are created equal:Perspectives for individualized treatment strategy[J].Cancer Sci,2016,107(9):1179-1186.
[43]JIA Y,JUAREZ J,LI J,et al.EGF816 Exerts anticancer effects in non-small cell lung cancer by irreversibly and selectively targeting primary and acquired activating mutations in the EGF receptor[J].Cancer Res,2016;76(6):1591-1602