非小细胞肺癌分子靶向治疗研究进展
摘要
肺癌是全球范围内肿瘤相关死亡的首要原因,其中80%～85%为非小细胞肺癌(NSCLC)。近年来,随着分子靶向药物治疗进展,NSCLC患者的生存时间不断延长。因其具有显著的疗效和较低的毒性,部分分子靶向药物已取代传统化疗成为标准一线治疗药物。但由于难以避免的获得性耐药,大多数患者在几年内出现复发进展。近年来用于克服耐药的新一代靶向药物也陆续问世,并获得了显著的疗效。本文主要综述目前NSCLC中明确的驱动基因及相应分子靶向治疗药物临床应用进展。
引文
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[21]SORIA J C,OHE Y,VANSTEENKISTE J,et al.Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer[J].N Engl J Med,2018,378(2):113-125.
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[29]KIM H R,KIM W S,CHOI Y J,et al.Epithelial-mesenchymal transition leads to crizotinib resistance in H2228lung cancer cells with EML4-ALK translocation[J].Mol Oncol,2013,7(6):1093-1102.
[30]CRYSTAL A S,SHAW A T,SEQUIST L V,et al.Patient-derived models of acquired resistance can identify effective drug combinations for cancer[J].Science,2014,346(6216):1480-1486.
[31]TANIZAKI J,OKAMOTO I,OKABE T,et al.Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK-positive non-small cell lung cancer[J].Clin Cancer Res,2012,18(22):6219-6226.
[32]MIYAWAKI M,YASUDA H,TANI T,et al.Overcoming EGFR bypass signal-induced acquired resistance to ALKtyrosine kinase inhibitors in ALK-translocated lung cancer[J].Mol Cancer Res,2017,15(1):106-114.
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[34]SHAW A T,KIM D W,MEHRA R,et al.Ceritinib in ALK-rearranged non-small-cell lung cancer[J].N Engl J Med,2014,370(13):1189-1197.
[35]SORIA J C,TAN D S W,CHIARI R,et al.First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer(ASCEND-4):A randomised,open-label,phase 3study[J].Lancet,2017,389(10072):917-929.
[36]PETERS S,CAMIDGE D R,SHAW A T,et al.Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer[J].N Engl J Med,2017,377(9):829-838.
[37]ZOU H Y,FRIBOULET L,KODACK D P,et al.PF-06463922,an ALK/ROS1inhibitor,overcomes resistance to first and second generation ALK inhibitors in preclinical models[J].Cancer Cell,2015,28(1):70-81.
[38]SHAW A T,FELIP E,BAUER T M,et al.Lorlatinib in non-small-cell lung cancer with ALK or ROS1rearrangement:An international,multicentre,open-label,single-arm first-inman phase1trial[J].Lancet Oncol,2017,18(12):1590-1599.
[39]YODA S,LIN J J,LAWRENCE M S,et al.Sequential ALKinhibitors can select for lorlatinib-resistant compound ALKmutations in ALK-positive lung cancer[J].Cancer Discov,2018,8(6):714-729.
[40]RIKOVA K,GUO A,ZENG Q,et al.Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer[J].Cell,2007,131(6):1190-1203.
[41]SHAW A T,OU S H,BANG Y J,et al.Crizotinib in ROS1-rearranged non-small-cell lung cancer[J].N Engl J Med,2014,371(21):1963-1971.
[42]WU Y L,YANG J C,KIM D W,et al.PhaseⅡstudy of crizotinib in east Asian patients with ROS1-positive advanced non-small-cell lung cancer[J].J Clin Oncol,2018,36(14):1405-1411.
[43]KATAYAMA R,KOBAYASHI Y,FRIBOULET L,et al.Cabozantinib overcomes crizotinib resistance in ROS1fusionpositive cancer[J].Clin Cancer Res,2015,21(1):166-174.
[44]CHONG C R,BAHCALL M,CAPELLETTI M,et al.Identification of existing drugs that effectively target NTRK1and ROS1rearrangements in lung cancer[J].Clin Cancer Res,2017,23(1):204-213.
[45]CUI J J,ZHAI D Y,DENG W,et al.P3.02a-009 TPX-0005:A multi-faceted approach to overcoming clinical resistances from current ALK or ROS1inhibitor treatment in lung cancer topic:ALK biomarkers[J].J Thorac Oncol,2017,12(1):S1164-S1165.
[46]PLANCHARD D,SMIT E F,GROEN H J M,et al.Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer:An open-label,phase 2trial[J].Lancet Oncol,2017,18(10):1307-1316.
[47]ABRAVANEL D L,NISHINO M,SHOLL L M,et al.An acquired NRAS Q61K mutation in BRAF V600E-mutant lung adenocarcinoma resistant to dabrafenib plus trametinib[J].J Thorac Oncol,2018,13(8):e131-e133.
[48]GAUTSCHI O,MILIA J,FILLERON T,et al.Targeting RET in patients with RET-rearranged lung cancers:Results from the global,multicenter RET registry[J].J Clin Oncol,2017,35(13):1403-1410.
[49]YOH K,SETO T,SATOUCHI M,et al.Vandetanib in patients with previously treated RET-rearranged advanced nonsmall-cell lung cancer(luret):An open-label,multicentre phase 2trial[J].Lancet Respir Med,2017,5(1):42-50.
[50]SUBBIAH V,GAINOR J F,RAHAL R,et al.Precision targeted therapy with BLU-667for RET-driven cancers[J].Can-cer Discov,2018,8(7):836-849.
[51]DRILON A E,SUBBIAH V,OXNARD G R,et al.A phase 1study of LOXO-292,apotent and highly selective RET inhibitor,in patients with RET-altered cancers[J].J Clin Oncol,2018,36(15_suppl):102.
[52]SCHROCK A B,FRAMPTON G M,SUH J,et al.Characterization of 298 patients with lung cancer harboring METexon 14skipping alterations[J].J Thorac Oncol,2016,11(9):1493-1502.
[2]FUKUOKA M,YANO S,GIACCONE G,et al.Multi-institutional randomized phaseⅡtrial of gefitinib for previously treated patients with advanced non-small-cell lung cancer(the IDEAL 1trial)[J].J Clin Oncol,2003,21(12):2237-2246.
[3]GATZEMEIER U,PLUZANSKA A,SZCZESNA A,et al.PhaseⅢstudy of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer:The tarceva lung cancer investigation trial[J].J Clin Oncol,2007,25(12):1545-1552.
[4]KIM E S,HIRSH V,MOK T,et al.Gefitinib versus docetaxel in previously treated non-small-cell lung cancer(interest):A randomised phaseⅢtrial[J].Lancet,2008,372(9652):1809-1818.
[5]THATCHER N,CHANG A,PARIKH P,et al.Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer:Results from a randomised,placebo-controlled,multicentre study(iressa survival evaluation in lung cancer)[J].Lancet,2005,366(9496):1527-1537.
[6]FUJIWARA K,KIURA K,UEOKA H,et al.Dramatic effect of ZD1839(‘Iressa’)in a patient with advanced nonsmall-cell lung cancer and poor performance status[J].Lung Cancer,2003,40(1):73-76.
[7]PAEZ J G,JNNE P A,LEE J C,et al.EGFR mutations in lung cancer:Correlation with clinical response to gefitinib therapy[J].Science,2004,304(5676):1497-1500.
[8]MORITA S,OKAMOTO I,KOBAYASHI K,et al.Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations[J].Clin Cancer Res,2009,15(13):4493-4498.
[9]ROSELL R,CARCERENY E,GERVAIS R,et al.Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive nonsmall-cell lung cancer(eurtac):A multicentre,open-label,randomised phase 3trial[J].Lancet Oncol,2012,13(3):239-246.
[10]KOBAYASHI S,BOGGON T J,DAYARAM T,et al.EGFRmutation and resistance of non-small-cell lung cancer to gefitinib[J].N Engl J Med,2005,352(8):786-792.
[11]YU H A,ARCILA M E,REKHTMAN N,et al.Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155patients with EGFR-mutant lung cancers[J].Clin Cancer Res,2013,19(8):2240-2247.
[12]LI D,AMBROGIO L,SHIMAMURA T,et al.BIBW2992,an irreversible EGFR/HER2inhibitor highly effective in preclinical lung cancer models[J].Oncogene,2008,27(34):4702-4711.
[13]MILLER V A,HIRSH V,CADRANEL J,et al.Afatinib versus placebo for patients with advanced,metastatic nonsmall-cell lung cancer after failure of erlotinib,gefitinib,or both,and one or two lines of chemotherapy(lux-lung 1):Aphase 2b/3randomised trial[J].Lancet Oncol,2012,13(5):528-538.
[14]HIRANO T,YASUDA H,TANI T,et al.In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in nonsmall-cell lung cancer[J].Oncotarget,2015,6(36):38789-38803.
[15]SEQUIST L V,YANG J C,YAMAMOTO N,et al.PhaseⅢstudy of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations[J].JClin Oncol,2013,31(27):3327-3334.
[16]WU Y L,CHENG Y,ZHOU X D,et al.Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer(archer 1050):A randomised,open-label,phase 3trial[J].Lancet Oncol,2017,18(11):1454-1466.
[17]JNNE P A,YANG J C H,KIM D W,et al.AZD9291in EGFR inhibitor-resistant non-small-cell lung cancer[J].NEngl J Med,2015,372(18):1689-1699.
[18]YANG J C,AHN M J,KIM D W,et al.Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer:AURA study phaseⅡextension component[J].J Clin Oncol,2017,35(12):1288-1296.
[19]MOK T S,WU Y L,AHN M J,et al.Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer[J].NEngl J Med,2017,376(7):629-640.
[20]GOSS G,TSAI C M,SHEPHERD F A,et al.CNS response to osimertinib in patients with T790M-positive advanced NSCLC:Pooled data from two phaseⅡtrials[J].Ann Oncol,2018,29(3):687-693.
[21]SORIA J C,OHE Y,VANSTEENKISTE J,et al.Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer[J].N Engl J Med,2018,378(2):113-125.
[22]TAKEZAWA K,PIRAZZOLI V,ARCILA M E,et al.HER2amplification:A potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation[J].Cancer Discov,2012,2(10):922-933.
[23]CAMIDGE D R,PAO W,SEQUIST L V.Acquired resistance to TKIs in solid tumours:Learning from lung cancer[J].Nat Rev Clin Oncol,2014,11(8):473-481.
[24]RAMALINGAM S S,YANG J C H,LEE C K,et al.Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer[J].JCO,2018,36(9):841-849.
[25]LIN J J,ZHU V W,YODA S,et al.Impact of EML4-ALKvariant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer[J].J Clin Oncol,2018,36(12):1199-1206.
[26]CAMIDGE D R,BANG Y J,KWAK E L,et al.Activity and safety of crizotinib in patients with ALK-positive non-smallcell lung cancer:Updated results from a phase 1study[J].Lancet Oncol,2012,13(10):1011-1019.
[27]SOLOMON B J,MOK T,KIM D W,et al.First-line crizoti-nib versus chemotherapy in ALK-positive lung cancer[J].NEngl J Med,2014,371(23):2167-2177.
[28]WU Y L,LU S,LU Y,et al.Results of profile 1 029,a phaseⅢcomparison of first-line crizotinib versus chemotherapy in east Asian patients with ALK-positive advanced nonsmall cell lung cancer[J].J Thorac Oncol,2018,13(10):1539-1548.
[29]KIM H R,KIM W S,CHOI Y J,et al.Epithelial-mesenchymal transition leads to crizotinib resistance in H2228lung cancer cells with EML4-ALK translocation[J].Mol Oncol,2013,7(6):1093-1102.
[30]CRYSTAL A S,SHAW A T,SEQUIST L V,et al.Patient-derived models of acquired resistance can identify effective drug combinations for cancer[J].Science,2014,346(6216):1480-1486.
[31]TANIZAKI J,OKAMOTO I,OKABE T,et al.Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK-positive non-small cell lung cancer[J].Clin Cancer Res,2012,18(22):6219-6226.
[32]MIYAWAKI M,YASUDA H,TANI T,et al.Overcoming EGFR bypass signal-induced acquired resistance to ALKtyrosine kinase inhibitors in ALK-translocated lung cancer[J].Mol Cancer Res,2017,15(1):106-114.
[33]KIM D W,TISEO M,AHN M J,et al.Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer:A randomized,multicenter phaseⅡtrial[J].J Clin Oncol,2017,35(22):2490-2498.
[34]SHAW A T,KIM D W,MEHRA R,et al.Ceritinib in ALK-rearranged non-small-cell lung cancer[J].N Engl J Med,2014,370(13):1189-1197.
[35]SORIA J C,TAN D S W,CHIARI R,et al.First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer(ASCEND-4):A randomised,open-label,phase 3study[J].Lancet,2017,389(10072):917-929.
[36]PETERS S,CAMIDGE D R,SHAW A T,et al.Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer[J].N Engl J Med,2017,377(9):829-838.
[37]ZOU H Y,FRIBOULET L,KODACK D P,et al.PF-06463922,an ALK/ROS1inhibitor,overcomes resistance to first and second generation ALK inhibitors in preclinical models[J].Cancer Cell,2015,28(1):70-81.
[38]SHAW A T,FELIP E,BAUER T M,et al.Lorlatinib in non-small-cell lung cancer with ALK or ROS1rearrangement:An international,multicentre,open-label,single-arm first-inman phase1trial[J].Lancet Oncol,2017,18(12):1590-1599.
[39]YODA S,LIN J J,LAWRENCE M S,et al.Sequential ALKinhibitors can select for lorlatinib-resistant compound ALKmutations in ALK-positive lung cancer[J].Cancer Discov,2018,8(6):714-729.
[40]RIKOVA K,GUO A,ZENG Q,et al.Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer[J].Cell,2007,131(6):1190-1203.
[41]SHAW A T,OU S H,BANG Y J,et al.Crizotinib in ROS1-rearranged non-small-cell lung cancer[J].N Engl J Med,2014,371(21):1963-1971.
[42]WU Y L,YANG J C,KIM D W,et al.PhaseⅡstudy of crizotinib in east Asian patients with ROS1-positive advanced non-small-cell lung cancer[J].J Clin Oncol,2018,36(14):1405-1411.
[43]KATAYAMA R,KOBAYASHI Y,FRIBOULET L,et al.Cabozantinib overcomes crizotinib resistance in ROS1fusionpositive cancer[J].Clin Cancer Res,2015,21(1):166-174.
[44]CHONG C R,BAHCALL M,CAPELLETTI M,et al.Identification of existing drugs that effectively target NTRK1and ROS1rearrangements in lung cancer[J].Clin Cancer Res,2017,23(1):204-213.
[45]CUI J J,ZHAI D Y,DENG W,et al.P3.02a-009 TPX-0005:A multi-faceted approach to overcoming clinical resistances from current ALK or ROS1inhibitor treatment in lung cancer topic:ALK biomarkers[J].J Thorac Oncol,2017,12(1):S1164-S1165.
[46]PLANCHARD D,SMIT E F,GROEN H J M,et al.Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer:An open-label,phase 2trial[J].Lancet Oncol,2017,18(10):1307-1316.
[47]ABRAVANEL D L,NISHINO M,SHOLL L M,et al.An acquired NRAS Q61K mutation in BRAF V600E-mutant lung adenocarcinoma resistant to dabrafenib plus trametinib[J].J Thorac Oncol,2018,13(8):e131-e133.
[48]GAUTSCHI O,MILIA J,FILLERON T,et al.Targeting RET in patients with RET-rearranged lung cancers:Results from the global,multicenter RET registry[J].J Clin Oncol,2017,35(13):1403-1410.
[49]YOH K,SETO T,SATOUCHI M,et al.Vandetanib in patients with previously treated RET-rearranged advanced nonsmall-cell lung cancer(luret):An open-label,multicentre phase 2trial[J].Lancet Respir Med,2017,5(1):42-50.
[50]SUBBIAH V,GAINOR J F,RAHAL R,et al.Precision targeted therapy with BLU-667for RET-driven cancers[J].Can-cer Discov,2018,8(7):836-849.
[51]DRILON A E,SUBBIAH V,OXNARD G R,et al.A phase 1study of LOXO-292,apotent and highly selective RET inhibitor,in patients with RET-altered cancers[J].J Clin Oncol,2018,36(15_suppl):102.
[52]SCHROCK A B,FRAMPTON G M,SUH J,et al.Characterization of 298 patients with lung cancer harboring METexon 14skipping alterations[J].J Thorac Oncol,2016,11(9):1493-1502.