2023胰腺导管腺癌靶向及免疫治疗进展全文.docx

2023胰腺导管腺癌靶向及免疫治疗进展（全文）摘要胰腺导管腺癌（PDAC）是一种侵袭性癌症，诊断时多为晚期，治疗手段有限，全身化疗只能带来局限的治疗效果。本文研究者系统回顾了针对不同PDAC分子亚型的靶向治疗和免疫治疗进展。聚焦当前支持这些治疗方法的临床前和临床证据，以及组合疗法改善PDAc患者生活质量的前景。正文一一PDAC的5年总生存率（OS）仅为11%。化疗方案的最新进展改善了可切除PDAC的患者预后；然而，80%的患者被诊断为晚期，无法进行治疗性手术。过去十年来，吉西他滨和氟嚓嚏为基础的联合方案已成为转移性胰腺癌症患者护理化疗的标准方案，尽管mOS仍保持在大约1年。与其他类型肿瘤形成鲜明对比的是，针对PDAC,使用靶向药物的多次大规模试验均未成功。然而，对PDAC的生物学和遗传学的进一步了解促使了新的靶向和基于免疫的疗法的出现，这些疗法可能在不久的将来适用于PDAC患者。研究者回顾了目前对PDAC分子特征和免疫治疗的理解，以开发靶向和基于免疫的疗法，并改善PDAc患者的预后。PDAC的靶向治疗方法识别关键致癌驱动因素可能产生新的治疗PDAC的方法。在本节中，研究者回顾了PDAC分子表征的研究进展以及针对潜在靶点的治疗策略。PDAC基因突变概览几项大规模的基因组研究已经对PDAC中的潜在驱动突变进行了梳理，从而实现了基因组指导的临床决策和治疗开发。对切除的PDAC肿瘤的早期二代测序（NGS研究表明，KRAS、TP53、CDKN2A和SMAD4显示出最高的突变频率，90%以上的个体具有致癌KRAS突变。国际癌症基因组联合会（ICGC）证实了这些发现，并描述了几个结构变异。此外，癌症基因组图谱（TCGA）计划报告了20个基因的突变频率低于10%其中包括染色质修饰基因（如ARID1A、KMT2D和KMT2C）、DNA修复基因（如BRCA1、BRCA2和PA1B2师其他癌基因（BRAFxMYC、FGFR1和其他）。在所有针对PDAC基因突变位点的研究中，局限性包括BRCA1、BRCA2或MSI-H以外的基因突变频率相对较低，以及对晚期疾病患者和通常表现不佳的患者进行临床试验的可及性。最近出现了针对KRAS野生型和KRAS基因突变的治疗方法，对于KRAS突变的PDAC可能会在不久的将来受益于基因型靶向治疗。图1.PDAC中KRAS靶向治疗演变PDAC中不同KRAS错义突变的相对频率。显示了针对指定KRAS突变位点的研究性和FDA批准的精确治疗。表1PDAC精准治疗方法Tab1e11PrecisionmedicineapproachesforPDACtherapyKRAStargetingsma11-mo1ecu1etherapeuticsinprec1inica1and/orc1inica1deve1opmentforthetreatmentofPDACDrugTargetMechanismPhaseoftria1Tria1designCancertypePrimaryoutcomePrec1inica1referenceC1inica1referenceSotorasib4(AMG-510)KRAS61xSma11-mo1ecu1ebindingofGDPboundStateofKRAScccIZHSequentia1,doseindigarmsWithdruggivenasamonotherapyandincombinationwithPD-IBaskettria1withmu1tip1etypesOfso1idtumorsenro11ed(KRAS尔mutation-positive)Treatment-re1atedadverseevents32,3336,37Adagrasib1(MRTX849)KRASWXSma11-mo1ecu1ebindingofGDP-bodSUteo(KRAStw1Sequentia1,dose-findingarmsWithdruggrvenasmonotherapyBaskettria1withmu1tip1etypesofso1idtumorsenro11ed(KRAS6,xmutation-positive)Treatment-re1atedadverseeventsandear1ydinica1activitysigna138411Sequentia1dose-findingarmstestedincombinationwithSHP2inhibitor(TNO155)Baskettria1withmu1tip1etypesofso1idtumorsenro11ed(KRAmutatipositive)Treatment-re1atedadverseevents42MRTX1133cKRASgoSma11-mo1ecu1ebindingofGOPandGTP-bondstatedKRAScuo*43Pendingtria1registrationRMC-629KRASwcTriconip1exinhibitor-46Pendingtria1registrationRMC6236,MuIti-RASTricomptexinhibrtor-BI1701963sPan-KRASSOSI-KRASinhibitorITwo-armtria1:druga1oneanddrugp1ustrametinibBaskettria1withKRASmutatedadvancedso1idtumorsMT(XoRRinextensioncohort4950Approvedandexperimenta1precisionmedkineapproachesinPDACDrUHS)TirgetIndicationFrequencyofaberrationKRASWiidtypeormutantResponsesinPOAC-ReferencesPembro1izumabeMMR-de<icient/MSI-HAdvancedMSI-HorMMRYefidentso1idtumors1-2%ofPDACStrongassociat>withmsandPS3wi1dtype4/22patientswithPOACwithobjectiveresponse-*13Z1412X>r211IarareCMMentrectinib4NTRK(genefusions)Adv>cedso1idtumorwithNTRKgenefusionRareeventinPDAC(<1%)KRASwi1dtypePR-8M&89.212Encorafenibb.brime<i1b*BRAFPatientswithBMQMmutatedPDACA11BMFaberrationsaccountfor10%ofKRAS-wi1d-typePDACKRASwUdtypeTna1ongoing74r80AfMicib”,zenocutuzumat/NRGIfusionsNRG1fusion>positiveadvancedPDACHighincidenceKRASwi1dtypeKftASwiIdtypeExce11entdurab1eresponses-92.213-215Gizotinib*,ceritinbr3ectnibfrA1KA1Kgenerearranged0.16%ofa11patientswithPDAGarxJ13%ofindividua1s<50yearso1dKftASwiIdtypeThreeoffourindividua1streatedwithA1Kinhibitorhaddiseasecontro193EntreCtin眇ROSIApprovedforROSIfusionNSC1CbutcasereportevidenceinPDACRareeventinPDAC(<1¼)KRASwiIdtypeOneindividua1withPDACwithminorresponse86TrastuzumaUderuxtecanfeHER2H£R2oVereXPreSSingadvancedso1idtumor(non-g1tricvnonbreast)Amp1ifiedin2%ofPDACcasesKRASc,2vOneindividua1withPDACtested(PR)-*21617Pri1setinib*(B1U-667)RETRfTfusionadvancedso1idtumors(threepatientswithPDAC)RareeventinPDAC(<1¼)KRASwi1dtype(1.35%)andKRASmutant(0.22%)ResponseinMpatientswithPDACtested-74,91KRAStargetingsma11-mo1ecu1etherapeuticsinpredinica1and/orc1inica1deve1opmentforthetreatmentofPDACDrugTargetMechanismPhaseoftria1Tria1designCancertypePrimaryoutcomePrec1inica1referenceC1inica1referenceGinka1tria1sva1uatmsDNAdamager*spome-Urgtedthraputkag«ntsinPOACDrUg(*)TargetPopuUtionTria1statmIria1dtsignPasoftria1PrimaryfindingsorendpointPic1inka1referenceC1inica1referenceO1apvibPARPPatientswithBRCA)-or8RCA2nutatedmetastaticPDACComp1eted(FDAapproved)TwoarvrandomizedPhMecontro1tria1IIIPFS：PUParibsuperiortoPUceboasmaintenance99799RucaparibPARPPitientswithBRCAhBRCA2orRA12muta(edmetastaticPDACComp1etedSing1mrmstudyI1PFS-rucaparibsuperiortoPUceboasmaintenance997101CiSPIM访,veiparibPARPandDNA(a1ky1ation)PitientswithRCA),BRCA2orRA1S2nuta(edmetastaticPDACComp1eted(NCCNrecommendatio)Tworvrandomi