2015ASCO黑色素瘤2015621郑宇12.pptx

2015ASCO黑色素瘤黑色素瘤进展展郑宇郑宇浙江大学附属邵逸夫医院浙江大学附属邵逸夫医院2015ASCO黑色素瘤部分90Abstractsformelanoma，10Oralu手术：9001 9002 u术后随访：9003u晚期 一线：LBA1 LBA102 9004 9006 9007 后线：9005 u耐药机制：9008对传统手术模式的挑战对于厚度2mm黑色素瘤患者，手术切缘1cmor3cm？（Abstract 9001）前哨淋巴结活检阳性的黑色素瘤患者需不需要行扩大淋巴结手术？（Abstract 9002）一项在高危黑色素瘤患者中比较不同手术切缘对长一项在高危黑色素瘤患者中比较不同手术切缘对长期生存影响的随机对照研究期生存影响的随机对照研究Long term follow up of survival in a randomised trial of wide or narrow excision margins in high risk primary melanomaAndrewJHayes,TheRoyalMarsdenNHSTrust,London,UnitedKingdomOralAbstractSessionAbstract9001研究设计躯干或肢体2mm的黑色素瘤手术切缘随机分为1cm或3cm未进行ELND和SNB未接受术后辅助治疗主要研究终点为局部复发率及DFS次要终点为MSS和OS研究结果中位生存随访8.8年（IQR6.3-11.3年）900患者入组494死亡359患者死于黑色素瘤125患者死于其他10患者死因不明总生存切缘1cm组死亡253例切缘3cm组死亡241例HazardRatio1.14（95%CL0.96-1.36）P=0.14MSS（恶黑特异性生存）切缘1cm组死亡194例切缘3cm组死亡165例HazardRatio1.24（95%CL1.00-1.52）P=0.05多变量生存分析结论与手术3cm切缘相比，1cm手术切缘有更高的局部复发及更高的恶黑相关死亡在总生存上，两组无统计学意义的差异一项多中心、随机一项多中心、随机DECOG研究：研究：SLNB阳性的黑色素阳性的黑色素瘤患者进行全淋巴结清扫与否的生存比较瘤患者进行全淋巴结清扫与否的生存比较Survival of SLNB-positive melanoma patients with and without complete lymph node dissection:A multicenter,randomized DECOG trialUlrikeLeiter,DepartmentofDermatooncology,UniversityofTuebingen,Tuebingen,GermanyOralAbstractSessionAbstract9002研究背景在肿瘤厚度1mm的黑色素瘤患者中，SLN的状况是预后的重要因素，且被包括进了AJCC分期系统SLNB阳性的患者接受全淋巴结清扫成为目前的标准治疗SLN阳性的患者接受全淋巴结清扫能否提高总生存？研究设计研究结果结论全淋巴结清扫组在区域淋巴结上显示了更好的疾病控制本研究显示全淋巴结清扫并不能带来无远处转移生存、无复发生存、黑色素瘤特异性生存的提高基于此研究的发现，对微转移的黑色素瘤患者并不推荐行全淋巴结清扫黑色素瘤内科药物治疗进展Pembrolizumab对初治及复制黑色素瘤患者长期有效性分析-KEYNOTE-001研究（Abstract9005）双靶向双靶向 vs单靶向单靶向 nivolumab(NIVO)+ipilimumab(IPI)vsIPIvsNIVO（AbstractLBA1）dabrafenib+trametinib vsdabrafenib（AbstractLBA102）nivolumab(NIVO)+ipilimumab(IPI)vsIPI（Abstract9004）cobimetinib(cobi)+vemurafenib(vem)vsvemurafenib（Abstract9006）encorafenib+binimetinib（Abstract9007）一项比较一项比较nivolumab(NIVO)或联合或联合ipilimumab(IPI)与与IPI在在初治的晚期黑色素瘤的有效性和安全性的初治的晚期黑色素瘤的有效性和安全性的III期研究期研究 Efficacy and safety results from a phase III trial of nivolumab(NIVO)alone or combined with ipilimumab(IPI)versus IPI alone in treatment-naive patients(pts)with advanced melanoma(MEL)(CheckMate 067)JeddD.Wolchok MemorialSloanKetteringCancerCenterandWeillCornellMedicalCollege,NewYork,PlenarySession 研究背景Lpilimumab（IPI)monotherapy in melanoma improves OS(20%of treated patients alive 3 years)1Phase III studies of nivolumab(NIVO)monotherapy in advanced melanoma:2,3_ 1-year OS rate of 73%and ORR of 40%in untreated melanoma(BRAF wild-type)_ ORR of 32%after progression on IPI,or IPI and a BRAF inhibitor if BRAF mutation-positive研究设计UnresectableorMetatasticMelanomaPreviouslyuntreated945patientsRandomized,double-blind,phase III studyto compare NIVO+IPI or NIVO alone to IPI aloneRandomize1:1:1Stratifyby:PD-L1expression*BRAFstatusAJCCMstageNIVO 1mg/kg+IPI 3mg/kg q3w for 4 dose then Nivo 3mg/kg q2wNIVO 3mg/kg Q2W+IPI-matched placeboIPI3mg/kgQ3Wfor4doses+NIVO matched placeboTreatuntilprogression*orunacceptabletoxicityN=314N=316N=315*Verified PD-L1 assay with 5%expression level was used for the stratification of patients;validated PD-L1 assay was used for efficacy analyses.*Patients could have been treated beyond progression under protocol-defined circumstancesCo-primaryendpoints：PFS andOSSecondaryendpoints：ORRandsafety基线病人特征NIVO+IPI(N=314)NIVO(N=316)IPI(N=315)Medianage,years(range)61(18-88)60(25-90)62(18-89)Age65years41.1%37.3%42.2%Sex-Male65.6%63.9%64.1%ECOGperformancestatusof0*73.2%75.3%71.1%MstageM1c57.6%58.2%58.1%LDH-ULN36.3%35.4%36.5%LDH-2xULN11.8%11.7%9.5%Brainmetastases3.5%2.5%4.8%PD-L1expression25%*21.7%25.3%23.8%BRAFV600mutant32.2%31.6%30.8%研究结果PFS（intenttotreat）ResponsetoTreatmentPFSbyPD-L1ExpressionLevel(5%)PD-L15%PD-L15%PFSbyPD-L1ExpressionLevel(1%)PD-L11%PD-L11%ORRbyPD-L1ExpressionLevel(5%)NIVO+IPI resulted in a numerically higher ORR vs.NIVO alone regardless of PD-L1 expressionNIVO+IPINIVOIPIPD-L1(5%)ORR,%(95%CI)72.1(59.9,82.3)57.5(45.9,68.5)21.3(12.7,32.3)PD-L1(5%)ORR,%(95%CI)54.8(47.8,61.6)41.3(34.6,48.4)17.8(12.8,23.8)SafetySummary67.5%of patients(81/120)who discontinued the NIVO+IPI combination due to treatment-related Aes developed a response*OnereportedintheNIVOgroup(neutropenia)andoneintheIPIgroup(cardiacarrest)Treatment-RelatedSelectAEsReportedin10%ofPatients结论在未经治疗的恶性黑色素瘤中，与IPI相比，单用NIVO或NIVO+IPI能显著提高PFS和ORR -与单用NIVO相比，NIVO+IPI能带来更长的PFS和更高的ORR -在PDL-1表达5%的患者中，单用NIVO或NIVO+IPI带来相似的PFS延 长，NIVO+IPI有更高的ORR率两药联合的安全性与既往研究相似 -两药联合组中有更高的AEs发生率 -大多数AEs能根据指南进行管理和解决基于目前的证据，联合用药组能提高预后，尤其在PD-L1表达50%提高了PFS：HR0.67,P0.001 降低33%进展或死亡风险毒副反应可控对于BRAFV600突变的转移性黑色素瘤患者，Dabrafenib联合Trametinib成为新的靶向治疗标准BRAF抑制剂获得性耐药：对耐药机制及临床意义的抑制剂获得性耐药：对耐药机制及临床意义的多中心多中心meta分析分析BRAF inhibitor acquired resistance:A multicenter meta-analysis of the spectrum and clinical implications of resistance mechanisms.DouglasBucknerJohnson,VanderbiltUniv,Nashville,TNOralAbstractSessionAbstract9008方法Datafromthreelargeresistancestudies100patientswith132accquiredresistancesamplesSpectrumofresistanceClinicalassociationsofresistanceAssessed:BaselinecharacteristicsTimingandpatternofprogressionSubsequentclinicaloutcomesNRASmutationsBrainmetastasesatbaseline(OR4.6,p=0.04)invemurafenib-treatedpatients(oddsratio3.5,p=0.05)ClinicalasssociationsofresistanceProgression-freesurvivalwassimilarregardlessofresiatancemechanismsPatternofprogressiodifferedbyresiatancemechanismNRASmorecommoninbrain(p=0.07),lesscommoninlungs(p=0.04)MEK1/2morecommoninliver(p=0.01)Post-progressionoutcomesSurvivalafterprogressionandoverallsurvivalweresimilarregardlessofresistancemechanism作者观点获得性耐药机制较多见于NRAS突变（17%）BRAF剪接变异（16%）BRAF扩增（13%）MEK1/2突变（7%）Non-MAPK通路（11%-PI3K-AKT通路）耐药机制的不同并没有影响OS或PFS的不同NRS突变更多见于vemurafenib治疗及发生颅内转移的患者2015ASCO黑色素瘤黑色素瘤小小结对传统手术模式的挑战对传统手术模式的挑战3cm扩切组在局部复发率、黑色素瘤特异死亡率均低于1cm扩切组。因此扩扩大大切除切除仍然是必须的仍然是必须的，但3cm切缘是否优于标准处理模式的2cm切缘有待进一步研究前哨淋巴结活检阳性患者彻底淋巴结清扫，仅可提高局部控制率但不能提但不能提高高 总总生存生存率率双靶双靶向治疗显示了良好的临床疗效，如何控制毒副反应？向治疗显示了良好的临床疗效，如何控制毒副反应？PD-1单抗+CTLA-4单抗BRAF抑制剂+MEK抑制剂生物标志物的分析生物标志物的分析PD-1表达阳性的患者较阴性患者疗效好，能否作为疗效预测因子?阳性及阴性表达的界值?BRAF抑制剂获得性耐药机制：突变的位点不同，没有特异性改变。与预后无明显相关