1、2015ASCO黑色素瘤进展黑色素瘤进展2015ASCO黑色素瘤部分90 Abstracts for melanoma，10 Oralu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1 cm or 3 cm？（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
2、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 melanomaAndrew J Hayes,The Royal Marsden NHS Trust,London,United KingdomOral Abstract SessionAbstract 9001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
3、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 HazardRatio 1.14 （95%CL 0.96-1.36）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 HazardRatio 1.24 （95%CL 1.00-1.52）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
4、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 trialUlrike Leiter,Department of Dermatooncology,University of Tuebingen,Tuebingen,GermanyOral Abs
5、tract SessionAbstract 9002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（A
6、bstract 9005）双靶向双靶向 vs单靶向单靶向 nivolumab(NIVO)+ipilimumab(IPI)vs IPI vs NIVO（Abstract LBA1）dabrafenib+trametinib vs dabrafenib（Abstract LBA102）nivolumab(NIVO)+ipilimumab(IPI)vs IPI（Abstract 9004）cobimetinib(cobi)+vemurafenib(vem)vs vemurafenib（Abstract 9006）encorafenib+binimetinib（Abstract 9007）一项比较一项
7、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)Jedd D.Wolc
8、hok Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College,New York,Plenary Session 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
9、 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Unresectable or Metatastic MelanomaPreviously untreated945 patientsRandomized,double-blind,phase III studyto compare NIVO+IPI or NIVO alone to IPI aloneRandomize1:1:
10、1Stratify by:PD-L1 expression*BRAF statusAJCC M stageNIVO 1mg/kg+IPI 3mg/kg q3w for 4 dose then Nivo 3mg/kg q2wNIVO 3mg/kg Q2W+IPI-matched placeboIPI 3 mg/kg Q3W for 4 doses+NIVO matched placeboTreat until progression*or unacceptable toxicityN=314N=316N=315*Verified PD-L1 assay with 5%expression lev
11、el 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-primary endpoints：PFS and OSSecondary endpoints：ORR and safety基线病人特征NIVO+IPI(N=314)NIVO(N=316)IPI(N=315)Medi
12、an age,years(range)61(18-88)60(25-90)62(18-89)Age65 years41.1%37.3%42.2%Sex-Male65.6%63.9%64.1%ECOG performance status of 0*73.2%75.3%71.1%M stageM1c57.6%58.2%58.1%LDH-ULN36.3%35.4%36.5%LDH-2x ULN11.8%11.7%9.5%Brain metastases3.5%2.5%4.8%PD-L1 expression 25%*21.7%25.3%23.8%BRAF V600 mutant32.2%31.6%
13、30.8%研究结果PFS（intent to treat）Response to TreatmentPFS by PD-L1 Expression Level(5%)PD-L15%PD-L15%PFS by PD-L1 Expression Level(1%)PD-L11%PD-L11%ORR by PD-L1 Expression Level(5%)NIVO+IPI resulted in a numerically higher ORR vs.NIVO alone regardless of PD-L1 expressionNIVO+IPINIVOIPIPD-L1(5%)ORR,%(95%
14、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)Safety Summary67.5%of patients(81/120)who discontinued the NIVO+IPI combination due to treatment-related Aes developed a response*One reported in the NIVO group(neutropenia)and one in th
15、e IPI group(cardiac arrest)Treatment-Related Select AEs Reported in 10%of Patients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
16、高预后，尤其在PD-L1表达50%提高了PFS：HR 0.67,P0.001 降低33%进展或死亡风险 毒副反应可控 对于BRAF V600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 mechani
17、sms.Douglas Buckner Johnson,Vanderbilt Univ,Nashville,TNOral Abstract SessionAbstract 9008方法Data from three large resistance studies100 patients with 132 accquired resistance samples Spectrum of resistanceClinical associations of resistanceAssessed:Baseline characteristics Timing and pattern of prog
18、ression Subsequent clinical outcomesNRAS mutations Brain metastases at baseline (OR 4.6,p=0.04)in vemurafenib-treated patients (odds ratio 3.5,p=0.05)Clinical asssociations of resistanceProgression-free survival was similar regardless of resiatance mechanismsPattern of progressio differed by resiata
19、nce mechanism NRAS more common in brain(p=0.07),less common in lungs(p=0.04)MEK1/2 more common in liver(p=0.01)Post-progression outcomes Survival after progression and overall survival were similar regardless of resistance mechanism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-
20、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结小结对传统手术模式的挑战对传统手术模式的挑战 3 cm 扩切组在局部复发率、黑色素瘤特异死亡率均低于 1 cm 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 3 cm 切缘是否优于标准处理模式的 2 cm 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
21、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 明显相关提问与解答环节Questions And Answers谢谢聆听 学习就是为了达到一定目的而努力去干,是为一个目标去战胜各种困难的过程,这个过程会充满压力、痛苦和挫折Learning Is To Achieve A Certain Goal And Work Hard,Is A Process To Overcome Various Difficulties For A Goal
