课件：黑色素瘤郑宇.pptx

2015ASCO黑色素瘤进展,郑宇 浙江大学附属邵逸夫医院,2015ASCO黑色素瘤部分,90 Abstracts for melanoma，10 Oral 手术： 9001 9002 术后随访：9003 晚期 一线：LBA1 LBA102 9004 9006 9007 后线：9005 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 melanoma Andrew J Hayes, The Royal Marsden NHS Trust, London, United Kingdom,Oral Abstract Session Abstract 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=0.14,MSS（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,一项多中心、随机DECOG研究：SLNB阳性的黑色素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 trial Ulrike Leiter, Department of Dermatooncology, University of Tuebingen, Tuebingen, Germany,Oral Abstract Session Abstract 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（Abstract 9005） 双靶向 vs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nivolumab(NIVO)或联合ipilimumab (IPI)与IPI在初治的晚期黑色素瘤的有效性和安全性的III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. Wolchok 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)1 Phase 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,Unresectable or Metatastic Melanoma Previously untreated 945 patients,Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone,Randomize 1:1:1,Stratify by: PD-L1 expression* BRAF status AJCC M stage,NIVO 1mg/kg+IPI 3mg/kg q3w for 4 dose then Nivo 3mg/kg q2w,NIVO 3mg/kg Q2W+IPI-matched placebo,IPI 3 mg/kg Q3W for 4 doses + NIVO matched placebo,Treat until progression* or unacceptable toxicity,N=314,N=316,N=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 circumstances,Co-primary endpoints：PFS and OS,Secondary endpoints：ORR and safety,基线病人特征,研究结果,PFS（intent to treat）,Response to Treatment,PFS 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 expression,Safety Summary,67.5% 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 the 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，联合用药组能提高预后，尤其在PD-L1表达5%的患者中,一项随机、双盲的III期研究（COMBI-d ）：比较dabrafenib 联合 trametinib 与dabrafenib联合安慰剂在BRAF V600E/K 突变的不可切除或转移性皮肤黑色素瘤的生存数据,Overall survival in COMBI-d, a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Georgina V. Long, Melanoma Institute Australia and The University of Sydney, North Sydney, Australia,Clinical Science Symposium Abstract LBA102,研究设计,研究结果（Overall Survival）,研究结果（PFS）,研究结果（Best Confirmed Response）,结论,Dabrafenib +Trametinib vs Dabrafenib 提高了OS: 中位OS 25.1 vs 18.7月,HR 0.71, P=0.011 降低29%死亡风险，2年OS 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多中心meta分析,BRAF inhibitor acquired resistance: A multicenter meta-analysis of the spectrum and clinical implications of resistance mechanisms. Douglas Buckner Johnson, Vanderbilt Univ, Nashville, TN,Oral Abstract Session Abstract 9008,方法,Data from three large resistance studies 100 patients with 132 accquired resistance samples,Spectrum of resistance,Clinical associations of resistance,Assessed: Baseline characteristics Timing and pattern of progression Subsequent clinical outcomes NRAS 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 resistance,Progression-free survival was similar regardless of resiatance mechanisms Pattern of progressio differed by resiatance 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 mechani