ASCO黑色素瘤课件

1、2015ASCO黑色素瘤进展2015ASCO黑色素瘤进展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： 90082015ASCO黑色素瘤部分90 Abstracts for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）对传统手术模式的挑战对于厚度 2m

2、m 黑色素瘤患者，手术切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 melanomaAndrew J Hayes, The Royal Marsden NHS Trust, London, United KingdomOral Abstract SessionAbstract 9001一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研究设计躯

3、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研究设计躯干或肢体2mm的黑色素瘤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患者死因不明研究结果中位生存随访8.8年（IQR6.3-11.3年）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总生存切缘1cm组死亡253例MSS（恶黑特异性生存）切缘1cm组死亡194例切缘3cm组

4、死亡165例HazardRatio 1.24 （95%CL 1.00-1.52） P=0.05MSS（恶黑特异性生存）切缘1cm组死亡194例多变量生存分析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 disse

5、ction: A multicenter, randomized DECOG trialUlrike Leiter, Department of Dermatooncology, University of Tuebingen, Tuebingen, GermanyOral Abstract SessionAbstract 9002一项多中心、随机DECOG研究：SLNB阳性的黑色素瘤患者进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？研究背

6、景在肿瘤厚度1mm的黑色素瘤患者中，SLN的状况是预研究设计研究设计研究结果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

7、 （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）黑色素瘤内科药物治疗进展Pembrolizumab对初治及复一项比较nivolumab(NIVO)或联合ipilimumab (

8、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 W

9、eill Cornell Medical College, New York, Plenary Session 一项比较nivolumab(NIVO)或联合ipilimum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 un

10、treated melanoma(BRAF wild- type)_ ORR of 32% after progression on IPI, or IPI and a BRAF inhibitor if BRAF mutation-positive研究背景Lpilimumab（IPI) monothera研究设计Unresectable or Metatastic MelanomaPreviously untreated945 patientsRandomized, double-blind, phase III studyto compare NIVO+IPI or NIVO alone

11、to IPI aloneRandomize1:1:1Stratify 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-L

12、1 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-primary endpoints：PFS and OSSecondary endpoints：ORR and safety研究设计Unresectab

13、le or Metatastic基线病人特征NIVO+IPI(N=314)NIVO(N=316)IPI(N=315)Median 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%

14、4.8%PD-L1 expression 25%*21.7%25.3%23.8%BRAF V600 mutant32.2%31.6%30.8%基线病人特征NIVO+IPINIVOIPIMedian ag研究结果PFS（intent to treat）研究结果PFS（intent to treat）Response to TreatmentResponse to TreatmentPFS by PD-L1 Expression Level(5%) PD-L15%PD-L15%PFS by PD-L1 Expression Level(PFS by PD-L1 Expression Level(1

15、%) PD-L11%PD-L11%PFS by PD-L1 Expression Level(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% 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,

16、48.4)17.8(12.8,23.8)ORR by PD-L1 Expression Level(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 the IPI group(cardiac arrest)Safety Summary67.5% of patientTrea

17、tment-Related Select AEs Reported in 10% of PatientsTreatment-Related Select AEs R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

18、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 结论Dabrafenib +Trametinib vs DaBRAF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

19、 mechanisms.Douglas Buckner Johnson, Vanderbilt Univ, Nashville, TNOral Abstract SessionAbstract 9008BRAF抑制剂获得性耐药：对耐药机制及临床意义的多中心met方法Data from three large resistance studies100 patients with 132 accquired resistance samples 方法Data from three large resistSpectrum of resistanceSpectrum of resistanceCl

20、inical associations of resistanceAssessed: Baseline characteristics Timing and pattern of progression 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 associations of resisClinical asssociations

21、 of resistanceProgression-free survival was similar regardless of resiatance mechanismsPattern 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) Clinical asssociations of resiPost-progression outcomes Survival after progression and overall survival were similar regardless of resistance mechanismPost-progression outcomes Surv作者观点获得性耐