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1、黑色素瘤治疗进展,保守估计，美国每年约新增7.5万人，中国每年新增2万人,2010年晚期黑色素瘤治疗情况,Vernon K Sondak.Discussion:Ipilimumab:The light at the end of the tunnel?2010,ASCO plenary session,晚期黑色素瘤治疗,2008ASCO 900例黑色素瘤肝转移 手术 VS 未手术 OS 29m VS 7m 5年OS 33%VS 5%,Ribas A.N Engl J Med.2012;366:2517-2519.Copyright 2012 Massachusetts Medical Soci
2、ety.Reprinted with permission from Massachusetts Medical Society.,CTLA-4 and PD-1/L1 Checkpoint Blockade for Cancer Treatment,阻断CTLA4/B7与阻断 PD-1/PD-L1之区别,里程碑：Ipilimumab2013年全球销售额高达5.77亿美元,1.Hodi FS,et al.N Engl J Med.2010;363:711-723.2.Robert C,et al.N Engl J Med.2011;364:2517-2526.,Ipi+gp100 Ipigp1
3、00,MedianOS,Mos,10.010.16.4,HR,0.680.66,P Value,.001.003,Ipi+D Placebo+D,MedianOS,Mos,11.29.1,HR,0.72,P Value,.001,Est 1,2,3-Yr Survival,%,47.3,28.5,20.836.3,17.9,12.2,Ipilimumab+gp100 vs gp1001,Ipilimumab vs Placebo2,OS(%),Mos,0,0,100,48,80,60,40,20,40,32,24,16,8,56,52,44,36,28,20,12,4,Patients Sur
4、vival(%),Mos,0,0,100,80,60,40,20,32,20,48,28,16,4,44,40,8,12,24,36,Ipilimumab+dacarbazine,Placebo+dacarbazine,Ipilimumab：30余年来首个药物证实改善晚期黑色素瘤总生存,Previously Treated Patients,Previously Untreated Patients,ODay S at al JCO 2010;28:18s(Abstract 4),免疫相关毒性irAE,Evolution of Response:Patient Example,Screenin
5、g,Week 12Initial increase in total tumour burden(mWHO PD),Week 16Responding,Week 72Durable&ongoing response without signs of IRAEs,Courtesy of K.Harmankaya,抗PD-1抗体Keytruda(pembrolizumab,MK3475)9月4日美国FDA批准Opdivo（nivolumab）日本已经上市,Nivolumab Activity(ORR)1Melanoma:28%NSCLC:18%RCC:27%,MK-3475 Activity(OR
6、R)2Melanoma:38%Highest dose:52%(assessed by RECIST 1.1 with confirmation by ICR),1.Topalian SL,et al.N Engl J Med.2012;366:2443-2454.Copyright 2012 Massachusetts Medical Society.Reprinted with permission from Massachusetts Medical Society.2.Hamid O,et al.N Engl J Med.2013;369:134-144.,Activity of An
7、ti-PD-1 Agents in Solid Tumors,81%of pts with response still on treatment at time of analysis(median followup:11 mos),Patient with metastatic melanoma,Pembrolizumab(MK-3475)in Advanced Melanoma:Phase I Trial,Melanoma expansion cohort of phase I KEYNOTE-001 studyAdvanced,unresectable disease with ECO
8、G PS 0-1Ipilimumab-treated patients must have PD with resolution of related AEs,Ribas A,et al.ASCO 2014.LBA9000.,IPI Naive 10 mg/kg q2w(n=41),IPI Naive 10 mg/kg q3w(n=24),IPI Naive2 mg/kg q3w(n=22),IPI Treated 10 mg/kg q2w(n=16),IPI Treated 10 mg/kg q3w(n=32),IPI Refractory 10 vs 2 mg/kg q3w(n=173),
9、IPI Nave 10 vs 2 mg/kg q3w(n=103),Nonrandomized cohorts(n=135),Randomized cohorts(n=276),Baseline January 2012,April 2012,Hamid O,et al.N Engl J Med.2013;369:134-144.Copyright 2013 Massachusetts Medical Society.Reprinted with permission from Massachusetts Medical Society.,54-yr-old male with desmopl
10、astic melanoma after progressing on ipilimumab,Clinical Activity of MK-3475 in a Patient With Metastatic Desmoplastic Melanoma,CTL Infiltrates in Regressing Metastatic Melanoma Lesion After MK-3475 Treatment,Baseline:February 29,2012,August 20,2012,Ribas A,et al.ASCO 2013.Abstract 9009.,Pembrolizuma
11、b(MK-3475)in Advanced Melanoma:AEs 10%Incidence,Similar safety profiles in ipilimumab-naive and ipilimumab-treated patientsOther grade 3/4 AE(1%incidence):ALT elevation,headache,hypothyroidism,decreased appetite,dyspnea,Ribas A,et al.ASCO 2014.Abstract LBA9000.,40,49,13,Pembrolizumab(MK-3475)in Adva
12、nced Melanoma:Response by PD-L1 Expression,PD-L1 positivity:staining in 1%of tumor cells125 patients evaluable for PD-L1 expression,PD-L1,PD-L1+,P=.0007*,Kefford R,et al.ASCO 2014.Abstract 3005.,*1-sided P values calculated by logistic regression,adjusting for dose/schedule.,Unselected(n=113),PD-L1+
13、(n=83),PD-L1(n=30),0,10,20,30,40,50,60,70,ORR(%),Pembrolizumab(MK-3475)in Advanced Melanoma:Survival by PD-L1 Expression,PD-L1 positivity:staining in 1%of tumor cells,PD-L1,P=.0051,P=.3165,Overall Survival,Progression-Free Survival,Kefford R,et al.ASCO 2014.Abstract 3005.,80,60,40,20,0,0,20,40,60,80
14、,100,PFS(%),Wks,PD-L1 positivePD-L1 negative,80,60,40,20,0,0,20,40,60,80,100,OS(%),Wks,PD-L1 positivePD-L1 negative,Phase I Nivolumab Study:Long-term Follow-up in IPI-Naive Pts With Melanoma,Primary endpoints:safety,tolerabilitySecondary endpoints:preliminary efficacy,dose-response relationshipsStud
15、y amended to collect OS dataSubgroup analysis of response by key patient featuresExploratory PD-L1 analysis:positive if tumor membrane stained at any intensity(cut-off:1%or 5%expression),Hodi FS,et al.ASCO 2014.Abstract 9002.,Patients with advanced melanoma,ECOG PS 0-2,1-5 lines of previous systemic
16、 therapy(N=107)Treatment max:96 weeks,Nivolumab 0.1 mg/kg IV q2w(n=17),Nivolumab 0.3 mg/kg IV q2w(n=18),Nivolumab 1 mg/kg IV q2w(n=35),Nivolumab 3 mg/kg IV q2w(n=17),Nivolumab 10 mg/kg IV q2w(n=20),Phase I Nivolumab Study in Advanced Melanoma:Select AEs,Select AE:associated with potential immunologi
17、c etiologies that require more frequent monitoring and/or unique interventionAll patients have 1 yr of follow-up,1Topalian S,et al.J Clin Oncol.2014;32:1020-30,Topalian S,et al.J Clin Oncol.2014;32:1020-1030.Hodi FS,et al.ASCO 2014.Abstract 9002.,-100,-50,0,50,100,150,200,Maximum%Response in Baselin
18、e Target Lesions,1%cutoff,Positive,PD-L1 status,Patient,Phase I Nivolumab Study in Advanced Melanoma:ORR by PD-L1 Expression,Tumor tissue collection retrospective;41 samples,Hodi FS,et al.ASCO 2014.Abstract 9002.,Negative,-100,-50,0,50,100,150,200,5%cutoff,Positive,PD-L1 status,Patient,Negative,Phas
19、e I Nivolumab Study in Advanced Melanoma:Expert Perspective,Longest follow-up of any PD-1 antibody studyResponse duration64%beyond 24 wksMedian DoR of 22.9 mosSurvival outcomes2-yr OS:48%;3-yr OS:41%Median OS:20.3 mos at 3 mg/kg dose for phase II/III studiesMedian PFS:9.7 mos at 3 mg/kg dose for pha
20、se II/III studiesGrade 3/4 irAEs:5%,Hodi FS,et al.ASCO 2014.Abstract 9002.,Phase I Study:Nivolumab+Ipilimumab in Stage III/IV Melanoma,Concurrent therapy study designSequenced therapy study design,Patients with stage III/IV melanoma with 3 previous therapies,InductionIpilimumab q3w x 4 cycles+Nivolu
21、mab q3w x 8 cycles,MaintenanceIpilimumab+Nivolumab q12w x 8 cycles,Patients with stage III/IV melanoma with 3 previous doses of ipilimumab(n=33),Nivolumab(1 or 3 mg/kg)q2w until progression,Wolchok JD,et al.N Engl J Med.2013;369:122-133.Sznol M,et al.ASCO 2014.LBA9003,MaintenanceNivolumab 3 mg/kg q2
22、w(max 48 doses),Cohort 8,Cohorts 6,7,Cohort 1,2,2a,3,(n=53),(n=41),InductionIpilimumab 1 mg/kg q3w x 4 cycles+Nivolumab 3 mg/kg q3w x 4 cycles,Phase I Study of Nivolumab+Ipilimumab in Advanced Melanoma:Safety,No new safety signals with 22 mos of follow-up for the initial concurrent cohorts22/94(23%)
23、patients discontinued treatment due to treatment-related adverse events1/94 drug-related death in trial;fatal multiorgan failure(as a result of colitis)in cohort 8,Sznol M,et al.ASCO 2014.Abstract LBA9003.,Phase I Study of Nivolumab+Ipilimumab in Melanoma:Response Characteristics,34 pts maintain an
24、ongoing responsePatients can continue to respond following treatment discontinuationMedian follow-up of 22 mos and 7 mos for cohorts 2 and 8,respectivelyFor 7 responding pts in cohort 2 who discontinued therapy for reasons other than disease progression,86%(6/7)responded for 16 wks since end of ther
25、apy89%(8/9)of pts in cohort 2 remained in response and 94%(16/17)of cohort 8 remained in response at the time of analysis,Sznol M,et al.ASCO 2014.Abstract LBA9003.,0,4,8,12,16,20,24,28,130,0,10,20,30,40,50,60,70,80,90,100,110,120,Wks,Mos,Cohort,Nivo 0.3/IPI 3Cohort 1,Nivo 1/IPI 3Cohort 2,Nivo 3/IPI
26、1Cohort 2a,Nivo 3/IPI 3Cohort 3,Nivo 1/IPI 3Cohort 8,Time to and duration of response while on treatment,Response duration following treatment discontinuation,Time to response,Ongoing response,Sznol M,et al.ASCO 2014.Abstract LBA9003.,Phase I Study of Nivolumab+Ipilimumab in Melanoma:OS for Concurre
27、nt Tx,100,90,80,70,60,50,40,30,20,10,0,Survival(%),48,0,3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,Mos,Pts at Risk,nNivo 0.3/IPI 3Nivo 1/IPI 3Nivo 3/IPI 1Nivo 3/IPI 3Concurrent,141716653,131716652,111615648,101515646,81515644,71413640,7144631,7132628,790319,740011,53008,23005,23005,22004,10001,10001,
28、00000,Nivo 0.3 mg/kg+IPI 3 mg/kgNivo 1 mg/kg+IPI 3 mg/kgNivo 3 mg/kg+IPI 1 mg/kgNivo 3 mg/kg+IPI 3 mg/kgConcurrent cohort,Censored,2-yr OS:50%,2-yr OS:79%,2-yr OS:88%,Concurrent Therapy With Ipilimumab and Nivolumab:Expert Perspective,42%ORR with 17%CRs and 82%in remission for all patients receiving
29、 concurrent treatment62%rate of grade 3/4 irAEs at optimal doses:LFTs,lipase,amylase,rash,colitisBRAF status,PD-L1 tumor staining not clearly associated with responseResponse in sequential patients associated with plasma ipilimumab levels prior to starting nivolumabConcurrent 2-yr OS of 79%=impressi
30、veBenefit worth the toxicity?,辅助治疗：高剂量干扰素1年方案,FDA 和EMAHDI-IIB,C和III期(高危患者）:20 MIU/m2 IV 5x/周，4周（诱导）10 MIU/m2 SC 3x/周，48周(维持),辅助治疗：EORTC 18071:Adjuvant Ipilimumab vs Placebo for Resected Stage III Disease,Eggermont A,et al.ASCO 2014.Abstract LBA9008.,Primary endpoint:RFS per IRC(time to local,regiona
31、l,distant metastasis,or death)Secondary endpoints:OS,DMFS,AE profile,health-related QoL,Patients with high-risk,completely resected stage III melanoma and ECOG PS 0/1(N=951),Ipilimumab 10 mg/kg q3w x 4then q12w for up to 3 yrs(n=475),Placebo q3w x 4then q12w for up to 3 yrs(n=476),Stratified by stag
32、e(IIIa vs IIIb vs IIIc with 1-3 positive LN vs IIIc with 4 positive LN),region(North America,Europe,Australia),Adjuvant Ipilimumab vs Placebo for Resected Stage III Disease:RFS,Eggermont A,et al.ASCO 2014.Abstract LBA9008.,*Stratified by stage.Data are not yet mature.,100,80,60,40,20,0,Patients Aliv
33、e Without Relapse(%),Median:26.1 mos,Median:17.1 mos,Ipilimumab 10 mg/kgPlacebo,60,0,12,24,36,48,Mos,Patients at Risk,nIpilimumabPlacebo,O234294,N475476,276260,205193,6762,54,00,Eggermont A,et al.ASCO 2014.Abstract LBA9008.,Events/Patients,Ipilimumab,Placebo,HR(CI*)(Ipilimumab:Placebo),AJCC 2002(CRF
34、)Stage IIIAStage IIIBStage IIIC,Type of LN+MicroscopicMacroscopic,UlcerationNoYesUnknown,Total,*95%CI for total,99%CI elsewhere.Unstratified analysis.,34/9899/213101/164,36/88121/207137/181,83/210151/265,108/193186/283,116/257106/19712/21,131/244146/20317/29,234/475(49.3%),294/476(61.8%),0.76(0.64-0
35、.91),0.84(0.61-1.17)0.67(0.48-0.93)1.08(0.40-2.87),0.68(0.47-0.99)0.83(0.63-1.10),0.91(0.49-1.68)0.77(0.54-1.08)0.73(0.52-1.02),0.25,0.5,1.0,2.0,4.0,Ipilimumabbetter,Placebobetter,Treatment effect P.01,Adj.Ipilimumab vs Placebo for Resected Stage III Disease:RFS by Subgroup,Adjuvant Ipilimumab vs Pl
36、acebo for Resected Stage III Disease:irAEs,Eggermont A,et al.ASCO 2014.LBA9008.,Adjuvant Ipilimumab in Stage III Melanoma:Expert Perspective,Median RFS in resected stage IIIa-c melanoma:17 mos with placebo to 26 mos with ipilimumab(HR:0.75;P=.0013)Improvement seen for all stages,ulcerated primary or
37、 not,microscopic or macroscopic LN burdenGrade 3/4 irAE rate:42%Is the benefit worth the toxicity?,局部免疫治疗：Oncolytic VirusT-vec,OPTiM:Talimogene Laherparepvec in Stage IIIB/IV Melanoma(Phase III Study),Talimogene laherparepvec:an oncolytic immunotherapy comprising a HSV-1 virus backbone containing th
38、e gene for GM-CSF,a potent immune stimulatorPrimary endpoint:durable response rate(CR or PR for 6 mos)Secondary endpoints:OS,ORR,TTF,safety,Patients with stage IIIb,IIIc,or IV unresectable melanoma,ECOG PS 0-1(N=436),Every 2 wks for up to 2 yrs,Up to 3 yrs of follow-up after treatment,T-Vec up to 4
39、mL(108 pfu/mL per injection)intralesionally q2w*(n=295),GM-CSF 125 g/m2 SCdaily for 2 wks,then 2 wks off(n=141),ClinicalTrials.gov.NCT00769704.Kaufman HL,et al.ASCO 2014.Abstract 9008a.,Randomized 2:1,*Initial dose 106 pfu/mL with 3 wks before subsequent dosing.,OPTiM Study of T-Vec in Stage IIIB/IV
40、 Melanoma:Response(ITT Population),DRR:16.3%with T-Vec vs 2.1%with GM-CSF(P.0001)Responses in both local and distant lesions,Kaufman HL,et al.ASCO 2014.Abstract 9008a.Andtbacka RH,et al.ASCO 2013.Abstract LBA9008.,OPTiM Study of T-Vec in Stage IIIB/IV Melanoma:OS,Events/N(%),Median(95%CI),in Mos,T-V
41、ec,189/295(64),23.3(19.5-29.6),GM-CSF,101/141(72),18.9(16.0-23.7),HR:0.79(95%CI:0.62-1.00;unadjusted log-rank P=.051),Kaufman HL,et al.ASCO 2014.Abstract 9008a.,100,80,60,40,20,0,OS(%),60,0,10,15,20,5,25,30,35,40,45,50,55,Pts at Risk,nT-VecGM-CSF,295141,269124,230100,18783,15963,14552,12546,9536,662
42、7,3615,165,20,00,T-Vec in Stage IIIB/IV Melanoma(OPTiM Study):Expert Perspective,T-Vec is an effective local intralesional therapy with response rates at injected lesions of 64%24-wk DRR endpoint met:16%with T-Vec vs 2%with GM-CSF(P.0001)Toxicities were minimalOS:borderline significant improvement w
43、ith T-Vec(HR:0.79;P=.051)T-Vec has locoregional activity and modest systemic effects,well suited for combination with checkpoint protein inhibitors as an immune-priming agent,*Only patients who received both T-Vec and IPI.CR,CRu,and PD included.1 patient with PD not shown in the plot because tumor b
44、urden could not be accurately calculated(missing postbaseline data).Percentage change from baseline:538Percentage change from baseline:265,100,50,0,25,50,100,200,Percentage Change From Baseline,Patients(N=17),Stage IV M1c(n=4),Stage IV M1b(n=5),Stage IV M1a(n=4),Stage IIIc(n=3),Stage IIIb(n=1),Puzan
45、ov I,et al.ASCO 2014.Abstract 9029.,T-Vec+IPI in Unresected Stage IIIB-IV Melanoma:Max Change in Tumor Burden,T-Vec+IPI in Unresected Stage IIIB-IV Melanoma:Expert Perspective,18 patients treated with T-Vec plus IPIORR:56%(4 CR,6 PR)plus 3 SDOnly 3 grade 3/4 irAEs from IPIMelan-Atargeting T cells in
46、creased in the peripheral blood after combination therapyImpressive early results addressing the hypothesis that T-Vec may prime an immune response amplified by IPI,靶向治疗：伊马替尼、恩度、威罗菲尼、达拉菲尼、达拉菲尼联合曲美替尼,C-KIT突变患者格列卫治疗有效中国人约10.8%C-kit突变,501 patients screened.43 pts treated and evaluatedResponse:(23.3%)10
47、 PR and 13 SD.No response in 15 dose escalation(600-800 mg/day)pts The median PFS:3.5m(15 weeks)The OS:14m(60 weeks),1-year OS 51%,Guo,et al.J Clin Oncol.2011,恩度+DTIC vs DTIC,恩度+DTIC vs DTIC,Endostar plus Dacarbazine improve mPFS vs.Dacarbazine alone as the 1st line therapyEstimated 1-and 2-yr survi
48、val rates1 yr:26.7%vs.56.3%，2 yr:12.7%vs.22.6%Might be a new regimen for the untreated pts with advanced melanoma.,靶向BRAF 突变、MEK BRAF突变率：中国人：20.6%，西方：50%,威罗菲尼：BRIM3试验肿瘤迅速缩小大于80%迅速缓解症状中位PFS7个月与DTIC比较早期即有生存获益,BREAK3：达拉非尼 Vs DTIC达拉非尼 187 入组 150mgbidDTIC 63入组 1g/m2PFS达拉非尼 Vs DTIC 6.9m vs 2.7m达拉非尼 OS大于18
49、m MEK抑制剂：曲美替尼177BRAF突变患者接受达拉非尼联合78既往未使用BRAF抑制剂 PFS 11mORR63-76%69既往使用BRAF抑制剂PFS3.6mORR9-15%,Phase II Study:Combined BRAF and MEK Inhibition in BRAFV600-Positive Melanoma,Primary endpoints:cuSCC,PFS,ORR,DoR,safetySecondary endpoints:population PK parameters,OS,*Crossover to combination dabrafenib+tra
50、metinib 150/2 after progression allowed.,Patients with metastatic melanoma,BRAFV600E/K mutations,ECOG PS 0-1,no previous BRAFi/MEKi(N=162),Dabrafenib 150 mg BID*(n=54),Dabrafenib 150 mg BIDTrametinib 2 mg QD(n=54),Dabrafenib 150 mg BIDTrametinib 1 mg QD(n=54),Flaherty KT,et al.N Engl J Med 2012;367:
