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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 Med
2、ical Society. 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：Ipilimumab 2013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;364:2517-2
3、526.,Ipi + gp100 Ipi gp100,Median OS, Mos,10.0 10.1 6.4,HR,0.68 0.66,P Value, .001 .003,Ipi + D Placebo + D,Median OS, Mos,11.2 9.1,HR,0.72,P Value, .001,Est 1, 2, 3-Yr Survival, %,47.3, 28.5, 20.8 36.3, 17.9, 12.2,Ipilimumab + gp100 vs gp1001,Ipilimumab vs Placebo2,OS (%),Mos,0,0,100,48,80,60,40,20
4、,40,32,24,16,8,56,52,44,36,28,20,12,4,Patients Survival (%),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
5、疫相关毒性irAE,Evolution of Response: Patient Example,Screening,Week 12 Initial increase in total tumour burden (mWHO PD),Week 16 Responding,Week 72 Durable & 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,Nivo
6、lumab Activity (ORR)1 Melanoma: 28% NSCLC: 18% RCC: 27%,MK-3475 Activity (ORR)2 Melanoma: 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 Mass
7、achusetts Medical Society. 2. Hamid O, et al. N Engl J Med. 2013;369:134-144.,Activity of Anti-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
8、Trial,Melanoma expansion cohort of phase I KEYNOTE-001 study Advanced, unresectable disease with ECOG PS 0-1 Ipilimumab-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 Naive 2 mg/kg q
9、3w (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),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
10、. Copyright 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.,54-yr-old male with desmoplastic melanoma after progressing on ipilimumab,Clinical Activity of MK-3475 in a Patient With Metastatic Desmoplastic Melanoma,CTL Infiltrates in Regressing Metast
11、atic Melanoma Lesion After MK-3475 Treatment,Baseline: February 29, 2012,August 20, 2012,Ribas A, et al. ASCO 2013. Abstract 9009.,Pembrolizumab (MK-3475) in Advanced Melanoma: AEs 10% Incidence,Similar safety profiles in ipilimumab-naive and ipilimumab-treated patients Other grade 3/4 AE ( 1% incid
12、ence): ALT elevation, headache, hypothyroidism, decreased appetite, dyspnea,Ribas A, et al. ASCO 2014. Abstract LBA9000.,40,49,13,Pembrolizumab (MK-3475) in Advanced Melanoma: Response by PD-L1 Expression,PD-L1 positivity: staining in 1% of tumor cells 125 patients evaluable for PD-L1 expression,PD-
13、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+ (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 Expres
14、sion,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.,80,60,40,20,0,0,20,40,60,80,100,PFS (%),Wks,PD-L1 positive PD-L1 negative,80,60,40,20,0,0,20,40,60,80,100,OS (%),Wks,PD-L1 positive PD
15、-L1 negative,Phase I Nivolumab Study: Long-term Follow-up in IPI-Naive Pts With Melanoma,Primary endpoints: safety, tolerability Secondary endpoints: preliminary efficacy, dose-response relationships Study amended to collect OS data Subgroup analysis of response by key patient features Exploratory P
16、D-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 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
