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1、恶性黑色素瘤 药物发展,Alexander M.M. Eggermont, MD, PhD ErasmusMC-Daniel den Hoed Cancer Center Rotterdam Shanghai, CSCO, 2008,黑色素瘤治疗靶点,全身治疗 化疗 细胞因子 抗体型疫苗 新的分子靶向药物 促凋亡剂 抗BRAF 抗VEGFR2 EGFR, MEK, ERK 抗整合素 抗血管生成制剂,转移潜能,无限增值,血管生成,自主生长信号,肿瘤抑制缺失,阻断 凋亡,(Hanahan & Weinberg, 2000),已知肿瘤细胞特征,IV期黑色素瘤的III期临床试验(1),Eggermon
2、t,IV期黑色素瘤含干扰素的III期临床试验 (2),IV期黑色素瘤的III期临床试验(1) 化疗+ IL-2 + IFN,黑色素瘤,生物化疗的纪念 (从今开始) 一线治疗的研究药物,CTLA4 阻断,抗CTLA-4 单克隆抗体,T细胞受体: MHC抗原,CD28: B7,CTLA-4: B7,疫苗?,CTLA-4: T细胞激活的“刹车”,Copyright 2003 by the National Academy of Sciences,断层扫描示治疗前病变(左侧)，治疗后达到完全缓解：病例13（A与B）及病例11（C-F）,Ipilimumab联合多肽类疫苗治疗进展期黑色素瘤(NCI),P
3、han GQ, et al. Proc. Natl. Acad. Sci. 2003;100:8372-8377.,一例进展期黑色素瘤患者Ipilimumab相关性皮疹,Ipilimumab 刺激黑色素细胞免疫识别 (A) 网状红斑样皮疹 (B) 血管周围淋巴细胞浸润突破表皮 (C) CD4+ T细胞临近死亡的黑色素细胞 (D) CD8+ T细胞临近死亡的黑色素细胞,1. Hodi SF, et al. Proc Natl Acad Sci. 2003;100:4712-4717.,1. Attia P, et al. J Clin Oncol. 2005;23:6043-6053. 2. B
4、eck K, et al. J Clin Oncol. 2006;24:2283-2289.,Overview of Gastrointestinal (GI) irAEs,Diarrhea is a frequent irAEs1,2 Most cases are mild or moderate Watery to frank blood Biopsy usually demonstrates inflammatory colitis Management algorithm established Most cases respond to either symptomatic trea
5、tment or steroids Can rarely lead to GI perforation (1%) requiring surgery2,1. Robinson et al. J Immunother. 2004;27:478. 2. Phan et al. Proc Natl Acad Sci USA. 2003;100:8372.,Ipilimumab-Induced Colitis Resembles IBD and Usually Resolves Without Sequela With Appropriate Therapy,Blansfield et al. J I
6、mmunother. 2005;28:593-598.,Overview of irAEs in Endocrine Organs,Hypophysitis Symptoms at presentation: memory loss, fatigue, impotence, headache Management Discontinue ipilimumab Temporary corticosteroid administration Hormonal replacement Patients are asymptomatic Slow return of some endocrine fu
7、nction,6/30/04 Baseline (4.5 mm),12/3/04 Headache/Fatigue after 5 doses (10.8 mm),Blansfield et al. J Immunother. 2005;28:593-598.,Ipilimumab-Related Pituitary Swelling and Dysfunction,Correlation Between IRAEs and Clinical Response,”Enterocolitis in Patients With Cancer After Antibody Blockade of C
8、ytotoxic T-LymphocyteAssociated Antigen 4” 198 patients treated Metastatic melanoma (MM) and Renal cell carcinoma (RCC) Overall objective response rate : 14% 21% of patients had grade 3-4 autoimmune toxicity Objective tumor response rate in MM patients with colitis 36% without colitis 11% Objective
9、tumor response rate in RCC patients with colitis 35% Without colitis 2%,p= 0.0065,p= 0.0016,Beck K, et al. J Clin Oncol. 2006;24:2283-2289.,NCI外科部门 162例患者 有效率 13.8% ABE (自体免疫紊乱事件: 40%) 结肠炎 33% 眼葡萄膜炎 5% 垂体炎 4%,抗CTLA-4,先前SD变为PR,PET = positron emission tomography Courtesy of Steven J. ODay, The Angeles
10、 Clinic and Research Institute,一例男性患者，59岁，1994年诊为右臂恶性黑色素瘤（原发病灶不明）, 接受了5年的疫苗治疗，2000年及2002年发生了腹部的移行复发，均给予手术治疗。2003年发生第三次的腹部移行复发（PET+），患者接受了4次 剂量为3mg/kg的ipilimumab治疗以及 6次达卡巴嗪治疗。 患者出现1级的瘙痒，患者入组研究后未再接受其他抗肿瘤治疗。至2005年3月份，仍未出现新发病灶。,Tumor size (%),Post-treatment initiation (weeks),SD (PET+),SD (PET-),SD,PR,无
11、新病灶,= ipilimumab治疗,0 6 12 18 24 30 36 42 48 54 60,先前明显PD的患者获得持续的完全缓解,患者接受 gp100疫苗 + 3 mg/kg ipilimumab 每3周 共5次，并出现4级的IRAEs垂体炎以及1级的瘙痒.,Tumor size (%),初始治疗后 (周),PR + non- 靶病灶 缓解,PD + 新病灶,= ipilimumab治疗,CR + 患者存活 超过4年 ipilimumab 治疗后,0 6 12 18 24 28,早期进展的患者是否需要时间达到免疫反应? 免疫浸润?,治疗前 12周后 (10/06),12/06,5/07
12、,4次盲剂量的 ipilimumab,4次剂量为10 mg/kg ipilimumab,无治疗,III期 (二线) IL2+多肽 vs CTLA-4 + IL2+多肽 III期 (一线) DTIC vs DTIC + Ipilimumab III期 III期辅助治疗 EORTC 18071 : Ipilimumab vs 安慰剂 1000例患者,II期 (二线) 单药数据 III期 (一线) Tremelimumab vs DTIC / TMZ 阴性 (ASCO 2008),大样本临床试验 Ipilimumab 与 Tremelimumab,非清髓性淋巴细胞删除化疗后输注过继细胞 治疗难治性转
13、移性黑色素瘤 Mark E. Dudley, John R. Wunderlich, James C. Yang, Richard M. Sherry, Suzanne L. Topalian, Nicholas P. Restifo, Richard E. Royal, Udai Kammula, Don E. White, Sharon A. Mavroukakis, Linda J. Rogers, Gerald J. Gracia, Stephanie A. Jones, David P. Mangiameli, Michelle M. Pelletier, Juan Gea-Bana
14、cloche, Michael R. Robinson, David M. Berman, Armando C. Filie, Andrea Abati, Steven A. Rosenberg Journal of Clinical Oncology, Vol 23, No 10 (April 1), 2005: pp. 2346-2357,NCI外科部 51例患者 有效率 51 % 采集浸润性淋巴细胞(TIL) +体外双倍扩增 福达拉滨 + 环磷酰胺 淋巴细胞删除治疗 终点细胞因子维持 TIL输注+ 体内100-1000倍扩增 所有患者均为多种治疗失败，包括高剂量白介素-2,淋巴细胞删除
15、及T-细胞输注治疗,非清髓性淋巴细胞删除化疗后输注过继细胞 治疗难治性转移性黑色素瘤,非清髓性淋巴细胞删除化疗后输注过继细胞 治疗难治性转移性黑色素瘤,Metastatic potential,Immortalization,Angiogenesis,Growth signal independence,Loss of tumor suppression,Blocked apoptosis,(Hanahan & Weinberg, 2000),Acquired Characteristics of Cancer Cells,BAY 43-9006 Sorafenib success in RC
16、C HCC in Stage IV Melanoma,BRAF in melanoma,MAP kinase pathway activated in melanoma Activating BRAF mutations in 70% of melanomas siRNA against mutant BRAF mRNA induces apoptosis Hingorani et al. Cancer Res,0,50,100,150,200,250,0.,0,1,10,Colo205,A375p,0.,0,1,10,D1,D3,D5,BAY 43-9006,Orally available
17、, well-tolerated at 400 mg PO BID,BAY 43-9006, carboplatin & paclitaxel Study schema,carboplatin carboplatin carboplatin & paclitaxel & paclitaxel & paclitaxel Day 1 2 3 19 20 21 22 23 40 43 BAY 43-9006 BAY 43-9006,Response evaluation every 2 cycles (RECIST) After 6 cycles, eligible to continue BAY
18、43-9006 alone,BAY 43-9006, carboplatin & paclitaxel Responses in relation to prior therapy and stage,Response rate by # of prior Rx: 0 23 48% 1 19 33% 2-4 12 20%,Response rate by stage: M1a 7 71% M1b 10 30% M1c 37 32%,Response rate by adjuvant IFN: Yes 19 37% No 35 37%,N ORR%,Progression-free surviv
19、al 6 months = 63% N=54 9 months = 40% N=50 12 months = 22% N=41 Flaherty et al, 2007,BAY 43-9006 is well tolerated with full doses of carboplatin & paclitaxel No evidence of additive toxicities or PK interactions Antitumor activity in metastatic melanoma patients Durable partial responses, all lasti
20、ng 6+ months 63% of patients on study for more than 6 months Antitumor activity was independent of BRAF mutational status,BAY 43-9006, carboplatin & paclitaxel Summary,BAY 43-9006 +Carbo + Taxol vs Carbo + Taxol ECOG/SWOG/EORTC PHASE III TRIAL IN 800 PATIENTS 1ST LINE BAY 43-9006 +Carbo + Taxol vs C
21、arbo + Taxol PRISM Trial in 250 PTS DTIC/TMZ FAILURES 2ND LINE FAILED,BAY 43-9006, carboplatin & paclitaxel PHASE III TRIALS,Metastatic potential,Immortalization,Angiogenesis,Growth signal independence,Loss of tumor suppression,Blocked apoptosis,(Hanahan & Weinberg, 2000),Acquired Characteristics of
22、 Cancer Cells,OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LDH STA-4783 ST-4783 + Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH VACCINES Allovectin, Vical DNA-vaccine vs DTIC,Phase III Trials in Advanced Melanoma 5
23、running/starting,OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LDH STA-4783 ST-4783 + Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH VACCINES Vical DNA-vaccine vs DTIC,Phase III Trials in Advanced Melanoma 5 running/s
24、tarting,Final common pathway of anticancer therapies,Bcl-2,Bcl-2,Bcl-2,Bcl-2,Bcl-2,Bcl-2 blocks apoptosis,GenasenseTM pretreatment results in decreased Bcl-2 levels,Oblimersen = Genasense enables apoptosis,Largest randomized trial in advanced melanoma Multicenter (139 sites, 9 countries), open-label
25、 Primary endpoint: overall survival Secondary endpoints: progression-free survival; antitumor response (RECIST); safety N = 771 (enrollment target reached January 2003) Cycles repeated every 3 weeks (up to 8 cycles),Genasense in melanoma: Phase III trial,GM301:overall survival (ITT) months,Overall S
26、urvival 24-Months Minimum Follow-up,Months,Proportion surviving,N = 771,Overall Survival Baseline LDH,Proportion surviving,Proportion surviving,Months, 1.1 x Upper Limit of Normal,Median HR P,11.4,DTIC,9.7,0.80 0.018,Genasense/ DTIC,Months, 1.1 x Upper Limit of Normal,N = 508,Relationship Between LD
27、H and Survival,N 274 234 157 76 19,LDH,Kaplan-Meier survival curves at 24-month minimum follow-up by LDH category: Study GM301 (overall p 0.0001),Survival curves at 24-month minimum follow-up among patients with baseline LDH value 0.8 x ULN,AGENDA TRIAL DTIC vs DTIC + Oblimersen in stage IV melanoma
28、 LDH 0.8 UNL Double blind placebo controlled randomized trial 350 pts ongoing,OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LDH ELESCLOMOL (STA-4783) ST-4783 + Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH VACCINES A
29、llovectin, Vical DNA-vaccine vs DTIC,Phase III Trials in Advanced Melanoma 5 running/starting,Elesclomol treatment induces ROS - apoptosis,Cytochrome C release, caspase 9 activation,APOPTOSIS,Hsp70,Chemotherapeutic agent,Elesclomol synergizes with chemotherapeutic agents which act via the intrinsic
30、mitochondrial apoptotic pathway,Elesclomol sensitizes the mitochondria to other cancer drugs, thus facilitating their ability to induce apoptosis without increasing their toxicity to normal cells,elesclomol,OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LDH STA-4783 ST-4783 + Taxol vs Taxol Up to 2x U
31、NL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNL LDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH VACCINES Allovectin, Vical DNA-vaccine vs DTIC,Phase III Trials in Advanced Melanoma 5 running/starting,ABRAXANE Albumine wrapped Paclitaxel,ABRAXANE IN BREAST CANCER,ABRAXANE in BREAST CANCER,
32、OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LDH STA-4783 ST-4783 + Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH VACCINES Allovectin, Vical DNA-vaccine vs DTIC,Phase III Trials in Advanced Melanoma 5 running/starti
33、ng,Thymosin alpha 1 is an immunomodulatory compound that promotes T cell maturation and upregulates T cell response. T1 showed clinical potential benefit in a previous pilot study in melanoma patients (Rasi et al. Melanoma Research, 2000).,Background THYMOSIN-alpha 1,Extensive Randomized Phase II tr
34、ials exploring various doses of Thymosin-alpha 1 + IFNalpha,Results Response Rate,Table 2. RESPONSE RATE, OVERALL AND BY STRATUM,*The null hypothesis was rejected,CR=Complete Response; PR=Partial Response; RR=Response Rate; C.I.=Confidence Interval,Results Survival in the ITT Population,Results Surv
35、ival in Normal LDH,Overall Survival in *Normal LDH,*Normal=LDHULN,time (months),Conclusions Thymosin-alpha 1,Thymosin alpha 1 was well tolerated at all doses and regimens Both arms with Thymosin 3.2 mg reached the response rate required to reject the null hypothesis Data on Overall Survival and Prog
36、ression Free Survival, particularly in the population with normal LDH level, support the conduction of a phase III program The best candidate regimen for a future phase III trial seems to be DTIC + Thymosin 3.2 mg The role of Interferon alpha in the therapeutic combination is debatable,OBLIMERSEN Ob
37、limersen + DTIC vs DTIC 0.8 UNL LDH STA-4783 ST-4783 + Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH VACCINES ALLOVECTIN DNA-vaccine vs DTIC,Phase III Trials in Advanced Melanoma 5 running/starting,OBLIMERSEN Oblime
38、rsen + DTIC vs DTIC 0.8 UNL LDH STA-4783 ST-4783 + Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH VACCINES Allovectin, Vical DNA-vaccine vs DTIC,AVASTIN Rand-Phase 2 CTA - Phase III in stage IV Phase III in stage IIB
39、-III VACCINES Vical DNA-vaccine vs DTIC GSK MAGE-3 vs DTIC or Placebo Biovex vs DTIC MoAb IL2-Mab contructs vs DTIC ONTAK,Phase III in Advanced Melanoma 5 running/starting / 4 preparing,WHAT IS NEXT IN ADJUVANT THERAPY IN MELANOMA,Alexander M.M. Eggermont, MD, PhD ErasmusMC-Daniel den Hoed Cancer Ce
40、nter Rotterdam SHANGHAI, CSCO, 2008,MACROSCOPIC NODAL INVOLVEMENT,EORTC 18071 Double blind placebo controlled randomisedPhase III trial : Anti-CTLA4 vs Placebo in macroscopic N-positive disease 1000 pts,SIGNIFICANCE OF ULCERATION,EORTC 18991 EORTC 18952 SIGNIFICANCE OF ULCERATION AND IFN-SENSITIVITY
41、,RFS in Pts with Ulceration,(years),0,1,2,3,4,5,6,0,10,20,30,40,50,60,70,80,90,100,P=0.05 , HR = 0.77 (99% CI: 0.55 , 1.09),(years),0,1,2,3,4,5,6,0,10,20,30,40,50,60,70,80,90,100,P=0.006 , HR = 0.59 (99% CI 0.35 , 0.98),Ulceration,Ulceration & N1:,OBSERVATION,Peg-IFN alfa-2b,O,N,116,181,108,192,O,N,
42、59,90,45,96,Eggermont,ULCERATION AND EFS,ULCERATION and SURVIVAL,EORTC 18081 RANDOMIZED PHASE III TRIAL in STAGE II ULCERATED PRIMARY MELANOMA 1mm 2 yrs PEG-IFN vs OBSERVATION 1000 pts,ULCERATION BIOLOGY,THANK YOU FOR YOUR ATTENTION,OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LDH STA-4783 ST-4783 +
43、 Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH,AVASTIN Stage IV ? Phase III in stage IIB-III VACCINES Vical DNA-vaccine vs DTIC GSK MAGE-3 vs DTIC or Placebo Biovex vs DTIC MoAb IL2-Mab contructs vs DTIC,III期 ：进展期黑色素瘤 4项进行/开始 / 4 准备,