肾癌靶向治疗_省肿瘤大会吴晓安

肾癌分子靶向药物治疗进展,解放军第一七四医院 吴晓安,肾癌的药物治疗发展史上的重大事件,1. Snow M, et al. Urology 1982; 20:177. 2. Rini BI, et al. Lancet 2009; 373:1119-1132.,靶向治疗时代,细胞因子时代,LAK、CIK、DC,过继免疫治疗,2010-11-23,杨姓女患者,46岁,2008-3-27外院手术切除右肾,病理为右肾乳头状细胞癌,20096-9腹腔肿物切除,2009-9-10超声示肝尾状叶占6.45.5cm占位.2010-10-9 在外院行生物化疗(CF+5FU,干扰素900万U,每周3次至2010-11-5 结束),2010-11-23,2010-11-23,2010-11-28,2010-11-28,FDA批准用于mRCC的药物,靶向药物抑制正常细胞生长和肿瘤涉及的多重信号传导通路,Rini BI and Small EJ. J Clin Oncol 2005;23:10281043, adapted with permission; Duensing A et al. Cancer Invest 2004;22:106116; Marmor MD et al. Int J Rad Oncol Biol Phys 2004;58:903913. Please see full prescribing information.,肿瘤细胞膜,VEGFR,P13K,AKT,mTOR,VEGFR,Raf,Mek,Ras,Erk,肿瘤血管内皮细胞基膜,PDGFR,KIT,PDGFR,内皮细胞,VEGF-A,VEGFR = 血管内皮生长因子受体; PDGFR= 血小板衍生生长因子受体;KIT= 干细胞因子受体,细胞核,转录因子,细胞黏附,细胞生存,细胞增殖,细胞凋亡,细胞分化,新生血管形成,舒尼替尼,舒尼替尼,贝伐单抗,替西罗莫司依维莫司,索拉非尼,索拉非尼,晚期肾癌的一线治疗,* 1类证据. 需选择患者.,一线治疗(透明细胞为主型) ? ? ?,NCCN指南-晚期肾癌的治疗策略,IV期(转移性),减瘤性肾切除术（若不能手术，则一线治疗）,舒尼替尼,索坦较干扰素显著延长PFS,Szczylik, et al. ASCO 2007 Abstract 5025.Motzer RJ, et al. J Clin Oncol 2009; 27:3584-3590.,进展风险46%,索坦一线治疗较IFN-显著降低死亡风险达18%全组人群,Motzer RJ, et al. J Clin Oncol 2009; 27:3584-3590.,晚期RCC：目前唯一突破2年OS的治疗,Total DeathSunitinib 190IFN-a 200,最终总生存期（OS）,Motzer RJ, et al. J Clin Oncol 2009,索坦一线治疗较IFN-显著降低死亡风险达35%,Motzer RJ, et al. J Clin Oncol 2009; 27:3584-3590.,35%,(排除未接受后续治疗患者),未接受后续治疗的患者的OS分析（提出后续治疗因素）,Motzer RJ, et al. J Clin Oncol 2009,同一对照药物IFN-，不同靶向药物的ORR不同,B=贝伐单抗；SOR=索拉非尼；SUN=索坦,1. Escudier B, et al. J Clin Oncol 2009; 27(15S): Abs. 5020. 2. Rini B, et al. J Clin Oncol 2009; 27(15S): LBA5019. 3. Escudier B, et al. J Clin Oncol 2009; 27:1280-1289. 4. Motzer RJ, et al. J Clin Oncol 2009; 27:3584-3590.,同一对照药物IFN-，不同靶向药物的PFS不同,B=贝伐单抗；SOR=索拉非尼SUN=索坦；PAZ=帕唑帕尼,*P0.05其余各组间差异都达到了统计学显著性差异,1. Escudier B, et al. J Clin Oncol 2009; 27(15S): Abs. 5020. 2. Rini B, et al. J Clin Oncol 2009; 27(15S): LBA5019. 3. Escudier B, et al. J Clin Oncol 2009; 27:1280-1289. 4. Motzer RJ, et al. J Clin Oncol 2009; 27:3584-3590.5. Stemberg CN, et al. J Clin Oncol 2010; 28:1061-1068.,同一对照药物IFN-，不同靶向药物的OS不同,1. Escudier B, et al. J Clin Oncol 2009; 27(15S): Abs. 5020. 2. Rini B, et al. J Clin Oncol 2009; 27(15S): LBA5019. 3. Motzer RJ, et al. J Clin Oncol 2009; 27:3584-3590.,B=贝伐单抗；SUN=索坦；*P0.05,索坦是迄今首个证实单药治疗mRCC患者总生存期可超过2年的靶向药物,Sunitinib 较IFN- 显著改善患者生活质量,Cella D, et al. J Clin Oncol 2008;27:3763-69,31.030.530.029.529.028.528.027.527.026.5,Sunitinib(Slope = 0.140; P=0.003),IFN-(Slope = 0.041; P=0.567),Estimated meanFKSI-DRS score,1234567891011,Time (months),患者自觉症状改善Sunitinib显著优于IFN-,FKSI-DRS（生活质量主要研究终点）,FACT-G量表、EQ-5D指数、 EQ-VAS评分和FKSI-15评分在两组间的差异均表明Suntinib治疗有利(P 1.5 x ULNHb 10 mg/dL全身治疗距诊断时间 1 年KPS 602处脏器转移(N = 626),替西罗莫斯 25 mg IV weekly(n = 209),IFN- 逐渐增量至 18 MU SC TIW(n = 207),替西罗莫斯 15 mg IV weekly +IFN- 6 MU SC TIW(n = 210),Hudes G, et al. N Engl J Med. 2007;356:2271-2281.,Hudes G, et al. N Engl J Med. 2007;356:2271-2281.,OS*,PFS*,*Kaplan-Meier estimates.,替西罗莫斯 vs IFN-OS， PFS,Probability of Survival,Months,0.00,0.25,0.50,0.75,1.00,0,5,10,15,20,25,30,Interferon,替西罗莫斯,Combination,Probability of PFS,Months,0.00,0.25,0.50,0.75,1.00,0,5,10,15,20,25,30,Interferon,替西罗莫斯,Combination,贝伐单抗,AVOREN:贝伐单抗+ IFN- vs IFN- （ III期试验）,终点主要：OS次要：PFS, TTP, TTF,复发率, 安全性,IFN- + Bevacizumab 10 mg/kg IV Q2W 直至进展 (n = 327),IFN- 9 MU SC TIW (Max 52 weeks; 允许减量) + 安慰剂 (n = 322),入选标准肾癌切除术后的晚期患者 分层国家MSKCC risk group(N = 649),1:1,Escudier B, et al. Lancet. 2007;370:2103-2111.,AVOREN中的PFS（根据MSKCC危险因素分层）,Risk factors associated with shorter survival are low Hb, high corrected calcium, high LDH, poor performance status, and an interval of 1 yr from diagnosis to treatment. *Motzer R, et al. J Clin Oncol. 2002;20:289-296.,Pazopanib（VS 安慰剂-III期临床 ）,研究设计,Pazopanib 800 mg qd(n = 290),Matching Placebo(n = 145),Option to receive pazopanib via an open-label study at progression.,StratificationECOG PS 0 vs 1Prior nephrectomyRx-naive (n = 233) vs 1 cytokine failure (n = 202),Patients with advanced RCC(N = 435),Randomization2:1,Pazopanib vs 安慰剂-总体人群PFS,1.0,0.0,0.2,0.4,0.6,0.8,0,5,10,15,20,Months,Proportion Progression-Free,Patients at risk Pazopanib 29015976296 Placebo 14538142,Hazard Ratio = 0.4695% CI (0.34, 0.62)P value 0.0000001Median PFSPazopanib:9.2 moPlacebo:4.2 mo,PazopanibPlacebo,1.0,0.0,0.2,0.4,0.6,0.8,0,5,10,15,20,Months,Proportion Progression-Free,Patients at risk Pazopanib 1553439111 Placebo 782272,Hazard Ratio = 0.4095% CI (0.27, 0.60)P value 0.0000001Median PFSPazopanib:11.1 moPlacebo: 2.8 mo,PazopanibPlacebo,Pazopanib vs安慰剂-初治患者PFS,1.0,0.0,0.2,0.4,0.6,0.8,0,5,10,15,20,Months,Proportion Progression-Free,Patients at risk Pazopanib 1357537185 Placebo 67167,Hazard Ratio = 0.5495% CI (0.35, 0.84)P value 0.001Median PFSPazopanib: 7.4 moPlacebo: 4.2 mo,PazopanibPlacebo,Pazopanib vs安慰剂-细胞因子失败的PFS,总体人群的OS（初步结果）,OBrien-Fleming boundary for futility / superiority: P = 0.201 / 0.004 (1-sided),1.0,0.0,0.2,0.4,0.6,0.8,0,5,10,15,20,Months,Proportion Surviving,Patients at risk Pazopanib 29025421411520 1 PlaceboHazard Ratio = 0.7395% CI (0.47, 1.12)P value = 0.02 (1-sided)Median OSPazopanib: 21.1 moPlacebo: 18.7 mo,PazopanibPlacebo,25,48% of placebo patients received pazopanib after PD,一线治疗小结,*Independent central review.,转移性肾癌一线治疗的临床试验,一线方案中的PFS（根据危险因素分层）,1. Motzer RJ, et al. N Engl J Med. 2007;356:115-124. 2. Szczylik C, et al. ASCO 2007. Abstract 5025. 3. Hudes G, et al. N Engl J Med. 2007;356:2271-2281. 4. Escudier B, et al. Lancet. 2007;370:2103-2111. 5. Rini BI, et al. ASCO GU 2008. Abstract 350.,一线治疗MRCC的临床试验（已有的和进行中的）,1. Motzer RJ, et al. N Engl J Med. 2007;356:115-124. 2. Szczylik C, et al. ASCO 2007. Abstract 5025. 3. Escudier B, et al. Lancet. 2007;370:2103-2111. 4. Hudes G, et al. N Engl J Med. 2007;356:2271-2281. 5. ClinicalT. NCT00631371. 6. ClinicalT. NCT00719264. 7. ClinicalT. NCT00720941. 8. ClinicalT. NCT00378703.,晚期肾癌 - 一线治疗,1类证据推荐：索坦Temsirolimus （高危） Bevacizumab+IFNPazopanib （新增）2A类证据推荐：High dose IL-2索拉菲尼,首选推荐,晚期肾癌的二线治疗,索拉非尼,细胞因子治疗失败后（TARGET试验） 索拉非尼 vs细胞因子（III期试验）,随机，双盲，多中心治疗终点：PD或毒性过大主要终点: OS次要终点: PFS,Placebo(n = 452),Sorafenib400 mg BID(n = 451),入选标准 透明细胞型 既往接受过细胞因子治疗 MSKCC 预测分值(中低) (N = 903),Escudier B, et al. N Engl J Med. 2007;356:125-134.,20,Probability of PFS (%),0,25,50,75,100,Time From Randomization (Mos),0,4,10,2,6,8,12,14,16,*Investigator assessment.,Escudier B, et al. N Engl J Med. 2007;356:125-134.,索拉非尼治疗细胞因子失败- PFS,Sorafenib (n = 451)Placebo (n = 452)HR (S/P)Censored observation,Median PFS,* Mos5.502.800.44,Bukowski RM, et al. ASCO 2007. Abstract 5023.,TARGET试验 初次 OS 分析:（未考虑交叉治疗）,TARGET 试验调整OS分析：（去除交叉治疗的因素）,100,75,50,25,0,20,24,28,32,36,16,0,4,8,12,Sorafenib: 17.8 mos,Placebo: 15.2 mos,HR (sorafenib/placebo): 0.88,95% CI: 0.74-104,P = .146*,OS (%),Time From Randomization (Mos),Sorafenib: 17.8 mos,Placebo: 14.3 mos,HR (sorafenib/placebo): 0.78,95% CI: 0.62-0.97,P = .0287,索拉非尼治疗细胞因子失败-OS,两组平均治疗时间Placebo exposure: 12.0 wksSorafenib exposure: 40.1 wks,561 events.*Nonsignificant; OBrien-Fleming threshold for statistical significance: = 0.037,40,100,75,50,25,0,20,24,28,32,36,16,0,4,8,12,OS (%),Time From Randomization (Mos),40,Censored at June 30, 2005, approx start of crossover.Statistically significant; OBrien-Fleming threshold for statistical significance: = 0.037,依维莫斯（RAD001, Everolimus ）,应用VEGFR抑制剂后进展的患者 Everolimus VS 安慰剂（III期试验）,N=410 （ 2006年9月 2007年10月）第2次中期总结: 2007年10月15日, 191 例患者无进展独立数据监测委员会建议终止试验,随机2:1,分层既往用过12种VEGFR抑制剂治疗MSKCC risk group好 (29%)中 (56%) 差 (15%)(N = 410),Everolimus + Best Supportive Care(n = 272),Placebo + Best Supportive Care(n = 138),Motzer RJ, et al. Lancet. 2008;372:449-456.,100,80,60,40,20,0,0,2,4,6,8,10,12,PFS (%),Months,Everolimus vs安慰剂-PFS,Motzer RJ, et al. Lancet. 2008;372:449-456.,Median PFSEverolimus (n = 272): 4.0 mosPlacebo (n = 138): 1.9 mosHR: 0.30 95% CI: 0.22-0.40Log rank P .0001,Motzer RJ, et al. Lancet. 2008;372:449-456.,Everolimus vs安慰剂（优势治疗人群）,Central reviewInvestigator reviewMSKCC risk Favorable Intermediate PoorPrevious treatment Sorafenib only Sunitinib only BothAge 65 yrs 65 yrsSex Male FemaleRegion US and Canada Europe Japan and Australia,HR,P Value,N, .0001 .0001 .0001 .0001 .009 .0001 .0001 .0001 .0001 .0001 .0001.002 .0001 .0001 .001,0,In favor of everolimus,0.300.310.35 0.25 0.390.29 0.30 0.280.32 0.290.29 0.360.24 0.37 0.10,410410118 231 61119 184 107259 151317 93130 251 29,In favor of placebo,0.2,0.4,0.6,0.8,1.0,1.2,1.4,舒尼替尼（贝伐单抗失败）,贝伐单抗失败的MRCC应用舒尼替尼 (II期试验): 最好疗效,*Assessed with RECIST.,Rini BI, et al. J Clin Oncol. 2008;26:3743-3748.,阿昔替尼, Axitinib（索拉非尼失败）,Rini B, et al. ASCO 2007. Abstract 5032.,索拉非尼失败的MRCCAxitinib的应用: 最好疗效,*1/14 patients who had previous sorafenib and sunitinib treatment had a PR.9/14 patients who had previous sorafenib and sunitinib treatment had tumor shrinkage.,二线治疗小结,2009年肾透明细胞癌的治疗原则（国外推荐）,Adapted from Atkins M, et al. ASCO 2009 and Bukowski R, et al. ASCO 2009. Abstract 5023.,晚期肾癌 二线治疗的药物推荐变化,低剂量IL-2+IFN-被从二线治疗去掉,新增Pazopanib一类证据,新增 RAD001 (依维莫司)一类证据,Motzer RJ, et al. J Clin Oncol 2006; 24: 16-24,Motzer RJ, et al. J Urol 2007; 178: 1883-7,#主要终点,索坦用于细胞因子失败的二线治疗依然有效,ORR仍可达33%以上,晚期肾癌二线治疗 索坦仍是选择,正在研发的新药,在研的治疗肾细胞癌的抗血管生成药物,VEGFR TKIsCediranibVandetanibPazopanibAxitinibDASTMotesanibTelatinibBrivanib,Integrin inhibitorsVolociximabVitaxinCNT-095CilengitideE7820ATN-161AMG-386 (angiopoietin),VEGF targetedBevacizumabAfliberceptPTC299INGN241VEGFR targetedIMC-1121BCDP791OthersCP-868596 (PDGFR),AngioceptABT-869OSI-930CEP-11981CHIR-258XL880XL820XL647,索坦一线治疗中国mRCC的多中心、单臂、开放、IV期临床研究中期分析,研究设计,开放、单臂、多中心 (11家三甲医院)、IV期临床研究评价索坦一线治疗中国mRCC患者的疗效及安全性主要终点：无进展生存期 (PFS)次要终点：客观缓解率 (ORR)总生存期 (OS),一年生存率安全性指标,入选标准,18岁ECOG 0-1经病理组织学检查，确诊具有透明细胞成分的转移性肾细胞癌，且无法手术治疗转移性肾癌，一线治疗有可测量病灶血常规、肝肾功能、凝血功能等基本正常心脏超声：LVEF 正常值低限(LLN)签署知情同意书,排除标准,无透明细胞成分的肾细胞癌既往接受针对转移性肾癌的治疗既往辅助治疗结束至入组的时间