肾癌靶向治疗省肿瘤大会吴晓安PPT学习教案

1、会计学1肾癌靶向治疗省肿瘤大会吴晓安肾癌靶向治疗省肿瘤大会吴晓安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)第2页/共79页2010-11-232010-11-232010-11-282010-11-28第3页/共79页时间药名开发商2005.12（）2006.1Sunitinib 辉瑞2007.5CCI-779 （）惠氏2007.12）基因泰克/罗氏

2、 2009.3RAD001（）诺华2009.10Pazopanib（）葛兰素第4页/共79页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.肿瘤细胞膜肿瘤细胞膜VEGFRP13KAKTmTORVEG

3、FRRafMekRasErk肿瘤血管内皮细胞基膜 PDGFRPPPPKITPDGFRPPPPPPPPPPPP内皮细胞内皮细胞 VEGF-AVEGFR = 血管内血管内皮生长因子受体皮生长因子受体; PDGFR= 血小板血小板衍生生长因子受衍生生长因子受体体;KIT= 干细胞因子干细胞因子受体受体细胞核转录因子细胞黏附细胞黏附细胞生存细胞生存细胞增殖细胞增殖细胞凋亡细胞凋亡细胞分化细胞分化新生血管形成新生血管形成PPPP舒尼替尼舒尼替尼舒尼替尼舒尼替尼贝伐单抗贝伐单抗替西罗莫司替西罗莫司依维莫司依维莫司索拉非尼索拉非尼索拉非尼索拉非尼第5页/共79页第6页/共79页* 1类证据. 需选择患者.一

4、线治疗一线治疗(透明细胞为主型) ? ? ?IV期(转移性)减瘤性肾切除术（若不能手术，则一线治疗）第7页/共79页第8页/共79页Szczylik, et al. ASCO 2007 Abstract 5025.Motzer RJ, et al. J Clin Oncol 2009; 27:3584-3590.无进展生存概率1.00.20.0时间 (月)一线治疗索坦 (n=375): 11.0mIFN- (n=375): 5.1mHR=0.538; 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

5、; 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.B+IFN1B+IFN2SOR3SUN4无进展生存期 (月)036912IFN-*11.05.54.

6、95.65.0PAZ511.12.8第15页/共79页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；*P0.0523.318.326.421.317.414.1IFN-B+IFN1B+IFN2SUN3中位生存期 (月)10152025302年索坦是迄今首个证实单药治疗mRCC患者

7、总生存期可超过2年的靶向药物第16页/共79页Cella D, et al. J Clin Oncol 2008;27:3763-69 31.030.530.029.529.028.528.027.527.026.5Sunitinib(Slope = 0.140; P=0.003)IFN-(Slope = 0.041; P=0.567)Estimated meanFKSI-DRS score1234567891011Time (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

8、-15评分在两组间的差异均表明Suntinib治疗有利(P 1.5 x ULN Hb 10 mg/dL 全身治疗距诊断时间 1 年 KPS 60 2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.第22页/共79页Hudes G, et al. N Engl J Med. 2007;356:2271-

9、2281.OS* PFS* *Kaplan-Meier estimates.Probability of SurvivalMonths0.000.250.500.751.00051015202530Interferon替西罗莫斯CombinationProbability of PFSMonths0.000.250.500.751.00051015202530Interferon替西罗莫斯Combination第23页/共79页第24页/共79页IFN- + Bevacizumab 10 mg/kg IV Q2W 直至进展 (n = 327)IFN- 9 MU SC TIW (Max 52 w

10、eeks; 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)1:1Escudier B, et al. Lancet. 2007;370:2103-2111.第25页/共79页第26页/共79页第27页/共79页第28页/共79页Median PFS, MosRisk Group%IFN- + Bev (n = 327)IFN- (n = 322)好好 (0个个)2712.97.6HR (P value)0.60 (.004)中中 (1-2 个个)5610.24.5HR (P value)0.55 (.0001

11、)差差 ( 3 个个)92.22.1HR (P value)0.81 (.457)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. 第29页/共79页第30页/共79页研究设计Pazopanib 800 mg q

12、d(n = 290)Matching Placebo(n = 145)Option to receive pazopanib via an open-label study at progression.Stratification ECOG PS 0 vs 1 Prior nephrectomy Rx-naive (n = 233) vs 1 cytokine failure (n = 202)Patients with advanced RCC(N = 435)Randomization2:1第31页/共79页1.00.00.805101520MonthsProporti

13、on Progression-Free Patients at risk Pazopanib 29015976296 Placebo 14538142Hazard Ratio = 0.4695% CI (0.34, 0.62)P value 0.0000001Median PFSPazopanib:9.2 moPlacebo:4.2 moPazopanibPlacebo第32页/共79页1.00.00.805101520MonthsProportion Progression-Free Patients at risk Pazopanib 1553439111 Placebo

14、 782272Hazard Ratio = 0.4095% CI (0.27, 0.60)P value 0.0000001Median PFSPazopanib:11.1 moPlacebo: 2.8 moPazopanibPlaceboPazopanib vs安慰剂-初治患者PFS第33页/共79页1.00.00.805101520MonthsProportion Progression-Free Patients at risk Pazopanib 1357537185 Placebo 67167Hazard Ratio = 0.5495% CI (0.35, 0.84

15、)P value 0.001Median PFSPazopanib: 7.4 moPlacebo: 4.2 moPazopanibPlaceboPazopanib vs安慰剂-细胞因子失败的PFS第34页/共79页 OBrien-Fleming boundary for futility / superiority: P = 0.201 / 0.004 (1-sided)1.00.00.805101520MonthsProportion Surviving Patients at risk Pazopanib 29025421411520 1 Placebo 14511593

16、526Hazard Ratio = 0.7395% CI (0.47, 1.12)P value = 0.02 (1-sided)Median OSPazopanib: 21.1 moPlacebo: 18.7 moPazopanibPlacebo 2548% of placebo patients received pazopanib after PD第35页/共79页第36页/共79页*Independent central review.Published inPatients, nPhaseTreatment ArmsORRC/CB, %Median PFS, MosMotzer et

17、 al. N Engl J Med. 2007;356:115-124.750IIISunitinib37 (31*)/84 (79*)11.0*IFN-9 (6*)/66 (55*)5.0*Escudier B, et al. 2007 Intl Symposium on TAT. 189IISorafenib55.7IFN-95.6Hudes G et al. N Engl J Med. 2007;356:2271-2281.626 (poor prognosis)IIITemsirolimus8.6/32.15.5IFN-4.8/15.53.1Temsirolimus +IFN-4.8/

18、15.54.7AVOREN trial Escudier B. Lancet. 2007;370:2103-2111.649IIIIFN- + Bevacizumab31/7710.2IFN-13/635.4CALGB Study 90206. Rini B. 2008 ASCO GU Cancers Symposium.732IIIIFN- + Bevacizumab25.58.5IFN-13.15.2Pazopanib vs Placebo VEG105192. 2009 ASCO435IIIPazopanib3211.1Placebo42.8第37页/共79页Agent(s)PFS, m

19、osGoodIntPoorSunitinib11114.510.63.7Sorafenib25.7?Temsirolimus33.7NANA3.7 Bev + IFN (AVOREN)410.212.910.22.2Bev + IFN (CALGB)58.51. 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. Escu

20、dier B, et al. Lancet. 2007;370:2103-2111. 5. Rini BI, et al. ASCO GU 2008. Abstract 350.第38页/共79页Agent Study Phase and PopulationNOR/TS, %PFS, MosSunitinib1Phase III: Untreated pts; ECOG PS 0 or 175031/NA11 Sorafenib2 Phase II: Sorafenib vs IFN in untreated pts1895/685.7 Bev + IFN3Phase III: Nephre

21、ctomized pts with advanced RCC (AVOREN and CALGB)64931/709-10 Temsirolimus4 Phase II: Temsirolimus vs temsirolimus + IFN in untreated pts with poor prognosis mRCC6268.6/NA5.5 Bev/temsirolimus5 Phase III: Bev + temsirolimus vs bev + IFN-800Rad001 + bev6 Phase II: Everolimus + bev vs IFN + bev360Sunit

22、inib7 Phase III: Sunitinib vs pazopanib876Bev, temsirolimus, and sorafenib combos8Phase II: Bev vs bev + temsirolimus, bev + sorafenib, and sorafenib + temsirolimus 3601. 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. 2

23、007;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.第39页/共79页1类证据推荐类证据推荐：索坦索坦Temsirolimus （高危）（高危） Bevacizumab+IFNPazopanib （新增）（新增）2A类证据

24、推荐类证据推荐：High dose IL-2索拉菲尼索拉菲尼第40页/共79页首选推荐第41页/共79页第42页/共79页第43页/共79页第44页/共79页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.第45页/共79页20Probability of PFS (%)0255075100Time From Randomization (Mos)0410268

25、121416*Investigator assessment.Escudier B, et al. N Engl J Med. 2007;356:125-134.Sorafenib (n = 451)Placebo (n = 452)Censored observationMedian PFS,* Mos5.502.800.44第46页/共79页Bukowski RM, et al. ASCO 2007. Abstract 5023.TARGET试验试验 初次初次 OS 分析分析:（未考虑交叉治疗）（未考虑交叉治疗）TARGET 试验调整试验调整OS分析：分析：（去除交叉治疗的因素）（去除交叉

26、治疗的因素） 100755025020242832361604812Sorafenib: 17.8 mosPlacebo: 15.2 mosHR (sorafenib/placebo): 0.8895% CI: 0.74-104P = .146*OS (%)Time From Randomization (Mos)Sorafenib: 17.8 mosPlacebo: 14.3 mosHR (sorafenib/placebo): 0.7895% CI: 0.62-0.97P = .0287561 events.*Nonsignificant; OBrien-Fleming threshold

27、 for statistical significance: = 0.03740100755025020242832361604812OS (%)Time From Randomization (Mos)40Censored at June 30, 2005, approx start of crossover.Statistically significant; OBrien-Fleming threshold for statistical significance: = 0.037第47页/共79页第48页/共79页随机2:1分层 既往用过12种VEGFR抑制剂治疗 MSKCC risk

28、 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.第49页/共79页100806040200024681012PFS (%)MonthsMedian PFSEverolimus (n = 272): 4.0 mosPlacebo (n = 138): 1.9 mosHR: 0.30 95% CI: 0.22-0.40Log

29、 rank P .0001第50页/共79页Motzer RJ, et al. Lancet. 2008;372:449-456.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 AustraliaHRP ValueN .0001 .0001 .0001 .00

30、01 .009 .0001 .0001 .0001 .0001 .0001 .0001.002 .00013 mSD3 m27%27%23%23%PFS (m)PFS (m)8.8OS (m)OS (m)16.416.423.923.9Motzer RJ, et al. J Clin Oncol 2006; 24: 16-24Motzer 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 索坦仍是选择第59页/共79页第60页/共79页Integrin inhibi

31、torsVolociximabVitaxinCNT-095CilengitideE7820ATN-161AMG-386 (angiopoietin)VEGF targetedBevacizumabAfliberceptPTC299INGN241VEGFR targetedIMC-1121BCDP791OthersCP-868596 (PDGFR)AngioceptABT-869OSI-930CEP-11981CHIR-258XL880XL820XL647第61页/共79页第62页/共79页一年生存率安全性指标l转移性肾细胞癌 (N=105)l组织学确诊有透明细胞成分l既往未经系统治疗 lECO

32、G PS 0-1索坦 50 mg/d口服 连用4周停用2周 PD或出现不能耐受的毒性第63页/共79页第64页/共79页第65页/共79页毒性反应1/2级3级4级维持原剂量水平 停药至毒性1级(非血液学毒性)或2级(血液学毒性)后，开始原剂量水平治疗 若再次出现3级反应，则下调1个剂量水平停药至毒性1级(非血液学毒性)或2级(血液学毒性)后，下调1个剂量水平开始治疗第66页/共79页男性75%平均年龄 (范围)54.6 (17-77)岁入组时T：X/0/1/2/3/4 (%)40.0/16.2/14.3/5.7/15.2/5.6入组时N：X/0/1/2/3 (%)16.2/57.1/6.7/1

33、9.0/1.0入组时M：0/+ (%)1.9/98.1转移部位：肺/淋巴结/肝/骨 (%)75.2/55.2/15.2/21.9转移灶数量：1/2/3/4+ (%)31.4/31.4/20.0/6.7完成的治疗周期数：平均/中位4.6/5.0第67页/共79页*一个完整的治疗周期定义为在一个周期中至少有26天服用了一剂索坦索坦 50mg/d 4w/2wN=105开始的周期数 平均值 (标准差)4.9 (2.25) 中位值 (范围)5 (1-9)*完成的周期数 平均值 (标准差)4.6 (2.36) 中位值 (范围)5 (0-9)相当于7个月第68页/共79页时间 (月)第69页/共79页评效结果病例数(n)比例(%)CR00PR3029.4 %SD5150 % (25.5% 24 周)PD1615.7 %ORR3029.4 %CBR*5679.4 %1年生存率77.2中位生存期与中位PFS未达到Motzer RJ, et al. N Engl J Med 2007;356:11524.第70页/共79页Motzer RJ, et al. N Engl J Med 2007;356:11524.时间 (月)中期分析第71页/共79页不良事件 (%)索坦 (N=105)1级2级3级4级 5级总计手足综合症6.734.319.00060.0疲乏29