聚焦结直肠癌精准治疗现状与展望医疗培训课件.pptx

1、Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.聚焦结直肠癌精准治疗现状与展望四川大学华西医院肿瘤中心李 秋Pour appropriate amount of CP and DP into beaker, stir

2、 well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.President Barack Obama, State of the Union Address, January 20, 2015精准医疗帮助人类抗击癌症，保持健康“Tonight, Im launching a new Precision Medicine Initi

3、ative to bring us closer to curing diseases like cancer and diabetes and to give all of us access to the personalized information we need to keep ourselves and our families healthier.” Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue

4、 B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.Similar disease, different mechanism and treatment相同的疾病，不同的机制，不同的治疗 基于每个个体的基因差异而进行的个体化治疗才是有效的，也更有效率，因而称为精准医学。Francis S. Collins, M.D., Ph.D., and Harold Varmus, M.D.何为精准医疗?Pour appropriate amount of

5、CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.结直肠癌严重威胁人类健康的癌症之一This is where all footnotes and references go.结直肠癌发病率排在第3位，死亡率排在第3位在我国发病率逐年提升http:/globocan.ia

6、rc.fr/Pages/fact_sheets_population.aspxPour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.在过去的几十年里，mCRC 的OS 获得显著提高Kopetz S, et al. J Cl

7、in Oncol 2009;27:3677368306048362412020406080100Time (months)Overall survival (%)199019911992199419951997199820002001200320042006来自MD Anderson和Mayo Clinics的2,470 名mCRC病人如何进一步提高？ 氟尿嘧啶 伊立替康 奥沙利铂 TAS-102 贝伐珠单抗/阿柏西普 西妥昔单抗/帕尼单抗 瑞格非尼 雷莫卢单抗Pour appropriate amount of CP and DP into beaker, stir well and pou

8、r in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.Cancer Genome Atlas Network. Nature 2012;487:330337CRC精准治疗的前提：知道并了解基因的改变Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A,

9、 then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.7从KRAS到RAS：目前临床确认的mCRC分子标志物检测位点SrcPIP2PI3KPIP3RASRAFMEKERKPTENAKTp70s6kMTORRictorMTORRaptorEGFTGF- HB-EGF上皮调节蛋白EGFR (HER1)生长因子基因转录RAS 突变KRAS外显子 1外显子 2外显子 3外显子 412

10、1359 61117 146NRAS外显子 1外显子 2外显子 3外显子 412 1359 61117 146Adapted from Siena, et al. JNCI 2009Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 m

11、inutes.8基于分子标志物的筛选删选优势人群 增加疗效随机研究中5,000患者的荟萃分析RAS MT53%RAS WT47%Sorich, et al. Ann Oncol 2015ITT 100%ITT KRAS RAS，筛选出真正的优势人群KRAS MT42%KRAS WT58%Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clo

12、ckwise for 3-4 minutes and counterclockwise for 3-4 minutes.15.620.619.9202526.920.22925.620.320.621.323.528.730.128.432.533.105101520253035IFLIFL + 贝伐FOLFOX/FOLFIRIFOLFOX/FOLFIRI+ 贝伐XELOX/FOLFOXXELOX/FOLFOX + 贝伐FOLFIRIFOLFIRI + 西妥昔FOLFIRI+ 贝伐FOLFIRI + 西妥昔FOLFOX+ 贝伐FOLFOX + 西妥昔FOLFIRIFOLFIRI + 西妥昔FO

13、LFOX+ 贝伐FOLFOX + 西妥昔AVF21071ITACA2NO169663CRYSTAL4FIRE-35CALGB 804056CRYSTAL7FIRE-39所有人群所有人群KRAS WTKRAS WT人群人群RAS WTRAS WT人群人群0.0010.0010.2780.2780.07690.07690.00930.0170.090.00240.011III期研究P P值值中位中位OSOS（月）（月）FOLFIRI+ 贝伐FOLFIRI + 西妥昔CALGB8040580.21.Hurwitz H,et al.N Engl J Med.2004;350(23):2335-42.

14、2.Passardi A,et al.J Clin Oncol 31,2013(suppl; abstr 3517). 3.Saltz LB,et al.J Clin Oncol.2008;26(12):2013-2019. 4.Van Cutsem E,et al.J Clin Oncol.2011;29(15):2011-9. 5.Heinemann V,et al.ASCO 2013(Abstract No. LBA3506).6.Venook A,et al.ASCO 2014(Abstract LBA3). 7.Ciardiello F,et al.J Clin Oncol 32:5

15、s,2014(suppl; abstr 3506). 8. Venook A,et al.2014 ASCO Abstract LBA3. 9.Stintzing S,et al.ECC 2013(Abstract No.LBA17).西妥昔单抗是肠癌唯一符合精准治疗的药物，能通过RAS检测筛选最优势人群，使患者获益最大化Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The met

16、hod is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.抗-EGFR获益研究生物标记物nOS HR (95% CI)CRYSTAL1,2KRAS6660.80 (0.670.95)抗-EGFR + CT vs CTRAS*3670.69 (0.540.88)PRIME3*KRAS6560.83 (0.700.98)RAS*5120.77 (0.640.94)FIRE-34,5KRAS5920.77 (0.620.96)西妥昔单抗+ CT vs贝伐珠单抗 + CTRAS*4000.70 (0.54

17、0.90)CALGB/SWOG 804056KRAS11370.92 (0.781.09)RAS*5260.90 (0.701.10)1.02.00.1抗-EGFR无法获益RAS 野生型人群的筛选能够提高抗-EGFR治疗的效果一系列III期研究探讨了抗-EGFR 方案一线治疗mCRC的效果1. Van Cutsem E, et al. J Clin Oncol 2015;33:692700; 2. Van Cutsem E, et. al. J Clin Oncol 2011;29:20112019; 3. Douillard J-Y, et al. N Engl J Med 2013;369

18、:10231034; 4. Stintzing S, et al. ESMO 2014 (Abstract No. LBA11), updated information presented at meeting: https:/ (accessed Sept 24 2015); 5. Heinemann V, et al. Lancet Oncol 2014;15:10651075; 6. Lenz H-J, et al. ESMO 2014 (Abstract No. 501O); updated information presented at meeting: https:/ (acc

19、essed Sept 24 2015); 7. Erbitux SmPC June/2014; 8. Vectibix SmPC February/2015; 9. Venook AP, et al. ASCO 2014 (Abstract No. LBA3), updated information presented at meeting: http:/meetinglibrary.asco.org/content/94399?media=sl (accessed Sept 24 2015)疗效指向一致*回顾性分析西妥昔单抗和帕尼单抗不允许用于携带RAS突变或RAS情况未知mCRC患者的治

20、疗7,8 FIRE-3研究未达到其主要终点，即在KRAS(外显子2)野生型患者中，显著提高基于研究者评估的总缓解率(ORR)5; CALGB/SWOG 80405研究未达到其主要终点，即在KRAS(外显子2)野生型mCRC 患者中，与贝伐珠单抗+ FOLFOX/FOLFIRI组相比，西妥昔单抗+ FOLFOX/FOLFIRI能显著延长患者OS 9; FIRE-3研究4中获得的西妥昔单抗+化疗vs贝伐珠单抗+化疗的RAS野生型mCRC患者的OS获益，在CALGB/SWOG 80405研究6中未得到确证;但是无论在III期研究或头对头研究中，西妥昔单抗+化疗都获得了32个月的一致的中位OS结果Po

21、ur appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.RAS基因突变型mCRC：如何治疗？RAS wt50%KRAS mt40%New RAS mt10%Codon 12 and13抗EGFR单抗 抗VEGF单抗? Pour

22、appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.酪氨酸激酶抑制剂(TKIs)瑞格非尼, 舒尼替尼 索拉非尼, 帕唑帕尼 凡德他尼, 阿帕替尼法米替尼抗VEGFR MAbs (雷莫芦单抗)信号传导RRKKVEGF抗VEGF MA

23、bs (贝伐珠单抗)可溶性受体(VEGF Trap, 阿柏西普) Modified from Tabernero, J et al. Ann Oncol 2005抗VEGF信号通路的药物VEGFRVEGFPour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwis

24、e for 3-4 minutes.KRAS：未证实对贝伐珠单抗具有疗效预测作用AVF2107研究：研究：KRASHurwitz HI, et al. Oncologist. 2009 ;14(1):22-28.Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and countercloc

25、kwise for 3-4 minutes.抗抗VEGF制剂制剂疾病疾病biomarker初步结论初步结论贝伐珠单抗结直肠癌血浆VEGF高表达OS短组织VEGFR2高表达PFS长组织MVD高表达OS短NSCLC血浆VEGF不能预测OS卵巢癌Ang1/ Tie2高Ang1/低Tie2PFS长胃癌血浆VEGF-A高表达OS长组织神经纤毛蛋白低表达OS长肾细胞癌VEGFR1 SNPs可预测PFS和OS索拉非尼肝细胞癌VEGF及VEGFR SNPs可预测PFS舒尼替尼肾细胞癌VEGFR1及VEGFR3 SNPs可预测PFS贝伐单抗潜在生物标记物的研究探索迄今为止，贝伐珠单抗仍无有效的生物标记物Pour

26、 appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.试验名称靶向药物化疗方案PFS OS一线AVF2107BevIFLNO16966BevFOLFOX/XELOXAVEXBevCapecitabine维持CARIO 3BevXE

27、LOXAIO 0207BevFP+OXASAKKBevChemo跨线ML18147BevChemo二线E3200BevFOLFOXVELOURAfliberceptFOLFIRIRAISERamucirumabFOLFIRI解救CORRECTRegorafenibCONCURRegorafenib抗VEGF药物在mCRC中的研究抗血管生成治疗药物二线使用，效果更好Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B

28、, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.肿瘤药物价值的评估在势在必行Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and coun

29、terclockwise for 3-4 minutes.ASCO 评价肿瘤治疗方案的方法评分等级总分CLINICAL BENEFIT0580TOXICITY-202020BONUS POINTS03030NET HEALTH BENEFITTotal 130COST(per month)Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir cl

30、ockwise for 3-4 minutes and counterclockwise for 3-4 minutes.成本未纳入分析: 欧洲范围内差异显著临床获益程度可治愈或不可治愈疾病预后HR中、长期疗效获益OSPFSRRQoL毒性反应ESMO-MCBS欧洲肿瘤内科学会临床获益评估标尺; RR,相对风险Cherny NI, et al. Ann Oncol 2015;26:15471573ESMO-MCBS一个能够严谨评估靶向制剂临床疗效相对大小的新标尺Pour appropriate amount of CP and DP into beaker, stir well and pour

31、 in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.ESMO-MCBS 评价Cherny NI, et al. Ann Oncol 2015;26:15471573Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropr

32、iate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.mCRC人群中ESMO-MCBS的测试 :非治愈性为目标的治疗方案* 95% CI下限; 这不包括脱发症，骨髓抑制，而是指慢性恶心，腹泻，疲劳等情况。级别4HR* 0.70 并且 生存期获益 5 个月或 仅3-年 生存期增加 10%3HR* 0.70并且 生存期获益 34.9 个月或 仅3-年 生存期增加为50.700.75 或者生存期获益 1.52.9 个

33、月 或 仅3-年 生存期增加 30.75 或生存期获益1.5 个月 或仅3-年 生存期增加 1 年 (表 2a)若能够改善QoL 和/或显著减少影响日常生活的3-4级毒性反应，则提升一个级别Cherny NI, et al. Ann Oncol 2015;26:15471573Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwis

34、e for 3-4 minutes and counterclockwise for 3-4 minutes.临床获益程度评级基于疗效, QoL, 和毒性反应标准的设置和描述1非治愈性级别设置: 1 (最低) - 5 (最高) *回顾性分析; 临床实践指南已不再推荐使用IFL 5抗-EGFR 制剂在治疗mCRC的测试中获得了ESMO-MCBS标准的高评级 1. Cherny NI, et al. Ann Oncol 2015;26:15471573; 2. Van Cutsem E, et al. J Clin Oncol 2015;33:692700;3. Douillard J-Y, et

35、 al. N Engl J Med 2013;369:10231034; 4. Hurwitz H, et al. New Engl J Med 2004;350:23352342; 5. NCCN Clinical Practice Guidelines; Colon Cancer, Version 1.2015; Available at www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Last accessed Sept 2015抗抗EGFR all RAS wt抗抗EGFR all KRAS wt抗抗VEGF in all

36、 line这种新的ESMO-MCBS 工具支持了抗-EGFR制剂+CT与抗VEGF+CT相比作为一线治疗方案治疗RAS 野生型 mCRC的PFS和OS临床获益1Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.我们的药

37、物经济学研究Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.mCRC精准治疗的现状: 靶向治疗+ 预测性生物标记物1. Stintzing S, et al. ESMO 2014 (Abstract No. LBA1

38、1), updated information presented at meeting: https:/ (accessed Sept 24 2015); 2. Lenz H-J, et al. ESMO 2014 (Abstract No. 501O); updated information presented at meeting: https:/ (accessed Sept 24 2015);3. Heinemann V, et al. Lancet Oncol 2014;15:10651075;4. Venook AP, et al. ASCO 2014 (Abstract No

39、. LBA3), updated information presented at meeting: http:/meetinglibrary.asco.org/content/94399?media=sl (accessed Sept 24 2015) 生物标记物检测治疗方案 A治疗方案B治疗方案COS研究显示，爱必妥 + CT一线治疗RAS 野生型 mCRC 患者，能够使OS32个月根据单个基因为基础的生物标记物检测 (RAS)结果， 选择合适的治疗方案FIRE-3研究未达到其主要终点，即在KRAS(外显子2)野生型患者中，显著提高基于研究者评估的总缓解率(ORR) 3CALGB/SWOG

40、 80405研究未达到其主要终点，即在KRAS(外显子2)野生型mCRC 患者中，与贝伐珠单抗+ FOLFOX/FOLFIRI组相比，西妥昔单抗+ FOLFOX/FOLFIRI能显著延长患者OS4CT, 化疗; OS, 总生存Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and coun

41、terclockwise for 3-4 minutes.基因组分析液态活检精准治疗将走向何方? 新药研发Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.CRC的遗传学改变Cancer Genome Atlas Ne

42、twork. Nature 2012;487:330337Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.基因组分析技术的创新Dienstmann R, et al. J Clin Oncol 2013;31:187

43、41884高通量基因分型平台(多重筛选) 检测: 选择性的体细胞突变或罕见突变 限于筛选已知变异 不适合GCN 变异、基因重排和小的插入/缺失的筛查高通量平行靶向测序 检测体细胞突变, GCN 变异, 及预先定义的基因重排 对于预先定义的感兴趣区域和药物基因组多态性的灵敏度和覆盖更高 不适合小的插入/缺失的筛查全外显子测序 检测: 点突变, 小的插入/缺失, 药物基因组多态性, GCN 变异 灵敏度增加 不适合检测基因重排全基因组测序 发现新的基因重排,复合插入/缺失,GCN 变异 不适合精确检测点突变GCN, 基因拷贝数更广泛分析, 发现新的生物标记物靶向性探查感兴趣的突变和区域Pour a

44、ppropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.mCRC治疗选择中可能发挥作用的新的生物标记物PIK3CAHER2EGFRMSITP53CTNNB1下一代分子标志物AKTPTENAREGEREGmiRNACaiazza, et

45、al. Biomark Med 2015BRAFPour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.基因组分析液态活检精准治疗将走向何方? 新药研发Pour appropriate amount of CP and DP

46、 into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.学者仍在不断探索新靶点的治疗药物BRAF V600E5-10% in mCRCBRAFi + anti-EGFR Ab + : RR 10-35%, DCR 80-100%HER25% in mCRCTrastuzumab + Lapati

47、nib: RR 35%, DCR 78%MSI-H5% in mCRC Anti-PD-1 Ab (Pembrolizumab): RR 62%, DCR 92%Ang2和和 VEGF-A 双通道抑制剂双通道抑制剂 mCRC其它靶点和靶向药物单抗Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir again, The method is to stir clockwise for 3-4 minute

48、s and counterclockwise for 3-4 minutes.Phase治疗药物NRR, %DCR, %NovartisPhase IB/IIE (BRAFi) + Cmab262377E (BRAFi) + Cmab + B (PI3Ki)283293GSKPhase I/IID (BRAFi) + Pmab201090D (BRAFi) + Pmab + T (MEKi) 352686RochePhase IBV (BRAFi) + Cmab + IRI1835100D: dabrafenib, E: encorafenib, V: vemurafenib, T: tram

49、etinib, B: BYL719多种抗体联合治疗BRAF V600E突变mCRC的初步研究结果Elez E, et al. ESMO-GI 2015. Van Cutsem E, et al. ESMO-GI 2015. Hong DS, et al. ASCO 2015.BRAF突变的mCRC预后差，中位PFS仅4-6个月，中位OS约12个月Pour appropriate amount of CP and DP into beaker, stir well and pour in glue A, then add appropriate amount of glue B, stir ag

50、ain, The method is to stir clockwise for 3-4 minutes and counterclockwise for 3-4 minutes.目前抗-PDL1/PD1在CRC中正在进行 的研究*靶点靶点治疗治疗期期研究设计研究设计研究编号研究编号抗抗-PDL1Atezolizumab(工程化工程化 IgG1, 无无ADCC)I实体肿瘤实体肿瘤NCT01375842Ib实体肿瘤实体肿瘤 (+ 贝伐珠单抗贝伐珠单抗 FOLFOX)NCT01633970IImCRC (+ 贝伐珠单抗贝伐珠单抗 + 氟尿嘧啶氟尿嘧啶) NCT02291289MEDI4736(修饰