刘天舒：晚期结直肠癌的规范化治疗

晚期结直肠癌的规范化治疗,Tianshu liu, M.D., Ph.D.Zhongshan Hospital, Fudan UniversityDept of Medical OncologyCenter of Evidence-based medicine,mCRC分组全程管理,整体治疗策略的应用显著延长了mCRC患者的OS,1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 2004; 3. Rothenberg, et al. JCO 20034. Hurwitz, et al. NEJM 2004; 5. Cunningham, et al. NEJM 2004; 6. Van Cutsem, et al. NEJM 20097. Van Cutsem, et al. JCO 2007; 8. Van Cutsem, et al, JCO 2012; 9. Grothey, Van Cutsem, et al. Lancet 2012,改善mCRC生存的关键,提高一线治疗的疗效- 个体化选择最佳治疗,创造“治愈的机会”- 转移灶的手术切除（和其他局部毁损性治疗）,采用“治疗的延续”- 在不同线数的治疗中采用最佳疗法,改善mCRC生存的关键,提高一线治疗的疗效- 个体化选择最佳治疗,创造“治愈的机会”- 转移灶的手术切除（和其他局部毁损性治疗）,采用“治疗的延续”- 在不同线数的治疗中采用最佳疗法,一线治疗决策制定的驱动因素,mCRC患者的一线治疗决策需充分考虑三大特征,化疗 +/- 贝伐珠单抗,化疗 +/-靶向药物,再评估/每2-3个月评估肿瘤缓解情况,RAS WT,RAS MT,BRAF MT,疾病控制,治疗特征,肿瘤特征,右半,左半,化疗 +/- 贝伐珠单抗,化疗 +/- 贝伐珠单抗,化疗 +/- 西妥昔单抗,Fit,Unfit,Unfit(但可能获益）,患者的临床分类,疾病进展,高强度治疗,继续治疗,暂停治疗,维持治疗,患者特征,化疗 +/- 西妥昔单抗,OXA,CPT-11,FOLFOXXELOXFLOX,FOLFIRIIFLXELIRI,5-FUCAPE,中国可获取的药物,氟尿嘧啶的作用机制,1. Longley DB, et al. Nat Rev Cancer 2003;3:330338;2. Peters GJ. Ther Adv Med Oncol 2015;7:340356;3. Wilson PM, et al. Nat Rev Clin Oncol 2014;11:282298;4. Van Cutsem E, et al. Ann Oncol 2014;25(Suppl 3):iii1iii9; 5. Lonsurf US PI, September 2015;6. Taiho Pharmaceuticals Co. Ltd. Available at: www.taiho.co.jp.; 7.http:/www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_Initial_authorisation/human/003897/WC500202369.pdf.,雷替曲赛,奥沙利铂1,2,奥沙利铂和伊立替康的作用机制,1. Adapted from Boulikas T, et al. Cancer Ther 2007;5:537583; 2. Oxaliplatin SmPC, September/2008; 3. Adapted from Frese S, Diamond B. Nat Rev Rheumatol 2011;7:733738; 4. Van Cutsem E, et al. Ann Oncol 2014;25(Suppl 3):iii1iii9.,DNA synthesis,Cell death,Inter- and intra-strand DNA cross-links,伊立替康,Induction of apoptosis,晚期结直肠癌尽量暴露于所有有效药物的理念,11个III期临床研究（n=5768）结果分析：晚期结直肠癌整个治疗过程中用过所有3个有效细胞毒药物（5-FU/LV、伊立替康和奥沙利铂）的患者生存期最长,Adapted from Grothey & Sargent. JCO 2005,0 10 20 30 40 50 60 70 80,静滴5-FU/LV + 伊立替康静滴5-FU/LV + 奥沙利铂静注5-FU/LV + 伊立替康伊立替康,+ 奥沙利铂静注5-FU/LV LV5FU2FOLFOXIRICAIRO,三药治疗患者比例(%),一线治疗方案,2007,Douillard JY, et al. Lancet 2000;355:10411047.,*Primary endpoint.,TTP,OS,p0.001,p=0.031,PFS probability,Months,OS probability,Months,Randomized Phase III trial of FOLFIRI vs 5-FU/LV in 1st line treatment of (K)RAS-unselected mCRC,4.4,6.7,14.1,17.4,FOLFIRI (n=198)5-FU/LV (n=187),FOLFIRI (n=198)5-FU/LV (n=187),FOLFIRI vs 5FU：显著的生存获益,*Primary endpoint.,FOLFOX vs 5FU：显著的生存获益,Randomized Phase III trial of FOLFOX4 vs 5-FU/LV in 1st line treatment of (K)RAS-unselected mCRC,de Gramont A, et al. J Clin Oncol 2000;18:29382947.,化疗药物的次序分布,mCRC,交叉研究设计,V308 疗效结果,Tournigand et al. J Clin Oncol. 2004;22:229-237.,FOLFOXIRIvsFOLFIRI：结果不一致,1. Falcone A, et al. J Clin Oncol 2007;25:16701676; 2. Souglakos J, et al. Br J Cancer 2006;94:798805.,*Primary endpoint; NR, not reported.GONO, Gruppo Oncologico Nord Ovest; HORG, Hellenic Oncology Research Group.,Italian GONO study1,Greek HORG study2,分子靶向治疗,肿瘤细胞,表达水平,正常细胞,靶点,细胞受体信号转导细胞周期血管生成,VEGF及受体家族,PlGF,VEGF-R1,VEGF-R3,VEGF-R2(most prominent),VEGF-A,VEGF-D,VEGF-C,Endothelial progenitor recruitment,Migration/invasion,Proliferation,Lymphangiogenesis,Permeability,Survival,Ligands: VEGF-A VEGF-CVEGF-D VEGF-E,Ligands: VEGF-C VEGF-D,Ligands: VEGF-A VEGF-B PlGF,VEGF-B,PlGF,VEGF-A,VEGF-B,VEGF-D,VEGF-C,VEGF-E,VEGF-A,1. Adapted from Wang T-F and Lockhart AC. Clin Med Insights Oncol 2012;6:1930; 2. Avastin SmPC, October/2015; 3. Zaltrap SmPC, September/2014; 4. Stivarga SmPC, October/2015; 5. Cyramza PI, April/2015.,PlGF,VEGF-R1,VEGF-R3,VEGF-R2(most prominent),VEGF-A,VEGF-D,VEGF-C,Ligands: VEGF-A VEGF-CVEGF-D VEGF-E,Ligands: VEGF-C VEGF-D,Ligands: VEGF-A VEGF-B PlGF,VEGF-B,PlGF,VEGF-A,VEGF-B,VEGF-D,VEGF-C,VEGF-E,VEGF-A,Aflibercept3,Bevacizumab2,Regorafenib4,Ramucirumab5,1. Adapted from Wang T-F and Lockhart AC. Clin Med Insights Oncol 2012;6:1930; 2. Lambrechts D, et al. J Clin Oncol 2013;31:121930; 3. Zaltrap SmPC, September/2014; 4. Stivarga SmPC, October/2015; 5. Cyramza PI, April/2015.,Endothelial progenitor recruitment,Migration/invasion,Proliferation,Lymphangiogenesis,Permeability,Survival,抗血管生成药物的作用机制,apatinib,贝伐珠单抗一线治疗,AVF2107药物注册研究,Hurwitz, et al. NEJM 2004,贝伐珠单抗一线治疗: NO16966研究,贝伐珠单抗一线治疗的III期研究,ARTIST（中国本土数据）,1.0,0.8,0.6,0.4,0.2,0.0,0,6,12,18,24,时间 (月),13.4m,18.7m,OS,贝伐珠单抗+mIFL (n=142)mIFL (n=72),HR=0.62 P=0.014,1.0,0.8,0.6,0.4,0.2,0.0,6,12,18,24,0,mlFL (n=72),贝伐珠单抗+mlFL (n=142),时间 (月),PFS,HR=0.44; 95%CI=0.31-0.63P0.001,4.2m,8.3m,EGFR单抗,1. Martinelli E, et al. Clin Exp Immunol 2009;158:19; 2. Brand TM, Wheeler DL. Small GTPases 2012;3:3439.,EGF, epidermal growth factor. TGF, transforming growth factor-.VEGF, vascular endothelial growth factor.,RAS,Cetuximab,Panitumumab,x,西妥昔单抗的一线治疗,CRYSTAL trial,Van Cutsem E, et al. J Clin Oncol,26,HR=0.69 (0.540.88)p=0.0024, = 8.2 months,HR=0.796 (0.670.95)p=0.0093,HR=0.878 (0.771.00)p=0.0419, = 3.5 months, = 1.3 months,1. Van Cutsem E, et al. J Clin Oncol 2011;29:20112019;2. Van Cutsem E, et al. J Clin Oncol 2015;33:692700;3. Douillard J-Y, et al. N Engl J Med 2013;369:10231034; 4. Erbitux SmPC June 2014; 5. Vectibix SmPC February 2015.,Figure adapted from data from Van Cutsem E, et al.2Cetuximab and panitumumab are approved in patients with RAS wt mCRC.4,5 Cetuximab and panitumumab are not indicated for the treatment of patients with mCRC whose tumors have RAS mutations or for whom RAS tumor status is unknown.4,5,Cetuximab + FOLFIRI (n=178),FOLFIRI (n=189),Cetuximab + FOLFIRI (n=599),FOLFIRI (n=599),Cetuximab + FOLFIRI (n=316),FOLFIRI (n=350),RAS wt2,KRAS exon 2 wt1,ITT (unselected)1,西妥昔单抗的疗效与RAS状态有关,HR, hazard ratio; IRC, independent review committee; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.,*In the case of non-PD treatment discontinuation, tumor assessment is continued.,EndpointsPrimary: PFS (by IRC according to RECIST 1.0), target HR = 0.70Key secondary: OS, ORR, safety/tolerabilityStatistical assumption for the primary endpoint247 events required, 80% power, = 0.05 (2-sided),TAILOR Study Design,1:1 R,First-line, RAS wt mCRC,R,Treatment until progressive disease or unacceptable toxicity*,Arm A:Cetuximab + FOLFOX-4,Arm B:FOLFOX-4 alone,Survival follow-up,Efficacy: Primary Endpoint of PFS by IRC,Adding cetuximab to FOLFOX-4 significantly improved the primary endpoint of PFS by IRC,RASWT一线治疗的选择头对头研究结果,1. Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506); 2. Naughton MJ, et al. ASCO 2013 (Abstract No. 3611); 3. NCT00265850; 4. Schwartzberg LS, et al. ASCO GI 2013 (Abstract No. 446),FIRE-31 (IST),CALGB 804052,3,PEAK4,Patients with untreated KRAS (exon 2) wt mCRCN=592,R,Cetuximab + FOLFIRI,Bevacizumab + FOLFIRI,Patients with untreated KRAS (exon 2) wt mCRCN1200 (after trial modification),Cetuximab + FOLFOX/FOLFIRI,Bevacizumab + FOLFOX/FOLFIRI,Bevacizumab + cetuximab + FOLFOX/FOLFIRI*,*Arm closed to accrual as of 09/10/2009,R,Panitumumab + mFOLFOX6,Bevacizumab + mFOLFOX6,R,Efficacy data expected Q2 2014,Phase II,Phase III,Patients with untreated KRAS (exon 2) wt mCRCN=285,ORR,OS,PFS,Primary endpoint,IST, investigator-sponsored trial,1. Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506) 2. Stintzing S, et al. ECC 2013 (Abstract No. LBA17),33.1months,25.6 months, Cetuximab + FOLFIRI (n=171) Bevacizumab + FOLFIRI (n=171),0.0,12,24,36,48,60,72,0.75,1.0,0.50,0.25,0.0,OS estimate,OS estimate,28.7months,25.0 months,0.755,1.0,0.50,0.255,0.0,12,24,36,48,60,72,Months since start of treatment,KRAS wt (exon 2)1,RAS* wt(KRAS and NRAS wt)2, Cetuximab+ FOLFIRI (n=297) Bevacizumab + FOLFIRI (n=295), = 3.7 months, = 7.5 months,Months since start of treatment,*Including KRAS exon 2, 3, 4 and NRAS exon 2, 3, 4,HR 0.77 (95% CI 0.620.96)p=0.017,HR 0.70 (95% CI 0.530.92)p=0.011,FIRE-3: KRAS以外RAS的意义OS的获益,0,0,主要研究终点,PFS（）,ORR（）,OS（）,贝伐珠单抗 VS 西妥昔单抗29 VS 29.9P=0.34,贝伐珠单抗 VS 帕尼单抗10.1 VS 10.9P=0.353,贝伐珠单抗 VS 西妥昔单抗58 VS 62P=0.183,2016年之前的观点，一线治疗中两类靶向药物总体疗效相当,2016：左右半结直肠癌具有不同的特点,1. Lee GH, et al. Eur J Surg Oncol. 2015;41(3):300-308.2. Price TJ ,et al. Cancer. 2015;121(6):830-8353. Snaebjornsson P, et al. Int J Cancer. 2010;127(11):2645-2653.4. Missiaglia E, et al. Ann Oncol. 2014;25(10):1995-2001.,EREG：表皮调节素，EGFR配体,CALGB/SWOG 80405的左右半数据结果KRAS WT,预测作用,预后作用,“19.3 MONTHS IS A BIG DIFFERENCE !”,*Adjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liver metastases,结论：野生型患者无论何种治疗方式，左半比右半有更好的OS,结论：西妥昔单抗和贝伐珠单抗一线治疗在左右半中有不同的疗效,Venook AP, et al. 2016 ASCO Abstract 3504,80405研究及FIRE-3*研究：不同肿瘤部位的中位OS (RAS全野生型患者),*Stintzing MD，个人口头交流*Stintzing et al, Lancet Oncology, 2016Venook A, et al. Presented at 2016 ESMO.,预后分析：OS,左侧肿瘤的预后显著优于右侧肿瘤,Arnold D. Presented at 2016 ESMO.,FOLFIRICET,FOLFIRI：+CET vs. +BEV,FOLFOX：+PMAB vs. +BEV,FOLFOXPMAB,FOLFIRIPMAB,化疗：+CET vs. +BEV,预测分析：OS,OS - 左侧肿瘤：化疗+抗EGFR药物更好；右侧肿瘤：化疗及贝伐珠单抗更好,Arnold D. Presented at 2016 ESMO.,交互检验的异质性：P=0.53交互检验的HR=1.53; 95%CI:1.21-1.93;P3,000位随机临床研究中的患者1,13.7%有其他RAS突变(KRAS 外显子 3 和 4, 和 NRAS 突变),无数已知存在于mCRC的额外基因突变拥有预测和/或预后的功能,PIK3CAPTENFGFR3ERBB2,CRC中的突变状态有预后作用: 野生型 RAS MT BRAF MT,Sinicrope. 2015.,以5-Fu为基础的辅助化疗的III期结直肠癌 (n = 737),0,10,20,30,40,50,60,70,80,90,100,0,12,347311265236215197270233187163148140 28 22 18 15 13 13 33 27 26 23 19 19 59 5146 44 40 39,24