结直肠癌靶向治疗进展

转移性结直肠癌靶向治疗进展2012,贝伐单抗相关研究西妥昔单抗相关研究其他靶向药物研究进展靶向药物在转移性结直肠癌挽救治疗中的相关研究总结,转移性结直肠癌靶向治疗进展2012,贝伐单抗相关研究西妥昔单抗相关研究其他靶向药物研究进展靶向药物在转移性结直肠癌挽救治疗中的相关研究总结,化疗联合贝伐单抗一线治疗后，贝伐单抗联合或不联合厄洛替尼维持治疗转移性结直肠癌患者的疗效及安全性结果：来自国际性期研究GERCOR DREAM,Christophe Tournigand, MD ,et al. 2012 ASCO Abstract LBA3500,Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial.,背景介绍,DREAM研究的主要目的是评价靶向药物的维持治疗VEGF抑制剂（贝伐单抗）联合含奥沙利铂或含伊立替康方案一线或二线化疗可改善生存1-3EGFR抑制剂（帕木单抗或西妥昔单抗）可改善Kras野生型肿瘤的生存4-7OPTIMOX1-2研究证实奥沙利铂间歇化疗模式的疗效8-9与肿瘤生长和生存有关的EGFR和VEGF通路间存在交叉作用mCRC的III期研究显示：EGFR和VEGF的单克隆抗体联合并无获益10,11结直肠癌异种移植模型中，VEGFR及EGFR的TKI类药物联合可产生协同抗肿瘤活性，而且对KRAS突变的模型也有效12临床前研究模型已探索贝伐单抗联合厄洛替尼的疗效13,1.Saltz LB et al. J Clin Oncol 2008; 2006:2013-9 2. Hunwitz et al. N Engl J Med 2004:350:2335-423.Giantonio BJ. J Clin Oncol 2007;25:1539-44 4. Van Cutsem E, et al. J Clin Oncol 2011;29:2011-95.Peeters M et al. J Clin Oncol 2010:28:4706-13 6.Karapetis CS, et al.N Engl J Med.2008;359:1757-657.Amado RG, et al. J Clin Oncol 2008;26:1626-34 8.Tournigand C, et al. J Clin Oncol 2006;24:394-4009.Chibaudei B, et al. J Clin Oncol 2009;27:5727-33 10.Hecht JR, et al. J Clin Oncol 2009;27:672-8011.Tol J , et al . N Engl J Med 2010;360:563-72 12.Poindessous v, et al . Clin Cancer Res 2011;17:6522-3013.Naumov CN, et al .Clin Cancer Res 2009;15:3484-94,贝伐单抗联合厄洛替尼对SW620结直肠癌异种移植模型的疗效,VELOUR 试验设计,入组时间：2007/1/4-2011/10/13a奥沙利铂 100mg/m2 d1(6周期);5-FU 2.4g/m2 d1-2; FA 400mg/m2 d1;贝伐单抗5mg/kg d1,q2w,6-12周期b奥沙利铂 100mg/m2 d1(6周期);卡培他滨1.25-1.5g/m2 bid d1-8 ;贝伐单抗5mg/kg d1,q2w,6-12周期c伊立替康 180mg/m2 d1 ;5-FU 2.4g/m2 d1-2; FA 400mg/m2 d1;贝伐单抗5mg/kg d1,q2w,12周期,研究终点,主要终点：维持治疗PFS次要终点：OS、自维持治疗的OS、无化疗间期、缓解率（RECIST标准）、根据KRAS突变状态的生存标本量：优效性研究，80效力，双侧检验=0.05中位维持治疗PFS：4.5月（贝伐单抗组）-6.5月（贝伐单抗厄洛替尼组）预计脱落率40计划入组700例患者评估418例患者要求发生231个事件,入组标准,组织学证实为结直肠腺癌可测量或可评估的转移灶不能手术完整切除转移灶未接受过化疗或靶向治疗1880岁WHO PS 0-2碱性磷酸酶6个月（如接受奥沙利铂治疗则2年）,基线特征,维持治疗PFS(自随机开始),联合组PFS更优,PFS（自注册开始，随机分组的患者）,治疗情况,毒性,结论,含贝伐单抗的诱导化疗后继续给予贝伐单抗联合厄洛替尼维持治疗较贝伐单抗单药显著改善维持治疗PFS贝伐单抗联合厄洛替尼耐受性良好，但腹泻和皮肤毒性明显加重研究结果显示厄洛替尼可能对转移性结直肠癌有效，并为VEGF和EGFR的双向抑制提供临床理论基础总生存及KRAS分析仍在进行中,VELOUR研究中预先应用贝伐单抗的疗效: 伊立替康+阿柏西普方案应用于奥沙利铂治疗失败后转移性结直肠癌患者的期临床试验,Carmen Joseph Allegra ,et al. 2012 ASCO Abstract NO.3505,Effects of prior bevacizumab (B) use on outcomes from the VELOUR study: A phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin regimen.,背景介绍,与单独应用FOLFOX4方案相比， 2线贝伐单抗联合FOLFOX4方案治疗转移性结直肠癌的3期临床试验显示其可显著改善生存受益：中位OS:12.9 vs 10.8 月，HR=0.75,P=0.001 中位PFS:7.3 vs 4.7 月，HR0.61.P9个月)上次使用BEV事件(42天,42天)基准ECOG PS 评分 (0/1,2),主要入组标准,包括病理确诊为mCRC的18岁以上患者ECOG PS评分 0-2PD(根据RECIST第一版,CT或MRI确定有1 可测量病灶),截至试验开始时4周先前接受过BEV+标准一线化疗方案治疗，不包括首发转移灶切除术后患者.排除诊断PD时,在最后一次使用BEV后超过3个月患者在一线治疗中的PFS 3个月接受一线持续BEV治疗 vs 3 mos) II-line CT,RANDOM,FOLFIRIFOLFOXFOLFOXIRIFluoropyrimidine mono-tx,*, FOLFIRI mFOLFOX-6,A. Second-line CTB. Second-line CT+ BV, Study conducted in 19 Italian centers, Supported by AIFA,Primary Objective - PFS,CT (85 events) median PFS = 4.97 mos,CT+ B (87 events) median PFS = 6.77 mos,HR=0.65 (95%CI 0.48-0.89)p=0.0062,Median follow up 18.0 mos,First-line Chemotherapy Bevacizumab in mCRC: Efficacy,1. Colucci G, et al. J Clin Oncol. 2005;23:4866-4875. 2. Cassidy J, et al. J Clin Oncol. 2008;26:2006-2012.3. Cassidy J, et al. Br J Cancer. 2011;105:58-64. 4. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342. 5. Saltz LB, et al. J Clin Oncol. 2008;26:2013-2019. 6. Bendell JC, et al. ASCO GI 2011. Abstract 480.,转移性结直肠癌靶向治疗进展2012,贝伐单抗相关研究西妥昔单抗相关研究其他靶向药物研究进展靶向药物在转移性结直肠癌挽救治疗中的相关研究总结,K. Tveit, T. Guren, B. Glimelius, P. Pfeiffer, H. Srbye, S. Pyrhonen,E. Kure, T. Ikdahl, E. Skovlund, T. Christoffersen, for the,Nordic Colorectal Cancer Biomodulation Group,Oslo University Hospital, Ullevl, Oslo, Norway; University Hospital and Karolinska Institutet, Uppsala andStockholm, Sweden; Odense University Hospital, Odense, Denmark; Haukeland University Hospital,Bergen, Norway; Turku University Hospital, Turku, Finland; School of Pharmacy, Oslo, Norway; University,of Oslo, Oslo, Norway,3,Background, 2005: Inclusion started, Basis,Nordic FLOX is a potent first line chemotherapy regimen in mCRC(Sorbye et al., JCO 2004; 22, 31-38), Question 1,Is there a clinical benefit of cetuximab added to Nordic FLOXin first line mCRC?, Question 2,Is intermittent FLOX (stop and go principle) with maintenancecetuximab better than FLOX alone until progression?, 2007: Inclusion ended, Question 3,Is a beneficial effect of cetuximab limited to patients with KRAS wildtype tumours? Amendment 31.10.07,4,5-FU / FAOxaliplatin,5-FU / FAOxaliplatin,Continuous FLOX until progression or toxicity,5-FU / FAOxaliplatinCetuximabContinuous FLOX and cetuximab until progression or toxicity,5-FU / FAOxaliplatin,Secondline,chemo-therapy,Irinotecanbased,Arm A,Arm B,Arm C,NORDIC VII study design571 patients randomised May 2005 - October 2007,CetuximabIntermittent FLOX and continuous cetuximab. FLOX 16 w, then stop,reintroduce FLOX at progression etcNordic FLOX: 2 weekly 5-FU i.v. bolus 500mg/m2 and FA 60 mg/m2 day 1-2,oxaliplatin 85mg/m2 day 1,Cetuximab:,400mg/m2 day 1, then 250 mg/m2 weekly,Randomisation: 1:1:1,Stratification: study centre,5,Nordic Colorectal Cancer Biomodulation Group, Hypothesis: Progression free survival (PFS) increases from 7months with FLOX alone to 10 months with FLOX + cetuximab Enrolment of 550 patients would lead to at least 80% powerallowing two pair wise comparisons (B vs A and C vs A) at the 2.5%level Planned enrolment period of 24 months and analysis of PFS 12months after last patient enrolled Amendment 31.10.07 after last patient was enrolled:analysis also of KRAS wild type and KRAS mutant populations No re-estimation of sample size,6,Nordic Colorectal Cancer Biomodulation Group,Inclusion of patients,7,Nordic Colorectal Cancer Biomodulation Group,NORDIC VII objectives Primary objectiveProgression-free survival, PFS of Nordic FLOX combined with cetuximabcompared to PFS of Nordic FLOX alone, in first line treatment of patientswith mCRC.PFS: Calculated from randomisation to first recorded progression or death Secondary objectives,Response rates in the three treatment armsSecondary surgical curative resection frequencySafety profile of the treatment armsOverall survival in the treatment groupsQuality of life in the treatment groups, Exploratory objectives,8,Nordic Colorectal Cancer Biomodulation Group,NORDIC VII Main inclusion criteria,Age 18 and 6 months beforeinclusionNo previous oxaliplatinNo current indications for resection with a curative intentAdequate haematological, renal and liver functionNo peripheral neuropathyNo other serious illness or medical conditionsWritten informed consent,9,Baseline characteristics, ITT (n=566),10,Progression free survival (PFS), ITTArm A median: 7.9Arm B median: 8.3Arm C median: 7.3B vs A: HR=0.89 (0.72-1.11), p=0.31,Arm A:Arm B:Arm C:,185194187,124137120,466237,152012,922,Number ofpatients at risk,11,Nordic Colorectal Cancer Biomodulation Group,Confirmed responsesand R0-resections, ITT,12,Arm A:Arm B:Arm C:,185194187,135143133,685964,151214,Number ofpatients at risk,Overall survival (OS), ITTArm A median: 20.4Arm B median: 19.7Arm C median: 20.3B vs A: HR=1.06 (0.83-1.35), p=0.67C vs A: HR=1.03 (0.81-1.32), p=0.79,13,Nordic Colorectal Cancer Biomodulation Group,Safety, WHO gr. 3/4 (% of patients),14,Nordic Colorectal Cancer Biomodulation Group,KRAS and BRAF mutation analyses,15,PFS and OS, KRAS populations,wtmutp=0.99Nordic Colorectal Cancer Biomodulation Group,wtmutp=0.96,16,PFS, OS and ORR, BRAF populations,wt, median: 8.3,mut median: 5.1p 0.001Nordic Colorectal Cancer Biomodulation Group,wt, median: 20.0,mut median: 9.5p 40% Cetuximab does not give significant additional benefit whencombined with Nordic FLOX FLOX given intermittently (stop and go) with continuous cetuximabgives similar survival as treatment until progression BRAF mutation is a strong negative prognostic factor KRAS mutation status was not found to be predictive for cetuximabeffect However, the study was not powered to investigate KRASsubpopulations An unexpected trend of a cetuximab effect (PFS and ORR) in mutatedcases may be explained simply by chance The NORDIC VII study indicates that oxaliplatin may not be a good,match for cetuximab in mCRC,Adjuvant FOLFOX4 with or withoutcetuximab (CTX) in patients (pts) withresected stage III colon cancer (CC): DFSand OS results and subgroup analyses ofthe PETACC8 Intergroup Phase III trialJ. Taeb,* J. Tabernero, E. Mini, F. Subtil, G. Folprecht, J-L. van Laethem,J. Thaler, J. Bridgewater, E.J.D. Van Cutsem, P. Rougier, L. Collette,M. Praet, M. Schneider, O. Bouch, C. Lepage, C. Girault, J-F. Emile,P. Laurent-Puig, L. Bedenne.,*Georges,Pompidou European Hospital, Paris, France,Fully resectedstage IIIcolon,R,Stratification factors:N-status (N1 vs N2)T-status (T1-3 vs T4)Obstruction/perforation status,Original 2-arm design for PETACC8FOLFOX4 (12 cycles)Every 2 weeks: Oxaliplatin 85 mg/m2 on d1 and LV 200 mg/m2, 5-FU bolus 400 mg/m2,followed by 5-FU 600mg/m2 22-hour IVon d1 and d2,cancer(N = 2000)FOLFOX4 + cetuximab,(12 cycles) FOLFOX4 Cetuximab d1 and d8- 400 mg/m2 initial dose- 250 mg/m2 weekly,Enrolment was restricted to wild-type KRAS and sample size increased in 2008,DFS rate,Disease-free survival: KRAS wt (N=1602),FOLFOX4 +cetuximab,FOLFOX4,No. of EventsDFS-Year 3,95% CI, %,n=79119075.1,71.7, 78.1,n=81117978.0,74.8, 80.8,HR for DFS 95% CIp-value (log-rank),1.047 0.853, 1.2860.6562,FOLFOX4 + cetuximab,791811,699732,505527,356381,24,132131,Number of patients at risk,FOLFOX4 + cetuximabFOLFOX4,00,0,2,4,6,5,1,3,0.0,0.2,0.4,FOLFOX40.80.6,1.0,Years,Forest plot for DFS: KRAS wt,1.0,0.2,Strata,ControlO/N,TreatmentO/N,Sex,Male,118 / 468,110 / 468,0.88 (0.68, 1.15),Female,61 / 343,80 / 323,1.45 (1.03, 2.03),*Log rank,Tumor localization,Right localizationLeft localization,66 / 284111 / 517,85 / 286104 / 499,1.40 (1.01, 1.94)0.88 (0.67, 1.15)10,FOLFOX4 + Cetuximab better,Age category,Age 70,13 / 73,23 / 76,1.97 (0.99, 3.93),p=0.051,p=0.043,Treatment effect within subgroupAdjusted HR (CI) p-value *,p=0.031,FOLFOX 4 better,Forest plot for DFS: KRAS wt,*Log rank,FOLFOX4 + Cetuximab better,FOLFOX 4 better,Strata,ControlO/N,TreatmentO/N,1.0,0.2,Pathological staging pT,pT1-2-3,115 / 668,131 / 628,1.26(0.98,1.62),pT4,64 / 142,58 / 161,0.71(0.50,1.02),p=0.061,Bowel obstr. or perfor.,None of both,126 / 665,145 / 644,1.16(0.91,1.48),Obstr. or perfor.,53 / 146,45 / 147,0.79(0.53,1.18),p=0.256,Histopathological grading,Histopat: G3-4,0.76(0.49,1.16)10,48 / 160,39 / 148,Histopat: G1-2,1.16(0.91,1.47),128 / 641,148 / 632,p=0.203,Treatment effect within subgroupAdjusted HR (CI) p-value *,DFS rate,FOLFOX4 + cetuximabFOLFOX4,7967,6448,3824,2815,00,167,Number of patients at risk,FOLFOX4 + CTXFOLFOX4,00,0,2,4,6,5,1,3,0.0,0.2,0.80.60.4,DFS: KRAS wt pT4N2 tumors1.0,Years,F + ctx,F,No. of Events,n=7932,n=6741,HR for DFS 95% CI,0.555 0.348, 0.885,p-value (log-rank),0.0122,Final analysis of the phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refractory,K-RAS wild-type (WT), metastatic colorectal carcinoma (mCRC): The NCIC Clinical Trials Group and AGITG CO.20 trial.,西妥昔单抗(CET)+丙氨酸布立尼布(BRIV)或安慰剂应在化疗失败,KRAS野生型的mCRC患者中的随机期临床试验分析: NCIC 临床试验组和AGITG CO.20 试验组,Lillian L. Siu et.al 2012 ASCO abstract NO.3504,Brivanib Alaninate,丙氨酸布立尼布(BRIV)是一种有效的,靶向肿瘤血管生成的口服多激酶抑制剂VEGFR-2(IC50 =23nM) FGFR-1(IC50 =150nM)VEGFR-3(IC50 =10nM) FGFR-2(IC50 =125nM) FGFR-3(IC50 =68nM),研究原理,-两个靶向药物的联合 西妥昔单抗靶向促肿瘤生长的EGFR信号 BRIV靶向促肿瘤血管生成因子受体-EGFR和VEGFR抑制剂的协同作用-在移植模型上证实在体内有效-两种药物即使是足量联用也是安全的.,NCIC CTG CO20:研究,随机分组,Bribanib +Cetuximab n=376,安慰剂 +Cetuximab n=374,1:1,首要终点:OS总样本数:750试验开始时间:2008年2月5日最后一例患者入组时间:2011年2月10日中期随访:最终分析:19个月(565例死亡)分析更新:36个月(694例死亡),按ECOG 0/1和2分层,次要终点:PFS，客观有效率，生存质量，经济效益评估，毒性和分子标记物,NCIC CTG CO.20:入组标准,病理确诊为转移性CRCK-RS野生型接受过嘧啶合成酶抑制剂的治疗.(如5-FU或卡培他滨)-伊立替康和奥沙利铂不耐受或治疗失败-未使用过抗EGFR药物治疗-可有一种抗VEGF(R)药物使用史-ECOG评分0,1或2,NCIC CTG CO.20:治疗计划,OS,亚组OS结果,PFS,NCIC CTG CO.20:疗效(RECIST 1.0 更新),NCIC CTG CO.20:3+级治疗不良反应,NCIC CTG CO.20:治疗中断(更新),最常见的Brivanib/Cetuximab中断是疲劳(5%),ALT(2%),呼吸困难(2%)仅有一例Brivanib组的患者死亡被认为可能和药物有关.,NCIC CTG CO.20:生存质量小结,96%患者的生存质量可评价生存质量基线平衡初始生存质量终点:评估在身体功能和全球EORTC QLQ-C30量表上的恶化(10点)时间.生存质量结果安慰剂 vs brivanib:-全球卫生:中位1.6 vs 1.1个月(p=0.02)-身体功能:中位 5.6 vs1.7个月(p0.0001),NCIC CTG CO.20:结论,本期试验中, Bribanib+Cetuximab对照安慰剂+Cetuximab组:首要终点OS未发现有改善客观有效率和无进展生存期有改善在身体功能和全球健康生存质量量表上的恶化时间变短.治疗相关不良反应与每种药物的单一用药反应一致.和Bribanib联用时, Cetuximab的剂量强度减小.,EGFR-Targeted Agents as First-line Therapy in KRAS WT mCRC: Efficacy,1.