轉(zhuǎn)移性結(jié)直腸癌靶向相關(guān)治療進(jìn)展

1、轉(zhuǎn)移性結(jié)直腸癌靶向相關(guān)治療進(jìn)展貝伐單抗相關(guān)研究西妥昔單抗相關(guān)研究其他靶向藥物研究進(jìn)展靶向藥物在轉(zhuǎn)移性結(jié)直腸癌挽救治療中的相關(guān)研究總結(jié)轉(zhuǎn)移性結(jié)直腸癌靶向治療進(jìn)展2012貝伐單抗相關(guān)研究西妥昔單抗相關(guān)研究其他靶向藥物研究進(jìn)展靶向藥物在轉(zhuǎn)移性結(jié)直腸癌挽救治療中的相關(guān)研究總結(jié)化療聯(lián)合貝伐單抗一線治療后，貝伐單抗聯(lián)合或不聯(lián)合厄洛替尼維持治療轉(zhuǎn)移性結(jié)直腸癌患者的療效及安全性結(jié)果：來(lái)自國(guó)際性期研究GERCOR DREAM Christophe Tournigand, MD ,et al. 2012 ASCO Abstract LBA3500Bevacizumab (Bev) with or without

2、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.背景介紹DREAM研究的主要目的是評(píng)價(jià)靶向藥物的維持治療VEGF抑制劑（貝伐單抗）聯(lián)合含奧沙利鉑或含伊立替康方案一線或二線化療可改善生存1-3EGF

3、R抑制劑（帕木單抗或西妥昔單抗）可改善Kras野生型腫瘤的生存4-7OPTIMOX1-2研究證實(shí)奧沙利鉑間歇化療模式的療效8-9與腫瘤生長(zhǎng)和生存有關(guān)的EGFR和VEGF通路間存在交叉作用mCRC的III期研究顯示：EGFR和VEGF的單克隆抗體聯(lián)合并無(wú)獲益10,11結(jié)直腸癌異種移植模型中，VEGFR及EGFR的TKI類藥物聯(lián)合可產(chǎn)生協(xié)同抗腫瘤活性，而且對(duì)KRAS突變的模型也有效12臨床前研究模型已探索貝伐單抗聯(lián)合厄洛替尼的療效13 1.Saltz LB et al. J Clin Oncol 2008; 2006:2013-9 2. Hunwitz et al. N Engl J Med 20

4、04:350:2335-423.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

5、: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 貝伐單抗聯(lián)合厄洛替尼對(duì)SW620結(jié)直腸癌異種移植模型的療效VELOUR

6、試驗(yàn)設(shè)計(jì)入組時(shí)間：2007/1/4-2011/10/13a奧沙利鉑 100mg/m2 d1(6周期);5-FU 2.4g/m2 d1-2; FA 400mg/m2 d1;貝伐單抗5mg/kg d1,q2w,6-12周期b奧沙利鉑 100mg/m2 d1(6周期);卡培他濱1.25-1.5g/m2 bid d1-8 ;貝伐單抗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;貝伐單抗5mg/kg d1,q2w,12周期mFOLFOX7+貝伐單抗a無(wú)PD隨機(jī)分組貝伐單抗（7.5mg/kg,q3w）+厄洛

7、替尼（150mg/d）直至PDN=222貝伐單抗（7.5mg/kg,q3w）直至PDN=224誘導(dǎo)化療（N=700）XELOX2+貝伐單抗bFOLFIRI+貝伐單抗c注冊(cè)研究終點(diǎn)主要終點(diǎn)：維持治療PFS次要終點(diǎn)：OS、自維持治療的OS、無(wú)化療間期、緩解率（RECIST標(biāo)準(zhǔn)）、根據(jù)KRAS突變狀態(tài)的生存標(biāo)本量：優(yōu)效性研究，80效力，雙側(cè)檢驗(yàn)中位維持治療PFS：月（貝伐單抗組）月（貝伐單抗厄洛替尼組）預(yù)計(jì)脫落率40計(jì)劃入組700例患者評(píng)估418例患者要求發(fā)生231個(gè)事件入組標(biāo)準(zhǔn)組織學(xué)證實(shí)為結(jié)直腸腺癌可測(cè)量或可評(píng)估的轉(zhuǎn)移灶不能手術(shù)完整切除轉(zhuǎn)移灶未接受過(guò)化療或靶向治療1880歲WHO PS 0-2堿性

8、磷酸酶6個(gè)月（如接受奧沙利鉑治療則2年）基線特征貝伐單抗組（n224），貝伐單抗厄洛替尼組（n222），年齡，70/7073/2774/26性別，男/女56/4466/34結(jié)腸/直腸/結(jié)直腸73/25/274/23/3輔助化療周期數(shù)911異時(shí)病灶/同時(shí)性灶17/8318/82PS，0/1/260/37/460/36/4化療方案FOLFOX-bev5959XELOX-bev3030FOLFIRI-bev1010血小板計(jì)數(shù)，40071/2974/26LDH,N/ULN47/5349/51堿性磷酸酶,N/ULN48/5250/50CEA,N/ULN15/8115/83維持治療PFS(自隨機(jī)開(kāi)始)聯(lián)合

9、組PFS更優(yōu)PFS（自注冊(cè)開(kāi)始，隨機(jī)分組的患者）治療情況貝伐單抗組貝伐單抗厄洛替尼組貝伐單抗貝伐單抗厄洛替尼總周期數(shù)156417631569每個(gè)患者平均周期數(shù)7.18.17.2足量周期數(shù)(%)1497（95.7）1716（97.3）1194（76.1）毒性3/4級(jí)毒性反應(yīng)，貝伐單抗組（n219）貝伐單抗厄洛替尼組（n218）中性粒細(xì)胞減少00貧血0.50.9血小板減少00.5粒缺性發(fā)熱00惡心0.50嘔吐01.4粘膜炎00.5手足綜合癥0.50靜脈血栓00蛋白尿0.50.9高血壓2.72.81級(jí)2級(jí)3級(jí)4級(jí)1級(jí)2級(jí)3級(jí)4級(jí)腹瀉，11110292090皮膚毒性，00002837191結(jié)論含貝伐單

10、抗的誘導(dǎo)化療后繼續(xù)給予貝伐單抗聯(lián)合厄洛替尼維持治療較貝伐單抗單藥顯著改善維持治療PFS貝伐單抗聯(lián)合厄洛替尼耐受性良好，但腹瀉和皮膚毒性明顯加重研究結(jié)果顯示厄洛替尼可能對(duì)轉(zhuǎn)移性結(jié)直腸癌有效，并為VEGF和EGFR的雙向抑制提供臨床理論基礎(chǔ)總生存及KRAS分析仍在進(jìn)行中VELOUR研究中預(yù)先應(yīng)用貝伐單抗的療效: 伊立替康+阿柏西普方案應(yīng)用于奧沙利鉑治療失敗后轉(zhuǎn)移性結(jié)直腸癌患者的期臨床試驗(yàn)Carmen Joseph Allegra ,et al. 2012 ASCO Abstract NO.3505 Effects of prior bevacizumab (B) use on outcomes f

11、rom 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.背景介紹與單獨(dú)應(yīng)用FOLFOX4方案相比， 2線貝伐單抗聯(lián)合FOLFOX4方案治療轉(zhuǎn)移性結(jié)直腸癌的3期臨床試驗(yàn)顯示其可顯著改善生存受益：中位OS:12.9 vs 10.8 月， 中位PFS:7.3 vs 4.7 月，HR本研究分析的目的在于評(píng)估之前已接受過(guò)

12、貝伐單抗治療的患者中，應(yīng)用阿柏西普(Afl)后的OS及PFS. VELOUR 試驗(yàn)設(shè)計(jì)轉(zhuǎn)移性結(jié)直腸癌隨機(jī)分組阿柏西普 4mg/kg IV 第一天+伊立替康 每?jī)芍芤淮伟参縿?IV 第一天+伊立替康 每?jī)芍芤淮尾∏檫M(jìn)展死亡首要終點(diǎn)： 總生存率 OS樣本大小：危險(xiǎn)比0.8.90%效力，雙邊第一類錯(cuò)誤 發(fā)生了863例死亡事件時(shí)進(jìn)行了最終的OS分析，（變量的雙側(cè)顯著性水平為）VELOUR 入組標(biāo)準(zhǔn)病理證實(shí)的已無(wú)法治愈的轉(zhuǎn)移性結(jié)直腸癌可測(cè)量病灶或不可測(cè)量病灶（RECIST標(biāo)準(zhǔn)）僅應(yīng)用過(guò)1種包含奧沙利鉑的化療方案在完成奧沙利鉑聯(lián)合化療后六個(gè)月內(nèi)復(fù)發(fā)的患者同樣符合條件VELOUR 研究整體結(jié)果阿柏西普+伊立

13、替康聯(lián)合應(yīng)用于接受過(guò)含奧沙利鉑化療方案的患者，可有顯著OS及PFS受益?；颊呋€特征參數(shù) 應(yīng)用貝伐單抗組 未應(yīng)用貝伐單抗組安慰劑./伊立替康 (n=187)阿柏西普/伊立替康（n=186）安慰劑./伊立替康 (n=427)阿柏西普/伊立替康（n=426）PS 評(píng)分，%057585757140404141男性，%56595860年齡，歲，中位（范圍）60（2786）59（3281）61（1984）61（2182）地區(qū)，%歐洲56545863南美282653其他國(guó)家16193734轉(zhuǎn)移器官1,%54575659應(yīng)用貝伐單抗的持續(xù)時(shí)間，月，中位（范圍）6（028）6（029）血管生成期2（121）2

14、（133）用和未用過(guò)貝伐單抗組的OS和PFS比較應(yīng)用貝伐單抗組未應(yīng)用貝伐單抗組安慰劑/伊立替康（n=187）阿柏西普/伊立替康(n=186)安慰劑/伊立替康（n=187）阿柏西普/伊立替康(n=186) OS(月)（95.34%CI）11.7(9.8-13.8)12.5(10.8-15.5)0.812.4(11.2-13.5)13.9(12.7-15.6)1.5PFS(月)(99.99%CI)3.9(2.9-5.4)6.7(4.8-8.7)2.85.4(4.2-6.7)6.9(5.8-8.2)1.5首要終點(diǎn):OS 有效率安全性：抗VEGF 相關(guān)事件應(yīng)用貝伐單抗組未應(yīng)用貝伐單抗組安慰劑/伊立替康

15、（n=172）阿柏西普/伊立替康（n=171）安慰劑/伊立替康（n=433）阿柏西普/伊立替康（n=440）不良反應(yīng)3/4級(jí)毒性3/4級(jí)毒性3/4級(jí)毒性3/4級(jí)毒性蛋白尿0.69.41.47.3高血壓0.616.41.820.5出血1.23.51.82.7 胃腸源性0.63.51.21.4頭疼00.60.52.0靜脈血栓栓塞2.92.33.75.5 肺栓塞0.61.80.51.8動(dòng)脈血栓栓塞0.61.80.51.8胃腸穿孔000.50.7安全性：不良事件安慰劑/伊立替康（n=172）阿柏西普/伊立替康（n=171）安慰劑/伊立替康（n=433）阿柏西普/伊立替康（n=440）嚴(yán)重不良事件325

16、23347導(dǎo)致死亡的不良事件6646各組中發(fā)生率10%的不良事件嗜中性白血球減少癥13202527腹瀉919720身體衰弱9161117感染814712口腔炎 411514安全性：導(dǎo)致用藥中止的不良事件安慰劑/伊立替康（n=172）阿柏西普/伊立替康（n=171）安慰劑/伊立替康（n=433）阿柏西普/伊立替康（n=440）導(dǎo)致永久性治療中止的不良事件9.325.713.227.3所有患者中發(fā)生率1%的導(dǎo)致治療中止的3/4級(jí)不良事件疲勞0.61.80.71.8腹瀉0.61.80.21.8高血壓0002.3肺栓塞00.61.61.4衰弱00.60.21.4脫水01.20.20.7直腸出血000中

17、性粒細(xì)胞減少性感染1.2000.5結(jié)論本次亞組分析顯示，不論之前是否接受過(guò)貝伐單抗的治療，阿柏西普都能顯著增加OS和PFS.既往接受過(guò)貝伐珠單抗治療對(duì)阿柏西普的安全性沒(méi)有顯著影響本研究證實(shí)阿柏西普+伊立替康聯(lián)合應(yīng)用于接受過(guò)含奧沙利鉑化療方案的患者，可有顯著OS及PFS受益。本次研究顯示,阿柏西普應(yīng)用于曾接受過(guò)貝伐單抗治療的患者中,OS和PFS與未接受過(guò)貝伐單抗治療的對(duì)照組相比無(wú)明顯差異.因此其在接受過(guò)貝伐單抗治療的患者中應(yīng)用是否有益處還不能下定論.在接受過(guò)BEV+化療的mCRC患者疾病進(jìn)展后持續(xù)應(yīng)用BEV聯(lián)合化療:隨機(jī)期臨床試驗(yàn)組內(nèi)研究結(jié)果(TML研究) Bevacizumab (BEV) p

18、lus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study). Dirk Arnold.et.al. 2012ASCO Abstract NO. 3503 背景（1）貝伐單抗(BEV)聯(lián)合5-FU為基礎(chǔ)的化療是中晚期結(jié)直腸癌標(biāo)準(zhǔn)一線治療方案.

19、貝伐單抗也能應(yīng)用于二線治療.VEGF是早期促腫瘤血管生長(zhǎng)因子.在臨床前研究中,持續(xù)VEGF抑制可使瘤體縮小.在mCRC患者非隨機(jī)觀察試驗(yàn)(BRiTE,ARIES)中,持續(xù)使用BEV+CT治療組比未持續(xù)使用BEV組試驗(yàn)延緩了疾病進(jìn)展并延長(zhǎng)了生存率.背景（2）在晚期結(jié)直腸癌第一次疾病進(jìn)展后,應(yīng)用BEV的有效性和毒性還未在隨機(jī)臨床試驗(yàn)中研究過(guò)TML(ML18147) 是第一個(gè)隨機(jī)期研究,用以評(píng)估持續(xù)BEV+標(biāo)準(zhǔn)二線化療方案應(yīng)用在BEV+一線化療方案失敗后的病情進(jìn)展的mCRC患者的療效.ML18147研究設(shè)計(jì)(期)PD隨機(jī)分組1:1BEV+標(biāo)準(zhǔn)一線化療(奧沙利鉑或伊立替康為基礎(chǔ))(n=820)標(biāo)準(zhǔn)二線

20、化療(奧沙利鉑或伊立替康為基礎(chǔ))直到病情進(jìn)展BEV(2.5mg/kg/wk)+標(biāo)準(zhǔn)二線化療(奧沙利鉑或伊立替康為基礎(chǔ))直到病情進(jìn)展首要終點(diǎn):隨機(jī)OSPFS最佳總反應(yīng)率毒性次要終點(diǎn):分層因素:一線化療(奧沙利鉑為基礎(chǔ),伊立替康為基礎(chǔ))一線PFS(9個(gè)月,9個(gè)月)上次使用BEV事件(42天,42天)基準(zhǔn)ECOG PS 評(píng)分 (0/1,2)主要入組標(biāo)準(zhǔn)包括病理確診為mCRC的18歲以上患者ECOG PS評(píng)分 0-2PD(根據(jù)RECIST第一版,CT或MRI確定有1 可測(cè)量病灶),截至試驗(yàn)開(kāi)始時(shí)4周先前接受過(guò)BEV+標(biāo)準(zhǔn)一線化療方案治療，不包括首發(fā)轉(zhuǎn)移灶切除術(shù)后患者.排除診斷PD時(shí),在最后一次使用BE

21、V后超過(guò)3個(gè)月患者在一線治療中的PFS 3個(gè)月接受一線持續(xù)BEV治療3個(gè)月患者基線特征（1）患者基線特征（2）研究中應(yīng)用的二線化療方案首要終點(diǎn):OS次要終點(diǎn):PFS和最佳總反應(yīng)率最佳總反應(yīng)率:可測(cè)量病灶毒性治療時(shí)長(zhǎng)(至毒性反應(yīng)出現(xiàn)時(shí)間)3-5級(jí)毒性反應(yīng)(發(fā)生率2%)毒性反應(yīng),%CT(N=409)BEV+CT(N=401)嗜中性粒細(xì)胞減少癥1316白細(xì)胞減少癥34腹瀉810嘔吐34惡心33腹痛34低位腸梗阻12衰弱46疲勞24粘膜感染13呼吸困難32肺栓塞23多發(fā)神經(jīng)炎23周圍神經(jīng)病變21低鉀血癥22食欲下降21BEV引起的不良反應(yīng)患者,% CT (n=409) BEV+CT (n=401)BE

22、V導(dǎo)致的不良反應(yīng)所有級(jí)別3-5級(jí)所有級(jí)別3-5級(jí)高血壓2164112蛋白尿71122出血1-51膿腫91262胃腸道穿孔-11心肌梗塞1132靜脈血栓栓塞4365動(dòng)脈血栓栓塞1111傷口愈合能力111 vs 3 mos) II-line CTRANDOMFOLFIRIFOLFOXFOLFOXIRIFluoropyrimidine mono-tx* FOLFIRI mFOLFOX-6A. Second-line CTB. Second-line CT+ BV Study conducted in 19 Italian centers Supported by AIFAPrimary Object

23、ive - PFSCT (85 events) median PFS = 4.97 mosCT+ B (87 events) median PFS = 6.77 mosHR=0.65 (95%CI 0.48-0.89)Median follow up 18.0 mosFirst-line Chemotherapy Bevacizumab in mCRC: EfficacyAuthorComparative RegimensPFS, MosHR(P Value)OS, MosHR(P Value)Colucci1FOLFIRI vs FOLFOX47.0 vs 7.0NR(.64)14.0 vs

24、 15.0NR(.28)Cassidy2,3XELOX vs FOLFOX47.3 vs 7.70.9619.0 vs 18.90.95Hurwitz4IFL/Bev vs IFL10.6 vs 6.20.54( .001)20.3 vs 15.60.66(18 and 6 months beforeinclusionNo previous oxaliplatinNo current indications for resection with a curative intentAdequate haematological, renal and liver functionNo periph

25、eral neuropathyNo other serious illness or medical conditionsWritten informed consent9Baseline characteristics, ITT (n=566)10Progression free survival (PFS), ITTArm A:Arm B:Arm C:185194187124137120466237152012922Number ofpatients at risk11Nordic Colorectal Cancer Biomodulation GroupConfirmed respons

26、esand R0-resections, ITT12Arm A:Arm B:Arm C:185194187135143133685964151214Number ofpatients at riskOverall survival (OS), ITT13Nordic Colorectal Cancer Biomodulation GroupSafety, WHO gr. 3/4 (% of patients)14Nordic Colorectal Cancer Biomodulation GroupKRAS and BRAF mutation analyses15PFS and OS, KRA

27、S populationswtmutNordic Colorectal Cancer Biomodulation Groupwtmut16PFS, OS and ORR, BRAF populationswtNordic Colorectal Cancer Biomodulation Groupwt17Progression free survival,KRAS populationsKRAS wild typeKRAS mutantArm A:Arm B:9797706529349960Number of patients at risk58724155122661132Number of

28、patients at risk18Nordic Colorectal Cancer Biomodulation GroupConfirmed responses,KRAS populations19Overall survival, KRAS populationsKRAS wild typeArm A Arm B Arm C KRAS mutantArm A Arm B Arm C Arm A:Arm B:Arm C:9797109727073382944979Number of patients at risk587265475551232320545Number of patients

29、 at risk20Validation of results - Quality testing KRAS mutation analyses (DxS kit) Internal validation- Scoring by two independent persons- Reanalyses same method (DxS kit)- Confirmation by Clamped-Probe-Assay and sequencing External validation: Reanalyses in reference lab (DxS kit) BRAF mutation an

30、alyses External validation: Reanalyses in reference lab Matching of tumour sample and patients id Allocation of tumour sample no. to patients trial no. DNA-fingerprinting of tumour and leucocytes New clinical and KRAS/BRAF databases New internal and external independent analyses of core data21 Nordi

31、c FLOX is confirmed to be effective in first line treatment ofmCRC, with median PFS 8 months, OS 20 months and ORR 40% Cetuximab does not give significant additional benefit whencombined with Nordic FLOX FLOX given intermittently (stop and go) with continuous cetuximabgives similar survival as treat

32、ment 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 expl

33、ained simply by chance The NORDIC VII study indicates that oxaliplatin may not be a goodmatch for cetuximab in mCRCAdjuvant 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 tr

34、ialJ. 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.*GeorgesPompidou European Hospital, Paris, FranceFully r

35、esectedstage IIIcolonRStratification factors:N-status (N1 vs N2)T-status (T1-3 vs T4)Obstruction/perforation statusOriginal 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/m2followed by 5-FU 600mg/m2 22-hour IVon d1 and d2cance

36、r(N = 2000)FOLFOX4 + cetuximab(12 cycles) FOLFOX4 Cetuximab d1 and d8- 400 mg/m2 initial dose- 250 mg/m2 weeklyEnrolment was restricted to wild-type KRAS and sample size increased in 2008DFS rateDisease-free survival: KRAS wt (N=1602)FOLFOX4 +cetuximabFOLFOX4No. of EventsDFS-Year 395% CI, %n=7911907

37、1.7, 78.1n=81117974.8, 80.8HR for DFS 95% CIp-value (log-rank)1.047 0.853, 1.286FOLFOX4 + cetuximab79181169973250552735638124132131Number of patients at riskFOLFOX4 + cetuximabFOLFOX4000246513FOLFOX4YearsForest plot for DFS: KRAS wtStrataControlO/NTreatmentO/NSexMale118 / 468110 / 4680.88 (0.68, 1.1

38、5)Female61 / 34380 / 3231.45 (1.03, 2.03)*Log rankTumor localizationRight localizationLeft localization66 / 284111 / 51785 / 286104 / 4991.40 (1.01, 1.94)0.88 (0.67, 1.15)10FOLFOX4 + Cetuximab betterAge categoryAge 7013 / 7323 / 761.97 (0.99, 3.93)Treatment effect within subgroupAdjusted HR (CI) p-v

39、alue *FOLFOX 4 betterForest plot for DFS: KRAS wt*Log rankFOLFOX4 + Cetuximab betterFOLFOX 4 betterStrataControlO/NTreatmentO/NPathological staging pTpT1-2-3115 / 668131 / 6281.26(0.98,1.62)pT464 / 14258 / 1610.71(0.50,1.02)Bowel obstr. or perfor.None of both126 / 665145 / 6441.16(0.91,1.48)Obstr. o

40、r perfor.53 / 14645 / 1470.79(0.53,1.18)Histopathological gradingHistopat: G3-40.76(0.49,1.16)1048 / 16039 / 148Histopat: G1-21.16(0.91,1.47)128 / 641148 / 632Treatment effect within subgroupAdjusted HR (CI) p-value *DFS rateFOLFOX4 + cetuximabFOLFOX4796764483824281500167Number of patients at riskFO

41、LFOX4 + CTXFOLFOX4000246513DFS: KRAS wt pT4N2 tumorsYearsF + ctxFNo. of Eventsn=7932n=6741HR for DFS 95% CI0.555 0.348, 0.885p-value (log-rank)Final analysis of the phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refr

42、actory,K-RAS wild-type (WT), metastatic colorectal carcinoma (mCRC): The NCIC Clinical Trials Group and AGITG CO.20 trial.西妥昔單抗(CET)+丙氨酸布立尼布(BRIV)或安慰劑應(yīng)在化療失敗,KRAS野生型的mCRC患者中的隨機(jī)期臨床試驗(yàn)分析: NCIC 臨床試驗(yàn)組和AGITG CO.20 試驗(yàn)組Brivanib Alaninate丙氨酸布立尼布(BRIV)是一種有效的,靶向腫瘤血管生成的口服多激酶抑制劑VEGFR-2(IC50 =23nM) FGFR-1(IC50 =15

43、0nM)VEGFR-3(IC50 =10nM) FGFR-2(IC50 =125nM) FGFR-3(IC50 =68nM)研究原理-兩個(gè)靶向藥物的聯(lián)合 西妥昔單抗靶向促腫瘤生長(zhǎng)的EGFR信號(hào) BRIV靶向促腫瘤血管生成因子受體-EGFR和VEGFR抑制劑的協(xié)同作用-在移植模型上證實(shí)在體內(nèi)有效-兩種藥物即使是足量聯(lián)用也是安全的. NCIC CTG CO20:研究隨機(jī)分組 Bribanib +Cetuximab n=376 安慰劑 +Cetuximab n=3741:1首要終點(diǎn):OS總樣本數(shù):750試驗(yàn)開(kāi)始時(shí)間:2008年2月5日最后一例患者入組時(shí)間:2011年2月10日中期隨訪:最終分析:19

44、個(gè)月(565例死亡)分析更新:36個(gè)月(694例死亡)按ECOG 0/1和2分層次要終點(diǎn):PFS，客觀有效率，生存質(zhì)量，經(jīng)濟(jì)效益評(píng)估，毒性和分子標(biāo)記物NCIC CTG CO.20:入組標(biāo)準(zhǔn)病理確診為轉(zhuǎn)移性CRCK-RS野生型接受過(guò)嘧啶合成酶抑制劑的治療.(如5-FU或卡培他濱)-伊立替康和奧沙利鉑不耐受或治療失敗-未使用過(guò)抗EGFR藥物治療-可有一種抗VEGF(R)藥物使用史-ECOG評(píng)分0,1或2NCIC CTG CO.20:治療計(jì)劃OS亞組OS結(jié)果PFSNCIC CTG CO.20:療效(RECIST 1.0 更新)NCIC CTG CO.20:3+級(jí)治療不良反應(yīng)不良反應(yīng)(p0.05)Br

45、ivanib+Cetuximab n=372安慰劑+Cetuximab n=373 患者數(shù)量(%)患者數(shù)量(%)疲勞100(27)40(11)高血壓39(11)4(1)皮疹38(10)20(5)腹痛37(10)20(5)呼吸困難34(9)20(5)腹瀉 28(8)11(3)脫水26(7)6(2)厭食20(5)5(1)總不良反應(yīng)例數(shù)301(81)201(54)AST升高64(17)23(6)ALT升高80(22)18(5)低鈉血癥54(15)29(8)TSH升高93(25)14(4)NCIC CTG CO.20:治療中斷(更新)Brivanib+Cetuximab n=372安慰劑+Cetuxi

46、mab n=373患者數(shù)(%)患者數(shù)(%)不良反應(yīng)導(dǎo)致的Cetuximab中斷30(8)15(4)不良反應(yīng)導(dǎo)致的Brivanib中斷86(23)13(4)病情進(jìn)展后接受抗癌治療69(18)87(23)最常見(jiàn)的Brivanib/Cetuximab中斷是疲勞(5%),ALT(2%),呼吸困難(2%)僅有一例Brivanib組的患者死亡被認(rèn)為可能和藥物有關(guān).NCIC CTG CO.20:生存質(zhì)量小結(jié) 96%患者的生存質(zhì)量可評(píng)價(jià)生存質(zhì)量基線平衡初始生存質(zhì)量終點(diǎn):評(píng)估在身體功能和全球EORTC QLQ-C30量表上的惡化(10點(diǎn))時(shí)間.生存質(zhì)量結(jié)果安慰劑 vs brivanib:-全球衛(wèi)生:中位個(gè)月(p

47、=0.02)-身體功能:中位 個(gè)月(p0.0001)NCIC CTG CO.20:結(jié)論本期試驗(yàn)中, Bribanib+Cetuximab對(duì)照安慰劑+Cetuximab組:首要終點(diǎn)OS未發(fā)現(xiàn)有改善客觀有效率和無(wú)進(jìn)展生存期有改善在身體功能和全球健康生存質(zhì)量量表上的惡化時(shí)間變短.治療相關(guān)不良反應(yīng)與每種藥物的單一用藥反應(yīng)一致.和Bribanib聯(lián)用時(shí), Cetuximab的劑量強(qiáng)度減小.EGFR-Targeted Agents as First-line Therapy in KRAS WT mCRC: EfficacyTrialComparative RegimensPFS, MosHR(P Val

48、ue)OS, MosHR(P Value)CRYSTAL1FOLFIRI/Cetux vs FOLFIRI9.9 vs 8.40.696 (.0012)23.5 vs 20.00.796 (.0093)COIN2FOLFOX/XELOX/Cetux vs FOLFOX/XELOX8.6 vs 8.60.96(.60)17.0 vs 17.91.04(.67)NORDIC VII3FLOX/Cetux vs FLOX7.9 vs 8.71.07(.66)20.1 vs 22.01.14(.66)PRIME4FOLFOX4/Pmab vs FOLFOX49.6 vs 8.00.80(.02)23.

49、9 vs 19.70.83(.072)1. Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019. 2. Maughan TS, et al. Lancet. 2011;377:2103-2114. 3. Tveit K, et al. ASCO GI 2011. Abstract 365. 4. Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705. Worse PFS outcome with panitumumab + FOLFOX4 in mutant KRAS disease4轉(zhuǎn)移

50、性結(jié)直腸癌靶向治療進(jìn)展2012貝伐單抗相關(guān)研究西妥昔單抗相關(guān)研究其他靶向藥物研究進(jìn)展靶向藥物在轉(zhuǎn)移性結(jié)直腸癌挽救治療中的相關(guān)研究總結(jié)Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC).Eric Van Cutsem, et,al. 2012 ASCOAbstract No:3502應(yīng)用regorafenib治療轉(zhuǎn)移性結(jié)直腸癌的期研究 ：CORRECTRegorafenib(BAY 73-4506),一種口服的,以多種腫瘤通路為作用靶點(diǎn)的多激酶阻滯劑Reforafenib治療mCRC的臨床原理

51、:期試驗(yàn)CRC患者38例:-用量增加階段:n=15 reforafenib 量 從60到220mg/日(用三周,停一周)-拓展階段:n=23推薦用量160 mg/日(用三周,停一周)最常見(jiàn)的毒性事件:手足皮膚反應(yīng),腹瀉,疲勞和聲音改變.27位患者療效可評(píng)價(jià):-疾病控制率(DCR):74% 部分控制 (PR):4%(n=1);病情穩(wěn)定(SD):70%(n=19)-PFS:中位107天(95%CI,66-161)-增強(qiáng)MRI顯示腫瘤血管灌注減少隨機(jī)分組Regorafenib+BSC(N=505)每日口服160mg,用三周,停一周安慰劑+BSC(n=255)用三周,停一周標(biāo)準(zhǔn)方案治療后的mCRC(患

52、者監(jiān)測(cè),n=1052;隨機(jī)分組,n=760)2:1維持治療直至病情進(jìn)展或嚴(yán)重毒性反應(yīng)或患者拒絕每8周行CT掃描胸腹部評(píng)估病情變化多中心,隨機(jī),雙盲,安慰劑對(duì)照,期 -分層:是否接受過(guò)抗VEGF治療,從確診到轉(zhuǎn)移的時(shí)間,國(guó)家和地區(qū)全球性試驗(yàn):16個(gè)國(guó)家,114個(gè)中心患者招募時(shí)間:2010年5月至2011年3月試驗(yàn)設(shè)計(jì)CORRECT 終點(diǎn)首要終點(diǎn):總生存率(OS)次要終點(diǎn):PFS,總有效率(ORR),DCR第三終點(diǎn):療效持續(xù)時(shí)間/SD,生存質(zhì)量(QoL),PK,生物標(biāo)記物入組標(biāo)準(zhǔn)有組織學(xué)或細(xì)胞學(xué)資料的結(jié)腸癌或直腸癌在接受標(biāo)準(zhǔn)方案治療后,病情在3月內(nèi)進(jìn)展,包括:-奧沙利鉑,5-fu,伊立替康-貝伐單

53、抗-西妥昔單抗或帕尼單抗(KRAS野生型)根據(jù)RECIST標(biāo)準(zhǔn),可測(cè)量病灶或不可測(cè)病灶年齡18歲,ECOG PS 0-1,預(yù)計(jì)生存期3個(gè)月骨髓,肝腎功能正常簽字同意參加試驗(yàn)患者基線特征腫瘤基線特征首要終點(diǎn):OS與安慰劑組相比,Regorafenib 顯著改善OS次要終點(diǎn):PFS與安慰劑組相比,Regorafenib 顯著改善PFS次要終點(diǎn):總生存率和控制率與安慰劑組相比, Regorafenib 顯著改善DCROS亞組分析（1）OS亞組分析（2）PFS亞組分析通過(guò)亞組分析可得知,與安慰劑組相比Regorafenib 組顯著獲益KRAS亞組分析Regorafenib 組在KRAS野生型組和KRA

54、S突變亞組都有OS和PFS獲益.KRAS突變?cè)诒狙芯恐胁荒茏鳛轭A(yù)后預(yù)測(cè)因子10%以上的患者出現(xiàn)藥物相關(guān)毒性事件毒性事件,%手足皮膚反應(yīng)疲勞高血壓腹瀉皮疹/脫皮厭食癥口腔粘膜炎血小板減少癥發(fā)熱惡心出血聲音改變體重減輕*5級(jí)藥物相關(guān)毒性: regorafenib組1.0% vs 安慰劑組0%生存質(zhì)量分析:曲線下時(shí)間區(qū)域安慰劑組與Regorafenib 組在生存質(zhì)量上無(wú)顯著差異CORRECT試驗(yàn)結(jié)果小結(jié)本研究在期中分析達(dá)到首要終點(diǎn)Regorafenib VS 安慰劑-個(gè)月-PFS:1.9vs1.7 個(gè)月亞組分析:-Regorafenib組顯示OS和PFS受益- Regorafenib療效與KRAS突

55、變無(wú)關(guān)未發(fā)現(xiàn)新的毒性反應(yīng)最常見(jiàn)的與Regorafenib相關(guān)的 3級(jí)毒性事件是手足皮膚反應(yīng)，疲勞，腹瀉，高血壓和皮疹。結(jié)論Regorafenib是第一種在mCRC中證實(shí)有效的口服多激酶阻滯劑.Regorafenib可使經(jīng)標(biāo)準(zhǔn)方案治療失敗患者的OS和PFS提高.副作用可控.Regorafenib可作為一種新的標(biāo)準(zhǔn)治療標(biāo)準(zhǔn)方案失敗的mCRC.Cediranib plus FOLFOX/XELOX versusplacebo plus FOLFOX/XELOX in patients withpreviously untreated metastatic colorectalcancer: a ra

56、ndomized, double-blind,Phase III study (HORIZON II)Paulo M Hoff,1 Andreas Hochhaus,2 Bernhard C Pestalozzi,3Niall C Tebbutt,4 Jin Li,5 Tae Won Kim,6Laura Pike,7Anitra Fielding,7 Jane Robertson7 and Mark P Saunders8on behalf of the HORIZON II study group1HospitalSrio Libans, Universidade de So Paulo,

57、 So Paulo, Brazil2Universittsklinikum Jena, Jena, Germany3University Hospital, Zrich, Switzerland4Austin Health, Melbourne, Australia5Shanghai Cancer Hospital of Fudan University, Shanghai, China6Asan Medical Centre, Seoul, South Korea7AstraZeneca, Macclesfield, UK8Christie Hospital and Radium Insti

58、tute, Manchester, UKIntroduction Cediranib is a highly potent VEGF signalling inhibitorwith activity against all three VEGF receptors1 Cediranib has demonstrated encouraging antitumouractivity in early-phase clinical evaluation incombination with FOLFOX2,3 HORIZON II is one of two pivotal studies of

59、 cediranibin first-line mCRC HORIZON II compared cediranib + FOLFOX/XELOXwith placebo + FOLFOX/XELOX in patients withpreviously untreated mCRC1.2.Wedge SR, et al. Cancer Res 2005;65:43894400;Drevs J, et al. J Clin Oncol 2007;25:30453054;3.Chen E, et al. Clin Cancer Res 2009;15:14811486;VEGF, vascula

60、r endothelial growth factorFOLFOX/XELOX + placebo(n=170)RandomizeFOLFOX/XELOX +cediranib 30 mg (n=170)FOLFOX/XELOX +cediranib 20 mg (n=170)Study designDose decision: 20 mg selectedFOLFOX/XELOX + placebo(n=350 total)FOLFOX/XELOX + cediranib20 mg* (n=530 total)*Following the dose decisionnew patients