1、,Avastin in ovarian cancer: clinical trials,Avastin在卵巢癌的相关研究,复发卵巢癌的 II 期临床试验Burger RA, et al. J Clin Oncol 2007Cannistra SA, et al. J Clin Oncol 2007Garcia AA, et al. J Clin Oncol 2008初治卵巢癌的 II 期临床试验Micha et al. Int J Gynecol Cancer 2007Penson et al, J Clin Oncol 2010初治卵巢癌的 III 期临床试验GOG-0218, ASCO 2
2、010ICON7/OVAR11, IGCS & ESMO 2010进行中/完成的临床试验OCEANS (铂类敏感)AURELIA (铂类耐药)GOG-0213 (铂类敏感),GOG 170D: Avastin单药治疗卵巢癌复发的 II 期临床试验 试验设计,主要研究终点: 6-month PFS 和 ORR 次要研究终点:安全性, OS, PFS第三研究终点:可能影响 PFS的因素,*12 prior cytotoxic regimens (first platinum-based, with a second platinum-based regimen if platinum-free i
3、nterval 12 months)Burger, et al. JCO 2007,PD,既往治疗后进展卵巢癌* (n=62),Avastin 15mg/kg every 3 weeks,GOG 170D: Avastin单药治疗卵巢癌复发的 II 期临床试验 特性,EOC = epithelial ovarian cancer; PPC = primary peritoneal cancerBurger, et al. JCO 2007,GOG 170D: Avastin单药治疗卵巢癌复发的 II 期临床试验 疗效总结,Data for the primary efficacy endpoi
4、nts are shown in boldBurger, et al. JCO 2007,疗效似乎更支持其他的单药治疗方案,*Assessed using RECIST criteria14 of 32 patients with stable disease had PFS 6 months,GOG 170D: Avastin单药治疗卵巢癌复发的 II 期临床试验 安全性,无胃肠道穿孔,瘘以及动脉栓塞发生无2级的出血事件发生,GI = gastrointestinal; ATE = arterial thromboembolic events; VTE = venous thromboemb
5、olic eventsBurger, et al. JCO 2007,没有发现新发或预期以外的毒性发生，3/4 不良事件的发生率与其他肿瘤类型一致,高血压,静脉血栓,蛋白尿,恶心,呕吐,肠梗阻,便秘,脱水,过敏,肺部疾病,肾脏泌尿系统疾病,体质改变,凝血,肝损,疼痛,其他出血,Patients (%),121086420,3级 4级,最常见的1/2级不良事件 为疼痛， 体质改变，肝损， 贫血，蛋白尿和生殖泌尿系统疾病,GOG 170D: Avastin单药治疗卵巢癌复发的 II 期临床试验总结,根据缓解率以及中位 PFS的结果, Avastin确保了未来卵巢癌复发治疗的相关研究Avastin
6、15mg/kg q3w对于既往接受过12次化疗方案的卵巢癌患者耐受性良好 副反应都在预料之中，且大多比较轻微，容易控制许多患者接受了 30 个周期的治疗基于此次试验的结果， GOG 开展了一项Avastin联合化疗的空白对照 III 期临床试验 (GOG-0218),Burger, et al. JCO 2007,Avastin联合治疗铂类敏感/耐药卵巢癌的 II 期临床试验,1. Burger, et al. JCO 2007; 2. Cannistra, et al. JCO 2007; 3. Smerdal, et al. ESMO 2009; 4. Garcia, et al. JCO
7、 2008 5. McGonigle, et al. ASCO 2008; 6. Kikuchi, et al. ASCO 2009; 7. Muggia, et al. ASCO 2009; 8. Nimeiri, et al. Gynecol Oncol 20089. Parmar, et al. Lancet 2003; 10. Pfisterer, et al. JCO 2006; 11. Pujade-Lauraine, et al. ASCO 2009; 12. Mutch, et al. JCO 200713. Ferrandina, et al. JCO 2007; 14. G
8、ordon, et al. JCO 2001,CP = carboplatin/paclitaxel; PLD = pegylated liposomal doxorubicin; NR = not reported; NRe = not reached,Avastin+CP Avastin维持一线治疗卵巢癌的 II 期临床试验 试验设计,主要研究终点:毒性, RR 和 PFS,*Eligible patients had epithelial ovarian, primary peritoneal, fallopian tube or papillary serous mllerian ca
9、rcinomaAvastin was not administered with the first cycle of carboplatin/paclitaxelPenson, et al. JCO 2010,新诊断的 IC期卵巢癌* (n=62),Carboplatin (AUC 5)/ paclitaxel 175mg/m2q3w x68 + Avastin 15mg/kg q3w,Avastin 15mg/kg q3wfor 12 months,Avastin+CP Avastin维持一线治疗卵巢癌的 II 期临床试验 特性,Penson, et al. JCO 2010,Avasti
10、n+CP Avastin维持一线治疗卵巢癌的 II 期临床试验 疗效总结,Efficacy compares favourably to data for carboplatin/paclitaxel in this setting,NR = not reached,Data for the primary efficacy endpoints are shown in boldPenson, et al. JCO 2010,Avastin+CP Avastin维持一线治疗卵巢癌的 II 期临床试验 化疗的安全性,3/4级不良事件的种类和发生率与已知的Avastin和CP的相关耐受分析相一致,
11、中性粒细胞减少,代谢疾病,高血压,血小板减少,神经病变,过敏反应*,肌肉骨骼疼痛,血栓栓塞,贫血,呕吐,胃肠道穿孔,肝功能异常,中性粒细胞减少性发热,Patients (%),1614121086420,3级 4级,*All allergic reactions were to paclitaxelPenson, et al. JCO 2010,Avastin+CP Avastin维持一线治疗卵巢癌的 II 期临床试验 与单药治疗安全性一致,Avastin 维持治疗耐受性良好,高血压,肌肉骨骼疼痛,血小板减少,蛋白尿,代谢疾病,中性粒细胞减少,6543210,发声困难,Penson, et a
12、l. JCO 2010,Patients (%),3级 4级,Avastin运用于卵巢癌中胃肠道穿孔的发生率,NA=not available1. Han, et al. Gynecol Oncol 2007; 2. Micha, et al. Int J Gynecol Cancer 2007; 3. Penson, et al. JCO 20104. Burger, et al. JCO 2005; 5. Muggia, et al. ASCO 2009; 6. Kikuchi , et al. ASCO 2009; 7. Garcia, et al. JCO 20088. Nimeiri
13、, et al. Gynecol Oncol 2008; 9. Cannistra, et al. JCO 2006; 10. Bidus, et al. Gynecol Oncol 2006; 11. Wright, et al. JCO 200612. Smerdel, et al. ECCO-ESMO 2009; 13. Monk, et al. Gynecol Oncol 2006; 14. Wright, et al. Cancer 2006,分析结果提示既往多次治疗后的卵巢癌患者使用Avastin后胃肠道穿孔的发生率增加 1,Avastin运用于卵巢癌: 可能增加胃肠道穿孔风险的因
14、素,卵巢癌中的肠道问题相对比较常见数据显示既往多次化疗以及肠壁增厚或梗阻可能会增加胃肠道穿孔的风险1卵巢癌多次化疗后接受Avastin治疗引起潜在胃肠道穿孔风险增高的原因可能是2 ：卵巢癌细胞侵犯肠道浆膜引起坏死以及潜在的穿孔卵巢癌患者往往发生腹腔扩散，肠梗阻风险仅次于肠道肿瘤以及术后肠粘连Avastin可以通过栓塞或血管收缩限制血液流向内脏血管，因此可能导致肠梗阻和肠穿孔卵巢癌患者发生胃肠道穿孔的明确原因尚未确定,1. Cannistra, et al. JCO 2007; 2. Simpkins, et al. Gynecol Oncol 2007,近期关于既往多次化疗后的卵巢癌患者不建议
15、使用Avastin为基础的治疗,Avastin运用于卵巢癌: 胃肠道穿孔总结,Avastin联合化疗(n=68)较单用化疗(n=195)相比，胃肠道穿孔和/或胃肠道瘘发生的风险并没有增加 (RR=1.09) 1,1. Sfakianos, et al. Gynecol Oncol 2009,卵巢癌中三个关键的III期临床研究,一线晚期卵巢癌,一线卵巢癌,复发铂类敏感卵巢癌,GOG-0218: 随机双盲 III 期研究,Stratification variablesGOG performance statusstage/debulking status,Bevacizumab 15mg/kg
16、q3w,15 months,Paclitaxel (P) 175mg/m2,Carboplatin (C) AUC6,Carboplatin (C) AUC6,Paclitaxel (P) 175mg/m2,Carboplatin (C) AUC6,Paclitaxel (P) 175mg/m2,Placebo q3w,Placebo q3w,Front-line: epithelial OV, PP or FT cancerStage III optimal (macroscopic)Stage III suboptimalStage IVN=1,873,I,II,III,Arm,1:1:1
17、,Burger, et al. Gynecologic Oncology Group.N Engl J Med. 2011 Dec 29;365(26):2473-83.,OV = ovarian; PP = primary peritonealFT = fallopian tube; Bev = bevacizumab,Bev 15mg/kg,RANDOMISE,GOG-0218: 主要入组条件,Burger, et al. NEJM 2011,病理诊断明确为EOV, PP, or FT cancer最大减瘤术后: stage III optimal (肉眼残余肿瘤 1 cm) or sub
18、optimal (1 cm), or stage IV既往未化疗术后112 周GOG PS 02既往无明显血管事件 既往无需要肠外营养支持的肠梗阻签署知情同意书,入组条件改变,Burger, et al. NEJM 2011Stuart, et al. Int J Gynecol Cancer 2011,最初入组条件: 只接受次优化减瘤术后患者(1cm)修改后入组条件: 接受优化减瘤术后患者入组( 1cm)需要注意的是，根据2010GCIG共识，研究中入组的所有患者接受的只是次优化减瘤术因此患者群预后较差,统计分析,Burger, et al. NEJM 2011,Primary analys
19、is:Comparison of PFS (investigator-assessed) in each bevacizumab arm vs control疾病进展决定于 RECIST or CA-125 onlyPlanned sample size of 1800 based on:90% power to detect a PFS hazard ratio (HR) 0.77Secondary analyses: Overall survival (OS), safety, quality of life and correlative laboratory studiesPrimar
20、y endpoint changed from OS to PFS; unblinding to treatment assignment allowed at time of progression,GOG-0218: 三组基线水平平衡,*Grade 3 includes all clear cell tumoursPercentages may not total 100% due to rounding or categorisation,Burger, et al. Gynecologic Oncology Group.N Engl J Med. 2011 Dec 29;365(26)
21、:2473-83.,23,*One patient in each group received Bev/placebo in cycle 1Percentages may not total 100% due to rounding or categorisation,GOG-0218: 因疾病进展而中断治疗的患者在单接受化疗组更多,Burger, et al. Gynecologic Oncology Group.N Engl J Med. 2011 Dec 29;365(26):2473-83.,GOG-0218: 持续 bevacizumab 治疗较标准化化疗明显延长PFS,Avast
22、in Summary of Product CharacteristicsRoche, data on file,0612182430364248,Time (months),1.0,0.8,0.6,0.4,0.2,0,PFS estimate,*p value boundary = 0.0116,+ Bev (Arm II),Chemo (Arm I),+ Bev continued Bev (Arm III),GOG-0218: CA-125 检测的频率可能影响PFS,Months,CP + Pl/B15(6 cycles),Maintenance Pl/B15(16 cycles),Im
23、aging*,CA-125,Exam,03691215,每项检测间隔相同:2年内每3个月评估一次之后3年内每6个月评估一次之后每年一次,Post-treatment follow-up,*Conventional CT or MRI,Burger, et al. Gynecologic Oncology Group.N Engl J Med. 2011 Dec 29;365(26):2473-83.,MRC OV05/EORTC 55955: 根据 CA-125 水平决定继续治疗导致下一步化疗提前,Rustin, et al. Lancet 2010,延误治疗,完全切除术后卵巢癌患者接受一线铂
24、类为基础化疗后，并具有正常水平 CA-125,注册每3个月检测 CA-125 水平,早期治疗,当 CA-125 2x 正常上限随机化,Number at riskEarly265231614111110109Delayed264177116916956494233,MRC OV05/EORTC 55955:根据 CA-125 水平决定继续治疗导致下一步化疗提前,Rustin, et al. Lancet 2010,Number at riskEarly265247211165131947239272215Delayed2642362031671291036946312516,Proportio
25、n surviving,Time since randomisation (months),06121824303642485460,1.00.750.500.250,MRC OV05/EORTC 55955:根据 CA-125 水平决定下一步化疗并没有提高生存,Rustin, et al. Lancet 2010,Median (months)Early, based on CA125 levels 2x ULN25.7Delayed, based on clinical features 27.1HR=0.98 (95% CI: 0.801.20), p=0.85,GOG-0218: CA
26、-125截尾数据分析显示继续使用bevacizumab 较化疗相比明显延长患者 PFS,0612182430364248,1.0,0.8,0.6,0.4,0.2,0,*p value boundary = 0.0116,Time since randomisation (months),PFS estimate,CP + B15 B15,CP + Pl,Avastin Summary of Product Characteristics; Roche, data on file,什么是生存分析中的截尾数据？,生存分析中主要的数据为生存时间, 通过下列参数定义 起始事件，例如，手术或药物治疗的开
27、始 终点事件，例如，死亡 两个事件之间的时间间隔即“生存时间” 生存时间与其它数值资料间主要的区别： 并非所有患者的生存时间都能获得。尚未发生事件者即为“截尾”。 生存分析“截尾”数据来自于在截尾日期时因下列原因尚未出现事件的患者 当前已知患者尚存活 末次联系时已知患者尚存活（失访，早期或随机截尾）,截尾数据对生存的影响,在特定时间点t ，截尾并不会影响生存概率过多的早期截尾（由于失访）可能会对分析造成影响,Data in purple represent comparison of arm II vs arm IData in grey represent comparison of arm
28、 III vs arm I,Burger, et al. NEJM 2011,GOG-0218: subgroup analyses of PFS,0.33,0.50,0.67,1.00,1.50,2.00,3.00,Avastin better,Control better,Burger, et al. NEJM 2011,GOG-0218: subgroup analyses of PFS (contd),0.33,0.50,0.67,1.00,1.50,2.00,3.00,Avastin better,Control better,Data in purple represent com
29、parison of arm II vs arm IData in grey represent comparison of arm III vs arm I,Avastin Summary of Product Characteristics,GOG-0218: independent review confirms the PFS benefit,Roche data on file,GOG-0218: final OS results,ATE = arterial thromboembolic event; VTE = venous thromboembolic event RPLS =
30、 reversible posterior leucoencephalopathy syndrome; aPerforation/fistula/necrosis/leak,Burger et al. NEJM 2011,治疗第二个周期至治疗结束后30天内的不良事件,100,80,60,40,20,0,Patients (%),GI events (grade 2),Hypertension (grade 2),Proteinuria (grade 3),Pain (grade 2),Neutropenia (grade 4),VTE (all grades),ATE (all grades)
31、,Wound healing complications,CNS bleeding (all grades),Non-CNA bleeding (grade 3),RPLS (all grades),Arm I (CP + Pl Pl; n=601)Arm II (CP + Av15 Pl; n=607)Arm III (CP + Av15 Av15; n=608),P6 months after last platinum,Platinum resistant: recurring 6 months after last platinum,Patients with recurrences,
32、GOG-0218: 一线是否使用Avastin对于患者复发时铂类敏感情况,Avastin与化疗相比铂类敏感患者比例高20.1%,Internal confidential data,Q Form=Study Follow-up Form; FUAT=Follow-Up Additional Treatments Form.,Roche data on file,GOG-0218: 后续治疗,GOG-0218: 总结,GOG-0218 肯定了bevacizumab用于晚期卵巢癌一线治疗时具有延长PFS的作用 CP + bevacizumab bevacizumab 单药 15mg/kg 持续使用
33、 15个月 (Arm III) 后患者PFS统计学上明显优于单用 CP (Arm I) 不良反应通常都是可控制的，安全性结果与bevacizumab运用于其他类型肿瘤的试验结果相似CP + bevacizumab bevacizumab 单药 15mg/kg 持续使用 15个月应该作为晚期卵巢癌一线治疗的标准方案,RANDOMISE,ICON7: 一项随机开放的 III 期临床试验,变量分层:疾病分期以及减瘤术范围: IIII期 残余病灶 1cm vs IIII期 残余病灶 1cm vs IV期以及不可切除的 III期病灶术后治疗开始时间: vs 术后4周GCIG group (*also c
34、hoice of AUC dose 5 AGO, NSGO, GINECO or 6),Paclitaxel 175mg/m2,Carboplatin AUC5 or 6*,Carboplatin AUC5 or 6*,Paclitaxel 175mg/m2,1:1,Stage IIIa (grade 3 or clear cell) or Stage IIbIV (all grades/ histologic types)Surgically debulked histologically confirmedOC, PP, FTC(n=1,528),Bevacizumab 7.5mg/kg
35、q3w,12 months,Control,Treatment(CP + B B7.5),Perren, et al.N Engl J Med. 2011 Dec 29;365(26):2484-96.,ICON7: 入组患者必须接受最大减瘤术后,病理证实为卵巢上皮癌，原发性腹膜癌或者输卵管癌 患者接受最大减瘤术后并且疾病进展前无进一步外科切除计划FIGO分期IIIA 高风险: 3级或透明细胞型 (10%)IIBIV: 任何分级和组织类型活检明确的无手术计划的不可手术切除 III/IV期患者 ECOG PS 02,Perren, et al.N Engl J Med. 2011 Dec 29;
36、365(26):2484-96,ICON7: 研究终点 根据RECIST评估PFS,主要研究终点: PFS疾病进展根据 RECIST 评估标准 CA-125 单独升高不作为疾病进展的依据1,528patients randomised over 2 years (684 events) 5% significance level, 90% power to detect:PFS HR of 0.78 increase of median PFS from 18 to 23 months次要研究终点: OS (due 2013), biologic PFS，response to therapy
37、,toxicity,Qol,Perren, et al. ESMO 2010,ICON7: 特征基线水平平衡,Perren, et al. ESMO 2010,*Stratification variable,ICON7:特征基线水平平衡,Perren, et al. ESMO 2010,17.3,19.0,CP,CP + B7.5 B7.5,ICON7: 连续使用bevacizumab较单用基础化疗相比显著提高PFS,Number at riskCP764723693556464307216143915025CP + B7.5 764748715647585399263144733619,0
38、36912151821242730,Time (months),Proportion alive without progression,1.000.750.500.250,Perren, et al. ESMO 2010,ICON7:连续使用bevacizumab较单用基础化疗相比显著提高PFS updated analysis,Kristensen, et al. ASCO 2011,CP,CP + B7.5 B7.5,Proportion alive without progression,Number at riskCP7646934743502211143950CP + B7.576
39、47165994302291072710,1.0,0.8,0.6,0.4,0.2,0,Time (months),0612182430364248,0.20.100.10.2,Treatment difference (research control),Time (months),036912151821242730,Perren, et al. NEJM 2011,Absolute difference in PFS,15.1%,ICON7: 在所有患者亚组中，连续的bevacizumab治疗都可以提供PFS获益,CP + B7.5 B7.5 better,CP better,Perren
40、, et al. ESMO 2010,ICON7: 高风险亚组的PFS分析,Number at riskCP2342059836142CP + B7.5 B7.523121315956101,1.000.750.500.250,Proportion alive without progression,Time (months),036912151821242730,CP,CP + B7.5 B7.5,Operated FIGO III with residuals 1cm and FIGO IV: 30% of total population,Perren, et al. ESMO 2010
41、,ICON7: 关于总体OS数据的中期分析结果,Kristensen, et al. ASCO 2011,*Based on immature OS data (378 of 715 required events, 53%) as required by regulatory authorities,Number at riskCP7647246726234212127160CP + B7.5 7647377026574592286940,1.000.750.500.250,Time (months),0612182430364248,Proportion value,ICON7:关于高风险
42、组OS数据的中期分析结果,Number at riskCP2342191941661074615CP + B7.5 2312222081861346513,1.000.750.500.250,Time (months),0612182430364248,Proportion value,Kristensen, et al. ASCO 2011,Operated FIGO III with residuals 1cm and FIGO IV: 30% of total population,ICON7:与bevacizumab相关的各级不良事件,ATE = arterial thromboemb
43、olism; CHF = congestive heart failure RPLS = reversible posterior leucoencephalopathy syndromeVTE = venous thromboembolism,CP (n=753)CP + B7.5 B7.5 (n=745),Perren, et al. ESMO 2010,Patients (%),403020100,ICON7: 3 级的与bevacizumab相关的不良事件,CP (n=753)CP + B7.5 B7.5 (n=745),*Grade 2,Perren, et al. ESMO 201
44、0,Patients (%),403020100,ICON7: 总结,ICON7的数据进一步证实了 GOG-0218 的结论：卵巢癌患者一线接受 bevacizumab 联合化疗后续 bevacizumab 单药治疗明显提高患者 PFS 13Bevacizumab治疗通常合并可控制的副反应， 目前无新的安全顾虑产生1ICON7中高风险亚组分析结果进一步支持 bevacizumab 运用于 III/IV期肿瘤残存的患者2 CP + bevacizumab continued single-agent bevacizumab 应该成为进展期卵巢癌一线治疗的标准方案,1. Burger, et al
45、. Gynecologic Oncology Group.N Engl J Med. 2011 Dec 29;365(26):2473-832. Perren, et al.N Engl J Med. 2011 Dec 29;365(26):2484-963. Avastin Summary of Product Characteristics,关于bevacizumab一线治疗的两个III期研究比较: 试验设计,1. Burger, et al. Gynecologic Oncology Group.N Engl J Med. 2011 Dec 29;365(26):2473-832. Pe
46、rren, et al. N Engl J Med. 2011 Dec 29;365(26):2484-96,GOG-0218 and ICON7: 试验设计和患者选择,Burger, et al. Gynecologic Oncology Group.N Engl J Med. 2011 Dec 29;365(26):2473-83Perren, et al. N Engl J Med. 2011 Dec 29;365(26):2484-96,GOG-0218 和 ICON7 都达到了主要研究终点，统计学上显著提高了患者 PFS,ICON7,0612182430364248,Time since randomisation (months),1.00.80.60.40.20,
