贝伐在卵巢癌研究课件

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 2007 Cannistra SA, et al. J Clin Oncol 2007 Garcia 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 2007 Penson et al, J Clin Oncol 2010 初治卵巢癌的 III 期临床试验 GOG-0218, ASCO 2010 ICON7/OVAR11, IGCS ATE = arterial thromboembolic events; VTE = venous thromboembolic events Burger, 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 (%) 12 10 8 6 4 2 0 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 l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 lAvastin 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 l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 n Prior regimens Platinum sensitive Platinum resistantStudy therapyOR (%) Median PFS (months) Median OS (months) Single-agent Avastin Burger 20071622Avastin214.717 Cannistra 200724423Avastin 164.4 Smerdel 2009338Median 5Avastin305.98.6 Avastin-based combination regimens Garcia 20084703Avastin + cyclophosphamide 247.2 (TTP)16.9 McGonigle 20085222Avastin + topotecan22 Kikuchi 20096221Avastin + PLD36NRNR Muggia 20097213Avastin + PLD Nimeiri 20088132Avastin + erlotinib154.111 Representative historical trials Platinum-sensitive91112Platinum paclitaxel, gemcitabine or PLD 31475.813.017.329.0 Platinum-resistant121412Topotecan, gemcitabine or PLD 6293.14.69.513.5 1. Burger, et al. JCO 2007; 2. Cannistra, et al. JCO 2007; 3. Smerdal, et al. ESMO 2009; 4. Garcia, et al. JCO 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 2008 9. Parmar, et al. Lancet 2003; 10. Pfisterer, et al. JCO 2006; 11. Pujade-Lauraine, et al. ASCO 2009; 12. Mutch, et al. JCO 2007 13. Ferrandina, et al. JCO 2007; 14. Gordon, 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 l主要研究终点:毒性, RR 和 PFS *Eligible patients had epithelial ovarian, primary peritoneal, fallopian tube or papillary serous m llerian carcinoma Avastin was not administered with the first cycle of carboplatin/paclitaxel Penson, et al. JCO 2010 新诊断的 IC期卵巢癌* (n=62) Carboplatin (AUC 5)/ paclitaxel 175mg/m2 q3w x68 + Avastin 15mg/kg q3w Avastin 15mg/kg q3w for 12 months Avastin+CP Avastin维持一线治疗卵巢癌的 II 期临床试验 特性 Characteristic(n=62) Median age, years (range)58 (1877) Performance status (%) 168 232 FIGO stage (%) Early10 III69 IV21 Primary site (%) Ovary73 Primary peritoneal16 Fallopian tube 8 Uterine papillary serous 5 Cytoreduction (%) Optimal79 Suboptimal21 Penson, et al. JCO 2010 Avastin+CP Avastin维持一线治疗卵巢癌的 II 期临床试验 疗效总结 Efficacy data(n=62) ORR (RECIST), % (95% CI)75 (6285) Complete response23 (1336) Partial response52 (3865) Stable disease (RECIST), % (95% CI) 25 (1537) Median PFS, months (95% CI)29.8 (17.3NR) Median OS (months)NR Efficacy compares favourably to data for carboplatin/paclitaxel in this setting NR = not reached Data for the primary efficacy endpoints are shown in bold Penson, 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 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 (%) 16 14 12 10 8 6 4 2 0 3级 4级 *All allergic reactions were to paclitaxel Penson, 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 蛋白尿 代谢疾病 中性粒细胞减少 6 5 4 3 2 1 0 发声困难 Penson, et al. JCO 2010 Patients (%) 3级 4级 Avastin运用于卵巢癌中胃肠道穿孔的发生率 StudyPrior regimens, median (range)Events, n (%) Micha, et al.200/20 (0) Penson, et al.30 1/62 (1.6) Burger, et al. (GOG-170D)42 (12)0/62 (0) Muggia, et al.52 (NA)0/24 (0) Kikuchi, et al.6NA (1) 1/22 (4.6) Garcia, et al.72 (13) 4/70 (5.7) Nimeiri, et al.82 (13) 2/13 (15.4) Cannistra, et al.92 (23) 5/44 (11.4) Bidus, et al.10NA (36)0/3 (0) Wright, et al.115 (NA) 4/62 (6.5) Smerdel, et al.125 (NA) 2/38 (5.3) Monk, et al.13 5 (210) 1/32 (3.1) Wright, et al.14 7 (215) 2/23 (8.7) Total22/475 (4.6) NA=not available 1. Han, et al. Gynecol Oncol 2007; 2. Micha, et al. Int J Gynecol Cancer 2007; 3. Penson, et al. JCO 2010 4. Burger, et al. JCO 2005; 5. Muggia, et al. ASCO 2009; 6. Kikuchi , et al. ASCO 2009; 7. Garcia, et al. JCO 2008 8. Nimeiri, et al. Gynecol Oncol 2008; 9. Cannistra, et al. JCO 2006; 10. Bidus, et al. Gynecol Oncol 2006; 11. Wright, et al. JCO 2006 12. 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素 l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 l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 l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 lStratification variables GOG performance status stage/debulking status Bevacizumab 15mg/kg 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 cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV N=1,873 I II III Arm 1:1:1 Burger, et al. Gynecologic Oncology Group.N Engl J Med. 2011 Dec 29;365(26):2473-83. OV = ovarian; PP = primary peritoneal FT = fallopian tube; Bev = bevacizumab Bev 15mg/kg R A N D O M I S E GOG-0218: 主要入组条件 Burger, et al. NEJM 2011 l病理诊断明确为EOV, PP, or FT cancer l最大减瘤术后: stage III optimal (肉眼残余肿瘤 1 cm) or suboptimal (1 cm), or stage IV l既往未化疗 l术后112 周 lGOG PS 02 l既往无明显血管事件 l既往无需要肠外营养支持的肠梗阻 l签署知情同意书 入组条件改变 Burger, et al. NEJM 2011 Stuart, et al. Int J Gynecol Cancer 2011 l最初入组条件: 只接受次优化减瘤术后患者(1cm) l修改后入组条件: 接受优化减瘤术后患者入组( 1cm) l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 l因此患者群预后较差 统计分析 Burger, et al. NEJM 2011 Primary analysis: lComparison of PFS (investigator-assessed) in each bevacizumab arm vs control l疾病进展决定于 RECIST or CA-125 only lPlanned sample size of 1800 based on: 90% power to detect a PFS hazard ratio (HR) 0.77 Secondary analyses: lOverall survival (OS), safety, quality of life and correlative laboratory studies lPrimary 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 Characteristic, % Arm I CP + Pl (n=625) Arm II CP + B15 Pl (n=625) Arm III CP + B15 B15 (n=623) Age in years, median (range) 60 (2586) 60 (2488) 60 (2289) GOG PS 0/1/2, %50/44/750/43/649/43/8 Stage/residual size % III optimal (macroscopic) III suboptimal IV 35 41 25 33 41 26 35 39 27 Histology % Serous Endometrioid Clear cell Mucinous 87 3 2 1 84 2 4 2x 正常上限 随机化 Proportion alive who have not started further chemotherapy Time since randomisation (months) Median (months) Early, based on CA125 levels 2x ULN0.8 Delayed, based on clinical features 5.6 HR=0.29 (95% CI: 0.240.35), p2x ULN25.7 Delayed, based on clinical features 27.1 HR=0.98 (95% CI: 0.801.20), p=0.85 GOG-0218: CA-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 I CP + Pl Pl (n=625) III CP + B15 B15 (n=623) Median PFS (months)12.018.2 Stratified analysis HR (95% CI) 0.62 (0.520.75) p value one-sided (log rank)1cm Arm II vs Arm I Arm III vs Arm I 510 496 0.981 0.763 IV Arm II vs Arm I Arm III vs Arm I 317 318 0.923 0.698 Histologic type Serous Arm II vs Arm I Arm III vs Arm I 1,066 1,068 0.913 0.701 Nonserous Arm II vs Arm I Arm III vs Arm I 184 180 0.893 0.713 Tumour grade 1 or 2 Arm II vs Arm I Arm III vs Arm I 232 235 1.039 0.578 3 Arm II vs Arm I Arm III vs Arm I 847 842 0.891 0.700 0.330.500.671.001.502.003.00 Avastin betterControl better Burger, et al. NEJM 2011 GOG-0218: subgroup analyses of PFS (contd) Risk factorTotal no. of patientsHazard ratio for Avastin (95% CI) GOG performance status score 0 Arm II vs Arm I Arm III vs Arm I 626 616 0.877 0.710 1 or 2 Arm II vs Arm I Arm III vs Arm I 624 632 0.961 0.690 Age 6 months after last platinum Platinum resistant: recurring 6 months after last platinum Patients with recurrences 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 CP + Pl Pl (n=625) CP + Av15 Pl (n=625) CP + Av15 Av15 (n=623) Use of any nonprotocol therapy (Q Form)78%79%73% Chemotherapy74%74%70% Use of any antiangiogenic treatments (FUAT)31%30%17% Avastin28%28%15% GOG-0218: 总结 lGOG-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 15个月 (Arm III) 后患者PFS统计学上明显优于 单用 CP (Arm I) l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 lCP + 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 R A N D O M I S E ICON7: 一项随机开放的 III 期临床试验 l变量分层: l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 l术后治疗开始时间: vs 术后4周 lGCIG group (*also choice 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 confirmed OC, PP, FTC (n=1,528) Bevacizumab 7.5mg/kg q3w 12 months Control Treatment (CP + B B7.5) Perren, et alN 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 l病理证实为卵巢上皮癌，原发性腹膜癌或者输卵管癌 l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 lFIGO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 lECOG PS 02 Perren, et alN Engl J Med. 2011 Dec 29;365(26):2484-96 ICON7: 研究终点 根据RECIST评估PFS l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 l次要研究终点: OS (due 2013), biologic PFS，response to therapy,toxicity,Qol Perren, et al. ESMO 2010 CharacteristicCP (n=764)CP + B7.5 B7.5 (n=764) Median age (range) 57 (1881)57 (2482) ECOG PS, n (%) 0 1 2 358 (47) 354 (47) 43 (6) 334 (45) 366 (49) 45 (6) Origin of cancer, n (%) Ovary Fallopian tube Primary peritoneal Multiple sites 667 (87) 29 (4) 56 (7) 12 (2) 673 (88) 27 (4) 50 (6) 14 (2) Histology Serous Clear cell Endometrioid Mucinous Mixed/other 529 (69) 60 (8) 57 (7) 15 (2) 103 (13) 525 (69) 67 (9) 60 (8) 19 (2) 93 (12) Grade, n (%) 1 2 3 Unknown 56 (7) 142 (19) 556 (74) 10 41 (5) 175 (23) 538 (71) 10 ICON7: 特征基线水平平衡 Perren, et al. ESMO 2010 Characteristic, n (%)CP (n=764)CP + B7.5 B7.5 (n=764) FIGO stage, n (%) I/IIA IIBIIIB IIIC/IV 75 (10) 160 (21) 529 (69) 67 (9) 155 (20) 542 (71) Debulking surgery residual tumor 1 cm residual tumor 1 cm No surgery 552 (74) 195 (26) 17 (2) 559 (74) 192 (26) 13 (2) FIGO stage and residuum* Stage IIII (1 cm) Stage IIII (1 cm) Stage III (inoperable)/IV 508 (66) 150 (20) 106 (14) 518 (68) 140 (18) 106 (14) Intent to start chemotherapy* 4 weeks from surgery 4 weeks from surgery 328 (43) 436 (57) 326 (43) 438 (57) *Stratification variable ICON7:特征基线水平平衡 Perren, et al. ESMO 2010 17.319.0 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 risk CP764723693556464307216143915025 CP + B7.5 764748715647585399263144733619 036912151821242730 Time (months) Proportion alive without progression 1.00 0.75 0.50 0.25 0 CP CP + B7.5 B7.5 Events, n (%) 392 (51)367 (48) Median, months 17.319.0 Log-rank testp=0.0041 HR (95% CI)0.81 (0.700.94) 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 risk CP7646934743502211143950 CP + B7.57647165994302291072710 CPCP + B7.5 Events, n (%) 464 (61)470 (62) Median, months 17.419.8 Log-rank testp=0.039 HR (95% CI)0.87 (0.770.99) 1.0 0.8 0.6 0.4 0.2 0 Time (months) 0612182430364248 0.2 0.1 0 0.1 0.2 Treatment difference (research control) Time (months) KM difference Smoothed difference 036912151821242730 Months PFS treatment difference (PFS estimate: control/research) 63.7% (92.1/95.8) 1215.1% (64.6/79.7) 187.6% (47.3/54.9) 242.5% (39.8/37.3) Perren, et al. NEJM 2011 Absolute difference in PFS CP CP + Av7.5 Av7.5 Restricted mean estimated at 36 months (months) 20.321.8 Difference (95% CI)1.5 (0.22.9) 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 betterCP better Perren, et al. ESMO 2010 ICON7: 高风险亚组的PFS分析 Number at risk CP2342059836142 CP + B7.5 B7.523121315956101 1.00 0.75 0.50 0.25 0 Proportion alive without progression Time (months) 036912151821242730 CP (n=234) CP + B7.5 B7.5 (n=231) Events, n (%) 173 (74)158 (68) Median, months 10.515.9 Log-rank testp1cm and FIGO IV: 30% of total population Perren, et al. ESMO 2010 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 risk CP7647246726234212127160 CP + B7.5 7647377026574592286940 1.00 0.75 0.50 0.25 0 Time (months) 0612182430364248 Proportion value CPCP + B7.5 Events, n (%)200 (26)178 (23) Median, monthsNot yet reached Log-rank testP=0.11 HR (95% CI)0.85 (0.691.04) 1-year OS rate (%)9295 ICON7:关于高风险组OS数据的中期分析结果 High-risk subgroup CP (n=234) CP + B7.5 (n=231) Events, n (%) 109 (47)79 (34) Median, months 28.836.6 Log-rank testP=0.002 HR (95% CI)0.64 (0480.85) 1-year OS rate (%)8692 Number at risk CP2342191941661074615 CP + B7.5 2312222081861346513 1.00 0.75 0.50 0.25 0 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 thromboembolism; CHF = congestive heart failure RPLS = reversible posterior leucoencephalopathy syndrome VTE = venous thromboembolism CP (n=753) CP + B7.5 B7.5 (n=745) Perren, et al. ESMO 2010 Patients (%) 40 30 20 10 0 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 2010 Patients (%) 40 30 20 10 0 ICON7: 总结 lICON7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 13 lBevacizumab治疗通常合并可控制的副反应， 目前无新的安 全顾虑产生1 lICON7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 lCP + 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. Gynecologic Oncology Group.N Engl J Med. 2011 Dec 29;365(26):2473-83 2. Perren, et alN Engl J Med. 2011 Dec 29;365(26):2484-96 3. 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):2473-83 2. Perren, et al. N Engl J Med. 2011 Dec 29;365(26):2484-96 Bevacizumab 15mg/kg q3w 15 months Paclitaxel 175mg/m2 Carboplatin AUC6 Carboplatin AUC6 Paclitaxel 175mg/m2 Carboplatin AUC6 Paclitaxel 175mg/m2 Placebo q3w Placebo q3w Front-line: epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV N=1,873 1:1:1 Bev 15mg/kg R A N D O M I S E GOG-0218 Stage IIIa (grade 3 or clear cell) or Stage IIbIV (all grades/ histologic types) debulked 1 cm or 1 cm OC, PP, FTC (n=1,528) 1:1 R A N D O M I S E Paclitaxel 175mg/m2 Carboplatin AUC5 or 6 Paclitaxel 175mg/m2 Carboplatin AUC5 or 6 Bevacizumab 7.5mg/kg q3w 12 months