肝细胞癌分子靶向治疗研究进展课件

肝细胞癌分子靶向治疗肝细胞癌分子靶向治疗 的研究进展的研究进展 南京八一医院全军肿瘤中心南京八一医院全军肿瘤中心 秦叔逵秦叔逵 2 1 HCC发生的分子机制 3 HCC的靶向治疗药物 概述 结语 4 3 概述 p 原发性肝癌是临床上最常见的恶性肿瘤之一，其中， 90%为肝细胞癌(HCC)，其他为胆管细胞癌(ICC)和混 合性肝癌等； p 全球的HCC发病率呈上升趋势，年发病约74.8万人， 居于恶性肿瘤发病率的第5位，中位年龄5060岁， 男：女=4：1； p HCC已成为癌症导致死亡的主要原因之一，全球每年 有近69.6万人死于该病。 4 概述 p 主要高发区为中国、东南亚、非洲东南部和地中海沿 岸国家； p 由于HCC的临床征象通常出现较晚，发现时往往已为 疾病的中晚期，因此，HCC的症状曾被认为是临终阶 段表现，多年来，并未引起医学界足够的重视； p 近年来，HCC的治疗有了重要突破，主要是分子靶向 治疗的巨大进步，石破天惊，引起广泛的关注，成为 治疗和研究的热点。 5 HCC:全球第6位常见肿瘤 1. Garcia M, et al. American Cancer Society, 2007. . Accessed March 20, 2008. 2. Pons-Renedo F, et al. Med Gen Med. 2003;5:11. 196,298 226,787 230,555 200,774 314,256 330,963 529,283 559,094 711,128 782,647 1,066,543 1,167,020 1,301,867 1,549,121 0200,000400,000600,000800,0001,000,0001,200,0001,400,0001,600,0001,800,000 Non-Hodgkins Lymphoma Corpus Uteri Ovary Oral Cavity Bladder Leukemia Esophagus Cervix Uteri Liver Prostate Stomach Colon/Rectal Breast Lung HCC is the third most common cause of cancer-related death Incidence is rising in US and Europe 6 CA: Cancer J Clin 2011. 全球癌症新发和死亡病例（2008） 7 近20年来，不管是在发达国家（如美国）还 是在发展中国家或贫穷落后国家， 原发性肝癌的发病率和病死率均呈上升趋势。 在中国，尽管采取了“改水、防霉、防肝炎”等一系列预防措施，但多年来肝癌 的发病率和病死率仍未见明显回落。 Thomas MB, et al. Hepatocellular Carcinoma: The Needs for Progress.J Clin Oncol,2005,23: 2892-9. HCC:流行病学 8 晚期HCC:基本概念 l 由于肝癌的侵袭性和生长迅速，大多数肝癌患者（特 别是亚洲患者）在确诊时已达局部晚期和/或远处转移 ，往往不适合手术切除、TACE或其他局部治疗，因此 归于晚期HCC, 包括BCLC分期为C期和D期的患者。 l 晚期HCC患者预后很差，如果仅仅进行对症支持治疗， 在西方国家其平均生存期在6-9个月，在东亚国家仅3- 4个月。 9 晚期 HCC:基本概念 l 一般认为, HCC的高度异质性是 东西方晚期HCC患者生存率存在 差异的主要原因。 l 亚洲和西方国家的HCC在病因学 、分期、生物学恶性行为、诊 治（治疗观念和临床实践指南 ）以及预后等方面都存在明显 差异;因此,有人认为可以看作 是”两种病”。 10 HCCHCC治疗：面临的挑战治疗：面临的挑战 一个患者同时并存两类疾 病，病情复杂,互相影响: l高度侵袭性的肝脏原发性肿瘤: 起病隐袭，生长迅速，倍增时间3 个月； 极易侵犯脉管和转移播散。 l约80%的患者合并有肝炎和肝硬化: 肝炎活动或纤维化，肝功能受损 ，往往失代偿； 肝硬化结节，肿瘤常是多中心发 生。 11 HCC的危险因素: 地域差异 20% 50-70% 70% 70% 10-20% 10-20% 10-20% 10% 丙肝 亚洲/非洲* *日本除外 酒精 其他 乙肝 日本 欧洲/北美 所有地区 Llovet JM, et al. Lancet 2003;362:190717 12 流行病学：亚太地区与美国 p亚洲 主要为乙型肝炎： 每年57%病例将患HCC 大多数亚洲国家 丙型肝炎-日本和印尼 排名第5 5年总存活率1500 patients: clinical findings in patients with liver dysfunction Jorge A. Marrero, M.D., M.S. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States R. Lencioni, M. Kudo, S. L. Ye, K. Nakajima, F. Cihon, A. Venook 40 背景介绍 Sorafenib is the only systemic therapy indicated to treat HCC1 In two Phase III studies (SHARP and Asia-Pacific), sorafenib significantly improved OS in patients with uHCC2-3 Pivotal studies generally included patients with preserved liver function Investigation of sorafenib in wider patient groups is needed4 GIDEON is the largest prospective study in uHCC ever conducted In total, 3322 patients have been enrolled from 39 countries uHCC, unresectable hepatocellular carcinoma; OS, overall survival; GIDEON, Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib 1. NCCN Guidelines, 2009; 2. Llovet et al, 2008; 3. Cheng et al, 2009; 4. Lencioni et al, 2010 41 GIDEON 研究设计和目标 GIDEON is a non-interventional study Primary objective: to evaluate safety of sorafenib in patients with uHCC who are candidates for systemic therapy and for whom the decision to treat with sorafenib was made in clinical practice Secondary objectives: efficacy, duration of therapy; methods of patient evaluation, diagnosis and follow-up; co-morbidities and practice patterns GIDEON will also provide information in patient subgroups where data are currently limited Including patients with Child-Pugh B status who were generally excluded from sorafenib Phase III trials in uHCC GIDEON, Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib; uHCC, unresectable hepatocellular carcinoma 42 GIDEON 研究: 疗效评价 GIDEON has a non-randomized, uncontrolled non-interventional study design Efficacy is a secondary, not a primary, objective All planned efficacy evaluations are descriptive in nature and subgroups are pre-specified Tumor assessment by RECIST is not mandated in GIDEON Assessment and analysis of time to radiological PD Time is days from start of treatment to date of first documented PD Only radiologically documented PD of the tumor is considered as PD TTP for patients without documented PD at time of analysis is censored at last date of tumor evaluation GIDEON, Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib; PD, progression of disease; RECIST, Response Evaluation Criteria In Solid Tumors; TTP, time-to-progression 43 GIDEON 研究: 第二次second 中期分析 GIDEON second interim analysis: Per protocol the second interim analysis was planned when 1500 treated patients were followed for 4 months 1571 patients in the safety population Includes patients who received 1 dose of sorafenib and had 1 follow -up assessment after start of treatment 1612 patients in the ITT population ITT population used for analysis of OS and TTP Includes patients who received 1 dose of sorafenib 2 days before study entry; excludes patients previously treated with sorafenib All statistical analyses performed were descriptive in nature Lencioni et al, 2010 GIDEON, Global Investigation of therapeutic Decisions in hepatocellular carcinoma and Of its treatment with sorafeNib; ITT, intent to treat; OS, overall survival; TTP, time-to-progression 44 根据治疗开始时Child-Pugh状态 选择的病例基线特征(1) aChild-Pugh status unknown for 5 patients; 207 patients are not evaluable and not tabulated ECOG PS, Eastern Cooperative Oncology Group performance status Totala (n=1571) Child-Pugh A (9) (n=35) Patients, % of n10061232 Male / female, % of n 82 / 1883 / 1781 / 1983 / 17 Median age, years (range) 62 (18-98)64 (18-94)61 (23-86)58 (39-82) ECOG PS, % of n 0 1 2 3 4 40 43 9 2 9) (n=35) TNM stage I II III IV 7 11 34 36 7 13 34 37 7 9 39 31 11 9 34 34 BCLC stage A B C D 7 19 54 6 8 20 58 4 5 21 54 4 3 0 11 77 46 初始时Child-Pugh状态 与 sorafenib 剂量 % of n Totala (n=1571) Child-Pugh A (9) (n=35) 800 mg74777169 600 mg1110 400 mg22202326 200 mg3236 100 mg9) (n=35) Mean daily dose, mgc 630631633619 Median daily dose, mgc 693680721680 Dose increase, % of n 1618133 Dose increase to 800 mg from lower initial doses, % of n 6650 Number of dose increases 1 2 3 4 12 3 1 0.2 13 4 1 0.1 10 2 1 0 3 0 0 0 48 Child-Pugh状态与Sorafenib 剂量中断和调整 % of n Totalb (n=1571) Child-Pugh A (9) (n=35) Dose interruption 24242220 Dose modification 42453734 Dose increase1618133 Dose reduction33372729 aData at study entry bDosing data missing for 8 patients; Child-Pugh status unknown for 5 patients 49 Child-Pugh状态与Sorafenib 治疗疗程 Total (n=1571) Child-Pugh A (9) (n=35) 4 weeks, %17132346 4-8 weeks, %18172323 8-20 weeks, %35382823 20-28 weeks, %121390 28 weeks, %1618146 Median treatment duration, weeks 121494 aData at study entry 50 Child-Pugh状态与总体 安全性数据 % of n Totalb (n=1571) Child-Pugh A (9) (n=35) AEs (all grades)83828986 Drug-related AEs (all grades)64676346 AEs (grade 3/4)30293134 Drug-related AEs (grade 3/4)23242223 SAEsb37295663 Drug-related SAEsc98156 AEs resulting in permanent discontinuation of sorafenibd 28243851 Deathse22163437 aData at study entry; bChild-Pugh status missing or not evaluable for 56 patients; cAn SAE is defined as any AE occurring at any dose that results in any of the following outcomes: death; life- threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability / incapacity; congenital anomaly / birth defect; medically important event; dAny AE; eTreatment- emergent deaths occurring up to 30 days after last sorafenib dose AEs, adverse events; SAEs, serious adverse events 51 Child-Pugh B 分值与总体 安全性数据 % of n Child- Pugh B (7-9) (n=367) Child- Pugh B (7) (n=196)b Child- Pugh B (8) (n=96)b Child- Pugh B (9) (n=69)b AEs (all grades)89889094 Drug-related AEs (all grades) 63676059 AEs (grade 3/4)31293336 Drug-related AEs (grade 3/4) 22212423 SAEsc56456577 Drug-related SAEsc15141519 AEs resulting in permanent discontinuation of sorafenibd 38363948 Deathse34303939 aData at study entry; bPatients with Child-Pugh status available; cAn SAE is defined as any AE occurring at any dose that results in any of the following outcomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability / incapacity; congenital anomaly / birth defect; medically important event; dAny AE; eTreatment-emergent deaths occurring up to 30 days after last sorafenib dose AEs, adverse events; SAEs, serious adverse events 52 Child-Pugh状态与药物 相关性不良事件a,b % of n Total Any grade (n=1571) Total G3/G4 (n=1571) Child-Pugh A (9) (n=35) Diarrhea253 / 026239 HFSR245 / 029153 Fatigue143 / 9) (n=13) HCC-related138 (40)61 (40)50 (40)4 (31) HCC- and liver- related 38 (11)15 (10)15 (12)3 (23) HCC- and liver- related, and MOF 9 (3)4 (3)2 (2)1 (8) Liver-related49 (14)22 (14)18 (14)2 (15) HCC-related and MOF 15 (4)8 (5)4 (3)0 MOF22 (6)10 (6)8 (6)1 (8) aIncidence 2% in total group; bPatients may be included in more than one cause of death category; bBy Child-Pugh status at study entry; dChild-Pugh status missing for 1 patient; eData missing for 7 Child-Pugh A and 7 Child-Pugh B patients HCC, hepatocellular carcinoma; MOF, multi-organ system failure 54 Child-Pugh状态与初步的OS Child Pugh A (9) (n=36), median (95% CI) 62 (46, 94) days 2.0 months 6005004003002001000 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time since start of treatment (days) Survival distribution function a207 patients not evaluable CI, confidence interval 55 Child-Pugh状态与初步的TTP Child Pugh A (9) (n=36), median (95% CI) 64 (28, 110) days 2.1 months 5004003002001000 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time since start of treatment (days) TTP distribution function aTTP was documented radiological disease progression; RECIST v 1.0 used for tumor evaluation; b207 patients not evaluable TTP, time-to-progression; RECIST, Response Evaluation Criteria In Solid Tumors 56 结论 (1) Based on the second interim analysis, there is no evidence suggesting that treating physicians use a different dosing strategy for Child-Pugh B patients compared with Child-Pugh A patients Duration of sorafenib therapy was shorter in Child- Pugh B patients than in Child-Pugh A patients Compared with Child-Pugh A patients, Child-Pugh B patients did not have a higher incidence of drug-related AEs, but had a higher incidence of liver-associated AEs In patients with moderate liver dysfunction, no unexpected AEs were observed AEs, adverse events; SAEs, serious adverse events 57 结论 (2) The vast majority of deaths were due to HCC or underlying liver disorders The differences in patient outcomes across Child-Pugh groups likely reflect differences in prognosis Consistent with previously reported studies, these preliminary data indicate that Child-Pugh status appears to be a useful prognostic factor for overall survival The GIDEON study is ongoing, and the safety, tolerability, and efficacy of sorafenib in HCC patients will continue to be evaluated HCC, hepatocellular carcinoma; GIDEON, Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib 58 阿霉素索拉非尼治疗HCC的II期研究 研究结果已经发表 59 阿霉素索拉非尼治疗HCC的II期研究 1.Abou-Alfa GK, et al. EJC Suppl. 2007;5(4):259. 2.ASCO-GI 2008.1报告. 月 无进展率 1.00 0 0.75 0.50 0.25 015.55.07.510.012.52.5 HR： 0.60 P = 0.076 阿霉素 + 索拉非尼 mTTP： 8.6个月 阿霉素 + 安慰剂 mTTP： 4.8个月 截尾数据 生存率 1.00 0 0.75 0.50 0.25 020.05.07.510.012.515.017.52.5 HR= 0.45 P = 0.0049 月 阿霉素 + 索拉非尼 mOS： 13.7个月 阿霉素 + 安慰剂 mOS： 6.5个月 ADM + Sor mTTP： 8.6个月 ADM + 安慰剂 mTTP：4.8个月 ADM + Sor mOS： 13.7个月 ADM + 安慰剂 mOS：6.5个月 截尾数据 ADM用量: 60 mg/m2 60 2 PR 62% 1 PR 29% 阿霉素索拉非尼治疗疗HCC的II期研究 61 阿霉素索拉非尼治疗HCC的III期研究 62 索拉非尼联合小剂量替加氟尿嘧啶 治疗晚期HCC的II期研究 结论：给予小剂量的替加氟尿嘧啶（125 mg/m2 BID）联合索拉非尼治疗晚期肝癌是安全有效的，可以有效 地提高索拉非尼的疗效 Hsu CH, et al. Journal of Hepatology 2010;53:126-131 纳入53例晚期HCC患者（72%为HBSAg阳性），单臂研究 100 80 60 40 20 0 0 510152025 PFS % mPFS 3.7 个月 （95%CI:1.95.5） 时间（月） 100 80 60 40 20 0 0 510152025 OS % mOS 7.4 个月 （95%CI:3.211.6） 63 3.索拉菲尼联合方案 Yau T, et al. 34th ESMO Multidisciplinary Congress (European Journal of Cancer Supplements, Berlin) 2009. p. 1-24 香港玛丽医院 51例亚洲晚期HCC患者 SECOX 84%的患者为HBV携带者，98%肝功能为 Child A 索拉非尼 400 mg bid d1-14 + OXA 85 mg/m2 d1， Xeloda 1700 mg/m2 d1-7 RR 16%, mPFS 7.3 m，mOS 10.8m 索拉非尼联合卡培他滨、奥沙利铂（SECOX) 治疗晚期HCC的II期研究 64 索拉非尼联合卡培他滨、奥沙利铂（SECOX) 治疗晚期HCC的II期研究 /ct2/results?term=SECOX+AND+HCC 纳入51例晚期HCC患者（84%为HBSAg阳性），单臂研究 结果：SECOX方案可以延长患者的mPFS和mOS 100 80 60 40 20 0 0 3691221 PFS % mPFS 7.1 个月 （95%CI: 1.619.9） 时间（月） 100 80 60 40 20 0 OS % mOS 10.2 个月 （95%CI: 2.120.5） 1518 0 36912211518 SECOX: 奥沙利铂 IV (85 mg/m2)， 第1天：卡培他滨 (850 mg/m BID)，第1-7天： 索拉非尼 (400 mg BID) , 第1-14天（连续给药）. 2周为一个疗程， (2)(2) 舒尼替尼舒尼替尼 66 舒尼替尼 vs.索拉非尼 KinaseSunitinib IC50 (nM) Sorafenib IC50 (nM) VEGFR-1 VEGFR-2 VEGFR-3 PDGFR- PDGFR- Raf-1 CSF-1R KIT FLT3 RET MET FGFR-1 2* 9* 17* ND 8* ND 510 4* 25 83 4000 ND 26 90 20 ND 57 6 ND 68 58 47 10000 580 *Ki (nM) values reported Value indicates inhibition of receptor phosphorylation; Data on file; Pfizer Inc., 2008. Values indicate IC50 for murine enzyme 67 例数剂量与方案受益率 mTTP 或PFS mOS安全性 37 50mg/d 4/2 37.8% 5.2月 TTP 10.9月 非血液学：为1/2级 3的血液学AE为血小板减少(35.1%),中 性粒细胞减少(24.3%; 全部为3级), 以及 贫血(21.6%) 29 37.5mg/d 4/2 10/29 1+9 2.8月 PFS 7.2月 严重AE（3级以上）发生率10%的 仅有 食欲减退、转氨酶升高、疲劳。 34 37.5mg/d 4/2 52% 4.1月 TTP 9.8月 不良反应可控，最常见：中性粒细胞减 少，淋巴细胞减少，血小板减少 转氨酶升高，疲劳和皮疹。 3级以上的血液学AE发生率：12% 45 37.5mg/d 连续给药 42% 2.8月 PFS 9.3月3级以上AE发生率10%的仅有 血少板减小(18%)和疲劳(26%)。 舒尼替尼的四项项II期临临床研究 68 舒尼替尼治疗晚期HCC 期研究结果 Lancet Oncol 2009; 10: 794800 舒尼替尼50mg/d治疗晚期HCC，根据RECIST 标准评估，没有达到主要终点，毒性明显。 69 舒尼替尼vs.索拉非尼治疗晚期HCC的III研究 Following a review by the IDMC, the study was discontinued based on a higher incidence of serious adverse events in the sunitinib arm compared to the sorafenib arm and the fact that sunitinib did not meet the criteria to demonstrate that it was either superior or non- inferior to sorafenib in the survival of patients with advanced HCC. 因疗效不足和SAE发生率过高,中途叫停! 70 舒尼替尼vs.索拉非尼治疗晚期HCC的III研究 Sorafenib 400mg BID (n=544) Sunitinib 37.5mg QD (n=529) ECOG PS = Eastern Cooperative Oncology Group Performance Status; MVI = OS = overall survival; PFS = time to progression free survival TTP = time to progression; DCR = disease control rate *Assessed using version 3.0 of the USA National Cancer Institute Common Terminology Criteria for Adverse Events Ann-Lii Cheng et al. ASCO 2011 Eligibility Advanced HCC ECOG PS 02 ChildPugh A No prior systemic therapy Stratification Geographic region Prior TACE Tumor invasion R A N D O M I S E Primary endpoints OS Secondary endpoints PFS TTP Safety* randomized 1:1 superiority/non-inferiority trial 71 终点指标 索拉非尼 (N=544) 舒尼替尼 (N=529) P value mOS for all pts (月，HR) 10.0 (1.31) 8.1 0.0019 mOS for pts with hepatitis B (Su 290/So 288) 7.8 (1.09) 7.90.236 m PFS (月，HR) 2.9 (1.12) 3.60.1386 mTTP (月，HR) 4.0 (1.13) 4.1 0.1783 AEs (%) 7382 - SAEs(%)3644- 舒尼替尼vs.索拉非尼治疗晚期HCC的III研究 （中期分析） (3)(3) BrivanibBrivanib (BMS 582664) (BMS 582664) 73 Brivanib的体外试验可以抑制HCC的生长 p 口服VEGFR-2和FGFR-1通路双重抑制剂 p 体外试验表明:Brivanib能够 显著抑制HCC细胞株的生 长1: 增加细胞凋亡 减少微血管密度 抑制细胞增殖 Clin Cancer Res 2008;14:6146-6153. 74 Brivanib一线和二线治疗HCC 的II期研究 Brivanib 800 mg QD 直至根据修订后WHO 标准确定为疾病进展 A组:55例 无HCC系统治疗史 B组：41例 接受过一种HCC抗血管 生成抑制剂治疗 不可切除的、局部晚期或转转移性HCC 经经活检证实检证实 经经CT或MRI增强影像验证验证 且 AFP400 ng/mL 且HBV 或HCV 阳性 CLIP评评分3 ECOG PS 0-2分 终终点指标标 疾病无进进展生存时间时间 疾病进进展时间时间 总总体生存 肿肿瘤应应答率 疾病控制率 安全性和耐受性 75 4.其他抗血管生成的靶向药物 p Brivanib (BMS 582664):口服，800 mg/d p 共入选96例HCC患者: 55例患者一线治疗 RR 5%, DCR 47%, TTP 2.8 个月, OS 10 个月 41例患者二线治疗疗 RR 2%, DCR 53%, TTP 2.0 个月, OS 9.8 个月 p 3/4级不良反应 Cohort A：疲劳(166%),AST升高(19%),高钠血症(41%) Cohort B：高血压(7.3%),腹泻(4.9%),头痛(4.9%) Brivanib一线和二线治疗HCC 的II期研究 Raoul et al. ASCO 2009 76 至疾病进展时间（TTP） 1st line（Group A） mTTP 2.7 months (95% CI,1.5-3.9) Overall 47 events；truncated 8 cases Survival Ratio 2nd line（Group B） mTTP 1.4 months (95% CI, 1.4-2.6) Overall 28 events；truncated 18 cases months Survival Ratio 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0246810 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 02468101214161820 months 77 总生存（OS） 1st line（Group A） mOS 10 months (95% CI,6.8-15.2) Death 35 cases; truncated 20 cases Brivinab5547393126232218151060 0246810121416182022 Brivinab5547393126232218151060 Survival Ratio 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 months 0246810121416182022 Brivinab5547393126232218151060 1.0 0246810121416182022 2nd line（Group B） mOS 9.5 months (95% CI, 5.5 -13.2) Death 28 cases; truncated 18 cases Brivinab qd months Survival Ratio 46423227241297210 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 02468101214161820 78 亚洲人群vs.非亚洲人群总生存 (OS) 2nd line（Group B） Asian: 9.8 months (95% CI, ) Non-Asian: 9.4 months (95% CI, 3.2，-) High-risk Patients Asian3128231816975210 Non-Asian1514998322000 AsianNon-Asian Survival Ratio 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 months 02468101214161820 High-risk Patients Asian35322622181514119530 Non-Asian201513988876530 Survival Ratio 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 months 0246810121416182022 AsianNon-Asian 1st line（Group A） Asian: 10.6 months (95% CI, 7.8,17.9) Non-Asian: 5.7 months (95% CI, 3.6-19.3) 79 Brivanib正在开展的期临床研究 p BRISK FL (CA182-033)： 晚期HCC患者Brivanib vs.索拉非尼一线治疗随机、双盲、多中心 III 期研究 NCT00858871,即将完成入组 p BRISK TA (CA182-037)： 不能切除HCC患者中Brivanib vs. 安慰剂作为TACE辅助治疗的随机、 双盲、多中心III期研究 NCT00908752 p BRISK PS (CA182-034)： Brivanib + BSC与安慰剂+BSC方案治疗索拉非尼失败或不耐受晚期 HCC患者的全球随机、双盲、多中心III期研究 NCT00825955 p BRISK PS (CA182-047)： Brivanib + BSC与安慰剂+BSC方案治疗索拉非尼失败或不耐受晚期 HCC患者的亚太区随机、双盲、多中心III期研究 NCT00825955 (4)(4) 其他其他抗血管生成的抗血管生成的 靶向药物靶向药物 81 贝伐株单抗治疗HCC的II期临床研究 Study RegimenNo. ofRR (%) mPFS PFS at mOS Pts (months)6m (%) (months) Siegel et al 5-10 mg/kg 46 13 6.9 65 12.4 Malka et al 5-10 mg/kg 24 12.5 NR NR NR Siegel et al, JCO, 2008; Malka et al,