1、肝细胞癌分子靶向治疗 的研究进展 南京八一医院全军肿瘤中心 秦叔逵,HCC发生的分子机制,3,HCC的靶向治疗药物,概述,结语,4,概述,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； 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； 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。,概述,主要高发区为中国、东南亚、非洲东南部和地中海沿岸国家； 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
2、是临终阶段表现，多年来，并未引起医学界足够的重视； 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。,HCC:全球第6位常见肿瘤,1. Garcia M, et al. American Cancer Society, 2007. www.cancer.org. Accessed March 20, 2008. 2. Pons-Renedo F, et al. Med Gen Med. 2003;5:11.,HCC is the third most common cause of cancer-related death Inc
3、idence is rising in US and Europe,CA: Cancer J Clin 2011.,全球癌症新发和死亡病例（2008）,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,晚期HCC:基本概念
4、,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。 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。,晚期 HCC:基本概念,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。 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”。,HCC治疗：面临的挑战,一个患
5、者同时并存两类疾病，病情复杂,互相影响: 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。 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。,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,流行病学：亚太地区与美国,亚洲 主要为乙型肝炎： 每年57%病例将患HC
6、C 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10% 年龄校正后的年发病率在27.6-36.6例/10万人/年 男女比例为4:1,美国 主要为丙型肝炎， 每年有28%病例将患HCC 排名第4（亚裔）第8（拉美裔） 5年总存活率为8% 年龄校正后的年发病率为3.4例/10万人 非洲裔和亚裔美国人的发病率为白人的1.7-4倍。 所有人种中，均以男性为主,1. Teo EK, et al. Dig Dis 2001;19:263-268; 2. Ahmed F, et al. Prev Chronic Dis CDC 2008;5(3); 3. NCCN Hepatobiliary
7、 cancers practice guideline 2009;2.,HCC发生的分子机制,3,HCC的靶向治疗药物,概述,结语,4,肝细胞癌发生的分子基础,HCC 的分子发病机制极其复杂 慢性HBV/HCV 感染或环境毒素,引发肝硬化并诱导肝细胞基因水平的病变 信号传导途径异常导致细胞异常增生及存活 异常的生长因子激活 (TGF-, EGFR) 细胞分裂信号途径的持续活化 (Raf/MEK/ERK, PI3K/AKT, Wnt ) 抗细胞凋亡信号途径失调 (p53, PTEN) 新生血管异常增生（如VEGF途径）, 促进肿瘤生长及进展,肝细胞癌发生的分子机制,Normal Liver,Li
8、ver Cirrhosis,Genetic Alterations,Epigenetic Alterations,HCC,Dysplastic Nodules,Lab Invest 2002; 852:547-554,肝细胞癌发生的分子机制,Oncogene , 2010,29, 49895005,肝细胞癌发生的分子机制,Nucleus,PI3K,AKT,STAT,mTOR,Transcription Factors,Cell proliferation,Angiogenesis,Metastases,Survival/ Apoptosis,VEGFR,PDGFR,EGFR,Bevacizum
9、ab,VEGF,Cetuximab,IMC-1121b,血管生成在肿瘤的发生发展中起重要作用,Cancer Letters 2006;242:151167,分子靶向治疗已成为肿瘤治疗的重要手段,血管生成在HCC生长转移中起重要作用,HCC是典型的富血管肿瘤 HCC的生长和代谢,需要持续的血管生成 HCC血管新生与其生长、浸润、转移、分期及预后有着密切联系,HCC与促血管新生因子,HCC分泌大量的促血管新生因子，包括： 血管内皮生长因子(VEGF) 血小板衍生性生长因子( PDGF) 胎盘生长因子 转化生长因子和 ( TGF、) 碱性成纤维细胞生长因子( bFGF) 表皮生长因子( EGF) 肝
10、细胞生长因子( HGF),VEGF在肿瘤生长转移过程中起重要作用,Nat Rev Cancer 2008;8(8):579-91.,HCC发生发展过程涉及多种信号通路,Nat. Rev. Gastroenterol. Hepatol 2009,6:423432,Raf/MEK/ERK信号通路与HCC密切相关,Expert Opin Emerg Drugs ,2006;11:469-87,与肝癌细胞生长和转移复发相关的分子通路,主要有4条：Ras/Raf/Mek/Erk、PI3k/Akt/mTOR、Wnt/-catenin和核因子-B （NFB）; Ras/Raf/Mek/Erk通路调节细胞增殖
11、、分化、血管生成和存活; 在HCC中过度活化,可能通过以下因素: 癌基因Ras突变 生长因子和其受体的异常过度表达导致 Raf组成性激活 肝炎病毒蛋白,HCC发生的分子机制,3,HCC的靶向治疗药物,概述,结语,4,分子靶向药物激光制导炸弹,主要是针对肿瘤发生、发展过程中的关键大分子，即参与肿瘤发生、发展过程中的细胞信号传导和其他生物学途径的重要靶点,或是通过强力阻止肿瘤血管生成，从而抑制肿瘤细胞的生长、增殖和转移播散，发挥特异性抗肿瘤作用。,在研的HCC靶向治疗药物作用的信号通路,Sunitinib Brivanib,靶点和药物EGFR:TKI: Erlotinib, LapatinibGe
12、fitinibAb: Cetuximab VEGFTKI: SorafenibSunitinibBrivanibAb: Bevacizumab RAFTKI: Sorafenib mTORRapamycin，CCI-779 蛋白酶体抑制剂Bortezomib,生长因子受体信号通路,分子靶向药物激光制导炸弹,主要是针对肿瘤发生、发展过程中的关键大分子，即参与肿瘤发生、发展过程中的细胞信号传导和其他生物学途径的重要靶点,或是通过强力阻止肿瘤血管生成，从而抑制肿瘤细胞的生长、增殖和转移播散，发挥特异性抗肿瘤作用。,在研的HCC靶向治疗药物的作用靶点,Clin Cancer Res 2010; 16(
13、2); 3907.,已发表的肝癌靶向治疗的临床研究,Clin Cancer Res ,2010; 16(2); 3907.,1. 抗血管生成的靶向药物 2. 靶向EGFR信号通路的药物 3. 靶向PI3K/AKT/mTOR信号通路的药物 4. 其他新型分子靶向药物,HCC的靶向治疗药物,研发中的VEGFR靶向治疗药物 for HCC,Verweij J, DeJorge M. J Clin Oncol. 2007;25(17):2340-2343.; National Cancer Institute Clinicial Trials Registry. Avaialbe at: http:/
14、www.clinicaltrials.gov. Accessed May 20, 2008.,(1) 索拉非尼,索拉非尼：同时抗肿瘤血管生成和细胞增殖,Clin Cancer Res 2004;64:7099-7109.,索拉非尼全球首个FDA批准的HCC靶向治疗药物,索拉非尼治疗HCC的基础和I期研究,索拉非尼在HCC临床前研究1： 抗HCC细胞增殖、诱导细胞凋亡和抗血管生成 抑制小鼠异体移植模型中HCC肿瘤的生长索拉非尼的 I 期临床研究2： 不同种族间,无显著药代动力学差异 ChildPugh A级和B级间无显著药代动力学差异 耐受良好，具有明确的临床获益,1. Cancer Res 2
15、006;66:11851-11858 2. Cancer Sci. 2007:1-7,索拉非尼治疗晚期HCC 的期研究,137/147例,抗肿瘤活性明显： 获得8%(11/137)的 PR或MR, 34%(46/137)的SD16 周 独立评价的mTTP为5.5 个月 独立评价的mOS为9.2 个月 患者的耐受性良好: ChildPugh A 和 B 级患者间无临床药代动力学差异 索拉非尼在两个Child-Pugh 亚组中均耐受良好,J Clin Oncol 2006;24:4293300,索拉非尼治疗晚期HCC 期研究： 显著改善总生存,1. N Engl J Med 2008;359:37
16、8-90. 2. Lancet Oncol 2009; 10: 2534,索拉非尼：开启了HCC靶向治疗新时代,迄今为止，在HCC领域开展的随机试验已经超过了100项; 索拉非尼是第一个被证实可以改善晚期HCC病人mOS的系统性治疗药物; 目前，索拉非尼在全球 超过60个国家/地区被批准用于晚期HCC/无法手术切除HCC的治疗； 现在, 多项索拉非尼治疗HCC的临床试验正在积极开展，覆盖了HCC的的不同阶段。,已完成或正在开展的索拉非尼治疗HCC的大型研究,GIDEON (Global Investigation of therapeutic DEcisions in hepatocellul
17、ar carcinoma HCC and Of its treatment with sorafeNib) second interim analysis in 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. Nakaj
18、ima, F. Cihon, A. Venook,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 uHCC2-3Pivotal studies generally included patients with preserved liver function Investigation of soraf
19、enib in wider patient groups is needed4GIDEON is the largest prospective study in uHCC ever conductedIn total, 3322 patients have been enrolled from 39 countries,uHCC, unresectable hepatocellular carcinoma; OS, overall survival; GIDEON, Global Investigation of therapeutic DEcisions in hepatocellular
20、 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,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 t
21、herapy 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 dat
22、a 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,G
23、IDEON 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 an
24、alysis 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 Investigatio
25、n 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,GIDEON 研究: 第二次second 中期分析,GIDEON second interim analysis: Per protocol the second interim analysis wa
26、s 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 Include
27、s 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 t
28、reatment with sorafeNib; ITT, intent to treat; OS, overall survival; TTP, time-to-progression,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,根据治疗开始时Child-Pugh状
29、态 选择的病例基线特征(2),aChild-Pugh status unknown for 5 patients; 207 patients are not evaluable and not tabulated BCLC, Barcelona Clinic Liver Cancer; TNM, tumor node metastases,初始时Child-Pugh状态 与 sorafenib 剂量,aInitial dosing data missing for 8 patients; Child-Pugh status unknown for 5 patients,初始时Child-Pug
30、h状态与Sorafenib 剂量和日平均剂量,aData at study entry; bDosing data missing for 8 patients; Child-Pugh status unknown for 5 patients; cAssessed in the 79% of patients for whom dosing data were available,Child-Pugh状态与Sorafenib 剂量中断和调整,aData at study entry bDosing data missing for 8 patients; Child-Pugh status
31、unknown for 5 patients,Child-Pugh状态与Sorafenib 治疗疗程,aData at study entry,Child-Pugh状态与总体 安全性数据,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;
32、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 adver
33、se events,Child-Pugh B 分值与总体 安全性数据,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 s
34、ignificant 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,Child-Pugh状态与药物 相关性不良事件a,b,aIncidence 5% in any group and any grad
35、e; bAt start of therapy HFSR, hand-foot skin reaction; NOS, not otherwise specified,Sorafenib治疗过程中或停止治疗 30天内死亡原因,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 mis
36、sing for 7 Child-Pugh A and 7 Child-Pugh B patients HCC, hepatocellular carcinoma; MOF, multi-organ system failure,Child-Pugh状态与初步的OS,Child Pugh A (7) (n=984), median (95% CI) 312 (284, 341) days 10.3 months,Child Pugh B (7-9) (n=376), median (95% CI) 147 (126, 189) days 4.8 months,Child Pugh C (9)
37、(n=36), median (95% CI) 62 (46, 94) days 2.0 months,600,500,400,300,200,100,0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,Time since start of treatment (days),Survival distribution function,a207 patients not evaluable CI, confidence interval,Child-Pugh状态与初步的TTP,Child Pugh A (7) (n=984), median (95% CI)
38、129 (119, 146) days 4.2 months,Child Pugh B (7-9) (n=376), median (95% CI) 109 (93, 140) days 3.6 months,Child Pugh C (9) (n=36), median (95% CI) 64 (28, 110) days 2.1 months,500,400,300,200,100,0,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,Time since start of treatment (days),TTP distribution funct
39、ion,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,结论 (1),Based on the second interim analysis, there is no evidence suggesting that treating phys
40、icians 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-rel
41、ated 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,结论 (2),The vast majority of deaths were due to HCC or underlying liver disorders The differences in patient outc
42、omes 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 effic
43、acy 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,阿霉素索拉非尼治疗HCC的II期研究 研究结果已经发表,阿霉素索拉非尼治疗HCC的II期研究,Abou-Alfa GK, et al. EJC Suppl. 2007;5(4)
44、:259. ASCO-GI 2008.1报告.,月,无进展率,1.00,0,0.75,0.50,0.25,0,15.5,5.0,7.5,10.0,12.5,2.5,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,1.00,0,0.75,0.50,0.25,0,20.0,5.0,7.5,10.0,12.5,15.0,17.5,2.5,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.
45、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/m2,2 PR,62%,1 PR,29%,阿霉素索拉非尼治疗HCC的II期研究,阿霉素索拉非尼治疗HCC的III期研究,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H
46、CC患者（72%为HBSAg阳性），单臂研究,100,80,60,40,20,0,0,5,10,15,20,25,PFS,%,mPFS 3.7 个月 （95%CI:1.95.5）,时间（月）,100,80,60,40,20,0,0,5,10,15,20,25,OS,%,mOS 7.4 个月 （95%CI:3.211.6）,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
47、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,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,http:/clinicaltrials.gov/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：
48、SECOX方案可以延长患者的mPFS和mOS,100,80,60,40,20,0,0,3,6,9,12,21,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）,15,18,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) 舒尼替尼,舒尼替尼 vs.索拉非尼,*Ki (nM) values reported Value indicates inhibition of receptor phosphorylation; Data on file; Pfizer Inc., 2008. Values indicate IC50 for murine enzyme,
