晚期HCC系统治疗研究进展

晚期HCC系统治疗研究进展

药物试验方案中位

TTP/PFS,月中位

OS,月晚期HCC的一线治疗SorafenibSHARPSorafenibvsplacebo4.9vs4.1[HR=0.58;P=0.77]10.7vs7.9[HR=0.69;P<0.001]SorafenibAsia-PacificSorafenibvsplacebo2.8vs1.4[HR=0.57;P<0.001]6.5vs4.2[HR=0.68;P=0.014]SunitinibSUN1170Sunitinibvssorafenib4.1vs3.8[HR=1.13;P=0.169]7.9vs10.2{HR=1.30;P=0.0019]BrivanibBRISK-FLBrivanibvssorafenib4.2vs4.1[HR=1.10;P=0.853]9.5vs9.9[HR=1.06;P=0.373]LinifanibLiGHTLinifanibvssorafenib5.4vs4.0[HR=0.76;P=0.001]9.1vs9.8[HR=1.05;P=NS]ErlotinibSEARCHErlotinib+sorafenibvsplacebo+sorafenib3.2vs4.0[HR=1.13;P=0.91]9.5vs8.5[HR=0.92;P=0.20]晚期HCC的二线治疗BrivanibBRISK-PSBrivanibvsplacebo4.2vs2.7[HR=0.56;P<0.001]9.4vs8.2[HR=0.89;P=0.331]EverolimusEVOLVE-1Everolimusvsplacebo3.0vs2.6[HR=0.93]7.6vs7.3[HR=1.27;P=0.68]RamucirumabREACHRamucirumabvsplacebo2.8vs2.1[HR=0.63;P<0.00]9.2vs.7.6[HR+0.87;{=0.14]Source:AdaptedfromChumaM,etal.HepatolRes.2014Dec4.doi:10.1111/hepr.12459.GhassanK.,etal.JClinOncol34,2016.既往的III期临床研究STUDY304是一项多中心、随机、开放、全球III期临床研究，对比了Lenvima与sorafenib一线治疗不可切除性肝细胞癌的疗效和安全性。主要终点:OS次要终点:TTP,PFS,ORR,PK,安全性

乐伐替尼12mg/8mg,po,qdN=478索拉非尼400mg,po,bid

n=476目标患者

(N=954)不可切除的HCC患者

R1:1据：全球肿瘤医生网.STUDY304：乐伐替尼一线治疗HCC患者结果：lenvatinib在OS方面达到了非劣效性的统计学标准，达到了研究的主要终点。PFS、TTP、ORR均表现出统计学显著和临床意义的改善。安全性方面，lenvatinib治疗组最常见的5种不良事件包括高血压、腹泻、食欲下降、体重减轻、疲劳。该研究中其余的次要终点，患者生活质量、血浆PK参数及安全性正在进行分析。入选标准:晚期肝癌不可行手术或局部治疗的或者手术或局部治疗后病情进展的ECOG评分0—1Nivolumab临床I/II期试验临床I/II期试验剂量升级非比较研究随机对照Nivolumab组非肝炎者丙肝感染者乙肝感染者

HCCNivolumab

+Ipilimumab组

Nivolumab

vs

索拉非尼终点：:Nivolumab的安全性Nivolumab的耐受性客观缓解率评估时间：最后一次用药后100天终点：:两种药物的安全性两种药物的耐受性客观缓解率评估时间：最后一次用药后100天终点:客观缓解率评估时间：至少随访6个月NCT01658878对比Nivolumab单药与Nivolumab联合Ipilimumab在治疗晚期肝癌患者方面的有效性、安全性和耐受性共有600名患者参加I/II期临床试验Nivolumab治疗晚期HCC的I/II期临床扩展试验StudyDesignUninfected(n=23)HCV(n=10)HBV(n=15)Total(N=48)客观缓解,n(%)完全缓解部分缓解疾病稳定疾病进展不可评估3(13)2(9)1(4)13(57)6(26)1(4)3(30)1(10)2(20)5(50)2(20)01(7)01(7)6(40)7(47)1(7)7(15)3(6)4(8)24(50)15(31)2(4)持续缓解,n(%)1(33)001(14)ASCO2016.El-KhoueiryAB,etal.Poster4012

CheckMate040：Nivolumab治疗晚期HCC的I/II期研究，剂量爬坡研究的中期分析TimetoResponseandDurationofResponseSafety纳入标准：晚期肝癌不适合手术治疗和/或局部治疗或手术/局部治疗后进展肝细胞癌局部治疗需在入组基线检查至少4周前完成ECOG评分

0/1Child-Pugh分级：A级试验组：纳武单抗阳性对照组：索拉非尼主要研究终点：疾病进展时间

(TTP)总生存期次要研究终点：总缓解率无进展生存期

(FPS)(PD)-L1表达情况时间窗：约33个月III期研究N=726III期研究：Nivolumab对比Sorafenib一线治疗HCC研究最终数据纳入时间：2017年5月研究完成时间：2019年六月试验编号：

NCT02576509RESORCE(NCT01774344)是一项多中心，随机，双盲,安慰剂对照的研究，旨在评估瑞戈非尼在既往索拉非尼治疗进展的HCC患者中的疗效与安全性分层因素:地理区域（亚洲vs非亚洲）ECOG评分（0vs1）AFP水平（<400ng/mlvs>400ng/ml）是否存在肝外转移/大血管侵犯

主要终点:OS次要终点:TTP,PFS,ORR,DCR第三级终点:反应持续时间，疾病稳定时间，生活质量，药代学，生物标记物分析安全性瑞戈非尼160mg,po,qd

(用药3周，停1周)+最佳对症支持治疗(4周/周期)安慰剂,po,qd

(用药3周，停1周)+最佳对症支持治疗(4周/周期)目标患者

(N=530)索拉非尼治疗进展后的HCC患者

R2:1C/NCT01774344.RESORCE研究：瑞戈非尼二线治疗HCC患者BruixJ,etal.ILCA2016presentationentitled:Efficacyandsafetyofregorafenibversusplaceboinpatientswithhepatocellularcarcinoma(HCC)progressingonsorafenib:Resultsoftheinternational,randomizedphase3RESORCEtrial.September9–11,2016;Vancouver,Canada.†*China,Japan,Korea,Singapore,Taiwan.Patientsmayhavehadmorethanoneetiology.NASH,nonalcoholic

steatohepatitis.瑞戈非尼

(N=379)安慰剂(N=194)男性,

%8888年龄,中位

(范围)64

(19–85)62

(23–83)种族,

%白种人3635亚洲4140黑人21其它/不明2124地理区域:

亚洲*3838ECOG评分,%

(0/1)65/

3567/

33

HCC病因†,

%酒精性2428乙型肝炎3838丙型肝炎2121NASH77其它75不明1716BCLC分期,%

(A/B/C)0.3/14/

860/11/

89Child-Pugh

分级*A9897B13大血管侵犯

(MVI),

%2928肝外转移

(EHD),

%7076大血管侵犯和/或肝外转移,

%8084AFP

≥400ng/mL,

%4345肝硬化†,

%7574RESORCE研究：患者基线特征瑞戈非尼

(n=379)安慰剂

(n=194)事件233

(61%)140

(72%)删失147

(39%)54

(28%)中位OS(95%

CI)10.6月(9.1,

12.1)7.8月(6.3,

8.8)风险比0.63(95%CI:0.50,

0.79)P<0.001

(2-sided)100806040200036924273033生存率l

(%)

12

15

18

21

Monthsfrom

randomization━

瑞戈非尼

n=379316224170122785434211040━

安慰剂

n=194149956237261685310BruixJ,etal.ILCA2016presentationentitled:Efficacyandsafetyofregorafenibversusplaceboinpatientswithhepatocellularcarcinoma(HCC)progressingonsorafenib:Resultsoftheinternational,randomizedphase3RESORCEtrial.September9–11,2016;Vancouver,Canada.L.CN.MA.11.2016.1558RESORCE研究：主要终点OSSUBGROUPHAZARDRATIO(95%

CI)n/EVENTSHAZARDRATIO(95%

CI)Agegroup:<65

years315/2050.65(0.49,

0.87)≥65

years258/1680.74(0.54,

1.02)Male504/3270.65(0.52,

0.82)Female69/460.88(0.48,

1.62)Geographicregion:

Asia216/1420.65(0.46,

0.92)Restof

world357/2310.68(0.52,

0.90)ECOGscore:

0377/2310.61(0.47,

0.80)1196/1420.78(0.55,

1.11)AFP:<400

ng/mL324/1940.67(0.50,

0.90)≥400

ng/mL249/1790.68(0.50,

0.92)Child-Pughscore:

A5362/2220.60(0.46,

0.79)A6199/1410.80(0.57,

1.13)Extrahepaticdisease(EHD):

No161/1030.97(0.63,

1.48)Yes412/2700.60(0.47,

0.77)Macrovascularinvasion(MVI):

No409/2590.67(0.52,

0.86)Yes164/1140.67(0.46,

0.98)MVIand/orEHD:

No107/680.98(0.58,

1.66)Yes466/3050.63(0.50,

0.79)HepatitisB:

No357/2380.73(0.56,

0.95)Yes216/1350.58(0.41,

0.82)HepatitisC:

No454/2950.65(0.51,

0.82)Yes119/780.79(0.49,

1.26)Alcoholuse:

No428/2730.59(0.46,

0.76)Yes145/1000.92(0.61,

1.38)0.02.00.5

1.0

1.5

Regorafenibbetter

Placebobetter

BruixJ,etal.ILCA2016presentationentitled:Efficacyandsafetyofregorafenibversusplaceboinpatientswithhepatocellularcarcinoma(HCC)progressingonsorafenib:Resultsoftheinternational,randomizedphase3RESORCEtrial.September9–11,2016;Vancouver,Canada.L.CN.MA.11.2016.1558RESORCE研究：OS亚组分析100806040200036924273033无进展生存率

(%)

12

15

18

21Monthsfrom

randomization瑞戈非尼

(n=379)安慰剂

（n=194)事件293

(77%)181

(93%)删失86

(23%)13

(7%)中位PFS

(95%

CI)3.1月

(2.8,

4.2)1.5月

(1.4,

1.6)风险比

0.46(95%CI:0.37,

0.56)P<0.001

(2-sided)瑞戈非尼n=37916676432714874000安慰剂n=1943715632110000BruixJ,etal.ILCA2016presentationentitled:Efficacyandsafetyofregorafenibversusplaceboinpatientswithhepatocellularcarcinoma(HCC)progressingonsorafenib:Resultsoftheinternational,randomizedphase3RESORCEtrial.September9–11,2016;Vancouver,Canada.L.CN.MA.11.2016.1558RESORCE研究：PFS0.0SUBGROUPHAZARDRATIO(95%

CI)n/EVENTSHAZARDRATIO(95%

CI)Agegroup:<65

years315/2670.46(0.36,

0.59)≥65

years258/2070.51(0.38,

0.68)Male504/4140.47(0.39,

0.58)Female69/600.55(0.32,

0.96)Geographicregion:

Asia216/1800.34(0.25,

0.47)Restof

world357/2940.54(0.43,

0.69)ECOGscore:

0377/3100.43(0.34,

0.54)1196/1640.62(0.45,

0.86)AFP:<400

ng/mL324/2620.45(0.35,

0.58)≥400

ng/mL249/2120.53(0.40,

0.70)Child-Pughscore:

A5362/2950.44(0.34,

0.56)A6199/1700.56(0.41,

0.76)Extrahepaticdisease(EHD):

No161/1270.52(0.36,

0.75)Yes412/3470.47(0.38,

0.59)Macrovascularinvasion(MVI):

No409/3410.45(0.36,

0.56)Yes164/1330.55(0.38,

0.78)MVIand/orEHD:

No107/890.47(0.30,

0.73)Yes466/3850.49(0.39,

0.60)HepatitisB:

No357/3000.53(0.41,

0.67)Yes216/1740.39(0.29,

0.54)HepatitisC:

No454/3730.46(0.37,

0.57)Yes119/1010.59(0.39,

0.90)Alcoholuse:

No428/3540.46(0.37,

0.57)Yes145/1200.53(0.37,

0.77)2.00.5

1.0

1.5

Regorafenibbetter

Placebobetter

BruixJ,etal.ILCA2016presentationentitled:Efficacyandsafetyofregorafenibversusplaceboinpatientswithhepatocellularcarcinoma(HCC)progressingonsorafenib:Resultsoftheinternational,rBaansdeodmonizmedREpChISaTse3RESORCEtrial.September9–11,2016;Vancouver,

Canada.L.CN.MA.11.2016.1558RESORCE研究：PFS亚组分析100806040200036924273033疾病进展率

(%)

12

15

18

21Monthsfrom

randomization瑞戈非尼

(n=379)

安慰剂(n=194)事件274

(72%)173

(89%)删失105

(28%)21

(11%)中位TTP

(95%

CI)3.2月(2.9,

4.2)1.5月

(1.4,

1.6)风险比0.44(95%CI:0.36,

0.55)P<0.001

(2-sided)瑞戈非尼n=37916475412714874000安慰剂n=1943615632110000BruixJ,etal.ILCA2016presentationentitled:Efficacyandsafetyofregorafenibversusplaceboinpatientswithhepatocellularcarcinoma(HCC)progressingonsorafenib:Resultsoftheinternational,randomizedphase3RESORCEtrial.September9–11,2016;Vancouver,Canada.L.CN.MA.11.2016.1558RESORCE研究：TTP0.01.01.50.5SUBGROUPHAZARDRATIO(95%

CI)n/EVENTSHAZARDRATIO(95%

CI)Agegroup:<65

years315/2520.45(0.35,

0.58)≥65

years258/1950.50(0.37,

0.68)Male504/3900.47(0.38,

0.57)Female69/570.53(0.30,

0.93)Geographicregion:

Asia216/1700.34(0.24,

0.47)Restof

world357/2770.53(0.41,

0.67)ECOGscore:

0377/2930.42(0.33,

0.54)1196/1540.61(0.44,

0.84)AFP:<400

ng/mL324/2480.43(0.33,

0.56)≥400

ng/mL249/1990.53(0.40,

0.71)Child-Pughscore:

A5362/2820.43(0.34,

0.56)A6199/1580.51(0.37,

0.71)Extrahepaticdisease(EHD):

No161/1220.51(0.35,

0.74)Yes412/3250.46(0.37,

0.58)Macrovascularinvasion(MVI):

No409/3210.45(0.35,

0.56)Yes164/1260.52(0.36,

0.75)MVIand/orEHD:

No107/840.46(0.29,

0.73)Yes466/3630.48(0.38,

0.59)HepatitisB:

No357/2840.51(0.40,

0.65)Yes216/1630.38(0.28,

0.53)HepatitisC:

No454/3510.45(0.36,

0.56)Yes119/960.57(0.37,

0.87)Alcoholuse:

No428/3340.45(0.36,

0.56)Yes145/1130.51(0.35,

0.75)2.0

Regorafenibbetter

Placebobetter

BruixJ,etal.ILCA2016presentationentitled:Efficacyandsafetyofregorafenibversusplaceboinpatientswithhepatocellularcarcinoma(HCC)progressingon

sorafenib:

Resultsoftheinternational,randomizedphase3RESORCEtrial.September9–11,2016;Vancouver,Canada.L.CN.MA.11.2016.1558RESORCE研究：TTP亚组分析*WorseningofECOGPS≥3orsymptomaticdeteriorationincludingincreaseinliverfunction

tests.mRECIST,modifiedRECIST;CR,completeresponse;PR,partialresponse;SD,stabledisease;PD,progressive

disease.BruixJ,etal.ILCA2016presentationentitled:Efficacyandsafetyofregorafenibversusplaceboinpatientswithhepatocellularcarcinoma(HCC)progressingonsorafenib:Resultsoftheinternational,randomizedphase3RESORCEtrial.September9–11,2016;Vancouver,Canada.mRECISTRECIST

1.1瑞戈非尼(N=379)安慰剂

(N=194)瑞戈非尼(N=379)安慰剂

(N=194)反应率,%10.64.16.62.6P-值(双边)0.0090.04疾病控制率,

%65.236.165.734.5P-值

(双边)<0.001<0.001CR,

%0.5000PR,

%10.04.16.62.6SD,

%54.432.058.832.0NonCR/nonPD,

%0.300.30PD,

%22.755.722.457.2不可评估5.04.15.04.6没有评估7.14.16.93.6临床进展*22.720.622.720.6L.CN.MA.11.2016.1558RESORCE研究：最佳肿瘤反应Patientswitheventstartingorworseningbetweenstartoftreatmentand30daysafterendof

treatment.NCI-CTCAE

v4.03.BruixJ,etal.ILCA2016presentationentitled:Efficacyandsafetyofregorafenibversusplaceboinpatientswithhepatocellularcarcinoma(HCC)progressingonsorafenib:Resultsoftheinternational,randomizedphase3RESORCEtrial.September9–11,2016;Vancouver,Canada.患者比例%治疗相关药物相关瑞戈非尼(N=379)安慰剂

(N=194)瑞戈非尼

(N=379)安慰剂

(N=194)任何级别1009393523级563246164级11740.55级

(死亡)13202*1†严重4447103导致剂量调整68315410导致永久停药2519104*Drug-relatedgrade5eventsintheregorafenibgroup(n=7):meningorrhagia;hemorrhagicshock;myocardialinfarction;duodenalperforation;deathnototherwisespecified;generalphysicalhealthdeterioration;hepatic

encephalopathy.†安慰剂组2例5级药物相关事件是由于肝功能衰竭L.CN.MA.11.2016.1558RESORCE研究：治疗相关不良反应AST,aspartateaminotransferase;HFSR,hand-footskinreaction;NA,not

applicable.NCI-CTCAE

v4.03.BruixJ,etal.ILCA2016presentationentitled:Efficacyandsafetyofregorafenibversusplaceboinpatientswithhepatocellularcarcinoma(HCC)progressingonsorafenib:Resultsoftheinternational,randomizedphase3RESORCEtrial.September9–11,2016;Vancouver,Canada.%患者比例治疗相关药物相关瑞戈非尼

(N=379)安慰剂

(N=194)瑞戈非尼

(N=379)安慰剂

(N=194)任何级别3级4级任何级别3级4级任何级别3级4