侖伐替尼研究解讀

ASCO-GI

2019關(guān)于侖伐替尼的報(bào)道Oral

presentation-探究REFLECT研究中OR狀態(tài)與OS的關(guān)系

PosterNo.316-探討REFLECT研究中，基于患者基線體重選擇侖伐替尼起始劑量對(duì)有效性和安全性的影響Poster

No.317-侖伐替尼用于肝細(xì)胞癌患者的總生存和不良事件相關(guān)性的分析Poster

No.371-REFLECT研究事后分析結(jié)果公布REFLECT研究設(shè)計(jì)全球多中心,隨機(jī)、開放性、III期非劣效性研究BCLC:巴塞羅那臨床肝癌；ECOGPS:東部合作腫瘤組的性能狀態(tài)；mRECIST:修訂的實(shí)體瘤反應(yīng)評(píng)價(jià)標(biāo)準(zhǔn)；ORR:客觀回應(yīng)率；OS:總存活期；PFS:無(wú)進(jìn)展存活期；:實(shí)體腫瘤反應(yīng)評(píng)價(jià)標(biāo)準(zhǔn)；TTP:疾病進(jìn)展時(shí)間；TakujiOkusaka,etal.SafetyandEfficacyofLenvatinibbyStartingDoseBasedonBodyweightinPatients(pts)WithUnresectableHepatocellularCarcinoma(uHCC)inREFLECT.ASCO-GI2019.PosterNo.316分層依據(jù)地區(qū)（亞太地區(qū)或西方國(guó)家）門靜脈浸潤(rùn)和/或肝外擴(kuò)散（是或否）ECOG-PS（0或1分）體重（<60kg或≥60kg）樂(lè)衛(wèi)瑪?（N

=

478

）12

mg（體重≥60

kg）或8

mg（體重<60

kg）每天一次索拉非尼（n=476

）400

mg每日兩次不可切除的肝細(xì)胞癌患者（N

=

954）未接受過(guò)任何全身治療BCLC分期B或C期根據(jù)mRECIST標(biāo)準(zhǔn),至少有一處可測(cè)量的靶病灶Child-Pugh評(píng)分A級(jí)ECOG-PS

0或1分良好的組織器官功能排除:肝臟占位≥50%、明顯的膽管浸潤(rùn)或門靜脈主干浸潤(rùn)隨機(jī)1:1主要終點(diǎn):OS次要終點(diǎn):研究者基于mRECIST標(biāo)準(zhǔn)評(píng)估的PFS,TTP,ORR生活質(zhì)量-安全性和耐 受性侖伐替尼藥代動(dòng)力學(xué) 暴露參數(shù)治療直至疾病進(jìn)展侖伐替尼治療肝細(xì)胞癌患者的III期研究（REFLECT）中OS和客觀緩解（OR）之間關(guān)系的分析1MasatoshiKudo,2RichardS.Finn,3ShukuiQin,4Kwang-HyubHan,5KenjiIkeda,6Ann-LiiCheng,7FabioPiscaglia,1KazuomiUeshima,8HiroshiAikata,9ArndtVogel,10CarlosLópezLópez,11MarcPracht,12ZhiqiangMeng,13BrunoDaniele,14Joong-WonPark,15DanielPalmer,16CorinaDutcus,17ToshiyukiTamai,16KenichiSaito,18RiccardoLencioni1KindaiUniversityFacultyofMedicine,Osaka,Japan;2GeffenSchoolofMedicine,UCLAMedicalCenter,SantaMonica,CA,USA;3NanjingBayiHospital,NanjingChina;4SeveranceHospital,YonseiUniversity,Seoul,RepublicofKorea;5ToranomonHospital,Tokyo,Japan;6NationalTaiwanUniversityHospitalandNationUniversityCancerCenter,Taipei,Taiwan;7UniversityofBologna,Bologna,Italy;8HiroshimaUniversityHospital,Hiroshima,Japan;9HannoverMedicalSchooGermany;10MarquésdeValdecillaUniversityHospital,Santander,Spain;11CancerInstituteEugèneMarquis,Rennes,France;12FudanUniversity,ShanghaiCanCenter,Shanghai,China;13OspedaledelMare,Napoli,Italy;14NationalCancerCenterKorea,Goyang-si,RepublicofKorea;15TheClatterbridgeCancerCentre,Birkenhead,England,UK;16EisaiInc.,WoodcliffLake,NJ,USA;17EisaiCo.,Ltd.,Tokyo,Japan;18UniversityofPisaSchoolofMedicine,Pisa,Italy;andtheMInstitute,Miami,FL,USAKudoM,et,al.Analysisofsurvivalandobjectiveresponse(OR)inpatientswithhepatocellularcarcinomainaphaseIIIstudyoflenvatinib(REFLECT)[R/OL].ASCO-GI,2019.Abstract186.背景-既往研究證實(shí),基于mRECIST評(píng)估的OR狀態(tài)是OS的獨(dú)立預(yù)測(cè)因子ORR=15.6%ORR=11.5%Objective

responseNo

objective

responseObjective

responseNo

objective

responseMeyerT,etal.LiverInt.2017Jul;37(7):1047-1055.LencioniR,etal.JHepatol.2017Jun;66(6):1166-1172.研究目的和方法KudoM,et,al.Analysisofsurvivalandobjectiveresponse(OR)inpatientswithhepatocellularcarcinomainaphaseIIIstudyoflenvatinib(REFLECT)[R/OL].ASCO-GI,2019.Abstract186.研究者按mRECIST標(biāo)準(zhǔn)評(píng)估分析經(jīng)侖伐替尼或索拉非尼治療的患者OR與OS之間的關(guān)系-將應(yīng)答者(CR或PR)的mOS與無(wú)應(yīng)答者(SD.PD或UNK/NE)的mOS進(jìn)行比較，不考慮治療方式。-在第2、4、6個(gè)月，以O(shè)R狀態(tài)為界標(biāo)，使用Cox回歸分析，分析OR及其他預(yù)后因素與OS之間的關(guān)系。結(jié)果-應(yīng)答者mOS顯著優(yōu)于無(wú)應(yīng)答者KudoM,et,al.Analysisofsurvivalandobjectiveresponse(OR)inpatientswithhepatocellularcarcinomainaphaseIIIstudyoflenvatinib(REFLECT)[R/OL].ASCO-GI,2019.Abstract186.根據(jù)OR狀態(tài)對(duì)OS進(jìn)行界標(biāo)點(diǎn)分析均提示應(yīng)答者mOS顯著優(yōu)于無(wú)應(yīng)答者2個(gè)月界標(biāo)點(diǎn)分析KudoM,et,al.Analysisofsurvivalandobjectiveresponse(OR)inpatientswithhepatocellularcarcinomainaphaseIIIstudyoflenvatinib(REFLECT)[R/OL].ASCO-GI,2019.Abstract186.4個(gè)月界標(biāo)點(diǎn)分析6個(gè)月界標(biāo)點(diǎn)分析KudREFLECT研究中OS相關(guān)預(yù)測(cè)因子的單/多變量分析參數(shù)（逐步選擇）單變量分析多變量分析HR[95%

CI]P-valueHR[95%

CI]P-value肉眼可見的門靜脈侵入（是vs否）1.55[1.30-1.85]<0.0011.37[1.14-1.64]<0.001基線AFP(ng/mL)(<200

vs≥200)0.52[0.45-0.61]<0.0010.56[0.48-0.66]<0.001基線時(shí)腫瘤病灶數(shù)量(2

vs

1)1.46[1.23-1.73]<0.0011.40[1.18-1.66]<0.001基線時(shí)腫瘤病灶數(shù)量(≥3

vs

1)2.24[1.84-2.72]<0.0012.02[1.66-2.47]<0.001肝臟腫瘤病灶（是vs否）2.31[1.67-3.20]<0.0011.68[1.20-2.33]0.002HBV引起(是vs否)1.23[1.06-1.43]0.0061.20[1.03-1.39]0.019HCC手術(shù)史(是vs否)0.67[0.57-0.77]<0.0010.84[0.72-0.99]0.032治療(LEN

vs

SOR)0.93[0.80-1.077]0.3260.85[0.73-0.996]0.044客觀緩解(是vs否)0

.61

[0

.49

-0

.76

]<

0

.0010

.61

[0

.49

-0

.76

]<

0

.001o

M,et,al.

Analysis

of

survival

and

objective

response

(OR)

in

patients

with

hepatocellular

carcinoma

in

a

phase

III

study

of

lenvatinib(REFLECT)[R/OL].

ASCO-GI，2019.

Abstract

186.基于非分層Cox回歸分析的OS獨(dú)立預(yù)測(cè)因子KudoM,et,al.Analysisofsurvivalandobjectiveresponse(OR)inpatientswithhepatocellularcarcinomainaphaseIIIstudyoflenvatinib(REFLECT)[R/OL].ASCO-GI,2019.Abstract186.結(jié)論對(duì)于HCC患者，無(wú)論接受何種治療，基于mRECIST評(píng)估的OR狀態(tài)是OS的獨(dú)立預(yù)測(cè)因子-在REFLECT研究中，基于mRECIST評(píng)估的OR狀態(tài)與OS的關(guān)系，其結(jié)果與既往報(bào)道相同；-對(duì)于HCC患者，其他OS的預(yù)測(cè)因子包括:MPVI、基線AFP水平、腫瘤數(shù)量、腫瘤累及部位、既往接受過(guò)至少1次治療、治療方式。達(dá)到OR的患者可獲得更長(zhǎng)的OS-OR狀態(tài)與OS之間的關(guān)系尚需更多研究驗(yàn)證基于患者體重使用不同起始劑量的侖伐替尼治療不可切除肝細(xì)胞癌的安全性和有效性（

REFLECT）TakujiOkusaka1,KenjiIkeda2,MasatoshiKudo3,RichardS.Finn4,ShukuiQin5,Kwang-HyubHan6,Ann-LiiCheng7,FabioPiscaglia8,MasahiroKobayashi2,MaxSung9,MinshanChen10,LucjanWyrwicz11,Jung-HwanYoon12,ZhenggangRen13,CorinaE.Dutcus14,ToshiyukiTamai15,MinRen14,SeiichiHayato15,HiromitsuKumada21NationalCancerCenterHospital,Tokyo,Japan;2ToranomonHospital,Tokyo,Japan;3KindaiUniversityFacultyofMedicine,Osaka,Japan;4GeffenSchoolofMedicine,UCLAMedicalCenter,SantaMonica,CA,USA;5NanjingBayiHospital,Nanjing,Jiangsu,China;6SeveranceHospital,YonseiUniversity,Seoul,RepublicofKorea;7NationalTaiwanUniversityHospital,Taipei,Taiwan;8UniversityofBologna,Bologna,Italy;9TischCancerInstituteatMountSinai,NewYork,NY,USA;10SunYat-senUniversityCancerCenter,Guangzhou,China;11CentrumOnkologii-Instytutim.,M.SklodowskiejCurie,Warsaw,Poland;12SeoulNationalUniversityHospital,Seoul,RepublicofKorea;13ZhongshanHospitalFudanUniversity,Shanghai,China;14EisaiInc.,WoodcliffLake,NJ,USA;15EisaiCo.,Ltd,Tokyo,Japan背景和目的TakujiOkusaka,etal.SafetyandEfficacyofLenvatinibbyStartingDoseBasedonBodyweightinPatients(pts)WithUnresectableHepatocellularCarcinoma(uHCC)inREFLECT.ASCO-GI2019.PosterNo.316侖伐替尼Ⅱ期研究結(jié)果（202研究）顯示,侖伐替尼12mg/d劑量用于不可切除的進(jìn)展期肝細(xì)胞癌在早期劑量調(diào)整和體重間存在相關(guān)性,因此REFLECT研究做了依據(jù)體重的劑量調(diào)整。該研究中,受試者隨機(jī)分配,其中體重<60kg的患者接受8mg/d侖伐替尼治療劑量,體重≥60kg的患者接受12mg/d的治療劑量。本研究旨在探討REFLECT研究中,基于患者基線體重選擇侖伐替尼起始劑量對(duì)有效性和安全性的影響TakujiOkusaka,etal.SafetyandEfficacyofLenvatinibbyStartingDoseBasedonBodyweightinPatients(pts)WithUnresectableHepatocellularCarcinoma(uHCC)inREFLECT.ASCO-GI2019.PosterNo.316侖伐替尼不同起始劑量組及索拉非尼組的患者基線特征相似類別侖伐替尼8

mg

(<60

kg)(n=151)侖伐替尼12

mg

(≥60

kg)(n=325)索拉非尼(n=475)年齡中位數(shù)，年（范圍）65.0

(20,

86)62.0

(24,

88)62.0

(22,

88)性別,n(%)男性女性106

(70.2)45

(29.8)297

(91.4)28

(8.6)400

(84.2)75

(15.8)地域,n(%)西方亞太21

(13.9)130

(86.1)134

(41.2)191

(58.8)156

(32.8)319

(67.2)體重,n(%)<

60

kg≥

60

kg151

(100.0)02

(0.6)323

(99.4)145

(30.5)330

(69.5)ECO

G

P

S

,

n

(%

)0193

(61.6)58

(38.4)211

(64.9)114

(35.1)301

(63.4)174

(36.6)肝功能分級(jí),n(%)

AB151

(100.0)0322

(99.1)3

(0.9)470

(99.0)5

(1.0)肉眼可見門靜脈侵犯，肝外播散，或兩者兼有,n(%)是否105

(69.5)46

(30.5)223

(68.6)102

(31.4)336

(70.7)139

(29.3)BCL

C分級(jí),n(%)

BC32

(21.2)119

(78.8)71

(21.8)254

(78.2)92

(19.4)383

(80.6)病因,n(%)乙肝丙肝酒精其他未知83

(55.0)40

(26.5)6

(4.0)8

(5.3)14

(9.3)167

(51.4)50

(15.4)30

(9.2)30

(9.2)48

(14.8)227

(47.8)126

(26.5)21

(4.4)32

(6.7)69

(14.5)基線甲胎蛋白濃度,n(%)<

200

ng/mL≥200

ng/mL未測(cè)出80

(53.0)71

(47.0)0

(0.0)174

(53.5)150

(46.2)1

(0.3)285

(60.0)187

(39.4)3

(0.6)侖伐替尼不同起始劑量亞組,與索拉非尼組間OS具有可比性體重＜60mg（侖伐替尼8mg）TakujiOkusaka,etal.SafetyandEfficacyofLenvatinibbyStartingDoseBasedonBodyweightinPatients(pts)WithUnresectableHepatocellularCarcinoma(uHCC)inREFLECT.ASCO-GI2019.PosterNo.316體重≥60mg（侖伐替尼12mg）侖伐替尼不同起始劑量亞組,與索拉非尼組間PFS具有可比性體重＜60mg（侖伐替尼8mg）體重≥60mg（侖伐替尼12mg）TakujiOkusaka,etal.SafetyandEfficacyofLenvatinibbyStartingDoseBasedonBodyweightinPatients(pts)WithUnresectableHepatocellularCarcinoma(uHCC)inREFLECT.ASCO-GI2019.PosterNo.316TakujiOkusaka,etal.SafetyandEfficacyofLenvatinibbyStartingDoseBasedonBodyweightinPatients(pts)WithUnresectableHepatocellularCarcinoma(uHCC)inREFLECT.ASCO-GI2019.PosterNo.316ORR在侖伐替尼不同起始劑量亞組間相似不同亞組和索拉非尼組OR具有可比性侖伐替尼8mg/d亞組vs索拉非尼組的ORR為:22.2%vs8.2%（OR=3.16；95%CI:1.56–6.41）侖伐替尼12mg/d亞組vs侖伐替尼組的ORR為:24.9%vs9.7%（OR=3.11；95%CI:2.00–4.85）侖伐替尼不同起始劑量亞組AE總體相似Study

202REFLECT侖伐替尼

12

mg(N=46)侖伐替尼<60

kg8

mg(n=151)侖伐替尼≥60

kg12

mg(n=325)索拉非尼(n=475)任何治療期不良事件治療相關(guān)46

(100.0)44

(95.7)151

(100.0)143

(94.7)319

(98.2)304

(93.5)472

(99.4)452

(95.2)任何治療期不良事件≥3治療相關(guān)45

(97.8)40

(87.0)100

(66.2)70

(46.4)257

(79.1)200

(61.5)316

(66.5)231

(48.6)任何嚴(yán)重不良事件治療相關(guān)嚴(yán)重不良事件22

(47.8)14

(30.4)58

(38.4)20

(13.2)147

(45.2)64

(19.7)144

(30.3)48

(10.1)與治療相關(guān)的不良事件導(dǎo)致患者:停藥減量藥物減量或中斷10

(21.7)32

(69.6)N/A16

(10.6)42

(27.8)65

(43.0)26

(8.0)134

(41.2)187

(57.5)34

(7.2)181

(38.1)236

(49.7)TakujiOkusaka,etal.SafetyandEfficacyofLenvatinibbyStartingDoseBasedonBodyweightinPatients(pts)WithUnresectableHepatocellularCarcinoma(uHCC)inREFLECT.ASCO-GI2019.PosterNo.316IkedaKetal.JGastroenterol.2017;52:512-519.EisaiInc.Dataonfile(Study202CSR).TakujiOkusaka,etal.SafetyandEfficacyofLenvatinibbyStartingDoseBasedonBodyweightinPatients(pts)WithUnresectableHepatocellularCarcinoma(uHCC)inREFLECT.ASCO-GI2019.PosterNo.316侖伐替尼不同起始劑量亞組AE譜及AE發(fā)生率相似首選術(shù)語(yǔ),n(%)侖伐替尼8

mg(<60

kg)(n=151)侖伐替尼12

mg(≥60

kg)(n=325)任何治療期不良事件151

(100.0)319

(98.2)高血壓65

(43.0)136

(41.8)腹瀉53

(35.1)131

(40.3)食欲不振50

(33.1)112

(34.5)體重下降43

(28.5)104

(32.0)疲勞42

(27.8)99

(30.5)手足綜合征35

(23.2)93

(28.6)蛋白尿37

(24.5)80

(24.6)發(fā)聲困難28

(18.5)85

(26.2)惡心24

(15.9)69

(21.2)侖伐替尼不同起始劑量對(duì)肝功能影響評(píng)估肝功能至Child-Pugh≥7分所需時(shí)間基線5分的患者侖伐替尼8mg/12mg劑量組、索拉非尼組,中位時(shí)間未達(dá)到基線6分的患者侖伐替尼8mg劑量組中位時(shí)間與索拉非尼組相似,長(zhǎng)于侖伐替尼12mg劑量組TakujiOkusaka,etal.SafetyandEfficacyofLenvatinibbyStartingDoseBasedonBodyweightinPatients(pts)WithUnresectableHepatocellularCarcinoma(uHCC)inREFLECT.ASCO-GI2019.PosterNo.316TakujiOkusaka,etal.SafetyandEfficacyofLenvatinibbyStartingDoseBasedonBodyweightinPatients(pts)WithUnresectableHepatocellularCarcinoma(uHCC)inREFLECT.ASCO-GI2019.PosterNo.316根據(jù)治療周期調(diào)整后,侖伐替尼不同起始劑量亞組AE譜及AE發(fā)生率相似首選術(shù)語(yǔ),n(不良反應(yīng)率)侖伐替尼8

mg(n=151)總持續(xù)時(shí)間=95.1年侖伐替尼12

mg(n=325)總持續(xù)時(shí)間=229.1年任何治療期不良事件18.2619.15高血壓0.790.78腹瀉1.060.99食欲不振0.630.59體重下降0.500.51疲勞0.520.47手足綜合征0.380.46蛋白尿0.560.48發(fā)聲困難0.300.45相同的用藥時(shí)間（年）,侖伐替尼不同起始劑量亞組AE譜及AE發(fā)生率相似TakujiOkusaka,etal.SafetyandEfficacyofLenvatinibbyStartingDoseBasedonBodyweightinPatients(pts)WithUnresectableHepatocellularCarcinoma(uHCC)inREFLECT.ASCO-GI2019.PosterNo.316結(jié)論不同侖伐替尼起始劑量亞組與索拉非尼組的有效性具有可比性。根據(jù)治療周期調(diào)整AE發(fā)生率后,不同起始劑量侖伐替尼亞組的AE譜及AE發(fā)生率相似。 以上REFLECT研究結(jié)果支持侖伐替尼一線治療8mg/d用于＜60kg、12mg/d用于≥60kg的uHCC患者。侖伐替尼治療肝細(xì)胞癌研究中不良事件與總生存之間關(guān)系的探究（REFLECT）MaxSung1,RichardS.Finn2,ShukuiQin3,Kwang-HyubHan4,KenjiIkeda5,Ann-LiiCheng6,MasatoshiKudo7,RyosukeTateishi8,MasafumiIkeda9,ValeryBreder10,Kun-MingRau11,YukTingMa12,AngelAlsina13,Baek-YeolRyoo14,ZhenggangRen15,KalgiMody16,CorinaDutcus16,ToshiyukiTamai17,KenichiSaito16,FabioPiscaglia181TischCancerInstituteatMountSinai,NewYork,USA;2GeffenSchoolofMedicine,UCLAMedicalCenter,SantaMonica,CA,USA;3NanjingBayiHospital,Nanjing,Jiangsu,China;4SeveranceHospital,YonseiUniversity,Seoul,Korea;5ToranomonHospital,Tokyo,Japan;6NationalTaiwanUniversityHospitalandNationalTaiwanUniversityCancerCenter,Taipei,Taiwan;7KindaiUniversityFacultyofMedicine,Osaka,Japan;8TheUniversityofTokyoHospital,Tokyo,Japan;9NationalCancerCenterHospitalEast,Chiba,Japan;10NationalMedicalResearchCenterofOncologyn,a,N.N.Blokhin,Russia;11E-DAHospital,Kaohsiung,Taiwan;12QueenElizabethHospital,Birmingham,England,UK;13TampaGeneralHospital,Tampa,FL,USA;14AsanMedicalCenter,UniversityofUlsanCollegeofMedicine,Seoul,RepublicofKorea;15ZhongshanHospitalFudanUniversity,Shanghai,China;16EisaiInc.,WoodcliffLake,NJ,USA;17EisaiCo.,Ltd,Tokyo,Japan;18UniversityofBologna,Bologna,Italy背景與目的既往有多個(gè)關(guān)于不良事件與治療藥物療效之間相關(guān)性的報(bào)道:-皮膚毒性反應(yīng)是一種表皮生長(zhǎng)因子抑制劑的常見不良事件，與臨床療效呈正相關(guān)；-有研究表明，索拉非尼不論用于轉(zhuǎn)移性腎癌還是肝癌，患者中出現(xiàn)手足綜合征者其臨床療效也明顯好于未出現(xiàn)該不良反應(yīng)者；-有研究顯示，在瑞戈非尼治療的肝癌患者中，手足綜合征與OS改善有關(guān)。本研究旨在探索侖伐替尼相關(guān)的不良事件與OS之間的相關(guān)性經(jīng)侖伐替尼治療的uHCC患者出現(xiàn)/未出現(xiàn)高血壓、腹瀉、蛋白尿或甲狀腺功能減退與OS顯著相關(guān)高血壓腹瀉蛋白尿甲狀腺功能減退出現(xiàn)上述不良事件的患者OS顯著長(zhǎng)于未出現(xiàn)者出現(xiàn)/未出現(xiàn)發(fā)聲困難患者間OS無(wú)顯著差異結(jié)論高血壓、腹瀉、蛋白尿或甲狀腺功能減退可作為侖伐替尼臨床獲益的有效預(yù)測(cè)指標(biāo) 接受侖伐替尼治療后的uHCC患者,出現(xiàn)高血壓、腹瀉、蛋白尿或甲狀腺功能減退的患者其OS顯著長(zhǎng)于未出現(xiàn)上述不良事件者侖伐替尼治療不可切除肝細(xì)胞癌III期研究（REFLECT）事后分析:一線侖伐替尼治療后的后續(xù)抗癌治療AngelAlsina1,MasatoshiKudo2,ArndtVogel3,Ann-LiiCheng4,WonYoungTak5,Baek-YeolRyoo6,TRJeffryEvans7,CarlosLópezLópez8,BrunoDaniele9,SoamnauthMisir10,MinRen10,NamikiIzumi11,ShukuiQin12,RichardS.Finn131TampaGeneralHospital,Tampa,FL,USA;2KindaiUniversityFacultyofMedicine,Osaka,Japan;3HannoverMedicalSchool,Hannover,Germany;4NationalTaiwanUniversityHospitalandNationalTaiwanUniversityCancerCenter,Taipei,Taiwan;5SchoolofMedicine,KyungpookNationalUniversity,Daegu,RepublicofKorea;6AsanMedicalCenter,UniversityofUlsanCollegeofMedicine,Seoul,RepublicofKorea;7UniversityofGlasgow,BeatsonWestofScotlandCancerCentre,Glasgow,UK;8MarquésdeValdecillaUniversityHospital,Santander,Spain;9OspedaledelMare,Napoli,Italy,10EisaiInc.,WoodcliffLake,NJ,USA;11MusashinoRedCrossHospital,Musashino,Tokyo,Japan;12NanjingBayiHospital,Nanjing,Jiangsu,China;13GeffenSchoolofMedicine,UCLAMedicalCenter,SantaMonica,CA,USAKudoM,et,al.Subsequentanticancermedicationfollowingfirst-linelenvatinib:Aposthocresponderanalysisfromthephase3REFLECTstudyinunresectablehepatocellularcarcinoma.ASCO-GI2019.PosterNo.371背景和目的 侖伐替尼是十多年來(lái)首個(gè)批準(zhǔn)用于不可切除HCC的一線治療藥物。其關(guān)鍵Ⅲ期REFLECT研究達(dá)到主要終點(diǎn)，侖伐替尼相比索拉非尼治療的總生存（OS）在統(tǒng)計(jì)學(xué)上具有非劣效性（中位OS:13.6個(gè)月vs.12.3個(gè)月；風(fēng)險(xiǎn)比[HR]:0.92；95%置信度區(qū)間[CI]:0.79-1.06）。在次要終點(diǎn)無(wú)進(jìn)展生存、至疾病進(jìn)展時(shí)間、客觀緩解率（ORR）方面，侖伐替尼顯著優(yōu)于索拉非尼。 一線和后續(xù)治療中新治療選擇的出現(xiàn)改變了不可切除肝癌的治療模式，這對(duì)藥物的合理選擇以及抗癌治療時(shí)間及順序等相關(guān)問(wèn)題帶來(lái)了挑戰(zhàn)。 該事后分析評(píng)估REFLECT研究中，侖伐替尼組和索拉非尼組接受后續(xù)抗癌治療的患者的OS；以及對(duì)侖伐替尼或索拉非尼有應(yīng)答的患者后續(xù)接受抗癌治療的情況。KudoM,et,al.Subsequentanticancermedicationfollowingfirst-linelenvatinib:Aposthocresponderanalysisfromthephase3REFLECTstudyinunresectablehepatocellularcarcinoma.ASCO-GI2019.PosterNo.371結(jié)果-約1/3患者接受后續(xù)抗癌藥物治療在生存隨訪期間,侖伐替尼組和索拉非尼組中分別有33%和39%的患者接受了后續(xù)抗癌藥物治療藥物治療,n(%)侖伐替尼(n=478)索拉非尼(n=476)在生存隨訪期間接受抗癌藥物治療的患者156

(32.6)184

(38.7)索拉非尼121

(25.3)56

(11.8)氟尿嘧啶20

(4.2)26

(5.5)順鉑18

(3.8)23

(4.8)研究藥物15

(3.1)45

(9.5)奧沙利鉑14

(2.9)22

(4.6)多柔比星7

(1.5)19

(4.0)卡培他濱7

(1.5)11

(2.3)吉西他濱7

(1.5)14

(2.9)卡博替尼0

(0)11

(2.3)對(duì)于一線接受侖伐替尼治療的患者,索拉非尼是最常見的后續(xù)抗癌治療藥物,25%的患者在生存隨訪期間接受了索拉非尼治療。而索拉非尼組有12%的患者在生存隨訪期間重新開始或繼續(xù)使用索拉非尼。侖伐替尼組有3%患者接受了其他在研抗癌藥物治療,而索拉非尼組為10%。使用侖伐替尼治療的患者后續(xù)接受在研藥物治療的機(jī)會(huì)有限,因?yàn)橥ǔ６€治療的臨床試驗(yàn)（如瑞戈非尼或卡博替尼）要求受試者一線索拉非尼治療失敗。KudoM,et,al.Subsequentanticancermedicationfollowingfirst-linelenvatinib:Aposthocresponderanalysisfromthephase3REFLECTstudyinunresectablehepatocellularcarcinoma.ASCO-GI2019.PosterNo.371治療中止時(shí),侖伐替尼組和索拉非尼組患者狀態(tài)相似參數(shù)侖伐替尼索拉非尼亞太地區(qū)(N=308)西方

(N=143)亞太地區(qū)(N=304)西方

(N=147)ECOG

PS評(píng)分,n(%)

012≥

3120

(39.0)153

(49.7)22

(7.1)13

(4.2)45

(31.5)67

(46.9)20

(14.0)9

(6.3)135

(44.4)132

(43.4)23

(7.6)14

(4.6)54

(36.7)70

(47.6)16

(10.9)6

(4.1)肝功能分級(jí),n(%)

ABC233

(75.6)67

(21.8)8

(2.6)106

(74.1)30

(21.0)5

(3.5)235

(77.3)65

(21.4)4

(1.3)110

(74.8)34

(23.1)2

(1.4)ALT中位數(shù),U/L(范圍)a30.0

(3–390)42.0

(9–726)38.0

(6–1032)40.5

(13–1105)AST中位數(shù),U/L(范圍)a47.0

(14–470)65.0

(10–2501)59.0

(13–1211)58.5

(17–1065)ALP中位數(shù),U/L(范圍)a123.0

(25–885)166.0

(42–1857)130.5

(41–972)169.0

(28–1457)膽紅素中位數(shù),μmol/L(范圍)a12.1

(2–276)15.2

(3–643)12.2

(3–408)13.3

(3–153)白蛋白中位數(shù),

g/L(范圍)a38.0

(21–51)37.0

(19–51)38.0

(22–52)37.0

(19–49)aIn

the

western

region,

2

patients

from

the

lenvatinib

arm

and

1

patient

from

the

sorafenib

arm

had

no

data.ALP,

alkaline

phosphata