非小細(xì)胞肺癌精準(zhǔn)治療新進(jìn)展-關(guān)注腦轉(zhuǎn)移

非小細(xì)胞肺癌個(gè)體化治療新進(jìn)展

---關(guān)注腦轉(zhuǎn)移內(nèi)容ALK+NSCLC腦轉(zhuǎn)移的治療EGFR+NSCLC腦轉(zhuǎn)移的治療PROFILE1014腦轉(zhuǎn)移亞組分析：

克唑替尼一線治療與化療比較的顱內(nèi)療效分析KeyentrycriteriaALK-positivebycentralFISHtestingaLocallyadvanced,recurrent,ormetastaticnon-squamousNSCLCNopriorsystemictreatmentforadvanceddiseaseECOGPS0?2MeasurablediseaseStablebtreatedbrainmetastasesallowedEndpointsPrimaryPFS(RECIST1.1,independentradiologicreview[IRR])SecondaryORROSIntracranialTTPeSafetyPatient-reportedoutcomesCrossovertocrizotinib

permittedafterprogressiond

N=343R

A

N

D

O

M

I

Z

EcCrizotinib250mgBIDPO,

continuousdosing(n=172)Pemetrexed500mg/m2

+

cisplatin75mg/m2orcarboplatinAUC5–6q3wfor≤6cycles(n=171)Intracranialefficacywasprospectivelyevaluated

intheITTpopulationandpatientswithandwithoutbrainmetastasesatbaselineeBaselineCharacteristicsofPatientsWith/withoutBrainMetastasesatBaselineaCarc.,carcinoma;abyIRR;bpreviouslytreatedperprotocol,althoughthiscriterionwasnotfulfilledinallcasescAtscreening;datafor1patientmissingforcrizotinibBrainmetastasesbpresentBrainmetastasesabsentCharacteristicCrizotinib(n=39)Chemo

(n=40)Crizotinib(n=132)Chemo(n=131)Age,yearsMedian(range)48(29?70)51(25?76)53(22?76)56(19?78)Sex,n(%)Male 20(51) 9(23) 47(36) 54(41)Race,n(%)CaucasianAsianOther 20(51) 17(44) 2(5) 19(48) 18(45) 3(8) 70(53) 60(45) 2(2) 66(50) 62(47) 3(2)Smoking,n(%)NeversmokedEx-smokerCurrentsmoker 23(59) 13(33) 3(8) 28(70) 12(30) 0 83(63) 43(33) 6(5) 84(64) 42(32) 5(4)Histology,n(%)Adenocarc.Largecellcarc.Adenosquamouscarc.Other 35(90) 1(3) 2(5) 1(3) 38(95) 0 1(3) 1(3) 123(93) 2(2) 3(2) 4(3) 121(92) 8(6) 0 2(2)ECOGPS,cn(%)0/12 35(90) 4(10) 34(85) 6(15) 125(95) 6(5) 129(98) 2(2)Timesincefirstdiagnosis,moMedian(range)2.4

(0?36.0)2.4(1.2?74.4)1.2

(0?114.0)1.2

(0?93.6)AntitumorActivity?PFSandORRaaByIRRbAtbaselinecTwo-sidedlog-ranktest(ITTpopulation:stratified;patientsubgroupswith/withoutbaselinebrainmetastases:unstratified)dCrizotinibvs.chemotherapyeTwo-sidedPearsonχ2testITTpopulationBrainmetastasespresentbBrainmetastases

absentbCrizotinib

(N=172)Chemo

(N=171)Crizotinib

(n=39)Chemo

(n=40)Crizotinib

(n=132)Chemo

(n=131)MedianPFS,mo

(95%CI)10.9

(8.3–13.9)7.0

(6.8–8.2)9.0

(6.8–15.0)4.0

(1.5–6.8)11.1

(8.3–14.0)7.2

(6.9–8.3) HR

(95%CI)0.45

(0.35–0.60)0.40

(0.23–0.69)0.51

(0.38–0.69)

Pc<0.001<0.001<0.001ORR,% (95%exactCI)74(67?81)45(37?53)77(61?89)28(15?44)74(66?82)50(42?59) Differenced

(95%exactCI)29(20?39)49(30?69)24(13?35) Pe<0.001<0.001<0.001IntracranialDCRainPatientsWith

BrainMetastasesatBaselineDCR,diseasecontrolrate(%CR+PR+SD)aByIRR;btwo-sidedPearsonχ2test12weeks24weeksIntracranialDCR(95%exactCI;%)Difference:40%

(95%CI:21–59)

P<0.001bDifference:31%

(95%CI:11–52)

P=0.006b100806040200IntracranialTTPainITTPopulationCrizotinib(n=172)Chemotherapy(n=171)Events,n(%)25(15)26(15)Median,moNR17.8HR(95%CI)0.60(0.34?1.05)Pb0.069NR,notreachedaTimefromrandomizationtofirstdocumentationofintracranialtumorprogressionbyIRRbTwo-sidedlog-ranktestProbabilityofnoprogression(%)1008060402000510152025303517217111910765394014213811000CrizotinibChemotherapyNo.atriskTime(months)結(jié)論無(wú)論有無(wú)腦轉(zhuǎn)移，對(duì)于ALK陽(yáng)性NSCLC，克唑替尼一線治療優(yōu)于標(biāo)準(zhǔn)化療。-克唑替尼12周和24周DCR優(yōu)于化療-克唑替尼在顱內(nèi)TTP方面，顯示出數(shù)值上的優(yōu)勢(shì)

克唑替尼是ALK陽(yáng)性NSCLC的標(biāo)準(zhǔn)治療，包括腦轉(zhuǎn)移患者三代ALK/ROS1TKI：lorlatinib(PF-06463922)在晚期ALK/ROS1NSCLC中的療效和安全性O(shè)RRLorlatinib對(duì)ALKG1202R突變的療效

顱內(nèi)病灶的療效Lorlatinib在ALK+和ROS1+NSCLC中顯示出了抗腫瘤活性，尤其是這些患者大部分具有腦轉(zhuǎn)移及經(jīng)過(guò)≥1TKI治療顯著的腦轉(zhuǎn)移的抗腫瘤活性表明lorlatinib能夠透過(guò)血腦屏障，達(dá)到有效的抗腫瘤活性內(nèi)容ALK+NSCLC腦轉(zhuǎn)移的治療EGFR+NSCLC腦轉(zhuǎn)移的治療

ErlotinibcombinedwithchemotherapyversusErlotinibaloneinChineseadvancedlungadenocarcinomawithbrainmetastases:aprospective,non-randomizedcocurrentcontrolledstudy(NCT01578668)Haihong

Yang,

Yalei

Zhan,

Meilin

Zhao,

Xin

Xu,

Yubao

GuanThoracic

Oncology,

The

First

Affiliated

Hospital

of

Guangzhou

MedicalUniversity,

China中國(guó)腺癌腦轉(zhuǎn)移患者，厄洛替尼聯(lián)合化療還是單藥厄洛替尼？?lung

adenocarcinomawith

brain

metastases?treatedby

no

more

thanthree

regimens

includingtwo

chemotherapyregimen

or

gefitinib.?not

receivedpemetrexedor

erlotinib

before?N=693)

+

erlotinib

d4-20

every

21

days

up

to

6

cycles;

subsequent

oral

erlotinib

150

mg/day

until

progressive

disease

or

unacceptable

toxicity;

N=34

erlotinib

150

mg/day

until

progressivediseaseorPrimary

endpoint:intracranial

ORR

(ORRi)Secondary

endpoints:?ORR?intracranialPFS

(PFSi)?PFS;?OS;?safetyE-P

1:1

E

unacceptabletoxicity;

N=35*poor

PS

was

caused

by

neurological

symptoms

MINI

05：EGFR

Mutant

Lung

Cancer

1

–

Haihong

Yangnon-randomized

cocurrent

controlled

pemetrexed

500

mg/m2

d1

and

cisplatin

20

mg/m2

d1-3

(if

PS<2)

or

cisplatin

30

mg

d1-2

(if

PS*

2

or研究設(shè)計(jì)ORRi

(%)70605040302010

080100

90EEEEE-PP=0.06P=0.30

E-PAll

patientsEGFR

mutationunknownEGFR

wildP=0.008

E-PP=0.12

E-PMINI05：EGFRMutantLungCancer1–HaihongYang在全人群，無(wú)論EGFR突變狀態(tài)，聯(lián)合方案顱內(nèi)ORR均比單藥高。但，只有全人群和野生型EGFR人群，具有統(tǒng)計(jì)學(xué)意義主要研究終點(diǎn):顱內(nèi)ORR（ORRi）---

EmPFS

2

months,

n=16HR=0.35

95%CI

0.15-0.83

Systemic

PFS—

E-P

mPFS

8

months,

n=18

intracranial

PFS—

E-P

mPFS

9

months,

n=18---

E

mPFS

2

months,

n=16HR=0.32

95%CI

0.13-0.92P=0.02

P=0.01

PFS

(months)MINI

05：EGFR

Mutant

Lung

Cancer

1

–

Haihong

Yang一線治療人群，無(wú)論系統(tǒng)性還是顱內(nèi)PFS，聯(lián)合方案均比單藥延長(zhǎng)Patientstreatwith1st-lineregimenSystemic

PFS

—

E-P

mPFS

8

months,

n=7

---

E

mPFS

4

months,

n=8

P=0.12

intracranial

PFS—

E-P

mPFS

9

months,

n=7---

E

mPFS

5

months,

n=8

P=0.13

（months)MINI

05：EGFR

Mutant

Lung

Cancer

1

–

Haihong

Yang而在EGFR突變?nèi)巳?，無(wú)論系統(tǒng)性還是顱內(nèi)PFS，聯(lián)合方案均沒(méi)有比單藥獲益EGFRmutationpositivepatients

treatwith1st-lineregimenPatients

(N=69)E

arm

(N,

%)E-P

arm

(N,

%)P

valueGrade

1-2

haemothologic

toxcities000

0

1,

2.918,

52.9

1,

2.9

1,

2.9

Anemia

Neutrophil

count

decreased

Platelet

count

decreasedGrade

3

Neutrophil

count

decreasedGrade

2-3

non-haemothologic

toxcities0.140

0.017

食欲降低

Vomiting

皮疹Diarrhea胃炎甲溝炎AST/ALT

elevation

2,

5.7

1,

2.9

7,

20.01，2.9001，2.9

7,

20.6

1,

2.9

16,

47.1

2，5.91，2.93，8.81，2.9MINI

05：EGFR

Mutant

Lung

Cancer

1

–

Haihong

Yang不良反應(yīng)MINI05：EGFRMutantLungCancer1–HaihongYang對(duì)于腺癌患者，相比厄洛替尼單藥，厄洛替尼聯(lián)合化療（培美）能夠提供顱內(nèi)緩解率。厄洛替尼聯(lián)合化療一線治療延長(zhǎng)系統(tǒng)性和顱內(nèi)PFS。毒性可耐受，厄洛替尼相關(guān)的不良反應(yīng)更高。結(jié)論MINI10.13

AZD3759,治療非小細(xì)胞肺癌腦及腦膜轉(zhuǎn)移的EGFR抑制劑---人體藥代動(dòng)力學(xué)，有效劑量及中樞神經(jīng)系統(tǒng)穿透性數(shù)據(jù)KanChenetal.20