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)論無論有無腦轉(zhuǎn)移，對于ALK陽性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

克唑替尼是ALK陽性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≥1TKI治療顯著的腦轉(zhuǎn)移的抗腫瘤活性表明lorlatinib能夠透過血腦屏障，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，無論系統(tǒng)性還是顱內(nèi)PFS，聯(lián)合方案均比單藥延長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)巳海瑹o論系統(tǒng)性還是顱內(nèi)PFS，聯(lián)合方案均沒有比單藥獲益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