非小細胞肺癌精準治療新進展-關注腦轉移

非小細胞肺癌個體化治療新進展

---關注腦轉移內容ALK+NSCLC腦轉移的治療EGFR+NSCLC腦轉移的治療PROFILE1014腦轉移亞組分析：

克唑替尼一線治療與化療比較的顱內療效分析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)結論無論有無腦轉移，對于ALK陽性NSCLC，克唑替尼一線治療優(yōu)于標準化療。-克唑替尼12周和24周DCR優(yōu)于化療-克唑替尼在顱內TTP方面，顯示出數值上的優(yōu)勢

克唑替尼是ALK陽性NSCLC的標準治療，包括腦轉移患者三代ALK/ROS1TKI：lorlatinib(PF-06463922)在晚期ALK/ROS1NSCLC中的療效和安全性ORRLorlatinib對ALKG1202R突變的療效

顱內病灶的療效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移及經過≥1TKI治療顯著的腦轉移的抗腫瘤活性表明lorlatinib能夠透過血腦屏障，達到有效的抗腫瘤活性內容ALK+NSCLC腦轉移的治療EGFR+NSCLC腦轉移的治療

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研究設計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ORR均比單藥高。但，只有全人群和野生型EGFR人群，具有統(tǒng)計學意義主要研究終點:顱內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突變人群，無論系統(tǒng)性還是顱內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PFS。毒性可耐受，厄洛替尼相關的不良反應更高。結論MINI10.13

AZD3759,治療非小細胞肺癌腦及腦膜轉移的EGFR抑制劑---人體藥代動力學，有效劑量及中樞神經系統(tǒng)穿透性數據KanChenetal.20