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PEMETREXED AS FIRSTPEMETREXED AS FIRST

LINE CHEMOTHERAPYLINE CHEMOTHERAPYFOR NSCLCFOR NSCLC

SURYANTI DWI PRATIWISURYANTI DWI PRATIWI

LAB/SMF PARU RSSAMALANG

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What is PemetrexedWhat is Pemetrexed

PEMETREXED is a novel multi-tarete! Anti-"olat in t#ePEMETREXED is a novel multi-tarete! Anti-"olat in t#e

treatment o" Non-Small Cell Lun Can$er t#at in#i%its &treatment o" Non-Small Cell Lun Can$er t#at in#i%its &

T#'mi!'late s'nt#ase (TS)T#'mi!'late s'nt#ase (TS)

Di#'!ro"olate re!u$tase (DHFR)Di#'!ro"olate re!u$tase (DHFR)

*l'$inami!e ri%onu$leoti!e "orm'ltrans"erase (*ARFT)*l'$inami!e ri%onu$leoti!e "orm'ltrans"erase (*ARFT)

Pemetre+e! #as a #i# %in!in a,nit' to "olat re$etor-Pemetre+e! #as a #i# %in!in a,nit' to "olat re$etor-

..// an! on$e in t#e $ell. it rai!l' $onverts to a$tivean! on$e in t#e $ell. it rai!l' $onverts to a$tive

ol'lutamate !erivativesol'lutamate !erivatives00

Pol'lutamation rolons its intra$ellular retention an!Pol'lutamation rolons its intra$ellular retention an!en#an$es emetre+e!1s intera$tion 2it#en#an$es emetre+e!1s intera$tion 2it# t#'mi!'late s'nt#aset#'mi!'late s'nt#ase

an! ot#eran! ot#er

"olate-!een!ent"olate-!een!ent

taret en3'mestaret en3'mes4.0-54.0-5

T#ese multile me$#anisms o" a$tion ma' e+lain #o2T#ese multile me$#anisms o" a$tion ma' e+lain #o2emetre+e!. $omare! 2it# ot#er antimeta%olites su$# as 5-emetre+e!. $omare! 2it# ot#er antimeta%olites su$# as 5-6uoroura$il. met#otre+ate. or raltitre+e!. #as s#o2n reater6uoroura$il. met#otre+ate. or raltitre+e!. #as s#o2n reateroten$' an! a %roa!er se$trum o" antitumor a$tivit'oten$' an! a %roa!er se$trum o" antitumor a$tivit'4.74.7

22

1. Shih ! et a". Ad# $%&'me Re()". 1**+,-+1-012.2. ha R! et a". "i% a%3er Res. 2444,5-5+60-5*.-. hatt7adh'a' S! et a". M" a%3er Ther. 2446,584808

4. Mendelsohn et al. Semin Oncol 1999;26(2 Suppl 6):42-7.5. a!lo" et al. # Med $hem 1992;%5(2%):445&-4.

6. $hen et al. '" # $ance" 199;7(Suppl %):27-%4.

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NHO

HO2C

CO2H

NH

N

NH

O

NH2

Pemetrexed 9A"imta:Pemetrexed 9A"imta:hemi3a" Str)3t)rehemi3a" Str)3t)re

N0;80;20920ami%08!60dih'dr080x01

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Pemetrexed ?e' I%tra3e"")"ar F"ate $%&'mePemetrexed ?e' I%tra3e"")"ar F"ate $%&'me Tar(ets Tar(ets

• TS: thymidylate synthase, 5-FU: 5-fluorouracil, GARFT: glycinamide ribonucleotide formyl transferase, !FR: dihydrofolate reductase, "A: deo#yribonucleic acid, R"A: ribonucleic acidTS: thymidylate synthase, 5-FU: 5-fluorouracil, GARFT: glycinamide ribonucleotide formyl transferase, !FR: dihydrofolate reductase, "A: deo#yribonucleic acid, R"A: ribonucleic acid

Kindler. Cancer 2002;95(4 Suppl):928-32.Kindler. Cancer 2002;95(4 Suppl):928-32.

5-F8. raltitre+e!Pemetre+e!

Met#otre+ate

!8MP !TMP

49-CHO-THF DHF

THF

*AR

"*AR

PRPP

AMP. *MP DNA. RNA

DNA

NADPH

NADP:

TS

TS

*ARF

T

*ARF

TDHFR

DHFR

5.49-CH/-THF

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GARFT RNA @DNAS'%thesis

AMP

GMP

D

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I%di3ati% C A"imtaI%di3ati% C A"imta

11stst "i%e Ad#a%3ed NSL! %% s)am)s t'7e"i%e Ad#a%3ed NSL! %% s)am)s t'7e m>i%ati% A"imta is7"ati%m>i%ati% A"imta is7"ati%

22%d%d "i%e Ad#a%3ed NSL! %% s)am)s t'7e"i%e Ad#a%3ed NSL! %% s)am)s t'7e

M%thera7' A"imtaM%thera7' A"imta SEit3h Mai%te%a%3e NSLSEit3h Mai%te%a%3e NSL

M%thera7' A"imtaM%thera7' A"imta

11stst "i%e Ma"i(%a%t P"e)ra" Mesthe"ima 9 MPM :"i%e Ma"i(%a%t P"e)ra" Mesthe"ima 9 MPM :

m>i%ati% A"imta is7"ati%m>i%ati% A"imta is7"ati%

55

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A!van$e!-Stae NSCLC an! PS 9-4

EF*R mutation an! AL;neative an!

nonsa77r7riate

Be#a3i&)ma>i%a77r7riate

E*FRmutationositive

$r"ti%i> r(eti%i>rst "i%e

%sider3ri&ti%i>

rst r se3%d"i%e

ELM=-AL;ositive

Ada7ted Crm Ga%dara DR! et a". "i% L)%( a%3er. 244*,14-*20-*8Ada7ted Crm Ga%dara DR! et a". "i% L)%( a%3er. 244*,14-*20-*8..

Pr7sed Treatme%t A"(rithm CrPr7sed Treatme%t A"(rithm Cr

Ad#a%3ed NSL First0"i%e Thera7'Ad#a%3ed NSL First0"i%e Thera7'

24122412

%sider3ar>7"ati%/7a3"itaxe" >e#a3i&)ma>

r3is7"ati%/emetre+

e! Be#a3i&)ma>

%sider3is7"ati% r3ar>7"ati%

3m>i%ed Eithd3etaxe" r

(em3ita>i%e r7a3"itaxe"

r3is7"ati%/#i%re">i

%e 3et)xima>


3m>i%ed Eithemetre+e!.d3etaxe" r


r3is7"ati%/#i%re">i%e

3et)xima>

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Mole$ular

A!van$e!-Stae NSCLC > PS 9-4

EF*R mutation an! AL;neative an!

nons a77r7riate

Be#a3i&)ma>i%a77r7riate

E*FRmutationositive

$r"ti%i> r(eti%i>rst "i%e

%sider3ri&ti%i>

rst r se3%d"i%e

ELM=-AL;ositive

U7dated Crm Ga%dara DR! et a". "i% L)%( a%3er. 244*,14-*20-*8.

Pr7sed Treatme%t A"(rithm CrPr7sed Treatme%t A"(rithm Cr

Ad#a%3ed NSL First0"i%eAd#a%3ed NSL First0"i%e

Thera7' 2412 Thera7' 2412

%sider3ar>7"ati%/7a3"itaxe" >e#a3i&)ma>

r3is7"ati%/7emetrexe

d >e#a3i&)ma>


3m>i%ed Eithd3etaxe" r


r3is7"ati%/#i%re">i

%e 3et)xima>


3m>i%ed Eithemetre+e!.d3etaxe" r


r3is7"ati%/#i%re">i%e

3et)xima>

Histolo'& Clini$al

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T The De#e"7me%t Che De#e"7me%t CPemetrexedPemetrexed

Pemetrexed has shE% a3ti#it' i% NSL

– Si%("e a(e%t 1st a%d 2%d0"i%e

– m>i%ati% Eith 7"ati%)m a(e%ts i% 1st0"i%e

SaCet' C A"imta has >ee% Ee"" 3hara3teri&ed – Txi3it' si(%i3a%t"' red)3ed aCter F"i3 A3id / B12

– Her' "E i%3ide%3e C %e)tr7e%ia! Ce>ri"e %e)tr7e%ia!

a%d ther %%0hemat"(i3 txi3ities

A 7i#ta" Phase III st)d' i% the treatme%t C 2%d0"i%e

NSL Eas i%di3ated

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Pemetrexed SaCet' Pr"ePemetrexed SaCet' Pr"e

As Eith mst a%tiC"ates! the 7rimar' txi3it' is

hemat"(i3

$ar"' data shEed that hi(h ser)m

hm3'stei%e

"e#e"s a s)rr(ate Cr C)%3ti%a" C"ate a%d/r

B12

de3ie%3' 3rre"ated Eith hi(her "e#e"s C

txi3it'

A de3isi% Eas made t s)77"eme%t a"" 7atie%ts

Eith

C"i3 a3id a%d #itami% B12

This res)"ted i% de3reased txi3it' Eith %

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Hitami% S)77"eme%tati% a%d Premedi3ati%Hitami% S)77"eme%tati% a%d Premedi3ati%

Cr Pemetrexed Admi%istrati%Cr Pemetrexed Admi%istrati%

m7a%' %de%tia"m7a%' %de%tia"7'ri(ht 2445 $"i Li""' a%d m7a%'7'ri(ht 2445 $"i Li""' a%d m7a%'1818

Foli$ a$i! (On$e !ail')& 4.-01m( tae% 1 Eee >eCre treatme%t a%d 3%ti%)ed )%ti" 21 da's C "ast dse

De+amet#asone (t2i$e !ail')& 8m( tae% tEi3e dai"' the da' >eCre! da' C a%d da' aCter treatme%t

?itamin @4/ (IM)& 1m( tae% 1 Eee >eCre treatme%t a%d re7eated e#er' * Eees. S)>se)e%t i%e3ti%s ma' >e (i#e%

% the same da' as 7emetrexed

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OMDB Lar(est e#er 3"i%i3a" tria" 3%d)3ted OMDB Lar(est e#er 3"i%i3a" tria" 3%d)3ted

i% 1i% 1stst "i%e NSL"i%e NSL 9N1!62:9N1!62:

2121S$aliotti. * ? et al B Clin On$ol /99 /7&05=0-0554

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OMDB

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OMDB A"imta/is7"ati% shEs s)7erir OMDB A"imta/is7"ati% shEs s)7erir

s)r#i#a" i%s)r#i#a" i% ade%3ar3i%maade%3ar3i%ma

hist"('hist"(' 9N+86:9N+86:

2-2-S$aliotti. * ? et al B Clin On$ol /99 /7&05=0-0554

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OMDB A"imta/is7"ati% shEs s)7erir s)r#i#a" OMDB A"imta/is7"ati% shEs s)7erir s)r#i#a"

i% "ar(e 3e"" 3ar3i%ma hist"(' 9N1-:i% "ar(e 3e"" 3ar3i%ma hist"(' 9N1-:


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Median PFS, mos Median OS, mos

Pemetrexed plus Cisplatin versus Gemcitabine plus Cisplatin

Pem/Cis Gem/Cis p-value Pem/Cis Gem/Cis p-valueNonsuamous

N!"2#2 #$% #$& &$%'( ""$& "&$" &$&""

SuamousN!')%

'$' #$# &$&&2 ($' "&$* &$&

Pemetrexed vs Placebo+

Pem Placebo p-value Pem Placebo p-valueNonsuamous

N!'*2'$' "$* &$&&&&" "'$' ($' &$&

Suamous

N!"*"2$' 2$# &$*( ($ ""$( &$2%"

.icac0 b0 Histolo10.icac0 b0 Histolo10

PFS !ata in!een!entl' revie2e! (N=09 nons

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OMDB $ast Asia% 7atie%ts Eith %%0s)am)s OMDB $ast Asia% 7atie%ts Eith %%0s)am)s

hist"(' s)r#i#e "%(er Eith A"imta/is7"ati%hist"(' s)r#i#e "%(er Eith A"imta/is7"ati%

2525Orlan!o M et al B Clin On$ol /G&45s. /99 (sul a%str9=5)

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OMDB A"imta/is7"ati% Jers si(%i3a%t OMDB A"imta/is7"ati% Jers si(%i3a%t

saCet' ad#a%ta(es i% 1saCet' ad#a%ta(es i% 1stst "i%e NSL"i%e NSL


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OMDB A"imta/is7"ati% Jers si(%i3a%t OMDB A"imta/is7"ati% Jers si(%i3a%t

saCet' ad#a%ta(es i% 1saCet' ad#a%ta(es i% 1stst "i%e NSL"i%e NSL

2+2+S$aliotti. * ? et al B Clin On$ol /99 /7&05=0-0554

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OMDB A"imta/is7"ati% %eeds OMDB A"imta/is7"ati% %eeds

"ess tra%sC)si%/s)77rti#e 3are"ess tra%sC)si%/s)77rti#e 3are

2*2*S$aliotti. * ? et al B Clin On$ol /99 /7&05=0-0554

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L)%( a%3er Thera7' 2412L)%( a%3er Thera7' 2412

Li%( FrEard t 241Li%( FrEard t 241

We are mai%( 7r(ressWe are mai%( 7r(ress $

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Evolution From Emiri$ toEvolution From Emiri$ to

Personali3e! T#era' inPersonali3e! T#era' in

NSCLCNSCLCFa$tors Aent Ae$te!

Clini$al

Asia%! %e#er0smer! Cema"e $r"ti%i>! (eti%i>

U%treated NS metastases! %hem7t'sis! )%3%tr""ed

h'7erte%si%Be#a3i&)ma>

Histoloi$

Ade%3ar3i%ma $r"ti%i>! (eti%i>

Nons!

7emetrexed

Th'mid'"ate s'%thase Pemetrexed

Mole$ular

EGFR m)tati% $r"ti%i>! (eti%i>

$R1/RRM1 P"ati%)m

RRM1 Gem3ita>i%e

KRAS m)tati% $r"ti%i>! (eti%i>

$GFR >' FIS< $r"ti%i> Geti%i>

$GFR >' I$ML80AL? C)si% ri&ti%i>

Ada7ted Crm Ga%dara DR!

et a". "i% L)%( a%3er.244*,1418+014.

-2-2

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T

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