enhanced efficacy with iressa (ahmad hudoyo)

7/21/2019 Enhanced Efficacy With Iressa (Ahmad Hudoyo)

1/49

Enhanced Efficacy ofGefitinib for NSCLC in

AsiansAhmad Hudoyo


2/49

Treatment Goals and 2 nd LineTreatment for Advanced NSCLC

Longer life Increasing overall survival !S"

#etter life Sym$tom im$rovement %rolonging $rogression free survival %&S" 'educed to(icity Im$roved )uality of life *oL"

Second+line treatment is an im$ortant issue ,ithlimited outcomes of current -st+line thera$y.


3/49

Gefitinib vs Ta(otere as 2nd line treatment for advanced NSCLC

INTE'EST / a global study of -011 $atients/ demonstratednon+inferiority of gefitinib relative to doceta(el in terms ofoverall survival ha ard ratio 3H'4 -.525/ 617 confidenceinterval 3CI4 5.658+-.-859 median survival :.1 vs ;.5 months"/,ith gefitinib having a more favorable tolerability and )ualityof life $rofile.

ISTANA conducted in


4/49

Gefitinib I'ESSA" versus doceta(el in$atients ,ith locally advanced or metastatic

non+small cell lung cancer $re+treated ,ith$latinum+based chemothera$y=a randomi ed/ o$en+label %hase III study

INTE'EST"

:2= -;56/ 255;


5/49

INTE'EST Study ?esign

Aged -; years

Life e($ectancy ; ,ee@s

%rogressive or recurrent

disease follo,ing

chemothera$y CT"

Considered candidates for

further CT ,ith doceta(el

- or 2 CT regimens -

$latinum"

%erformance status 5+2

%rimary Co+$rimary analyses of !verall survival !S"

non+inferiority in all $atientsand su$eriority in $atients,ith high EG&' gene co$ynumber"

Secondary %rogression+free survival

%&S" !b ective res$onse rate *uality of life ?isease+related sym$toms Safety and tolerability

I'ESSA

285 mgBday

?oceta(el

:8 mgBm > every> ,ee@s

%atients End$oints

-=- randomisation

:2= -;56/ 255;


6/49

'ecruitment by geogra$hical region

SA and Canada -87

Asia China/ Hong


7/49

?oceta(el

Gefitinib

%ost+discontinuation treatmentsITT $o$ulation"

Nothing a$art from further EG&' T


8/49

!verall survival

:2>86> ;2.57"

:-58:1 ;-.-7"

NEvents

%rimary Co( analysis ,ithout covariates

H' 617 CI" -.525 5.658/ -.-85 "

Dedian !S months"-+year survival

:.1>27

;.5>07

Gefitinib ?oceta(el

Conclude non+inferiorityin the overall %% $o$ulation

:2> >>1 228 ->- ;> 85 >- -0 5 5:-5 >>6 22; ->6 ;6 01 20 : 5 5

8-;85>

5 0 ; -2 -1 25 20 2; >2 >1 05

5.5

5.2

5.0

5.1

5.;

-.5

Donths

%

r o b a

b i l i t y o

f s u r v

i v a

l

At ris@ =Gefitinib?oceta(el

The study met its $rimary ob ective of demonstrating non+inferiority of gefitinib relative todoceta(el in terms of overall survival


9/49

!b ective tumour res$onse rate via 'ECIST"

Gefitinib ,as similar to doceta(el in terms of !b ective 'es$onse 'ate

!' 687 CI" -.22 5.;2/ -.;0"$ 5.>28:

7 $

a t i e n

t s r e s $ o n

d i n g

n 186 n 18:


10/49

At ris@ =Gefitinib 186 :: >0 -; 6 8 > 5 5 5?oceta(el 18: 02 -1 0 2 - 5 5 5 5

-6025;

% r o

b a

b i l i t y o

f $ r o g r e s s i o n +

f r e e s u r v

i v a

l

5 0 ; -2 -1 25 20 2; >2 >1 05

5.5

5.2

5.0

5.1

5.;

-.5

Donths

%rogression+free survival

F H' - im$lies a lo,er ris@ of $rogression on gefitinib

H' 687 CI" -.50 5.6>/ -.-;"/ $ 5.018;

NEvents

Co( analysis ,ith covariates

Dedian %&S months"0 months1 months

18686> 65.57"

18:800 ;2.;7"

2.2>27-67

2.:>;7-;7

Gefitinib ?oceta(el

Gefitinib ,as similar to doceta(el in terms of %rogression &ree Survival

PROGRESSION FREE

PROGRESSION FREE


11/49

!S by smo@ing historyNever+smo@er

% r o

b a

b i l i t y o

f s u r v

i v a

l Gefitinib

?oceta(el

Ever+smo@er

% r o

b a

b i l i t y o

f s u r v

i v a

l

Gefitinib?oceta(el

At ris@=

-0;-0>

->5--6

----5-

;-::

8-82

>0>8

-6-:

->:

>-

55

55

8:881:

>;;>;0

2282>;

-00-8-

;5;:

0680

>-26

-;-:

--1

55

55

Gefitinib

?oceta(el

N

Events

Dedian mo"

Gefitinib

8:8

060

1.0

?oceta(el

81:

0:;

1.6

H' 687 CI" -.58 5.6>/ -.-6" $ 5.022-

N

Events

Dedian mo"

Gefitinib

-0;

66

-0.-

?oceta(el

-0>

6;

->.6

H' 687 CI" 5.6> 5.:5/ -.2>" $ 5.122:

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

Donths

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

Donths


12/49

!S by gender &emale Dale

% r o

b a

b i l i t y o

f s u r v

i v a

l

efitiniboceta(el

At ris@=2102>1

25;-;>

-1>->8

--160

1:8;

01>;

2022

->--

80

55

55

0860:0

>-5>25

-:>250

-56->0

10;-

>:8-

2120

-;->

6>

55

55

Gefitinib?oceta(el

N

Events

Dedian mo"

Gefitinib

086

>65

1.-

?oceta(el

0:0

>6:

:.5

H' 687 CI" -.56 5.68/ -.28" $ 5.2>18

N

Events

Dedian mo"

Gefitinib

210

25>

--.2

?oceta(el

2>1

-:6

-5.5

H' 687 CI" 5.68 5.:;/ -.-:" $ 5.1822

% r o

b a

b i l i t y o

f s u r v

i v a

l

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

Donths

Gefitinib?oceta(el

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

Donths


13/49

!S by histology Non+adenocarcinomaAdenocarcinoma

% r o

b a

b i l i t y o

f s u r v

i v a

l

Gefitinib?oceta(el

05;050

>5>268

2->2-0

-85-06

6;60

8;12

>8>2

2>-:

;0

55

55

At ris@=

% r o

b a

b i l i t y o

f s u r v

i v a

l

>-8>51

2-825;

-2>-28

:8:6

>>08

282:

-8-0

;:

1>

55

55

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >105

Donths

Gefitinib?oceta(el

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

Donths

Gefitinib?oceta(el

N

Events

Dedian mo"

Gefitinib

>-8

2:0

1.0

?oceta(el

>51

286

1.6

H' 687 CI" -.5: 5.65/ -.2:" $ 5.001:

N

Events

Dedian mo"

Gefitinib

05;

>-6

;.8

?oceta(el

050

>-:

;.6

H' 687 CI" 5.66 5.;0/ -.-8" $ 5.;10:


14/49

!S by racial origin Non+Asian originAsian origin

% r o

b a

b i l i t y o

f s u r v

i v a

l

% r o

b a

b i l i t y o

f s u r v

i v a

l

Gefitinib

?oceta(el

-80

-15

-2:

->>

61

--5

12

::

>6

08

21

2:

-;

-1

->

:

8

-

5

5

5

5

At ris@=

816

885

>6-

>:5

205

226

-1>

-8-

62

60

8:

12

>2

>5

-;

-:

6

1

5

5

5

5

Gefitinib?oceta(el

Gefitinib?oceta(el

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

Donths

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

Donths

N

Events

Dedian mo"

Gefitinib

816

0;-

1.6

?oceta(el

885

086

1.6

H' 687 CI" -.5- 5.;6/ -.-0" $ 5.6286

N

Events

Dedian mo"

Gefitinib

-80

--2

-5.0

?oceta(el

-15

--:

-2.2

H' 687 CI" -.50 5.;5/ -.>8" $ 5.::--


15/49

High EG&' gene co$y number ,as notassociated ,ith clinical characteristics

A d e n

o c a r c

i n o m a

N o n

+ a d e n

o c a r c

i n o m a

% S 5 + -

% S

2

N e v e

r + s m o

@ e d

E v e r +

s m o @

e d

S e c o

n d + l i n

e

T h i r d

+ l i n e

D a l e

& e m a

l e A s

i a n

N o n + A

s i a n

7 of sam$les,ith highEG&'+gene+co$ynumber

15

85

05

>5

25

-5

5

!verall high EG&'+gene+co$y number rate= 01.87 -:0B>:0"


16/49

!verall survival by EG&'+gene+co$ynumber status ITT $o$ulation"

High EG&'+gene+co$y number

EG&'+gene+co$y number status by treatment interaction test $+value 5.8-1>

% r o

b a b

i l i t y o

f s u r v

i v a

l Gefitinib n ;8"?oceta(el n ;6"

Lo, EG&'+gene+co$y number

% r o

b a b

i l i t y o

f s u r v

i v a

l Gefitinib n 6>"?oceta(el n -5:"

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

%rimary Co( analysis ,ithout covariates

DonthsDonths

H' 687 CI" 5.6> 5.1;/ -.21" $ 5.10-1

Dedian survival mo"= gefitinib 1.0/ doceta(el :.:

H' 687 CI" -.56 5.:;/ -.8-" $ 5.1-66

Dedian survival mo"= gefitinib ;.0/ doceta(el :.8


17/49

EG&' mutation a$$eared to be associated,ith some clinical characteristics

A d e n

o c a r c

i n o m a

N o n

+ a d e n

o c a r c

i n o m a

% S 5 + -

% S

2

N e v e

r + s m o

@ e d

E v e r +

s m o @

e d

S e c o

n d + l i n

e

T h i r d

+ l i n e

D a l e

& e m a

l e A s

i a n

N o n + A

s i a n

7 of sam$lesEG&'mutation$ositive

15

85

05

>5

25

-5

5

!verall EG&' mutation $ositive rate -0.;7 00B26:"


18/49

!b ective res$onse rate by treatment andbiomar@er status E&' $o$ulation"

->

:.8 6

-8.;

02.-

1.1

5

6.1:.0

-5.- -- 6.;

>.:1.-

2-.-

--.6

5

-5

25

>5

05

85Gefitinib

?oceta(el

$+values from logistic regression ,ith covariates9 NC/ not calculated

EG&'+gene+co$y number

:: ;- ;5 66

EG&' $roteine($ression

-22 ->1 >; 06

EG&' mutation

-6 -6 -51 -2> 25 2: -56N

$ 5.5>1- $ 5.>:25$ 5.2:0-$ 5.1815$ 5.21;;$ 5.5>;: $ NC $ 5.1262

!''7"

$ositive negativeHigh Lo, $ositive ,ild+ty$e


19/49

!verall survival by EG&' mutation statusITT $o$ulation"

EG&' mutation $ositive

EG&' mutation status by treatment interaction test $+value 5.8;;8

% r o

b a b

i l i t y o

f s u r v

i v a

l Gefitinib n 22"?oceta(el n 22"

EG&' mutation ,ild+ty$e

% r o

b a b

i l i t y o

f s u r v

i v a

l Gefitinib n --6"?oceta(el n ->0"

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

Donths

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

Donths

Co( analysis ,ithout covariates

H' 687 CI" -.52 5.:;/ -.>>" $ 5.6->-

Dedian survival mo"= gefitinib 1.0/ doceta(el 1.5

H' 687 CI" 5.;> 5.0-/ -.1:" $ 5.150>

Dedian survival mo"= gefitinib -0.2/ doceta(el -1.1


20/49

%rogression+free survival by EG&' mutationstatus E&' $o$ulation"

EG&' mutation $ositive

Co( analysis ,ith covariates

% r o

b a

b i l i t y o

f % & S

Gefitinib n -6"?oceta(el n -6"

EG&' mutation ,ild+ty$e

% r o

b a

b i l i t y o

f % & S

Gefitinib n -51"?oceta(el n -2>"

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

Donths

-.5

5.;

5.1

5.0

5.2

5.55 0 ; -2 -1 25 20 2; >2 >1 05

Donths

H' 687 CI" -.20 5.60/ -.10" $ 5.->8>

Dedian %&S mo"= gefitinib -.:/ doceta(el 2.1

H' 687 CI" 5.-1 5.58/ 5.06" $ 5.55-2

Dedian %&S mo"= gefitinib :.5/ doceta(el 0.-


21/49

*oL and sym$tom im$rovement rates

P


22/49

Summary of INTE'EST

This ,as the first time an EG&'+T


23/49

A randomi ed o$en+label study of gefitinibversus doceta(el in $atients ,ith

advancedBmetastatic non+small+cell lungcancer NSCLC" ,ho have $reviously

received $latinum+based chemothera$y

ISTANA Iressa as S econd line Thera$y in Advanced NSCLC+


24/49

ISTANA study design

Gefitinib 285mg daily

?oceta(el :8mgBm 2

every > ,ee@s

Aged -; years Life e($ectancy of at least -2 ,ee@s %rogressive or recurrent disease follo,ing $rior chemothera$y Considered candidates for further chemothera$y ,ith doceta(el %revious chemothera$y regimens must have contained $latinum" %S 5 2 2 nd +line Target number of $rogression events= -25 in ITT $o$ulation 'andomi ation stratified for histology adenocarcinoma vs. others"/ se(/ %S 5+- vs. 2"/

$rior thera$y refractory vs. received"/ smo@ing history ever vs. never" and center.

%rimary end$oint=

%&S-=- 'andomisation


25/49

End$oints of ISTANAThe $rimary end$oint

- Progression-free surviva !P"S#

The Secondary end$oints

- Overa surviva !OS#- O$%e&'ive 'u(or res)onse ra'e !O**#- +o- Safe' an 'o era$i i'


26/49

Dethods of ISTANAStatistical methods -"

The sam$le si e ,as calculated assuming a >:7reduction in the ris@ of $rogression ,ith gefitinib trueH' 5.1>".

nder this assum$tion -25 $rogression events ,ould$rovide ;57 $o,er to detect su$eriority of gefitinib todoceta(el at the 87 -+sided significance level.

!ne hundred and fifty $atients ,ere $lanned to berecruited to allo, the -25 events to be detected ,ithin areasonable timeframe

All efficacy analyses ,ere $erformed in the intent+to+

treat $o$ulation ITT/ all randomi ed $atients".*oL ,as analy ed in the evaluable+for+*oL $o$ulationand safety ,as analy ed in the evaluable+for+safety$o$ulation


27/49

Dethods of ISTANA

Statistical methods 2" nad usted Co( $ro$ortional ha ards model ,as used

to com$are %&S and overall survival bet,een treatmentgrou$s.Su$$ortive analyses using a Co( $ro$ortional ha ardsmodel ad usting for gender/ histology/ smo@ing history/$erformance status/ and disease stage ,ere also$erformed.H's and their associated 657 for %&S" or 687 foroverall survival" CIs and $+values ,ere estimated

!''/ *oL im$rovement rates/ and sym$tomim$rovement ,ere com$ared bet,een treatment grou$susing the Chi+s)uared test


28/49

Dethods of ISTANA*oL and Sym$tom im$rovement assessment

+ &ACT+L )uestionnaires/ com$leted ) >,ee@s until visit :/then ) 0 ,ee@s.

+ &ACT+L consists of >0 )uestions ,hich cover all as$ects

of life= $hysical ,ell being % #"/ functional ,ell being& #"/ socialBfamilial ,ell being S #"/ emotional ,ellbeing E #"/ lung cancer subscale LCS".

+ Trial !utcome Inde( T!I" is the sum of the % #/ & #

and LCS domains.

+ Clinically relevant im$rovement ,as defined as 1 $ointim$rovement for &ACT+L and T!I/ 2 $oint im$rovement forLCS/ maintained for at least 2- days


29/49

%atient characteristics ITT $o$ulation"

Dedian age range"/ years&emale/ 7

H! %S/ 7

5-2

Never+smo@er/ 7Adenocarcinoma/ 7

#est res$onse to last CT%?BNEBun@no,n/ a 7Locally advanced disease/ 7

Gefitinibn ;2"

8: 2-+:0">>

265:

>:11

21

->

?oceta(eln :6"

8; 25+:>"0>

0651

01:5

28

-;

a?efinition of refractory used as one of the stratification factorsH!/ orld Health !rgani ation9 %S/ $erformance status9 CT/ chemothera$y9

%?/ $rogressive disease9 NE/ not evaluable


30/49

?emogra$hy in $atients of Asian racial origin

ISTANAGefitinib

n ;2"

ISTANA?oceta(el

n :6"

INTE'EST

AsianGefitinib

n -80"

INTE'EST

Asian?oceta(el

n -16"

INTE'ESToveralln -011"

ISELAsiansn >02"

Adeno 117 :57 :-7 :-7 8:7 107

%S 5/- 6>7 607 ;67 ;87 ;;7 :27

Never smo@ers >:7 017 827 857 257 0-7

2 nd +line -557 -557 :>7 :07 ;07 8:7

&emale >>7 0>7 0:7 027 >87 057

18 yrs :;7 :87 :07 :;7 107 1-7

#est res$onse to$rior chemoC'B%'

>07 >;7 -;7 -67 267 2-7

#est res$onse to$rior chemo

%?BNE

217 287 0>7 >:7 >-7 087


31/49

'esults of ISTANA%atients

At data cut+off for %&S/ -25 $rogression events:0.87 maturity" and 88 deaths >0.27

maturity" had occurred


32/49

%rogression+free survival ITT $o$ulation"


33/49

!' 687 CI" 0.:0 -.;-/ -2.0-"9 $ 5.555: 2+sided"

%atients7"

n ;2" n :6"

!' M - im$lies a greater chance of res$onse on gefitinib

!b ective 'es$onse rate via 'ECIST ITT"


34/49

&irst $ost+discontinuation treatment

/o&e'a e

efi'ini$

o' ing a)ar' fro( fur' er 4 "* 5 71

! o' ing 20 , gefi'ini$:er o'ini$ 3 #

/o&e'a e 26

O' er in&. & e(o' era) 31

o' ing a)ar' fro( fur' er o&e'a e30

! o' ing 30 , o&e'a e 1 #

4 "* 5 7 a' an )oin' 62

O' er ;


35/49

Early loo@ of overall survival ITT $o$ulation"


36/49

Dost common adverse events evaluable for safety$o$ulation" 3-4

Adverse event/ n 7"All adverse events

Gastrointestinal disorders

?iarrheaNauseaConsti$ation

omitingStomatitis a

?ys$e$siaGeneral disorders

Asthenic conditions a

Chest $ain%ain

All grades:6 6:.8"

2- 28.6"-> -1.5"6 --.-"0 0.6"> >.:"

-5 -2.>"

25 20.:": ;.1"; 6.6"

Grade >B0-: 2-.5"

- -.2"5 5.5"5 5.5"5 5.5"5 5.5"5 5.5"

- -.2"5 5.5"2 2.8"

All grades:2 60.:"

-2 -8.;"-0 -;.0"6 --.;"; -5.8"6 --.;"8 1.1"

2; >1.;"-2 -8.;"

8 1.1"

Grade >B02- 2:.1"

5 5.5"5 5.5"5 5.5"5 5.5"- -.>"5 5.5"

> >.6"5 5.5"5 5.5"

Gefitinib 285 mgn ;-"

?oceta(el :8 mgBm 2n :1"

a

Grou$ed term sum of several $referred terms


37/49

Dost common adverse events evaluable for safety$o$ulation" 324

Adverse event/ n 7"

Detabolism and nutritiondisorders

Anore(iaa

Dusculos@eletal andconnective tissue disorders

Dyalgia

Arthralgia

Nervous system disorders

Neuroto(icity a

?i iness

%sychiatric disorders

Insomnia

All grades

26 >8.;"

0 0.6"> >.:"

-: 2-.5"6 --.-"

-> -1.5"

Grade >B0

5 5.5"

5 5.5"5 5.5"

5 5.5"5 5.5"

5 5.5"

All grades

>1 0:.0"

26 >;.2"6 --.;"

2- 2:.1": 6.2"

-; 2>.:"

Grade >B0

2 2.1"

5 5.5"5 5.5"

5 5.5"5 5.5"

5 5.5"



a



38/49

Dost common adverse events evaluable for safety$o$ulation" 3>4

Adverse event/ n 7"'es$iratory/ thoracic andmediastinal disordersCough?ys$nea%roductive coughHemo$tysis

S@in and subcutaneousdisorders

'ashBAcnes a%ruritus a

Alo$ecia?ry s@inNail and nail bed conditions a

All grades

28 >5.6"25 20.:"2- 28.6"6 --.-"

1- :8.>"05 06.0"

0 0.6"-2 -0.;"

2 2.8"

Grade >B0

5 5.5"> >.:"5 5.5"5 5.5"

> >.:"2 2.8"5 5.5"5 5.5"5 5.5"

All grades

28 >2.6"2- 2:.1"-; 2>.:"

0 8.>"

1 :.6"8 1.1"

>> 0>.0"5 5.5"

6 --.;"

Grade >B0

5 5.5"> >.6"5 5.5"5 5.5"

5 5.5"- -.>"5 5.5"5 5.5"5 5.5"



a



39/49

Summaries of ISTANA

The enrolled $atients ,ere more natural Asian $o$ulation,ho $rogressed after - st line treatment com$ared ,ith theAsian $atients in INTE'EST trial.

The !'' ,as higher ,ith gefitinib com$ared ,ith doceta(el/,hich ,as also different from INTE'EST.

%&S ,as longer ,ith gefitinib com$ared ,ith doceta(el. This,as statistically significant at the $re+defined -+sided 87significance level -+sided $ 5.500-".

An early analysis of overall survival suggests that survivalmay be longer ,ith gefitinib com$ared ,ith doceta(el/ but

the number of events ,as small and follo,+u$ is ongoing.


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D'S O-I'ESSA NI 25-5

LI 25-5 da$at ber alan/ bisamela@sana@an tugas sebagai

guru berdiri dide$an @las tan$a@eluhan.

Evaluasi AN A'I 25--'es$on thera$i sangat bai@


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CHEST O 'AJNI 25-5

CT SCAN TTH!'AO NI 25 5


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CT SCAN TTH!'AO NI 25-5


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C O ' AN A'I 25--


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CT SCAN TH!'AO AN A'I 25--


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#'!NCH!SC!%J 25--


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Conclusion

Gefitinib offers an im$ortant alternative todoceta(el and is $referred 2 nd line treatment that is effective and ,ell tolerated for $atientsin Asian $o$ulation ,ith locally advanced ormetastatic NSCLC ,ho have received $rior$latinum+based chemothera$y and areconsidered candidates for furtherchemothera$y.


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Ta@e Home Dessages

Gefitinib demonstrated e)uivalent survivalas a 2 nd line treatment in all ty$es of$atients regardless of racial ethnicity/gender/ smo@ing history and histology.


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Than@ Jou for Jour AttentionP

enhanced efficacy with iressa (ahmad hudoyo)

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