La target therapy: cosa ci aspettiamo Paolo G. Casali [email protected].

La target therapy:cosa ci aspettiamo

Paolo G. [email protected]

Imatinib

SCF

Terapia molecolare mirata

Imatinib

chemioterapia

OS

months

0 +2 sett

Le “differenze”

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 3 6 9 12 15 18 21 24

p <0.05

Le “differenze”

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 3 6 9 12 15 18 21 24

Lasota J et al, Histopathology 2008

esone 9 (~10%)

esone 11 (~70%)

esone 13 (~5%)

esone 17 (~5 %)

PDGFRA (~10%) KIT(~80%) WT (~10%)

Heinrich MC, J Clin Oncol 2003;21:4342

KIT exon 9

KIT esone 9

PDGFRA

Corless CL, J Clin Oncol 2005, 23: 5357

PDGFRA

GIST in sindromi

GIST pediatrici 0 – 18+ aa

Mussi C, Clin Cancer Res 2008;14:4550

Neurofibromatosi, tipo 1

Agaram NP et al, Clin Cancer Res 2008;14:3204

Imatinib

SCF

Terapia molecolare mirata

Negri T al, J Natl Cancer Inst 2009;101:194

Imatinib 400 mg d

Imatinib 800 mg d

R

EORTC/ISG/AGITG #62005

(years)

0 1 2 3 4

0

10

20

30

40

50

60

70

80

90

100

400 mg 800 mg

Progression free survival

Overall Logrank test: p=0.108

Casali PG et al, ECCO Ann Meet 2005

“More is better”?

Judson I et al, Cancer Chemother Pharmacol 2005;55:379

Farmacocinetica

Risposta tumorale

50%

30%

WHO/ECOG

RECIST

Criteri di risposta tumorale

Choi’s

RECIST

10%

15%

Choi’s criteria: Risposta tumorale

5 HU

57 HU39 HU

13 HU

61 HU

15 HU83 HU

36 HU

57 HU9 HU 52 HU

3 HU

- 2 HU

- 18 HU -34 HU

9 HU

5 HU-9 HU

-13 HU

3 HU20 HU

10 HU

Stacchiotti S et al, Radiology 2009;epub

PET scan

0 +3-4 sett +12 mm +18 mm

50 mg/day, 4 weeks on, 2 weeks off

SUNITINIB

Van den Abbeele AD et al, ECCO Ann meet 2005

Progressione intervallare

BFR14 study

Rstop Imatinib

continue Imatinib

ImatinibCRPRSD

12 mos surgery if feasible

Resistenza secondaria

Sunitinib

VEGFR-2

VEGFR-1

VEGFR-3

PDGFR-

KIT

FLT-3PDGFR-

NH

O

NH

F

H3C

CH3

NH

O

N

CH3

CH3

RET

Imatinib

Sunitinib

Nilotinib

Vatalanib

Sorafenib Dasatanib Masitinib

PKC412

AMG706 IPI504

…..

Resistenza primaria

Resistenza secondaria

Heinrich MC, JCO, 2006;24:4764

Eterogeneità molecolare

KITPDGRA VEGFR

……..

KITPDGRA VEGFR

Hsp90

……..

KITPDGRA VEGFR

PI3K

AKT

mTOR ……..

Imatinib + Nilotinib

Il “nodulo nel nodulo”

0 +1 mm

GIST: rechallenge con Imatinib

DeMatteo R et al, Lancet 2009

R

Imatinib x 1 aa

placebo

R OSrelapse

RFS

OSImatinib

Imatinib

R Rrelapse

Rrelapse

Imatinib

Imatinib

Imatinib

Paolo G. Casali Study Chair & ISG CoordinatorJean-Yves Blay EORTC CoordinatorAxel Le Cesne FSG CoordinatorAndres Poveda GEIS CoordinatorJohn Zalcberg AGITG Coordinator Martine van Glabbeke Study StatisticianSandrine Marraud Coordinating PhysicianAnne Kirkpatrick Study Data Manager

Intermediate and high risklocalized, completely resected,gastrointestinal stromal tumors (GIST) expressing KIT receptor:a controlled randomized trial on adjuvant Imatinib mesylate (Glivec™) versus no further therapy after complete surgery

R

Imatinib x 2 aa

controllo

R

Imatinib x 3 aa

Imatinib x 1 aa

German/Scandinavian trial

Stratificazione del rischiocm M/50HPF gastric jejunal/

ilealduodenal rectal

1 <2 <5 0none

0none

0none

0none

2 >2<5 <5 1.9%very low

4.3%low

8.3%low

8.5% low

3a >5<10 <5 3.6%low

24% moderate

3b >10 <5 12% moderate

52%high

34% high

57% high

4 <2 >5 0 50% 54% high

5 >2<5 >5 16% moderate

73%high

50%high

52%high

6a >5<10 >5 55%high

85% high

6b >10 >5 86%high

90%high

86%high

71%high

Miettinen M. Semin Diagn Pathol 2006; 23: 70

Terapia citoriduttiva preoperatoria

Metastatic GIST in response to IM

Followfor

PFS & OS

Imatinib

Imatinib + surgery at best response

(within 1 yr)

EORTC trial with ISG, FSG, SSG, AGITSG

Surgery of residualprogressive disease

Surgery of residualresponsive disease

n = 27

n = 8

Gronchi A, Ann Surg 2007; 245:341

Raut CP, J Clin Oncol 2006;24:2325

Il metodo clinico Diagnosi

Early case finding Diagnosi nosografica Staging

Trattamento Decision-making Management del paziente

Valutazione dell’esito Risposta tumorale

clinica patologica

Tossicità Qualità di vita Sopravvivenza

Prognosi Follow-up

Imatinib

SCF

chemioterapia

[email protected]

La target therapy: cosa ci aspettiamo Paolo G. Casali [email protected].

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