La target therapy:
cosa ci aspettiamo
Paolo G. Casali
[email protected]
Terapia molecolare mirata
SCF
Imatinib
OS
Imatinib
chemioterapia
months
0
+2 sett
Le “differenze”
1
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
D
p <0.05
0
3
6
9
12
15
18
21
24
Le “differenze”
1
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
D
0
3
6
9
12
15
18
21
24
Le “differenze”
1
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
D
0
3
6
9
12
15
18
21
24
KIT
KIT(~80%)
PDGFRA (~10%)
WT (~10%)
esone 9 (~10%)
esone 11 (~70%)
esone 13 (~5%)
esone 17 (~5 %)
Lasota J et al, Histopathology 2008
Heinrich MC, J Clin Oncol 2003;21:4342
KIT exon 9
KIT esone 9
PDGFRA
PDGFRA
Corless CL, J Clin Oncol 2005, 23: 5357
GIST in sindromi
GIST pediatrici
0 – 18+ aa
Neurofibromatosi, tipo 1
Mussi C, Clin Cancer Res 2008;14:4550
Agaram NP et al, Clin Cancer Res 2008;14:3204
Terapia molecolare mirata
SCF
Imatinib
Negri T al, J Natl Cancer Inst 2009;101:194
EORTC/ISG/AGITG #62005
Imatinib 400 mg d
R
Imatinib 800 mg d
Progression free survival
100
90
80
70
60
50
40
30
20
Overall Logrank test: p=0.108
10
0
(years)
0
1
400 mg
2
3
4
800 mg
Casali PG et al, ECCO Ann Meet 2005
“More is better”?
Farmacocinetica
Judson I et al, Cancer Chemother Pharmacol 2005;55:379
Risposta tumorale
Criteri di risposta tumorale
WHO/ECOG
50%
RECIST
30%
Choi’s
RECIST
Choi’s criteria:
Risposta tumorale
10%
15%
15 HU
36 HU
83 HU
9 HU
52 HU
-13 HU
9 HU
- 18 HU -34 HU
5 HU
-9 HU
57 HU
- 2 HU
61 HU
3 HU
13 HU
39 HU
5 HU
57 HU
20 HU
10 HU
3 HU
Stacchiotti S et al, Radiology 2009;epub
PET scan
0
+3-4 sett
+12 mm
+18 mm
SUNITINIB
50 mg/day, 4 weeks on, 2 weeks off
Van den Abbeele AD et al, ECCO Ann meet 2005
Progressione intervallare
t
BFR14 study
Imatinib
CR
PR
SD
R
 12 mos
 surgery if feasible
stop Imatinib
continue Imatinib
Resistenza secondaria
Sunitinib
CH3
O
H3C
N
H
N
H
F
N
CH3
CH3
O
N
H
VEGFR-1
KIT
VEGFR-2
PDGFR-a
PDGFR-b
FLT-3
RET
VEGFR-3











Imatinib
Sunitinib
Nilotinib
Vatalanib
Sorafenib
Dasatanib
Masitinib
PKC412
AMG706
IPI504
…..
Resistenza primaria
Resistenza secondaria
Eterogeneità molecolare
Heinrich MC, JCO, 2006;24:4764
PDGRA
KIT
VEGFR
……..
Hsp90
PDGRA
KIT
VEGFR
……..
PDGRA
VEGFR
KIT
PI3K
AKT
mTOR
……..
Imatinib + Nilotinib
Il “nodulo nel nodulo”
GIST: rechallenge con Imatinib
0
+1 mm
DeMatteo R et al, Lancet 2009
Imatinib x 1 aa
R
placebo
RFS
OS
OS
Imatinib
R
Imatinib
relapse
RFS
OS
Imatinib
R
Imatinib
R
relapse
Imatinib
R
relapse
Imatinib
R
Imatinib
R
relapse
Imatinib
R
relapse
Imatinib
R
Imatinib
R
relapse
Imatinib
R
relapse
Imatinib
R
Imatinib
R
relapse
Imatinib
R
relapse
Intermediate and high risk
localized, 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
Paolo G. Casali
Jean-Yves Blay
Axel Le Cesne
Andres Poveda
John Zalcberg
Martine van Glabbeke
Sandrine Marraud
Anne Kirkpatrick
Study Chair & ISG Coordinator
EORTC Coordinator
FSG Coordinator
GEIS Coordinator
AGITG Coordinator
Study Statistician
Coordinating Physician
Study Data Manager
Imatinib x 2 aa
R
controllo
German/Scandinavian trial
Imatinib x 3 aa
R
Imatinib x 1 aa
Stratificazione del rischio
cm
M/50HPF
gastric
jejunal/
ileal
duodenal
rectal
1
<2
<5
0
none
0
none
0
none
0
none
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%
5
>2<5
>5
16%
moderate
73%
high
6a
>5<10
>5
55%
high
85%
high
6b
>10
>5
86%
high
90%
high
54%
high
50%
high
52%
high
86%
high
71%
high
Miettinen M. Semin Diagn Pathol 2006; 23: 70
Terapia citoriduttiva
preoperatoria
EORTC trial with
ISG, FSG, SSG, AGITSG
Imatinib
Follow
for
PFS & OS
Metastatic GIST
in response to IM
Imatinib
+ surgery at best response
(within 1 yr)
Surgery of residual
progressive disease

Surgery of residual
responsive disease

n = 27
n=8
Gronchi A, Ann Surg 2007; 245:341
Raut CP, J Clin Oncol 2006;24:2325
Il metodo clinico

Diagnosi




Trattamento



Early case finding
Diagnosi nosografica
Staging
Decision-making
Management del paziente
Valutazione dell’esito

Risposta tumorale
 clinica
 patologica





Tossicità
Qualità di vita
Sopravvivenza
Prognosi
Follow-up
SCF
Imatinib
chemio
terapia
[email protected]