imatinib nei gist e sarcomi - home - facoltà di …pacs.unica.it/pacs/oncologiamedica1/1-62.pdf ·...
TRANSCRIPT
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N
N
N
O
H H
N
N
N
N
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Proteina di fusione con elevata attività tirosina-chinasica
22
bcr
abl
9
Ph
Bcr-Abl
9+Chromosome
Chromosome
Chromosome
Chromosome
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Imatinib(Glivec®)
SCF
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Imatinib(Glivec®)
Terapia “molecolare mirata”…
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Joensuu H, et al. N Engl J Med 2001; 344: 1052
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aprile 2001
febbraio 2002
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Fase II - US
147 pz400 600 mg
Demetri GD et al,NEJM 2002; 347: 472
RP 54%INV 28%PRO 14%
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Risposta “dimensionale”…
0 +11 mm
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Risposta “complicata”…
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Risposta “tissutale” …
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Risposta “funzionale” …
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0 +3-4 sett +12 mm +18 mm
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Imatinib
chemioterapia
OS
mesi
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Fase II - US
OS
Blanke CD et al. ASCO GI Meet 2004
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TTF
Blanke CD et al. ASCO GI Meet 2004
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Resistenza secondaria…
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attività efficacia
non RR complicata
0
0,2
0,4
0,6
0,8
1
0 4 8 12 16 20 24 28 32 36
no
prolungata
mantenuta
R tissutale
R dimensionale
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Imatinib nei GIST…
127 pzc-kit esoni 9, 11, 13, 17
0
20
40
60
80
100
esone 11 esone 9 no
p PR
Heinrich MC, J Clin Oncol 2003;21:4342
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0 +2 sett
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SU11248 nei GIST…
c-kit no PDGFRαesone 9 esone 11 esone 18
p PR
Demetri GD, ASCO 2004
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ESONE 9 (~10%)
ESONE 11 (~70%)
ESONE 13 (~ 5%)
ESONE 17 (~ 5%)
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Predizione di risposta…
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KIT nei tumori solidi…
GIST 100%disgerminoma ovaio 100%gonadoblastoma ovaio 100%seminoma 84%oncocitoma rene 80%ca adenocistico 65%t. fillode 46%ca cromofobo rene 46%melanoma 36%t. Brenner ovaio 33%adenoca collo utero 33%ca follicolare tiroide 23%ca midollare mammella 21%adenoma pleiomorfo gh. saliv. 21%..... (n=47) <20%
120neoplasie!
Went PT, et al. J Clin Oncol 2004; 22: 4514
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Mutazioni di c-kit e PDGFRalfa...
Sihto H, et al. J Clin Oncol 2005; 23: 1
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Sa. sinoviale t(X;18)(p11;q11) SSX1-SYTSSX2-SYT
t(X;18)(p13;q11) SSX1-SYTLiposa. mixoide t(12;16)(q13;p11) CHOP-TLS
t(12;22)(q13;q12) EWS-CHOPLiposa. ben diff. 12 ringCondrosa mix. extra. t(9;22)(q22;q12) WT1-EWSSa. cell. chiare t(12;22)(q13;q12) ATF1-EWSDermatofibrosa. 17 e 22 ring COL1A1-PDGFB
t(17;22)(q21;q13) COL1A1-PDGFB EFT t(11;22)q24;q12) FLI1-EWST. desmopl. c. rot. t(11;22)(q13;q12) WT1-EWSRabdomiosa. alv. t(2;13)(q35;q14) PAX3-FKHR
t(1;13)(p36;q14) PAX7-FKHRRabdomiosa. embr. trisomia 2q, 8, 20.....
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Sa. sinoviale t(X;18)(p11;q11) SSX1-SYTSSX2-SYT
t(X;18)(p13;q11) SSX1-SYTLiposa. mixoide t(12;16)(q13;p11) CHOP-TLS
t(12;22)(q13;q12) EWS-CHOPLiposa. ben diff. 12 ringCondrosa mix. extra. t(9;22)(q22;q12) WT1-EWSSa. cell. chiare t(12;22)(q13;q12) ATF1-EWSDermatofibrosa. 17 e 22 ring COL1A1-PDGFB
t(17;22)(q21;q13) COL1A1-PDGFB EFT t(11;22)q24;q12) FLI1-EWST. desmopl. c. rot. t(11;22)(q13;q12) WT1-EWSRabdomiosa. alv. t(2;13)(q35;q14) PAX3-FKHR
t(1;13)(p36;q14) PAX7-FKHRRabdomiosa. embr. trisomia 2q, 8, 20.....
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Fibromatosi aggressiva…
Mace J et al. Cancer 2002; 95: 2373
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Dermatofibrosarcoma...
Rubin BP et al. JCO 2002; 20: 3586
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Cordoma…
Casali PG, et al. Cancer 2004; 101:2086
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Casali PG et al. ASCO 2005; #9012
IP = PDGFRbeta WBC- C+ Tumor
α PDGFR beta
9 pz
9 pz
α pTyr
RTPCRMWM C+ Tumors C-
PDGFB
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Risposta “funzionale”…
baselineSUV median = 2.2 g/mlSUV max = 5.0 g/ml
1 mosSUV median = 1.8 g/mlSUV max = 3.8 g/ml
3 mosSUV median = 1.5 g/mlSUV max = 3.3 g/ml
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Risposta “tissutale” …
40
47 1237
2610
12 4
0 +4 mm
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0 +2 mm +8 mm
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+2 mm +8 mm
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0 +1 mo
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Risposta prolungata...
100 sett…
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Risposta resistenza secondaria...
0 +2 mm +10 mm
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Efficacia...
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96
no
prolungata
mantenuta
wks
PFS
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Necrosi colliquativa...
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PDGFRB
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Phase II, US...
OS
Blanke CD et al. ASCO GI Meet 2004
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Cordoma…
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Studio BFR14 - FSG…
stop Imatinib
Blay J-Y et al. ESMO Ann Meet 2004
RCRPRSD
Imatinib
continue Imatinib12 mossurgery if feasible
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Months from randomization
1211109876543210
Pro
gres
sion
-free
sur
viva
l pro
babi
lity
1,0
,9
,8
,7
,6
,5
,4
,3
,2
,1
STOP group (n = 32)
CONT group (n = 26)
P = 0.0002
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t
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Chirurgiadel residuo in progressione isolata…
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+9 mm +12 mm +16 mm
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Chirurgiadel residuo in risposta…
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Meccanismi di resistenza...
Nuove mutazioniAmplificazione genicaAttivazione di altre TKResistenza funzionale…..
Fletcher JA et al. ASCO 2003; 22: #100681
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GIST resistenti a Imatinib…
SU0112482
progressioneR SU011248
placebo1
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SU11248 TTP = 6.3 mosplacebo TTP = 1.5 mos
HR = 0.335
p<0.00001
Demetri GD et al. ASCO 2005; #4000
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Studi clinici aperti in Italia…
SU11248PTK787AMG706AMN107 + Imatinib…..
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Phase III – EUR/Austr…
143 (/946) ptsin PD at 400 mg400 800 mg
PFS 1 yr 26%
Zalcberg JR et al. ASCO 2004
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Fase “adiuvante”(malattia minima residua!)…
Imatinib x 2 aa
R
controllo
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Attività eccezionale!Rapida conferma!Dose!
Fase IFase IIFase III
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Intermediate and high risk localized, completelyresected, 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 Study Chair & ISG CoordinatorJean-Yves Blay EORTC CoordinatorAxel Le Cesne FSG CoordinatorAndres Poveda GEIS CoordinatorMartine van Glabbeke Study StatisticianKonstantin Stoichkov Study Medical AdviserAllan van Oosterom Translational research CoordinatorAnne Kirkpatrick Study Data Manager
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relapse
R
RFS
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OS
R OS
relapse
RFS