La target therapy: cosa ci aspettiamo Paolo G. Casali paolo.casali@istitutotumori.mi.it
Terapia molecolare mirata SCF Imatinib
Imatinib chemioterapia OS months
+2 sett
Le “differenze” D p <0.05
Le “differenze” D
Le “differenze” D
KIT
Lasota J et al, Histopathology 2008 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
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%
-13 HU 9 HU 15 HU 36 HU 83 HU - 18 HU -34 HU -9 HU 5 HU 9 HU 52 HU 57 HU - 2 HU 61 HU 3 HU 13 HU 5 HU 20 HU 39 HU 3 HU 57 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 50 mg/day, 4 weeks on, 2 weeks off
Van den Abbeele AD et al, ECCO Ann meet 2005
Progressione intervallare
t
R BFR14 study stop Imatinib CR PR Imatinib SD continue Imatinib 12 mos surgery if feasible continue Imatinib
Resistenza secondaria
Sunitinib VEGFR-1 KIT VEGFR-2 PDGFR-a VEGFR-3 PDGFR-b FLT-3 RET H3C O F H3C CH3 VEGFR-1 KIT VEGFR-2 PDGFR-a VEGFR-3 PDGFR-b FLT-3 RET
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 KIT VEGFR PI3K AKT …….. mTOR
Imatinib + Nilotinib
Il “nodulo nel nodulo”
GIST: rechallenge con Imatinib +1 mm
DeMatteo R et al, Lancet 2009
Imatinib x 1 aa R placebo
RFS OS
Imatinib OS R Imatinib OS relapse RFS
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 Imatinib R 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 Study Chair & ISG Coordinator Jean-Yves Blay EORTC Coordinator Axel Le Cesne FSG Coordinator Andres Poveda GEIS Coordinator John Zalcberg AGITG Coordinator Martine van Glabbeke Study Statistician Sandrine Marraud Coordinating Physician Anne Kirkpatrick 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 none 2 >2<5 1.9% very low 4.3% low 8.3% 8.5% 3a >5<10 3.6% 24% moderate 3b >10 12% 52% high 34% 57% 4 >5 50% 54% 5 16% 73% 6a 55% 85% 6b 86% 90% 71% Miettinen M. Semin Diagn Pathol 2006; 23: 70
Terapia citoriduttiva preoperatoria
EORTC trial with ISG, FSG, SSG, AGITSG Imatinib Patients were randomized into 2 groups, receiving either imatinib mesylate 400 mg/d or 800 mg/d. Crossover from the 400-mg to the 800-mg treatment arm was possible if disease progression occurred. Follow for PFS & OS Metastatic GIST in response to IM Imatinib + surgery at best response (within 1 yr) Benjamin RS, Rankin C, Fletcher C, et al. Phase III dose-randomized study of imatinib mesylate (STI571) for GIST: Intergroup S0033 early results. Proc Am Soc Clin Oncol. 2003;22:814. Abstract 3271. Rankin C, von Mehren M, Blanke C, et al. Dose effect of imatinib (IM) in patients (pts) with metastatic GIST – phase III Saroma Group Study S0033. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9005. Verweij J, Casali PG, Zalcberg J, et al. Early efficacy comparison of two doses of imatinib for the treatment of advanced gastrointestinal stromal tumors (GIST): interim results of a randomized phase III trial from the EORTC-STBSG, ISG and AGITG. Proc Am Soc Clin Oncol. 2003;22:814. Abstract 3272.
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 Valutazione dell’esito Prognosi 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
SCF Imatinib
chemio terapia
paolo.casali@istitutotumori.mi.it