La target therapy: cosa ci aspettiamo Paolo G. Casali

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1 La target therapy: cosa ci aspettiamo Paolo G. Casali

2

3 Terapia molecolare mirata
SCF Imatinib

4 Imatinib chemioterapia OS months

5 +2 sett

6 Le “differenze” D p <0.05

7 Le “differenze” D

8 Le “differenze” D

9 KIT

10 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

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12 Heinrich MC, J Clin Oncol 2003;21:4342

13 KIT exon 9

14 KIT esone 9 PDGFRA

15 PDGFRA Corless CL, J Clin Oncol 2005, 23: 5357

16 GIST in sindromi GIST pediatrici 0 – 18+ aa

17 Neurofibromatosi, tipo 1
Mussi C, Clin Cancer Res 2008;14:4550

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

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21 Terapia molecolare mirata
SCF Imatinib

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

24 EORTC/ISG/AGITG #62005 Imatinib 400 mg d R Imatinib 800 mg d

25 Casali PG et al, ECCO Ann Meet 2005

26 “More is better”?

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

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30 Risposta tumorale

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35 Criteri di risposta tumorale
WHO/ECOG 50% RECIST 30%

36 Choi’s RECIST

37 Choi’s criteria: Risposta tumorale
10% 15%

38 -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

39 Stacchiotti S et al, Radiology 2009;epub

40 PET scan

41 sett mm mm

42 50 mg/day, 4 weeks on, 2 weeks off
SUNITINIB 50 mg/day, 4 weeks on, 2 weeks off

43 Van den Abbeele AD et al, ECCO Ann meet 2005

44 Progressione intervallare

45

46 t

47 R BFR14 study stop Imatinib CR PR Imatinib SD continue Imatinib 12 mos
surgery if feasible continue Imatinib

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49 Resistenza secondaria

50 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

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52 Imatinib Sunitinib Nilotinib Vatalanib Sorafenib Dasatanib Masitinib PKC412 AMG706 IPI504 …..

53 Resistenza primaria

54 Resistenza secondaria

55 Eterogeneità molecolare
Heinrich MC, JCO, 2006;24:4764

56 PDGRA KIT VEGFR ……..

57 Hsp90 PDGRA KIT VEGFR ……..

58 PDGRA KIT VEGFR PI3K AKT …….. mTOR

59 Imatinib + Nilotinib

60 Il “nodulo nel nodulo”

61 GIST: rechallenge con Imatinib
+1 mm

62 DeMatteo R et al, Lancet 2009

63 Imatinib x 1 aa R placebo

64

65 RFS OS

66 Imatinib OS R Imatinib OS relapse RFS

67 Imatinib R relapse Imatinib R Imatinib R relapse

68 Imatinib R relapse Imatinib R Imatinib R relapse

69 Imatinib R relapse Imatinib R Imatinib R relapse

70 Imatinib R relapse Imatinib R Imatinib R relapse

71 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

72 Imatinib x 2 aa R controllo

73 German/Scandinavian trial
Imatinib x 3 aa R Imatinib x 1 aa

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75 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

76 Terapia citoriduttiva preoperatoria

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78 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.

79 Surgery of residual progressive disease
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80 Surgery of residual responsive disease
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81 n = 27 n = 8 Gronchi A, Ann Surg 2007; 245:341

82 Raut CP, J Clin Oncol 2006;24:2325

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84 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

85 SCF Imatinib

86 chemio terapia

87