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EORTC – ISG - AGITG Prognostic factors for initial and late resistance to Imatinib in patients with advanced GIST Martine Van Glabbeke, Jaap Verweij, Paolo.

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Presentation on theme: "EORTC – ISG - AGITG Prognostic factors for initial and late resistance to Imatinib in patients with advanced GIST Martine Van Glabbeke, Jaap Verweij, Paolo."— Presentation transcript:

1 EORTC – ISG - AGITG Prognostic factors for initial and late resistance to Imatinib in patients with advanced GIST Martine Van Glabbeke, Jaap Verweij, Paolo G. Casali, John Zalcberg, Axel Le Cesne, Peter Reichardt, Jean-Yves Blay, Marcus Schlemmer, Allan T. van Oosterom, Pancras Hogendoorn, Konstantin Stoitchkov, Ian R. Judson EORTC STBSG

2 EORTC – ISG - AGITG Background (1) Progression free survival 036912151821242730 0 10 20 30 40 50 60 70 80 90 100 400 mg o.d.400 mg b.i.d. Overall Logrank test: p=0.026 (months) Same “shape” of the PFS curves in Rankin et al, ASCO 2004 Demetri et al, NEJM 347, 2002 Verweij et al, Lancet 364, 2004 Imatinib in advanced / metastatic GIST

3 EORTC – ISG - AGITG Background (2) New mutations Genomic amplification Loss of KIT expression Functional resistance J. Fletcher, ASCO 2003 M. Debiec-Rychter, Gastroenterology, 2004 Different biological mechanisms are responsible for initial and late resistance to imatininb Different mechanisms of resistance may be predicted by different prognostic factors

4 EORTC – ISG - AGITG Objectives of the analysis Identify factors that may predict initial resistance to imatininb Identify factors that may predict late resistance to imatininb Explore the dose/efficacy relationship in the important prognostic subgroups

5 EORTC – ISG - AGITG Material EORTC – ISG – AGITC trial 62005 946 patients with advanced / metastatic GIST Randomized to imatinib 400 mg o.d. 400 mg b.i.d. Median follow-up: 25 months

6 EORTC – ISG - AGITG End-points for each objective Initial resistance : documented progression within 3 months 116 progressions / 934 evaluable cases Logistic regression models Late resistance : time to progression after 3 months 3 months landmark period 347 progressions / 818 evaluable cases Cox regression model

7 EORTC – ISG - AGITG Investigated co-factors Imatinib dose (randomized) Age, gender, PS Site of disease origin Site and size of lesions at entry Prior therapies Hematological and biological parameters Results For each end-point: univariate and multivariate analysis Overall TTP curve for important prognostic factors Comparison of treatment arms in prognostic subgroups

8 EORTC – ISG - AGITG FactorUnivariate ORP-value Lung metasases0.323< 0.0001 Hemoglobin1.421< 0.0001 Granulocytes0.9260.0049 PS0.7340.0079 Platelets (/ 100)0.8450.0082 Albumin1.0400.0186 Liver metastases1.6110.0212 Time since diag1.2970.0488 Results : Prognostic factors for initial resistance

9 EORTC – ISG - AGITG FactorUnivariateMultivariate ORP-valueORP-value Lung metastases0.323< 0.00010.3320.0001 Hemoglobin1.421< 0.00011.3800.0004 Granulocytes0.9260.00490.9350.0208 PS0.7340.0079 Platelets (/ 100)0.8450.0082 Albumin1.0400.0186 Liver metastases1.6110.02121.8160.0055 Time since diag1.2970.0488 Results : Prognostic factors for initial resistance

10 EORTC – ISG - AGITG Results : Prognostic factors for late resistance FactorUnivariate HRP-value Granulocytes1.064< 0.0001 Largest diameter1.0330.0001 WBC1.0510.0001 PS1.2410.0014 Stomach origin0.7120.0042 Sm.bowel origin1.3850.0053 Albumin0.9760.0095 Prior chemo1.2980.0184 Imatinib dose0.7790.0202

11 EORTC – ISG - AGITG Results : Prognostic factors for late resistance FactorUnivariateMultivariate HRP-valueHRP-value Granulocytes1.064< 0.00011.0510.0009 Largest diameter1.0330.00011.0230.0095 WBC1.0510.0001 PS1.2410.0014 Stomach origin0.7120.00420.7310.0088 Sm.bowel origin1.3850.0053 Albumin0.9760.0095 Prior chemo1.2980.0184 Imatinib dose0.7790.02020.7540.0093

12 EORTC – ISG - AGITG Summary : factors predicting resistance to imatininb Factor Initial resistance (P-value) Late resistance (P-value) Low imatinib dosens0.0093 High granulocytes0.02080.0009 Low hemoglobin0.0004ns Large lesionsns0.0095 Origin outside of stomachns0.0088 Lung metastases0.0001ns No liver metastases0.0055ns

13 EORTC – ISG - AGITG Lung and liver metastases at entry Loss of significance in the subgroup of patients with confirmed GIST Misdiagnosed patients ???

14 EORTC – ISG - AGITG Hemoglobin Also a PF in CML Influences PK Advanced disease (mucosal ulceration, bleeding) 14.17 mg/100 ml

15 EORTC – ISG - AGITG Granulocytes Inflammatory reaction in aggressive types of tumors ?

16 EORTC – ISG - AGITG Largest tumor size Tumor size is a PF for primary disease Advanced stage of disease ? Increasing risk rate ?

17 EORTC – ISG - AGITG Largest tumor size – logarithmic scale Increased risk of progression At +/- 18 months In large tumors Delayed mechanism of resistance ?

18 EORTC – ISG - AGITG Site of origin of disease Stomach vs small bowel PF for primary disease % benign/malignant - high in stomach - low in sm.bowel Correlation with mitotic index ? (months) 061218243036 0 10 20 30 40 50 60 70 80 90 100 Retro-int.abd.StomachSmall bowelOther GI Extra abd. Time to progression by original tumor site

19 EORTC – ISG - AGITG Impact of initial imatininb dose on TTP : subgroup analysis SubgroupTotalFailures Hazard ratio P-value All patients9464630.8010.017 Granulocytes < 5 10 9 /l5142070.8740.3368 Granulocytes > 5 10 9 /l4322560.6780.0020 Largest diam. < 12 cm7283360.7930.0337 Largest diam. > 12 cm2181270.7960.2025 Stomach origin3161310.8360.3077 Small bowel origin2381301.0250.8886 Other GI origin2391210.5760.0029

20 EORTC – ISG - AGITG Patients with high granulocytes

21 EORTC – ISG - AGITG Tumors of “other” GI origin Duodenal89 Omentum47 Rectum44 Colon23 Esophag.11 ….25

22 EORTC – ISG - AGITG Conclusions Initial and late resistance are predicted by different factors Initial imatinib dose has No impact on initial resistance Impact on late resistance In patients with high GRA In tumors of “unusual” GI origin Not in patients with small bowel origin Hypotheses to be confirmed by immunohistochemical / molecular parameters The models should be externally validated

23 EORTC – ISG - AGITG

24 Material : EORTC-ISG-AGITG phase III trial Eligibility criteria Advanced or metastatic GIST; c-KIT positive PS 0-3; no upper age limit; any prior therapy HGB > 9 g/dl (5.6 mmol/l) - transfusion allowed Randomization Imatinib, 400 mg od; cross-over if PD Imatinib, 400 mg bid (800 mg/day) Data set 946 patients randomized Median follow-up: 25 months; 1 year: 98%; 2 years: 58%

25 EORTC – ISG - AGITG Analyzed end-points Initial resistance : progression within 3 months 3 months: includes 1 st eval. / excludes 2 nd eval. Binary variable: 116 PD / 818 no PD Exclude 11 early deaths (no PD) and 1 lfu (ineligible) Logistic model Late resistance : progression after 3 months 3 months landmark period Time to event variable (event = progression) Deaths without progression censored 347 events – 24 death no PD – 447 alive & prog.free Cox model

26 EORTC – ISG - AGITG Results : Prognostic factors for initial resistance FactorUnivariateMultivariate ORP-valueORP-value Lung metastases0.323< 0.00010.3320.0001 Hemoglobin1.421< 0.00011.3800.0004 Granulocytes0.9260.00490.9350.0208 PS0.7340.0079 Platelets (/ 100)0.8450.0082 Albumin1.0400.0186 Liver metastases1.6110.02121.8160.0055 Time since diag1.2970.0488

27 EORTC – ISG - AGITG Results : Prognostic factors for late resistance FactorUnivariateMultivariate HRP-valueHRP-value Granulocytes1.064< 0.00011.0510.0009 Largest diameter1.0330.00011.0230.0095 WBC1.0510.0001 PS1.2410.0014 Stomach origin0.7120.00420.7310.0088 Sm.bowel origin1.3850.0053 Albumin0.9760.0095 Prior chemo1.2980.0184 Imatinib dose0.7790.02020.7540.0093

28 EORTC – ISG - AGITG Site of origin of disease Stomach vs sm. bowel PF for primary disease % benign/malignant - high in stomach - low in sm.bowel Correlation with mitotic index ?

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