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EORTC STBSG

EORTC STBSG.

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EORTC STBSG

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  1. EORTCSTBSG Prognostic factors for initial and late resistance to Imatinibin patients with advanced GISTMartine 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

  2. 100 90 80 70 60 50 40 30 20 Overall Logrank test: p=0.026 10 0 0 3 6 9 12 15 18 21 24 27 30 400 mg o.d. 400 mg b.i.d. Background (1) Imatinib in advanced / metastatic GIST Progression free survival Same “shape” of the PFS curves in • Rankin et al, ASCO 2004 • Demetri et al,NEJM 347, 2002 • Verweij et al, Lancet 364, 2004 (months)

  3. 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 andlateresistance to imatininb Background (2) Different mechanisms of resistance may be predicted by different prognostic factors

  4. 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 relationshipin the important prognostic subgroups

  5. 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. 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. 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 armsin prognostic subgroups

  8. Results : Prognostic factors for initial resistance

  9. Results : Prognostic factors for initial resistance

  10. Results : Prognostic factors for late resistance

  11. Results : Prognostic factors for late resistance

  12. Summary : factors predicting resistance to imatininb

  13. Lung and liver metastases at entry • Loss of significance in the subgroup of patients with confirmed GIST • Misdiagnosed patients ???

  14. Hemoglobin • Also a PF in CML • Influences PK • Advanced disease (mucosal ulceration, bleeding) < 11.2711.27 - 12.8812.88 - 14.17> 14.17 mg/100 ml

  15. Granulocytes • Inflammatory reaction in aggressive types of tumors ?

  16. Largest tumor size • Tumor size is a PF for primary disease • Advanced stage of disease ? • Increasing risk rate ?

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

  18. Time to progression by original tumor site 100 90 80 70 60 50 40 30 20 10 0 (months) 0 6 12 18 24 30 36 Retro-int.abd. Stomach Small bowel Other GI Extra abd. 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 ?

  19. Impact of initial imatininb dose on TTP : subgroup analysis

  20. Patients with high granulocytes

  21. Tumors of “other” GI origin • Duodenal 89 • Omentum 47 • Rectum 44 • Colon 23 • Esophag. 11 • …. 25

  22. 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. 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%

  24. Analyzed end-points • Initial resistance : progression within 3 months • 3 months: includes 1st eval. / excludes 2nd 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

  25. Results : Prognostic factors for initial resistance

  26. Results : Prognostic factors for late resistance

  27. 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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