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Prognostic Factors for Resistance to Imatinib in Advanced GIST Patients

Study on factors predicting initial and late resistance to Imatinib in GIST patients, analyzing dose efficacy relationships and identifying prognostic subgroups.

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Prognostic Factors for Resistance to Imatinib in Advanced GIST Patients

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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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