1. Predicting toxicity for patients with advanced Gastrointestinal Stromal Tumors (GIST) treated with imatinib mesylate : an EORTC/ISG/AGITG randomized trial M. Van Glabbeke, J. Verweij, P.G. Casali, J. Simes, A. Le Cesne, P. Reichardt, R. Issels, J.R. Judson, A.T. van Oosterom, J.-Y. Blay EORTC STBSG

2. Material Randomized phase III study comparing daily doses of imatinib (400 mg od vs 400 mg bid) for the treatment of patients with advanced GIST 946 patients randomized 942 patients started therapy 310 patients still under therapy Follow-up Median: 42 months (3.5 years) At 1, 2, 3 and 4 years: 99%, 90%, 81% and 4%

3. Methods Prognostic factors analyses End-points (binary) : occurrence of Grade 3-4 anemia, neutropenia Grade 2-4 edema, fatigue, nausea, diarrhea, skin rash Investigated co-factors Imatinib dose Age, sex, PS, baseline laboratory parameters Time since GIST diagnosis, site of origin, lesion size Prior therapies Logistic univariate / multivariate regression models Univariate model: select variables if P < 0.05 Multivariate model: keep variable if P < 0.01

4. Cumulative incidence of toxicities (non hemato.grade 2+, hemato. grade 3+) Edema - Skin rash - Fatigue - Nausea - Diarrhea Anemia - Neutropenia 400 mg o.d.400 mg b.i.d.

5. Multivariate models : non hematological grade 2+ toxicities EdemaFatigueRashNauseaDiarrh. Dose++++ ++ Age++ ++++ Sex (F)++++ ++ Perform.status+++++++ Identified GI origin++ Tumor size--- Prior chemo.+++ ++ : P < 0.01, --- : P < 0.001, +++ : P < 0.001, ++++ : P < 0.0001

6. Multivariate models : hematological grade 3+ toxicities AnemiaNeutropenia Dose++++ Initial hemoglobin level ------ Initial neutrophils count ---- -- : P < 0.01, ---- : P < 0.0001, ++++ : P < 0.0001

7. Interactive risk calculator www.eortc.be / tools / imatinibtoxicity Interactive version Downloads (Excel) - For PC - For PDA

8. Interactive risk calculator for predicting imatinib toxicities in GIST patients

9. Validation Validation data set EORTC phase I-II trial of imatinib 91 patients with advanced or metastatic sarcoma Daily doses: 400 mg, 600 mg, 800 mg, 1000 mg Patients classified in “risk group” according to probability of each toxicity estimated with the model 40% or 20% Comparison with the observed proportion of events Within the expected range for 10/13 risk groups (> 10 pts) Overlap with the 95% confidence interval in all groups Underestimation of edema & nausea (low risk groups) Underestimation in male patients ?

10. Conclusion (I) All toxicities are highly dose dependent, except neutropenia Anemia and neutropenia only depend on baseline hematological factors Risk of non hematological toxicity increase with age, poor PS and in female Confirmation of other series Other factors Prior chemotherapy (fatigue) Small lesions (rash) Identified GI origin (diarrhea)

11. Conclusions (II) Interactive risk calculator to estimate the risk of toxicity for individual patients May be used in the clinic Available on the internet (Excel spreadsheet) May be used to customized treatment ? Validation Based on a limited data set Underestimate of edema and nausea in male patients ? Should be validated on larger data series