1. CO-I KNTM/K i CzS M. Sklodowska-Curie Memorial Cancer Center-Institute of Oncology Medical University of Warsaw; Warsaw, POLAND Medical University of Gdansk; Gdansk, Poland The updated outcomes of metastatic and/or unresectable gastrointestinal stromal tumor (GIST) patients treated surgically after the response to targeted therapy with imatinib (IM) P. Rutkowski, Z. Nowecki, P. Nyckowski, W. Dziewirski, U. Grzesiakowska, A. Nasierowska-Guttmejer, W. Michej, A. Woźniak, Z. Żurawski, M.Krawczyk, W. Ruka rutkowskip@coi.waw.pl

2. CO-I KNTM/K i CzS AIM Analyze the outcomes of treatment of inoperable/metastatic GIST CD 117(+) patients, who initially responded to imatinib (IM) therapy in terms of the results of post-IM surgery.

3. CO-I KNTM/K i CzS MATERIAL AND METHODS 170 advanced CD117 (+) GIST patients (inoperable and/or metastatic) [from total number 228 pts we excluded 27 with primary resistance; 17 with SD – <10% tumor shrinkage and 14 with too short follow-up time)] September 2001 – June 2006 98 male (58%) and 72 female (42%); Median age: 56 years (range: 17-83) Imatinib therapy in the dose of 400-800 mg/d At least minor response (>10% according to RECIST) Median follow-up time: 25 months (range: 3 - 58) Last evaluation date: 29th September 2006 Primary tumor location: 59 - gastric (35%); small intestine – 78 (46%); large intestine – 14 (8%); others – 19 (11%). Mutational status known in 65 cases (70% c-KIT exon 11 mutations)

4. CO-I KNTM/K i CzS Results Group I: 41 patients (24%) - resections of residual disease as adjuvant treatment due to initially inoperable and/or metastatic GIST CD117(+) after radiological complete/partial/minor response (according to RECIST) and lack of further response to imatinib therapy [17 M, 24 F; median age 55] median duration of IM treatment before surgery - 13 months (4-32) Imatinib continued postoperatively in all cases 36 (88%) R0/R1 resections; no major complications (prolonged ileus in 3 cases) 5 PD (12%) & 1 DoD (2.4%) after 52 months from the IM start Mutational status: exon 11 Kit mutations 17/19 cases

5. CO-I KNTM/K i CzS Results Group II: 129 patients (76%) without resections of residual during imatinib therapy due to inoperable and/or metastatic GIST CD117(+) after complete/partial/minor response (according to RECIST) [81 M, 48 F; median age 56] 47 PD (36%) & 27 DoD (20.9%) Mutational status: exon 11 Kit mutations 28/46 cases

6. CO-I KNTM/K i CzS RESULTS: Overall Survival and Progression-Free Survival (from the date of start of imatinib therapy) in all patients

7. CO-I KNTM/K i CzS RESULTS: Overall Survival (from the date of start of imatinib therapy) in relation to surgery during IM treatment

8. CO-I KNTM/K i CzS Progression-Free Survival (from the date of start of imatinib therapy) in relation to surgery during IM treatment (median: group I- 49 m; group II – 39 months)

9. CO-I KNTM/K i CzS Progression-free survival (from date of surgery) of GIST patients operated during imatinib treatment: after CR/PR and continued imatinib therapy

10. CO-I KNTM/K i CzS

12. Viable GIST cells were not detected histologically in resection specimens in 5 patients (12%) only Immunohistochemistry positive staining for CD 117 of gastric GIST before imatinib treatment (diffuse staining) and of the specimen after partial gastrectomy after IM therapy (single cells)

13. CO-I KNTM/K i CzS Multivariate analysis of prognostic factors for PFS ---------------------------------------------------------------------------------------------------------- Negative factor Risk ratio Wald P-value ---------------------------------------------------------------------------------------------------------- Baseline WHO performance status ≥2 5.3 20.1 0.00001 No surgical resection of residual disease 3.98 8.1 0.004 Baseline high NE count 1.88 4.5 0.03 Baseline low ALB level 1.11 0.07 0.8 Low baseline HGB level 0.77 0.39 0.52 Initially overtly malignant disease 1.15 0.95 0.32 High risk primary tumor n.s. MI > 10/50HPF n.s. Genetic alterations vs. exon 11 KIT mutations n.s. GIST type other than spindle-cell n.s. Primary tumor size >10 cm n.s. CD34 positivity n.s. Male gender n.s. Primary location outside the stomach n.s. Age < 45 n.s. Liver metastases n.s. ---------------------------------------------------------------------------------------------------------

14. CO-I KNTM/K i CzS PFS according to baseline WHO performance status

15. CO-I KNTM/K i CzS PFS according to baseline neutrocyte count

16. CO-I KNTM/K i CzS Multivariate analysis of prognostic factors for OS ---------------------------------------------------------------------------------------------------------- Negative factor Risk ratio Wald P-value ---------------------------------------------------------------------------------------------------------- No surgical resection of residual disease 15.5 6.6 0.01 Baseline WHO performance status ≥2 5.03 10.6 0.001 Baseline high NE count 1.29 0.33 0.56 Baseline low ALB level 1.7 0.86 0.35 Low baseline HGB level 1.44 0.38 0.53 Initially overtly malignant disease 0.99 0.001 0.97 High risk primary tumor n.s. MI > 10/50HPF n.s. Genetic alterations vs. exon 11 KIT mutations n.s. GIST type other than spindle-cell n.s. Primary tumor size >10 cm n.s. CD34 positivity n.s. Male gender n.s. Primary location outside the stomach n.s. Age < 45 n.s. Liver metastases n.s. ---------------------------------------------------------------------------------------------------------

17. CO-I KNTM/K i CzS Discussion Timing for operation? The plot of the response to imatinib therapy in time (years from the date of the first IM administration) in group of 72 patients responding to IM therapy (estimation of GEE model with gamma distribution and link function ln with empirical confidence interval) After maximal response; Before secondary resistance; Usually 6 – 18 months from imatinib start

18. CO-I KNTM/K i CzS Discussion Other published studies Hohenberger et al. ASCO 2003; ASCO 2006 Gronchi A et al. ASCO 2005 Antbacka et al. SSO 2005 Bauer et al. Int J Cancer 2005 Scaife et al. Am J Surg 2003 Bonvalot et al. Ann Surg Oncol Raut S.C. et al. J Clin Oncol 2006 Rutkowski et. al J Surg Oncol 2006 Conclusions: maintenance of imatinib therapy after surgery is crucial; final impact on survival and time of implementation of surgery is controversial Bias of this study? super-selection of the cases?

19. CO-I KNTM/K i CzS Conclusions: 1.Surgical removal of residual disease during imatinib treatment may allow for complete remission (approx. 20%) in selected GIST patients after response to therapy, probably prolonging durable remission. We are convinced that surgical downstaging of GIST patients during imatinib therapy is beneficial. The time of the implementation of surgical treatment warrants further studies. 2.For group of GIST patients responding to imatinib therapy besides lack of surgical treatment we found two additional independent negative predictive factors for PFS: baseline poor performance status and baseline high neutrocyte count.

20. CO-I KNTM/K i CzS All doctors participating of Polish Clinical GIST Registry and our patients; colleagues from EORTC STBSG for stimulating discussion ACKNOWLEDGEMENTS

21. CO-I KNTM/K i CzS Cancer Center – Institute, Warsaw, Poland Thank you for your attention!