1. Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Gastrointestinal Stromal Tumors Charles D. Blanke, MD, FACP Associate Professor of Medicine Director of the Oregon Cancer Center’s Gastrointestinal Malignancies Focus Group

2. Case 1: Fully Resected Tumor Patient is a 63-year-old male –Presents with fatigue, headache, light-headedness –Mild HTN but no other medical history –Physical exam benign except guiac-positive stool Laboratory data: –Hemoglobin: 6.6 g/dL –Normal WBC, platelets –Normal liver function tests CT scan: 2.8 cm mass arising from small bowel

3. Decision Point What is your major differential diagnosis? Are there any other tests you would like to do? Do you want a biopsy?

4. Case 1: Fully Resected Tumor (cont.) Patient goes directly to surgery Small mass arising from the small bowel is resected –No metastases are seen Recovery is uneventful Pathology: 2.0 cm GIST, CD-117+, arising from small bowel –Ulcerated –negative margins –<1 mitosis/10 HPFs

5. Case 1: Additional Decisions Do you want additional testing on the specimen? Do you tell the patient his tumor is benign or malignant? Do you treat the patient adjuvantly? How do you monitor him?

6. Case 1: Therapeutic Options Observe only Imatinib mesylate 400 mg/day for 1-year Imatinib mesylate 800 mg/day for 1-year Sunitinib malate 50 mg/day weeks 4/6 for 1-year Clinical trial

7. Resected GIST: Defining Risk Categories RiskSize (cm)Mitotic Rate Very Low<2<5/50 HPF Low2-5<5/50 HPF Intermediate<56-10/50 HPF 5-10<5/50 HPF High>5>5/50 HPF >10Any >10/50 HPF

8. R. DeMatteo et al. ASCO 2007 Abstract: 10079 Adjuvant Imatinib Mesylate Increases Recurrence Free Survival (RFS) in Patients with Completely Resected Localized Primary Gastrointestinal Stromal Tumor (GIST): North American Intergroup Phase III Trial ACOSOG Z9001 R. DeMatteo, K. Owzar, R. Maki, P. Pisters, M. Blackstein, C. Antonescu, C. Blanke, G. Demetri, M. von Mehren, K. Ballman, and the American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team

9. Primary GIST > 3 cm Complete Gross Resection Tumor KIT + 1° - Recurrence-free survival 2° - Overall survival, Safety Imatinib x 1 yr Placebo x 1 yr Double-blind Cross-over if recur Courtesy Ron DeMatteo Z9001 Randomized Trial R. DeMatteo et al. ASCO 2007 Abstract: 10079

10. Z9001: Results One-year RFS 83% (placebo) versus 97% imatinib –HR 0.33, P <0.001 No difference in overall survival seen 33% of patients on imatinib arm could not complete one year of therapy R. DeMatteo et al. ASCO 2007 Abstract: 10079

11. Case 1: Therapeutic Options Which treatment option would you recommend?  Observe only  Imatinib mesylate 400 mg/day for 1-year  Imatinib mesylate 800 mg/day for 1-year  Sunitinib malate 50 mg/day weeks 4/6 for 1-year  Clinical trial

12. Case 1: Therapeutic Recommendation Which treatment option would you recommend?  Observe only  Imatinib mesylate 400 mg/day for 1-year  Imatinib mesylate 800 mg/day for 1-year  Sunitinib malate 50 mg/day weeks 4/6 for 1-year  Clinical trial Recommended Approach: Observe only

13. Case 1 Variant Fully resected Tumor Tumor is 3.2 cm in size

14. Decisions Point Do you want additional testing on the specimen? Do you tell the patient his tumor is benign or malignant? Do you treat the patient adjuvantly? How do you monitor him?

15. Case 1 Variant: Therapeutic Options Which treatment option would you recommend?  Observe only  Imatinib mesylate 400 mg/day for 1-year  Imatinib mesylate 800 mg/day for 1-year  Sunitinib malate 50 mg/day weeks 4/6 for 1-year  Clinical trial

16. Case 1 Variant: Therapeutic Recommendation Which treatment option would you recommend?  Observe only  Imatinib mesylate 400 mg/day for 1-year  Imatinib mesylate 800 mg/day for 1-year  Sunitinib malate 50 mg/day weeks 4/6 for 1-year  Clinical trial Recommended Approach: Imatinib mesylate 400 mg/day for 1-year

17. Monitoring Patients with GIST Depends on risk of recurrence Includes labs, CT; not PET Different time-table if on imatinib

18. Case 1b: Treatment Patient develops weight loss, abdominal pain, early satiety 3 years later Physical exam shows hepatomegaly Labs essentially normal CT: multiple liver and peritoneal masses

19. Decision Point What is your major differential diagnosis? Are there any other tests you would like to do? Do you want a biopsy?

20. Case 1b: Therapeutic Options Observe only Imatinib mesylate 400 mg/day Imatinib mesylate 800 mg/day Sunitinib malate 50 mg/day weeks 4/6 Clinical trial Debulk

21. SCREENSCREEN RANDOMIZERANDOMIZE 400 mg/d (N = 73) 600 mg/d (N = 74) Progression 800 mg/d (N = 147) Core Study 3 Yrs Extension 4 Yrs (total 7 Yrs) Follow-up of > 52 Months Study Design NEJM Volume 347:472-480 August 15, 2002

22. 400 mg N=73 n (%) 600 mg N=74 n (%) All Patients N=147 n (%) Complete Response 02 (2.7)2 (1.4) Partial Response50 (68.5)48 (64.9)98 (66.7) Stable Disease10 (13.7)13 (17.6)23 (15.6) Progression11 (15.1)6 (8.1)17 (11.6) Not evaluable/ Unknown 2 (2.7)5 (6.8)7 (4.8) Best Response NEJM Volume 347:472-480 August 15, 2002

23. Number at Risk 0 73 40 63 80 60 Wks:Treatment 400mg Median Duration 248 Wks 95% CI LL UL 150 N/A 0 74 40 70 80 62 Wks:Treatment 600mg Median Duration N/A 95% CI LL UL 190 N/A 0 147 40 133 80 122 Wks:Treatment Pooled Median Duration 248 Wks 95% CI LL UL 190 N/A Hazard Ratio: 0.887, Log-Rank test p=0.6274 All Patients: Median OS 248 wks (58 months) Overall Survival (Kaplan-Meier Estimate) NEJM Volume 347:472-480 August 15, 2002

24. PD (N=17): Median 36 wks PR (N=98): Median 248 wks CR (N=2; median OS n/a) and unknown/NE (N=7; median OS 144 wks) are not displayed Overall Survival by Best Response (Kaplan-Meier Estimate) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Weeks Post First Dose 01224364860728496108120132144156168180192204216228240252264 NEJM Volume 347:472-480 August 15, 2002

25. Comparison of Two Doses of Imatinib for the Treatment of Gastrointestinal Stromal Tumors (GIST): A Meta-analysis Based on 1640 Patients M.M. Van Glabbeke, K. Owzar, C. Rankin, J. Simes, J. Crowley, GIST Meta-analysis Group (MetaGIST) M.M. Van Glabbeke et al. ASCO 2007: 10004

26. Design Phase 3 randomized, intergroup, international trials assessing the clinical activity of imatinib at 2 dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) expressing the KIT receptor tyrosine kinase (CD117) 2 trials originally planned together Primary end point: overall survival (US-CDN) / progression-free survival (EU-AUS) Imatinib mesylate 400 mg/day until progression Imatinib mesylate 800 mg/day until progression PD Cross- over RANDOMIZERANDOMIZE PD Off study PD, progressive disease. M.M. Van Glabbeke et al. ASCO 2007: 10004

27. MetaGIST Results 400 mg/day800 mg/dayP Med PFS (mo)19230.04 Med OS (mo)49 0.97 Med PFS exon 96190.017 Med PFS other~24 NS Med OS exon 928350.15 M.M. Van Glabbeke et al. ASCO 2007: 10004

28. Case 1b: Therapeutic Recommendation Which treatment option would you recommend?  Observe only  Imatinib mesylate 400 mg/day  Imatinib mesylate 800 mg/day  Sunitinib malate 50 mg/day weeks 4/6  Clinical trial  Debulk Recommended Approach: Imatinib mesylate 400 mg/day or 800 mg/day

29. Case 2: Advanced GIST 54-year-old female presents for “screening” CT –6 cm peritoneal mass found –Biopsy: CD-117+ GIST, exon 11 mutant –No other disease –No major PMH

30. Case 2: Therapeutic Options Which treatment option would you recommend?  Observation  Imatinib mesylate 400 mg/day indefinitely  Imatinib followed by resection  Sunitinib malate 50 mg/day weeks 4/6  Immediate resection

31. Case 2: Therapeutic Recommendation Which treatment option would you recommend?  Observation  Imatinib mesylate 400 mg/day indefinitely  Imatinib followed by resection  Sunitinib malate 50 mg/day weeks 4/6  Immediate resection Recommended Approach: Imatinib followed by resection

32. Case 2 Variant Everything identical EXCEPT: –PMH Small bowel leiomyosarcoma resected 6 years ago

33. Case 2 Variant: Therapeutic Options Which treatment option would you recommend?  Observation  Imatinib mesylate 400 mg/day indefinitely  Imatinib followed by resection  Sunitinib malate 50 mg/day weeks 4/6  Immediate resection

34. Case 2 Variant: Therapeutic Recommendation Which treatment option would you recommend?  Observation  Imatinib mesylate 400 mg/day indefinitely  Imatinib followed by resection  Sunitinib malate 50 mg/day weeks 4/6  Immediate resection Recommended Approach: Imatinib followed by resection

35. Case 2 Variant 2 Patient receives imatinib mesylate, 400 mg/day, neoadjuvantly Tumor rapidly progresses

36. Case 2 Variant 2: Therapeutic Options Which treatment option would you recommend?  Continue imatinib mesylate 400 mg/day  Increase imatinib to 800 mg/day  Sunitinib malate 50 mg/day weeks 4/6  Sunitinib malate 37.5 mg/day continuously

37. Case 2 Variant 2: Therapeutic Recommendation Which treatment option would you recommend?  Continue imatinib mesylate 400 mg/day  Increase imatinib to 800 mg/day  Sunitinib malate 50 mg/day weeks 4/6  Sunitinib malate 37.5 mg/day continuously Recommended Approach: Increase imatinib to 800 mg/day Sunitinib malate 50 mg/day weeks 4/6 Sunitinib malate 37.5 mg/day continuously

38. Resistant GIST 25-33% of patients benefit from an imatinib dose- increase –However, actual responses are rare Sunitinib malate has activity against multiple receptor tyrosine kinases + anti-angiogenic activity A phase III trial showed marked survival benefits for salvage sunitinib versus placebo

39. Sunitinib Phase III Trial: Overall Survival Time (Months) Estimated survival probability (%) 100 90 80 70 60 50 40 30 20 10 0 036912 SU11248 (N=207) Placebo (N=105) Hazard ratio = 0.491 P=0.00674

40. Additional ASCO 2007 Findings Continuous daily sunitinib dosing @ 37.5 mg is probably as safe and effective as 50 mg intermittently –George et al. PASCO 2007, abstr #10015 Nilotinib (TKR-inhibitor of KIT, PDGFR) has promising activity in GIST pts resistant to imatinib –Von Mehren et al. PASCO 2007, abstr #10023 IPI-504 (inhibitor of heat shock protein 90 chaperone) has potential activity in pts resistant to imatinib and sunitinib –Demetri et al. PASCO 2007, abstr #10024

41. Other Drugs/Targets in GIST SU11248-PDGFR, VEGFR, KIT, and FLT3 AMG706-VEGFR, PDGFR, KIT, Ret PKC412-PKC AMN107-KIT, PDGFRA, BCR/ABL BAY43-9006-Raf, KIT, VEGFR, PDGFRβ, FLT3, RET BMS 354825-Src, abl, KIT, PDGFR IPI-504-Heat shock protein 90 Genasense-bcl-2

42. ASCO 2007: GIST Conclusions Treat patients with resected tumors ≥ 3 cm with at least 1-year of imatinib 400 mg/day remains the standard dose in metastatic disease –Exon 9 patients should probably get 800 mg/day Sunitinib malate is the standard of care salvage drug for patients with imatinib resistance –Treat with 37.5 mg/day continuously New drugs are expected