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Charles D. Blanke, MD, FACP Associate Professor of Medicine

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. Case 1: Fully Resected Tumor.

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Charles D. Blanke, MD, FACP Associate Professor of Medicine

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  1. Challenging Cases in Cancer:Integration of Findings from ASCO 2007Gastrointestinal 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

  8. 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 R. DeMatteo et al. ASCO 2007 Abstract: 10079

  9. Primary GIST > 3 cm Complete Gross Resection Tumor KIT + Placebo x 1 yr Imatinib x 1 yr Double-blind Cross-over if recur 1° - Recurrence-free survival 2° - Overall survival, Safety Z9001 Randomized Trial Courtesy Ron DeMatteo 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. Study Design 400 mg/d (N = 73) R A N D O M I Z E S C R E E N Extension 4 Yrs (total 7 Yrs) Core Study 3 Yrs Progression 600 mg/d (N = 74) Progression (N = 147) 800 mg/d Follow-up of > 52 Months NEJM Volume 347:472-480 August 15, 2002

  22. Best Response NEJM Volume 347:472-480 August 15, 2002

  23. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Median Median Median 95% CI 95% CI 95% CI Number at Risk 0.3 Duration Duration Duration LL UL LL UL LL UL Treatment Treatment Treatment Wks: Wks: Wks: 0 0 0 40 40 40 80 80 80 248 Wks 150 N/A 400mg 73 63 60 0.2 N/A 190 N/A 600mg 74 70 62 Pooled 147 133 122 248 Wks 190 N/A 0.1 0.0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 252 264 Weeks Post First Dose Overall Survival(Kaplan-Meier Estimate) Hazard Ratio: 0.887, Log-Rank test p=0.6274 All Patients: Median OS 248 wks (58 months) NEJM Volume 347:472-480 August 15, 2002

  24. Median Median Median Median Median 95% CI 95% CI 95% CI 95% CI 95% CI Number at Risk Best Response Best Response Best Response Best Response Best Response Wks: Wks: Wks: Wks: Wks: 0 0 0 0 0 40 40 40 40 40 80 80 80 80 80 Duration Duration Duration Duration Duration LL UL LL UL LL UL LL UL LL UL N/A 172 N/A CR 2 2 2 PR 98 97 92 248 Wks 226 N/A 1.0 N/A 149 N/A SD 23 22 20 PD 17 7 4 36 Wks 15 56 0.9 UNK 7 5 4 144 Wks 18 223 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 252 264 0.0 Weeks Post First Dose Overall Survival by Best Response(Kaplan-Meier Estimate) 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 NEJM Volume 347:472-480 August 15, 2002

  25. Comparison of Two Doses of Imatinibfor 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. 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 PD RANDOMIZ E Imatinib mesylate400 mg/day until progression Cross-over Off study Imatinib mesylate800 mg/day until progression PD Design Primary end point: overall survival (US-CDN) / progression-free survival (EU-AUS) M.M. Van Glabbeke et al. ASCO 2007: 10004 PD, progressive disease.

  27. MetaGIST Results 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 100 90 80 70 60 50 40 30 20 10 0 Estimated survival probability (%) SU11248 (N=207)Placebo (N=105) Hazard ratio = 0.491P=0.00674 0 3 6 9 12 Time (Months)

  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. 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 Other Drugs/Targets in GIST

  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

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