1. Gastrointestinal Stromal Tumor GIST New Therapeutic Approaches Prof. Mohamed Abdulla A. Professor of Clinical Oncology Kasr El-Aini School of Medicine Cairo University. IMC – Cairo – October 30 th, 2007

2. GIST: Definition Mesenchymal (connective tissue) neoplasms Located primarily in the GI tract, omentum, and mesentery 0.2% of all GI tumors 80% of GI sarcomas Usually stain positive for KIT

3. GIST: Epidemiology An estimated 10-20 cases per million of GIST are diagnosed in the United States each year –5000-6000 cases per year are diagnosed in the United States 2 Incidence in the Netherlands 3 and Sweden: 12.7-14.5 cases per million Highest incidence among group aged 50-65 years –Similar male/female incidence, although some reports suggest higher incidence in men

4. Gene mutation key event in malignant transformation in most cases 1,2 Gene mutation key event in malignant transformation in most cases 1,2 –KIT: 80%-85% –PDGFRA: 5%-7% –Wild Type: 12% Mutation results in expression of abnormal, constitutively activated receptor tyrosine kinase activity Mutation results in expression of abnormal, constitutively activated receptor tyrosine kinase activity GIST: Pathogenesis

5. GIST: Pathogenesis (Continued) Extracellular domain (exon 9) Transmembrane domain Juxtamembrane domain (exon 11) ATP Tyrosine kinase domain (exon 13/14) Kinase insert Tyrosine kinase domain II (exon 17) = Mutation site = Imatinib contact point Proliferation Survival Adhesion Invasion Metastasis Angiogenesis In GIST where mutant KIT is expressed, ATP-dependent signal transduction occurs in the absence of SCF 1-3

6. Histopathology At diagnosis, GIST generally is 2-30 cm 1 At diagnosis, GIST generally is 2-30 cm 1 GIST can be classified into 3 broad categories 2 GIST can be classified into 3 broad categories 2 –Spindle-cell type (70%) –Epithelioid-cell type (20%) –Mixed spindle-cell and epithelioid-cell type (nested morphology) (10%) Spindle cell Epithelioid cellMixed morphology

7. Historical Classification of GISTs as Other Soft-Tissue Sarcomas Nilsson B et al. Cancer. 2005;103:821-829. GIST Leiomyoma Leiomyosarcoma Leiomyoblastoma Other 7% 13% 18% 34% 28% N = 600 A retrospective Swedish study determined that 60% of GI tumors now identified as GIST originally were classified as other tumors

8. Immunohistochemistry: CD117 Positivity Is a Reliable Marker of GIST Spectrum of staining for KIT (CD117) in GIST Approximately 95% of GISTs stain positive for CD117 (KIT) 1 Of those that do not, about 1/3 harbor a mutation in PDGFRA 2

9. Variable Pattern of KIT (CD117) Staining in GIST

10. Differential Diagnosis of KIT-Undetectable Tumors Suspected to be GIST KIT (CD117)CD34SMADesmin S- 100 GIST++ (60%-70%) + (30%- 40%) Very rare + (5%) Smooth muscle tumor −+ (10%-15%)++Rare Schwannoma− (usually Antoni B) −−+ Fibromatosis Disputed * Rare+ Rare cells − KIT (CD117)is not detected in ~5% of GIST Immunohistology for other protein markers or genetic analysis for KIT and PDGFRA may support a GIST diagnosis Suspected GISTs without evidence of KIT (CD117) expression should be referred to an experienced GIST pathologist

11. Emerging Marker: PKCθ GIST ×10 KIT PKCθ 85%-100% of GISTs stain positive for PKCθ Other similar mesenchymal neoplasias do not stain positive for PKCθ3

12. GIST: Risk Assessment Accurate assessment of risk of aggressive malignant behavior in GIST poses a challenge Morphologic features most predictive of outcome –Mitotic rate –Tumor size Mutational status is useful in predicting treatment response and risk of progression

13. Risk of Aggressive Tumor Behavior Size (cm) Mitotic Count (HPF) Very low risk<2<5/50 Low risk2-5<5/50 Intermediate risk <5 5-10 6-10/50 <5/50 High risk>5 >10 Any size >5/50 Any mitotic rate >10/50 All GISTs should be considered to have potential for malignant behavior 1,2

14. Overall Survival by Risk Group Nilsson B et al. Cancer. 2005;103:821-829. 2005 American Cancer Society. 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Estimated Proportion Surviving 01234567891011121314151617 Years Since Diagnosis Normal population Intermediate High Overtly malignant Very low Low GIST Risk Groups

15. Circumstances of GIST Detection Incidental Symptomatic Autopsy 69% 21% 10% Approximately 1/3 of GISTs are asymptomatic

16. Common Tumor Sites Colon Other (rectum, esophagus, mesentery, retroperitoneum) 50% 10% 15% 25% Small intestine Stomach GIST may occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum

17. Clinical Presentation Most patients present with nausea, vomiting, pain, weight loss, palpable tumor masses, and bleeding leading to anemia 2 Average duration of presenting symptoms is 4-6 months 2 Symptoms of GIST at Diagnosis SymptomOccurrence Rate Abdominal pain50%-70% GI bleeding50%

19. Chemotherapy, Radiation, and Surgery in GIST Chemotherapy Ineffective in sarcomas Response limited: ~5% Survival: no impact Surgery Principal treatment for resectable primary GIST Radiation Results in injury to adjacent organs Tumors exhibit radioresistance Possible therapeutic role in rectal tumors

20. Poor Historical Survival Rates During the Pre-Imatinib Era Months After Diagnosis Proportion Surviving 1.0 0.8 0.6 0.4 0.2 0 01224364860 GIST Leiomyosarcoma P < 0.05

21. GIST: Current Treatment Options Surgery Treatment of choice for localized primary resectable GIST Imatinib First-line treatment of malignant unresectable or metastatic GIST 1,2

22. Surgery for Primary Tumors Risks Rupture of tumor increases risk of Bleeding Dissemination Warnings Segmental resection of stomach or intestine Margins should be clear No benefit in wide margins Inspect abdomen for metastases Peritoneal surfaces Liver Goal of Surgery Complete gross resection of tumor with pseudocapsule intact GIST often can be lifted from surrounding organs

23. Survival Following Surgical Treatment of Primary GIST Adapted with permission from DeMatteo RP et al. Ann Surg. 2000;231:51-58.

24. GIST Recurrence After Surgery Recurrence of GIST following surgery is common –Majority of high-risk patients experience recurrence –Median time to recurrence is 2 years Only 10% of patients remain disease-free after extended follow-up 5-year survival rates are ~30%-60% Investigational protocols are under way, with the goal of reducing the rate of recurrence after resection Recurrent disease should be treated as metastatic disease

25. Primary GIST: Risk Factors for Recurrence After Surgery 0 0.25 0.50 0.75 1.0 020406080 <5 cm 5-10 cm >10 cm P = 0.03 Months RFS 0 0.25 0.50 0.75 1.0 20406080 Months  3 mitoses/30 HPF >3 to  15 mitoses/30 HPF >15 mitoses/30 HPF P = 0.0001 0 RFS Rates of RFS were predicted by mitotic index and tumor size

26. Surgery for Recurrent or Metastatic GIST Recurrent GIST should be treated as metastatic disease –Imatinib indicated as first-line treatment in both instances Potential role for surgery after maximum response to imatinib mesylate Resection of imatinib mesylate – resistant clones (under investigation) Surgery for liver metastases –Often unsuitable for multifocal disease in liver –Consider RFA or hepatic artery embolization Complementary use of surgery may benefit patients whose disease is stable on imatinib therapy

27. Imatinib First-Line Treatment of Unresectable or Metastatic GIST Indicated for the treatment of adult patients with KIT- (CD117-) positive unresectable or metastatic malignant GIST

31. Studies of Imatinib Therapy in GIST PilotPhase 1Phase 2Phase 3 Pilot Study Exploratory Study (N = 1) Dose-Finding Study (N = 40) US Finland B2222 Open-Label Study (N = 147) EORTC 62005 Randomized Study (N = 946) 1 patient 400 mg/d Efficacy and safety 400 vs 1000 mg/d Metastatic GIST (EORTC) Efficacy and safety 400 vs 600 mg/d Metastatic or unresectable GIST Efficacy and safety 400 vs 800 mg/d Metastatic or unresectable KIT- positive GIST EORTC Phase 2 study (N = 51) US Intergroup S0033 Study (N = 746) Efficacy and safety Advanced or metastatic GIST and other soft-tissue sarcomas Efficacy and safety 400 and 800mg/d Metastatic or unresectable KIT- positive GIST

32. Phase 3 Trials: Overview Two Parallel Phase 3 Studies of Imatinib in GIST US Intergroup S0033 study US and Canada (N = 746) EORTC 62005 study Europe and Australia/Asia (N = 946) Aim: Efficacy and safety evaluation of imatinib 400 vs 800 mg/d in metastatic or unresectable KIT-positive GIST Major findings PFS at 3 years follow-up not significantly different with 800- mg vs 400-mg dose Similar rates of response for the 2 dosing arms 36% of 400-mg/d nonresponders benefited from 800-mg/d dose 2 In general, 800 mg/d is well tolerated, with higher rates of grade 3/4 toxicities

33. Phase 3 EORTC 62005 Study: PFS (Primary End Point)

34. Response Rates of Phase 3 Studies: EORTC 62005 and US Intergroup S0033 Study Best Overall Response (ITT analysis) EORTC 62005 Study (N = 461) US Intergroup S0033 Study (N = 462) Patients, % 5 6 45 48 32 13 9 33 45 27 26 25 Imatinib 400 mg/d Imatinib 800 mg/d

35. US Intergroup S0033 and EORTC 62005 Studies: Similar PFS Regardless of Dose Administered Months 0612182430 0 10 20 30 40 50 60 70 80 90 100 Overall Logrank test: Intergroup S0033 P = 0.026 EORTC 62005 P = 0.13 400 mg 800 mg 400 mg 800 mg EORTC 62005 Intergroup S0033 36

36. Phase 3 Studies: Response Rates After Crossover to Imatinib mg/d Phase 3 Studies: Response Rates After Crossover to Imatinib 800 mg/d Patients, % 0 2.3 27.1 59.4 0 10 20 30 40 50 60 70 CRPRSDPD AI 62005 Trial 1 0 6 32 48 13 0 10 20 30 40 50 60 CRPRSDPD Patients, % AI S0033 Trial 2 One third of patients benefited from dose increase at progression

37. Phase 3 Studies: Conclusions Two parallel phase 3 studies compared imatinib 400 mg/d and 800 mg/d in patients with metastatic unresectable GIST –US Intergroup S0033 study (N = 746) –EORTC 62005 study (N = 946) EORTC 62005 study results 1 –According to standard RECIST criteria, no significant difference in ORR between standard-dose and high-dose groups (50% vs 54%, respectively) –No significant advantage in PFS at 800 mg/d (P = 0.108) 2 US Intergroup S0033 study results 3 –Doses similar in confirmed ORR (both 48%) –Similar 2-year PFS for standard dose vs high dose (47% vs 52%, respectively; P = 0.13)

38. Discontinuation of Imatinib Increases Risk of GIST Progression Patients, % Months After Randomization 1614121086420 100 80 60 40 20 0 Stop therapy (n = 25) Median PFS: 6 months Continuous therapy (n = 23) P = 0.0001 Study BFR14 Patients who achieved clinical benefit after 12 months were randomized to continue or stop imatinib therapy Stop-therapy arm was discontinued because of high rates of disease progression Reintroduction of imatinib enabled tumor control in all those patients